DESCRIPTION

ELECTRON WITHDRAWING GROUP SUBSTITUTED AND MACROCYCLIC PGJ ₃

ANALOGS AND METHODS OF TREATMENT THEREOF

[0001] This application claims the benefit of United States Provisional Application No. 62/311,132, filed on March 21, 201 , the entirety of which is hereby incorproated by reference.

BACKGROUND

[0002] The invention was made with government support under Grant No. AI055475 awarded by the National Institutes of Health. The government has certain rights in the invention.

1. Field

[0003] The present disclosure relates generally to the field of oncology and chemotherapeutics. More particularly, it concerns electron withdrawing group substituted PGJ ₃ and macrocyclic derivatives thereof.

2. Description of Related Art

[0004] Leukemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts." Leukemia is a broad term covering a spectrum of diseases. In turn, it is part of the even broader group of diseases affecting the blood, bone marrow, and lymphoid system, which are all known as hematological neoplasms. Leukemia can affect people at any age. In 2000, approximately 256,000 children and adults around the world had developed some form of leukemia, and 209,000 have died from it. About 90% of all leukemias are diagnosed in adults.

[0005] Leukemia is a treatable disease. Most treatments involve chemotherapy, medical radiation therapy, hormone treatments, or bone marrow transplant. The rate of cure depends on the type of leukemia as well as the age of the patient. Children are more likely to be permanently cured than adults. Even when a complete cure is unlikely, most people with a chronic leukemia and many people with an acute leukemia can be successfully treated for years. Nonetheless, new and improved treatments for the disease would provide a greater chance of survival for some leukemia patients, and potentially increased survival for many others.

[0006] One of the particularly challenging aspects of treating leukemia is the presence of cancer stem cells. Leukemia stem cells are notoriously refractory to conventional drugs; consequently, their eradication is an important unrealized therapeutic goal. It was shown recently (Hegde et al. , 2011 ), that A ¹² -PGJ ₃ , a naturally-occurring cyclopentenone prostaglandin derived biosynthetically from the dietary fish-oil omega-3 polyunsaturated fatty acid eicosapentaenoic acid 20:5(n-3), alleviates the development of leukemia in two well-studied murine models of leukemia. Intraperitoneal administration of Δ -PGJ ₃ to mice infected with Friend erythroleukemia virus or those expressing chronic myelogenous leukemia (CML) oncoprotein BCR-abl in the hematopoietic stem cell (HSC) pool completely restored normal hematological parameters, splenic histology, and enhanced the survival of such mice. More importantly, A ¹² -PGJ ₃ selectively targets and induces apoptosis of leukemia stem cells (LSCs) in mice spleen and bone marrow. The treatment completely eradicated LSCs in vivo as demonstrated by the inability of donor cells from treated mice to cause leukemia in secondary transplants. This appears to be the first example of a compound that eradicates leukemia stem cells and effectively cures CML in a mouse model, thereby prolonging life of the leukemic mice indefinitely. Given the potency of A ¹² -PGJ ₃ and the well-known refractoriness of LSC to currently used clinical agents, this natural product represents a highly interesting target for a chemical total synthesis, both, to provide sufficient quantities of so far only scarcely available A ¹² -PGJ ₃ (1) and, furthermore, of analogs with enhanced and fine-tuned physico-chemical and pharmacological properties. While A ¹² -PGJ3 shows activity of against leukemia, there remains a need to develop new compounds for the treatment of leukemia and other cancers.

SUMMARY

[0007] In some aspects, the present disclosure provides electron withdrawing substituted cyclopentenone PGI ₃ derivatives and macrocylic PGJ ₃ derivatives. In some embodiments, the present disclosure provides compounds of the formula:

(I)

wherein:

Ri is hydrogen or an electron withdrawing group;

P2 is alkyl(c<i2), alkenyl ₍ c<i2), alkynyl ₍ c≤i2), aryl ₍ c<i2), aralkyl ₍ c<i2), aralkenyl ₍ c<i2), heteroaryl(c<i2), heteroaralkyl(c<i2), heteroaralkenyl(c<i2), or a substituted version of any of these groups;

Yi is -0-, -S-, or -NR _a -; wherein: R _a is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

Xi is hydrogen or alkyl,c<8), acyl(c<8), or a substituted version of either of these groups; or Xi and X2 are taken together and are a covalent bound; or Xi is taken together with the X2 of a second compound of formula I and form an oligomer;

X2 is amino, hydroxy, or alkoxy(c<8), alkylaminO(c<8), dialkylaminO(c<8), or a substituted version of the last three groups; or X2 and Xi are taken together and are a covalent bound; or X2 is taken together with the Xi of a second compound of formula I and form an oligomer; and

n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

provided that when Ri is hydrogen, then Xi and X2 are taken together and are either a covalent bond or an oligomer and the com ound is not:

or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds are further defined as:

wherein:

Ri is an electron withdrawing group;

R2 is alkyl(c<i2), alkenyl(c<i2), alkynyl(c<i2), aryl(c<i2), aralkyl(c<i2), aralkenyl ₍ c≤i2), heteroaryl(c<i2), heteroaralkyl(c<i2), heteroaralkenyl(c<i2), or a substituted version of any of these groups;

Yi is -0-, -S-, or -NR _a -; wherein: R _a is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

Xi is hydrogen or alkyl ₍ c<8), acyl(c<8), or a substituted version of either of these groups; or Xi and X2 are taken together and are a covalent bound; or Xi is taken together with the X2 of a second compound of formula I and form an oligomer;

X2 is amino, hydroxy, or alkoxy(c<8), alkylaminO(c<8), dialkylaminO(c<8), or a substituted version of the last three groups; or X2 and Xi are taken together and are a covalent bound; or

X2 is taken together with the Xi of a second compound of formula I and form an oligomer; and

n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds are further defined as: (I)

wherein:

Ri is an electron withdrawing group;

R2 is alkyl(c<i2), alkenyl ₍ c<i2), alkynyl ₍ c≤i2), aryl ₍ c<i2), aralkyl ₍ c<i2), aralkenyl ₍ c<i2), heteroaryl(c<i2), heteroaralkyl(c<i2), heteroaralkenyl(c<i2), or a substituted version of any of these groups;

Yi is -0-, -S-, or -NR _a -; wherein: R _a is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

Xi and X2 are taken together and are a covalent bound; or Xi is taken together with the X2 of a second compound of formula I and form an oligomer; and

n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds are further defined as:

(II)

wherein:

R2 is alkyl(c<i2), alkenyl ₍ c<i2), alkynyl ₍ c≤i2), aryl ₍ c<i2), aralkyl ₍ c<i2), aralkenyl ₍ c<i2), heteroaryl(c<i2), heteroaralkyl(c<i2), heteroaralkenyl(c<i2), or a substituted version of any of these groups;

Yi is -0-, -S-, or -NR _a -; wherein: R _a is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

Xi and X2 are taken together and are a covalent bound; or Xi is taken together with the X2 of a second compound of formula I and form an oligomer; and

n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

provided that the compound is not:

armaceutically acceptable salt thereof. In some embodiments, the compounds are further defined

(II)

wherein:

R2 is alkyl ₍ c<i2), alkenyl ₍ c<i2), alkynyl ₍ c<i2), aryl ₍ c<i2), aralkyl ₍ c<i2), aralkenyl ₍ c<i2), heteroaryl(c<i2), heteroaralkyl(c<i2), heteroaralkenyl(c<i2), or a substituted version of any of these groups;

Yi is -0-, -S-, or -NR _a -; wherein: R _a is hydrogen, alkyl(c<8), or substituted alkyl(c<8);

Xi is taken together with the X2 of a second compound of formula I and form an oligomer; and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, Ri is an electron withdrawing group. In some embodiments, the electron withdrawing group is a halo such as fluoro, chloro, or iodo. In other embodiments, the electron withdrawing group is alkoxy(c<i2), acyloxy(c<i2), alkylthio(c<i2), acylthio(c<i2), alkylarninO(c<i2), dialkylamino(c<i2), amido(c<i2), or a substituted version of any of these groups. In some embodiments, Ri is hydrogen.

[0009] In some embodiments, R2 is alkyl(c<i2) or substituted alkyl(c<i2) such as pentyl or 5,5,5- trifluoropentyl. In other embodiments, R2 is alkenyl(c<i2) or substituted alkenyl(c<i2) such as 2-pentenyl, 5,5,5-trifluoropent-2-enyl, or oct-2,5-dienyl. In other embodiments, R2 is alkynyl(c<i2) or substituted alkynyl(c<i2) such as pent-2-ynyl. In other embodiments, R2 is aralkyl(c<i2) or substituted aralkyl(c<i2) such as 2-(3-trifluoromethylphenyl)ethyl. In other embodiments, R2 is heteroaralkyl(c<i2) or substituted heteroaralkyl(c≤i2) such as 2-(3-methyl-2-A'-methylpyrazolyl)ethyl or 2-(4-2-methylthiothiazolyl)ethyl.

[0010] In some embodiments, Yi is -0-. In other embodiments, Yi is -NR _a -; wherein: R _a is hydrogen, alkyl(c<8), or substituted alkyl(c<8). In some embodiments, Yi is -NH- or -NCH3-. [0011] In some embodiments, Xi is hydrogen. In other embodiments, Xi and X2 are taken together and are a covalent bound. In other embodiments, Xi is taken together with the X2 of a second compound of formula I and form an oligomer. In some embodmients, the oligomer comprises 2, 3, 4, 5, or 6 repeating units of formula I. In some embodiments, the oligomer comprises 2, 3, or 4 repeating units of formula I. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 2, 3, or 4.

[0012] In some embodiments, the compounds are further defined as:

-7-

- 10-

-13-

- 14-

or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is present as at least 80% of the specific stereoisomer shown. In some embodiments, the compound is present as at least 90% of the specific stereoisomer shown. In some embodimentss, the compound is present as at least 95% of the specific stereoisomer shown. In some embodiments, the compound is present as at least 98% or at least 99% of the specific stereoisomer shown.

[0014] In another aspect, the present disclosure provides pharmaceutical compositions comprising:

(A) a compound described herein; and

(B) an excipient. [0015] In some embodiments, the pharmaceutical composition is formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctivally, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in cremes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion. In some embodiments, the pharmaceutical composition is formulated as a unit dose. [0016] In still another aspect, the present disclosure provides methods of treating cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound or composition described herein. In some embodiments, the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma. In some embodiments, the cancer is of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gall bladder, gastrointestinal tract, genitalia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicle, or thyroid. In some embodiments, the cancer is leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, breast cancer, or prostate cancer. In some embodiments, the method comprises killing cancer stem cells. In some embodiments, the method comprises a second cancer therapy. In some embodiments, the second cancer therapy is a second chemotherapeutic compound, radiotherapy, immunotherapy, or surgery. In some embodiments, the patient is a mammal such as a human. In some embodiments, the method comprises administering the compound once. In other embodiments, the method comprises administering the compound two or more times. [0017] In yet another aspects, the present disclosure provides methods of killing cancer stem cells comprising contacting the cancer stem cell with a compound or composition described herein. In some embodiments, the cancer stem cells are leukemia stem cells. In some embodiments, the method is performed in vivo.

[0018] Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0020] FIGS. 1A-1TT show the NCI 60 Panel activity results for compounds 1 (FIG. 1A), 2 (FIG. IB), 3 (FIG. 1C), 4 (FIG. ID), 5 (FIG. IE), 6 (FIG. IF), 7 (FIG. lG), 8 (FIG. 1H), 9 (FIG. II), 10 (FIG. 1J), 11 (FIG. IK), 12 (FIG. 1L), ent-1 (FIG. 1M), ent-2 (FIG. IN), ent-U (FIG. 10), 13 (FIG. IP), 14 (FIG. 1Q), 15 (FIG. 1R), 16 (FIG. IS), 17 (FIG. IT), 18 (FIG. 1U), 19 (FIG. IV), 20 (FIG. 1W), 21 (FIG. IX), 22 (FIG. 1Y), 23 (FIG. 1Z), 24 (FIG. 1AA), 25 (FIG. IBB), 26 (FIG. ICC), 27 (FIG. 1DD), 28 (FIG. 1EE), 29 (FIG. IFF), 30 (FIG. 1GG), 31 (FIG. 1HH), 32 (FIG. Ill), 33 (FIG. IJJ), 34 (FIG. IKK), 35 (FIG. ILL), 36 (FIG. IMM), 38 (FIG. INN), 39 (FIG. 100), 40 (FIG. 1PP), 41 (FIG. 1QQ), 42 (FIG. 1RR), 43 (FIG. 1SS), and 44 (FIG. ITT). [0021] FIGS. 2A-2F show the cytotoxicity of several compounds in HEK 293T cells (FIGS.

2A & 2B), in MES SA cells (FIGS. 2C & 2D), and in MES SA DX (FIGS. 2E & 2F).

[0022] FIGS. 3A-3C show the dose response curve of the tested compounds with MES SA (FIG. 3A), MES SA DX (FIG. 3B), and HEK 293T (FIG. 3C) cell lines.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0023] In some aspects, the present disclosure provides new A ¹² -PGJ ₃ derivatives which may be used in the treatment of cancer. In some embodiments, the A ¹² -PGJ ₃ derivatives include derivatives in which the cyclopentenone group is substituted with an electron withdrawing group such as a halogen. In some embodiments, the A ¹² -PGJ ₃ derivatives form a macrocycle between the carboxylic acid of one arm and an amine or hydroxy group on the other arm of the same or different derivatives. In this case, the A ¹² -PGJ ₃ derivatives that may be used can form either a cyclic monomer or a macrocyclic oligomer. These compounds may be used in pharmaceutical formulations and/or in methods of treating cancer or other hyperproliferative disease.

I. A ¹ -PGJ3 Derivatives of the Present Disclosure

[0024] The A ¹² -PGJ ₃ derivatives of the present disclosure are shown, for example, above, in the summary section and in the claims below. They may be made using the synthetic methods outlined in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (2013), which is incorporated by reference herein. In addition, the synthetic methods may be further modified and optimized for preparative, pilot- or large-scale production, either batch or continuous, using the principles and techniques of process chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Anderson, Practical Process Research & Development - A Guide for Organic Chemists (2012), which is incorporated by reference herein.

[0025] All of the A ¹² -PGJ ₃ derivatives of the present disclosure may be useful for the prevention and treatment of one or more diseases or disorders discussed herein. In some embodiments, one or more of the compounds characterized or exemplified herein as an intermediate, a metabolite, and/or prodrug, may nevertheless also be useful for the prevention and treatment of one or more diseases or disorders. As such unless explicitly stated to the contrary, all of the compounds of the present disclosure are deemed "active compounds" and "therapeutic compounds" that are contemplated for use as active pharmaceutical ingredients (APIs). Actual suitability for human or veterinary use is typically determined using a combination of clinical trial protocols and regulatory procedures, such as those administered by the Food and Drug Administration (FDA). In the United States, the FDA is responsible for protecting the public health by assuring the safety, effectiveness, quality, and security of human and veterinary drugs, vaccines and other biological products, and medical devices. [0026] In some embodiments, the A ¹² -PGJ3 derivatives of the present disclosure have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the indications stated herein or otherwise.

[0027] The A ¹² -PGJ ₃ derivatives of the present disclosure may contain one or more asymmetrically-substituted carbon or nitrogen atoms, and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present disclosure can have the S or the R configuration. [0028] Chemical formulas used to represent A ¹² -PGJ ₃ derivatives of the present disclosure will typically only show one of possibly several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which one is most prevalent, all tautomers of a given chemical formula are intended.

[0029] In addition, atoms making up the A ¹² -PGJ3 derivatives of the present disclosure are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³ C and ¹⁴ C.

[0030] The A ¹² -PGJ ₃ derivatives of the present disclosure may also exist in prodrug form. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compounds employed in some methods of the disclosure may, if desired, be delivered in prodrug form. Thus, the disclosure contemplates prodrugs of compounds of the present disclosure as well as methods of delivering prodrugs. Prodrugs of the compounds employed in the disclosure may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Accordingly, prodrugs include, for example, compounds described herein in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a subject, cleaves to form a hydroxy, amino, or carboxylic acid, respectively.

[0031] It should be recognized that the particular anion or cation forming a part of any salt form of a compound provided herein is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.

[0032] It will appreciated that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates." Where the solvent is water, the complex is known as a "hydrate." It will also be appreciated that many organic compounds can exist in more than one solid form, including crystalline and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof are within the scope of the present disclosure.

II. Cancer and Other Hyperproliferative Diseases

[0033] While hyperproliferative diseases can be associated with any disease which causes a cell to begin to reproduce uncontrollably, the prototypical example is cancer. One of the key elements of cancer is that the cell's normal apoptotic cycle is interrupted and thus agents that interrupt the growth of the cells are important as therapeutic agents for treating these diseases. In this disclosure, the Δ ¹² - PGJ ₃ derivatives described herein may be used to lead to decreased cell counts and as such can potentially be used to treat a variety of types of cancer lines. In some aspects, it is anticipated that the A ¹² -PGJ ₃ derivatives described herein may be used to treat virtually any malignancy.

[0034] Cancer cells that may be treated with the compounds of the present disclosure include but are not limited to cells from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, pancreas, testis, tongue, cervix, or uterus. In addition, the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepifhelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo- alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; Paget's disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w/squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; androblastoma, malignant; Sertoli cell carcinoma; Leydig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malignant melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; Mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; Brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; Kaposi's sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; Ewing's sarcoma: odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; Hodgkin's disease; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-Hodgkin's lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia. In certain aspects, the tumor may comprise an osteosarcoma, angiosarcoma, rhabdosarcoma, leiomyosarcoma, Ewing sarcoma, glioblastoma, neuroblastoma, or leukemia. A. Leukemia

[0035] Clinically and pathologically, leukemia is subdivided into a variety of large groups. The first division is between its acute and chronic forms. Acute leukemia is characterized by a rapid increase in the number of immature blood cells. Crowding due to such cells makes the bone marrow unable to produce healthy blood cells. Immediate treatment is required in acute leukemia due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. Acute forms of leukemia are the most common forms of leukemia in children. Chronic leukemia is characterized by the excessive build up of relatively mature, but still abnormal, white blood cells. Typically taking months or years to progress, the cells are produced at a much higher rate than normal, resulting in many abnormal white blood cells. Whereas acute leukemia must be treated immediately, chronic forms are sometimes monitored for some time before treatment to ensure maximum effectiveness of therapy. Chronic leukemia mostly occurs in older people, but can theoretically occur in any age group.

[0036] Additionally, the diseases are subdivided according to which kind of blood cell is affected. This split divides leukemias into lymphoblastic or lymphocytic leukemias and myeloid or myelogenous leukemias. In lymphoblastic or lymphocytic leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form lymphocytes, which are infection-fighting immune system cells. Most lymphocytic leukemias involve a specific subtype of lymphocyte, the B cell. In myeloid or myelogenous leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form red blood cells, some other types of white cells, and platelets.

[0037] Combining these two classifications provides a total of four main categories. Within each of these four main categories, there are typically several subcategories. Finally, some rarer types are usually considered to be outside of this classification scheme:

• Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in young children. This disease also affects adults, especially those age 65 and older. Standard treatments involve chemotherapy and radiotherapy. The survival rates vary by age: 85% in children and 50% in adults. Subtypes include precursor B acute lymphoblastic leukemia, precursor T acute lymphoblastic leukemia, Burkitt's leukemia, and acute biphenotypic leukemia.

· Chronic lymphocytic leukemia (CLL) most often affects adults over the age of 55. It sometimes occurs in younger adults, but it almost never affects children. Two-thirds of affected people are men. The five-year survival rate is 75%. It is incurable, but there are many effective treatments. One subtype is B-cell prolymphocytic leukemia, a more aggressive disease. • Acute myelogenous leukemia (AML) occurs more commonly in adults than in children, and more commonly in men than women. AML is treated with chemotherapy. The five- year survival rate is 40%, except for acute promyelocyte leukemia (APL), which is over 90%. Subtypes of AML include acute promyelocytic leukemia (APL), acute myeloblasts leukemia, and acute megakaryoblastic leukemia.

• Chronic myelogenous leukemia (CML) occurs mainly in adults; a very small number of children also develop this disease. Treatment is with imatinib (Gleevec in United States, Glivec in Europe) or other drugs. The five-year survival rate is 90%. One subtype is chronic monocytic leukemia.

• Hairy cell leukemia (HCL) is sometimes considered a subset of chronic lymphocytic leukemia, but does not fit neatly into this pattern. About 80% of affected people are adult men. No cases in children have been reported. HCL is incurable, but easily treatable. Survival is 96% to 100% at ten years.

• T-cell prolymphocyte leukemia (T-PLL) is a very rare and aggressive leukemia affecting adults; somewhat more men than women are diagnosed with this disease. Despite its overall rarity, it is also the most common type of mature T cell leukemia; nearly all other leukemias involve B cells. It is difficult to treat, and the median survival is measured in months.

• Large granular lymphocytic leukemia may involve either T-cells or NK cells; like hairy cell leukemia, which involves solely B cells, it is a rare and indolent (not aggressive) leukemia.

[0038] Adult T-cell leukemia is caused by human T-lymphotropic virus (HTLV), a virus similar to HIV. Like HIV, HTLV infects CD4+ T-cells and replicates within them; however, unlike HIV. it does not destroy them. Instead, HTLV "immortalizes" the infected T-cells, giving them the ability to proliferate abnormally. Human T cell lymphotropic virus types I and II (HTLV-I/II) are endemic in certain areas of the world.

III. Pharmaceutical Formulations and Routes of Administration

[0039] For the purpose of administration to a patient in need of such treatment, pharmaceutical formulations (also referred to as a pharmaceutical preparations, pharmaceutical compositions, pharmaceutical products, medicinal products, medicines, medications, or medicaments) comprise a therapeutically effective amount of a A ¹² -PGJ ₃ derivative of the present disclosure formulated with one or more excipients and/or drug carriers appropriate to the indicated route of administration. In some embodiments, the compounds of the present disclosure are formulated in a manner amenable for the treatment of human and/or veterinary patients. In some embodiments, formulation comprises admixing or combining one or more of the compounds of the present disclosure with one or more of the following excipients: lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol. In some embodiments, e.g., for oral administration, the pharmaceutical formulation may be tableted or encapsulated. In some embodiments, the compounds may be dissolved or slurried in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Pharmaceutical formulations may be subjected to conventional pharmaceutical operations, such as sterilization and/or may contain drug carriers and/or excipients such as preservatives, stabilizers, wetting agents, emulsifiers, encapsulating agents such as lipids, dendrimers, polymers, proteins such as albumin, or nucleic acids, and buffers, etc. [0040] Pharmaceutical formulations may be administered by a variety of methods, e.g., orally or by injection (e.g., subcutaneous, intravenous, intraperitoneal, etc.). Depending on the route of administration, the A ¹² -PGJ ₃ derivatives of the present disclosure may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound. To administer the active compound by other than parenteral administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. For example, the active compound may be administered to a patient in an appropriate carrier, for example, liposomes, or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes.

[0041] The A ¹² -PGJ ₃ derivatives of the present disclosure may also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

[0042] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. [0043] The A ¹² -PGJ3 derivatives of the present disclosure can be administered orally, for example, with an inert diluent or an assimilable edible carrier. The compounds and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, the compounds of the present disclosure may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The percentage of the therapeutic compound in the compositions and preparations may, of course, be varied. The amount of the therapeutic compound in such pharmaceutical formulations is such that a suitable dosage will be obtained. [0044] In some embodiments, the therapeutic compound may also be administered topically to the skin, eye, or mucosa. Alternatively, if local delivery to the lungs is desired the therapeutic compound may be administered by inhalation in a dry-powder or aerosol formulation.

[0045] In some embodiments, it may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. In some embodiments, the specification for the dosage unit forms of the disclosure are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of a selected condition in a patient. In some embodiments, active compounds are administered at a therapeutically effective dosage sufficient to treat a condition associated with a condition in a patient. For example, the efficacy of a compound can be evaluated in an animal model system that may be predictive of efficacy in treating the disease in a human or another animal. [0046] In some embodiments, the effective dose range for the therapeutic compound can be extrapolated from effective doses determined in animal studies for a variety of different animals. In general a human equivalent dose (HED) in mg kg can be calculated in accordance with the following formula (see, e.g., Reagan-Shaw et ai, FASEB J., 22(3): 659-661, 2008, which is incorporated herein by reference): HED (mg kg) = Animal dose (mg/kg) x (Animal K _m /Human K _m )

[0047] Use of the K _m factors in conversion results in more accurate HED values, which are based on body surface area (BSA) rather than only on body mass. K _m values for humans and various animals are well known. For example, the K _m for an average 60 kg human (with a BSA of 1.6 m ² ) is 37, whereas a 20 kg child (BSA 0.8 m ² ) would have a _m of 25. K _m for some relevant animal models are also well known, including: mice K _m of 3 (given a weight of 0.02 kg and BSA of 0.007); hamster K _m of 5 (given a weight of 0.08 kg and BSA of 0.02); rat K _m of 6 (given a weight of 0.15 kg and BSA of 0.025) and monkey K _m of 12 (given a weight of 3 kg and BSA of 0.24). [0048] Precise amounts of the therapeutic composition depend on the judgment of the practitioner and are peculiar to each individual. Nonetheless, a calculated HED dose provides a general guide. Other factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment and the potency, stability and toxicity of the particular therapeutic formulation. [0049] The actual dosage amount of a A ¹² -PGJ ₃ derivatives of the present disclosure or composition comprising a A ¹² -PGJ ₃ derivatives of the present disclosure administered to a subject may be determined by physical and physiological factors such as type of animal treated, age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the subject and on the route of administration. These factors may be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject. The dosage may be adjusted by the individual physician in the event of any complication.

[0050] In some embodiments, the therapeutically effective amount typically will vary from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 100 mg/kg to about 500 mg/kg, from about 1 mg/kg to about 250 mg/kg, from about 10 mg/kg to about 150 mg/kg in one or more dose administrations daily, for one or several days (depending of course of the mode of administration and the factors discussed above). Other suitable dose ranges include 1 mg to 10,000 mg per day, 100 mg to 10,000 mg per day, 500 mg to 10,000 mg per day, and 500 mg to 1,000 mg per day. In some particular embodiments, the amount is less than 10,000 mg per day with a range of 750 mg to 9,000 mg per day.

[0051] In some embodiments, the amount of the active compound in the pharmaceutical formulation is from about 2 to about 75 weight percent. In some of these embodiments, the amount if from about 25 to about 60 weight percent.

[0052] Single or multiple doses of the agents are contemplated. Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation. As an example, subjects may be administered two doses daily at approximately 12 hour intervals. In some embodiments, the agent is administered once a day. [0053] The agent(s) may be administered on a routine schedule. As used herein a routine schedule refers to a predetermined designated period of time. The routine schedule may encompass periods of time which are identical or which differ in length, as long as the schedule is predetermined. For instance, the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there-between. Alternatively, the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc. In other embodiments, the disclosure provides that the agent(s) may be taken orally and that the timing of which is or is not dependent upon food intake. Thus, for example, the agent can be taken every morning and/or every evening, regardless of when the subject has eaten or will eat.

IV. Methods of Treatment

[0054] In particular, the compositions that may be used in treating cancer in a subject (e.g., a human subject) are disclosed herein. The compositions described above are preferably administered to a mammal (e.g., rodent, human, non-human primates, canine, bovine, ovine, equine, feline, etc.) in an effective amount, that is, an amount capable of producing a desirable result in a treated subject (e.g., causing apoptosis of cancerous cells). Toxicity and therapeutic efficacy of the compositions utilized in methods of the disclosure can be determined by standard pharmaceutical procedures. As is well known in the medical and veterinary arts, dosage for any one animal depends on many factors, including the subject's size, body surface area, body weight, age, the particular composition to be administered, time and route of administration, general health, the clinical symptoms of the infection or cancer and other drugs being administered concurrently. A composition as described herein is typically administered at a dosage that inhibits the growth or proliferation of a cancer cell or induces death of cancerous cells (e.g., induces apoptosis of a cancer cell), as assayed by identifying a reduction in hematological parameters (complete blood count - CBC), or cancer cell growth or proliferation. In some embodiments, amounts of the A ¹² -PGJ ₃ derivatives described therein used to induce apoptosis of the cancer cells is calculated to be from about 0.01 mg to about 10,000 mg/day. In some embodiments, the amount is from about 1 mg to about 1,000 mg/day. In some embodiments, these dosings may be reduced or increased based upon the biological factors of a particular patient such as increased or decreased metabolic breakdown of the drug or decreased uptake by the digestive tract if administered orally. Additionally, the A ¹² -PGJ ₃ derivatives described therein may be more efficacious and thus a smaller dose is required to achieve a similar effect. Such a dose is typically administered once a day for a few weeks or until sufficient reducing in cancer cells has been achieved.

[0055] The therapeutic methods of the disclosure (which include prophylactic treatment) in general include administration of a therapeutically effective amount of the compositions described herein to a subject in need thereof, including a mammal, particularly a human. Such treatment will be suitably administered to subjects, particularly humans, suffering from, having, susceptible to, or at risk for a disease, disorder, or symptom thereof. Determination of those subjects' "at risk" can be made by any objective or subjective determination by a diagnostic test or opinion of a subject or health care provider (e.g., genetic test, enzyme or protein marker, marker (as defined herein), family history, and the like).

[0056] In one embodiment, the disclosure provides a method of monitoring treatment progress. The method includes the step of determining a level of changes in hematological parameters and/or cancer stem cell (CSC) analysis with cell surface proteins as diagnostic markers (which can include, for example, but are not limited to CD34, CD38, CD90, and CD117) or diagnostic measurement (e.g., screen, assay) in a subject suffering from or susceptible to a disorder or symptoms thereof associated with cancer (e.g., leukemia) in which the subject has been administered a therapeutic amount of a composition as described herein. The level of marker determined in the method can be compared to known levels of marker in either healthy normal controls or in other afflicted patients to establish the subject's disease status. In preferred embodiments, a second level of marker in the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of disease or the efficacy of the therapy. In certain preferred embodiments, a pre-treatment level of marker in the subject is determined prior to beginning treatment according to the methods described herein; this pre-treatment level of marker can then be compared to the level of marker in the subject after the treatment commences, to determine the efficacy of the treatment. V. Combination Therapies

[0057] It is envisioned that the A ¹² -PGJ3 derivatives described therein may be used in combination therapies with one or more cancer therapies or a compound which mitigates one or more of the side effects experienced by the patient. It is common in the field of cancer therapy to combine therapeutic modalities. The following is a general discussion of therapies that may be used in conjunction with the therapies of the present disclosure.

[0058] To treat cancers using the methods and compositions of the present disclosure, one would generally contact a tumor cell or subject with a compound and at least one other therapy. These therapies would be provided in a combined amount effective to achieve a reduction in one or more disease parameter. This process may involve contacting the cells/subjects with the both agents/therapies at the same time, e.g., using a single composition or pharmacological formulation that includes both agents, or by contacting the cell/subject with two distinct compositions or formulations, at the same time, wherein one composition includes the compound and the other includes the other agent.

[0059] Alternatively, the A ¹² -PGJ3 derivatives described therein may precede or follow the other treatment by intervals ranging from minutes to weeks. One would generally ensure that a significant period of time did not expire between the time of each delivery, such that the therapies would still be able to exert an advantageously combined effect on the cell/subject. In such instances, it is contemplated that one would contact the cell with both modalities within about 12-24 hours of each other, within about 6-12 hours of each other, or with a delay time of only about 1-2 hours. In some situations, it may be desirable to extend the time period for treatment significantly; however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations.

[0060] It also is conceivable that more than one administration of either the compound or the other therapy will be desired. Various combinations may be employed, where a compound of the present disclosure is "A," and the other therapy is "B," as exemplified below:

A/B/A B/A/B B/B/A A/A/B B/A/A A/B/B B/B B/A B B/A/B

A/A/B/B A/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B B/B/B/A

A/A/A/B B/A A/A A/B/A/A A/A/B/A A/B/B/B B/A/B/B B/B/A/B

[0061] Other combinations are also contemplated. The following is a general discussion of cancer therapies that may be used combination with the compounds of the present disclosure.

1. Chemotherapy

[0062] The term "chemotherapy" refers to the use of drugs to treat cancer. A "chemotherapeutic agent" is used to connote a compound or composition that is administered in the treatment of cancer. These agents or drugs are categorized by their mode of activity within a cell, for example, whether and at what stage they affect the cell cycle. Alternatively, an agent may be characterized based on its ability to directly cross-link DNA, to intercalate into DNA, or to induce chromosomal and mitotic aberrations by affecting nucleic acid synthesis. Most chemotherapeutic agents fall into the following categories: alkylating agents, antimetabolites, antitumor antibiotics, mitotic inhibitors, and nitrosoureas.

[0063] Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γΐ and calicheamicin col ; dynemicin, including dynemicin A; uncialamycin and derivatives thereof; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cy nomoφholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalarnycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, or zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2' ,2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel and docetaxel; chlorambucil; gemcitabine; 6- thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g. , CPT-11); topoisomerase inhibitor RFS 2000; difluorometlhylornithine (DMFO); retinoids such as retinoic acid; capecitabine; cisplatin (CDDP), carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP 16), tamoxifen, raloxifene, estrogen receptor binding agents, taxol, paclitaxel, docetaxel, gemcitabien, navelbine, farnesyl-protein tansferase inhibitors, transplatinum, 5-fluorouracil, vincristin, vinblastin and methotrexate and pharmaceutically acceptable salts, acids or derivatives of any of the above.

2. Radiotherapy

[0064] Radiotherapy, also called radiation therapy, is the treatment of cancer and other diseases with ionizing radiation. Ionizing radiation deposits energy that injures or destroys cells in the area being treated by damaging their genetic material, making it impossible for these cells to continue to grow. Although radiation damages both cancer cells and normal cells, the latter are able to repair themselves and function properly.

[0065] Radiation therapy used according to the present disclosure may include, but is not limited to, the use of γ-rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells. Other forms of DNA damaging factors are also contemplated such as microwaves and UV-irradiation. It is most likely that all of these factors induce a broad range of damage on DNA, on the precursors of DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes. Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (3 to 4 wk), to single doses of 2000 to 6000 roentgens. Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.

[0066] Radiotherapy may comprise the use of radiolabeled antibodies to deliver doses of radiation directly to the cancer site (radioimmuno therapy). Antibodies are highly specific proteins that are made by the body in response to the presence of antigens (substances recognized as foreign by the immune system). Some tumor cells contain specific antigens that trigger the production of tumor- specific antibodies. Large quantities of these antibodies can be made in the laboratory and attached to radioactive substances (a process known as radiolabeling). Once injected into the body, the antibodies actively seek out the cancer cells, which are destroyed by the cell-killing (cytotoxic) action of the radiation. This approach can minimize the risk of radiation damage to healthy cells.

[0067] Conformal radiotherapy uses the same radiotherapy machine, a linear accelerator, as the normal radiotherapy treatment but metal blocks are placed in the path of the x-ray beam to alter its shape to match that of the cancer. This ensures that a higher radiation dose is given to the tumor. Healthy surrounding cells and nearby structures receive a lower dose of radiation, so the possibility of side effects is reduced. A device called a multi-leaf collimator has been developed and may be used as an alternative to the metal blocks. The multi-leaf collimator consists of a number of metal sheets which are fixed to the linear accelerator. Each layer can be adjusted so that the radiotherapy beams can be shaped to the treatment area without the need for metal blocks. Precise positioning of the radiotherapy machine is very important for conformal radiotherapy treatment and a special scanning machine may be used to check the position of internal organs at the beginning of each treatment.

[0068] High-resolution intensity modulated radiotherapy also uses a multi-leaf collimator. During this treatment the layers of the multi-leaf collimator are moved while the treatment is being given. This method is likely to achieve even more precise shaping of the treatment beams and allows the dose of radiotherapy to be constant over the whole treatment area.

[0069] Although research studies have shown that conformal radiotherapy and intensity modulated radiotherapy may reduce the side effects of radiotherapy treatment, it is possible that shaping the treatment area so precisely could stop microscopic cancer cells just outside the treatment area being destroyed. This means that the risk of the cancer coming back in the future may be higher with these specialized radiotherapy techniques.

[0070] Scientists also are looking for ways to increase the effectiveness of radiation therapy. Two types of investigational drugs are being studied for their effect on cells undergoing radiation. Radiosensitizers make the tumor cells more likely to be damaged, and radioprotectors protect normal tissues from the effects of radiation. Hyperthermia, the use of heat, is also being studied for its effectiveness in sensitizing tissue to radiation.

3. Immunotherapy

[0071] In the context of cancer treatment, immunotherapeutics, generally, rely on the use of immune effector cells and molecules to target and destroy cancer cells. Trastuzumab (Herceptin™) is such an example. The immune effector may be, for example, an antibody specific for some marker on the surface of a tumor cell. The antibody alone may serve as an effector of therapy or it may recruit other cells to actually affect cell killing. The antibody also may be conjugated to a drug or toxin (chemo therapeutic, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc. ) and serve merely as a targeting agent. Alternatively, the effector may be a lymphocyte carrying a surface molecule that interacts, either directly or indirectly, with a tumor cell target. Various effector cells include cytotoxic T cells and NK cells. The combination of therapeutic modalities, i.e., direct cytotoxic activity and inhibition or reduction of ErbB2 would provide therapeutic benefit in the treatment of ErbB2 overexpressing cancers.

[0072] In one aspect of immunotherapy, the tumor cell must bear some marker that is amenable to targeting, i.e., is not present on the majority of other cells. Many tumor markers exist and any of these may be suitable for targeting in the context of the present disclosure. Common tumor markers include carcinoembryonic antigen, prostate specific antigen, urinary tumor associated antigen, fetal antigen, tyrosinase (p97), gp68, TAG-72, HMFG, Sialyl Lewis Antigen, MucA, MucB, PLAP, estrogen receptor, laminin receptor, erb B and pl55. An alternative aspect of immunotherapy is to combine anticancer effects with immune stimulatory effects. Immune stimulating molecules also exist including: cytokines such as IL-2, IL-4, IL-12, GM-CSF, γ-IFN, chemokines such as MIP-1, MCP-1, IL-8 and growth factors such as FLT3 ligand. Combining immune stimulating molecules, either as proteins or using gene delivery in combination with a tumor suppressor has been shown to enhance anti-tumor effects (Ju et al, 2000). Moreover, antibodies against any of these compounds may be used to target the anti-cancer agents discussed herein.

[0073] Examples of immunotherapies currently under investigation or in use are immune adjuvants e.g., Mycobacterium bovis, Plasmodium falciparum, dinitrochlorobenzene and aromatic compounds (U.S. Patents 5,801,005 and 5,739,169; Hui and Hashimoto, 1998; Christodoulides et al, 1998), cytokine therapy, e.g., interferons α, β, and γ; IL-1, GM-CSF and TNF (Bukowski et al, 1998; Davidson et al, 1998; Hellstrand et al, 1998) gene therapy, e.g., TNF, IL-1, IL-2, p53 (Qin et al, 1998; Austin-Ward and Villaseca, 1998; U.S. Patents 5,830,880 and 5,846,945) and monoclonal antibodies, e.g., anti-ganglioside GM2, anti-HER-2, anti-pl85 (Pietras et al, 1998; Hanibuchi et al, 1998; U.S. Patent 5,824,311). It is contemplated that one or more anti-cancer therapies may be employed with the gene silencing therapies described herein.

[0074] In active immunotherapy, an antigenic peptide, polypeptide or protein, or an autologous or allogenic tumor cell composition or "vaccine" is administered, generally with a distinct bacterial adjuvant (Ravindranath and Morton, 1991; Morton et al, 1992; Mitchell et al, 1990; Mitchell et al, 1993).

[0075] In adoptive immunotherapy, the patient' s circulating lymphocytes, or tumor infiltrated lymphocytes, are isolated in vitro, activated by lymphokines such as IL-2 or transduced with genes for tumor necrosis, and readministered (Rosenberg et al, 1988; 1989).

4. Surgery

[0076] Approximately 60% of persons with cancer will undergo surgery of some type, which includes preventative, diagnostic or staging, curative, and palliative surgery. Curative surgery is a cancer treatment that may be used in conjunction with other therapies, such as the treatment of the present disclosure, chemotherapy, radiotherapy, hormonal therapy, gene therapy, immunotherapy and/or alternative therapies. [0077] Curative surgery includes resection in which all or part of cancerous tissue is physically removed, excised, and/or destroyed. Tumor resection refers to physical removal of at least part of a tumor. In addition to tumor resection, treatment by surgery includes laser surgery, cryosurgery, electrosurgery, and microscopically controlled surgery (Mohs' surgery). It is further contemplated that the present disclosure may be used in conjunction with removal of superficial cancers, precancers, or incidental amounts of normal tissue.

[0078] Upon excision of part or all of cancerous cells, tissue, or tumor, a cavity may be formed in the body. Treatment may be accomplished by perfusion, direct injection or local application of the area with an additional anti-cancer therapy. Such treatment may be repeated, for example, every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, 4, and 5 weeks or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. These treatments may be of varying dosages as well.

[0079] In some particular embodiments, after removal of the tumor, an adjuvant treatment with a compound of the present disclosure is believe to be particularly efficacious in reducing the reoccurance of the tumor. Additionally, the compounds of the present disclosure can also be used in a neoadjuvant setting.

5. Other Agents

[0080] It is contemplated that other agents may be used with the present disclosure. These additional agents include immunomodulatory agents, agents that affect the upregulation of cell surface receptors and GAP junctions, cytostatic and differentiation agents, inhibitors of cell adhesion, agents that increase the sensitivity of the hyperproliferative cells to apoptotic inducers, or other biological agents. Immunomodulatory agents include tumor necrosis factor; interferon alpha, beta, and gamma; IL-2 and other cytokines; F42K and other cytokine analogs; or MIP-1, ΜΙΡ-Ιβ, MCP-1, RANTES, and other chemokines. It is further contemplated that the upregulation of cell surface receptors or their ligands such as Fas/Fas ligand, DR4 or DR5/TRAIL (Apo-2 ligand) would potentiate the apoptotic inducing abilities of the present disclosure by establishment of an autocrine or paracrine effect on hyperproliferative cells. Increases intercellular signaling by elevating the number of GAP junctions would increase the anti -hyperproliferative effects on the neighboring hyperproliferative cell population. In other embodiments, cytostatic or differentiation agents may be used in combination with the present disclosure to improve the anti-hyerproliferative efficacy of the treatments. Inhibitors of cell adhesion are contemplated to improve the efficacy of the present disclosure. Examples of cell adhesion inhibitors are focal adhesion kinase (FAKs) inhibitors and Lovastatin. It is further contemplated that other agents that increase the sensitivity of a hyperproliferative cell to apoptosis, such as the antibody c225, could be used in combination with the present disclosure to improve the treatment efficacy. [0081] There have been many advances in the therapy of cancer following the introduction of cytotoxic chemo therapeutic drugs. However, one of the consequences of chemotherapy is the development acquisition of drug-resistant phenotypes and the development of multiple drug resistance. The development of drug resistance remains a major obstacle in the treatment of such tumors and therefore, there is an obvious need for alternative approaches such as gene therapy. [0082] Another form of therapy for use in conjunction with chemotherapy, radiation therapy or biological therapy includes hyperthermia, which is a procedure in which a patient' s tissue is exposed to high temperatures (up to 106°F). External or internal heating devices may be involved in the application of local, regional, or whole-body hyperthermia. Local hyperthermia involves the application of heat to a small area, such as a tumor. Heat may be generated externally with high- frequency waves targeting a tumor from a device outside the body. Internal heat may involve a sterile probe, including thin, heated wires or hollow tubes filled with warm water, implanted microwave antennae, or radiofrequency electrodes.

[0083] A patient' s organ or a limb is heated for regional therapy, which is accomplished using devices that produce high energy, such as magnets. Alternatively, some of the patient's blood may be removed and heated before being perfused into an area that will be internally heated. Whole-body heating may also be implemented in cases where cancer has spread throughout the body. Warm-water blankets, hot wax, inductive coils, and thermal chambers may be used for this purpose.

[0084] The skilled artisan is directed to "Remington's Pharmaceutical Sciences" 15th Edition, chapter 33, in particular pages 624-652. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject. Moreover, for human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards. [0085] It also should be pointed out that any of the foregoing therapies may prove useful by themselves in treating cancer.

VI. Definitions

[0086] When used in the context of a chemical group: "hydrogen" means -H; "hydroxy" means -OH; "oxo" means =0; "carbonyl" means -C(=0)-; "carboxy" means -C(=0)OH (also written as -COOH or -CO2H); "halo" means independently -F, -CI, -Br or -I; "amino" means -N¾; "hydroxyamino" means -NHOH; "nitro" means -NO2; imino means =NH; "cyano" means -CN; "isocyanate" means -N=C=0; "azido" means -N3; in a monovalent context "phosphate" means -OP(0)(OH)2 or a deprotonated form thereof; in a divalent context "phosphate" means -OP(0)(OH)0- or a deprotonated form thereof; "mercapto" means -SH; and "thio" means =S; "sulfonyl" means -S(0) ₂ -; and "sulfinyl" means -S(0)-.

[0087] In the context of chemical formulas, the symbol "-" means a single bond, "=" means a double bond, and "≡" means triple bond. The symbol " " represents an optional bond, which if present is either single or double. The symbol " rrrz" represents a single bond or a double bond. Thus, the formula and s?. And it is understood that no one such ring atom forms part of more than one double bond. Furthermore, it is noted that the covalent bond symbol when connecting one or two stereogenic atoms, does not indicate any preferred stereochemistry. Instead, it covers all stereoisomers as well as mixtures thereof. The symbol " «ΛΛΛ " _{5 w} hen drawn perpendicularly across a bond (^.g., |— CH ₃ for methyl) indicates a point of attachment of the group. It is noted that the point of attachment is typically only identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point of attachment. The symbol " " means a single bond where the group attached to the thick end of the wedge is "out of the page." The symbol " ""HI " means a single bond where the group attached to the thick end of the wedge is "into the page". The symbol ' ^{1 >ΛΛΛ} " means a single bond where the geometry around a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper.

[0088] When a group "R" is depicted as a "floating group" on a ring system, for example, in the formula: then R may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed. When a group "R" is depicted as a "floating group" on a fused ring system, as for example in the formula:

then R may replace any hydrogen attached to any of the ring atoms of either of the fused rings unless specified otherwise. Replaceable hydrogens include depicted hydrogens (e.g., the hydrogen attached to the nitrogen in the formula above), implied hydrogens (e.g., a hydrogen of the formula above that is not shown but understood to be present), expressly defined hydrogens, and optional hydrogens whose presence depends on the identity of a ring atom (e.g., a hydrogen attached to group X, when X equals -CH-), so long as a stable structure is formed. In the example depicted, R may reside on either the 5- membered or the 6-membered ring of the fused ring system. In the formula above, the subscript letter "y" immediately following the group "R" enclosed in parentheses, represents a numeric variable. Unless specified otherwise, this variable can be 0, 1, 2, or any integer greater than 2, only limited by the maximum number of replaceable hydrogen atoms of the ring or ring system.

[0089] For the chemical groups and compound classes, the number of carbon atoms in the group or class is as indicated as follows: "Cn" defines the exact number (n) of carbon atoms in the group/class. "C<n" defines the maximum number (n) of carbon atoms that can be in the group/class, with the minimum number as small as possible for the group/class in question, e.g. , it is understood that the minimum number of carbon atoms in the group "alkenyl(c<8)" or the class "alkene(c<8)" is two. Compare with "alkoxy(c≤io)", which designates alkoxy groups having from 1 to 10 carbon atoms. "Cn- n'" defines both the minimum (n) and maximum number (η') of carbon atoms in the group. Thus, "alkyl(C2-ioi" designates those alkyl groups having from 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical groups or class it modifies and it may or may not be enclosed in parenthesis, without signifying any change in meaning. Thus, the terms "C5 olefin", "C5- olefin", "olefinccs)", and "olefincs" are all synonymous. When any of the chemical groups or compound classes defined herein is modified by the term "substituted", any carbon atom(s) in a moiety replacing a hydrogen atom is not counted. Thus me hoxyhexyl, which has a total of seven carbon atoms, is an example of a substituted alkyl(ci-6).

[0090] The term "saturated" when used to modify a compound or chemical group means the compound or chemical group has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted versions of saturated groups, one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine/enamine tautomerism are not precluded. When the term "saturated" is used to modify a solution of a substance, it means that no more of that substance can dissolve in that solution. [0091] The term "aliphatic" when used without the "substituted" modifier signifies that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic hydrocarbon compound or group. In aliphatic compounds/groups, the carbon atoms can bejoined together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds/groups can be saturated, that is joined by single carbon-carbon bonds (alkanes/alkyl), or unsaturated, with one or more carbon-carbon double bonds (alkenes/alkenyl) or with one or more carbon-carbon triple bonds (alkynes/alkynyl).

[0092] The term "aromatic" when used to modify a compound or a chemical group refers to a planar unsaturated ring of atoms with 4ra +2 electrons in a fully conjugated cyclic π system. [0093] The term "alkyl" when used without the "substituted" modifier refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen. The groups -CH ₃ (Me), -CH2CH3 (Et), -CH2CH2CH3 (n-Pr or propyl), -CH(CH ₃ ) ₂ (i-Pr, 'Pr or isopropyl), -CH2CH2CH2CH3 (ra-Bu), -CH(CH ₃ )CH ₂ CH ₃ (sec-butyl), -CH ₂ CH(CH ₃ )2 (isobutyl), -C(CH ₃ ) ₃ (tert-but l, f-butyl, f-Bu or *Bu), and -CH2C(CH ₃ ) ₃ (weo-pentyl) are non-limiting examples of alkyl groups. The term "alkanediyl" when used without the "substituted" modifier refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon- carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups -CH2- (methylene), -CH2CH2-, -CH ₂ C(CH ₃ ) ₂ CH2-, and -CH ₂ CH ₂ CH ₂ - are non-limiting examples of alkanediyl groups. The term "alkylidene" when used without the "substituted" modifier refers to the divalent group =CRR' in which R and R' are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include: =C¾, =CH(CH2CH ₃ ), and =C(CH ₃ )2. An "alkane" refers to the class of compounds having the formula H-R, wherein R is alkyl as this term is defined above. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(0)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -C(0)NH ₂ , -C(0)NHCH ₃ , -C(0)N(CH ₃ ) ₂ , -OC(0)CH ₃ , -NHC(0)CH ₃ , -S(0) ₂ OH, or -S(0) ₂ NH ₂ . The following groups are non-limiting examples of substituted alkyl groups: -CH2OH, -CH2CI, -CF ₃ , -CH ₂ CN, -CH ₂ C(0)OH, -CH ₂ C(0)OCH ₃ , -CH ₂ C(0)NH ₂ , -CH ₂ C(0)CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OC(0)CH ₃ , -CH ₂ NH ₂ , -CH ₂ N(CH ₃ )2, and -CH2CH2CI. The term "haloalkyl" is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to halo (i.e. -F, -CI, -Br, or -I) such that no other atoms aside from carbon, hydrogen and halogen are present. The group, -CH2CI is a non-limiting example of a haloalkyl. The term "fluoroalkyl" is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to fluoro such that no other atoms aside from carbon, hydrogen and fluorine are present. The groups -C¾F, -CF ₃ , and -CH ₂ CF ₃ are non-limiting examples of fluoroalkyl groups.

[0094] The term "cycloalkyl" when used without the "substituted" modifier refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, said carbon atom forming part of one or more non-aromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: -CH(CH ₂ )2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). The term "cycloalkanediyl" when used without the "substituted" modifier refers to a divalent saturated aliphatic group with two carbon atoms as points of attachment, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen.

The group non-limiting example of cycloalkanediyl group. A "cycloalkane" refers to the class of compounds having the formula H-R, wherein R is cycloalkyl as this term is defined above. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -N0 ₂ , -C0 ₂ H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH ₃ , -NHCH3, -NHCH2CH3, -N(CH ₃ ) ₂ , -C(0)NH ₂ , -C(0)NHCH ₃ , -C(0)N(CH ₃ ) ₂ , -OC(0)CH ₃ , -NHC(0)CH ₃ , -S(0) ₂ OH, or -S(0) ₂ NH ₂ . [0095] The term "alkenyl" when used without the "substituted" modifier refers to an monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: -CH=CH ₂ (vinyl), -CH=CHCH ₃ , -CH=CHCH ₂ CH , -CH ₂ CH=CH ₂ (allyl), -CH ₂ CH=CHCH , and -CH=CHCH=CH ₂ . The term "alkenediyl" when used without the "substituted" modifier refers to a divalent unsaturated aliphatic group, with two carbon atoms as points of attachment, a linear or branched, a linear or branched acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups -CH=CH- -CH=C(CH ₃ )CH ₂ - -CH=CHCH ₂ - and -CH ₂ CH=CHCH ₂ - are non-limiting examples of alkenediyl groups. It is noted that while the alkenediyl group is aliphatic, once connected at both ends, this group is not precluded from forming part of an aromatic structure. The terms "alkene" and "olefin" are synonymous and refer to the class of compounds having the formula H-R, wherein R is alkenyl as this term is defined above. Similarly the terms "terminal alkene" and "a-olefin" are synonymous and refer to an alkene having just one carbon-carbon double bond, wherein that bond is part of a vinyl group at an end of the molecule. When any of these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -NO2, -CO2H, -C0 ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(0)CH ₃ , -NHCH ₃ , -NHC¾CH ₃ , -N(CH ₃ )¾ -C(0)NH ₂ , -C(0)NHCH ₃ , -C(0)N(CH ₃ ) ₂ , -OC(0)CH ₃ , -NHC(0)CH ₃ , -S(0) ₂ OH, or -S(0) ₂ NH ₂ . The groups -CH=CHF, -CH=CHC1 and -CH=CHBr are non-limiting examples of substituted alkenyl groups.

[0096] The term "alkynyl" when used without the "substituted" modifier refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not preclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups -C≡CH, -C≡CCH ₃ , and -CH ₂ C≡CCH ₃ are non-limiting examples of alkynyl groups. An "alkyne" refers to the class of compounds having the formula H-R, wherein R is alkynyl. When any of these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -NO2, -CO2H, -C0 ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(0)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -C(0)NH ₂ , -C(0)NHCH ₃ , -C(0)N(CH ₃ ) ₂ , -OC(0)CH ₃ , -NHC(0)CH ₃ , -S(0) ₂ OH, or -S(0) ₂ NH ₂ . [0097] The term "aryl" when used without the "substituted" modifier refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more six-membered aromatic ring structure, wherein the ring atoms are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl or aralkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), mefhylphenyl, (dimethyl)phenyl, -C6H4CH2CH3 (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl. The term "arenediyl" when used without the "substituted" modifier refers to a divalent aromatic group with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structure(s) wherein the ring atoms are all carbon, and wherein the monovalent group consists of no atoms other than carbon and hydrogen. As used herein, the term does not preclude the presence of one or more alkyl, aryl or aralkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings may be connected via one or more of the following: a covalent bond, alkanediyl, or alkenediyl groups (carbon number limitation permitting). Non-limiting examples of arenediyl groups include:

An "arene" refers to the class of compounds having the formula H-R, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes. When any of these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by

-OH, -F, -CI, -Br, -I, -NH ₂ , -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH ₃ , -NHCH3, -NHCH2CH3, -N(CH ₃ ) ₂ , -C(0)NH ₂ , -C(0)NHCH ₃ , -C(0)N(CH ₃ ) ₂ , -OC(0)CH ₃ , -NHC(0)CH ₃ , -S(0) ₂ OH, or -S(0) ₂ NH ₂ .

[0098] The term "aralkyl" when used without the "substituted" modifier refers to the monovalent group -alkanediyl-aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl. When the term aralkyl is used with the "substituted" modifier one or more hydrogen atom from the alkanediyl and/or the aryl group has been independently replaced by -OH, -F,

-CI, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH ₃ , -NHCH3, -NHCH2CH3, -N(CH ₃ ) ₂ , -C(0)NH ₂ , -C(0)NHCH ₃ , -C(0)N(CH ₃ ) ₂ , -OC(0)CH ₃ , -NHC(0)CH ₃ , -S(0)20H, or -S(0) ₂ NH ₂ . Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)- methyl, and 2-chloro-2-phenyl-eth-l-yl.

[0099] The term "aralkenyl" when used without the "substituted" modifier refers to the monovalent group -alkenediyl-aryl, in which the terms alkenediyl and aryl are each used in a manner consistent with the definitions provided above. When the term aralkenyl is used with the "substituted" modifier one or more hydrogen atom from the alkenediyl and/or the aryl group has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -N0 ₂ , -C0 ₂ H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH ₃ , -NHCH3, -NHCH2CH3, -N(CH ₃ ) ₂ , -C(0)NH ₂ , -C(0)NHCH ₃ , -C(0)N(CH ₃ ) ₂ , -OC(0)CH ₃ , -NHC(0)CH ₃ , -S(0) ₂ OH, or -S(0) ₂ NH2. [00100] The term "heteroaryl" when used without the "substituted" modifier refers to a monovalent aromatic group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl, aryl, and/or aralkyl groups (carbon number limitation permitting) attached to the aromatic ring or aromatic ring system. Non-limiting examples of heteroaryl groups include furanyl, imidazolyl, indolyl, indazolyl (Im), isoxazolyl, methylpyridinyl, oxazolyl, phenylpyridinyl, pyridinyl (pyridyl), pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term 'W-heteroaryl" refers to a heteroaryl group with a nitrogen atom as the point of attachment. A "heteroarene" refers to the class of compounds having the formula H-R, wherein R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes. When these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -C(0)NH ₂ , -C(0)NHCH ₃ , -C(0)N(CH ₃ ) ₂ , -OC(0)CH ₃ , -NHC(0)CH ₃ , -S(0) ₂ OH, or -S(0) ₂ NH ₂ .

[00101] The term "hetero aralkyl" when used without the "substituted" modifier refers to the monovalent group -alkanediyl-heteroaryl, in which the terms alkanediyl and heteroaryl are each used in a manner consistent with the definitions provided above. When the term aralkyl is used with the "substituted" modifier one or more hydrogen atom from the alkanediyl and/or the heteroaryl group has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -NO2, -CO2H, -C0 ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH2CH3, -C(0)CH ₃ , -NHCH3, -NHCH2CH3, -N(CH ₃ ) ₂ , -C(0)NH ₂ , -C(0)NHCH ₃ , -C(0)N(CH ₃ ) ₂ , -OC(0)CH ₃ , -NHC(0)CH ₃ , -S(0) ₂ OH, or -S(0) ₂ NH ₂ . [00102] The term "heteroaralkenyl" when used without the "substituted" modifier refers to the monovalent group -alkenediyl-heteroaryl, in which the terms alkenediyl and heteroaryl are each used in a manner consistent with the definitions provided above. When the term aralkenyl is used with the "substituted" modifier one or more hydrogen atom from the alkenediyl and/or the heteroaryl group has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -N0 ₂ , -C0 ₂ H, -C0 ₂ CH ₃ , -CN, -SH, -OCH3, -OCH ₂ CH ₃ , -C(0)CH ₃ , -NHCH3, -NHCH ₂ CH ₃ , -N(CH ₃ ) _¾ -C(0)NH ₂ , -C(0)NHCH ₃ , -C(0)N(CH ₃ ) ₂ , -OC(0)CH ₃ , -NHC(0)CH ₃ , -S(0) ₂ OH, or -S(0) ₂ NH ₂ .

[00103] The term "acyl" when used without the "substituted" modifier refers to the group -C(0)R, in which R is a hydrogen, alkyl, cycloalkyl, or aryl as those terms are defined above. The groups, -CHO, -C(0)CH ₃ (acetyl, Ac), -C(0)CH ₂ CH ₃ , -C(0)CH(CH ₃ ) ₂ , -C(0)CH(CH ₂ ) ₂ , -C(0)C6H5, and -C(0)CeH4CH ₃ are non-limiting examples of acyl groups. A "thioacyl" is defined in an analogous manner, except that the oxygen atom of the group -C(0)R has been replaced with a sulfur atom, -C(S)R. The term "aldehyde" corresponds to an alkyl group, as defined above, attached to a -CHO group. When any of these terms are used with the "substituted" modifier one or more hydrogen atom (including a hydrogen atom directly attached to the carbon atom of the carbonyl or thiocarbonyl group, if any) has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -NO ₂ , -CO ₂ H, -C0 ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(0)CH ₃ , -NHCH ₃ , -NHC¾CH ₃ , -N(CH ₃ ) ₂ , -C(0)NH ₂ , -C(0)NHCH ₃ , -C(0)N(CH ₃ ) ₂ , -OC(0)CH ₃ , -NHC(0)CH ₃ , -S(0) ₂ OH, or -S(0) ₂ NH ₂ . The groups, -C(0)CH ₂ CF ₃ , -C0 ₂ H (carboxyl), -C0 ₂ CH ₃ (methylcarboxyl), -C0 ₂ CH ₂ CH ₃ , -C(0)NH ₂ (carbamoyl), and -CON(CH ₃ ) ₂ , are non-limiting examples of substituted acyl groups.

[00104] The term "alkoxy" when used without the "substituted" modifier refers to the group -OR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: -OCH ₃ (methoxy), -OCH ₂ CH ₃ (ethoxy), -OCH ₂ CH ₂ CH ₃ , -OCH(CH ₃ ) ₂ (isopropoxy), -OC(CH ₃ ) ₃ (tert- butoxy), -OCH(CH ₂ ) ₂ , -O-cyclopentyl, and -O-cyclohexyl. The terms "cycloalkoxy", "alkenyloxy", "alkynyloxy", "aryloxy", "aralkoxy", "heteroaryloxy", "heterocycloalkoxy", and "acyloxy", when used without the "substituted" modifier, refers to groups, defined as -OR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The term "alkylthio" and "acylthio" when used without the "substituted" modifier refers to the group -SR, in which R is an alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group. The term "ether" corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy group. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -N0 ₂ , -C0 ₂ H, -C0 ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(0)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -C(0)NH ₂ , -C(0)NHCH ₃ , -C(0)N(CH ₃ ) ₂ , -OC(0)CH ₃ , -NHC(0)CH ₃ , -S(0) ₂ OH, or -S(0) ₂ NH ₂ . [00105] The term "alkylamino" when used without the "substituted" modifier refers to the group -NHR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: -NHCH3 and -NHCH2CH3. The term "dialkylamino" when used without the "substituted" modifier refers to the group -NRR', in which R and R' can be the same or different alkyl groups, or R and R' can be taken together to represent an alkanediyl. Non-limiting examples of dialkylamino groups include: -N(CH ₃ ) ₂ and -N(CH ₃ )(CH ₂ CH ₃ ). The terms "cycloalkylamino", "alkenylamino", "alkynylamino", "arylamino", "aralkylamino", "heteroarylamino", "heterocycloalkylamino", "alkoxyamino", and "alkylsulfonylamino" when used without the "substituted" modifier, refers to groups, defined as -NHR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, alkoxy, and alkylsulfonyl, respectively. A non-limiting example of an arylamino group is -NHC6¾. The term "amido" (acylamino), when used without the "substituted" modifier, refers to the group -NHR, in which R is acyl, as that term is defined above. A non-limiting example of an amido group is -NHC(0)CH3. The term "alkylimino" when used without the "substituted" modifier refers to the divalent group =NR, in which R is an alkyl, as that term is defined above. When any of these terms is used with the "substituted" modifier one or more hydrogen atom attached to a carbon atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -NO2, -CO2H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH ₃ , -NHCH3, -NHCH2CH3, -N(CH ₃ ) ₂ , -C(0)NH ₂ , -C(0)NHCH ₃ , -C(0)N(CH ₃ )¾ -OC(0)CH ₃ , -NHC(0)CH ₃ , -S(0) ₂ OH, or -S(0) ₂ NH ₂ . The groups -NHC(0)OCH ₃ and -NHC(0)NHCH3 are non-limiting examples of substituted amido groups. [00106] The use of the word "a" or "an," when used in conjunction with the term

"comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one."

[00107] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.

[00108] An "active ingredient" (AI) (also referred to as an active compound, active substance, active agent, pharmaceutical agent, agent, biologically active molecule, or a therapeutic compound) is the ingredient in a pharmaceutical drug or a pesticide that is biologically active. The similar terms active pharmaceutical ingredient (API) and bulk active are also used in medicine, and the term active substance may be used for pesticide formulations.

[00109] The terms "comprise," "have" and "include" are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes" and "including," are also open-ended. For example, any method that "comprises," "has" or "includes" one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps.

[00110] The term "effective," as that term is used in the specification and/or claims, means adequate to accomplish a desired, expected, or intended result. "Effective amount," "Therapeutically effective amount" or "pharmaceutically effective amount" when used in the context of treating a patient or subject with a compound means that amount of the compound which, when administered to a subject or patient for treating or preventing a disease, is an amount sufficient to effect such treatment or prevention of the disease.

[00111] The term "electron withdrawing group" is any chemical atom or group which has the net effect of reducing the elctron density around the attached atom. Some non-limiting examples of an electron withdrawing group include halo, amino, hydroxy, cyano, nitro, alkoxy, acyloxy, aryloxy, aralkoxy, alkylthio, acylthio, arylthio, aralkylthio, alkylamino, dialkylamino, arylamino, diarylamino, amido, aralkylamino, diaralkylamino, an ester, a sulfone, sulfoxide, or substituted versions of any of these groups. [00112] An "excipient" is a pharmaceutically acceptable substance formulated along with the active ingredient(s) of a medication, pharmaceutical composition, formulation, or drug delivery system. Excipients may be used, for example, to stabilize the composition, to bulk up the composition (thus often referred to as "bulking agents," "fillers," or "diluents" when used for this purpose), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients include pharmaceutically acceptable versions of antiadherents, binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles. The main excipient that serves as a medium for conveying the active ingredient is usually called the vehicle. Excipients may also be used in the manufacturing process, for example, to aid in the handling of the active substance, such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life. The suitability of an excipient will typically vary depending on the route of administration, the dosage form, the active ingredient, as well as other factors.

[00113] The term "hydrate" when used as a modifier to a compound means that the compound has less than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) water molecules associated with each compound molecule, such as in solid forms of the compound. [00114] As used herein, the term "IC50" refers to an inhibitory dose which is 50% of the maximum response obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological, biochemical or chemical process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. [00115] An "isomer" of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs.

[00116] An "oligomer" is a polymer comprising the condensation of one portion of the molecule to a second portion of the same molecule thus forming a macrocyclic structure with two or more molecules of the same or related formulas. For example, the compounds provided herein may be joined by the Xi of one molecule to the X2 of a second molecule but each of those compounds may have a different Yi, Ri or R2 chemical group.

[00117] As used herein, the term "patient" or "subject" refers to a living organism, such as a human, monkey, horse, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In some embodiments, the patient or subject is a mammal. In some embodiments, the patient or subject is a primate. Non-limiting examples of human patients are adults, juveniles, infants and fetuses.

[00118] As generally used herein "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.

[00119] "Pharmaceutically acceptable salts" means salts of compounds of the present disclosure which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene-l-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, <?-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triefhanolamine, tromethamine, -methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this disclosure is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

[00120] A "pharmaceutically acceptable carrier," "drug carrier," or simply "carrier" is a pharmaceutically acceptable substance formulated along with the active ingredient medication that is involved in carrying, delivering and/or transporting a chemical agent. Drug carriers may be used to improve the delivery and the effectiveness of drugs, including for example, controlled-release technology to modulate drug bioavailability, decrease drug metabolism, and/or reduce drug toxicity. Some drug carriers may increase the effectiveness of drug delivery to the specific target sites. Examples of carriers include: liposomes, microspheres (e.g., made of poly(lactic-co-glycolic) acid), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, erythrocytes, virosomes, and dendrimers.

[00121] A "pharmaceutical drug" (also referred to as a pharmaceutical, pharmaceutical preparation, pharmaceutical composition, pharmaceutical formulation, pharmaceutical product, medicinal product, medicine, medication, medicament, or simply a drug) is a drug used to diagnose, cure, treat, or prevent disease. An active ingredient (AI) (defined above) is the ingredient in a pharmaceutical drug or a pesticide that is biologically active. The similar terms active pharmaceutical ingredient (API) and bulk active are also used in medicine, and the term active substance may be used for pesticide formulations. Some medications and pesticide products may contain more than one active ingredient. In contrast with the active ingredients, the inactive ingredients are usually called excipients (defined above) in pharmaceutical contexts.

[00122] "Prevention" or "preventing" includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and/or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.

[00123] "Prodrug" means a compound that is convertible in vivo metabolically into an inhibitor according to the present disclosure. The prodrug itself may or may not also have activity with respect to a given target protein. For example, a compound comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound. Suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- -hydroxynaphthoate, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, and the like. Similarly, a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.

[00124] A "repeat unit" is the simplest structural entity of certain materials, for example, oligomers and/or polymers, whether organic, inorganic or metal-organic. In the case of an oligomer or polymer chain, repeat units are linked together successively along the chain, like the beads of a necklace. For example, in polyethylene, -[-( ¾( ¾-]„-, the repeat unit is -CH ₂ CH ₂ -. The subscript "n" denotes thethe number of repeat units linked together. When the value for "n" is left undefined or where "n" is absent, it simply designates repetition of the formula within the brackets as well as the polymeric nature of the material. The concept of a repeat unit applies equally to where the connectivity between the repeat units extends three dimensionally, such as in macrocyclic oligomers, metal organic frameworks, modified polymers, thermosetting polymers, etc.

[00125] A "stereoisomer" or "optical isomer" is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs. "Enantiomers" are stereoisomers of a given compound that are mirror images of each other, like left and right hands. "Diastereomers" are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbon), the total number of hypothetically possible stereoisomers will not exceed 2", where n is the number of tetrahedral stereocenters. Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and/or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures. As used herein, the phrase "substantially free from other stereoisomers" means that the composition contains < 15%, more preferably < 10%, even more preferably < 5%, or most preferably < 1% of another stereoisomer(s).

[00126] "Treatment" or "treating" includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatology), and/or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.

[00127] The above definitions supersede any conflicting definition in any reference that is incorporated by reference herein. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used are believed to describe the disclosure in terms such that one of ordinary skill can appreciate the scope and practice the present disclosure.

VI. Examples [00128] The following examples are included to demonstrate preferred embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

Example 1 - Synthesis

A. Synthesis of A ¹² -PGJ ₃ Methyl Ester 2 and Lactone 11

[00129] The methyl ester (2) and lactone (11) derivatives of A ¹² -PGJ ₃ were synthesized through the use of TMSCHN ₂ (93% yield) and MNBA/DMAP (Shiina method, (Shiina and Mukaiyama, 1994) 71% yield), respectively, as summarized in Scheme 1. Derivatives 2 and 11 showed improved over activity and stability relative to A ¹² -PGJ ₃ (1) which inspired further molecular designs along these structural types. Scheme 1. S nthesis of A ¹² -PGJ ₃ Methyl Ester 2 and Lactone 11"

"Reagents and conditions: (a) TMSCHN ₂ (2 M in Et ₂ 0, 1.5 equiv), 3:2 CeHe/MeOH, 25 °C, 30 min, 93%; (b) MNBA (1.4 equiv), DMAP (6.0 equiv), CH ₂ C1 ₂ , 25 °C, 17 h, 74%; MNBA = 2-methyl-6- nitrobenzoic anhydride, DMAP = 4-dimethylaminopyridine.

B. Synthesis of A ¹² -PGJ ₃ Ester (3-5, and 10), Amide Analogs (6-9) and hydroxy derivative 12

[00130] Ester derivatives of A ¹² -PGJ ₃ (3-5 and 10, Scheme 2) were synthesized via their TBS-ether precursors (46-49, respectively) prepared from TBS-ether 45 (Nicolaou et al, 2014) by EDCLOMAP-facilitated esterification (Scheme 2). The latter were desilylated by exposure to aq. HF. In addition to the esters and in a similar manner, a series of amide analogs (6-9, Scheme 3) was synthesized from TBS-ether 45 (Nicolaou et al, 2014) by standard methods (B0C2O/NH4HCO3 or EDCI7HOBt) via their TBS-ether derivatives (50-53, respectively, Scheme 3). The Cl-hydroxy analog 12 was prepared from OPMB derivative 54 (Nicolaou et al, 2014) through desilylation (aq. HF) and deprotection (DDQ) via intermediate 55 (Scheme 4).

Scheme 2. S nthesis of A ¹² -PGJ ₃ Ester Analogs 3-5, and 10"

Ph (86%) 10: R = (CH ₂ ) ₂ S0 ₂ Ph (76%)

"Reagents and conditions: (a) 46: EDCl (2.0 equiv), DMAP (0.05 equiv), i ^' -PrOH (1.5 equiv), CH2CI2, 0 °C, 6 h, 79%; 47: EDCl (2.0 equiv), DMAP (0.05 equiv), C10H21OH (1.5 equiv), CH ₂ C1 ₂ , 0 to 25 °C, 12 h, 76%; 48: EDCl (2.0 equiv), DMAP (0.05 equiv), C20H41OH (1.5 equiv), CH2CI2, 0 to 25 °C, 12 h, 71%; 49: EDCl (1.5 equiv), DMAP (0.1 equiv), PhS0 ₂ (CH ₂ )20H (1.5 equiv), CH ₂ C1 ₂ , 0 °C, 6 h, 86%; (b) 3: HF NEt ₃ (50 equiv), MeCN, 0 to 25 °C, 48 h, 80%; 4: HF (50% aq., 100 equiv), MeCN, 0 °C, 30 min, 79%; 5: HF (50% aq., 100 equiv), MeCN, 0 °C, 30 min, 76%; 10: HF (50% aq., 50 equiv), MeCN, 0 °C, 30 min, 76%; EDCl = l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide

Scheme 3. Synthesis of A ¹² -PGJ ₃ Amide Analogs 6-9"

"Reagents and conditions: (a) B0C2O (2.6 equiv), (NH4)HC03 (2.4 equiv), pyridine (1.2 equiv), CH2CI2, 0 to 25 °C, 6 h, 68%; (b) 51: EDCl (2.0 equiv), HOBt (2.0 equiv), H ₂ NMe (2.0 M in THF, 2.0 equiv), CH2CI2, 0 to 25 °C, 2 h, 78%; 52: EDCl (2.0 equiv), HOBt (2.0 equiv), H ₂ Ni-Pr (1.0 M in THF, 2.0 equiv), CH2CI2, 0 to 25 °C, 2 h, 71%; 53: EDCl (1.5 equiv), HOBt (1.5 equiv), HNMe ₂ (1.0 M in THF, 1.2 equiv), CH2CI2, 0 to 25 °C, 3 h, 71%; (c) 6: HF (50% aq. _; 100 equiv), MeCN, 0 °C, 30 min, 68%; 7: HF (50% aq., 100 equiv), MeCN, 0 °C, 30 min, 78%; 8: HF (50% aq., 100 equiv), MeCN, 0 °C, 30 min, 75%; 9: HF (50% aq., 100 equiv), MeCN, 0 °C, 30 min, 84%; B0C2O = di-terf-butyl dicarbonate, HOBt = hydroxybenzotriazole.

Scheme 4. Synthesis of A ¹² -PGJ3 Hydroxy Analog 12"

54: R = TBS —1 . _{u c /Q70/} .

a) aq. HF 87%)

55: R = H -*— ¹

"Reagents and conditions: (a) HF (50% aq., 50 equiv), MeCN, 0 °C, 2 h, 87%; (b) DDQ (1.5 equiv), 4: 1 CH2CI2/H2O, 0 °C, 1 h, 92%; DDQ = 2,3-dichloro-5,6-dicyano-l,4-benzoquinone.

C. Synthesis of ent-A ¹² -FGJi Analogs ent-1, ent-2, and ent-ll"

[00131] The enantiomer of A ¹² -PGJ3, eref-A ¹² -PGJ3, ent-l and its derivatives, methyl ester (ent-2) and lactone (ent-ll) were prepared. As seen in Scheme 5, the menthol-chiral approach (Nicolaou et al, 2016) the required enantiomeric enone ent-57 was generated from 56. Ent-57 was converted by an aldol reaction with enantiomeric aldehyde ent-SS, (WO 2015/048268) to product 59 (mixture of diastereomers), which was transformed (MsCl, DMAP) to cross-dienone ent-54 (single isomer) in 49% yield for the two steps. The rest of the synthesis of ent-1, ent-2, and ent-ll proceeded through the same steps and in similar yields as the synthesis of 1 (Nicolaou et al., 2016) and shown in Scheme 5 (through intermediates 60-eraf-45). Scheme 5. Synthesis of ent-A ⁿ -PG Analogs ent-1, ent-2, and ent-11"

ent-2: R = Me

"Reagents and conditions: (a) DIBAL-H (1.5 equiv), CH ₂ C1 ₂ , -10 °C, 30 min, 76%; (b) LDA (2.0 equiv); then ent-57 (1.0 equiv); then ent-58 (1.2 equiv), THF, -78 °C, 30 min; (c) MsCI (2.0 equiv), DMAP (10 equiv), CH ₂ C1 ₂ , 0 to 25 °C, 6 h, 49% for two steps; (d) DDQ (1.5 equiv), 16: 1 CH ₂ C1 ₂ /H ₂ 0, 0 °C, 45 min, 87%; (e) PCC (2.0 equiv), CH ₂ C1 ₂ , 25 °C, 2 h; (f) NaC10 ₂ (3.0 equiv), NaH ₂ P0 ₄ (3.0 equiv), 2-methyl-2-butene (10 equiv), r-BuOH, 25 °C, 30 min, 86% for two steps; (g) HF (50% aq., 100 equiv), MeCN, 0 °C, 45 min, 92%; (h) TMSCHN ₂ (2 M in Et ₂ 0), 3:2 C ₆ H ₆ /MeOH, 25 °C, 30 min, 93%; (i) MNBA ( 1.4 equiv), DMAP (6.0 equiv), CH ₂ C1 ₂ , 25 °C, 17 h, 74%; DIBAL-H = diisobutylaluminium hydride, LDA = lithium diisopropylamide, MsCI = methanesulfonyl chloride, PCC = pyridinium chlorochromate.

D. Synthesis of Dehydrated A ^{12 14} -PGJ ₃ Analog 13, and its Methyl Ester 14 [00132] The dehydrated counterparts of the parent compounds 1 and 2, 15-dehydroxy-

A ^{12 14} -PGJ3 (13) and its methyl ester analog 14, were synthesized from enone 57 (Scheme 6). The intermediate 57 (obtained from the corresponding menthol-enone through DIB AL reduction) (Nicolaou et al., 2016) was deprotected (DDQ, 94% yield), the resulting hydroxy enone (62) was silylated (TBSCl, 89% yield), and the resulting product (63) was coupled with conjugated aldehyde 64 (WO 2014/048268) under the aldol conditions (LDA,-78 °C) to afford a mixture of alcohols (65). Compound 65 was treated with MsCl in the presence of DMAP (0 -25 °C) to furnish conjugated enone 66 in 31% overall yield for the two steps. Desilylation of enone 66 (aq. HF, 87% yield) was followed by stepwise oxidation (PCC, 68; NaC10 ₂ (Bal et al , 1981)) to furnish the 15- deoxy-A ^{12 14} -PGJ ₃ (13), from which methyl ester derivative 14 was generated by exposure to TMSCHN ₂ (90% yield).

Scheme 6. S nthesis of Dehydrated A ^1¾14 -PGJ ₃ Analog 13, and its Methyl Ester 14"

I h) TMSCHN2 (90 %)

14: R = Me-*- ¹ "Reagents and conditions: (a) DDQ (1.5 equiv), 20: 1 CH ₂ C1 ₂ /H ₂ 0, 0 °C, 2 h, 94%; (b) TBSC1 (1.5 equiv), imid. (3.0 equiv), CH ₂ C1 ₂ , 0 to 25 °C, 4 h, 89%; (c) LDA (2.0 equiv), THF, -78 °C; then 63 (1.0 equiv); then 64 (1.2 equiv), 15 min; (d) MsCl (2.0 equiv), DMAP (10 equiv), CH ₂ C1 ₂ , 0 to 25 °C, 6 h, 31 % for two steps; (e) HF (50% aq., 50 equiv), MeCN, 0 °C, 45 min, 87%; (f) PCC (2.0 equiv), CH ₂ C1 ₂ , 25 °C, 2 h; (g) NaC10 ₂ (1.5 equiv), NaH ₂ P0 ₄ (1.5 equiv), 2-methyl-2-butene (10 equiv), r-BuOH, 25 °C, 30 min, 67% for two steps; (h) TMSCHN ₂ (2 in Et ₂ 0, 1.5 equiv), 3:2 C ₆ ¾/MeOH, 25 °C, 30 min, 90%; TBSC1 = tert-butyldimethylsilyl chloride, imid. = 1 //-imidazole.

E. Synthesis of 15-Deoxy-A ¹² -PGJ ₃ (15) and its Methyl Ester 16"

[00133] In order to determine the 15-hydroxy group' s importance for biological activity, the 15-deoxy-A ¹² -PGJ3 analogs 15 and 16 (Scheme 7) were synthesized. The enone 57 (Nicolaou et al , 2016) was reacted with aldehyde fragment 69 (WO 2015/048268) under aldol conditions (LDA, -78 °C), and the resulting mixture of alcohols (70) was exposed to the action of MsCl and DMAP to afford enone PMB derivative 71 in 61% overall yield for the two steps. The latter was oxidized fully and in one step by treatment with oxo-piperidinium tetrafluoroborate salt 72 (Pradham et al. 2009) to afford the targeted analog 15 in 45% yield. Treatment of the latter with TMSCHN ₂ furnished methyl ester analog 16 (90% yield).

Scheme 7. Synthesis of 15-Deoxy-A ¹² -PGJ ₃ (15) and its Methyl Ester 16"

"Reagents and conditions: (a) LDA (2.0 equiv), THF, -78 °C; then 57 (1.0 equiv); then 69 (1.2 equiv), 15 min; (b) MsCl (2.0 equiv), DMAP (10 equiv), CH ₂ C1 ₂ , 0 to 25 °C, 6 h, 61% for two steps; (c) 4- (acetylamino)-2,2,6,6-tetramethyl-l-oxo-piperidinium tetrafluoroborate (6.0 equiv), 9: 1 MeCN/H ₂ 0, 25 °C, 30 min, 45%; (d) TMSCHN ₂ (2 M in Et ₂ 0, 2.0 equiv), 3:2 C ₆ H ₆ /MeOH, 25 °C, 30 min, 90%.

F. Synthesis of A ¹² -PGJ ₃ Analogs 17 and 18"

[00134] The truncated A ¹² -PGJ ₃ analogs 17 and 18 (TMSCHN ₂ ) were synthesized from key building blocks, enone 57 (Nicolaou et al, 2016) and propionaldehyde (73) via intermediates 74 and 75 (Scheme 8).

Scheme 8. Synthesis of A ¹² -PGJ ₃ Analogs 17 and 18"

"Reagents and conditions: (a) LDA (2.0 equiv), THF, -78 °C; then 57 (1.0 equiv); then C ₂ H ₅ CHO (1.5 equiv), 15 min; (b) MsCl (2.0 equiv), DMAP (10 equiv), CH ₂ C1 ₂ , 0 to 25 °C, 6 h, 63% for two steps; (c) 4-(acetylarnino)-2,2,6,6-tetramethyl-l-oxo-piperidiniurn tetrafluoroborate (6.0 equiv), 9:1 MeCN/H ₂ 0, 25 °C, 30 min, 57%; (d) TMSCHN ₂ (2 M in Et ₂ 0, 1.5 equiv), 3:2 C ₆ H ₆ MeOH, 25 °C, 30 min, 93%.

F. Synthesis of A ¹² -PGJ ₃ Analog 19, its Methyl Ester 20, and Lactone 21"

[00135] C20-trifluoro A ¹² -PGJ ₃ analogs 19, 20, and 21 were prepared from starting materials 76, (Reddy and Rao, 2010) 77, (Liu and Kumar, 2010) and 57 (Nicolaou et al, 2016) through intermediates 78-85 by standard methods (Scheme 9). Without wishing to be bound by any theory, it is believed that a fluorinated end group may reduce metabolic oxidation. Furthermore, fluorine has been shown to enhance pharmacological properties (Purser et al, 2008).

Scheme 9. Synthesis of A ¹² -PGJ ₃ Analog 19, its Methyl Ester 20, and Lactone 21"

PMB "— I I 84: R = CHO 1 g) NaCI0 ₂

f) DDQ (92%)

83: R ^: 85

"Reagents and conditions: (a) 3,3,3-trifluoropropylphosphonium iodide (2.0 equiv), NaHMDS (1.9 equiv), 0 to 25 °C, 1 h; then 76, -78 to 25 °C, THF, 5 h, 88%; (b) DDQ (1.5 equiv), 20: 1 CH2CI2 H2O, 0 to 25 °C, 5 h, 91% ; (c) DMP (2.0 equiv), CH2CI2, 0 to 25 °C, 2 h, 76%; (d) LDA (2.0 equiv), THF, -78 °C; then 57 (1.0 equiv); then 80 (1.2 equiv), 15 min; (e) MsCI (2.0 equiv), DMAP (10 equiv), CH2CI2, 0 to 25 °C, 6 h, 43% for two steps; (f) DDQ (1.5 equiv), 20:1 CH2CI2 H2O, 0 °C, 2 h, 92%; (g) PCC (2.0 equiv), CH2CI2, 25 °C, 2 h; (h) NaC10 ₂ (3.0 equiv), NaH ₂ P0 ₄ (3.0 equiv), 2-methyl-2-butene (30 equiv), f-BuOH, 25 °C, 30 min, 84% for two steps; (i) HF (50% aq., 100 equiv), MeCN, 0 °C, 45 min, 90%; (j) TMSCHN ₂ (2 M in Et ₂ 0, 1.5 equiv), 3:2 CeHe/MeOH, 25 °C, 30 min, 60%; (k) MNBA (1.4 equiv), DMAP (6.0 equiv), CH ₂ C1 ₂ , 25 °C, 17 h, 62%; NaHMDS = sodium bis(trimethylsilyl)amide, DMP = Dess-Martin periodinane.

G. Synthesis of Alkyne A ¹² -PGJ3 Analog 22, its Methyl Ester 23, and Lactone 24°

[00136] Acetylenic A ¹² -PGJ ₃ analogs 22 and 23 were synthesized from key building blocks 86, (PCT Publication No. WO 2015/048268) and 57 (Nicolaou et al, 2016) through the standard sequence via intermediates 88-93 (Scheme 10). The 1,5-lactone 24 was prepared by exposing the hydroxy acid 22 to MNBA and DMAP (Scheme 10).

Scheme 10. Synthesis of Alkyne A ¹² -PGJ ₃ Analog 22, its Methyl Ester 23, and Lactone 24"

"Reagents and conditions: (a) DDQ (1.5 equiv), 20: 1 CH ₂ C1 ₂ /H ₂ 0, 0 to 25 °C, 2 h, 90%; (b) DMP (1.5 equiv), CH ₂ C1 ₂ , 0 to 25 °C, 2 h, 88%; (c) LDA (2.0 equiv), THF, -78 °C; then 57 (1.0 equiv); then 88 (1.2 equiv), 15 min; (d) MsCI (2.0 equiv), DMAP (10 equiv), CH ₂ C1 ₂ , 0 to 25 °C, 6 h, 36% for two steps; (e) DDQ (2.0 equiv), 10: 1 CH ₂ C1 ₂ /H ₂ 0, 0 °C, 2 h, 98%; (f) PCC (2.0 equiv), CH ₂ C1 ₂ , 25 °C, 40 min.; (g) NaC10 ₂ (1.5 equiv), NaH ₂ P0 ₄ (1.5 equiv), 2-methyl-2-butene (10 equiv), r-BuOH, 25 °C, 30 min, 80% for two steps; (h) HF (50% aq., 100 equiv), MeCN, 0 °C, 30 min, 74%; (i) TMSCHN ₂ (2 M in Et ₂ 0, 2.0 equiv), 3:2 C ₆ H ₆ /MeOH, 25 °C, 0.5 h, 90%; (j) MNBA (1.4 equiv), DMAP (6.0 equiv),

H. Synthesis of A ¹² -PGJ ₃ Analog 25, its Methyl Ester 26, and Lactone 27" [00137] A ¹² -PGJ3 analogs 25-27 carrying a trifluoromethyl phenyl residue was synthesized from building blocks 57 (Nicolaou et at, 2016), lactol 94 (Mohapatra et al. 2014) and phosphonium salt 95 (U.S. Patent 5,266,593) (Scheme 11). The Wittig reaction of the ylide derived from 95 with lactol 94 in the presence of ?i-BuLi gave an inconsequential mixture of olefinic isomers 96 (65:35, 72% yield) and reduction of which (10% Pd/C, ¾) led to primary alcohol 97 (91 % yield). The latter was oxidized (DMP, 83% yield) to aldehyde 98, which was coupled with enone 57 through an aldol reaction to afford coupling product 99 (mixture of diastereomers) which was used to generate analogs 25-27 through the standard sequence and intermediates 100-103 (Scheme 11).

Scheme 11. Synthesis of A ¹² -PGJ ₃ Analog 25, its Methyl Ester 26, and Lactone 27"

25: R = H i j) TMSCHN ₂

26: R = Me -*— I (86%)

"Reagents and conditions: (a) n-BuLi (1.5 equiv), 95 (1.5 equiv), THF, -78 °C, 2 h; then 94 (1.0 equiv), -78 °C, 30 min, 40 °C, 24 h, 72% [(£):(¾ = 65:35]; (b) 10% Pd/C (10 wt%), H ₂ , MeOH, 3 h, 91 %; (c) DMP (2.0 equiv), CH ₂ C1 ₂ , 25 °C, 1 h, 83%; (d) LDA (2.0 equiv), THF, -78 °C; then 57 (1.0 equiv); then 98 (1.2 equiv), 15 min; (e) MsCl (2.0 equiv), DMAP (10 equiv), CH ₂ C1 ₂ , 0 to 25 °C, 6 h, 45% for two steps; (f) DDQ (1.5 equiv), 20: 1 CH ₂ C1 ₂ /H ₂ 0, 0 °C, 2 h, 86%; (g) PCC (2.0 equiv), CH ₂ C1 ₂ , 25 °C, 2 h; (h) NaC10 ₂ (3.0 equiv), NaH ₂ P0 ₄ (3.0 equiv), 2-methyl-2-butene (30 equiv), f-BuOH, 25 °C, 30 min, 72% for two steps; (i) HF (50% aq., 100 equiv), MeCN, 0 °C, 45 min, 84%; (j) TMSCHN ₂ (2 M in Et ₂ 0, 2.0 equiv), 3:2 C ₆ H ₆ /MeOH, 25 °C, 0.5 h, 86%; (k) MNBA (1.4 equiv), DMAP (6.0 equiv), CH ₂ C1 ₂ , 25 °C, 17 h, 61%. I. Synthesis of A ¹² -PGJ ₃ Analog 28, its Methyl Ester 29, and Lactone 30"

[00138] Inspired by docosahexaenoic acid (DHA) and the potential activity, the synthesis of A ¹² -PGJ3 analogs 28-30 was developed. Synthesis started with the construction of key building block 112 (Scheme 12a). Its synthesis began with TMS-acetylene which reacted in the presence of ra-BuLi with readily available epoxide 104 (Frick et al , 1992; Wullschleger et al, 2010) to afford alcohol 105 (88%), whose desilylation (TBAF) led to terminal acetylene 106 (94% yield). Coupling of 106 with propargyl bromide 107 in the presence of Cul and K2CO3 furnished bis-acetylene 108 which was selectively reduced with NaBFL-Fb in the presence of Ni(OAc)2- 4H2O (Brown and Brown, 1963; Brown and Ahuja, 1973) to give bis-olefin 109 with both olefinic bonds formed in the desired (Z)- geometry (Oger et al, 2010) (77% overall yield from 106). The hydroxy group of the latter intermediate was protected as a TBS-ether (TBSC1, 91% yield), and the resulting product (110) was sequentially treated with DDQ (66% yield) and DMP (80% yield) to afford required aldehyde 112 through intermediate 111. The construction of the other required fragment, enone 118 (containing one less carbon in its side chain than the corresponding enone for A ¹² -PGJ ₃ ), its coupling with segment 112, and elaboration of the product to the targeted analogs 28, 29, and 30 was carried out as described in Scheme 12b.

[00139] The cyclopentene methyl ester 113 (Nicolaou et al, 2016) (inconsequential mixture of diastereomers) was reduced with DIBAL to afford aldehyde 114 which was reacted with the ylide derived from phosphonium salt 115 (NaHMDS) to furnish, after desilylation (TBAF), hydroxy olefin 117 (mixture of diastereomers, 68% overall yield for the three steps from 113). PCC oxidation of 117 led to enone 118 (92% yield) whose aldol reaction with aldehyde 112 furnished hydroxy enone 119 (mixture of diastereomers). Exposure of 119 to MsCl and EtsN followed by treatment of the resulting mixture of mesylates (120) to AI2O3 gave the desired cross-conjugated dienone 121 in 30% overall yield for the three steps from 118. Removal of the PMB group from 121 (DDQ, 66% yield) followed by PCC oxidation led to aldehyde 123, whose further oxidation with NaClC afforded TBS- ether carboxylic acid 124 in 78% overall yield from 122. Desilylation of the latter (aq. HF) afforded analog 28, from which methyl ester 29 was prepared by exposure to TMSCHN ₂ (72% yield). Cyclization of 28 in the presence of MNBA and DMAP afforded lactone 30 (62% yield). Scheme 12. Synthesis of A ¹² -PGJ ₃ Analog 28, its Methyl Ester 29, and Lactone 30°

109: R = H— 108

~^~| e)TBSCI (91° %/ )

110: R = TBS

f) DDQ (66%)

g) DMP

(80%)

112

"a. Synthesis of aldehyde 112: Reagents and conditions: (a) TMS-acetylene (1.5 equiv), w-BuLi (1.3 equiv), BF ₃ Et ₂ 0 (1.3 equiv), -78 to 25 °C, 2 h, 88%; (b) TBAF (1.0 M in THF, 1.2 equiv), THF, 0 to 25 °C, 2 h, 94%; (c) 107 (1.2 equiv), K ₂ C0 ₃ (1.3 equiv), Cul (1.3 equiv), Nal (1.3 equiv), DMF, 25 °C, 15 h; (d) Ni(OAc)2-4H ₂ 0 (0.32 equiv), NaBH ₄ (0.77 equiv), 1,2-diaminoethane (3.6 equiv), ¾, EtOH, 25 °C, 18 h, 77% for two steps; (e) TBSCl (1.5 equiv), imid. (3.0 equiv), CH ₂ C1 ₂ , 12 h, 91%; (f) DDQ (1.5 equiv), 10: 1 CH2CI2/H2O, 0 °C, 105 min, 66%; (g) DMP (1.5 equiv), CH2CI2, 0 to 25 °C, 1.5 h, 80%; b. Synthesis of A ¹² -PGJ ₃ analog 28, methyl ester 29, and lactone 30: Reagents and conditions: (a) DIBAL-H (1.1 equiv), CH2CI2, -78 °C, 45 min; (b) 115 (1.5 equiv), NaHMDS (2.0 equiv), THF, 0 to 25 °C, 15.5 h; (c) TBAF (1.2 equiv), THF, 0 to 25 °C, 3 h, 68% for three steps; (d) PCC (1.9 equiv), CH2CI2, 25 °C, 2 h, 92%; (e) LDA (2.2 equiv), then 112 (1.3 equiv), THF, -78 °C, 30 min; (f) MsCl (5.0 equiv), Et ₃ N (10 equiv), CH ₂ C1 ₂ , 0 °C, 30 min; (g) A1 ₂ 0 ₃ (21 equiv), CH ₂ C1 ₂ , 25 °C, 6 h, 30% for three steps; (h) DDQ (1.7 equiv), 10: 1 CH2CI2 H2O, 0 °C 105 min, 66%; (i) PCC (2.0 equiv), CH ₂ C1¾ 25 °C, 75 min; (j) 2-methyl-2-butene (10 equiv), NaH ₂ P0 ₄ (1.5 equiv), NaC10 ₂ (1.5 equiv), r-BuOH, 25 °C, 30 min, 78% for two steps; (k) aq. HF (ca. 100 equiv), MeCN, 0 °C, 75 min, 81%; (1) TMSCHN ₂ (2 M in Et ₂ 0, 2.0 equiv), 3:2 C ₆ H ₆ /MeOH, 25 °C, 30 min, 72%; (m) MNBA (1.4 equiv), DMAP (6.0 equiv), CH ₂ CI ₂ , 25 °C, 17 h, 62%; TBAF = tetra-re-butylammonium fluoride.

J. Synthesis of C1-A ¹² -PGJ ₃ Analog 31, its Methyl Ester 32, and Lactone 33"

[00140] The synthesis of the 10-chloro analogs (31-33, Scheme 13) is shown in

Scheme 13. Starting from the PMB-ether enone 57 (Nicolaou et at, 2016), the PMB-ether enone was selectively epoxidized with H ₂ O ₂ and KOH to afford epoxy ketone 125 whose exposure to LiCl and Amberlyst-15 furnished a mixture of PMB-ether chloroenone 126 (24% yield) and hydroxy chloroenone 127 (28% yield), the latter being easily converted to the former through the action of PMB- trichloroacetimidate and Sc(OTf (80% yield). Chloroenone 126 underwent aldol reaction with aldehyde 58 (LDA, -78 °C) and the resulting mixture of alcohols (128) so formed was treated with MsCl and DMAP to yield cross-conjugated chloroenone 129 in 45% yield for the two steps. Removal of the PMB group (DDQ, 86% yield) followed by sequential oxidation with PCC and NaC10 ₂ gave carboxylic acid 132 via aldehyde 131 in 84% yield for the two steps. The targeted compounds 10- chloro-A ¹² -PGJ ₃ (31, aq. HF, 88% yield), its methyl ester (32, TMSCHN2, 56% yield) and lactone (33, MNBA, DMAP, 73% yield) were generated from 132 by the standard conditions (Scheme 13).

Scheme 13. Synthesis of C1-A ¹² -PGJ3 Analog 31, its Methyl Ester 32, and Lactone 33"

"Reagents and conditions: (a) H ₂ 0 ₂ (2.0 equiv), KOH (10% in H ₂ 0, 0.2 equiv), MeOH, -20 °C, 6 h; (b) LiCl (10.0 equiv), Amberlyst-15 (200 wt%), MeCN, 25 ³ C, 24 h, 126 (24%) and 127 (28%); (c) PMBC(=NH)C1 ₃ (2.0 equiv), Sc(OTf) ₃ (0.1 equiv), CH2CI2, 25 °C, 4 h, 80%; (d) LDA (2.0 equiv), THF, -78 °C; then 126 (1.0 equiv); then 58 (1.3 equiv), 15 min; (e) MsCI (2.0 equiv), DMAP (10 equiv), CH2CI2, 0 °C to 25 °C, 12 h, 45% for two steps; (f) DDQ (2.0 equiv), 20: 1 CH2CI2/H20, 0 °C, 2 h, 86%; (g) PCC (2.0 equiv), CH2CI2, 25 °C, 2 h; (h) NaC10 ₂ (3.0 equiv), NaH ₂ P0 ₄ (3.0 equiv), 2-methyl-2- butene (30 equiv), r-BuOH, 25 °C, 30 min, 84% for two steps; (i) HF (50% aq., 100 equiv), MeCN, 0 °C, 45 min, 88%; (j) TMSCHN ₂ (2 M in Et ₂ 0, 2.0 equiv), 3:2 C ₆ H ₆ MeOH, 25 °C, 30 min, 56%; (k) MNBA (1.5 equiv), DMAP (4.0 equiv), CH2CI2, 25 °C, 12 h, 73%.

K. Synthesis of 8-Methyl-A ¹² -PGJ ₃ Methyl Esters 34 and 36, and Lactones 35 and 37

[00141] The synthesis of the 8-methyl-A ¹² -PGJ ₃ methyl ester (34 and 36) and lactone

(35 and 37) analogs is shown in Scheme 14. The required 8-mefhyl (PG numbering) enone 137 was prepared from (+)-menthol vinylogous ester 133 (Nicolaou et al, 2016) through a three-step sequence involving methylation (LDA, DMI, Mel, 76% yield), alkylation with allylic bromide 135 (Nicolaou et al, 2016) (LDA, DMI, 73% yield) and DIBAL-induced removal of the chiral auxiliary (76% yield) affording racemic 137 via intermediate 136 (ca. 55:45 dr). Enone 137 was synthesized using the standard aldol-mesylation/elimination-oxidation sequence as shown in Scheme 14 to produce TBS- ether carboxylic acid 141 (mixture of diastereomers ca. 66:33 dr). Without wishing to be bound by any theory, it is believed that the sluggishness and low yield of the aldol reaction in this case is attributed to steric hindrance introduced by the C8 quaternary center adjacent to the reactive site. Desilylation of 141 led to hydroxy acid 142 as a mixture of diastereomers (75% yield, ca. 65:35 dr) whose chromatographic separation proved challenging. The difficulties of separating the C8-epimers of carboxylic acid 142 were reduced upon methylation (TMSCHN ₂ , 82% yield) to produce methyl ester analogs 34 (57%) and 36 (25%) (chromatographically separated on silica gel) or upon lactone formation (MNBA, DMAP, 59% yield) to afford lactones 35 (38%) and 37 (21%) (chromatographically separated on silica gel). The absolute configuration of the C8-stereocenter was not discernable from the NMR spectral data and, therefore, the depicted structures should be considered interchangeable.

Scheme 14. Synthesis of 8-Methyl-A ¹² -PGJ ₃ Methyl Esters 34 and 36, and Lactones 35 and 37

"Reagents and conditions: (a) LDA (1.05 equiv), THF, -78 °C; then 133 (1.0 equiv), 0.5 h, then Mel (1.3 equiv), DMI, 12 h, 76%; (b) LDA (1.05 equiv), THF, -78 °C; then 134 (1.0 equiv); then 135 (1.3 equiv), DMI, 12 h, 73% (mixture of diastereomers, ca. 55:45 dr); (c) DIBAL-H (1.5 equiv), CH ₂ C1 ₂ , -10 °C, 6 h, 76%; (d) LDA (2.0 equiv), THF, -78 °C; then 137 (1.0 equiv); then 58 (1.2 equiv), 30 min, 17% (57% brsm); (e) MsCI (2.0 equiv), DMAP (10 equiv), CH ₂ C1 ₂ , 0 to 25 °C, 6 h, 67% for two steps (mixture of diastereomers, ca. 67:33 dr); (f) DDQ (2.0 equiv), 20: 1 CH ₂ C1 ₂ /H ₂ 0, 0 °C, 2 h, 88% (mixture of diastereomers, ca. 68:32 dr); (g) PCC (2.0 equiv), CH ₂ C1¾ 25 °C, 2 h; (h) NaC10 ₂ (3.0 equiv), NaH ₂ P0 ₄ (3.0 equiv), 2-mefhyl-2-butene (10 equiv), f-BuOH, 25 °C, 30 min, 78% for two steps (mixture of diastereomers, ca. 66:33 dr); (i) HF (50% aq., 50 equiv), MeCN, 0 °C, 45 min, 75% (mixture of diastereomers, ca. 65:35 dr); (j) TMSCHN ₂ (2 M in Et ₂ 0, 1.5 equiv), 3:2 C ₆ ¾/MeOH, 25 °C, 0.5 h, 82% (57% for 34; 25% for 36); (k) MNBA (1.4 equiv), DMAP (6.0 equiv), CH ₂ C1 ₂ , 25 °C, 12 h, 59% (38% for 35; 21% for 37): DMI = l,3-dimethyl-2-imidazolidinone.

L. Synthesis of 15-Fluoro-A ¹² -PGJ ₃ (38) and its Methyl Ester 39"

[00142] The 15-fluoro-A ¹² -PGJ ₃ analogs 38 and 39 were prepared from enone 57 (Nicolaou et al, 2016) and aldehyde ent-5S, (WO 2015/048268) as shown in Scheme 15. Building blocks 57 (Nicolaou et al , 2016) and ent-58 (WO 2015/048268) were joined through the standard aldol protocol to afford diastereomeric mixture 143, which was converted to cross-conjugated enone 144 through sequential treatment with MsCl-EtsN and AI2O3. The latter was desylilated (3HF-Et3N) to give alcohol 145 whose exposure to PhenoFluor at 80 °C furnished fluoride 146 (35% yield) with the inversion of configuration at C15 (Sladojevich et al, 2013). Precursor 146 was converted in one step to the targeted 15-fluoro-A ¹² -PGJ3 analog 38 with piperidinium tetrafluoroborate 72 (Pradham et al, 2009) in 45% yield. 15-Fluoro-A ¹² -PGJ ₃ methyl ester (39) was prepared from 38 by treatment with TMSCHN ₂ (50% yield) (Scheme 15).

[00143] Truncated compounds 40-43 (Figure 1) were also synthesized to test the effects of shorter "top" side chains on the biological activity in the series, while 17,18-dihydro lactone analog 44 was also constructed to probe the effect of "lower" side chain modification. Scheme 15. Synthesis of 15-Fluoro-A ¹² -PGJ ₃ (38) and its Methyl Ester 39°

"Reagents and conditions: (a) LDA (2.0 equiv), THF, -78 °C; then 57 (1.0 equiv); then ent-58 (1.2 equiv), 30 min, 86%; (b) MsCl (5.0 equiv), Et ₃ N (10 equiv), CH2CI2, 0 °C, 5 min; (c) AI2O3 (42 equiv), CH2CI2, 25 °C, 8 h, 65% for two steps; d) 3HF Et ₃ N (23 equiv), THF, 0→ 25 °C, 3.5 d, 88%; (e) PhenoFluor (6.0 equiv), KF (9.0 equiv), i ^' -Pr ₂ NEt (9.0 equiv), toluene, 80 °C, 2.5 h, 35%; (f) 4- (acetylarnino)-2,2,6,6-tetramethyl-l-oxo-piperidinium tetrafluoroborate (6.0 equiv), MeCN:H20 (9:1), 25 °C, 45%; (g) TMSCHN ₂ (2.0 M in Et ₂ 0, 1.5 equiv), C ₆ H ₆ :MeOH (3:2), 25 °C, 35 min., 50%; PhenoFluor = l,3-bis(2,6-diisopropylphenyl)-2,2-difluoro-2,3-dihydro-l /-imidazole.

M. Synthesis of Cyclic and Macrocyclic Analogs

[00144] Scheme 16 summarizes the synthesis of aldehyde building blocks 152a and

152b, starting from epoxide 147 (Nicolaou, et al, 2016a; Nicolaou, et al, 2016b). In this synthesis, treatment of 147 with BF3*Et20 and butyl magnesium bromide or 4-trifluoromethyl butyl magnesium bromide which provided alcohols 149a (72%) and 149b (76%) respectively. Compounds 149a and 149b were silylated using TBSC1 and imidazole to furnish the corresponding TBS ethers 150a (90% yield) and 150b (93% yield), respectively. Removal of the PMB group from 150a and 150b then led to alcohols 151a (DDQ, 90% yield) and 151b (DDQ, 88% yield), respectively, which were subsequently oxidized to the desired aldehydes 152a (84% yield) and 152b (76% yield) using DMP.

Scheme 16: Synthesis of aldehydes 152a and 152b.

PMBO

"Reagents and conditions: (a) 147 (1.0 equiv), Cul (0.17 equiv), then 148a, b (1.7 equiv), THF, -78 °C, 1 h; then 0 °C, 1 h, 72% (149a), 76% (149b); (b) TBSCI (1.3 equiv), imid. (2.6 equiv), CH ₂ C1 ₂ , 0 to 25 °C, 12 h, 90% (150a), 93% (150b); (c) DDQ (1.5 equiv), CH ₂ Cl2:H ₂ 0 (20: 1), 0 °C, 90 min, 90% (151a), 88% (151b); (d) DMP (2.0 equiv), CH ₂ C1 ₂ , 0 to 25 °C, 2 h, 84% (152a), 76% (152b).

[00145] Scheme 17 summarizes the process for the synthesis of A ¹² -PGJ ₂ and its macrocyclic analogues 169, 172, 175 and 178. Stereospecific Michael addition of a allyl copper reagent generated from the Cul- LiCl complex and allyl magnesium bromide to the optically pure enone 153 (Tanaka and Ogasawara, 1995) in the presence of TMSC1 provided the 1,4 allyl substituted cyclopentenone intermediate, which upon refluxing in 1,2-dichlorobenzene delivered enone 154 in 77% yield for the two steps as shown in Scheme 1. Enone 154 serves as a common intermediate for the synthesis of other PGJ ₂ analogues. Reaction between enone 154 and aldehyde 152a in the presence of LDA furnished a mixture of diastereomeric aldol products, which were converted to the dienone 155 (40% overall yield) through their corresponding mesylates (MsCl, DMAP). Treatment of dienone 155 with excess alkene 156 (prepared in 72% by treating 160 with MgCh and B0C ₂ O) in the presence of Grubbs catalyst 158 (Herbert and Grubbs, 2015) gave exclusively the desired ris-olefin 159 in 42 % [86% brsm, >95% (Z)-isomer]. Compound 159 was converted to A ¹² -PGJ ₂ (168) in 71% yield (aq. HBF ₄ ) following previously reported procedure (Nicolaou, et al, 2016a). With seco acid 168 in hand the monomeric lactone 169 was prepared in 72% yield following the previously reported high dilution macrolactonisation conditions (MNBA and DMAP). Next, the direct conversion of seco acid 168 to the oligomeric prostaglandin J analogues 172, 175 and 178 was attempted using macrolactonisation conditions. The treatment of seco acid with MNBA, NEt3 and cat. DMAP in DCM under concentrated conditions gave the desired dimer 172, trimer 175 and tetramer 178 in 27%, 10% and 9 % yield respectively.

Scheme 17: S nthesis of analogues 169-180.

"Reagents and conditions: (a) Cul (2.2 equiv), LiCl (2.2 equiv), THF, 25 °C, 10 min, allyl magnesium bromide (1.0 M in ether, 2.0 equiv), -78 °C; TMSC1 (2.0 equiv), -78 °C for 6 h and -78 °C to 25 °C, 4 h, 94%; (b) 1,2-dichloro benzene, 200 °C, 6 h, 82%; (c) 152a (1.5 equiv), -78 °C, 30 min; LDA (0.66 M in THF, 2.0 equiv), THF, -78 °C; 30 min; (d) MsCl (3.0 equiv), DMAP (10 equiv), CH ₂ C1 ₂ , 0 °C, 12 h; 40% for two steps; (e) catalyst 158 (0.1 equiv), THF, 35 °C, 12 h, 42% (85% brsm, >95% (Z)-isomer); (f) HBF ₄ (48% aq., 25 equiv), CH ₃ CN, 0 °C, 3 h, 71%; (g) MNBA (1.5 equiv), DMAP (3.0 equiv), CH2CI2, 25 °C, 12 h; 72%; (h) MNBA (1.5 equiv), NEt ₃ (2.0 equiv), DMAP (0.1 equiv), CH2CI2, 25 °C, 12 h; 172 (27%), 175 (10%), and 178 (9%); (i) MgCh (0.1 equiv), Boc ₂ 0 (2.0 equiv), r-BuOH, 40 °C, 48 h; 72%; (j) H ₂ 0 ₂ (1.0 equiv), KOH (10% in H ₂ 0, 0.2 equiv), MeOH, -20 °C, 2 h; (k) LiCl (10.0 equiv), Amberlyst-15 (600 wt%), MeCN, 25 °C, 24 h, 60% for two steps; (1) 152a or 152b (1.5 equiv), -78 °C, 30 min; LDA (0.66 M in THF, 2.0 equiv), THF, -78 °C; 30 min; (m) MsCl (3.0 equiv), DMAP (10 equiv), CH ₂ C1 ₂ , 0 °C, 12 h; 162 (36%), 163 (33%), for two steps; (n) for 164: catalyst 157 (0.1 equiv), THF, 35 °C 12 h, 164 (55%, 81% brsm, (Z)/(£)=90/10), for 165: catalyst 158 (0.1 equiv), THF, 35 °C, 12 h, 61% (after two cycles, >95% (Z)-isomer); (o) HBF ₄ (48% aq., 25 equiv), CH ₃ CN, 0 °C, 3h, 34 (91%, (Z)/(£)=90/10), 167 (71%); (p) MNBA (1.5 equiv), DMAP (3.0 equiv), CH ₂ C1 ₂ , 25 °C, 12 h; 169 (69%), 170 (73%); (q) MNBA (1.5 equiv), NEt ₃ (2.0 equiv), DMAP (0.1 equiv), CH ₂ C1 ₂ , 25 °C, 12 h: dimers: 173 (20%), 174 (19%), trimers: 176 (8%), 177 (9%) and tetramers: 179 (4%), 180 (8%);

[00146] The synthesis of analogues 170, 171, 173, 174, 176, 177, 179 and 180 proceeded along the previously described route as shown in Scheme 2. First, enone 154 was converted to chloro cyclopentenone 161 (KOH, H ₂ 0 ₂ ; LiCl, Amberlyst 15 H ⁺ , 60 % yield) in two steps (i.e., epoxidation followed by epoxide opening with chloride and subsequent dehydration). Compound 161 was converted to dienones 162 (36% overall yield for two steps) and 163 (33% overall yield, unoptimized) by condensation with aldehyde fragments 152a or 152b and subsequent dehydration of the β-hydroxy group using MsCl and DMAP. Treatment of dienone 162 or 163 with excess alkene 156 in the presence of Grubbs catalyst 157 or 158 gave exclusively the desired ds-olefin 164 (55% yield, (Z)/(£)=90/10 using catalyst 157) and 165 (61% yield after two cycles, >95% (Z) using catalyst 158). One step deprotection of the f-butyl ester and TBS ether was smoothly carried out using aq. HBF ₄ yielding the seco acids 166 (91% yield, (Z)/(£)=90/10) and 167 (71% yield), respectively. The seco acids 166 and 167 were converted to lactones 170 (69% yield) and 171 (73% yield), respectively, using MNBA and DMAP. Finally, following the previously described oligomerization conditions 178 and 179 were converted to their corresponding macrolactones: dimer 174 (20%, yield), trimer 176 (8%, yield) and tetramer 179 (5%, yield), and dimer 173 (19%, yield), trimer 177 (9%, yield) and tetramer 180 (8%, yield).

Example 2 - Materials and Methods

[00147] All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Dry tetrahydrofuran (THF), toluene, diethyl ether (Et ₂ 0), dimethylformamide (DMF), acetonitrile (MeCN), methylene chloride (dichloromethane; CH ₂ C1 ₂ ), triethylamine (EtsN), diisopropylamine, and pyridine were obtained by passing commercially available pre-dried, oxygen-free formulations through activated alumina columns. Anhydrous benzene, acetone, chloroform (CHCI ₃ ), methanol (MeOH), ethanol (EtOH), and nitromethane (MeN0 ₂ ) were purchased from commercial suppliers and stored under argon. Yields refer to chromatographically and spectroscopically (¾ NMR) homogeneous materials, unless otherwise stated. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F ₂ 54) using UV light as visualizing agent and an ethanolic solution of phosphomolybdic acid, an aqueous solution of cerium sulfate or an aqueous solution of potassium permanganate and heat as developing agents. Acros Organics silica gel (60 A, particle size 0.035-0.070 mm) was used for flash column chromatography. Preparative thin-layer chromatography (PTLC) separations were carried out on 0.25 mm E. Merck silica gel plates (60F ₂ 54). NMR spectra were recorded on a Bruker Avance III HD 600 MHz equipped with a 5 mm DCH cryoprobe, a Bruker DRX-600, a Bruker Avance III 500 MHz, and a Bruker 400 MHz instrument, calibrated using residual undeuterated solvent for Ή NMR [δ _Η = 7.26 (CHC1 ₃ ), 7.16 (C ₆ D ₅ H), and 2.50 (DMSO-ife) ppm] and deuterated solvent for ¹³ C NMR [5c = 77.16 (CDC1 ₃ ), 128.06 (C ₆ D ₆ ), and 39.52 (DMSO-^) ppm] as an internal reference at 298 K. The following abbreviations were used to indicate the multiplicities: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sept = septet, and m = multiplet. IR spectra were recorded on a Perkin-Elmer Spectrum 100 FT-IR spectrometer. High-resolution mass spectra (HR-MS) were recorded on an Agilent Ion Trap-Time of Flight Mass Spectrometer operated with an ESI (electrospray ionization) source interface or an Agilent ESTTOF (time of flight) mass spectrometer using MALDI (matrix-assisted laser desorption ionization) or ESI (electrospray ionization). Optical rotations were measured on a Schmidt+Haensch Polartronic M100 polarimeter at 589.44 nm using 100 mm cells and the solvent and concentration indicated [in units of 10 ^_1 (deg cm ² g ^-1 )]. UV-vis spectra were recorded on a Varian Cary 5000 UV-vis-NIR-spectrometer and a Beckman DU 7500 spectrophotometer using 10 mm quartz-cells and the solvent and concentration indicated.

Example 3 - Characterization

[00148] Methyl (5Z,12£,15S,17Z)-15-hydroxy-ll-oxoprosta-5,9,12,17-tetraen- l-oate (2): To a stirred solution of A ¹² -PGJ ₃ (1) (Nicolaou et al, 2014) (5.0 mg, 15 μηιοΐ, l.O equiv) in CeH6:MeOH (3:2, 0.5 mL) at 25 °C was dropwise added a solution of trimethylsilyl diazomethane (2 M in Et20, 12 μί, 23 μπιοΐ, 1.5 equiv) (yellow color persists). After stirring for 30 min, the reaction mixture was concentrated. Flash column chromatography (S1O ₂ , hexanes:EtOAc, 2: 1→3:2) yielded pure title compound (2, 4.9 mg, 14 μπιοΐ, 93 % yield) as a colorless oil. 2: R _f = 0.53 (hexanes:EtOAc, 1 : 1); [αβ ⁵ = +206.3 (c = 0.4 in C ₆ ¾); IR (film): v _max = 3446, 3009, 2956, 2927, 2872, 2855, 1736, 1700, 1651, 1579, 1436, 1208, 1049 cm ^"1 ; >H NMR (500 MHz, CDCI3) δ 7.51 (ddd, 7=6.0, 2.7, 1.0 Hz, 1 H), 6.65 - 6.62 (m, 1 H), 6.34 (dd, 7=6.0, 1.8 Hz, 1 H), 5.62 - 5.57 (m, 1 H), 5.49 - 5.43 (m, 1 H), 5.40 - 5.33 (m, 2 H), 3.84 (quint, 7= 6.4 Hz, 1 H), 3.66 (s, 3 H), 3.50 (ddd, 7= 6.6, 3.9, 2.0 Hz, 1 H), 2.66 - 2.61 (m, 1 H), 2.56 - 2.43 (m, 2 H), 2.31 - 2.19 (m, 5 H), 2.09 - 2.01 (m, 4 H), 1.98 (brs, 1 H), 1.67 (quint, 7= 7.4 Hz, 2 H), 0.96 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C NMR (125 MHz, CDC1 ₃ ) δ 196.50, 174.17, 161.81, 139.49, 135.87, 135.08, 131.79, 131.67, 125.95, 123.85, 70.64, 51.73, 43.45, 36.66, 35.00, 33.48, 30.41, 26.83, 24.77, 20.90, 14.37 ppm; HR-MS (ESI-TOF): calcd for C ₂ iH ₃ o0 ₄ Na [M+Na] ⁺ : 369.2036, found: 369.2046.

[00149] (5Z,12£',15S,17Z)-l,15-Epox prosta-5,9,12,17-tetraene-l,ll-dione (11): To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (15 mg, 42 μιηοΐ, 1.4 equiv) and 4- dimethylaminopyridine (22 mg, 180 qmol, 6.0 equiv) in CH2CI2 (20 mL) was added a solution of A ¹² -PG ^T 3 (1) (10 mg, 30 μπιοΐ, 1.0 equiv) in CH2CI2 (10 mL) at 25 °C dropwise via syringe pump over 15 h. After stirring for an additional 2 h, the reaction mixture was washed sequentially with sat. aq. NaHC0 ₃ -solution (10 mL), aq. HCl (0.2 M, 10 mL), and brine (10 mL). The organic layer was dried (Na ₂ S0 ₄ ), filtered, and concentrated under reduced pressure. Flash column chromatography (S1O2, hexanes:EtOAc, 3: 1) yielded pure title compound (11, 7.0 mg, 22 μπιοΐ, 74 % yield) as a white solid. 11: R _f = 0.35 (hexanes:EtOAc, 3: 1); mp = 62-65 °C; [α¾ ⁵ = +65.2 (c= 0.6 in C ₆ ¾); IR (film): Vmax = 3010, 2961, 2927, 2855, 1727, 1704, 1655, 1581, 1456, 1440, 1239, 1151, 1024 cm ^"1 ; Ή NMR (600 MHz, C ₆ D ₆ ) δ 6.81 (ddd, 7 = 6.1, 2.7, 1.0 Hz, 1 H), 6.59 (dd, 7 = 11.7, 4.4 Hz, 1 H), 6.19 (dd, 7 = 6.1, 1.9 Hz, 1 H), 5.49 - 5.43 (m, 1 H), 5.30 - 5.26 (m, 1 H), 5.19 - 5.14 (m, 1 H), 5.13 - 5.05 (m, 2 H), 3.21 - 3.18 (m, 1 H), 2.54 (ddd, 7 = 14.6, 9.7, 5.2 Hz, 1 H), 2.39 - 2.27 (m, 3 H), 2.23 - 2.18 (m, 1 H), 2.11 - 1.92 (m, 6 H), 1.81 - 1.76 (m, 1 H), 1.30 - 1.25 (m, 2 H), 0.88 (t, 7 = 7.5 Hz, 3 H) ppm; ¹³ C NMR (151 MHz, C ₆ D ₆ ) δ 194.78, 172.28, 159.81, 140.31, 135.57, 134.99, 131.82, 130.85, 125.40, 123.52, 72.82, 43.21, 33.70, 32.82, 32.13, 28.44, 26.05, 24.65, 21.03, 14.37 ppm; HR-MS (ESI-TOF): calcd for C20H27O3 [M+H] ⁺ : 315.1955, found: 315.1955.

[00150] Isopropyl (5Z,12£,15S,17Z)-15-{[icrt-butyl(dimethyl)silyl]oxy}-ll-oxo prosta-

5,9,12,17-tetraen-l-oate (46): 46: R _f = 0.60 (hexanes:EtOAc, 3:2); [a]j¾ ⁵ = +127.5 (c = 1.0 in CHCI3); IR (film): v _max = 3012, 2956, 2930, 2857, 1731, 1706, 1654, 1462, 1251, 1088, 835, 776 cm ^"1 ; Ή NMR (600 MHz, CDCI3) δ 7.49 (dd, 7= 6.0, 2.6 Hz, 1 H), 6.60 (t, 7= 8.2 Hz, 1 H), 6.32 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.49 - 5.45 (m, 2 H), 5.39 - 5.35 (m, 2 H), 5.00 (sept, 7= 6.3 Hz, 1 H), 3.89 (quint, 7= 6.0 Hz, 1 H), 3.45 (ddd, 7= 8.0, 3.8, 1.8 Hz, 1 H), 2.64 - 2.40 (m, 1 H), 2.45 - 2.40 (m, 2 H), 2.29 - 2.13 (m, 5 H), 2.06 - 1.95 (m, 4 H), 1.66 (quint, 7= 7.2 Hz, 2 H), 1.22 (d, 7=6.3 Hz, 6 H) 0.94 (t, 7= 7.5 Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm; ¹³ C NMR (151 MHz, CDC1 ₃ ) δ 196.35, 173.08, 161.57, 138.83, 135.05, 134.12, 132.66, 131.61, 126.12, 124.41, 71.68, 67.63, 43.47, 36.91, 35.30, 34.19, 30.65, 26.85, 25.97, 24.92, 21.99, 20.89, 18.20, 14.31, -4.43 ppm; HR-MS (ESI-TOF): calcd for C ₂₉ H ₄₈ 0 ₄ SiNa [M+Na] ⁺ : 511.3204, found: 511.3214.

[00151] Isopropyl (5Z,12£',15S,17Z)-15-hydroxy-ll-oxoprosta-5,9,12,17-tetraen -l- oate (3): To a stirred solution of carboxylic acid 46 (10 mg, 20 μιηοΐ, 1.0 equiv) in CH2CI2 (1 mL) at 0 °C was dropwise added a solution of HF: NEt ₃ (190 μί, l.O mmol, 50 equiv) in CH ₂ C1 ₂ (0.5 mL). After stirring for 48 h at room temperature, the reaction mixture was quenched by addition of saturated brine (3 mL) and extracted with EtOAc (5 x 10 mL). The combined organic extracts were dried (Na ₂ S04), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Purification by flash column chromatography (S1O2, hexanes: EtOAc, 3:l→3:2) gave pure title compound (3, 6.1 mg, 16 μπιοΐ, 80 % yield) as a colorless oil. 3: R _f = 0.20 (hexanes: EtOAc, 3:2); [α]¾ ⁵ = +158.2 (c = 0.5 in C ₆ ¾); IR (film): _Vma x = 3449, 2963, 2933, 1728, 1708, 1651, 1456, 1374, 1216, 1180, 1109, 531 cm ^"1 ; 'H-NMR (600 MHz, C ₆ D ₆ ) δ 6.94 (dd, 7=6.2, 2.4 Hz, 1 H), 6.84 (t, 7=7.5 Hz, 1 H), 6.20 (dt, 7= 6.1, 1.5 Hz, 1 H), 5.51 - 5.47 (m, 1 H), 5.39 - 5.35 (m, 1 H), 5.31 - 5.27 (m, 1 H), 5.21 - 5.17 (m, 1 H), 5.01 (sept, 7= 6.2 Hz, 1 H), 3.54 (quint, 7=6.2 Hz, 1 H), 3.12 - 3.10 (m, 1 H), 2.43 (dt, 7= 14.4, 5.3 Hz, 1 H), 2.31 (dt, 7= 14.7, 7.3 Hz, 1 H), 2.24 - 2.02 (m, 6 H), 1.92 (quint, 7= 7.5 Hz, 2 H), 1.89 (q, 7= 7.5 Hz, 2 H), 1.56 (quint, 7= 7.4 Hz, 2 H), 1.05 (d, 7= 6.3 Hz, 6 H), 0.89 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 194.83, 172.23, 160.20, 139.17, 134.86, 134.31, 131.40, 131.17, 125.97, 124.50, 70.22, 67.08, 43.06, 36.54, 35.01, 33.62, 30.20, 26.57, 24.73, 21.50, 20.70, 14.05 ppm; HR-MS (ESI-TOF): calcd for CzjEv Na [M+Na] ⁺ : 397.2349, found: 397.2344.

[00152] Decyl (5Z,12£',15S,17Z)-15-{[icrt-butyl(dimethyl)silyl]oxy}-ll-ox oprosta-

5,9,12,17-tetraen-l-oate (47): 47: R _f = 0.30 (hexanes:EtOAc, 4: 1); [c¾ ⁵ = +117.0 (c= 1.0 in C ₆ ¾); IR (film): v _max = 3009, 2955, 2927, 2856, 1735, 1707, 1658, 1462, 1251, 1088, 836, 775 cm ^"1 ; 'H-NMR (600 MHz, CDCI3) δ 7.48 (ddd, 7=6.0, 2.6, 1.0 Hz, 1 H), 6.60 (t, 7= 8.2 Hz, 1 H), 6.32 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.50 - 5.44 (m, 2 H), 5.39 - 5.34 (m, 2 H), 4.05 (t, 7= 6.8 Hz, 2 H), 3.89 (quint, 7= 6.0 Hz, 1 H), 3.45 (ddd, 7= 8.9, 4.1, 2.1 Hz, 1 H), 2.63 - 2.59 (m, 1 H), 2.44 - 2.41 (m, 2 H), 2.29 - 2.14 (m, 5 H), 2.05 - 1.96 (m, 4 H), 1.67 (quint, 7= 7.5 Hz, 2 H), 1.62 - 1.55 (m, 2 H), 1.37 - 1.21 (m, 14 H), 0.94 (t, 7=7.5 Hz, 3 H), 0.89 - 0.85 (m, 12 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.29, 173.59, 161.52, 135.06, 134.97, 134.11, 134.04, 132.65, 132.57, 131.55, 126.12, 124.40, 71.68, 71.57, 64.62, 43.43, 36.87, 35.26, 33.81, 31.97, 30.64, 30.57, 29.61, 29.38, 28.74, 26.82, 26.01, 25.87, 24.85, 22.76, 20.85, 18.15, 14.26, 14.19, -4.45, -4.49 ppm; HR-MS (ESI-TOF): calcd for C ₃ 6H ₆₂ 0 ₄ SiNa [M+Na] ⁺ : 609.4310, found: 609.4297.

[00153] Decyl (5Z,12£,15S,17Z)-15-hydroxy-ll-oxoprosta-5,9,12,17-tetraen- l-oate (4): To a stirred solution of decyl ester 47 (20 mg, 34 μιηοΐ, 1.0 equiv) in MeCN (1 mL) at 0 °C was dropwise added a solution of HF (50 % aq., 140 μί, ca. 3.4 mmol, ca. 100 equiv) in MeCN (0.5 mL). After stirring for 30 min at this temperature, the reaction mixture was quenched with brine (3 mL) and extracted with EtOAc (5 x 5 mL). The combined organic extracts were dried (Na2S04), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Purification by flash column chromatography (S1O ₂ , hexanes:EtOAc, 3:2) gave pure title compound (4, 13 mg, 27 μιηοΐ, 79 % yield) as a colorless oil. 4: R _f = 0.20 (hexanes: EtOAc, 2: 1); [a]¾ ⁵ = +116.8 (c = 0.50 in C ₆ H ₆ ); IR (film): v _max = 3445, 2925, 2856, 1734, 1703, 1654, 1457, 1179, 1179, 1053, 1033, 804, 723 cm ^"1 ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 6.94 (ddd, 7= 6.0, 2.6, 0.9 Hz, 1 H), 6.83 (t, 7= 7.6 Hz, 1 H), 6.21 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.49 (dtt, 7= 10.5, 7.2, 1.6 Hz, 1 H), 5.38 - 5.27 (m, 2 H), 5.22 - 5.17 (m, 1 H), 4.05 (t, 7= 6.7 Hz, 2 H), 3.50 (quint, 7= 7.0 Hz, 1 H), 3.12 (ddq, 7= 8.7, 4.2, 2.0 Hz, 1 H), 2.44 (dddd, 7= 14.4, 6.2, 4.2, 1.5 Hz, 1 H), 2.30 (dt, 7= 14.7, 7.3 Hz, 1 H), 2.21 (ddd, 7= 14.7, 8.0, 5.4 Hz, 1 H), 2.17 - 2.01 (m, 5 H), 2.00 - 1.86 (m, 4 H), 1.58 (quint, 7= 7.0 Hz, 3 H), 1.54 - 1.45 (m, 2 H), 1.35 - 1.15 (m, 14 H), 0.92 (t, 7= 7.1 Hz, 3 H), 0.89 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 195.03, 173.13, 160.40, 139.60, 135.29, 134.77, 131.57, 126.39, 124.82, 70.60, 64.59, 43.44, 36.91, 35.35, 33.68, 32.32, 30.62, 29.97, 29.77, 29.67, 29.15, 26.97, 26.35, 25.11, 23.13, 21.08, 14.43, 14.39 ppm; HR-MS (ESI-TOF): calcd for C ₃ oH ₄₈ 0 ₄ Na [M+Na] ⁺ : 495.3445, found: 495.3460.

[00154] Icosyl (5Z,12£ ^' ,15S,17Z)-15-{[tcrt-butyl(dimethyl)silyl]oxy}-ll-oxopr osta- 5,9,12,17-tetraen-l-oate (48): 48: R _f = 0.36 (hexanes: EtOAc, 4: 1); [a = +88.2 (c = 1.0 in C ₆ ¾); IR (film): v = 3008, 2925, 2854, 1736, 1707, 1659, 1582, 1463, 1212, 1251, 1088, 836, 775 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.48 (ddd, 7= 6.0, 2.6, 1.0 Hz, 1 H), 6.60 (t, 7= 8.2 Hz, 1 H), 6.32 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.49 - 5.44 (m, 2 H), 5.39 - 5.34 (m, 2 H), 4.04 (t, 7= 6.8 Hz, 2 H), 3.89 (quint, 7= 6.0 Hz, 1 H), 3.45 (ddt, 7= 8.8, 4.0, 2.0 Hz, 1 H), 2.65 - 2.58 (m, 1 H), 2.44 - 2.40 (m, 2 H), 2.29 - 2.14 (m, 5 H), 2.05 - 1.97 (m, 4 H), 1.67 (quint, 7= 7.5 Hz, 2 H), 1.62 - 1.58 (m, 2 H), 1.33 - 1.23 (m, 34 H), 0.94 (t, 7= 7.5 Hz, 3 H), 0.88 - 0.85 (m, 12 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.27, 173.58, 161.50, 138.78, 134.97, 134.04, 132.64, 131.48, 126.05, 124.40, 71.68, 64.62, 43.43, 36.87, 35.26, 33.80, 32.01, 30.64, 29.79, 29.40, 28.74, 26.82, 25.87, 24.85, 22.78, 20.85, 18.15, 14.28, 14.20, -4.45, -4.49 ppm; HR-MS (ESI-TOF): calcd for C46H ₈ 20 ₄ SiNa [M+Na] ⁺ : 749.5875, found: 749.5854.

[00155] Icosyl (5Z,12£,15S,17Z)-15-hydroxy-ll-oxoprosta-5,9,12,17-tetraen- l-oate

(5): To a stirred solution of TBS ether 48 (20.0 mg, 27.5 μηιοΐ, 1.0 equiv) in MeCN (1 mL) at 0 ³ C was dropwise added a solution of HF (50 % aq., 110 ί, ca. 2.75 mmol, ca. 100 equiv) in MeCN (0.5 mL). After stirring for 30 min at this temperature, the reaction mixture was quenched with brine (3 mL) and extracted with EtOAc (5 x 5 mL). The combined organic extracts were dried (Na2S04), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Purification by flash column chromatography (S1O ₂ , hexanes:EtOAc, 3:2) gave pure title compound (5, 12.8 mg, 20.9 μιηοΐ, 76 % yield) as a colorless oil. 5: R _f = 0.40 (hexanes: EtOAc, 7:3); [αβ ⁵ = +101.0 (c= 0.5 in C ₆ ¾); IR (film): v _max = 3410, 2917, 2850, 1735, 1700, 1651, 1467, 1178, 1048, 803, 721 cm ^"1 ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 6.94 (dd, 7= 6.2, 2.6 Hz, 1 H), 6.83 (t, 7= 7.6 Hz, 1 H), 6.21 (dd, 7= 6.1, 1.8 Hz, 1 H), 5.50 (dtt, 7= 10.5, 7.2, 1.6 Hz, 1 H), 5.38 -5.27 (m, 1 H), 5.25 -5.16 (m, 1 H), 4.06 (t, 7=6.7 Hz, 2 H), 3.51 (p, 7= 6.3, 5.7 Hz, 1 H), 3.12 - 3.10 (m, 1 H), 2.49 - 2.39 (m, 1 H), 2.30 (dt, 7= 14.7, 7.3 Hz, 1 H), 2.21 (ddd, 7= 14.7, 8.1, 5.4 Hz, 1 H), 2.17 - 2.01 (m, 5 H), 2.00 - 1.87 (m, 4 H), 1.59 (quint, 7= 7.3 Hz, 3 H), 1.51 (quint, 7= 6.9 Hz, 2 H), 1.36 - 1.19 (m, 34 H), 0.92 - 0.97 (m, 6 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 195.01, 173.13, 160.39, 139.61, 135.30, 134.78, 131.55, 131.52, 126.40, 124.81, 70.60, 64.59, 43.44, 36.91, 35.35, 33.68, 30.62, 30.24, 30.22, 30.16, 30.08, 30.02, 29.86, 29.16, 26.97, 26.37, 25.11, 23.15, 21.08, 14.44, 14.40 ppm; HR-MS (ESI-TOF): calcd for C^HesCWa [M+Na] ⁺ : 635.5010, found: 635.4991.

[00156] 2-(Phenylsulfonyl)ethyl (5Z,12£,15S,17Z)-15-{[icrt-butyl(dimethyl)silyl]oxy}- ll-oxoprosta-5,9,12,17-tetraen-l-oate (49): 49: R _f = 0.60 (hexanes: EtOAc, 2:3); [d =+114.8 (c = 0.45 in C ₆ H ₆ ); IR (film) : vmax = 3008, 2956, 2929, 2856, 1740, 1702, 1655, 1462, 1447, 1323, 1251, 1086, 836 cm ^"1 ; Ή-NMR (600 MHz, CDCL) δ 7.93 - 7.91 (m, 2 H), 7.67 (tt, 7= 7.4, 1.1 Hz, 1 H), 7.58 (t, 7= 7.5 Hz, 2 H), 7.47 (dd, 7= 6.1, 2.7 Hz, 1 H), 6.60 (t, 7= 7.6 Hz, 1 H), 6.32 (dd, 7=6.0, 1.8 Hz, 1 H), 5.49 - 5.44 (m, 1 H), 5.43 - 5.34 (m, 3 H), 4.40 (t, 7= 6.2 Hz, 2 H), 3.88 (quint, 7=6.2 Hz, 1 H), 3.45 (t, 7= 6.2 Hz, 3 H), 2.59 (dt, 7= 14.4, 5.4 Hz, 1 H), 2.46 - 2.37 (m, 2 H), 2.28 - 2.15 (m, 3 H), 2.07 (t, 7= 7.6 Hz, 2 H), 2.03 - 1.94 (m, 4 H), 1.54 (quint, 7= 7.5 Hz, 2 H), 0.94 (t, 7= 7.5 Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.33, 172.80, 161.50, 139.59, 138.79, 135.10, 134.16, 134.07, 132.70, 131.24, 129.49, 128.26, 126.33, 124.39, 71.67, 57.60, 55.17, 43.38, 36.91, 35.30, 33.23, 30.63, 26.69, 25.97, 24.47, 20.89, 18.20, 14.31, -4.43 ppm; HR-MS (ESI- TOF): calcd for C ₃ 4H ₅ o0 ₆ SSiNa [M+Na]: 637.2994, found: 637.2982.

[00157] 2-(Phenylsulfonyl)ethyl (5Z,12£,15S,17Z)-15-hydroxy-ll-oxoprosta-

5,9,12,17-tetraen-l-oate (10): To a stirred solution of dienone sulfonate ester 49 (4.0 mg, 6.5 μιηοΐ, l.O equiv) in MeCN (1 mL) at 0 °C was dropwise added a solution of HF (50 % aq., 13 μί, ca. 0.32 mmol, ca. 50 equiv) in MeCN (0.5 mL). After stirring for 30 min at this temperature, the reaction mixture was quenched with brine (3 mL) and extracted with EtOAc (5 x 5 mL). The combined organic extracts were dried (Na2S04), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Purification by flash column chromatography (S1O ₂ , hexanes:EtOAc, 2:3) gave pure title compound (10, 2.4 mg, 4.9 μηιοΐ, 76 % yield) as a colorless oil. 10: R _f = 0.20 (hexanes: EtOAc, 2:3); [a] j¾ ⁵ = +99.3 (c = 0.20 in CHC1 ₃ ); IR (film): Vmax = 3425, 2925, 1738, 1697, 1651, 1447, 1321, 1142, 1085, 726 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 7.93 - 7.91 (m, 2 H), 7.67 (tt, 7= 7.4, 1.1 Hz, 1 H), 7.58 (t, 7= 7.5 Hz, 2 H), 7.49 (dd, 7= 6.1, 2.7 Hz, 1 H), 6.63 (t, 7=7.6 Hz, 1 H), 6.34 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.62 - 5.57 (m, 1 H), 5.43 - 5.34 (m, 3 H), 4.41 (t, 7= 6.2 Hz, 2 H), 3.88 - 3.82 (m, 1 H), 3.52 - 3.50 (m, 1 H), 3.45 (t, 7= 6.3 Hz, 2 H), 2.61 (dt, 7= 14.4, 5.4 Hz, 1 H), 2.54 - 2.43 (m, 2 H), 2.28 (t, 7= 6.8 Hz, 2 H), 2.23 (dt, 7= 15.6, 7.2 Hz, 1 H), 2.10 - 2.03 (m, 4 H), 1.97 (q, 7= 7.7 Hz, 2 H), 1.90 (d, 7= 4.4 Hz, 1 H), 1.55 (quint, 7= 6.8 Hz, 2 H), 0.96 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.43, 172.93, 161.70, 139.56, 139.48, 135.91, 135.11, 134.10, 131.80, 131.44, 129.51, 128.26, 126.08, 123.82, 70.66, 57.61, 55.17, 43.35, 36.66, 35.05, 33.19, 30.39, 26.69, 24.43, 20.89, 14.34 ppm; HR-MS (ESI-TOF): calcd for C28H ₃ 60 ₆ SNa [M+Na] ⁺ : 523.2125, found: 521.2122.

[00158] (5Z,12£',15S,17Z)-15-{[tert-Butyl(dimethyl)silyl]oxy}-ll-ox oprosta-5,9,12,17- tetraen-l-amide (50): 50: R _f = 0.40 (hexanes:EtOAc, 1 :4); [a]¾ ⁵ = +142.6 (c = 1.0 in C ₆ H ₆ ); IR (film): _Vmax = 3347, 3198, 3009, 2955, 2930, 2857, 1698, 1655, 1461, 1253, 1060, 1033, 836, 775 cm ^"1 ; 'H-NMR (600 MHz, C ₆ D ₆ ) δ 7.02 (dd, 7= 6.2, 2.5 Hz, 1 H), 6.84 (t, 7= 7.6 Hz, 1 H), 6.27 (s, 1 H), 6.23 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.53 - 5.43 (m, 2 H), 5.37 - 5.33 (m, 1 H), 5.26 - 5.20 (m, 1 H), 4.88 (s, 1 H), 3.79 (quint, 7=6.0 Hz, 1 H), 3.19 - 3.18 (m, 1 H), 2.44 (dt, 7= 14.6, 5.7 Hz, 1 H), 2.39 - 2.36 (m, 2 H), 2.29 - 2.19 (m, 2 H), 2.10 (dt, 7= 14.8, 8.4 Hz, 1 H), 2.01 - 1.89 (m, 4 H), 1.83 (t, 7= 7.3 Hz, 2 H), 1.58 (quint, 7= 7.0 Hz, 2 H), 0.97 (s, 9 H), 0.91 (t, 7=7.5 Hz, 3 H), 0.10 (s, 3 H), 0.07 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 195.29, 174.83, 160.87, 139.33, 135.22, 134.10, 131.95, 131.87, 126.16, 124.88, 71.98, 43.48, 37.03, 35.63, 34.93, 30.83, 27.03, 26.13, 25.46, 21.16, 18.32, 14.44, -4.32, -4.35 ppm; HR-MS (ESI-TOF): calcd for C26H ₄₃ 03SiNa [M+Na] ⁺ : 468.2904, found: 468.2890.

[00159] (5Z,12£,155,17Z)-15-Hydroxy-ll-oxoprosta-5,9,12,17-tetraen- l-amide (6):

To a stirred solution of amide 50 (24 mg, 53 μπιοΐ, 1.0 equiv) in MeCN (1 mL) at 0 °C was dropwise added a solution of HF (50 % aq., 210 μί, ca. 5.3 mmol, ca. 100 equiv) in MeCN (0.2 mL). After stirring for 30 min at this temperature, the reaction mixture was quenched with brine (3 mL) and extracted with EtOAc (5 x 5 mL). The combined organic extracts were dried (Na ₂ SC¼), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Purification by flash column chromatography (S1O2, MeOH:CH2Cb, 6:94) gave pure title compound (6, 12 mg, 36 μπιοΐ, 68 % yield) as a colorless oil. 6: R _f = 0.20 (EtOAc); [a]^ ⁵ = +128.6 (c = 0.50 in C ₆ ¾); IR (film): v _max = 3347, 3211, 3009, 2965, 2936, 2844, 1738, 1648, 1578, 1458, 1405, 1345, 1210, 1054, 1033, 1012, 807, 692 cm ^"1 ; 'H-NMR (600 MHz, C ₆ D ₆ ) δ 7.00 (dd, 7= 6.0, 2.6 Hz, 1 H), 6.85 (t, 7= 7.6 Hz, 1 H), 6.20 (dd, 7= 6.0, 1.8 Hz, 1 H), 6.06 (s, 1 H), 5.56 - 5.49 (m, 2 H), 5.38 - 5.31 (m, 1 H), 5.24 - 5.19 (m, 1 H), 3.85 (s, 1 H), 3.77 (quint, 7= 6.3 Hz, 1 H), 3.17 (ddt, 7= 8.8, 4.3, 2.0 Hz, 1 H), 2.53 - 2.46 (m, 2 H), 2.36 - 2.26 (m, 3 H), 2.12 - 2.06 (m, 1 H), 2.04 - 1.92 (m, 4 H), 1.91 - 1.83 (m, 2 H), 1.62 - 1.49 (m, 2 H), 1.29 (s, 1 H), 0.92 (t, 7=7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 195.81, 175.60, 161.06, 139.58, 135.20, 134.28, 132.53, 131.95, 126.26, 125.27, 70.87, 43.75, 37.26, 35.35, 34.66, 30.52, 26.95, 25.41, 21.15, 14.49 ppm; HR-MS (ESI-TOF): calcd for C ₂ oH ₂₉ N0 ₃ Na [M+Na] ⁺ : 354.2040, found: 354.2027.

[00160] (5Z,12£,155,17Z)-15-{[iert-Butyl(dimethyl)silyl]oxy}-N-meth yl-ll-oxoprosta- 5,9,12,17-tetraen-l-amide (51): 51: Rf= 0.60 (hexanes:EtOAc, 1:4); [a]¾ ⁵ = +115.3 (c = 2.0 in CHCl ₃ ); IR (film): v _ma* = 3309, 3010, 2955, 2930, 2857, 1702, 1651, 1543, 1462, 1361, 1253, 1085, 835, 776 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.49 (dd, 7= 5.8, 2.7 Hz, 1 H), 6.58 (t, 7= 7.6 Hz, 1 H), 6.30 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.56 (br s, 1 H), 5.48 - 5.42 (m, 2 H), 5.37 - 5.31 (m, 2 H), 3.89 - 3.85 (m, 1 H), 3.45 - 3.44 (m, 1 H), 2.77 (d, 7= 4.8 Hz, 3 H), 2.58 (dt, 7= 14.4, 4.2 Hz, 1 H), 2.43 - 2.37 (m, 2 H), 2.27 - 2.11 (m, 5 H), 2.03 - 1.96 (m, 4 H), 1.66 (quint, 7= 7.8 Hz, 2 H), 0.92 (t, 7=7.5 Hz, 3 H), 0.86 (s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 196.39, 173.32, 161.66, 138.84, 134.97, 134.11, 132.61, 131.71, 125.93, 124.32, 71.64, 43.41, 36.87, 36.00, 35.26, 30.56, 26.92, 26.36, 25.93, 25.51, 20.85, 18.16, 14.27, -4.46, -4.47ppm; HR-MS (ESI-TOF): calcd for C27H46NO3S1 [M+H] ⁺ : 460.3241, found: 460.3258.

[00161] (5Z,12£,15S,17Z)-15-Hydroxy-A ^r -methyl-ll-oxoprosta-5,9,12,17-tetraen-l- amide (7): To a stirred solution of -methylamide 51 (24 mg. 52 μπιοΐ, 1.0 equiv) in MeCN (1 mL) at 0 °C was dropwise added a solution of HF (50 % aq., 210 pL, ca. 5.2 mmol, ca. 100 equiv) in MeCN (0.5 mL). After stirring for 30 min at this temperature, the reaction mixture was quenched with brine (3 mL) and extracted with CH2CI2 (5 x 5 mL). The combined organic extracts were dried ( a2S04), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Purification by flash column chromatography (S1O2, hexanes:EtOAc, 1 :9) gave pure title compound (7, 14 mg, 41 pmol, 78 % yield) as a colorless oil. 7: R _f = 0.20 (EtOAc); [a]¾ ⁵ = +153.6 (c = 0.70 in CHCI3); IR (film): v _max = 3328, 3009, 2935, 1697, 1649, 1562, 1411, 1208, 1047, 807, 717 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 7.52 (dd, 7= 5.8, 2.7 Hz, 1 H), 6.61 (t, 7=7.6 Hz, 1 H), 6.34 (dd, 7= 6.0, 1.7 Hz, 1 H), 5.60 - 5.55 (m, 1 H), 5.48 - 5.44 (m, 1 H), 5.42 - 5.37 (m, 1 H), 5.36 - 5.32 (m, 1 H), 3.86 - 3.82 (m, 1 H), 3.52 - 3.49 (m, 1 H), 2.79 (d, 7= 4.9 Hz, 3 H), 2.67 - 2.63 (m, 1 H), 2.59 - 2.53 (m, 2 H), 2.49 - 2.45 (m, 1 H), 2.29 (t, 7= 6.8 Hz, 2 H), 2.23 (dt, 7= 15.6, 8.6 Hz, 1 H), 2.15 (t, 7= 7.4 Hz, 2 H), 2.08 - 2.03 (m, 4 H), 1.71 - 1.63 (m, 3 H), 0.96 (t, 7= 7.5 Hz, 3 H) ppm; ¹ C-NMR (151 MHz, CDC1 ₃ ) δ 196.53, 173.54, 161.78, 139.49, 135.49, 135.07, 131.97, 131.93, 125.78, 124.05, 70.72, 43.59, 36.86, 35.83, 34.91, 30.34, 26.97, 26.45, 25.47, 20.88, 14.32 ppm; HR-MS (ESI-TOF): calcd for C ₂ iH ₃ iN0 ₃ Na [M+Na] ⁺ : 368.2196, found: 368.2191.

[00162] (5Z,12£,15S,17Z)-15-{[iert-Butyl(dimethyl)silyl]oxy}-N-isop ropyl-ll- oxoprosta-5,9,12,17-tetraen-l-amide (52): 52: R _f = 0.60 (hexanes:EtOAc, 1:4); [α] =+117.4 (c = 2.0 in CHCL); IR (film): v _m „ = 3301, 2958, 2930, 2858, 1702, 1646, 1543, 1461, 1252, 1063, 835 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 7.48 (dd, 7= 5.8, 2.7 Hz, 1 H), 6.59 (ddt, 7= 8.3, 6.8, 1.2 Hz, 1 H), 6.31 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.48 - 5.44 (m, 2 H), 5.38 - 5.32 (m, 2 H), 5.26 (d, 7=6.1 Hz, 1 H), 4.10 - 4.02 (m, 1 H), 3.88 (quint, 7= 5.9 Hz, 1 H), 3.45 (ddd, 7= 8.6, 4.1, 2.1 Hz, 1 H), 2.59 (dt, 7= 14.4, 4.2 Hz, 1 H), 2.46 - 2.37 (m, 2 H), 2.27 - 2.15 (m, 3 H), 2.09 (t, 7= 6.6 Hz, 2 H), 2.02 - 1.97 (m, 3 H), 1.76 (s, 1 H), 1.66 (quint, 7= 7.5 Hz, 2 H), 1.13 (d, 7=6.6 Hz, 6 H), 0.93 (t, 7=6.6 Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 196.39, 171.76, 161.65, 138.85, 135.01, 134.13, 132.63, 131.77, 125.94, 124.37, 71.65, 43.42, 41.35, 36.88, 36.35, 35.28, 30.59, 26.91, 25.95, 25.89, 25.56, 22.94, 20.86, 18.18, 14.29, -4.45 ppm; HR-MS (ESI-TOF): calcd for C29H50NO3S1 [M+H] ⁺ : 488.3554, found: 488.3571.

[00163] (5Z,12£,15S,17Z)-15-Hydroxy-^V-isopropyl-ll-oxoprosta-5,9,1 2,17-tetraen-l- amide (8) : To a stirred solution of dienone iV-wo-propylamide 52 (22 mg. 45 μιηοΐ, 1.0 equiv) in MeCN (1 mL) at 0 °C was dropwise added a solution of HF (50 % aq., 180 μί, ca. 4.5 mmol. ca. 100 equiv) in MeCN (0.5 mL). After stirring for 30 min at this temperature, the reaction mixture was quenched with brine (3 mL) and extracted with EtOAc (5 x 5 mL). The combined organic extracts were dried (Na ₂ S0 ₄ ), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Purification by flash column chromatography (S1O ₂ , hexanes: EtOAc, 1 :10) gave pure title compound (8, 12 mg, 34 μιηοΐ, 75 % yield) as a colorless oil. 8: R _f =0.30 (EtOAc); [α ⁵ = +122.9 (c= 1.2 in CHCI3); IR (film): v _max = 3301, 2966, 2932, 1697, 1643, 1544, 1457, 1366, 1175, 1047, 809, 717 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.52 (dd, 7=5.9, 2.2 Hz, 1 H), 6.62 (t, 7=7.7 Hz, 1 H), 6.33 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.59 - 5.54 (m, 1 H), 5.49 - 5.44 (m, 1 H), 5.42 - 5.31 (m, 2 H), 4.09 - 4.01 (m, 1 H), 3.86 - 3.81 (m, 1 H), 3.51 - 3.49 (m, 1 H), 2.65 (dt, 7= 14.8, 5.7 Hz, 1 H), 2.61 (d, 7= 3.7 Hz, 1 H), 2.57 - 2.52 (m, 1 H), 2.49 - 2.45 (m, 1 H), 2.28 (t, 7=7.0 Hz, 2 H), 2.22 (dt, 7= 15.7, 8.3 Hz, 1 H), 2.11 (t, 7= 7.3 Hz, 2 H), 2.07 - 2.02 (m, 4 H), 1.76 (brs, 1 H), 1.71 - 1.62 (m, 2 H), 1.12 (d, 7=6.7 Hz, 6 H), 0.95 (t, 7= 7.6 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 196.50, 171.94, 161.77, 139.43, 135.43, 135.06, 131.98, 131.92, 125.74, 124.07, 70.69, 43.59, 41.42, 36.83, 36.18, 34.89, 30.34, 26.95, 25.55, 22.92, 20.87, 14.31 ppm; HR-MS (ESI-TOF): calcd for C23H36NO3 [M+H] ⁺ : 374.2690, found: 374.2694.

[00164] (5Z,12£',15S,17Z)-15-{[icrt-Butyl(dimethyl)silyl]oxy}-N^V-d imethyl-ll- oxoprosta-5,9,12,17-tetraen-l-amide (53): 53: R _f =0.60 (EtOAc); [αβ ⁵ = +123.3 (c = 0.60 in C ₆ H ₆ ); IR (film): v _max = 3009, 2955, 2929, 2856, 1703, 1653, 1462, 1397, 1256, 1083, 836, 776 cm ^"1 ; 'H-NMR (600 MHz, CDCI3) δ 7.49 (dd, 7=5.8, 2.7 Hz, 1 H), 6.60 (t, 7=7.6 Hz, 1 H), 6.31 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.55 - 5.45 (m, 2 H), 5.38 - 5.33 (m, 2 H), 3.88 (quint, 7= 6.2 Hz, 1 H), 3.47 - 3.44 (m, 1 H), 2.98 (s, 3 H), 2.93 (s, 3 H), 2.62 (dt, 7= 14.4, 5.7 Hz, 1 H), 2.47 - 2.38 (m, 2 H), 2.28 (t, 7=7.5 Hz, 2 H), 2.25 - 2.15 (m, 3 H), 2.10 - 1.97 (m, 4 H), 1.68 (quint, 7= 7.5 Hz, 2 H), 0.93 (t, 7= 7.5 Hz, 3 H), 0.87 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.41, 172.78, 161.70, 138.87, 135.00, 134.13, 132.61, 132.05, 125.85, 124.41, 71.68, 43.48, 37.33, 36.91, 35.50, 35.30, 32.78, 30.65, 27.12, 25.97, 24.99, 20.88, 18.20, 14.31, -4.43 ppm; HR-MS (ESI-TOF): calcd for C28H ₄₇ 0 ₃ Si a [M+Na] ⁺ : 496.3217, found: 496.3201.

[00165] (5Z,12£',15S,17Z)-15-Hydroxy-N^V-dimethyl-ll-oxoprosta-5,9, 12,17-tetraen- 1 -amide (9): To a stirred solution of dienone iVN-dimethylamide 53 (6.0 mg, 13 μιηοΐ, 1.0 equiv) in MeCN (1 mL) at 0 °C was dropwise added a solution of HF (50 % aq., 46 μί, ca. 1.3 mmol, ca. 100 equiv) in MeCN (0.5 mL). After stirring for 30 min at this temperature, the reaction mixture was quenched with brine (3 mL) and extracted with CH2CI2 (5 x 5 mL). The combined organic extracts were dried (Na ₂ S0 ₄ ), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Purification by flash column chromatography (S1O2, hexanes:EtOAc, 1 : 10) gave pure title compound (9, 3.8 mg, 11 μπιοΐ, 84 % yield) as a colorless oil. 9: R _f =0.30 (EtOAc); [αβ ⁵ = +116.0 (c = 0.3 in CHCI3); IR (film): v = 3419, 3409, 3008, 2959, 2927, 2872, 1697, 1626, 1579, 1400, 1260, 1048, 801 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.53 (dd, 7= 5.8, 2.7 Hz, 1 H), 6.62 (t, 7=7.6 Hz, 1 H), 6.34 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.59 - 5.54 (m, 1 H), 5.52 - 5.47 (m, 1 H), 5.43 - 5.33 (m, 2 H), 3.86 - 3.81 (m, 1 H), 3.52 - 3.49 (m, 1 H), 2.99 (s, 3 H), 2.93 (s, 3 H), 2.71 - 2.67 (m, 2 H), 2.58 (dt, 7= 14.6, 7.1 Hz, 1 H), 2.48 (ddd, 7= 14.6, 8.2, 6.5 Hz, 1 H), 2.31 - 2.28 (m, 4 H), 2.21 (dt, 7= 15.8, 8.8 Hz, 1 H), 2.11 - 2.03 (m, 4 H), 1.71 - 1.64 (m, 2 H), 0.96 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC ) δ 196.50, 172.91, 161.75, 139.47, 135.35, 135.07, 132.22, 131.97, 125.68, 124.19, 70.71, 43.72, 37.40, 36.95, 35.64, 34.86, 32.61, 30.43, 27.20, 24.95, 20.89, 14.34 ppm; HR-MS (ESI-TOF): calcd for C ₂₂ H ₃₃ N0 ₃ Na [M+Na] ⁺ : 382.2353, found: 382.2365.

[00166] (5Z,12£,15S,17Z)-15-Hydroxy-l-[(4-methoxybenzyl)oxy]prosta- 5,9,12,17- tetraen-ll-one (55): 55: R _f =0.51 (hexanes:EtOAc, 1: 1); [a]^ ⁵ =+142.5 (c= 1.0 in C ₆ ¾); IR (film): _Vmax = 3430, 3007, 2931, 2856, 1700, 1651, 1612, 1583, 1513, 1461, 1246, 1173, 1097, 1036 cm ^"1 ; Ή-NMR (500 MHz, CDC1 ₃ ) δ 7.50 (ddd, 7= 6.1, 2.6, 1.0 Hz, 1 H), 7.25 (d, 7= 8.8 Hz, 2 H), 6.87 (d, 7= 8.6 Hz, 2 H), 6.63 (tt, 7=7.0, 1.4 Hz, 1 H), 6.33 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.63 - 5.54 (m, 1 H), 5.51 - 5.44 (m, 1 H), 5.41 - 5.27 (m, 2 H), 4.42 (s, 2 H), 3.80 (s, 3 H), 3.48 (dq, 7= 6.6, 2.1 Hz, 1 H), 3.42 (t, 7= 6.5 Hz, 2 H), 2.60 (dddd, 7= 12.5, 6.4, 4.5, 2.1 Hz, 1 H), 2.54 - 2.41 (m, 2 H), 2.31 - 2.17 (m, 3 H), 2.10 - 1.92 (m, 6 H), 1.62 - 1.54 (m, 2 H), 1.40 (dq, 7= 10.1, 7.5 Hz, 2 H), 0.96 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (125 MHz, CDCI3) δ 196.53, 161.98, 159.22, 139.55, 135.85, 134.94, 132.72, 131.68, 130.73, 129.37, 125.05, 123.84, 113.86, 72.67, 70.57, 69.97, 55.40, 43.48, 36.58, 35.03, 30.43, 29.50, 27.30, 26.28, 20.89, 14.36 ppm; HR-MS (ESI-TOF): calcd for CaHaeCWa [M+Na] ⁺ : 461.2662, found: 461.2647.

[00167] (5Z,12£ ^' ,15S,17Z)-l,15-Dihydroxyprosta-5,9,12,17-tetraen-ll-on e (12): To a vigorously stirred solution of A ¹² -PGJs /jara-mefhoxybenzylether 55 (9.0 mg, 21 μηιοΐ, 1.0 equiv) in a mixture of (4: 1, 0.5 mL) at 0 °C was added in one portion 2,3-dichloro-5,6-dicyano-l,4- benzoquinone (7.0 mg, 31 μιχιοΐ, 1.5 equiv). After stirring at this temperature for 60 min, the reaction mixture was diluted with Et20 (5 mL), filtered through Celite®, washed with Et20, and concentrated to a volume of ca. 0.1 mL (not to dryness!). Flash column chromatography (S1O2, hexanes:EtOAc, 1 : 1→0: 1) yielded pure title compound (12, 6.0 mg, 19 μιηοΐ, 92 % yield) as a colorless oil. 12: R _f = 0.21 (hexanes:EtOAc, 1 : 1); [αβ = +151.2 (c = 0.6 in C ₆ ¾); IR (film): v _ma x = 3385, 3009, 2928, 2857, 1695, 1648, 1579, 1456, 1210, 1048 cm ^"1 ; Ή-NMR (500 MHz, CDCI3) δ 7.52 (ddd, 7=6.0, 2.6, 1.0 Hz, 1 H), 6.63 (ddt, 7= 8.3, 7.0, 1.3 Hz, 1 H), 6.34 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.60 (dtt, 7= 10.5, 7.3, 1.5 Hz, 1 H), 5.53 - 5.44 (m, 1 H), 5.40 - 5.29 (m, 2 H), 3.84 (quint, 7= 6.3 Hz, 1 H), 3.63 (t, 7= 6.5 Hz, 2 H), 3.54 - 3.47 (m, 1 H), 2.63 (dddd, 7= 13.0, 6.4, 4.3, 2.2 Hz, 1 H), 2.58 - 2.42 (m, 2 H), 2.31 - 2.19 (m, 3 H), 2.04 (dddd, 7= 17.6, 8.3, 7.3, 1.6 Hz, 4 H), 1.60 - 1.51 (m, 2 H), 1.46 - 1.37 (m, 2 H), 0.96 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (125 MHz, CDC1 ₃ ) δ 196.59, 161.97, 139.61, 135.93, 135.01, 132.67, 131.72, 125.15, 123.81, 70.65, 62.76, 43.53, 36.62, 35.01, 32.36, 30.45, 27.21, 25.80, 20.90, 14.37 ppm; HR-MS (ESI-TOF): calcd for C2oH ₃ o0 ₃ Na [M+Na] ⁺ : 341.2087, found: 341.2078.

[00168] (4S)-4-{(2Z)-7-[(4-Methoxybenzyl)oxy]hept-2-en-l-yl}cyclopen t-2-en-l-one

(ent-57): ent-57: R _f = 0.57 (hexanes:EtOAc, 2: 1); [a]5 ⁵ = -88.5 (c= 1.0 in C ₆ H ₆ ); lit.: [a]¾ ⁵ = +90.5 (c = 1.0 in C6¾) for the other enantiomer. All other analytical data were identical to those reported in the literature. ¹

[00169] (5Z,8p,12£',15 ?,17Z)-15-{[tert-Butyl(dimethyl)silyl]oxy}-l-[(4- methoxybenzyl)oxy]prosta-5,9,12,17-tetraen-ll-one (ent-54): ent-54: Rf = 0.70 (hexanes:EtOAc, 4: 1); [α¾ ⁵ = -124.1 (c = 1.0 in C ₆ H ₆ ); lit.: [a¾ ⁵ = +125.0 (c = 1.0 in C ₆ ¾) for the other enantiomer. All other analytical data were identical to those reported for its enantiomer. ¹

[00170] (5Z,8p,12£,15S,17Z)-15-{[tert-Butyl(dimethyl)silyl]oxy}-l-h ydroxyprosta- 5,9,12,17-tetraen-ll-one (60): 60: R _f = 0.38 (hexanes:EtOAc, 2: 1); [α ⁵ = -140.7 (c= 1.0 in C ₆ H ₆ ); lit.: [α]ο = +146.7 (c = 1.0 in C6¾) for the other enantiomer. All other analytical data were identical to those reported in the literature (Nicolaou et al, 2016).

[00171] (5Z,8 ,12£,15S,17Z)-15-{[tert-Butyl(dimethyl)silyl]oxy}-ll-oxopro sta- 5,9,12,17- tetraen-l-oic acid (ent-45): ent-45: R _f = 0.57 (CH ₂ Cl ₂ :EtOH, 10: 1); [a]^ ⁵ = -143.8 (c = 0.5 in ΟόΗβ); lit.: [α] _β = +140.5 (c - 1.0 in C6¾) for the other enantiomer. All other analytical data were identical to those reported in the literature (Nicolaou et al, 2016).

enf-1

[00172] (5Z,8p,12£ ^' ,15/?,17Z)-15-Hydroxy-ll-oxoprosta-5,9,12,17-tetraen-l -oic acid (ent-1): To a stirred solution of eraf-A ¹² -PGJ ₃ -15-f-butyldimethylsilyl-ether (ent-45) (80 mg, 0.18 mmol, l .O equiv) in MeCN (1.5 mL) at 0 °C was dropwise added a solution of HF (50 % aq., 720 μί, ca. 18 mmol, ca. 100 equiv) in MeCN (0.5 mL). After stirring for 45 min at this temperature, the reaction mixture was quenched with sat. brine (30 mL) and extracted with EtOAc (5 x 50 mL). The combined organic extracts were dried (Na ₂ S0 ₄ ), filtered, and concentrated to a volume of ca. 1 mL (not to dryness !). Hash column chromatography (S1O ₂ , ClrbCkEtOH, 15: 1) yielded the pure title compound (ent-1, 53 mg, 0.16 mmol, 92 % yield) as a colorless oil. ent-1: R _f = 0.56 (CH ₂ Cl ₂ :EtOH, 10: 1), [αβ ⁵ = -128.2 (c = 1.0 in C ₆ H ₆ ), lit.: [αβ ⁵ = +129.0 (c = 0.5 in C ₆ H ₆ ) for the other enantiomer. All other analytical data were identical to those reported in the literature. [00173] Methyl (5Z,8p,12£,15«,17Z)-15-hydroxy-ll-oxoprosta-5,9,12,17-tetr aen-l- oate (ent-2): To a stirred solution of ent-A ¹² -VGh (ent-l) (10 mg, 30 μηιοΐ, 1.0 equiv) in C6¾:MeOH (3:2, 1.0 mL) at 25 °C was dropwise added a solution of trimethylsilyl diazomethane (2 M in Et20, 23 μί, 45 μηιοΐ, 1.5 equiv) (yellow color persists). After stirring for 30 min, the reaction mixture was concentrated. Rash column chromatography (S1O ₂ , hexanes :EtO Ac, 2: 1→3:2) yielded pure title compound (ent-2, 9.0 mg, 28 μιηοΐ, 93 % yield) as a colorless oil. ent-2: R _f = 0.53 (hexanes:EtOAc, 1 : 1); [a]j¾ ⁵ = +194.3 (c = 0.9 in C ₆ ¾); lit.: [a]¾ ⁵ = +206.3 (c = 0.4 in C ₆ ¾) for the other enantiomer. All other analytical data were identical to those reported in the literature.

[00174] (5Z,8p,12£',15/?,17Z)-l,15-Epoxyprosta-5,9,12,17-tetraene-l ,ll-dione

11): To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (15 mg, 42 μηιοΐ, 1.4 equiv) and 4- dimethylaminopyridine (22 mg, 180 μπιοΐ, 6.0 equiv) in CH ₂ CI ₂ (20 mL) was added a solution of ent- A ¹² -PGJ3 (ent-l) (10 mg, 30 μπιοΐ, 1.0 equiv) in CH2CI2 (10 mL) at 25 °C dropwise via syringe pump over 15 h. After stirring for an additional 2 h, the reaction mixture was washed sequentially with sat. aq. NaHC0 ₃ -solution (10 mL), aq. HC1 (0.2 M, 10 mL), and sat. brine (10 mL). The organic layer was dried (Na2S04), filtered, and concentrated. Hash column chromatography (S1O2, hexanes: EtOAc, 3: 1) yielded pure title compound (ent-\\, 7.1 mg, 22 μιηοΐ, 74 % yield) as a white solid, ent-11: R _f = 0.35 (hexanes:EtOAc, 3: 1); mp = 62-65 °C; [αβ = -64.0 (c = 0.7 in CHC ); lit: [αβ ⁵ = +65.2 (c = 0.6 in C6¾) for the other enantiomer. All other analytical data were identical to those reported in the literature (Nicolaou <?f a/., 2016)

[00175] (4 ?)-4-[(2Z)-7-Hydroxyhept-2-en-l-yl]cyclopent-2-en-l-one (62): 62:

Rf = 0.38 (hexanes:EtOAc, 2: 1); [α ⁵ = +80.1 (c = 0.47 in CHC1 ₃ ); IR (film): v _max = 3421, 3008, 2931, 2860, 1706, 1670, 1585, 1184, 1056, 785 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.62 (dd, 7= 5.8, 2.7 Hz, 1 H), 6.17 (dd, /= 5.9, 2.0 Hz, 1 H), 5.53 - 5.49 (m, 1 H), 5.39 - 5.34 (m, 1 H), 3.64 (t, /= 6.5 Hz, 3 H), 3.03 - 2.98 (m, 1 H), 2.51 (dd, /= 19.7, 6.5 Hz, 1 H), 2.33 - 2.28 (m, 1 H), 2.24 - 2.19 (m, 1 H), 2.08 - 2.00 (m, 3 H), 1.60 - 1.55 (m, 2 H), 1.46 - 1.41 (m, 2 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 210.00, 168.06, 134.25, 132.46, 126.00, 62.88, 41.51, 40.62, 32.43, 32.09, 27.19, 25.82 ppm; HR-MS (ESI- TOF): calcd for C12H19O2 [M+H] ⁺ : 195.1386, found: 195.1377.

[00176] (4/?)-4-[(2Z)-7-{[teri-Butyl(dimethyl)silyl]oxy}hept-2-en-l- l]cyclopent-2-en- 1-one (63): 63: R _f = 0.40 (hexanes:EtOAc, 4: 1); [a]^ ⁵ = +93.3 (c = 1.00 in C ₆ H ₆ ); IR (film): v _ma x = 3008, 2929, 2857, 1716, 1587, 1472, 1408, 1254, 1180, 1099, 1006, 835, 776 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.62 (dd, 7= 5.8, 2.7 Hz, 1 H), 6.16 (dd, 7= 5.9, 2.0 Hz, 1 H), 5.53 - 5.48 (m, 1 H), 5.37 - 5.33 (m, 1 H), 3.59 (td, 7= 6.5, 1.3 Hz, 2 H), 3.01 - 2.98 (m, 1 H), 2.51 (dd, 7= 18.8, 6.5 Hz, 1 H), 2.32 - 2.27 (m, 1 H), 2.24 - 2.19 (m, 1 H), 2.05 - 1.99 (m, 3 H), 1.53 - 1.48 (m, 2 H), 1.42 - 1.36 (m, 2 H), 0.88 (s, 9 H), 0.03 (s, 6 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 209.97, 168.08, 134.23, 132.77, 125.74, 63.11, 41.55, 40.64, 32.58, 32.08, 27.26, 26.09, 25.77, 18.47, -5.15 ppm; HR-MS (ESI-TOF): calcd for Ci ₈ H ₃₃ 0 ₂ Si [M+H] ⁺ : 309.2251, found: 309.2234.

66

[00177] (5Z,12£,14£,17Z)-l-{[^ri-Butyl(dimethyl)silyl]oxy}prosta-5 ,9,12,14,17- pentaen-ll-one (66): 66: R _f = 0.70 (hexanes:EtOAc, 4: 1); [a]j¾ ⁵ = +58.1 (c = 0.90 in C ₆ H ₆ ); IR (film): v _max = 2941, 2865, 1697, 1633, 1462, 1207, 1104, 1067, 882 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 7.48 (dd, 7= 6.0, 2.4 Hz, 1 H), 6.96 (d, 7= 11.8 Hz, 1 H), 6.37 - 6.33 (m, 2 H), 6.21 (dt, 7= 13.1, 6.1 Hz, 1 H), 5.56 - 5.47 (m, 2 H), 5.40 - 5.31 (m, 2 H), 3.60 - 3.55 (m, 3 H), 2.97 (t, 7= 6.9 Hz, 2 H), 2.63 - 2.58 (m, 1 H), 2.27 (dt, 7= 15.3, 8.7 Hz, 1 H), 2.09 - 2.04 (m, 2 H), 2.02 - 1.90 (m, 2 H), 1.52 - 1.55 (m, 2 H), 1.40 - 1.34 (m, 2 H), 0.98 (t, 7= 7.8 Hz, 3 H), 0.89 (s, 9 H), 0.04 (s, 3 H), 0.04 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 197.48, 160.95, 144.24, 135.68, 135.36, 134.10, 132.90, 131.42, 125.84, 125.07, 124.60, 63.15, 43.77, 32.65, 31.14, 30.99, 27.28, 26.08, 25.99, 20.70, 18.44, 14.32, -5.22 ppm; HR-MS (ESI-TOF): calcd for C26H ₄₃ 0 ₂ Si [M+H] ⁺ : 415.3027, found: 415.3021.

67

[00178] (5Z,12£,14£,17Z)-l-Hydroxyprosta-5,9,12,14,17-pentaen-ll-o ne (67): 67: 0.30 (hexanes:EtOAc, 2: 1); [α = +134.2 (c = 0.40 in C ₆ H ₆ ); IR (film): v _max = 3423, 3009, 2930, 2859, 1686, 1626, 1578, 1456, 1298, 1206, 1067, 976, 818, 725, 519 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.48 (dd, 7=6.0, 2.4 Hz, 1 H), 6.96 (d, 7= 11.8 Hz, 1 H), 6.37 - 6.33 (m, 2 H), 6.22 (dt, 7= 13.5, 6.7 Hz, 1 H), 5.55 - 5.46 (m, 2 H), 5.40 - 5.32 (m, 2 H), 3.63 (t, 7= 6.5 Hz, 3 H), 3.57 (m, 1 H), 2.98 (t, 7= 6.7 Hz, 2 H), 2.60 (dt, 7= 12.4, 5.9 Hz, 1 H), 2.29 (dt, 7= 15.1, 9.0 Hz, 1 H), 2.09 - 2.04 (m, 4 H), 1.57 - 1.53 (m, 2 H), 1.43 - 1.38 (m, 2 H), 0.98 (t, 7= 7.8 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 197.49, 160.88, 144.32, 135.68, 135.42, 134.12, 132.62, 131.46, 125.81, 125.27, 124.60, 62.93, 43.70, 32.47, 31.15, 30.94, 27.19, 25.84, 20.71, 14.32 ppm; HR-MS (ESI-TOF): calcd for C ₂ oH ₂₈ 0 ₂ Na [M+Na] ⁺ : 323.1986, found: 323.1976.

13

[00179] (5Z,12£,14£,17Z)-ll-Oxoprosta-5,9,12,14,17-pentaen-l-oic acid (13): To a vigorously stirred solution of hydroxy trienone 67 (20 mg, 66 μιηοΐ, 1.0 equiv) in CH ₂ CI ₂ (2 mL) at 25 °C was added in one portion pyridinium chlorochromate (30 mg, 130 μηιοΐ, 2.0 equiv). After stirring for 2 h, the reaction mixture was directly, and without any further work-up, loaded onto a column. Flash column chromatography (S1O ₂ , hexanes:EtOAc, 7: 1→5: 1) gave the intermediate aldehyde, which was immediately used in the next reaction. To a vigorously stirred solution of the aldehyde in f-BuOH (1.5 mL) at 25 °C were sequentially added 2-methyl-2-butene (46 μί, 0.66 mmol, 10 equiv), a solution of NaH ₂ P0 ₄ (0.30 M in H2O, 0.33 mL, 0.10 mmol, 1.5 equiv) and a solution of NaC10 ₂ (80 % purity, 11 mg, 0.10 mmol, 1.5 equiv) in ¾0 (0.5 mL). After stirring for 30 min, the reaction mixture was diluted with a solution of NaH ₂ P04 (0.30 M, 4 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried (Na ₂ S0 ₄ ), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Purification by flash column chromatography (S1O ₂ , hexanes:EtOAc, 1:9) gave pure title compound (13, 14 mg, 44 μπιοΐ, 67 % yield for the two steps) as a colorless oil. 13: R _f = 0.60 (EtOAc); [o¾ ⁵ =+134.2 (c=0.40 in C ₆ ¾); IR (film): v _max = 3015, 2962, 2932, 1706, 1624, 1406, 1211, 997, 526 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.47 (dd, 7= 6.0, 2.4 Hz, 1 H), 6.96 (d, 7= 11.8 Hz, 1 H), 6.37 - 6.32 (m, 2 H), 6.22 (dt, 7= 13.5, 6.7 Hz, 1 H), 5.56 - 5.51 (m, 1 H), 5.48 - 5.43 (m, 1 H), 5.40 - 5.35 (m, 2 H), 3.60 - 3.57 (m, 1 H), 2.97 (t, 7=6.7 Hz, 2 H), 2.59 (dt, 7= 14.8, 5.8 Hz, 1 H), 2.34 - 2.27 (m, 3 H), 2.09 - 2.03 (m, 4 H), 1.68 (quint, 7=7.5 Hz, 2 H), 0.98 (t, 7=7.6 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 197.52, 178.35, 160.83, 144.49, 135.53, 135.49, 134.13, 131.60, 131.48, 126.16, 125.76, 124.58, 43.58, 33.26, 31.14, 30.84, 26.68, 24.55, 20.70, 14.31 ppm; HR-MS (ESI-TOF): calcd for C ₂ oH260 ₃ Na [M+Na] ⁺ : 337.1774, found: 337.1769.

[00180] Methyl (5Z,12£,14£',17Z)-ll-oxoprosta-5,9,12,14,17-pentaen-l-oate (14): To a stirred solution of 15-deoxy-A ^{12 14} -PGJ ₃ (13) (4.0 mg, 13 μηιοΐ, 1.0 equiv) in C ₆ H ₆ :MeOH (3:2, 0.5 mL) at 25 °C was dropwise added a solution of trimethylsilyl diazomethane (2.0 M in Et ₂ 0, 10 μί, 19 μηιοΐ, 1.5 equiv) (yellow color persists). After stirring for 30 min, the reaction mixture was concentrated under reduced pressure. Purification by flash column chromatography (S1O2, hexanes:EtOAc, 2: 1→3:2) gave pure title compound (14, 3.6 mg, 12 μιηοΐ, 90 % yield) as a colorless oil. 14: Rf = 0.53 (hexanes:EtOAc, 1 : 1); [a]j¾ ^{5 =} +189.2 (c = 0.70 in C ₆ H ₆ ); IR (film): v _mai = 3010, 2932, 1736, 1693, 1631, 1579, 1436, 1365, 1205, 983, 837, 728 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.47 (dd, 7= 6.0, 2.4 Hz, 1 H), 6.96 (d, 7= 11.8 Hz, 1 H), 6.37 - 6.32 (m, 2 H), 6.21 (dt, 7= 13.5, 6.7 Hz, 1 H), 5.56 - 5.51 (m, 1 H), 5.48 - 5.43 (m, 1 H), 5.40 - 5.35 (m, 2 H), 3.66 (s, 3 H), 3.59 - 3.56 (m, 1 H), 2.97 (t, 7= 6.7 Hz, 2 H), 2.59 (dt, 7= 14.8, 5.8 Hz, 1 H), 2.30 - 2.25 (m, 3 H), 2.09 - 2.01 (m, 4 H), 1.67 (quint, 7= 7.5 Hz, 2 H), 0.98 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 197.42, 174.01, 160.78, 144.40, 135.57, 135.47, 134.10, 131.63, 131.49, 126.03, 125.78, 124.59, 51.63, 43.62, 33.52, 31.14, 30.87, 26.79, 24.82, 20.70, 14.31 ppm; HR-MS (ESI-TOF): calcd for C2iH ₂ 80 ₃ Na [M+Na] ⁺ : 351.1931, found: 351.1923.

[00181] (5Z,12£',17Z)-l-[(4-Methoxybenzyl)oxy]prosta-5,9,12,17-tetr aen-ll-one (71):

71: R _f = 0.60 (hexanes:EtOAc, 3: 1); [a]^ ⁵ = +136.3 (c = 1.00 in C ₆ H ₆ ); IR (film): v _ma* = 3005, 2933, 2858, 1702, 1654, 1613, 1583, 1513, 1458, 1301, 1247, 1172, 1099, 1036, 820 cm ^"1 ; 'H-NMR (600 MHz, CDCI3) δ 7.47 (dd, 7= 6.0, 2.4 Hz, 1 H), 7.25 (d, 7= 8.6 Hz, 2 H), 6.87 (d, 7= 8.6 Hz, 2 H), 6.57 (t, 7= 7.5 Hz, 1 H), 6.32 (dd, 7= 6.0, 1.7 Hz, 1 H), 5.50 - 5.45 (m, 1 H), 5.43 - 5.38 (m, 1 H), 5.34 - 5.28 (m, 2 H), 4.42 (s, 2 H), 3.80 (s, 3 H), 3.49 - 3.46 (m, 1 H), 3.43 (t, 7= 6.6 Hz, 2 H), 2.59 - 2.54 (m, 1 H), 2.33 - 2.17 (m, 3 H), 2.09 (q, 7= 7.3 Hz, 2 H), 2.04 - 1.98 (m, 4 H), 1.61 - 1.53 (m, 4 H), 1.44 - 1.39 (m, 2 H), 0.95 (t, 7= 7.6 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 196.55, 161.73, 159.26, 137.83, 135.92, 135.04, 132.74, 132.62, 130.82, 129.34, 128.21, 125.19, 113.89, 72.70, 70.03, 55.41, 43.52, 30.49, 29.54, 28.90, 28.79, 27.29, 26.89, 26.31, 20.70, 14.45 ppm; HR-MS (ESI-TOF): calcd for C28H ₃ 80 ₃ Na [M+Na] ⁺ : 445.2725, found: 445.2728.

[00182] (5Z,12£',17Z)-ll-Oxoprosta-5,9,12,17-tetraen-l-oic acid (15): To a stirred solution of dienone 71 (20 mg, 47 μηιοΐ, 1.0 equiv) in MeCNiEhO (9:1, 0.4 rriL) at 25 °C was dropwise added 4-(acetylamino)-2,2,6,6-tetramethyl-l-oxo-piperidinium tetrafluoroborate 72 (85 mg, 280 μιηοΐ, 6.0 equiv). After stirring for 30 min, the reaction mixture was diluted with a solution of ¾0 (2 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (5 mL), dried (Na ₂ SO/ , filtered, and concentrated under reduced pressure to a volume of ca. 1 mL (not to dryness!). Purification by flash column chromatography (S1O ₂ , hexanes:EtOAc, 1:9) gave pure title compound (15, 6.9 mg, 21 μιηοΐ, 45 % yield) as a colorless oil. 15: Rf=0.40 (hexanes:EtOAc, 1 :9); [a] =+171.5 (c = 1.00 in C ₆ ¾); IR (film): v _ma x = 3007, 2961, 2932, 1704, 1652, 1579, 1479, 1237, 679 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.48 (dd, 7= 6.0, 2.4 Hz, 1 H), 6.58 (t, 7= 8.0 Hz, 1 H), 6.34 (dd, 7=6.0, 1.8 Hz, 1 H), 5.48 - 5.43 (m, 1 H), 5.42 - 5.34 (m, 1 H), 5.32 - 5.27 (m, 2 H), 3.51 - 3.48 (m, 1 H), 2.57 (dt, 7= 14.6, 5.5 Hz, 1 H), 2.33 (t, 7= 7.6 Hz, 2 H), 2.31 - 2.19 (m, 3 H), 2.10 - 1.99 (m, 6 H), 1.68 (quint, 7= 7.6 Hz, 2 H), 1.56 (quint, 7= 7.6 Hz, 2 H), 0.94 (t, 7=7.6 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.94, 179.19, 161.68, 137.69, 136.20, 135.10, 132.74, 131.36, 128.17, 126.19, 43.37, 33.40, 30.38, 28.89, 28.74, 26.84, 26.68, 24.50, 20.68, 14.42 ppm; HR-MS (ESI-TOF): calcd for C ₂ oH ₂ 80 ₃ Na [M+Na] ⁺ : 339.1931, found: 339.1937.

16

[00183] Methyl (5Z,12£,17Z)-ll-oxoprosta-5,9,12,17-tetraen-l-oate (16): To a stirred solution of 15-deoxy A ¹² -PGJ ₃ (15) (3.3 mg, 10 μηιοΐ, 1.0 equiv) in C ₆ H ₆ :MeOH (3:2, 0.5 mL) at 25 °C was dropwise added a solution of trimethylsilyl diazomethane (2.0 M in Et20, 10 μί, 20 μπιοΐ, 2.0 equiv) (yellow color persists). After stirring for 30 min, the reaction mixture was concentrated under reduced pressure. Purification by flash column chromatography (S1O ₂ , hexanes:EtOAc, 6:1→3:2) gave pure title compound (16, 3.0 mg, 9.0 μπιοΐ, 90 % yield) as a colorless oil. 16: Rf = 0.53 (hexanes:EtOAc, 1 : 1); [a]j¾ ⁵ = +162.5 (c = 0.40 in C6H ₆ ); IR (film): v _m « = 3006, 1932, 1737, 1702, 1654, 1581, 1436, 1365, 1215, 1173, 517 cm- ¹ ; >H-NMR (600 MHz, CDCb) 57.46 (dd, 7=6.0, 2.4 Hz, 1 H), 6.56 (t, 7= 8.0 Hz, 1 H), 6.31 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.46 - 5.42 (m, 1 H), 5.41 - 5.27 (m, 3 H), 3.64 (s, 3 H), 3.50 - 3.47 (m, 1 H), 2.56 (dt, 7= 15.1, 5.8 Hz, 1 H), 2.31 - 2.18 (m, 5 H), 2.08 (q, 7= 7.4 Hz, 2 H), 2.04 - 1.98 (m, 4 H), 1.68 (quint, 7=7.6 Hz, 2 H), 1.57 (quint, 7= 7.6 Hz, 2 H), 0.93 (t, 7= 7.6 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 196.73, 173.94, 161.51, 137.69, 135.93, 135.09, 132.70, 131.48, 128.16, 126.02, 51.59, 43.36, 34.46, 30.37, 28.85, 28.74, 26.83, 26.76, 24.75, 20.66, 14.40 ppm; HR-MS (ESI- TOF): calcd for C ₂ iH ₃ o0 ₃ Na [M+Na] ⁺ : 353.2087, found: 353.2094.

[00184] (4S,5£)-4-{(2Z)-7-[(4-Methoxybenzyl)oxy]hept-2-en-l-yl}-5- propylidenecyclopent-2-en-l-one (75): 75: R _f =0.68 (hexanes:EtOAc, 3: 1); [a = +141.2 (c= 1.00 in

C ₆ ¾); IR (film): v _max = 2934, 2857, 1702, 1655, 1613, 1513, 1460, 1301, 1247, 1099, 1034, 811 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 7.47 (dd, 7=6.2, 2.7 Hz, 1 H), 7.25 (d, 7= 8.6 Hz, 2 H), 6.87 (d, 7= 8.6 Hz, 2 H), 6.54 (t, 7=7.9 Hz, 1 H), 6.32 (dd, 7=6.0, 1.6 Hz, 1 H), 5.50 - 5.45 (m, 1 H), 5.34 - 5.30 (m, 1 H), 4.42 (s, 2 H), 3.80 (s, 3 H), 3.50 - 3.47 (m, 1 H), 3.43 (t, 7= 6.5 Hz, 2 H), 2.56 (dt, 7= 14.2, 5.0 Hz, 1 H), 2.33 - 2.25 (m, 2 H), 2.21 (dt, 7= 14.8, 8.3 Hz, 1 H), 2.00 (q, 7=7.0 Hz, 2 H), 1.59 (quint, 7= 7.6 Hz, 2 H), 1.41 (quint, 7= 7.6 Hz, 2 H), 1.11 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 197.00, 161.70, 159.25, 137.47, 137.09, 135.03, 132.59, 130.81, 129.33, 125.20, 113.88, 72.69, 70.01, 55.40, 43.45, 30.50, 29.52, 27.27, 26.29, 22.75, 13.27 ppm; HR-MS (ESI-TOF): calcd for C ₂ 3H ₃ o0 ₃ Na [M+Na] ⁺ : 377.2087, found: 377.2098.

[00185] (5Z)-7-[(lS,5£')-4-Oxo-5-propylidenecyclopent-2-en-l-yl]hep t-5-enoic acid (17): To a stirred solution of dienone 75 (10 mg, 30 μπΐοΐ, 1.0 equiv) in MeCN:H ₂ 0 (9:1, 0.4 mL) at 25 °C was dropwise added 4-(acetylamino)-2,2,6,6-tetramethyl-l-oxo-piperidinium tetrafluoroborate 72 (54 mg, 15 μηιοΐ, 6.0 equiv). After stirring for 30 min, the reaction mixture was diluted with H ₂ 0 (2 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (5 mL), dried (Na ₂ S04), filtered, and concentrated under reduced pressure to a volume of ca. 1 mL (not to dryness!). Purification by flash column chromatography (Si0 ₂ , hexanes:EtOAc, 1 :9) gave pure title compound (17, 4.2 mg, 17 μπιοΐ, 57 % yield) as a colorless oil. 17: Rf= 0.40 (hexanes:EtOAc, 1: 10); [αβ ⁵ =+142.5 (c= 1.00 in C ₆ ¾); IR (film): v _max = 3010, 2966, 2934, 2874, 1728, 1700, 1641, 1578,

1215, 1150, 810 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 7.47 (dd, 7=6.2, 2.7 Hz, 1 H), 6.55 (t, 7= 7.9 Hz, 1 H), 6.33 (dd, 7= 6.0, 1.6 Hz, 1 H), 5.47 - 5.43 (m, 1 H), 5.38 - 5.34 (m, 1 H), 3.52 - 3.49 (m, 1 H), 2.57 (dt, 7= 14.2, 5.3 Hz, 1 H), 2.33 (t, 7=7.6 Hz, 2 H), 2.32 - 2.26 (m, 2 H), 2.22 (dt, 7= 15.2, 8.3 Hz, 1 H), 2.05 (q, 7= 7.0 Hz, 2 H), 1.68 (quint, 7= 7.6 Hz, 2 H), 1.10 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.94, 174.00, 161.54, 137.56, 136.99, 135.14, 131.50, 126.08, 43.34, 33.50, 30.42, 26.78, 24.78, 22.76, 13.27 ppm; HR-MS (ESI-TOF): calcd for Ci ₅ H ₂ o0 ₃ Na [M+Na] ⁺ : 271.1305, found: 271.1304.

[00186] Methyl (5Z)-7-[(lS,5£')-4-oxo-5-propylidenecyclopent-2-en-l-yl]hep t-5- enoate (18): To a stirred solution of compound 17 (10 mg, 40 μιηοΐ, 1.0 equiv) in C6¾:MeOH (3:2, 0.5 mL) at 25 °C was dropwise added a solution of trimefhylsilyl diazomethane (2.0 M in Et20, 30 μί, όθ μηιοΐ, 1.5 equiv) (yellow color persists). After stirring for 30 min, the reaction mixture was concentrated under reduced pressure. Purification by flash column chromatography (S1O ₂ , hexanes:EtOAc, 2:l→3:2) gave pure title compound (18, 9.0 mg, 36 μιηοΐ, 90 % yield) as a colorless oil. 18: R _f = 0.53 (hexanes:EtOAc, 1 :1); [a]fi = +168.3 (c = 0.30 in C ₆ H ₆ ); IR (film): Vmax = 3009, 2950, 2874, 1736, 1702, 1654, 1580, 1436, 1212, 1151, 809 cm ^"1 ; Ή-NMR (600 MHz, CDCh) δ 7.48 (dd, 7= 6.2, 2.7 Hz, 1 H), 6.55 (t, 7= 7.9 Hz, 1 H), 6.33 (dd, 7= 6.0, 1.6 Hz, 1 H), 5.47 - 5.43 (m, 1 H), 5.38 - 5.34 (m, 1 H), 3.66 (s, 3 H), 3.52 - 3.49 (m, 1 H), 2.57 (dt, 7= 14.2, 5.3 Hz, 1 H), 2.33 - 2.26 (m, 4 H), 2.22 (dt, 7= 15.2, 8.3 Hz, 1 H), 2.03 (q, 7= 7.5 Hz, 2 H), 1.67 (quint, 7= 7.6 Hz, 2 H), 1.11 (t, 7=7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.93, 173.99, 161.53, 137.55, 136.98, 135.13, 131.50, 126.07, 51.64, 43.35, 33.50, 30.43, 26.79, 24.78, 22.77, 13.27 ppm; HR-MS (ESI-TOF): calcd for CieHaOsNa [M+Na] ⁺ : 285.1461, found: 285.1472.

[00187] teri-Butyl(dimethyl)({(3S,5Z)-8,8,8-trifluoro-l-[(4-methoxyb enzyl)oxy]oct-5- en-3-yl}oxy)-silane (78): 78: R _f =0.60 (hexanes:EtOAc, 10: 1); [a]^ = + 13.5 (c= 1.00, C ₆ H ₆ ); IR (film): v _max = 3092, 2953, 2935, 2858, 1613, 1514, 1251, 1033, 836, 677 cm ^"1 ; 'H-NMR (600 MHz, CDCh) δ 7.25 (d, 7= 8.5 Hz, 2 H), 6.88 (d, 7= 8.5 Hz, 2 H), 5.79 - 5.75 (m, 1 H), 5.49 - 5.44 (m, 1 H), 4.44 (d, 7= 11.4 Hz, 1 H), 4.38 (d, 7= 11.4 Hz, 1 H), 3.91 (dt, 7= 7.1, 5.4 Hz, 1 H), 3.80 (s, 3 H), 3.49 (t, 7= 6.9 Hz, 2 H), 2.83 - 2.77 (m, 2 H), 2.22 (t, 7=6.9 Hz, 2 H), 1.77 - 1.65 (m, 2 H), 0.88 (s, 9 H) 0.04 (s, 6 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 159.26, 132.61, 130.64, 129.40, 126.25 (q, 7= 276.4 Hz), 118.65 (q, 7= 3.5 Hz), 113.86, 72.77, 68.86, 66.64, 55.36, 36.95, 35.62, 32.52 (q, 7= 32.5 Hz), 25.92, 18.12, -4.34, -4.66 ppm; HR-MS (ESI-TOF): calcd for C22H ₃ 5F ₃ 03Si [M+Na] ⁺ : 455.2200, found: 455.2198. OTBS 79

[00188] (3S,5Z)-3-{[^-Butyl(dimethyl)silyl]oxy}-8,8,8-trifluorooct-5 -en-l-ol (79):

79: R _f = 0.47 (hexanes:EtOAc, 7:3); [αβ ⁵ =+17.9 (c= 1.0, CHCI3); FT-IR (neat): v _max = 2952, 2935, 2860, 1473, 1347, 1253, 1138, 1070, 836, 775 cm ^"1 ; Ή-NMR (600 MHz, CDC ) 55.78 - 5.68 (m, 1 H), 5.53 - 5.46 (m, 1 H), 4.03 - 3.94 (m, 1 H), 3.84 - 3.77 (m, 1 H), 3.75 - 3.69 (m, 1 H), 2.92 - 2.77 (m, 2 H), 2.30 (t, 7= 7.0 Hz, 2 H), 2.11 (br s, 1 H), 1.82 - 1.73 (m, 1 H), 1.69 - 1.61 (m, 1 H), 0.89 (s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 132.22, 126.20 (q, 7= 276.6 Hz), 119.09 (q, 7= 3.5 Hz), 70.81, 60.17, 38.10, 35.23, 32.60 (q, 7= 32.5 Hz), 25.92, 18.09, -4.31, -4.68 ppm; HR-MS (ESI) calcd for C14H28O2F3S1 [M+H] ⁺ : 313.1805, found: 313.1793.

[00189] (3S,5Z)-3-{[^rt-Butyl(dimethyl)silyl]oxy}-8,8,8-trifluorooct -5-enal (80): 80:

Rf= 0.66 (hexanes:EtOAc, 8:2); [a]j¾ ⁵ =+13.7 (c = 1.6, CHCI3); FT-IR (neat): v _max = 2956, 2931, 2859, 1726, 1473, 1348, 1252, 1135, 1102, 1085, 835, 776 cm ^"1 ; 'H-NMR (600 MHz, CDCI3) 59.78 (t, 7= 2.1 Hz, 1 H), 5.78 - 5.70 (m, 1 H), 5.56 - 5.51 (m, 1 H), 4.27 (quint, 7 = 6.1 Hz, 1 H), 2.88 - 2.79 (m, 2 H), 2.55 - 2.50 (m, 2 H), 2.36 - 2.27 (m, 2 H), 0.86 (s, 9 H), 0.07 (s, 3 H), 0.05 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) 8201.62, 131.54, 126.14 (q, 7=276.5 Hz), 119.86 (q, 7= 3.5 Hz), 67.47, 50.63, 35.69, 32.55 (q, 7= 32.5 Hz), 25.81, 18.06, -4.40, -4.74 ppm; HR-MS (ESI) calcd for Ci4H ₂ 5F ₃ 02SiNa [M+Na] ⁺ : 333.1468, found: 333.1463.

[00190] (5Z,12£,15S,17Z)-15-{[iert-Butyl(dimethyl)silyl]oxy}-20,20, 20-trifluoro-l-[(4- methoxy-benzyl)oxy]prosta-5,9,12,17-tetraen-ll-one (82): 82: Rf= 0.50 (hexanes:EtOAc, 2:1); [αβ ⁵ =+103.4 (c= 1.0, CHC1 ₃ ); FT-IR (neat): v _ma* = 2930, 2856, 1704, 1656, 1613, 1584, 1513, 1463, 1249, 1132, 1095, 836, 776 cm ^"1 ; ¹ H-NMR (600 MHz, CDCI3) 57.49 (ddd, 7= 6.0, 2.7, 1.0 Hz, 1 H), 7.25 (d, 7=9.0 Hz, 2 H), 6.87 (d, 7= 8.6 Hz, 2 H), 6.56 (t, 7= 7.8 Hz, 1 H), 6.33 - 6.31 (m, 1 H), 5.80 - 5.76 (m, 1 H), 5.53 - 5.46 (m, 2 H), 5.34 - 5.30 (m, 1 H), 4.42 (s, 2 H), 3.93 (quint, 7=5.9 Hz, 1 H), 3.80 (s, 3 H), 3.42 (t, 7= 6.5 Hz, 3 H), 2.88 - 2.74 (m, 2 H), 2.60 - 2.56 (m, 1 H), 2.47 - 2.38 (m, 2 H), 2.30 - 2.22 (m, 2 H), 2.21 - 2.12 (m, 1 H), 2.03 - 1.95 (m, 2 H), 1.62 - 1.54 (m, 2 H), 1.41 (quint, 7= 7.6 Hz, 2 H), 0.87 (s, 9 H), 0.05 (s, 6 H) ppm; ¹³ C-NMR (151 MHz, CDCI ₃ ) 5 196.35, 161.87, 159.22, 139.20, 134.93, 134.07, 132.70, 132.09, 131.68, 129.34, 126.21 (q, 7= 276.8 Hz), 125.13, 119.33 (q, 7= 3.5 Hz), 113.86, 72.68, 70.97, 70.01, 55.39, 43.48, 37.03, 35.38, 32.60 (q, 7= 32.6 Hz), 30.66, 29.54, 27.30, 26.31, 25.91, 18.14, -4.42, -4.51 ppm; HR-MS (ESI) calcd for CsA^sSiNa [M+Na] ⁺ : 629.3244, found: 629.3240.

[00191] (5Z,12£,15S,17Z)-15-{[tert-Butyl(dimethyl)silyl]oxy}-20,20, 20-trifluoro-l- hydroxyprosta-5,9,12,17-tetraen-ll-one (83): 83: R _f = 0.13 (hexanes:EtOAc, 2: 1); [αβ ⁵ = +111.4 (c = 1.02, CHC1 ₃ ); FT-IR (neat): v _ma * = 3444, 2930, 2858, 1702, 1654, 1580, 1463, 1347, 1253, 1200, 1135, 1083, 837, 776 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) 87.50 (dd, 7= 5.5, 2.7 Hz, 1 H), 6.56 (t, 7= 7.8 Hz, 1 H), 6.33 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.80 - 5.76 (m, 1 H), 5.53 - 5.48 (m, 2 H), 5.37 - 5.32 (m, 1 H), 3.96 - 3.92 (m, 1 H), 3.64 (t, 7 = 6.5 Hz, 2 H), 3.45 - 3.43 (m, 1 H), 2.89 - 2.74 (m, 2 H), 2.63 - 2.58 (m, 1 H), 2.48 - 2.39 (m, 2 H), 2.29 - 2.14 (m, 3 H), 2.04 - 2.00 (m, 2 H), 1.59 - 1.54 (m, 2 H), 1.45 - 1.39 (m, 2 H), 0.88 (s, 9 H), 0.06 (s, 6 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.30, 161.72, 139.20, 134.93, 132.55, 132.03, 131.65, 126.29 (q, 7= 276.3 Hz), 125.25, 119.35 (q, 7= 3.4 Hz), 70.99, 62.82, 43.47, 37.03, 35.36, 32.56 (q, 7= 32.6 Hz), 32.40, 30.67, 27.18, 25.90, 25.79, 18.11, -4.43, -4.53 ppm; HR-MS (ESI) calcd for 9, found: 509.2661.

[00192] (5Z,12£',15S,17Z)-15-{[iert-Butyl(dimethyl)silyl]oxy}-20,20 ,20-trifluoro-ll- oxoprosta-5,9,12,17-tetraen-l-oic acid (85): 85: R _f = 0.40 (CH ₂ Cl ₂ :EtOH, 19: 1); [αβ = +110.0 (c = 1.07, CHCI3); FT-IR (neat): v _ma* = 3013, 2954, 2929, 2857, 1705, 1654, 1462, 1360, 1251, 1134, 1082, 836, 775 cm ^"1 ; 'H-NMR (600 MHz, CDC1 ₃ ) 57.50 (dd, 7= 6.5, 2.7 Hz, 1 H), 6.57 (t, 7 = 7.8 Hz,

1 H), 6.34 (dd, 7 = 6.0, 1.9 Hz, 1 H), 5.79 - 5.75 (m, 1 H), 5.53 - 5.45 (m, 2 H), 5.40 - 5.36 (m, 1 H), 3.97 - 3.93 (m, 1 H), 3.45 - 3.43 (m, 1 H), 2.89 - 2.74 (m, 2 H), 2.63 - 2.59 (m, 1 H), 2.48 - 2.39 (m,

2 H), 2.34 (t, 7 = 7.3 Hz, 2 H), 2.30 - 2.21 (m, 2 H), 2.19 - 2.14 (m, 1 H), 2.08 - 2.04 (m, 2 H), 1.68 (quint, 7= 7.0 Hz, 2 H), 0.88 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI ₃ )

5 196.31, 178.61, 161.68, 139.10, 135.00, 132.00, 131.81, 131.43, 126.17, 126.11 (q, 7= 279.1 Hz), 119.38 (q, 7= 3.5 Hz), 71.04, 43.42, 37.04, 35.37, 33.30, 32.58 (q, 7= 32.6 Hz), 30.60, 26.69, 25.90, 24.53, 18.15, -4.44, -4.52 ppm; HR-MS (ESI) calcd for CzeHs^FsSiNa [M+Na] ⁺ : 523.2462, found: 523.2444.

[00193] (5Z,12£,15S,17Z)-20,20,20-Trifluoro-15-hydroxy-ll-oxoprosta -5,9,12,17- tetraen-l-oic acid (19): To a stirred solution of A ¹² -PGJ ₃ -15-f-butyldimethylsilyl-ether CF ₃ analog (85) (60 mg, 120 μπιοΐ, 1.0 equiv) in MeCN (0.8 mL) at 0 °C was dropwise added a solution of HF (50 % aq., 440 ,uL, ca. 12.0 mmol, ca. 100 equiv) in MeCN (0.8 mL). After stirring at this temperature for 45 min, the reaction was quenched by the addition of sat. brine (5 mL) and extracted with EtOAc (5 X 5 mL). The combined organic extracts were dried (Na2S04), filtered, and concentrated. Flash column chromatography (Si0 ₂ , CThC^EtOH, 20: 1→15: 1) yielded pure title compound (19, 39 mg, 110 pmol, 90 % yield) as a colorless oil. 19: R _f = 0.24 (CH ₂ Cl ₂ :MeOH, 19: 1); [a¾ ⁵ = +89.8 (c = 1.05, CHCI3); FT- IR (neat): Vmax = 3423, 2942, 1701, 1646, 1581, 1429, 1344, 1251, 1136, 1059, 916, 834 cm ^"1 ; Ή-NMR (500 MHz, CDCI3) 57.57 (ddd, 7 = 6.0, 2.6, 1.1 Hz, 1 H), 6.57 (t, 7= 7.8, 1 H), 6.34 (dd, 7= 6.0, 1.9 Hz, 1 H), 6.07 (t, 7 = 11.4 Hz, 1 H), 5.82 - 5.78 (m, 1 H), 5.62 - 5.58 (m, 1 H), 5.52 - 5.47 (m, 1 H), 5.45 - 5.40 (m, 1 H), 3.96 - 3.92 (m, 1 H), 3.48 - 3.45 (m, 1 H), 2.91 - 2.85 (m, 2 H), 2.73 - 2.64 (m, 1 H), 2.62 - 2.58 (m, 1 H), 2.52 - 2.46 (m, 1 H), 2.37 - 2.32 (m, 4 H), 2.15 - 2.08 (m, 3 H), 1.70 (quint, 7= 7.2 Hz, 2 H) ppm; ¹³ C-NMR (125 MHz, CDCI3) δ 196.40, 177.00, 161.91, 139.99, 134.97, 131.68, 131.52, 130.92, 126.08 (q, 7= 275.7 Hz), 126.07, 120.71 (q, 7= 3.5 Hz), 70.57, 43.73, 36.61, 34.82, 32.91, 32.43 (q, 7= 32.6 Hz), 30.53, 26.54, 24.51 ppm; HR-MS (ESI) calcd for C ₂ oH ₂ 50 ₄ F ₃ Na [M+Na] ⁺ : 409.1597, found: 409.1579.

[00194] Methyl (5Z,12£,15S,17Z)-20,20,20-trifluoro-15-hydroxy-ll-oxoprosta -

5,9,12,17-tetraen-l-oate (20): To a stirred solution of trifluoromethyl-A ¹² -PGJ3 analog (19) (10 mg, 26 pmol, 1.0 equiv) in C6He:MeOH (3:2, 1.0 mL) at 25 °C was added dropwise a solution of trimethylsilyl diazomethane (2 M in Et20, 20 pL, 40 pmol, 1.5 equiv) (yellow color persists). After stirring for 15 min, the reaction mixture was concentrated. Flash column chromatography (S1O ₂ , hexanes:EtOAc, 3: 1→3:2) yielded pure title compound (20, 6.1 mg, 15 pmol, 60 % yield) as a colorless oil. 20: R _f = 0.32 (hexanes: EtOAc, 2: 1), [a]^ ⁵ = +143.7 (c = 0.80, C ₆ H ₆ ), FT-IR (neat): _Vmas = 3445, 3011, 2930, 1735, 1720, 1700, 1651, 1580, 1437, 1349, 1252, 1135, 1065 cm ^"1 ; Ή-NMR (500 MHz, CDCI3) 87.52 (ddd, 7= 5.0, 2.6, 1.3 Hz, 1 H), 6.60 (t, 7= 7.8 Hz, 1 H), 6.35 (dd, 7= 6.1, 1.4 Hz, 1 H), 5.84 - 5.79 (m, 1 H), 5.62 - 5.57 (m, 1 H), 5.50 - 5.45 (m, 1 H), 5.38 - 5.33 (m, 1 H), 3.93 - 3.87 (m, 1 H), 3.66 (s, 3 H), 3.51 - 3.48 (m, 1 H), 2.93 - 2.83 (m, 1 H), 2.64 (dt, 7= 15.1, 5.7 Hz, 1 H), 2.54 (dt, 7= 14.4, 7.1 Hz, 1 H), 2.49 - 2.44 (m, 1 H), 2.33 - 2.17 (m, 5 H), 2.08 - 2.03 (m, 3 H), 1.70 - 1.65 (m, 2 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) 5 196.39, 174.22, 161.85, 139.79, 135.07, 133.75, 131.77, 131.19, 126.17 (q, 7= 276.3 Hz), 125.85, 120.48 (q, 7= 3.5 Hz), 70.31, 51.72, 43.44, 36.87, 35.19, 33.46, 32.62 (q, 7= 28.7 Hz), 30.40, 26.83, 24.76 ppm; HR-MS (ESI) calcd for C2iH ₂ 7F ₃ 0 ₄ Na [M+Na] ⁺ : 423.1754, found: 423.1738.

[00195] (5Z,12£,15S,17Z)-20,20,20-Trifluoro-l,15-epoxyprosta-5,9,12 ,17-tetraene- 1,11-dione (21): To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (25.0 mg, 72.5 μπιοΐ, 1.4 equiv) and 4-dimethylaminopyridine (37.9 mg, 311 μιηοΐ, 6.0 equiv) in CH2CI2 (20 mL) was added a solution of trifluoromethyl-A ¹² -PGJ ₃ analog (19) (20.0 mg, 51.8 μιηοΐ, 1.0 equiv) in CH2CI2 (10 mL) at 25 °C dropwise via syringe pump over 15 h. After stirring for an additional 2 h, the reaction mixture was washed sequentially with sat. aq. NaHC03-solution (5 mL), aq. HCl (0.2 M, 10 mL), and sat. brine (10 mL). The organic layer was dried (Na2SC>4), filtered, and concentrated. Flash column chromatography (S1O2, hexanes:EtOAc, 3: 1) yielded pure title compound (21, 11.6 mg, 31.6 μπιοΐ, 62 % yield) as a colorless oil. 21: R _f = 0.35 (hexanes:EtOAc, 7:3); [α ⁵ = +57.4 (c = 0.9 in C ₆ ¾); IR (film): v _max = 3008, 2921, 1729, 1704, 1657, 1581, 1536, 1456, 1349, 1238, 1151, 994 cm ^"1 ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 6.74 (dd, 7= 6.3, 2.6 Hz, 1 H), 6.56 - 6.51 (m, 1 H), 6.19 (dd, 7=6.0, 1.9 Hz, 1 H), 5.41 - 5.35 (m, 1 H), 5.32 - 5.26 (m, 1 H), 5.18 - 5.13 (m, 1 H), 5.08 - 5.02 (m, 1 H), 4.94 (dtd, 7= 9.1, 6.3, 2.6 Hz, 1 H), 3.17 - 3.15 (m, 1 H), 2.52 - 2.41 (m, 3 H), 2.35 - 2.21 (m, 2 H), 2.08 - 2.02 (m, 3 H), 1.96 - 1.91 (m, 2 H), 1.89 - 1.85 (m, 1 H), 1.80 - 1.74 (m, 1 H), 1.33 - 1.22 (m, 2 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) 5 194.69, 172.27, 159.69, 140.45, 135.61, 131.80, 130.91, 130.24, 126.60 (q, 7= 276.3 Hz), 125.29, 120.19 (q, 7= 3.5 Hz), 72.13, 43.13, 33.55, 32.67, 32.28 (q, 7= 29.6 Hz), 32.13, 28.39, 26.00, 24.54 ppm; HR-MS (ESI-TOF): calcd for C2oH230 ₃ F ₃ Na [M+Na] ⁺ : 391.1491, found: 391.1492.

[00196] (3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}oct-5-yn-l-ol (87): 87: R _f =0.50 (hexanes:EtOAc, 4: 1); [ο¾ ⁵ = +26.7 (c= 1.0, CHC1 ₃ ); FT-IR (neat): v _max = 3362, 2949, 2929, 2857, 1472, 1462, 1254, 1095, 1063, 1021, 834, 775 cm ^"1 ; Ή-NMR (500 MHz, CDCI3) 54.01 (dddd, 7= 7.7, 6.6, 5.4, 3.9 Hz, 1 H), 3.83 (ddd, 7= 10.8, 8.3, 4.3 Hz, 1 H), 3.73 (ddd, 7= 10.8, 5.9, 4.9 Hz, 1 H), 2.41 - 2.30 (m, 3 H), 2.17 - 2.11 (m, 2 H), 1.95 (dddd, 7= 14.2, 8.4, 4.9, 3.8 Hz, 1 H), 1.78 (dddd, 7= 14.2, 6.7, 5.8, 4.3 Hz, 1 H), 1.09 (t, 7=7.6 Hz, 3 H), 0.88 (s, 9 H), 0.10 (s, 6 H) ppm; ¹³ C-NMR (125 MHz, CDCls) 583.96, 75.96, 71.03, 60.18, 37.80, 27.41, 25.89, 18.09, 14.28, 12.55, -4.42, -4.75 ppm; HR-MS (ESI) calcd for C14H29O2S1 [M+H] ⁺ : 257.1931, found: 257.1925.

[00197] (3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}oct-5-ynal (88): 88: R _f =0.60

(hexanes:EtOAc, 4: 1), [a]j¾ ⁵ = +22.7 (c= 1.0, CHC1 ₃ ), FT-IR (neat): v _max = 2955, 2930, 2857, 1726, 1472, 1463, 1253, 1101, 1004, 835, 775 cm ^"1 ; 'H-NMR (500 MHz, CDC1 ₃ ) 59.81 (dd, 7= 2.8, 1.9 Hz, 1 H), 4.29 (dddd, 7= 8.0, 7.2, 5.0, 4.4 Hz, 1 H), 2.72 (ddd, 7= 16.0, 4.4, 1.9 Hz, 1 H), 2.61 (ddd, 7= 16.0, 7.2, 2.8 Hz, 1 H), 2.41 (ddt, 7= 16.4, 4.9, 2.4 Hz, 1 H), 2.32 (ddt, 7= 16.4, 8.0, 2.4 Hz, 1 H), 2.17 - 2.11 (m, 2 H), 1.10 (t, 7= 7.5 Hz, 3 H), 0.85 (s, 9 H), 0.09 (s, 3 H), 0.06 (s, 3 H) ppm; ¹³ C-NMR (125 MHz, CDCI3) 5201.88, 84.75, 75.32, 67.62, 50.57, 28.23, 25.82, 18.08, 14.19, 12.52, -4.37, -4.74 ppm; HR-MS (ESI) calcd for C14H27O2S1 [M+H] ⁺ : 255.1775, found: 255.1779.

90

[00198] (5Z,12£',15 i)-15-{[tert-Butyl(dimethyl)silyl]oxy}-l-[(4- methoxybenzyl)oxy]prosta-5,9,12-trien-17-yn-ll-one (90): 90: Rf= 0.65 (hexanes:EtOAc, 7:3); [a]j3 ⁵ =+97.1 (c = 0.86, CHC1 ₃ ), FT-IR (neat): v _ma* = 2929, 2855, 1704, 1656, 1613, 1512, 1246, 1095, 1036, 835, 776 cm ^"1 ; ¹ H-NMR (600 MHz, CDC1 ₃ ) 57.49 (ddd, 7=6.0, 2.6, 1.0 Hz, 1 H), 7.25 (d, 7= 8.6 Hz, 2 H), 6.87 (d, 7= 8.6 Hz, 2 H), 6.64 - 6.61 (m, 1 H), 6.31 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.51 - 5.45 (m, 1 H), 5.37 - 5.31 (m, 1 H), 4.42 (s, 2 H), 3.93 (tt, 7= 6.6, 5.3 Hz, 1 H), 3.80 (s, 3 H), 3.50 - 3.47 (m, 1 H), 3.42 (t, 7= 6.5 Hz, 2 H), 2.67 - 2.59 (m, 2 H), 2.50 (dt, 7= 14.6, 6.8 Hz, 1 H), 2.33 - 2.29 (m, 2 H), 2.21 - 2.11 (m, 3 H), 1.99 (q, 7= 7.6 Hz, 2 H), 1.61 - 1.56 (m, 2 H), 1.43 - 1.37 (m, 2 H), 1.09 (t, 7=7.6 Hz, 3 H), 0.87 (s, 9 H), 0.08 (s, 3 H), 0.05 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) 5 196.42, 161.86, 159.21, 139.20, 134.92, 132.55, 132.22, 130.78, 129.33, 125.38, 113.85, 84.15, 75.97, 72.68, 70.92, 70.02, 55.39, 43.49, 36.63, 30.73, 29.53, 27.96, 27.28, 26.32, 25.91, 18.18, 14.30, 12.56, -4.47, -4.56 ppm; HR-MS (ESI) calcd for C34H ₅₀ O ₄ SiNa [M+Na] ⁺ : 573.3371, found: 573.3344.

[00199] (5Z,12£',15«)-15-{[tert-Butyl(dimeth l)silyl]oxy}-l-hydrox prosta-5,9,12- trien-17-yn-ll-one (91): 91: R _f = 0.30 (hexanes: EtOAc, 7:3); [α ⁵ = +121.2 (c= 1.0, CHC1 ₃ ); FT-IR (neat): v = 3434, 2928, 2856, 1700, 1652, 1580, 1462, 1252, 1090, 967, 835, 775 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) 57.51 (ddd, 7= 6.0, 2.6, 1.0 Hz, 1 H), 6.62 (ddt, 7= 8.4, 7.1, 1.3 Hz, 1 H), 6.32 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.51 - 5.46 (m, 1 H), 5.38 - 5.33 (m, 1 H), 3.94 (tt, 7= 6.7, 5.4 Hz, 1 H), 3.63 (t, 7= 6.5 Hz, 2 H), 3.52 - 3.48 (m, 1 H), 2.69 - 2.60 (m, 2 H), 2.50 (dt, 7= 14.6, 6.8 Hz, 1 H), 2.33 - 2.29 (m, 2 H), 2.22 - 2.11 (m, 3 H), 2.02 (t, 7= 7.5 Hz, 2 H), 1.65 - 1.53 (m, 3 H), 1.44 - 1.38 (m, 2 H), 1.09 (t, 7= 7.5 Hz, 3 H), 0.87 (s, 9 H), 0.08 (s, 3 H), 0.05 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI ₃ ) δ 196.49, 161.88, 139.21, 134.95, 132.45, 132.31, 125.51, 84.19, 75.96, 70.93, 62.86, 43.52, 36.68, 32.44, 30.75, 27.97, 27.21, 25.92, 25.84, 18.20, 14.30, 12.57, -4.51, -4.55 ppm; HR-MS (ESI) calcd for C ₂ 6H ₄ 20 ₃ SiNa [M+Na] ⁺ : 453.2795, found: 453.2788.

93

[00200] (5Z,12£',15R)-15-{[tert-Butyl(dimethyl)silyl]oxy}-ll-oxopro sta-5,9,12-trien- 17-yn-l-oic acid (93): 93: R _f = 0.50 (CH ₂ Cl ₂ :EtOH, 19: 1); [αβ ⁵ = +122.8 (c = 1.0, CHC1 ₃ ); FT-IR (neat): v =2929, 2856, 1705, 1654, 1462, 1433, 1361, 1251, 1091, 836, 808, 776 cm ^"1 ; 'H-NMR (600 MHz, CDCI3) 57.50 (ddd, 7= 6.0, 2.6, 1.0 Hz, 1 H), 6.63 (ddt, 7= 8.3, 7.0, 1.2 Hz, 1 H), 6.34 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.49 - 5.37 (m, 2 H), 3.94 (quint, 7=6.0 Hz, 1 H), 3.52 - 3.48 (m, 1 H), 2.69 - 2.60 (m, 2 H), 2.51 (dt, 7= 14.7, 6.7 Hz, 1 H), 2.36 - 2.29 (m, 4 H), 2.21 - 2.11 (m, 3 H), 2.06 (q, 7= 7.5 Hz, 2 H), 1.71 - 1.65 (m, 2 H), 1.09 (t, 7=7.5 Hz, 3 H), 0.87 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H) ppm; ¹ C-NMR (151 MHz, CDC1 ₃ ) δ 196.48, 178.71, 161.77, 139.12, 135.04, 132.41, 131.35, 126.42, 84.23, 75.94, 71.00, 43.46, 36.67, 33.38, 30.69, 27.93, 26.70, 25.92, 24.58, 18.22, 14.29, 12.57, -4.48, -4.54 ppm; HR-MS (ESI) calcd for C ₂ 6H4o0 ₄ SiNa [M+Na] ⁺ : 467.2588, found: 467.2571.

22

[00201] (5Z,12£',15«)-15-Hydroxy-ll-oxoprosta-5,9,12-trien-17-yn-l -oic acid (22): To a stirred solution of TBS ether 93 (100 mg, 0.23 mmol, 1.0 equiv) in MeCN (2.0 mL) at 0 °C was added dropwise a solution of HF (50 % aq., 570 μί, ca. 23 mmol, ca. 100 equiv) in MeCN (0.2 mL). After stirring for 30 min, the reaction was quenched by addition of sat. brine (3 mL) and extracted with EtOAc (5 mL). The organic extract was dried (Na ₂ SC¼), filtered, and concentrated to a volume of ca. 0.5 mL (not to dryness!). Flash column chromatography (SiC% CH ₂ Cl ₂ :EtOH, 99: 1→97:3→95:5→93:7) yielded pure title compound (22, 56 mg, 0.17 mmol, 74 % yield) as a colorless oil. 22: R _f = 0.40 (CH ₂ Cl2:EtOH, 19: 1); [αβ ⁵ = +88.0 (c = 0.62, CHC1 ₃ ); FT-IR (neat): v _ma x = 3407, 2974, 2935, 1698, 1646, 1433, 1406, 1237, 1182, 1061, 1047 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) 57.55 (dd, J= 6.0, 2.5 Hz, 1 H), 6.57 (t, 7= 7.7 Hz, 1 H), 6.35 (d, 7= 6.0 Hz, 1 H), 5.51 - 5.47 (m, 1 H), 5.44 - 5.40 (m, 1 H), 3.95 (quint, 7= 6.3 Hz, 1 H), 3.52 - 3.48 (m, 1 H), 2.70 (dt, 7= 12.7, 5.9 Hz, 1 H), 2.65 - 2.54 (m, 2 H), 2.52 - 2.44 (m, 2 H), 2.40 - 2.33 (m, 3 H), 2.20 - 2.09 (m, 5 H), 1.72 - 1.67 (m, 2 H), 1.13 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.42, 177.01, 161.86, 139.93, 135.06, 131.67, 130.93, 126.18, 85.64, 74.58, 69.67, 43.72, 35.85, 33.05, 30.61, 27.22, 26.62, 24.62, 14.30, 12.57 ppm; HR-MS (ESI) calcd for C^C^Na [M+Na] ⁺ : 353.1723, found: 353.1729.

23

[00202] Methyl (5Z,12£,15/?)-15-hydroxy-ll-oxoprosta-5,9,12-trien-17-yn-l- oate (23): To a stirred solution of 17, 18-didehydro-A ¹² -PGJ ₃ (22) (2.0 mg, 6.1 μπιοΐ, l.O equiv) in CeH6:MeOH (3:2, 0.25 mL) at 25 °C was added dropwise a solution of trimethylsilyl diazomethane (2 M in Et ₂ 0, 6.0 μί, 12 μηιοΐ, 2.0 equiv) (yellow color persists). After stirring for 15 min, the reaction mixture was concentrated. Flash column chromatography (S1O2, hexanes:EtOAc, 3: 1→3:2) yielded the pure title compound (23, 1.8 mg, 5.2 μπιοΐ, 90 % yield) as a colorless oil. 23: R _f = 0.26 (hexanes:EtOAc, 2: 1); [a]5 ⁵ = +129.2 (c = 0.18, C ₆ H ₆ ); FT-IR (neat): v _max = 3444, 2922, 2852, 1735, 1699, 1651, 1580, 1436, 1367, 1209, 1176, 1068 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) 57.51 (dd, 7= 6.0, 2.6 Hz, 1 H), 6.61 (t, 7= 7.8 Hz, 1 H), 6.35 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.51 - 5.44 (m, 1 H), 5.36 (dtt, 7= 10.9, 8.2, 1.6 Hz, 1 H), 3.91 (dt, 7= 6.5, 5.3 Hz, 1 H), 3.67 (s, 3 H), 3.58 - 3.52 (m, 1 H), 2.65 - 2.61 (m, 1 H), 2.57 (dd, J = 7.8, 6.4 Hz, 2 H), 2.47 (ddt, 7= 16.5, 4.8, 2.4 Hz, 1 H), 2.35 (ddt, 7= 16.5, 6.2, 2.4 Hz, 1 H), 2.31 (t, 7= 7.3 Hz, 2 H), 2.28 - 2.21 (m, 2 H), 2.19 (qt, 7= 7.5, 2.4 Hz, 2 H), 2.05 (q, 7= 7.0 Hz, 1 H), 1.67 (quint, 7= 7.4 Hz, 2 H), 1.13 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) 5 196.39, 174.13, 161.78, 139.71, 135.09, 131.72, 131.16, 125.95, 85.50, 74.74, 69.44, 51.73, 43.41, 36.08, 33.50, 30.46, 27.51, 26.85, 24.81, 14.34, 12.58 ppm; HR-MS (ESI) calcd for C ₂ iH ₂ 80 ₄ N [M+Na] ⁺ : 367.1880, found: 367.1883.

[00203] (δΖ,Ι ^,Ιδ^-Ι,Ιδ-Ε ο ^ρΓθδΙα-δ^,Ι -Ιηεη-Π^ηε-Ι,ΙΙ-άϊοηε (24): To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (23 mg, 63 μηιοΐ, 1.4 equiv) and 4-dimethylaminopyridine (33 mg, 270 μπιοΐ, 6.0 equiv) in CH2CI2 (20 mL) was added a solution of 17,18-didehydro-A ¹² -PGJ ₃ (22) (15 mg, 45 μπιοΐ, 1.0 equiv) in CH2CI2 (10 mL) at 25 °C dropwise via syringe pump over 15 h. After stirring for an additional 2 h, the reaction mixture was washed sequentially with sat. aq. NaHC03-solution (10 mL), aq. HQ (0.2 M, 10 mL), and sat. brine (10 mL). The organic layer was dried (Na2S04), filtered, and concentrated under reduced pressure. Flash column chromatography (S1O2, hexanes:EtOAc, 3: 1) yielded pure title compound (24, 7.0 mg, 22 μηιοΐ, 50 % yield) as a colorless oil. 24: R _f = 0.40 (hexanes:EtOAc, 7:3); [α ⁵ = +42.5 (c = 0.7 in C ₆ H ₆ ); IR (film): v _ma* = 2924, 2855, 1726, 1703, 1655, 1581, 1535, 1457, 1440, 1348, 1252, 1132, 1084, 1057, 1018, 920, 804 cm ^"1 ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 6.72 (ddd, 7= 6.2, 2.6, 1.0 Hz, 1 H), 6.58 - 6.50 (m, 1 H), 6.19 (dd, 7= 6.1, 1.9 Hz, 1 H), 5.14 (tdd, 7= 10.9, 5.0, 1.6 Hz, 1 H), 5.05 (tdd, 7= 10.7, 4.9, 1.8 Hz, 1 H), 4.99 (dddd, 7=9.4, 6.9, 4.3, 2.8 Hz, 1 H), 3.18 - 3.12 (m, 1 H), 2.75 (ddd, 7= 14.7, 10.3, 4.6 Hz, 1 H), 2.62 (ddd, 7= 14.8, 12.0, 10.6 Hz, 1 H), 2.57 - 2.47 (m, 2 H), 2.25 (ddt, 7= 16.7, 4.6, 2.4 Hz, 1 H), 2.09 - 1.91 (m, 6 H), 1.77 - 1.67 (m, 1 H), 1.38 - 1.31 (m, 1 H), 1.25 - 1.18 (m, 1 H), 0.98 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 194.77, 172.12, 159.70, 140.34, 135.73, 131.96, 130.39, 125.13, 84.52, 74.93, 71.14, 42.92, 33.34, 32.67, 28.38, 25.94, 24.69, 24.52, 14.35, 12.74 ppm; HR-MS (ESI-TOF): calcd for C ₂ oH ₂₄ 0 ₃ Na [M+Na] ⁺ : 335.1618, found: 335.1615.

96 [00204] (3/?,4£')-3-{[tert-Butyl(dimethyl)silyl]oxy}-5-[3-(trifluor omethyl)phenyl]pent-

4-en-l-ol (96): 96 (c«-isomer): R _f = 0.46 (hexanes:EtOAc, 7:3); [αβ =+13.5 (c= U in C ₆ H ₆ ); IR (film): vmax = 3421, 3011, 2954, 2931, 2887, 2859, 1472, 1329, 1255, 1165, 1128, 1073, 1033, 837, 777 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.53 (d, 7= 7.8 Hz, 1 H), 7.48 - 7.45 (m, 2 H), 7.38 (d, 7= 7.6 Hz, 1 H), 6.46 (d, 7= 11.7 Hz, 1 H), 5.84 (dd, 7= 11.9, 9.1 Hz, 1 H), 4.86 - 4.82 (m, 1 H), 3.90 - 3.86 (m, 1 H), 3.81 - 3.79 (m, 1 H), 2.31 (t, 7= 5.0 Hz, 1 H), 1.95 - 1.86 (m, 2 H), 0.83 (s, 9 H), -0.07 (s, 3 H), -0.11 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 137.53, 137.23, 131.80, 130.85 (q, 7= 32.3 Hz), 128.89, 127.19, 125.41 (q, 7= 3.8 Hz), 124.11 (q, 7=276.3 Hz), 123.93 (q, 7= 3.5 Hz), 68.05, 60.30, 39.61, 25.80, 18.07, -4.28, -5.06 ppm; HR-MS (ESI-TOF): calcd for

[M+Na] ⁺ : 383.1634, found: 383.1634. 96 (trans -isomer): R _f =0.36 (hexanes:EtOAc, 7:3); [a]^ =+31.0 (c= 1.0 in C ₆ H6); IR (film): v _m ax = 3366, 3006, 2954, 2932, 2887, 2859, 1472, 1361, 1331, 1126, 1075, 1055, 1033, 835, 777 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.59 (s, 1 H), 7.53 (d, 7= 7.7 Hz, 1 H), 7.49 (d, 7=7.8 Hz, 1 H), 7.43 (t, 7=7.7 Hz, 1 H), 6.59 (d, 7= 15.9 Hz, 1 H), 6.30 (dd, 7= 15.9, 6.0 Hz, 1 H), 4.51 - 4.45 (m, 1 H), 3.88 - 3.84 (m, 1 H), 3.77 - 3.74 (m, 1 H), 2.34 (s, 1 H), 1.96 - 1.91 (m, 1 H), 1.86 - 1.80 (m, 1 H), 0.94 (s, 9 H), 0.13 (s, 3 H), 0.08 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 137.64, 134.31, 131.14 (q, 7= 32.3 Hz), 129.60, 129.14, 128.28, 124.18 (q, 7= 3.8 Hz), 124.18 (q, 7= 276.3 Hz), 123.10 (q, 7= 3.5 Hz), 72.53, 60.11, 39.65, 25.93, 18.24, -4.20, -4.86 ppm; HR-MS (ESI-TOF): calcd for C^vFsC^SiNa [M+Na] ⁺ : 383.1634, found: 383.1634.

[00205] (3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-5-[3-(trifluoromethy l)phenyl]pentan- l-ol (97): 97: R _f =0.36 (hexanes:EtOAc, 7:3); [αβ ⁵ =+1.8 (c = 0.8 in C ₆ H ₆ ); IR (film): v _max = 3366, 2953, 2931, 2859, 1463, 1361, 1256, 1163, 1073, 1033, 836, 775, 702 cm ^"1 ; 'H-NMR (600 MHz, CDCI ₃ ) δ 7.47 - 7.42 (m, 2 H), 7.40 (t, 7=7.6 Hz, 1 H), 7.36 (d, 7= 7.7 Hz, 1 H), 4.00 - 3.97 (m, 1 H), 3.87 - 3.82 (m, 1 H), 3.77 - 3.73 (m, 1 H), 2.75 - 2.66 (m, 2 H), 2.17 (t, 7= 5.1 Hz, 1 H), 1.89 - 1.84 (m, 3 H), 1.78 - 1.72 (m, 1 H), 0.92 (s, 9 H), 0.10 (s, 3 H), 0.09 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 143.16, 131.78, 130.83 (q, 7= 32.3 Hz), 128.91, 125.05 (q, 7= 3.8 Hz), 124.30 (q, 7= 276.3 Hz), 122.85 (q, 7= 3.5 Hz), 70.84, 60.12, 38.59, 38.14, 31.58, 25.92, 18.09, -4.36, -4.53 ppm; HR-MS (ESI-TOF): calcd for Ci8H ₃ oF ₃ 0 ₂ Si [M+H] ⁺ : 363.1963, found: 363.1958.

[00206] (3S)-3-{[ferf-Butyl(dimethyl)silyl]oxy}-5-[3- (trifluoromethyl)phenyl]pentanal (98): 98: R _f = 0.60 (hexanes:EtOAc, 4: 1); [αβ ⁵ = -2.2 (c = 3.7 in C ₆ H ₆ ); IR (neat): v _miK = 2954, 2931, 2859, 1726, 1450, 1328, 1254, 1163, 1073, 1033, 1005, 835, 775, 702 cm ^"1 ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 9.46 (t, 7= 2.0 Hz, 1 H), 7.38 (s, 1 H), 7.26 (d, 7=7.6 Hz, 1 H), 6.94 (dt, 7= 15.2, 7.7 Hz, 2 H), 3.91 (quint, 7= 5.7 Hz, 1 H), 2.42 - 2.30 (m, 2 H), 2.20 - 2.26 (m, 1 H), 2.02 - 1.98 (m, 1 H), 2.54 - 1.49 (m, 1 H), 1.02 - 0.99 (m, 1 H), 0.91 (m, 9 H), -0.02 (s, 6 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 199.70, 143.23, 131.92, 131.06 (q, 7= 32.3 Hz), 129.20, 125.30 (q, 7= 3.8 Hz), 125.09 (q, 7= 276.3 Hz), 123.10 (q, 7= 3.5 Hz), 67.48, 50.94, 39.32, 31.37, 25.97, 18.19, -4.47, -4.50 ppm; HR-MS (ESI-TOF): calcd for C18H28F3O2S1 [M+H] ⁺ : 361.1805, found: 361.1789.

[00207] (4S,5£)-5-{(3S)-3-{[icrt-Butyl(dimethyl)silyl]oxy}-5-[3- (trifluoromethyl)phenyl]pentylidene}-4-{(2Z)-7-[(4-methoxybe nzyl)oxy]hept-2-en-l- yl}cyclopent-2-en-l-one (100): 100: R _f = 0.53 (hexanes:EtOAc, 4: 1); [αβ ⁵ = +34.2 (c= 0.4 in C ₆ H ₆ ); IR (film): v _m ax = 3006, 2951, 2935, 2858, 1704, 1657, 1513, 1328, 1249, 1125, 1033, 836, 776 cm ^"1 ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 7.42 (s, 1 H), 7.26 - 7.24 (m, 3 H), 6.99 (d, J = 1.1 Hz, 1 H), 6.94 - 6.91 (m, 2 H), 6.84 - 6.78 (m, 3 H), 6.18 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.45 - 5.40 (m, 1 H), 5.24 - 5.20 (m, 1 H), 4.35 (s, 2 H), 3.67 - 3.63 (m, 1 H), 3.34 - 3.32 (s, 5 H), 3.14 - 3.12 (m, 1 H), 2.58 (ddd, 7= 13.7, 10.4, 6.1 Hz, 1 H), 2.45 - 2.33 (m, 3 H), 2.26 - 2.22 (m, 1 H), 2.07 (td, 7= 11.0, 7.2 Hz, 1 H), 1.98 - 1.90 (m, 2 H), 1.63 - 1.55 (m, 4 H), 1.45 - 1.40 (m, 2 H), 0.97 (s, 9 H), 0.07 (s, 3 H), 0.02 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 194.84, 160.43, 159.76, 143.51, 139.48, 135.23, 132.70, 131.97, 131.37, 130.98 (q, 7= 32.3 Hz), 130.95, 129.39, 129.24, 125.49, 125.34 (q, 7= 3.8 Hz), 125.09 (q, 7= 276.3 Hz), 123.04 (q, 7= 3.5 Hz), 114.13, 72.87, 71.28, 69.97, 54.82, 43.49, 39.14, 37.37, 31.62, 30.94, 29.96, 27.58, 26.75, 26.05, 18.29, -4.10, -4.47 ppm; HR-MS (ESI-TOF): calcd for [M+Na]: 679.3401, found: 679.3398.

[00208] (4S,5£)-5-{(3S)-3-{[tcrt-Butyl(dimethyl)silyl]oxy}-5-[3- (trifluoromethyl)phenyl]pentylidene}-4-[(2Z)-7-hydroxyhept-2 -en-l-yl]cyclopent-2-en-l-one (101): 101: R _f = 0.10 (hexanes:EtOAc, 4: 1); [a]¾ ⁵ = +126.1 (c = 0.7 in C ₆ H ₆ ); IR (film): v _m « = 3421, 2951, 2935, 2860, 1722, 1650, 1462, 1329, 1256, 1163, 1073, 1033, 836 cm ^"1 ; 'H-NMR (600 MHz, C ₆ D ₆ ) δ 7.43 (s, 1 H), 7.26 (d, 7= 7.7 Hz, 1 H), 7.02 (d, 7= 7.7 Hz, 1 H), 6.98 (dd, 7= 6.1, 2.5 Hz, 1 H), 6.95 (t, 7= 7.7 Hz, 1 H), 6.78 (t, 7= 7.8 Hz, 1 H), 6.20 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.43 - 5.39 (m, 1 H), 5.24 - 5.19 (m, 1 H), 3.70 - 3.66 (m, 1 H), 3.42 (t, 7= 6.3 Hz, 2 H), 3.14 - 3.12 (m, 1 H), 2.60 (ddd, 7= 13.7, 10.4, 6.1 Hz, 1 H), 2.43 (ddt, 7= 9.9, 7.3, 5.3 Hz, 2 H), 2.36 (dt, 7= 14.8, 6.3 Hz, 1 H), 2.26 (ddd, 7= 14.9, 8.5, 6.4 Hz, 1 H), 2.06 (dt, 7= 14.9, 8.5 Hz, 1 H), 1.96 - 1.84 (m, 2 H), 1.67 - 1.54 (m, 2 H), 1.44 - 1.39 (m, 2 H), 1.35 - 1.30 (m, 2 H), 0.96 (s, 9 H), 0.07 (s, 3 H), 0.02 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CeDe) δ 195.18, 160.76, 143.53, 139.49, 135.16, 132.75, 132.01, 131.21, 130.98 (q, 7= 32.3 Hz), 129.25, 125.41, 125.34 (q, 7= 3.8 Hz), 125.09 (q, 7= 276.3 Hz), 123.04 (q, 7= 3.9 Hz), 71.32, 62.40, 43.55, 39.15, 37.42, 32.70, 31.65, 30.90, 27.49, 26.22, 26.09, 18.30, -4.11, -4.47 ppm; HR-MS (ESI-TOF): calcd for CscftsFsOsSiNa [M+Na] ⁺ : 559.2826, found: 559.2819.

[00209] (5Z)-7-[(lS,5£)-5-{(3S)-3-{[tert-Butyl(dimethyl)sil l]oxy}-5-[3- (trifluoromethyl)phenyl]-pentylidene}-4-oxocyclopent-2-en-l- yl]hept-5-enoic acid (103): 103: +95.3 (c = 0.5 in C ₆ H ₆ ); IR (film): v _max = 3010, 2952, 2934, 2859, 1706, 1657, 1472, 1455, 1389, 1328, 1256, 1200, 1163, 1073, 1033, 836, 776 cm- ¹ ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 7.44 (s, 1 H), 7.26 (d, 7= 7.7 Hz, 1 H), 7.02 (d, .7=7.7 Hz, 1 H), 6.95 - 6.93 (m, 2 H), 6.79 (t, 7= 7.5 Hz, 1 H), 6.22 (dd, 7=6.0, 1.8 Hz, 1 H), 5.28 - 5.23 (m, 1 H), 5.22 - 5.17 (m, 1 H), 3.66 - 3.60 (m, 1 H), 3.12 - 3.09 (m, 1 H), 2.61 (ddd, 7= 13.8, 10.5, 6.0 Hz, 1 H), 2.45 - 2.33 (m, 3 H), 2.26 (ddd, 7= 14.9, 8.5, 6.5 Hz, 1 H), 2.08 (t, 7=7.2 Hz, 2 H), 2.01 (dt, 7= 14.1, 8.4 Hz, 1 H), 1.88 - 1.81 (m, 2 H), 1.67 - 1.56 (m, 2 H), 1.50 (quint, 7= 7.3 Hz, 2 H), 0.97 (s, 9 H), 0.08 (s, 3 H), 0.03 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 195.06, 178.54, 160.52, 143.49, 139.41, 135.22, 131.99, 131.46, 131.21, 130.98 (q, 7= 32.3 Hz), 129.24, 126.33, 125.36 (q, 7= 3.8 Hz), 125.09 (q, 7= 276.3 Hz), 123.06 (q, 7= 3.5 Hz), 71.43, 43.38, 39.13, 37.41, 33.21, 31.66, 30.82, 26.76, 26.08, 24.62, 18.31, -4.13, -4.49 ppm; HR-MS (ESI-TOF): calcd for C3oH4iF ₃ 0 ₄ SiNa [M+Na] ⁺ : 573.2618, found: 573.2617.

[00210] (5Z)-7-[(lS,5£)-5-{(3S)-3-Hydroxy-5-[3- (trifluoromethyl)phenyl]pentylidene}-4-oxocyclo-pent-2-en-l- yl]hept-5-enoic acid (25): To a stirred solution of 15-f-butyldimethylsilyl ether 103 (90 mg, 0.16 mmol, 1.0 equiv) in MeCN (1.5 mL) at 0 °C was dropwise added a solution of HF (50 % aq., 650 μί, ca. 16 mmol, ca. 100 equiv) in MeCN (1.5 mL). After stirring for 45 min at this temperature, the reaction mixture was quenched with sat. brine (10 mL) and extracted with EtOAc (5 x 50 mL). The combined organic extracts were dried (Na2SC»4), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Flash column chromatography (S1O ₂ , hexanes:EtOAc, 1:4) yielded pure title compound (25, 57 mg, 0.14 mmol, 84 % yield) as a colorless oil. 25: R _f =0.20 (hexanes: EtOAc, 1:4); [α ⁵ = +108.9 (c = 0.3 in C ₆ H ₆ ); IR (film): _Vmax = 3397, 3011 cm ^"1 ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 7.47 (s, 1 H), 7.27 (d, 7= 7.8 Hz, 1 H), 7.07 (d, 7= 7.7 Hz, 1 H), 7.00 (dd, 7= 5.9, 2.7 Hz, 1 H), 6.97 (t, 7= 7.6 Hz, 1 H), 6.77 (t, 7= 7.5 Hz, 1 H), 6.22 (dd, 7= 6.0, 1.7 Hz, 1 H), 5.33 - 5.26 (m, 1 H), 5.24 - 5.19 (m, 1 H), 3.63 - 3.58 (m, 1 H), 3.09 - 3.08 (m, 1 H), 2.75 - 2.70 (m, 1 H), 2.55 - 2.48 (m, 2 H), 2.36 (dt, 7= 14.9, 7.4 Hz, 1 H), 2.20 - 2.10 (m, 3 H), 1.94 (q, 7= 7.4 Hz, 3 H), 1.68 - 1.60 (m, 1 H), 1.59 - 1.47 (m, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 196.12, 177.58, 161.60, 143.46, 139.87, 135.02, 132.22, 132.06, 131.62, 130.92 (q, J = 323 Hz), 129.17, 126.49, 125.54 (q, 7= 3.8 Hz), 125.09 (q, 7= 276.3 Hz), 123.00 (q, 7= 3.5 Hz), 70.37, 43.74, 38.56, 37.74, 33.00, 32.00, 30.70, 26.63, 24.66 ppm; HR-MS (ESI-TOF): calcd for C24H27F ₃ 0 ₄ Na [M+Na] ⁺ : 459.1754, found: 459.1765.

[00211] Methyl (5Z)-7-[(lS,5E)-5-{(3S)-3-hydroxy-5-[3-

(trifluoromethyl)phenyl]pentylidene}-4-oxo-cyclopent-2-en -l-yl]hept-5-enoate (26): To a stirred solution of A ¹² -PGJ ₃ analog 25 (13 mg, 30 μιηοΐ, 1.0 equiv) in C ₆ H ₆ :MeOH (3:2, 2.0 mL) at 25 °C was dropwise added a solution of trimethylsilyl diazomethane (2 M in Et20, 30 μί, 60 μπιοΐ, 2.0 equiv) (yellow color persists). After stirring for 30 min, the reaction mixture was concentrated. Flash column chromatography (S1O ₂ , hexanes:EtOAc, 2: 1→3:2) yielded pure title compound (26, 12 mg, 26 μιηοΐ, 86 % yield) as a colorless oil. 26: R _f = 0.51 (hexanes:EtOAc, 1 : 1); [αβ ⁵ = +103.8 (c = 0.3 in C ₆ H ₆ ); IR (film): v _max = 3444, 3007, 2952, 2923, 1735, 1698, 1649, 1656, 1456, 1328 1121, 1072, 1015, 799 cm ^"1 ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 7.41 (s, 1 H), 7.26 (d, 7= 7.7 Hz, 1 H), 6.99 (d, 7= 7.7 Hz, 1 H), 6.94 - 6.92 (m, 2 H), 6.73 (t, 7= 7.5 Hz, 1 H), 6.20 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.27 (dt, 7= 10.8, 7.3 Hz, 1 H), 5.19 - 5.15 (m, 1 H), 3.38 - 3.33 (m, 4 H), 3.07 (ddt, 7= 8.2, 3.8, 1.9 Hz, 1 H), 2.61 (ddd, 7= 14.5, 9.7, 5.4 Hz, 1 H), 2.44 - 2.38 (m, 2 H), 2.19 (dt, 7= 14.9, 7.5 Hz, 1 H), 2.08 - 1.97 (m, 4 H), 1.87 - 1.84 (m, 2 H), 1.66 (d, 7= 1.7 Hz, 1 H), 1.54 - 1.43 (m, 4 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 195.13, 173.52, 160.59, 143.54, 139.77, 135.26, 132.16, 131.58, 131.29, 130.93 (q, 7= 32.6 Hz), 129.11, 126.23, 125.46 (q, 7= 3.8 Hz), 125.09 (q, 7= 276.3 Hz), 122.99 (q, 7= 3.8 Hz), 69.85, 51.13, 43.38, 38.77, 37.90, 33.24, 31.95, 30.55, 26.89, 24.92. ppm; HR-MS (ESI-TOF): calcd for C25H29F ₃ 0 ₄ Na [M+Na] ⁺ : 473.1910, found: 473.1908.

[00212] (1£,3S,9Z,1 la5)-3-{2- [3-(trifluoromethyl)phenyl]ethyl}-2,6,7,8,l 1,1 la- hexahydro-3H-cyclo-penta[c]oxacyclotridecine-5,14-dione (27): To a stirred solution of 2-mefhyl- 6-nitrobenzoic anhydride (12 mg, 34 μηιοΐ, 1.4 equiv) and 4-dimethylaminopyridine (11 mg, 93 μηιοΐ, 6.0 equiv) in CH ₂ CI ₂ (20 mL) was added a solution of A ¹² -PGJ ₃ analog 25 (10 mg, 23 μηιοΐ, 1.0 equiv) in CH2CI2 (10 mL) at 25 °C drop wise via syringe pump over 6 h. After stirring for an additional 12 h, the reaction mixture was washed sequentially with sat. aq. NaHC0 ₃ -solution (3 mL), a and sat. brine (3 mL). The organic layer was dried (Na ₂ S0 ₄ ), filtered, and concentrated. Rash column chromatography (S1O ₂ , hexanes:EtOAc, 3:2) yielded pure title compound (27, 6.1 mg, 14 μηιοΐ, 61 % yield) as a colorless oil. 27: R _f = 0.35 (hexanes:EtOAc, 3: 1); [ajg ⁵ = +33.0 (c = 0.4 in C ₆ ¾); IR (film): v _max = 3010, 2961, 2927, 2855, 1727, 1704, 1655, 1581, 1456, 1440, 1239, 1151, 1024 cm ^"1 ; 'H-NMR (600 MHz, C ₆ D ₆ ) δ 7.33 (s, 1 H), 7.26 (d, 7= 7.3 Hz, 1 H), 6.95 -6.90 (m, 2 H), 6.77 (dd, 7= 6.1, 2.6 Hz, 1 H), 6.59 (dd, 7= 11.4, 4.6 Hz, 1 H), 6.19 (dd, J = 6.0, 1.9 Hz, 1 H), 5.18 (td, 7= 10.3, 5.8 Hz, 1 H), 5.12 - 5.07 (m, 1 H), 5.06 - 5.01 (m, 1 H), 3.21 - 3.18 (m, 1 H), 2.40 (ddd, 7= 14.6, 9.3, 5.7 Hz, 1 H), 2.36 - 2.25 (m, 3 H), 2.17 (ddd, 7= 15.1, 11.4, 9.5 Hz, 1 H), 2.13 - 2.07 (m, 2 H), 1.97 - 1.89 (m, 2 H), 1.79 (dq, 7= 13.8, 6.8 Hz, 1 H), 1.67 - 1.60 (m, 1 H), 1.39 - 1.24 (m, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) 5 ¹³ C-NMR(151 MHz, C ₆ D ₆ ) 5 194.64, 172.44, 159.60, 142.61, 140.45, 135.59, 132.04, 131.79, 130.94 (q, 7= 32.6 Hz), 130.33, 129.19, 125.47, 125.46 (q, 7= 3.8 Hz), 125.09 (q, 7= 276.3 Hz), 122.96 (q, 7= 3.6 Hz), 72.52, 43.42, 35.63, 34.14, 32.66, 31.84, 28.40, 26.04, 24.56 ppm; HR-MS (ESI-TOF): calcd for C24H26F3O3 [M+H] ⁺ : 441.1648, found: 441.1634.

[00213] (3S)-l-[(4-Methoxybenzyl)oxy]-6-(trimethylsilyl)hex-5-yn-3-o l (105): 105:

R _f = 0.57 (hexanes:EtOAc, 7:3); [a]j¾ ⁵ = +4.4 (c= 1.0, C ₆ ¾); IR (film): v _m » = 3446, 2956, 2933, 2861, 2175, 1612, 1514, 1248, 1096, 1035, 842 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.26 - 7.22 (m, 2 H), 6.90 - 6.85 (m, 2 H), 4.45 (s, 2 H), 3.94 (dtd, 7= 9.2, 6.3, 3.1 Hz, 1 H), 3.80 (s, 3 H), 3.71 (ddd, 7= 9.3,

6.2, 4.5 Hz, 1 H), 3.63 (ddd, 7=9.4, 7.8, 4.3 Hz, 1 H), 2.49 - 2.37 (m, 2 H), 1.90 (dddd, 7= 14.0, 6.2,

4.3, 3.1 Hz, 1 H), 1.85 - 1.77 (m, 1 H), 1.14 (br s, 1 H), 0.15 (s, 9 H) ppm; ¹ C-NMR (151 MHz, CDCI ₃ ) δ 159.43, 130.13, 129.46, 114.00, 103.51, 87.21, 73.10, 69.71, 68.44, 55.42, 35.44, 28.72, 0.23 ppm; HR-MS (ESI-TOF): calcd for CnftvOaSi [M+H] ⁺ : 307.1724, found: 307.1722. [00214] (3S)-l-[(4-Methoxybenzyl)oxy]hex-5-yn-3-ol (106): 106: ft =0.34

(hexanes:EtOAc, 7:3); [αβ ⁵ = +8.0(c= 1.0, C ₆ H ₆ ); IR (film): v = 3426, 3291, 2920, 2861, 1612, 1513, 1247, 1174, 1085, 1033, 820 cm ^"1 ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 7.16 - 7.09 (m, 2 H), 6.79 - 6.74 (m, 2 H), 4.19 - 4.15 (m, 2 H), 3.88 (dtd, 7= 9.3, 6.2, 3.4 Hz, 1 H), 3.42 (ddd, 7= 9.3, 6.3, 4.7 Hz, 1 H), 3.32 (ddd, 7=9.3, 7.5, 4.7 Hz, 1 H), 3.30 (s, 3 H), 2.76 (s, 1 H), 2.28 (ddd, 7= 16.6, 5.8, 2.7 Hz, 1 H), 2.20 (ddd, 7= 16.6, 6.6, 2.7 Hz, 1 H), 1.76 - 1.66 (m, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 159.83, 130.67, 129.45, 114.16, 81.44, 73.00, 70.72, 69.52, 68.26, 54.80, 35.89, 27.61 ppm.

[00215] (3S,5Z,8Z)-l-[(4-Methoxybenzyl)oxy]undeca-5,8-dien-3-ol (109): 109: R _f = 0.54 (hexanes:EtOAc, 7:3); [a]j¾ ⁵ = +5.1 (c= 1.0, C ₆ ¾); IR (film): v _max = 3425, 3008, 2960, 2933, 2861, 1612, 1512, 1302, 1246, 1173, 1084, 1034, 820 cm ^"1 ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 7.15 (d, 7= 5.9 Hz, 2 H), 6.79 - 6.75 (m, 2 H), 5.55 - 5.47 (m, 2 H), 5.44 - 5.36 (m, 2 H), 4.25 - 4.21 (m, 2 H), 3.82 (dtt, 7= 9.1, 6.1, 3.0 Hz, 1 H), 3.49 (ddd, 7= 9.2, 6.2, 4.8 Hz, 1 H), 3.42 (s, 1 H), 3.40 (ddd, 7= 9.3, 7.7, 4.7 Hz, 1 H), 3.30 (s, 3 H), 2.80 (t, 7=5.5 Hz, 2 H), 2.64 (d, 7= 3.1 Hz, 1 H), 2.35 - 2.29 (m, 1 H), 2.22 (ddd, 7= 13.8, 6.2, 5.1 Hz, 1 H), 2.04 - 1.96 (m, 1 H), 1.69 (dddd, 7= 13.7, 8.8, 7.7, 4.8 Hz, 1 H), 1.62 (dddd, 7= 14.1, 6.2, 4.6, 3.0 Hz, 1 H), 0.90 (t, 7=7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 159.82, 132.09, 130.80, 130.62, 129.46, 127.58, 126.42, 114.17, 73.06, 70.82, 68.75, 54.80, 36.65, 35.96, 26.15, 20.95, 14.50 ppm; HR-MS (ESI-TOF): calcd for C19H29O3 [M+H] ⁺ : 305.2111, found: 305.2110.

[00216] ter<-Butyl({(3S,5Z,8Z)-l-[(4-methoxybenzyl)oxy]undeca-5,8 -dien-3- yl}oxy)dimethylsilane (110): 110: R _f = 0.43 (hexanes:Et ₂ 0, 19:1); [αβ ⁵ = +9.0 (c= 1.0, C ₆ H ₆ ); IR (film): v _max = 3009, 2955, 2930, 2930, 2856, 1742, 1613, 1513, 1248, 1093, 1039, 835, 774 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.26 - 7.25 (m, 2 H), 6.88 - 6.86 (m, 2 H), 5.46 - 5.35 (m, 3 H), 5.33 - 5.25 (m, 1 H), 4.44 (d, 7= 11.5 Hz, 1 H), 4.39 (d, 7= 11.4 Hz, 1 H), 3.91 - 3.84 (m, 1 H), 3.80 (s, 3 H), 3.54 - 3.48 (m, 2 H), 2.79 - 2.74 (m, 1 H), 2.29 - 2.18 (m, 2 H), 2.10 - 1.99 (m, 2 H), 1.78 (dtd, 7= 14.2, 7.2, 4.3 Hz, 1 H), 1.72 - 1.64 (m, 1 H), 1.37 - 1.23 (m, 1 H), 0.97 (t, 7= 7.5 Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm; ¹ C-NMR (151 MHz, CDC1 ₃ ) δ 159.25, 132.08, 130.83, 130.01, 129.42, 127.26, 125.85, 113.89, 72.76, 69.39, 67.00, 55.42, 36.94, 35.73, 26.03, 25.88, 20.71, 18.23, 14.42, -4.18, -4.59 ppm; HR-MS (ESI-TOF): calcd for C25H43O3S1 [M+H] ⁺ : 419.2976, found: 419.2974.

[00217] (3S,5Z,8Z)-3-{[iert-Butyl(dimethyl)silyl]ox }undeca-5,8-dien-l-ol (111): 111:

R _f = 0.40 (hexanes:EtOAc, 4: 1); [α ⁵ = +31.5 (c = 1.0, CHCI3); IR (film): v _ma x = 3350, 3011, 2956, 2929, 2857, 1472, 1463, 1361, 1254, 1091, 1067, 834, 774 cm ^"1 ; 'H-NMR (600 MHz, CDCI ₃ ) δ 5.47 - 5.34 (m, 3 H), 5.31 - 5.27 (m, 1 H), 3.98 - 3.94 (m, 1 H), 3.83 (ddd, 7 = 10.7, 8.3, 4.3 Hz, 1 H), 3.72 (dt, / = 10.7, 5.4 Hz, 1 H), 2.83 - 2.74 (m, 1 H), 2.36 - 2.28 (m, 2 H), 2.23 (br s, 1 H), 2.07 (quint, 7 = 7.5 Hz, 2 H), 1.81 (ddt, 7 = 14.2, 8.6, 4.3 Hz, 1 H), 1.65 (dtd, 7 = 14.2, 6.4, 4.3 Hz, 1 H), 0.97 (t, 7 = 7.5 Hz, 3 H), 0.90 (s, 9 H), 0.104 (s, 3 H), 0.097 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCh) δ 132.28, 130.46, 126.98, 125.36, 71.87, 60.49, 37.79, 35.11, 25.97, 25.90, 20.74, 18.13, 14.40, -4.21, -4.67 ppm; HR-MS (ESI-TOF): calcd for CnHs^Siff [M+H] ⁺ : 299.2401, found: 299.2410.

[00218] (3S,5Z,8Z)-3-{[tert-Butyl(dimethyl)silyl]oxy}undeca-5,8-dien al (112): 112:

Rf= 0.50 (hexanes:EtOAc, 9: 1); [α ⁵ = +23.7 (c = 1.0, CHCI3); IR (film): v _max = 3012, 2957, 2930, 2857, 1727, 1472, 1463, 1255, 1101, 836, 776 cm ^"1 ; ¹ H-NMR (600 MHz, CDCI3) δ 9.80 (br s, 1 H), 5.51 - 5.47 (m, 1 H), 5.42 - 5.36 (m, 2 H), 5.30 - 5.26 (m, 1 H), 4.25 (quint, 7 = 5.8 Hz, 1 H), 2.81 - 2.73 (m, 2 H), 2.54 - 2.49 (m, 2 H), 2.38 - 2.27 (m, 2 H), 2.06 (quint, J = 1.5 Hz, 2 H), 0.97 (t, 7 = 7.5 Hz, 3 H), 0.87 (s, 9 H), 0.09 (s, 3 H), 0.06 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 202.27, 132.39, 131.27, 126.78, 124.66, 68.23, 50.63, 35.80, 25.89, 25.87, 20.75, 18.13, 14.39, -4.22, -4.67 ppm; HR-MS (ESI- TOF): calcd for CnHssOaSi [M+H] ⁺ : 297.2244, found:297.2236.

IPh ₃ r

OPMB

115

[00219] {4-[(4-Methoxybenzyl)oxy]butyl}(triphenyl)phosphonium iodide (115): 115:

R _f = 0.40 (CH ₂ Cl ₂ :MeOH, 19: 1); FT-IR (neat): v _max = 3055, 3010, 2932, 2861, 2793, 2187, 1611, 1586, 1511, 1437, 1302, 1246, 1178, 1111, 1028, 915, 718 cm ^"1 ; ¹ H-NMR (600 MHz, CDCI ₃ ) δ 7.82 - 7.74 (m, 10 H), 7.69 - 7.62 (m, 5 H), 7.17 (d, 7= 8.6 Hz, 2 H), 6.81 (d, 7= 8.6 Hz, 2 H), 4.39 (s, 2 H), 3.78 (s, 3 H), 3.74 - 3.67 (m, 2 H), 3.58 (t, 7=5.7 Hz, 2 H), 1.99 (quint, 7=6.4 Hz, 2 H), 1.82 - 1.72 (m, 2 H) ppm; ¹³ C-NMR (151 MHz, CDCI ₃ ) δ 159.24, 135.13 (d, 7= 2.9 Hz), 133.86 (d, 7= 10.0 Hz), 130.60 (d, 7= 12.5 Hz), 129.51, 118.34 (d, 7= 86.1 Hz), 113.86, 72.56, 68.57, 55.46, 29.63 (d, 7= 16.4 Hz), 22.49 (d, 7=50.0 Hz), 19.74 (d, 7= 4.1 Hz) ppm; ³¹ P-NMR (162 MHz, CDCI ₃ ) δ 24.81 ppm; HR-MS (ESI) calcd for C3oH ₃ 20 ₂ P ⁺ [M-IJ ⁺ : 455.2134, found: 455.2138.

[00220] (4 ?)-4-{(2Z)-6-[(4-Methoxybenzyl)oxy]hex-2-en-l-yl}c clopent-2-en-l-ol (117): 117: R _f = 0.32 (hexanes:EtOAc, 2: 1); [a]^ ⁵ = +17.2 (c = 1.0, CHCI ₃ ); FT-IR (neat): v _mas = 3391, 3004, 2931, 2853, 1612, 1586, 1512, 1301, 1245, 1172, 1095, 1033, 819, 758 cm- ¹ ; Ή-NMR (600 MHz, CDCI3) δ 7.26 (d, 7= 8.3 Hz, 2 H), 6.89 (d, 7= 8.3 Hz, 2 H), 5.88 - 5.83 (m, 1 H), 5.81 - 5.78 (m, 1 H), 5.49 - 5.43 (m, 1 H), 5.43 - 5.36 (m, 1 H), 4.77 (t, 7= 5.9 Hz, 1 H), 4.43 (s, 2 H), 3.80 (s, 3 H), 3.44 (t, 7= 6.5 Hz, 2 H), 2.63 (quint, 7= 7.1 Hz, 1 H), 2.45 (dt, 7= 13.7, 7.7 Hz, 1 H), 2.25 - 2.18 (m, 1 H), 2.16 - 2.09 (m, 3 H), 1.80 (br s, 1 H), 1.66 (quint, 7= 7.0 Hz, 2 H), 1.26 (dt, 7= 13.7, 4.9 Hz, 1 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 159.19, 138.22, 133.59, 130.76, 130.75, 129.34, 128.07, 113.85, 77.29, 72.62, 69.52, 55.36, 44.52, 39.81, 33.66, 29.74, 24.08 ppm; HR-MS (ESI) calcd for Ci ₉ H260 ₃ Na [M+Na] ⁺ : 325.1774, found: 325.1781.

[00221] (4/?)-4-{(2Z)-6-[(4-Methoxybenzyl)oxy]hex-2-en-l-yl}cyclopen t-2-en-l-one (118): 118: R _f = 0.59 (hexanes:EtOAc, 3:2); [a]^ ⁵ = +86.1 (c = 1.1, CHC1 ₃ ); FT-IR (neat): v _mas = 3006, 2934, 2855, 1707, 1612, 1586, 1512, 1302, 1246, 1179, 1097, 1034, 820, 783 cm ^"1 ; Ή-NMR (500 MHz, CDCI3) δ 7.59 (dd, 7= 5.7, 2.5 Hz, 1 H), 7.24 (d, 7= 8.6 Hz, 2 H), 6.86 (d, 7= 8.6 Hz, 2 H), 6.14 (dd, 7= 5.7, 2.0 Hz, 1 H), 5.53 - 5.46 (m, 1 H), 5.39 - 5.32 (m, 1 H), 4.41 (s, 2 H), 3.79 (s, 3 H), 3.42 (t, 7= 6.4 Hz, 2 H), 3.01 - 2.94 (m, 1 H), 2.49 (dd, 7= 18.8, 6.4 Hz, 1 H), 2.32 - 2.25 (m, 1 H), 2.23 - 2.13 (m, 1 H), 2.10 (q, 7= 7.3 Hz, 2 H), 1.99 (dd, 7= 18.8, 2.2 Hz, 1 H), 1.65 (dt, 7= 13.5, 6.6 Hz, 2 H) ppm; ¹³ C-NMR (125 MHz, CDC1 ₃ ) δ 209.83, 168.00, 159.20, 134.16, 132.03, 130.67, 129.28, 126.17, 113.83, 72.65, 69.34, 55.34, 41.45, 40.56, 31.92, 29.62, 24.08 ppm; HR-MS (ESI) calcd for Ci ₉ H ₂₄ 0 ₃ Na [M+Na] ⁺ : 323.1618, found: 323.1614.

121

[00222] (4S,5£)-5-[(3S,5Z,8Z)-3-{[fert-Butyl(dimethyl)silyl]oxy}und eca-5,8-dien-l- ylidene]-4-{(2Z)-6-[(4-methoxybenzyl)oxy]hex-2-en-l-yl}cyclo pent-2-en-l-one (121): 121:

R _f = 0.60 (hexanes:EtOAc, 4: 1); [a]^ ⁵ = +108.8 (c= 1.0, CHC1 ₃ ); FT-IR (neat): v _max = 3009, 2954, 2931, 2856, 1704, 1656, 1613, 1513, 1462, 1248, 1095, 1038, 835, 775 cm ^"1 ; 'H-NMR (600 MHz, CDCI3) δ 7.47 (ddd, 7= 5.9, 2.4, 0.8 Hz, 1 H), 7.24 (d, 7= 8.5 Hz, 2 H), 6.87 (d, 7= 8.5 Hz, 2 H), 6.60 (dd, 7= 8.5, 6.9 Hz, 1 H), 6.31 (dd, J= 6.0, 1.8 Hz, 1 H), 5.51 - 5.32 (m, 5 H), 5.28 - 5.24 (m, 1 H), 4.41 (s, 2 H), 3.90 (quint, 7= 6.0 Hz, 1 H), 3.80 (s, 3 H), 3.46 - 3.41 (m, 3 H), 2.78 - 2.69 (m, 2 H), 2.63 - 2.59 (m, 1 H), 2.45 - 2.39 (m, 2 H), 2.30 - 2.15 (m, 3 H), 2.10 - 2.01 (m, 4 H), 1.64 (quint, 7= 7.0 Hz, 2 H), 0.96 (t, 7= 7.5 Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) 5 196.39, 161.72, 159.28, 138.95, 134.99, 132.51, 132.25, 132.15, 130.74, 130.66, 129.34, 127.00, 125.64, 125.34, 113.91, 72.74, 71.60, 69.53, 55.42, 43.54, 36.97, 35.39, 30.65, 29.74, 25.99, 25.90, 24.18, 20.74, 18.22, 14.40, -4.39, -4.41 ppm; HR-MS (ESI) calcd for CseH^SiNa [M+Na] ⁺ : 601.3684, found: 601.3661.

122 [00223] (4S,5£)-5-[(3S,5Z,8Z)-3-{[tert-Butyl(dimethyl)sil l]oxy}undeca-5,8-dien-l- ylidene]-4-[(2Z)-6-hydroxyhex-2-en-l-yl]cyclopent-2-en-l-one (122): 122: Rf= 0.30 (hexanes:EtOAc, 7:3); [a]¾ ⁵ = +138.3 (c= 1.0, CHC1 ₃ ); FT-IR (neat): v _max = 3444, 3010, 2955, 2929, 2856, 1701, 1652, 1462, 1254, 1071, 835, 775 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) 57.50 (ddd, 7= 6.0, 2.5, 0.8 Hz, 1 H), 6.62 - 6.59 (m, 1 H), 6.33 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.53 - 5.35 (m, 5 H), 5.29 - 5.24 (m, 1 H), 3.91 (quint, 7= 6.0 Hz, 1 H), 3.64 (t, 7= 6.4 Hz, 2 H), 3.48 - 3.44 (m, 1 H), 2.79 - 2.69 (m, 2 H), 2.67 - 2.63 (m, 1 H), 2.47 - 2.42 (m, 2 H), 2.31 - 2.18 (m, 3 H), 2.12 - 2.08 (m, 2 H), 2.04 (quint, 7= 7.3 Hz, 2 H), 1.61 (quint, 7= 7.1 Hz, 2 H), 0.96 (t, 7= 7.5 Hz, 3 H), 0.88 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) 5 196.37, 161.61, 138.94, 135.07, 132.58, 132.28, 131.99, 130.69, 126.99, 125.87, 125.32, 71.63, 62.47, 43.54, 36.97, 35.42, 32.58, 30.65, 25.99, 25.90, 23.84, 20.74, 18.23, 14.40, -4.38, -4.40 ppm; HR-MS (ESI) calcd for C28H ₄ 60 ₃ SiNa [M+Na] ⁺ : 481.3108, found: 481.3103.

123

[00224] (4Z)-6-{(lS,5£)-5-[(3S,5Z,8Z)-3-{[tcrt-Butyl(dimethyl)silyl ]oxy}undeca-5,8- dien-l-ylidene]-4-oxocyclopent-2-en-l-yl}hex-4-enal (123): 123: R _f = 0.50 (hexanes:EtOAc, 7:3); [αβ ⁵ = +136.3 (c = 1.0, CHCI3); FT-IR (neat): v _ma* = 3011, 2957, 2930, 2856, 1726, 1704, 1656, 1255, 1089, 836, 808, 776 cm ^"1 ; 'H-NMR (600 MHz, CDCI3) δ 9.76 (br s, 1 H), 7.48 (dd, 7= 6.0, 2.6 Hz, 1 H), 6.61 (t, 7= 7.7 Hz, 1 H), 6.34 (dd, 7= 6.0, 1.2 Hz, 1 H), 5.49 - 5.36 (m, 5 H), 5.29 - 5.23 (m, 1 H), 3.91 (quint, 7= 6.0 Hz, 1 H), 3.48 - 3.46 (m, 1 H), 2.79 - 2.69 (m, 2 H), 2.67 - 2.63 (m, 1 H), 2.50 - 2.46 (m, 2 H), 2.45 - 2.41 (m, 2 H), 2.36 - 2.21 (m, 5 H), 2.04 (quint, 7= 7.4 Hz, 2 H), 0.96 (t, 7= 7.5 Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm; ^1J C-NMR (151 MHz, CDC1 ₃ ) 5201.54, 196.24, 161.34, 138.79, 135.20, 132.70, 132.27, 130.69, 130.26, 126.98, 126.75, 125.29, 71.58, 43.68, 43.32, 36.97, 35.42, 30.60, 25.99, 25.90, 20.74, 20.22, 18.22, 14.40, -4.39, -4.41 ppm; HR-MS (ESI) calcd for CAOsSiNa [M+Na] ⁺ : 479.2952, found: 479.2935.

124

[00225] (4Z)-6-{(lS,5£)-5-[(3S,5Z,8Z)-3-{[tcrt-Butyl(dimethyl)silyl ]oxy}undeca-5,8- dien-l-ylidene]-4-oxocyclopent-2-en-l-yl}hex-4-enoic acid (124): 124: R _f = 0.45 (CH ₂ Cl ₂ :EtOH, 19:1); [α ⁵ = +93.4 (c= 1.0, CHC1 ₃ ); FT-IR (neat): v _max = 3011, 2956, 2929, 2856, 1707, 1654, 1462, 1253, 1087, 966, 835, 808, 775 cm ^"1 ; 'H-NMR (600 MHz, CDC1 ₃ ) 57.48 (ddd, /= 6.0, 2.6, 1.0 Hz, 1 H), 6.61 (t, 7= 7.7 Hz, 1 H), 6.34 (dd, 7=6.0, 1.8 Hz, 1 H), 5.49 - 5.35 (m, 5 H), 5.29 - 5.24 (m, 1 H), 3.91 (quint, 7=6.0 Hz, 1 H), 3.49 - 3.46 (m, 1 H), 2.78 - 2.70 (m, 2 H), 2.67 - 2.63 (m, 1 H), 2.45 - 2.43 (m, 2 H), 2.40 - 2.38 (m, 2 H), 2.35 - 2.20 (m, 5 H), 2.04 (quint, 7= 7.3 Hz, 2 H), 0.96 (t, 7= 7.5 Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) 5 196.33, 176.70, 161.44, 138.81, 135.16, 132.74, 132.27, 130.69, 130.12, 127.00, 126.96, 125.32, 71.63, 43.36, 36.96, 35.40, 33.54, 30.59, 25.99, 25.90, 22.75, 20.74, 18.23, 14.40, -4.39, -4.41 ppm; HR-MS (ESI) calcd for CAC^SiNa [M+Na] ⁺ : 495.2901, found: 495.2882.

[00226] (4Z)-6-{(lS,5£)-5-[(3S,5Z,8Z)-3-Hydroxyundeca-5,8-dien-l-yl idene]-4- oxocyclopent-2-en-l-yl}hex-4-enoic acid (28): To a stirred solution of TBS ether 124 (15 mg, 0.032 mmol, 1.0 equiv) in MeCN (0.6 mL) at 0 °C was added dropwise a solution of HF (50 % aq., 60 \lL, ca. 1.7 mmol, ca. 50 equiv) in MeCN (0.1 mL). After stirring for 30 min, additional HF (50 % aq., 60 llL, ca. 1.7 mmol, ca. 50 equiv) in MeCN (0.1 mL) was added. After stirring for an additional 45 min, the reaction was quenched by addition of sat. brine (3 mL) and extracted with EtOAc (3 mL). The organic extract was dried (Na ₂ SC ), filtered, and concentrated. Hash column chromatography (Si0 ₂ , CH ₂ Cl ₂ :EtOH, 99: 1→98:2→97:3→96:4) yielded the pure title compound (28, 8.9 mg, 0.026 mmol, 81 % yield) as a colorless oil. 28: R _f = 0.60 (CH ₂ Cl ₂ :EtOH, 9: 1); [a] ⁵ = +65.1 (c = 0.59, CHCI ₃ ); UV (EtOH) _max (log ε) = 245 (3.89) nm; FT-IR (neat): v _max = 3408, 3011, 2963, 2932, 1705, 1646, 1430, 1240, 1210, 1068, 1035, 839, 719 cm ^"1 ; 'H-NMR (600 MHz, CDCI3) 57.51 (dd, 7=5.8, 2.5 Hz, 1 H), 6.64 (t, 7= 7.6 Hz, 1 H), 6.34 (dd, 7= 5.9, 1.3 Hz, 1 H), 5.60 - 5.54 (m, 1 H), 5.50 - 5.34 (m, 4 H), 5.32 - 5.26 (m, 1 H), 3.88 (quint, J= 6.2 Hz, 1 H), 3.55 - 3.52 (m, 1 H), 2.82 - 2.78 (m, 2 H), 2.70 - 2.64 (m, 1 H), 2.56 - 2.45 (m, 2 H), 2.40 - 2.30 (m, 7 H), 2.06 (quint, 7= 7.3 Hz, 2 H), 0.97 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 196.54, 176.76, 161.79, 139.56, 135.15, 132.53, 132.37, 131.95, 130.32, 126.71, 126.66, 124.73, 70.83, 43.32, 36.56, 35.00, 33.68, 30.16, 25.88, 23.03, 20.76, 14.40 ppm; HR-MS (ESI) calcd for C22H31O4 [M+H] ⁺ : 359.2217, found: 359.2215.

[00227] Methyl (4Z)-6-{(lS,5£)-5-[(3S,5Z,8Z)-3-hydroxyundeca-5,8-dien-l-yl idene]- 4-oxocyclopent-2-en-l-yl}hex-4-enoate (29): To a stirred solution of carboxylic acid 28 (23 mg, 67 μηιοΐ, 1.0 equiv) in C6H6:MeOH (3:2, 2.2 mL) at 25 °C was added dropwise a solution of trime hylsilyl diazomethane (2 M in Et ₂ 0, 50 μί, 100 μιηοΐ, 1.5 equiv) (yellow color persists). After stirring for 30 min, the reaction mixture was concentrated. Flash column chromatography (S1O2, hexanes:EtOAc, 3: 1→2: 1) yielded the pure title compound (29, 18 mg, 48 μπιοΐ, 72 % yield) as a colorless oil. 29: R _f = 0.57 (hexanes:EtOAc, 1 : 1); [a]j¾ ⁵ = +147.7 (c = 0.39, CHCI3); UV (EtOH) λ™ _χ (log ε) = 242 (4.15) nm; FT-IR (neat): v _max = 3402, 3016, 2961, 2924, 2853, 1737, 1701, 1650, 1579, 1437, 1370, 1263, 1163, 1063 cm ^"1 ; 'H-NMR (600 MHz, CDC1 ₃ ) 6 7.50 (dd, 7= 6.0, 2.6 Hz, 1 H), 6.54 (t, 7= 6.9 Hz, 1 H), 6.34 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.61 - 5.53 (m, 1 H), 5.48 - 5.33 (m, 4 H), 5.31 - 5.24 (m, 1 H), 3.86 (quint, 7= 6.2 Hz, 1 H), 3.66 (s, 3 H), 3.54 - 3.50 (m, 1 H), 2.80 (t, 7= 7.3 Hz, 2 H), 2.71 - 2.63 (m, 1 H), 2.56 - 2.43 (m, 2 H), 2.37 - 2.24 (m, 7 H), 2.09 - 2.01 (m, 2 H), 1.97 (br s, 1 H), 0.96 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.39, 173.61, 161.63, 139.50, 135.13, 132.48, 132.25, 131.84, 130.60, 126.72, 126.45, 124.82, 70.65, 51.78, 43.36, 36.72, 35.15, 33.92, 30.32, 25.87, 23.03, 20.74, 14.37 ppm; HR-MS (ESI) calcd for C23H ₃₂ 0 ₄ Na [M+Na] ⁺ : 395.2193, found: 395.2183.

[00228] (l£,3S,9Z,llaS)-3-[(2Z,5Z)-Octa-2,5-dien-l-yl]-2,6,7,8,ll,l la-hexahydro-3H- cyclopenta[e]-oxacyclotridecine-5,14-dione (30): To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (53.8 mg, 156 μπιοΐ, 1.4 equiv) and 4-dimethylaminopyridine (81.8 mg, 670 μπιοΐ, 6.0 equiv) in CH ₂ CI ₂ (80 mL) was added a solution of compound 29 (40.0 mg, 112 μπιοΐ, 1.0 equiv) in CH ₂ CI ₂ (40 mL) at 25 °C dropwise via syringe pump over 15 h. After stirring for an additional 2 h, the reaction mixture was washed sequentially with sat. aq. NaHCCVsolution (40 mL), aq. HCl (0.2 M; 40 mL), and brine (40 mL). The organic layer was dried (MgSO.4), filtered, and concentrated under reduced pressure. Flash column chromatography (S1O2, hexanes: EtOAc, 3:1) yielded pure title compound (23.7 mg, 69.6 μπιοι, 62 % yield) as a colorless oil. 30: Rf=0.54 (hexanes :EtO Ac, 1 :1); 3353, 3011, 2922, 2852, 1724, 1655, 1441, 1336, 1251, 1194, 1148, 1024, 673 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 7.42 (ddd, 7= 6.0, 2.7, 0.9 Hz, 1 H), 6.71 (dd, 7= 13.0, 4.1 Hz, 1 H), 6.45 (dd, 7= 6.0, 2.0 Hz, 1 H), 5.54 - 5.47 (m, 1 H), 5.45 - 5.33 (m, 3 H), 5.34 - 5.25 (m, 1 H), 5.08 - 5.04 (m, 1 H), 5.03 - 4.95 (m, 1 H), 3.66 (br s, 1 H), 2.95 - 2.82 (m, 2 H), 2.82 - 2.74 (m, 1 H), 2.61 (dt, 7= 14.5, 7.5 Hz, 1 H), 2.56 - 2.43 (m, 2 H), 2.43 - 2.27 (m, 3 H), 2.20 - 1.98 (m, 5 H), 1.01 - 0.93 (t, 7= 7.6 Hz, 3 H); ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 196.62, 174.46, 162.06, 139.62, 135.73, 132.61, 131.83, 129.75, 129.55, 126.68, 124.93, 124.29, 73.69, 41.53, 34.79, 31.73, 29.63, 28.21, 25.93, 24.74, 20.76, 14.40 ppm; HR-MS (ESI-TOF): calcd for C22H ₂ 80 ₃ Na [M+Na] ⁺ : 363.1931, found: 363.1939.

[00229] (4/?)-2-Chloro-4-{(2Z)-7-[(4-methoxybenzyl)oxy]hept-2-en-l-y l}cyclopent-2- en-l-one (126): 126: R _f =0.60 (hexanes:EtOAc, 4: 1); [a] ⁵ = +87.2 (c= 1.5 in C ₆ ¾); IR (neat): Vmax = 3006, 2981, 2936, 2861, 2845, 1722, 1612, 1596, 1512, 1456, 1247, 1033, 1016, 823 cm ^"1 ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 7.25 (d, 7= 8.5 Hz, 2 H), 6.82 (d, 7= 8.5 Hz, 2 H), 6.73 - 6.66 (m, 1 H), 5.32 (dt, 7= 10.6, 7.4 Hz, 1 H), 4.97 - 4.88 (m, 1 H), 4.35 (s, 2 H), 3.33 - 3.31 (m, 5 H), 2.06 - 1.99 (m, 2 H), 1.80 - 1.77 (m, 2 H), 1.68 - 1.62 (m, 2 H), 1.59 - 1.50 (m, 3 H), 1.39 - 1.34 (m, 2H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 198.61, 159.77, 159.30, 136.14, 132.80, 131.37, 129.41, 125.55, 114.13, 72.88, 69.93, 54.83, 39.21, 38.10, 31.80, 29.79, 27.32, 26.65 ppm; HR-MS (ESI-TOF): calcd for C2oH ₂ 5C10 ₃ Na [M+Na] ⁺ : 371.1384, found: 371.1374. 127: R _f =0.30 (hexanes: EtOAc, 4: 1); [αβ ⁵ =+40.0 (c = 0.3 in C ₆ H ₆ ); IR (neat): Vmax = 3421, 3007, 2981, 2937, 2864, 2845, 1721, 1596, 1456, 1289, 1171, 1055, 957, 750 cm ^"1 ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 6.75 (d, 7=2.5 Hz, 1 H), 5.36 - 5.28 (m, 1 H), 4.98 - 4.93 (m, 1 H), 3.41 (t, 7= 6.4 Hz, 2 H), 2.11 - 2.04 (m, 2 H), 1.78 (q, 7=7.0 Hz, 2 H), 1.72 - 1.67 (m, 2 H), 1.65 - 1.58 (m, 1 H), 1.40 - 1.34 (m, 2 H), 1.31 - 1.25 (m, 2 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 199.03, 159.70, 136.03, 132.86, 125.51, 62.42, 39.23, 38.15, 32.56, 31.78, 27.27, 26.09 ppm; HR-MS (ESI-TOF): calcd for C12H17CIO2 [M+Na] ⁺ : 229.0990, found: 229.0985.

[00230] (5Z,12£',15S,17Z)-15-{[iert-Butyl(dimethyl)silyl]oxy}-10-ch loro-l-[(4- methoxybenzyl)oxy]-prosta-5,9,12,17-tetraen-ll-one (129): 129: R _f =0.70 (hexanes: EtOAc, 4:1); [α] =+124.2 (c = l.O in CeHg); IR (film): v _max = 3008, 2954, 2932, 2856, 1712, 1660, 1655, 1514, 1461, 1362, 1172, 1097, 1034, 835 cm ^"1 ; ¹ H-NMR (600 MHz, C ₆ D ₆ ) δ 7.26 (d, 7= 8.5 Hz, 2 H), 6.86 - 6.82 (m, 4 H), 5.53 - 5.46 (m, 1 H), 5.42 (dt, 7= 9.3, 7.2 Hz, 1 H), 5.39 - 5.34 (m, 1 H), 5.10 (dt, 7= 10.5, 7.3 Hz, 1 H), 4.36 (s, 2 H), 3.71 (quint, /= 5.8 Hz, 1 H), 3.35 (t, 7=6.3 Hz, 2 H), 3.32 (s, 3 H), 3.00 - 2.96 (m, 1 H), 2.39 - 2.34 (m, 1 H), 2.32 - 2.14 (m, 4 H), 1.98 - 1.87 (m, 5 H), 1.60 - 1.55 (m, 2 H), 1.43 - 1.38 (m, 2 H), 0.95 (s, 9 H), 0.90 (t, 7= 7.6 Hz, 3 H), 0.06 (s, 3 H), 0.04 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 187.24, 159.76, 153.40, 137.66, 137.10, 134.41, 134.22, 133.12, 131.40, 129.39, 124.98, 124.62, 114.12, 72.87, 71.70, 69.99, 54.82, 41.71, 36.87, 35.68, 30.77, 29.94, 27.51, 26.70, 26.07, 21.16, 18.27, 14.39, -4.36, -4.39 ppm; HR-MS (ESI-TOF): calcd for C ₃₄ H ₅ iC10 ₄ SiNa [M+Na] ⁺ : 609.3137, found: 609.3138.

[00231] (5Z,12£,15S,17Z)-15-{[iert-Butyl(dimethyl)silyl]oxy}-10-chl oro-l- hydroxyprosta-5,9,12,17-tetraen-ll-one (130): 130: R _f = 0.21 (hexanes:EtOAc, 4: 1); [αβ ⁵ = +56.3 (c = 0.3 in C ₆ H ₆ ); IR (film): v _m ax = 3423, 2932, 1709, 1654, 1559, 1538, 1460, 1256, 1062, 836 cm ^"1 ; 'H-NMR (600 MHz, C ₆ D ₆ ) δ 6.85 - 6.72 (m, 2 H), 5.51 - 5.47 (m, 1 H), 5.44 - 5.40 (m, 1 H), 5.38 - 5.33 (m, 1 H), 5.12 - 5.07 (m, 1 H), 3.72 (quint, 7= 6.7 Hz, 1 H), 3.34 (t, 7= 6.3 Hz, 2 H), 3.01 - 2.98 (m, 1 H), 2.39 - 2.35 (m, 1 H), 2.32 - 2.10 (m, 4 H), 1.98 - 1.91 (m, 3 H), 1.86 - 1.81 (m, 2 H), 1.27 - 1.32 (m, 2 H), 1.25 - 1.24 (m, 2 H), 0.89 (s, 9 H), 0.84 (t, 7=7.5 Hz, 3 H), 0.06 (s, 3 H), 0.04 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 187.29, 153.43, 137.65, 137.10, 134.47, 134.24, 133.11, 124.95, 124.61, 71.73, 62.43, 41.72, 36.90, 35.67, 32.60, 30.77, 27.40, 26.11, 26.06, 21.15, 18.27, 14.39, -4.37, -4.39 ppm; HR-MS (ESI-TOF): calcd for C26H ₄₃ C103SiNa [M+Na] ⁺ : 489.2562, found: 489.2547.

[00232] (5Z,12£',15S,17Z)-15-{[iert-Butyl(dimethyl)silyl]oxy}-10-ch loro-ll-oxoprosta- 5,9,12,17-tetraen-l-oic acid (132): 132: R _f =0.57 (hexanes:EtOAc, 1 :4); [a]¾ ⁵ = +59.5 (c = 0.4 in C ₆ H ₆ ); IR (film): v _m „ = 2931, 2857, 1710, 1660, 1559, 1460, 1406, 1255, 1087, 836 cm ^"1 ; ¹ H-NMR (600 MHz, C ₆ D ₆ ) δ 6.86 - 6.83 (m, 2 H), 5.52 - 5.48 (m, 1 H), 5.45 - 5.41 (m, 1 H), 5.23 - 5.19 (m, 1 H), 5.10 - 5.06 (m, 1 H), 3.73 (quint, 7= 5.9 Hz, 1 H), 3.00 - 2.98 (m, 1 H), 2.37 - 2.13 (m, 5 H), 2.08 (t, 7= 7.4 Hz, 2 H), 2.01 - 1.86 (m, 3 H), 1.84 - 1.74 (m, 2 H), 1.49 (quint, 7=7.4 Hz, 2 H), 0.96 (s, 9 H), 0.91 (t, 7= 7.5 Hz, 3 H), 0.07 (s, 3 H), 0.06 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 187.31, 179.62, 153.34, 137.70, 137.01, 134.58, 134.26, 131.81, 125.90, 124.60, 71.78, 41.61, 36.89, 35.66, 33.37, 30.63, 26.73, 26.07, 24.63, 21.16, 18.29, 14.40, -4.37, -4.39 ppm; HR-MS (ESI-TOF): calcd for C26H ₄ iC10 ₄ SiNa [M+Na] ⁺ : 503.2355, found: 503.2358.

[00233] (5Z,12£',15S,17Z)-10-Chloro-15-hydroxy-ll-oxoprosta-5,9,12, 17-tetraen-l- oic acid (31): To a stirred solution of 10-chloro-A ¹² -PGJ ₃ -15-f-butyldimethylsilyl-ether (132, 76 mg, 0.16 rnmol, l.O equiv) in MeCN (2.0 mL) at 0 °C was dropwise added a solution of HF (50 % aq., 630 μί, ca. 16 rnmol, ca. 100 equiv) in MeCN (1.0 mL). After stirring for 45 min at this temperature, the reaction mixture was quenched with sat. brine (30 mL) and extracted with EtOAc (5 x 50 mL). The combined organic extracts were dried (Na ₂ S0 ₄ ), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Flash column chromatography (S1O2, hexanes:EtOAc, 1:4) yielded pure title compound (31, 51 mg, 0.14 rnmol, 88 % yield) as a colorless oil. 31: R _f = 0.51 (EtOAc); [a]j¾ ⁵ = +95.0 (c = 1.0 in C ₆ H ₆ ); IR (film): v _max = 3010, 2933, 1738, 1654, 1587, 1559, 1406, 1289, 1046, 871 cm ^"1 ; 'H-NMR (600 MHz, C ₆ D ₆ ) δ 6.85 (d, = 2.9 Hz, 1 H), 6.81 (t, /= 7.6 Hz, 1 H), 5.53 - 5.49 (m, 1 H), 5.39 - 5.35 (m, 1 H), 5.25 - 5.20 (m, 1 H), 5.11 - 5.07 (m, 1 H), 3.66 - 3.61 (m, 1 H), 2.99 - 2.96 (m, 1 H), 2.45 - 2.41 (m, 1 H), 2.33 (dt, /= 14.6, 7.2 Hz, 1 H), 2.26 - 2.19 (m, 2 H), 2.17 - 2.07 (m, 3 H), 1.98 (quint, /= 7.5 Hz, 2 H), 1.91 - 1.79 (m, 3 H), 1.50 - 1.43 (m, 2 H), 0.93 (t, /= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 187.75, 178.03, 153.76, 137.54, 135.02, 134.39, 131.94, 128.59, 125.98, 124.43, 70.91, 41.89, 36.53, 34.94, 33.06, 30.44, 26.64, 24.65, 21.10, 14.41 ppm; HR-MS (ESI-TOF): calcd for C ₂ oH ₂₇ C10 ₄ Na [M+Na] ⁺ : 389.1490, found: 389.1478.

[00234] Methyl (5Z,12£',15S,17Z)-10-chloro-15-hydroxy-ll-oxoprosta-5,9,12, 17- tetraen-l-oate (32): To a stirred solution of 10-chloro-A ¹² -PGJ3 (31) (11 mg, 33 μιηοΐ, l .O equiv) in CeH6:MeOH (3:2, 1.0 mL) at 25 °C was dropwise added a solution of trimethylsilyl diazomethane (2 M in Et ₂ 0, 33 μί, 66 μπιοΐ, 2.0 equiv) (yellow color persists). After stirring for 30 min, the reaction mixture was concentrated. Flash column chromatography (S1O2, hexanes:EtOAc, 2: 1→3:2) yielded pure title compound (32, 7.3 mg, 19 μηιοΐ, 56 % yield) as a colorless oil. 32: R _f = 0.70 (hexanes: EtOAc, 1 : 1); [αβ = +168.3 (c = 0.1 in C ₆ H ₆ ); IR (film): 3441, 2932, 1710, 1654, 1559, 1506 cm ^"1 ; 'H-NMR (600 MHz, C ₆ D ₆ ) δ 6.82 - 6.79 (m, 2 H), 5.53 - 5.46 (m, 1 H), 5.32 - 5.27 (m, 1 H), 5.23 - 5.19 (m, 1 H), 5.07 - 5.02 (m, 1 H), 3.43 - 3.38 (m, 1 H), 3.34 (s, 3 H), 2.94 - 2.91 (m, 1 H), 2.34 - 2.29 (m, 1 H), 2.18 (dt, = 14.8, 7.4 Hz, 1 H), 2.11 - 2.02 (m, 4 H), 1.97 - 1.87 (m, 3 H), 1.83 - 1.77 (m, 2 H), 1.55 - 1.46 (m, 2 H), 1.41 (d, /= 4.3 Hz, 1 H), 0.88 (t, /=7.5 Hz, 3 H) ppm; ^U C-NMR (151 MHz, C ₆ D ₆ ) δ 187.37, 173.39, 153.32, 137.66, 137.33, 134.98, 134.23, 132.00, 125.68, 124.56, 70.37, 51.11, 41.53, 36.64, 35.37, 33.23, 30.31, 26.82, 24.87, 21.07, 14.40 ppm; HR-MS (ESI-TOF): calcd for C ₂ iH ₂ 9C10 ₄ Na [M+Na] ⁺ : 403.1647, found: 403.1659.

[00235] (5Z,12£,15S,17Z)-10-Chloro-l,15-epoxyprosta-5,9,12,17-tetra ene-l,ll-dione (33): To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (28.0 mg, 82.0 μπιοΐ, 1.5 equiv) and 4-dimethylaminopyridine (26.7 mg, 218 μιηοΐ, 4.0 equiv) in CH2CI2 (40 mL) was added a solution of carboxylic acid 31 (20.0 mg, 54.6 μπιοΐ, 1.0 equiv) in CH2CI2 (20 mL) at 25 °C dropwise via syringe pump over 10 h. After stirring for an additional 2 h, the reaction mixture was washed sequentially with sat. aq. NaHC03-solution (10 mL), aq. HC1 (0.2 M, 10 mL), and sat. brine (10 mL). The organic layer was dried (Na2SC>4), filtered, and concentrated. Flash column chromatography (S1O2, hexanes:EtOAc, 3: 1) yielded pure title compound (33, 14.8 mg, 40.0 μπιοΐ, 73 % yield) as a light yellow solis. 33: 3011, 2963, 2931, 1718, 1702, 1662, 1587, 1279, 1164, 1033, 941, 893 cm ^"1 ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 6.59 - 6.56 (m, 2 H), 5.49 - 5.44 (m, 1 H), 5.27 - 5.22 (m, 1 H), 5.10 - 5.03 (m, 2 H), 4.96 - 4.92 (m, 1 H), 2.99 - 2.97 (m, 1 H), 2.40 (ddd, /= 14.6, 9.8, 5.2 Hz, 1 H), 2.29 - 2.21 (m, 3 H), 2.19 - 2.14 (m, 1 H), 2.04 (ddd, J= 15.4, 8.9, 3.2 Hz, 1 H), 1.98 - 1.86 (m, 5 H), 1.75 - 1.69 (m, 1 H), 1.28 - 1.19 (m, 2 H), 0.89 (t, /=7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 187.12, 172.16, 152.78, 138.06, 137.61, 135.16, 133.43, 132.30, 124.71, 123.28, 72.60, 41.28, 33.52, 32.76, 32.04, 28.43, 25.99, 24.56, 21.04, 14.35 ppm; HR-MS (ESI-TOF): calcd for C ₂ oH25C10 ₃ Na [M+Na] ⁺ : 371.1384, found: 371.1395.

[00236] 5-Methyl-3-{[(l ?,2S,5/?)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}cyclopent-2 - en-l-one (134): 134: R _f = 0.39 (hexanes:Et ₂ 0, 1: 1); IR (film): v _ma* = 2955, 2927, 2870, 1695, 1586, 1455, 1332, 1249, 1194, 982, 966, 819 cm ^"1 ; Ή-NMR (600 MHz, CDCI3, mixture of diastereomers) δ 5.23 (s, 1 H), 3.94 (tt, J= 10.7, 3.9 Hz, 1 H), 2.80 (dddd, = 27.1, 17.5, 7.3, 1.1 Hz, 1 H), 2.54 - 2.44 (m, 1 H), 2.18 (dddd, /= 28.9, 17.6, 2.9, 1.1 Hz, 1 H), 2.11 (dtt, /= 11.9, 3.7, 1.8 Hz, 1 H), 1.98 (dddd, /= 14.0, 9.4, 5.7, 2.3 Hz, 1 H), 1.75 - 1.67 (m, 3 H), 1.52 - 1.47 (m, 1 H), 1.45 - 1.41 (m, 1 H), 1.20 (d, 7=7.4, 3 H), 1.10 - 0.99 (m, 2 H), 0.95 - 0.88 (m, 6 H), 0.76 - 0.74 (m, 3 H) ppm; ^U C-NMR (151 MHz, CDCls, mixture of diastereomers) 5 209.12, 188.05, 188.04, 102.99, 102.93, 82.40, 82.39, 47.54, 47.52, 39.61, 39.56, 39.52, 39.48, 37.64, 37.63, 34.25, 31.49, 26.46, 26.40, 23.73, 23.67, 22.09, 20.70, 20.68, 16.92, 16.91, 16.79, 16.75 ppm; HR-MS (ESI-TOF): calcd for C16H27O2 [M+H] ⁺ : 251.2006, found: 251.1996.

[00237] 5-{(2Z)-7-[(4-Methox benzyl)oxy]hept-2-en-l-yl}-5-methyl-3-{[(l ?,2S,5 ?)-5- methyl-2-(propan-2-yl)cyclohexyl]oxy}cydopent-2-en-l-one (136): 136: Rf= 0.64 (hexanes:EtOAc, 2: 1); IR (film) : vmax = 2953, 2927, 2868, 1691, 1579, 1512, 1331, 1245, 1096, 1035, 823 cm ^"1 ; Ή-NMR (600 MHz, CDCI ₃ , mixture of diastereomers) δ 7.25 (d, /= 8.6 Hz, 2 H), 6.87 (d, /= 8.3 Hz, 2 H), 5.50 - 5.41 (m, 1 H), 5.27 - 5.17 (m, 2 H), 4.42 (s, 2 H), 3.97 - 3.89 (m, 1 H), 3.80 (s, 3 H), 3.43 (td, /= 6.6, 1.7 Hz, 2 H), 2.54 - 2.45 (m, 1 H), 2.30 - 2.16 (m, 3 H), 2.13 - 2.01 (m, 3 H), 2.01 - 1.90 (m, 1 H), 1.74 - 1.66 (m, 3 H), 1.63 - 1.56 (m, 2 H), 1.53 - 1.44 (m, 1 H), 1.46 - 1.37 (m, 3 H), 1.15 - 1.14 (m, 3 H), 1.10 - 0.99 (m, 2 H), 0.96 - 0.88 (m, 6 H), 0.76 - 0.74 (m, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3, mixture of diastereomers) δ 210.52, 210.47, 187.38, 187.28, 159.23, 132.83, 132.78, 130.89, 129.34, 124.84, 124.77, 113.89, 102.43, 102.31, 82.48, 82.36, 72.66, 70.11, 55.41, 47.56, 47.50, 47.04, 46.98, 41.80, 41.78, 39.69, 39.53, 35.66, 35.29, 34.26, 31.50, 31.49, 29.55, 29.53, 27.26, 27.24, 26.61, 26.50, 26.43, 26.38, 24.07, 23.86, 23.81, 23.76, 22.10, 22.09, 20.66, 20.58, 16.88, 16.79 ppm; HR-MS (ESI- TOF): calcd for C ₃ iH ₄₆ 0 ₄ Na[M+Na] ⁺ : 505.3288, found: 505.3270.

[00238] 4-{(2Z)-7-[(4-Methoxybenzyl)oxy]hept-2-en-l-yl}-4-methylcycl opent-2-en-l- one (137): 137: R _f = 0.53 (hexanes:EtOAc, 2: 1); IR (film): v _max = 3007, 2932, 2858, 1711, 1611, 1511, 1456, 1301, 1245, 1172, 1095, 1033, 817 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.42 (d, .7=5.6 Hz, 1 H), 7.25 (d, /= 8.8 Hz, 2 H), 6.87 (d, /= 8.6 Hz, 2 H), 6.04 (d, /= 5.6 Hz, 1 H), 5.56 - 5.45 (m, 1 H), 5.32 - 5.23 (m, 1 H), 4.42 (s, 2 H), 3.80 (s, 3 H), 3.43 (t, 7= 6.5 Hz, 2 H), 2.29 (d, J= 18.5 Hz, 1 H), 2.27 (ddd, J= 14.4, 8.3, 1.4 Hz, 1 H), 2.16 (ddd, J= 14.2, 6.9, 1.5 Hz, 1 H), 2.10 (d, J= 18.5 Hz, 1 H), 2.05 - 1.99 (m, 2 H), 1.63 - 1.56 (m, 2 H), 1.42 (dq, /= 9.7, 7.5 Hz, 2 H), 1.22 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 209.89, 172.61, 159.25, 133.29, 132.21, 130.83, 129.34, 124.42, 113.89, 72.69, 70.02, 55.40, 47.64, 45.27, 37.89, 29.52, 27.25, 26.30, 26.22 ppm; HR-MS (ESI-TOF): calcd for C2iH ₂ 80 ₃ Na [M+Na] ⁺ : 351.1931, found: 351.1914.

[00239] (5Z,12£',15S,17Z)-15-{[iert-Butyl(dimethyl)silyl]oxy}-l-[(4 - methoxybenzyl)oxy]-8-methyl-prosta-5,9,12,17-tetraen-ll-one (139): 139: Rf=0.71 (hexanes:EtOAc, 2:1); IR (film): _Vm a _X = 3009, 2955, 2930, 2856, 1703, 1651, 1612, 1586, 1512, 1462, 1360, 1247, 1084, 833, 775 cm ^"1 ; Ή-NMR (600 MHz, CDC , mixture of diastereomers) δ 7.28 - 7.19 (m, 3 H), 6.90 - 6.84 (m, 2 H), 6.64 - 6.56 (m, 1 H), 6.22 (d, /= 5.9 Hz, 1 H), 5.51 - 5.43 (m, 1 H), 5.44 - 5.31 (m, 2 H), 5.20 - 5.09 (m, 1 H), 4.42 (s, 2 H), 3.88 - 3.81 (m, 1 H), 3.79 (s, 3 H), 3.42 (t, /= 6.5 Hz, 2 H), 2.54 - 2.35 (m, 4 H), 2.30 - 2.19 (m, 2 H), 2.07 - 1.94 (m, 4 H), 1.62 - 1.54 (m, 2 H), 1.44 - 1.35 (m, 2 H), 1.34 - 1.32 (m, 3 H), 0.96 - 0.94 (m, 3 H), 0.89 - 0.87 (m, 9 H), 0.09 - 0.03 (m, 6 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ , mixture of diastereomers) δ 196.73, 196.72, 167.53, 167.49, 159.23, 142.13, 142.08, 134.11, 132.67, 132.60, 132.56, 132.49, 132.42, 130.81, 129.30, 124.52, 124.50, 124.43, 124.40, 113.87, 72.67, 71.97, 71.87, 70.04, 55.37, 47.70, 36.06, 36.02, 35.69, 35.55, 29.54, 27.36, 27.33, 26.31, 26.29, 25.98, 25.97, 24.20, 24.03, 20.90, 18.18, 18.17, 14.31, -4.38, -4.39, -4.43 ppm; HR-MS (ESI-TOF): calcd for CssHs^SiNa [M+Na] ⁺ : 589.3684, found: 589.3672.

[00240] (5Z,12£',15S,17Z)-15-{[iert-Butyl(dimethyl)silyl]oxy}-l-hyd roxy-8- methylprosta-5,9,12,17-tetraen-ll-one (140): 140: R _f =0.29 (hexanes:EtOAc, 2: 1); IR (film): _Vmax = 3406, 3011, 2956, 2929, 2857, 1698, 1648, 1586, 1461, 1254, 1067, 835, 775 cm ^"1 ; Ή-NMR (600 MHz, CDCI ₃ , mixture of diastereomers) δ 7.26 - 7.21 (m, 1 H), 6.63 - 6.56 (m, 1 H), 6.23 (d, /= 5.9 Hz, 1 H), 5.51 - 5.31 (m, 3 H), 5.22 - 5.11 (m, 1 H), 3.85 (p, /= 6.0 Hz, 1 H), 3.63 (t, 7= 6.5 Hz, 2 H), 2.55 - 2.35 (m, 4 H), 2.32 - 2.19 (m, 2 H), 2.07 - 1.97 (m, 4 H), 1.59 - 1.51 (m, 2 H), 1.43 - 1.37 (m, 2 H), 1.35 - 1.33 (m, 3 H), 0.97 - 0.94 (m, 3 H), 0.88 - 0.87(m, 9 H), 0.08 - 0.02 (m, 6 H) ppm; ¹³ C-NMR (151 MHz, CDCI3, mixture of diastereomers) δ 196.79, 196.77, 167.53, 167.49, 142.16, 142.12, 134.16, 132.74, 132.65, 132.52, 132.47, 132.41, 124.60, 124.57, 124.53, 72.02, 71.90, 62.90, 62.89, 47.73, 36.10, 36.07, 35.69, 35.58, 32.49, 32.47, 27.30, 27.26, 26.00, 25.99, 25.84, 24.21, 24.04, 20.93, 18.21, 18.20, 14.33, -4.36, -4.37, -4.41 ppm; HR-MS (ESI-TOF): calcd for CavfteOsSiNa [M+Na] ⁺ : 469.3108, found: 469.3094.

- I ll -

[00241] (5Z,12£',15S,17Z)-15-{[iert-Butyl(dimethyl)silyl]oxy}-8-met h l-ll-oxoprosta- 5,9,12,17-tetraen-l-oic acid (141): 141: R _f = 0.20 (hexanes:EtOAc, 1 : 1); IR (film): v _max = 3403, 2959, 2928, 1707, 1645, 1456, 1248, 1183, 1055, 974, 836 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ , mixture of diastereomers) δ 7.26 - 7.18 (m, 1 H), 6.66 - 6.56 (m, 1 H), 6.25 (d, /= 5.9 Hz, 1 H), 5.52 - 5.32 (m, 3 H), 5.32 - 5.16 (m, 1 H), 3.90 - 3.80 (m, 1 H), 2.55 - 2.37 (m, 4 H), 2.34 (t, J= 1A Hz, 2 H), 2.31 - 2.16 (m, 2 H), 2.12 - 1.97 (m, 4 H), 1.73 - 1.63 (m, 2 H), 1.36 - 1.33 (m, 3 H), 0.95 (t, J= 7.5 Hz, 3 H), 0.90 - 0.87 (m, 9 H), 0.09 - 0.03 (m, 6 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ , mixture of diastereomers) δ 196.79, 196.76, 177.97, 167.46, 167.41, 142.11, 142.08, 134.22, 132.79, 132.74, 132.65, 131.33, 131.29, 125.58, 124.52, 72.14, 71.99, 48.01, 47.68, 36.10, 36.06, 36.04, 36.00, 35.65, 35.57, 33.25, 33.21, 26.79, 26.74, 26.01, 26.00, 24.58, 24.55, 24.19, 24.03, 20.94, 20.87, 18.24, 18.23, 14.33, -4.35, -4.36, -4.39 ppm; HR-MS (ESI-TOF): calcd for C2 ₇ H440 ₄ SiNa [M+Na] ⁺ : 483.2901, found: 483.2901.

[00242] (5Z,12£,15S,17Z)-15-Hydroxy-8-methyl-ll-oxoprosta-5,9,12,17 -tetraen-l-oic acid (142): To a stirred solution of compound 141 (140 mg, 304 μιηοΐ, 1.0 equiv) in MeCN (3.0 mL) at 0 °C was dropwise added a solution of HF (50 % aq., 530 pL, ca. 15.2 mmol, ca. 50 equiv) in MeCN (3.0 mL). After stirring for 75 min at this temperature, the reaction mixture was quenched by addition of sat. brine (30 mL) and extracted with EtOAc (5 x 50 mL). The combined organic extracts were dried (MgSC ), filtered, and concentrated under reduced pressure to a volume of ca. 1 mL (not to dryness!). Flash column chromatography (S1O2, hexanes:EtOAc, 10: 1→ 1 : 1) yielded pure title compound (142, 79.0 mg, 228 pmol, 75 % yield, mixture of diastereomers, 2: 1 dr) as a colorless oil. 142: R _f = 0.40 (hexanes:EtOAc, 1 :4); IR (film): v _max = 3412, 2960, 2931, 1716, 1653, 1459, 1376, 1244, 1062 cm ^"1 ; 'H-NMR (600 MHz, CDCL, mixture of diastereomers) δ 7.31 (t, = 6.2 Hz, 1 H), 6.64 - 6.54 (m, 1 H), 6.27 (d, = 5.9 Hz, 1 H), 5.64 - 5.56 (m, 1 H), 5.47 - 5.41 (m, 1 H), 5.41 - 5.34 (m, 1 H), 5.28 - 5.19 (m, 1 H), 3.89 - 3.81 (m, 1 H), 2.63 - 2.47 (m, 3 H), 2.37 - 2.28 (m, 4 H), 2.15 - 2.01 (m, 5 H), 1.73 - 1.63 (m, 2 H), 1.37 - 1.35 (m, 3 H), 0.97 (t, /= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCL, mixture of diastereomers) δ 196.91, 196.90, 177.75, 167.72, 167.69, 143.12, 143.10, 135.93, 135.92, 132.67, 131.64, 131.45, 125.44, 125.34, 123.86, 123.83, 71.23, 70.95, 47.72, 47.66, 35.98, 35.95, 35.74, 35.64, 34.87, 34.84, 33.27, 33.17, 26.77, 26.68, 24.67, 24.55, 24.01, 23.86, 20.92, 20.88, 14.38, 14.35 ppm; HR-MS (ESI-TOF): calcd for C ₂ iH ₃ o0 ₄ Na [M+Na] ⁺ : 369.2036, found: 369.2021.

[00243] Methyl (5Z,12£',15S,17Z)-15-hydroxy-8-methyl-ll-oxoprosta-5,9,12,1 7- tetraen-l-oate (34) and methyl (5Z,8P,12£,15S,17Z)-15-hydroxy-8-methyl-ll-oxoprosta- 5,9,12,17-tetraen-l-oate (36): To a stirred solution of compound 142 (20.0 mg, 60.2 μπιοΐ, 1.0 equiv) in ΟδΗβΐΜεΟΗ (3:2, 1.5 mL) at 25 °C was dropwise added a solution of trimethylsilyl diazomethane (2.0 M in Et ₂ 0, 60.0 μί, 120 μπιοΐ, 1.5 equiv) (yellow color persists). After stirring for 30 min, the reaction mixture was concentrated under reduced pressure. Purification by flash column chromatography (S1O2, hexanes:EtOAc, 2: 1) gave pure title compounds (34, 12.4 mg, 34.4 pmol, 57 % yield, and 36, 5.52 mg, 16.1 μιηοΐ, 27 % yield) as colorless oils. 34: Rf=0.56 (hexanes:EtOAc, 1: 1); [αβ ⁴ = +46.1 (c=0.18, C ₆ H ₆ ); IR (film): v _max = 3461, 3011, 2958, 2928, 2872, 1736, 1702, 1649, 1454, 1436, 1210, 1170, 1053, 815 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 7.26 (dd, 7= 5.9, 0.9 Hz, 1 H), 6.61 (t, 7= 7.7 Hz, 1 H), 6.26 (d, 7= 5.9 Hz, 1 H), 5.64 - 5.56 (m, 1 H), 5.43 - 5.34 (m, 2 H), 5.19 (dtt, 7= 10.8, 7.5, 1.6 Hz, 1 H), 3.82 (pd, 7= 6.2, 3.7 Hz, 1 H), 3.67 (s, 3 H), 2.52 (ddd, 7= 7.6, 6.3, 4.0 Hz,

2 H), 2.48 (ddd, 7=7.4, 3.1, 1.5 Hz, 2 H), 2.33 - 2.27 (m, 4 H), 2.12 - 2.03 (m, 2 H), 2.06 - 2.00 (m, 2 H), 1.93 (d, 7= 3.9 Hz, 1 H), 1.66 (p, 7= 7.4 Hz, 2 H), 1.37 (s, 3 H), 0.97 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-

NMR (151 MHz, CDCh) δ 196.69, 174.03, 167.50, 142.62, 135.68, 132.59, 131.48, 131.38, 125.14, 123.83, 70.79, 51.56, 47.59, 35.83, 35.70, 34.99, 33.36, 26.74, 24.62, 24.10, 20.78, 14.21 ppm; HR-MS (ESI-TOF): calcd for C22H ₃ 20 ₄ Na [M+Na] ⁺ : 383.2193, found: 383.2174. 36: R _f =0.50 (hexanes:EtOAc, 1 : 1); [α ⁴ = -17.6 (c = 0.33, C ₆ H ₆ ); IR (film): v _max = 3423, 2956, 2923, 2852, 1736, 1649, 1454, 1439, 1259, 1169, 808 cm ^"1 ; 'H-NMR (600 MHz, CDCh) δ 7.19 (dd, 7=6.0, 0.8 Hz, 1 H), 6.55 (t, 7=7.7 Hz, 1 H), 6.19 (d, 7= 5.9 Hz, 1 H), 5.57 - 5.50 (m, 1 H), 5.37 - 5.27 (m, 2 H), 5.15 - 5.08 (m, 1 H), 3.80 - 3.72 (m, 1 H), 3.60 (s, 3 H), 2.49 (ddd, 7= 15.3, 8.1, 7.2 Hz, 1 H), 2.45 - 2.35 (m,

3 H), 2.23 (t, 7= 7.3 Hz, 4 H), 2.04 - 1.91 (m, 4 H), 1.74 (d, 7= 3.8 Hz, 1 H), 1.59 (p, 7=7.2 Hz, 2 H), 1.32 (s, 3 H), 0.91 (t, 7=7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 196.83, 174.08, 167.66, 142.90, 135.92, 132.72, 131.61, 131.42, 125.27, 123.93, 70.83, 51.70, 47.77, 35.99, 35.77, 35.14, 33.51, 26.90, 24.78, 24.33, 20.94, 14.36 ppm; HR-MS (ESI-TOF): calcd for C22H ₃₂ 0 ₄ Na [M+Na] ⁺ : 383.2193, found: 383.2179.

[00244] (5Z,12£,17Z)-8-Methyl-l,15-epoxyprosta-5,9,12,17-tetraene-l ,ll-dione (35) and (5Z,8p,12£,17Z)-8-Methyl-l,15-epoxyprosta-5,9,12,17-tetraen e-l,ll-dione (37): To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (69.6 mg, 202 μπιοι, 1.4 equiv) and 4- dimethylaminopyridine (106 mg, 866 μιηοΐ, 6.0 equiv) in CH2CI2 (100 mL) was added a solution of compound 142 (50.0 mg, 144 μιηοΐ, 1.0 equiv) in CH2CI2 (50 mL) at 25 °C dropwise via syringe pump over 15 h. After stirring for an additional 2 h, the reaction mixture was washed sequentially with sat. aq. NaHCC -solution (50 mL), aq. HC1 (0.2 M; 50 mL), and brine (50 mL). The organic layer was dried (MgS0 ₄ ), filtered, and concentrated. Flash column chromatography (S1O2, hexanes: EtOAc, 3: 1) yielded pure title compounds (35, 17.9 mg, 54.5 μιηοΐ, 38 % yield, and 37, 10.1 mg, 30.8 μηιοΐ, 21 % yield) as colorless oils. 35: R _f = 0.48 (hexanes :EtO Ac, 2: 1); [αβ ⁴ = +43.0 (c= 0.384, C ₆ ¾); IR (film): Vmax = 3010, 2962, 2930, 2872, 1729, 1705, 1654, 1585, 1455, 1239, 1155, 1045, 829 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.23 (dd, 7= 5.9, 0.9 Hz, 1 H), 6.39 (ddd, 7= 12.3, 3.1, 0.9 Hz, 1 H), 6.28 (d, 7= 5.9 Hz, 1 H), 5.62 - 5.54 (m, 1 H), 5.36 (dtt, 7= 10.8, 7.5, 1.6 Hz, 1 H), 5.28 - 5.21 (m, 1 H), 5.13 - 5.02 (m, 2 H), 3.07 (dd, 7= 14.5, 11.3 Hz, 1 H), 2.86 (ddd, 7= 15.6, 12.3, 11.1 Hz, 1 H), 2.69 (ddt, 7= 14.1, 11.5, 8.4 Hz, 1 H), 2.55 - 2.49 (m, 1 H), 2.48 - 2.43 (m, 1 H), 2.41 (ddd, 7= 15.7, 3.2, 2.3 Hz, 1 H), 2.32 (ddd, 7= 15.3, 10.4, 2.4 Hz, 1 H), 2.19 (ddd, 7= 15.3, 8.4, 2.3 Hz, 1 H), 2.14 - 2.06 (m, 3 H), 1.88 - 1.78 (m, 1 H), 1.73 (dddd, 7= 19.0, 10.7, 4.4, 2.3 Hz, 1 H), 1.40 (s, 3 H), 1.40 - 1.30 (m, 1 H), 0.99 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCb) δ 196.55, 173.03, 166.92, 142.80, 135.47, 133.07, 131.73, 131.46, 125.44, 122.82, 73.41, 48.03, 35.78, 34.06, 32.98, 32.60, 26.06, 25.97, 24.79, 20.90, 14.31 ppm; HR-MS (ESI-TOF): calcd for C2iH ₂ 80 ₃ Na [M+Na] ⁺ : 351.1931, found: 351.1921. 37: R _f = 0.53 (hexanes :EtO Ac, 2: 1); [a]¾ ⁴ = +4.93 (c = 0.142, C ₆ H ₆ ); IR (film): v _max = 3010, 2963, 2931, 2871, 1763, 1730, 1703, 1652, 1538, 1455, 1346, 1241, 1211, 1165, 1062, 804 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.21 (dd, 7= 6.0, 0.9 Hz, 1 H), 6.71 (dd, 7= 12.2, 2.7 Hz, 1 H), 6.34 (d, 7= 5.9 Hz, 1 H), 5.56 - 5.47 (m, 1 H), 5.32 - 5.24 (m, 1 H), 5.23 - 5.16 (m, 1 H), 5.13 (dtd, 7= 9.3, 5.0, 1.8 Hz, 1 H), 5.00 (tt, 7= 10.6, 2.6 Hz, 1 H), 3.02 (ddd, 7= 16.8, 12.3, 4.8 Hz, 1 H), 2.90 (dd, 7= 15.9, 10.3 Hz, 1 H), 2.63 - 2.56 (m, 1 H), 2.53 - 2.45 (m, 1 H), 2.35 - 2.27 (m, 3 H), 2.23 - 2.16 (m, 1 H), 2.13 - 2.05 (m, 3 H), 1.91 - 1.81 (m, 2 H), 1.50 - 1.42 (m, 1 H), 1.35 (s, 3 H), 0.97 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C- NMR (151 MHz, CDC1 ₃ ) δ 196.87, 173.03, 167.65, 142.77, 135.30, 133.15, 130.76, 128.85, 125.53, 123.39, 71.51, 47.70, 35.06, 32.25, 30.92, 29.27, 25.54, 25.04, 23.49, 20.96, 14.30 ppm; HR-MS (ESI- TOF): calcd for C2iH ₂₈ 0 ₃ Na [M+Na] ⁺ : 351.1931, found: 351.1919.

144

[00245] (5Z,12£',15«,17Z)-15-{[tert-Butyl(dimethyl)silyl]oxy}-l-[( 4- methoxybenzyl)oxy]prosta-5,9,12,17-tetraen-ll-one (144): 144: R _f = 0.58 (hexanes:EtOAc, 3: 1); [αβ ⁵ = +87.2 (c = 1.0 in C ₆ H ₆ ); IR (film): v _max = 2930, 2856, 1704, 1656, 1513, 1247, 1095, 835, 775 cm ^"1 ; Ή-NMR (600 MHz, CDCI3) δ 7.46 (ddd, 7= 6.1, 2.7, 1.0 Hz, 1 H), 7.25 (d, 7= 8.5 Hz, 2 H), 6.87 (d, 7= 8.5 Hz, 2 H), 6.65 - 6.59 (m, 1 H), 6.31 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.52 - 5.43 (m, 2 H), 5.38 - 5.27 (m, 2 H), 4.42 (s, 2 H), 3.85 (tt, 7= 6.8, 4.8 Hz, 1 H), 3.80 (s, 3 H), 3.52 - 3.45 (m, 1 H), 3.42 (t, 7= 6.5 Hz, 2 H), 2.54 (dddd, 7= 14.5, 6.7, 4.2, 1.6 Hz, 1 H), 2.46 - 2.34 (m, 2 H), 2.31 - 2.15 (m, 4 H), 2.07 - 1.95 (m, 4 H), 1.63 - 1.54 (m, 2 H), 1.41 (tt, 7= 10.0, 6.3 Hz, 2 H), 0.94 (t, 7= 7.5 Hz, 3 H), 0.85 (s, 9 H), 0.04 (s, 3 H), 0.00 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.37, 161.67, 159.24, 139.25, 135.00, 134.16, 133.04, 132.60, 130.81, 129.31, 125.18, 124.49, 113.88, 72.68, 71.76, 70.02, 55.39, 43.51, 36.85, 35.76, 30.57, 29.54, 27.29, 26.31, 25.92, 20.88, 18.13, 14.32, -4.39, -4.53 ppm; HR-MS (ESI-TOF): calcd for C ₃₄ H5 ₂ 0 ₄ SiNa [M+Na] ⁺ : 575.3527, found: 575.3507.

145

[00246] (5Z,12£,15«,17Z)-15-Hydroxy-l-[(4-methoxybenzyl)oxy]prosta -5,9,12,17- tetraen-ll-one (145): 145: R _f = 0.39 (hexanes:EtOAc, 1 : 1); [αβ ⁵ = +133.8 (c = 1.0 in C ₆ ¾); IR (film): v _max = 3430, 2933, 2859, 1699, 1651, 1513, 1247, 1097, 1036, 819 cm ^"1 ; Ή-NMR (600 MHz, CDCI ₃ ) δ 7.49 (ddd, 7= 6.1, 2.6, 1.0 Hz, 1 H), 7.25 (d, 7= 8.6 Hz, 2 H), 6.87 (d, 7= 8.6 Hz, 2 H), 6.64 (dd, 7= 9.1, 6.6 Hz, 1 H), 6.33 (dd, 7= 5.9, 1.8 Hz, 1 H), 5.64 - 5.56 (m, 1 H), 5.51 - 5.44 (m, 1 H), 5.40 - 5.34 (m, 1 H), 5.34 - 5.28 (m, 1 H), 4.42 (s, 2 H), 3.84 - 3.78 (m, 1 H), 3.80 (s, 3 H), 3.56 - 3.50 (m, 1 H), 3.42 (t, 7= 6.5 Hz, 2 H), 2.62 - 2.54 (m, 1 H), 2.48 (ddd, 7= 15.1, 6.4, 4.8 Hz, 1 H), 2.45 - 2.40 (m, 1 H), 2.35 - 2.17 (m, 3 H), 2.10 - 2.03 (m, 2 H), 2.03 - 1.96 (m, 2 H), 1.85 (br s, 1 H), 1.63 - 1.55 (m, 2 H), 1.41 (tt, 7= 7.5, 7.5 Hz, 2 H), 0.97 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.47, 161.95, 159.26, 139.76, 135.78, 134.96, 132.73, 131.93, 130.79, 129.35, 125.04, 123.92, 113.90, 72.70, 70.77, 70.00, 55.42, 43.50, 36.58, 35.26, 30.46, 29.54, 27.32, 26.32, 20.90, 14.35 ppm; HR-MS (ESI-TOF): calcd for C ₂₈ H ₃₈ 0 ₄ Na [M+Na] ⁺ : 461.2662, found: 461.2657.

146

[00247] (5Z,12£',15S,17Z)-15-Fluoro-l-[(4-methoxybenzyl)oxy]prosta- 5,9,12,17- tetraen-ll-one (146): 146: R _f =0.27 (hexanes:EtOAc, 4: 1); [ojg ⁵ = +137.9 (c=0.80 in C ₆ H ₆ ); IR (film): Vmax = 2933, 2857, 1703, 1657, 1513, 1246, 1098, 1035, 820 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 7.50 (ddd, 7=6.1, 2.6, 1.0 Hz, 1 H), 7.25 (d, 7= 8.6 Hz, 2 H), 6.87 (d, 7= 8.6 Hz, 2 H), 6.59 (dd, 7= 8.2, 6.8 Hz, 1 H), 6.33 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.60 - 5.53 (m, 1 H), 5.52 - 5.45 (m, 1 H), 5.40 - 5.34 (m, 1 H), 5.34 - 5.29 (m, 1 H), 4.65 (dtt, 7= 47.9, 6.7, 5.3 Hz, 1 H), 4.42 (s, 2 H), 3.80 (s, 3 H), 3.51 - 3.45 (m, 1 H), 3.43 (t, 7= 6.5 Hz, 2 H), 2.70 - 2.51 (m, 3 H), 2.51 - 2.36 (m, 2 H), 2.25 - 2.17 (m, 1 H), 2.08 - 1.96 (m, 4 H), 1.63 - 1.55 (m, 2 H), 1.46 - 1.38 (m, 2 H), 0.96 (t, 7= 7.6 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 196.31, 161.92, 159.27, 139.94, 135.47, 134.95, 132.86, 130.83, 129.59 (d, 7= 6.7 Hz), 129.35, 124.95, 122.21 (d, 7= 6.3 Hz), 113.90, 92.15 (d, 7= 174.3 Hz), 72.71, 70.02, 55.42, 43.42, 34.50 (d, 7= 22.6 Hz), 32.75 (d, 7= 21.4 Hz), 30.44, 29.54, 27.31, 26.31, 20.88, 14.21 ppm; HR-MS (ESI-TOF): calcd for C28H ₃ 7F0 ₃ Na [M+Na] ⁺ : 463.2619, found: 463.2618.

38

[00248] (5Z,12£,15S,17Z)-15-Fluoro-ll-oxoprosta-5,9,12,17-tetraen-l -oic acid (38):

To a stirred solution of iluorodienone 146 (10 mg, 23 μιηοΐ, 1.0 equiv) in CH ₃ CN (90 μί) and ¾0 (10 μί,) at 25 °C was added 4-acetylamino-2,2,6,6-tetramethyl-l-oxo-piperidinium tetrafluoroborate (16 mg, 140 μηιοΐ, 6.0 equiv). After stirring at 25 °C for 35 min, the reaction mixture was diluted with water (2 mL). The aqueous layer was extracted with ether (3 x 5 rnL). The combined organic extracts were washed with brine (10 mL), dried over Na ₂ S0 ₄ and concentrated under reduced pressure. Purification by preparative thin layer chromatography (S1O2, EtOAc) gave pure title compound (28, 3.4 mg, 10 μπιοΐ, 45 % yield) as a yellow oil. 38: R _f = 0.27 (EtOAc); [αβ ⁵ = +106.5 (c = 0.2 in C ₆ H ₆ ); IR (film): v _ma x = 2926, 1705, 1657, 1213, 1033 cm ^"1 ; 'H-NMR (600 MHz, CDC1 ₃ ) δ 7.51 (ddd, 7= 6.0, 2.6, 1.0 Hz, 1 H), 6.60 (t, 7= 7.6 Hz, 1 H), 6.35 (dd, 7= 6.0, 1.8 Hz, 1 H), 5.62 - 5.52 (m, 1 H), 5.52 - 5.44 (m, 1 H), 5.44 - 5.32 (m, 2 H), 4.67 (dtt, 7= 47.9, 6.9, 5.3 Hz, 1 H), 3.56 - 3.45 (m, 1 H), 2.73 - 2.51 (m, 3 H), 2.51 - 2.38 (m, 2 H), 2.35 (t, 7= 7.3 Hz, 2 H), 2.28 - 2.20 (m, 1 H), 2.10 - 2.01 (m, 4 H), 1.70 (tt, 7= 7.4 Hz, 2 H), 0.97 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.31, 177.09, 161.75, 139.86, 135.51, 135.09, 131.60, 129.76 (d, 7= 6.4 Hz), 126.03, 122.20 (d, 7=6.2 Hz), 92.21 (d, 7= 174.3 Hz), 43.31, 34.51 (d, 7=22.5 Hz), 32.98, 32.76 (d, 7= 21.4 Hz), 30.39, 26.70, 24.53, 20.89, 14.21 ppm; HR-MS (ESI-TOF): calcd for C2oH ₂₇ F0 ₃ Na [M+Na] ⁺ : 357.1836, found: 357.1827.

39

[00249] Methyl (5Z,12£,15S,17Z)-15-fluoro-ll-oxoprosta-5,9,12,17-tetraen-l -oate

(39): To a stirred solution of carboxylic acid 38 (2.5 mg, 7.5 μηιοΐ, 1.0 equiv) in C6¾:MeOH (3:2, 0.35 mL) at 25 °C was added trimethylsilyl diazomethane (2.0 M in diethyl ether, 5.6 μί, 11.2 μιηοΐ, 1.5 equiv) (yellow color persisted). After stirring at 25 °C for 35 min, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (hexanes:EtOAc, 4: 1) to give the pure title compound (39, 1.3 mg, 3.7 μιηοΐ, 50 % yield) as a light yellow oil. 39: R _f = 0.45 (hexanes:EtOAc, 2: 1); [a]j¾ ⁵ = +163.6 (c = 0.18 in C ₆ ¾); IR (film): v _max = 2926, 1736, 1705, 1657, 1026 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 7.51 (dd, 7= 6.1, 2.6 Hz, 1 H), 6.60 (t, 7= 7.6 Hz, 1 H), 6.35 (d, 7= 6.1 Hz, 1 H), 5.60 - 5.53 (m, 1 H), 5.51 - 5.44 (m, 1 H), 5.41 - 5.33 (m, 2 H), 4.66 (dtt, 7= 48.0, 6.0, 6.0 Hz, 1 H), 3.66 (s, 3 H), 3.54 - 3.46 (m, 1 H), 2.71 - 2.52 (m, 3 H), 2.51 - 2.37 (m, 2 H), 2.30 (t, 7= 7.4 Hz, 2 H), 2.27 - 2.19 (m, 1 H), 2.09 - 1.99 (m, 4 H), 1.68 (tt, 7= 7.5, 7.5 Hz, 2 H), 0.97 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 196.28, 174.00, 161.76, 139.85, 135.49, 135.06, 131.78, 129.72 (d, 7= 6.6 Hz), 125.83, 122.21 (d, 7= 6.3 Hz), 92.16 (d, 7= 174.4 Hz), 51.67, 43.32, 34.51 (d, 7= 22.5 Hz), 33.51, 32.77 (d, 7= 21.4 Hz), 30.37, 26.83, 24.80, 20.89, 14.22 ppm; HR-MS (ESI-TOF): calcd for C2iH ₂₉ F0 ₃ Na [M+Na] ⁺ : 371.1993, found: 371.2006.

149

[00250] l-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)cyclopent-2-en-l- ol (149): 149:

R _f = 0.40 (hexanes:EtOAc, 5: 1); IR (film): = 3421, 3055, 2954, 2857, 1541, 1472, 1360, 1254, 1084, 1033, 1006, 835, 775 cm ^"1 ; 'H-NMR (600 MHz, CDCI3) δ 5.84 (dt, 7= 5.7, 2.3 Hz, 1 H), 5.78 (dt, 7= 5.6, 2.1 Hz, 1 H), 3.95 (br s, 1 H), 3.90 - 3.88 (m, 2 H), 2.50 - 2.45 (m, 1 H), 2.27 - 2.21 (m, 1 H), 1.96 (ddd, 7= 13.3, 8.4, 4.2 Hz, 1 H), 1.93 - 1.80 (m, 3 H), 0.89 (s, 9 H), 0.08 (s, 3 H), 0.08 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 136.21, 132.93, 85.78, 61.37, 41.31, 38.11, 30.85, 25.93, 18.15, -5.50 ppm; HR-MS (ESI-TOF): calcd for CoHzeOzSiNa [M+Na] ⁺ : 265.1599, found: 265.1589.

[00251] 3-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)cyclopent-2-en-l- one (150): 150:

R _f = 0.50 (hexanes:EtOAc, 3:2); IR (film): v _nm = 2954, 2928, 2857, 1709, 1674, 1617, 1472, 1255, 1094, 776 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 6.00 (s, 1 H), 3.84 (t, 7= 6.2 Hz, 2 H), 2.63 - 2.61 (m, 4 H), 2.40 - 2.39 (m, 2 H), 0.87 (s, 9 H), 0.04 (s, 6 H) ppm; ¹³ C-NMR (151 MHz, CDCI ₃ ) 5210.37, 180.45, 130.75, 60.84, 36.82, 35.35, 32.12, 25.94, 18.32, -5.29, -5.30 ppm; HR-MS (ESI-TOF): calcd for C13H25O2S1 [M+H] ⁺ : 241.1618, found: 241.1622.

[00252] (5£)-3-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-5-[(3S,5Z) -3-{[fert- butyl(dimethyl)silyl]oxy}-oct-5-en-l-ylidene]cyclopent-2-en- l-one (152): 152: R _f = 0.73 (hexanes:EtOAc, 3: 1); [a]^ ⁵ = +16.3 c = 1.0 in C ₆ ¾); IR (film): v _max = 2955, 2929, 2886, 2856, 1704, 1663, 1611, 1472, 1361, 1254, 1091 cm ^"1 ; 'H-NMR (500 MHz, C ₆ D ₆ ) δ 6.85 - 6.75 (m, 1 H), 6.17 - 6.11 (m, 1 H), 5.55 - 5.39 (m, 2 H), 3.80 - 3.69 (m, 1 H), 3.48 (td, 7= 6.3, 0.5 Hz, 2 H), 2.90 - 2.72 (m, 2 H), 2.32 - 2.14 (m, 6 H), 1.99 (ddt, 7= 7.9, 7.3, 6.3 Hz, 2 H), 0.97 (s, 9 H), 0.93 (s, 9 H), 0.92 (t, 7= 7.5 Hz, 3 H), 0.07 (d, 7= 0.4 Hz, 3 H), 0.06 (d, 7= 0.4 Hz, 3 H), -0.01 (s, 6 H) ppm; ¹³ C-NMR (125 MHz, C ₆ D ₆ ) δ 194.49, 170.62, 137.55, 133.92, 132.72, 129.85, 125.06, 71.94, 60.98, 37.60, 36.36, 35.84, 35.42, 26.08, 26.03, 21.15, 18.36, 18.27, 14.44, -4.38, -4.39, -5.32 ppm; HR-MS (ESI-TOF): calcd for C27H ₅ i0 ₃ Si2 [M+H] ⁺ : 479.3371, found: 479.3375.

[00253] (5£')-3-(2-Hydroxyethyl)-5-[(3S,5Z)-3-hydroxyoct-5-en-l-yli dene]cyclopent-

2-en-l-one (40): To a stirred solution of dienone 152 (30.0 mg, 62.6 μπιοΐ, 1.0 equiv) in MeCN (0.6 mL) at 0 °C was dropwise added a solution of HF (50 % aq., 124 μί, ca. 3.10 mmol, ca. 50 equiv.) in MeCN (0.6 mL). After stirring for 1 h at this temperature, the reaction mixture was quenched by addition of sat. aq. NaHCCVsolution (10 mL), and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with sat. brine (5 mL), dried (Na ₂ SC>4), filtered, and concentrated under reduced pressure to a volume of ca. 0.1 mL (not to dryness!). Flash column chromatography (S1O ₂ , EtOAc) yielded pure title compound (40, 15.5 mg, 62.0 pmol, 99 % yield) as a colorless oil. 40: R _f = 0.25 (EtOAc); [α = +9.8 (c = 1.0 in C ₆ ¾); IR (film): v _max = 3372, 2960, 2930, 1692, 1648, 1603, 1413, 1334, 1275, 1048 cm ^"1 ; 'H-NMR (500 MHz, C ₆ D ₆ ) δ 6.80 (tt, 7= 7.8, 1.7 Hz, 1 H), 6.22 (s, 1 H), 5.59 - 5.50 (m, 2 H), 4.00 (s, 2 H), 3.81 (quint, 7= 6.1 Hz, 1 H), 3.69 (t, 7= 6.1 Hz, 1 H), 2.96 (d, J = 21.2 Hz, 1 H), 2.82 (d, 7= 21.2 Hz, 1 H), 2.43 - 2.23 (m, 6 H), 2.11 - 2.02 (m, 2 H), 0.96 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (125 MHz, C ₆ D ₆ ) δ 196.83, 174.27, 137.83, 134.27, 132.35, 131.51, 125.33, 70.85, 59.86, 37.50, 36.51, 35.72, 35.32, 21.19, 14.53 ppm; HR-MS (ESI-TOF): calcd for Ci ₅ H ₂ 20 ₃ Na [M+Na] ⁺ : 273.1461, found: 273.1465.

[00254] (5£')-3-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-5-[(2£', 5Z)-octa-2,5-dien-l- ylidene]cyclo-pent-2-en-l-one (154): 154: R _f = 0.69 (hexanes: EtOAc, 3: 1); IR (film): v _ma x = 2955, 2929, 2856, 1702, 1662, 1257, 1091 cm ^"1 ; Ή-NMR (500 MHz, C ₆ D ₆ ) δ 6.81 (ddt, 7= 8.1, 7.3, 1.9 Hz, 1 H), 6.26 (ddd, 7= 17.5, 10.6, 0.7 Hz, 1 H), 6.08 (ddt, 7= 1.7, 1.2, 0.6 Hz, 1 H), 5.56 - 5.39 (m, 2 H), 5.21 (dt, 7= 17.5, 0.8 Hz, 1 H), 5.02 - 4.92 (m, 1 H), 3.80 - 3.68 (m, 1 H), 3.02 - 2.76 (m, 2 H), 2.33 - 2.15 (m, 4 H), 2.04 - 1.91 (m, 2 H), 0.95 (s, 9 H), 0.89 (t, 7= 7.5 Hz, 3 H), 0.05 (s, 3 H), 0.05 (s, 3 H) ppm; ¹³ C-NMR (125 MHz, C ₆ D ₆ ) δ 194.24, 163.95, 137.20, 133.96, 133.82, 133.11, 130.58, 125.00, 121.00, 71.92, 37.57, 35.84, 30.42, 26.04, 21.14, 18.25, 14.40, -4.41, -4.43 ppm; HR-MS (ESI-TOF): calcd for C ₂ iH ₃ 40 ₂ SiNa [M+Na] ⁺ : 369.2220, found: 369.2216.

[00255] (5£')-3-(2-Hydroxyethyl)-5-[(2£',5Z)-octa-2,5-dien-l-ylide ne]cyclopent-2-en- 1-one (41): To a stirred solution of TBS-protected trienone 154 (20.0 mg, 57.8 μιηοΐ, l .O equiv) in MeCN (2 mL) at 0 °C was dropwise added a solution of HF (50 % aq., 100 μί, ca. 2.89 mmol, ca. 50 equiv) in MeCN (1 mL). After stirring for 15 min at this temperature, the reaction mixture was quenched by addition of sat. brine (5 mL) and extracted with EtOAc (5 x 5 mL). The combined organic extracts were dried (Na2S04), filtered, and concentrated to a volume of ca. 1 mL (not to dryness!). Purification by flash column chromatography (S1O ₂ , hexanes:EtOAc, 1 :4) gave pure title compound (41, 11.5 mg, 50.2 μιηοΐ, 87 % yield) as a colorless oil. 41: R _f = 0.74 (EtOAc); IR (film): v _max = 3419, 2962, 2930, 1693, 1650, 1621, 1564, 1418, 1349, 1271, 1200, 1049 cm ^"1 ; >H-NMR (600 MHz, CDCI3) δ 6.90 (d, 7= 10.0 Hz, 1 H), 6.22 - 6.14 (m, 3 H), 5.53 - 5.49 (m, 1 H), 5.37 - 5.33 (m, 1 H), 3.92 (t, 7= 6.3 Hz, 2 H), 3.24 (s, 3 H), 2.94 (t, 7= 6.1 Hz, 2 H), 2.72 (t, 7=6.5 Hz, 2 H), 2.05 (quint, 7= 7.2 Hz, 2 H), 0.97 (t, 7=7.6 Hz, 3 H) ppm; ¹³ C-NMR (125 MHz, CDC1 ₃ ) δ 197.19, 171.39, 143.49, 133.95, 133.21, 132.83, 130.48, 126.32, 124.70, 60.31, 36.23, 35.39, 31.08, 20.67, 14.29 ppm; HR-MS (ESI- TOF): calcd for C15H21O2 [M+H] ⁺ : 233.1536, found: 233.1538.

155a

[00256] Cobalt alkyne complex 155a: 155a: R _f = 0.95 (pentane:Et ₂ 0, 9: 1); IR (film): Vmax = 2957, 2930, 2860, 2092, 2047, 1997, 1256, 1098, 834 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 5.94 (s, 1 H), 3.75 (t, 7= 7.0 Hz, 2 H), 2.97 (d, 7= 7.0 Hz, 2 H), 0.83 (s, 9 H), 0.00 (s, 6 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 199.93, 92.39, 73.65, 63.59, 37.16, 25.91, 18.33, -5.38 ppm.

[00257] 2-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)cyclopent-2-en-l- one (157): 157:

R _f = 0.17 (hexanes:Et ₂ 0, 9:1); IR (film): v _max = 2954, 2928, 2856, 1703, 1251, 1098 cm-'; 'H-NMR (600 MHz, CDCI3) δ 7.44 - 7.37 (m, 1 H), 3.69 (t, 7=6.4 Hz, 2 H), 2.55 (dq, 7= 4.5, 2.2 Hz, 2 H), 2.37 (ddd, 7= 12.3, 5.8, 3.8 Hz, 4 H), 0.85 (s, 9 H), 0.00 (s, 6 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 209.85, 159.42, 143.28, 61.04, 34.36, 28.34, 26.65, 25.88, 18.25, -5.34 ppm; HR-MS (ESI-TOF): calcd for C ₁₃ H ₂ 5O ₂ S1 [M+H] ⁺ : 241.1618, found: 241.1607.

[00258] (5£')-2-(2-Hydroxyethyl)-5-[(3S,5Z)-3-hydroxyoct-5-en-l-yli dene]cyclopent- 2-en-l-one (42): To a stirred solution of diisopropylamine (0.13 mL, 0.98 mmol, 1.3 equiv) in THF (8 mL) at 0 °C was dropwise added n-butyl lithium (2.5 M in hexanes, 0.33 mL, 0.83 mmol, 1.1 equiv). After stirring for 20 min at this temperature, the clear solution was cooled to -78 °C and a solution of enone 157 (0.18 g, 0.77 mmol, l.O equiv) in THF (2 mL) was added dropwise. After stirring the resulting slightly yellow solution for an additional 20 min at this temperature, a solution of aldehyde 58 (0.19 g, 0.77 mmol, 1.0 equiv) in THF (2 mL) was added dropwise and stirring at this temperature was continued for an additional 30 min. The reaction mixture was then quenched by addition of sat. aq. NH4Cl-solution (20 mL), diluted with Et20 (20 mL), and allowed to warm to 25 °C. The phases were separated, the aqueous layer was extracted with Et ₂ 0 (2 x 25 mL), and the combined organic extracts were washed with brine (50 mL), dried (NazSC^), filtered, and concentrated under reduced pressure. The crude aldol product was taken to the next step without further purification.

[00259] To a stirred solution of aldol product (0.38 g, 0.77 mmol, 1.0 equiv) in CH ₂ CI ₂ (10 mL) at 0 °C was added Et ₃ N (1.0 mL, 7.7 mmol, 10 equiv), and then, slowly and dropwise, methanesulfonyl chloride (0.29 mL, 3.9 mmol, 5.0 equiv). After stirring for 2 h at 25 °C, the reaction mixture was quenched by addition of H2O (20 mL) and diluted with CH2CI2 (20 mL). The phases were separated, the aqueous layer was extracted with CH ₂ CI ₂ (2 x 20 mL), and the combined organic extracts were washed with H2O (20 mL), dried (Na2S04), filtered, and concentrated. The crude mesylate was taken to the next step without further purification.

[00260] To a vigorously stirred solution of above mesylate (0.44 g, 0.77 mmol, 1.0 equiv) in CH2CI2 (25 mL) at 25 °C was added A1 ₂ 0 ₃ (0.78 g, 7.7 mmol, 10 equiv). After 16 h the resulting suspension was then filtered through Celite®, washed with EtOAc, and the filtrate was concentrated under reduced pressure. Flash column chromatography (S1O2, hexanes:EtOAc, 8.5:1.5) gave pure TBS protected intermediate 159 (0.15 g, 0.31 mmol 40 % yield for the three steps) as a light yellow oil.

[00261] To a stirred solution of above TBS protected intermediate 159 (66 mg, 0.13 mmol, 1.0 equiv) in MeCN (1.5 mL) at 0 °C was added dropwise HF (50 % aq., 0.14 mL, 4.1 mmol, 30 equiv). After stirring for 30 min at this temperature, the reaction mixture was quenched by addition of sat. brine (5 mL) and diluted with EtOAc (10 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3 x 5 mL), and the combined organic extracts were washed with saturated aqueous NaHC0 ₃ -solution (20 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (S1O ₂ , hexanes:EtOAc, 8:2) gave pure title compound (42, 13 mg, 0.051 mmol, 38 % yield) as a colorless oil. 42: R _f = 0.70 (hexanes:EtOAc, 9:1), [a]¾ ⁵ =-3.53 (c = 0.34 in CHCI3); IR (film): Vmax = 2947, 2921, 1727, 1546, 1343, 1272, 1169 cm ^"1 ; 'H-NMR (600 MHz, CDC1 ₃ ) δ 7.34 (s, 1 H), 6.73 (t, 7= 7.8 Hz, 1 H), 5.66 - 5.54 (m, 1 H), 5.44 - 5.32 (m, 1 H), 3.93 - 3.81 (m, 1 H), 3.78 (t, 7=5.8 Hz, 2 H), 3.23 - 3.13 (m, 2 H), 2.59 (t, 7=6.0 Hz, 2 H), 2.44 (q, 7=7.5, 6.7 Hz, 2 H), 2.29 (quint, 7= 7.9 Hz, 2 H), 2.14 - 2.01 (m, 2 H), 0.99 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.84, 152.83, 145.81, 136.74, 135.68, 132.36, 123.74, 70.49, 61.21, 36.90, 35.05, 30.71, 30.05, 20.76, 14.20 ppm; HR-MS (ESI-TOF): calcd for C^C Na [M+Na] ⁺ : 273.1461, found: 273.1452.

161

[00262] (5£)-2-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-5-[(2£,5Z )-octa-2,5-dien-l- ylidene]cyclo-pent-2-en-l-one (161): 161: R _f =0.78 (hexanes:EtOAc _: 8:2); IR (film): v _max = 3012, 2955, 2927, 2855, 1689, 1638, 1627, 1253, 1093, 831 cm ^"1 ; 'H-NMR (600 MHz, CDC1 ₃ ) δ 7.25 (m, 1 H), 6.95 (d, 7= 10.8 Hz, 1 H), 6.26 - 6.12 (m, 2 H), 5.56 - 5.44 (m, 1 H), 5.42 - 5.27 (m, 1 H), 3.79 - 3.68 (m, 2 H), 3.18 - 3.11 (m, 2 H), 2.94 (t, 7=6.7 Hz, 2 H), 2.48 (t, 7= 6.4 Hz, 2 H), 2.10 - 1.97 (m, 2 H), 1.03 - 0.92 (m, 3 H), 0.86 - 0.85 (m, 9 H), 0.00 (s, 6 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 196.62, 150.74, 145.43, 143.21, 133.75, 132.73, 131.00, 126.36, 124.62, 61.03, 30.98, 30.56, 29.06, 25.88, 20.55, 18.23, 14.16, -5.35 ppm: HR-MS (ESI-TOF): calcd for C2iH ₃ 40 ₂ SiNa [M+Na] ⁺ : 369.2220, found: 369.2223.

[00263] (5£)-2-(2-Hydroxyethyl)-5-[(2£,5Z)-octa-2,5-dien-l-ylidene ]cyclopent-2-en- 1-one (43): To a stirred solution of TBS protected analog 95 (15 mg, 43 μπιοΐ, 1.0 equiv) in MeCN (0.5 mL) at 0 °C was dropwise added HF (50 % aq., 0.04 mL, 1.3 mmol, 30 equiv). After stirring for 30 min at this temperature the reaction mixture was then quenched by addition of sat. brine (5 mL) and diluted with EtOAc (10 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3 x 5 mL), and the combined organic extracts were washed with sat. aq. NaHC03-solution (20 mL), dried (Na2SO/ , filtered, and concentrated under reduced pressure. Purification by flash column chromatography (Si0 ₂ , hexanes:EtOAc, 8:2) gave pure title compound (43, 7.0 mg, 30 μπιοΐ, 70 % yield) as a colorless oil. 43: R _f = 0.60 (EtOAc); IR (film): v _max = 3405, 2962, 2930, 2874, 1776, 1679, 1624, 1046 cm ^"1 ; ¹ H-NMR (600 MHz, CDCb) δ 7.23 (s, 1 H), 6.97 (d, 7= 8.5 Hz, 1 H), 6.23 - 6.13 (m, 2 H), 5.48 (q, 7= 7.8 Hz, 1 H), 5.38 - 5.27 (m, 1 H), 3.72 (t, 7= 5.8 Hz, 2 H), 3.20 - 3.10 (m, 2 H), 2.92 (t, 7= 5.7 Hz, 2 H), 2.54 (t, 7=5.9 Hz, 2 H), 2.02 (quint, 7=7.4 Hz, 2 H), 0.93 (t, 7= 7.5 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 197.84, 151.74, 146.36, 144.25, 133.94, 132.52, 132.16, 126.19, 124.46, 61.36, 31.05, 30.76, 30.29, 20.58, 14.18 ppm; HR-MS (ESI-TOF): calcd for Ci ₅ H ₂ o0 ₂ Na [M+Na] ⁺ : 255.1356, found: 255.1365. OTBS

162

[00264] (3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}octan-l-ol (162): 162: R _f =0.50 (hexanes:EtOAc, 4: 1); [a]¾ ⁵ =+11.7 (c= 2.1, C ₆ H ₆ ); FT-IR (neat): v _max = 3363, 2955, 2930, 2858, 1601, 1471, 1463, 1378, 1256, 1058, 1005, 835, 774 cm ^"1 ; ¹ H-NMR (600 MHz, CDC1 ₃ ) δ 3.93 - 3.89 (m, 1 H), 3.87 - 3.82 (m, 1 H), 3.71 (dt, 7= 10.8, 5.4 Hz, 1 H), 2.44 (s, 1 H), 1.85 - 1.79 (m, 1 H), 1.67 - 1.62 (m, 1 H), 1.54 - 1.50 (m, 2 H), 1.32 - 1.24 (s, 6 H), 0.89 - 0.88 (m, 12 H), 0.09 (s, 3 H), 0.08 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 72.12, 60.41, 37.73, 36.87, 32.04, 25.92, 25.11, 22.70, 18.06, 14.09, -4.33, -4.63 ppm; HR-MS (ESI) calcd for C14H33O2S1 [M+H] ⁺ : 261.2244, found: 261.2231.

163

[00265] (3S)-3-{[tert-Butyl(dimethyl)silyl]oxy}octanal (163): 163: R _f =0.60 (hexanes:EtOAc, 10: 1); [αβ ⁵ =-6.1 (c= 1.0, CHC1 ₃ ); FT-IR (neat): v _max = 2956, 2929, 2858, 1727, 1471, 1361, 1254, 1100, 1053, 1005, 835, 774 cm ^"1 ; H-NMR (600 MHz, CDCI3) δ 9.81 (t, 7= 2.5 Hz, 1 H), 4.18 (quint, 7= 5.9 Hz, 1 H), 2.52 - 2.45 (m, 2 H), 1.58 - 1.47 (m, 2 H), 1.36 - 1.22 (m, 6 H), 0.90 - 0.87 (m, 12 H), 0.07 (s, 3 H), 0.06 (s, 3 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 202.60, 68.40, 50.92, 37.91, 31.87, 25.86, 24.90, 22.67, 18.09, 14.08, -4.32, -4.59 ppm; HR-MS (ESI) calcd for CwHsoChSiNa [M+Na] ⁺ : 281.1907, found: 281.1909.

[00266] (5Z,12£',15S)-l,15-Epoxyprosta-5,9,12-triene-l,ll-dione (44): To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (11 mg, 31 μπιοΐ, 2.0 equiv) and 4-dimethylaminopyridine (10 mg, 91 μιηοΐ, 6.0 equiv) in CH2CI2 (10 mL) was added a solution of Δ ¹² - PGJ ₂ (164) (Acharya and Kobayashi, 2006) (5.0 mg, 15 μηιοΐ, 1.0 equiv) in CH2CI2 (5 mL) at 25 °C dropwise via syringe pump over 15 h. After stirring for an additional 2 h, the reaction mixture was washed sequentially with sat. aq. NaHC0 ₃ -solution (10 mL), aq. HC1 (0.2 M, 10 mL), and sat. brine (10 mL). The organic layer was dried (Na ₂ S0 ₄ ), filtered, and concentrated under reduced pressure. Flash column chromatography (S1O2, hexanes:EtOAc, 3: 1) gave pure title compound (3.4 mg, 11 μηιοΐ, 72 % yield) as a colorless oil. 44: R _f = 0.40 (hexanes:EtOAc, 7:3); [a]^ = +26.4 (c = 0.3 in C ₆ ¾); IR (film): vmax = 2930, 2859, 1727, 1704, 1655, 1581, 1456, 1328, 1243, 1151, 1048, 833 cm ^"1 ; ¹ H-NMR (600 MHz, C ₆ D ₆ ) δ 6.78 (ddd, 7= 6.1, 2.6, 0.9 Hz, 1 H), 6.66 (ddt, 7= 11.4, 4.8, 1.3 Hz, 1 H), 6.20 (dd, J= 6. l, 1.9 Hz, 1 H), 5.20 - 5.08 (m, 3 H), 3.22 - 3.20 (m, 1 H), 2.43 (ddd, 7= 14.5, 9.2, 5.7 Hz, 1 H), 2.37 - 2.31 (m, 1 H), 2.26 (ddd, 7= 15.1, 11.4, 9.5 Hz, 1 H), 2.15 - 2.07 (m, 2 H), 2.04 - 1.96 (m, 2 H), 1.86 - 1.81 (m, 1 H), 1.56 - 1.46 (m, 1 H), 1.41 - 1.08 (m, 9 H), 0.87 (t, 7= 7.2 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 194.69, 172.42, 159.56, 140.28, 135.60, 131.83, 130.91, 125.53, 73.20, 43.47, 34.40, 34.14, 32.75, 31.90, 28.45, 26.06, 25.51, 24.64, 22.92, 14.22 ppm; HR-MS (ESI-TOF): calcd for C2oH ₂ 80 ₃ Na [M+Na] ⁺ : 339.1931, found: 339.1925.

[00267] (5Z,12£,15S)-l,15-Epoxyprosta-5,9,12-triene-l,ll-dione (169): To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (15 mg, 42 μηιοΐ, 1.4 equiv) and 4- dimethylaminopyridine (22 mg, 180 μπιοΐ, 6.0 equiv) in CH2CI2 (20 mL) was added a solution of Δ ¹² - PGJ2 (168, 10 mg, 30 μπιοΐ, 1.0 equiv) in CH2CI2 (10 mL) at 25 °C dropwise via syringe pump over 15 h. After stirring for an additional 2 h, the reaction mixture was washed sequentially with sat. aqueous NaHC0 ₃ -solution (10 mL), aqueous HC1 (0.2 M; 10 mL), and brine (10 mL). The organic layer was dried (Na2S04), filtered, and concentrated under reduced pressure. Flash column chromatography (S1O2; hexanes:EtOAc, 3: 1) yielded pure title compound (169, 6.8 mg, 22 μιηοΐ, 72 %) as a white solid. 169: R _f = 0.40 (silica gel, hexanes:EtOAc, 7:3); [αβ ⁵ = +26 (c=0.3 in C ₆ ¾); IR (film): v _max 2930, 2859, 1727, 1704, 1655, 1581, 1456, 1328, 1243, 1151, 1048, 833 cm ^"1 ; Ή-NMR (600 MHz, C ₆ D ₆ ) δ 6.78 (ddd, 7= 6.1, 2.6, 0.9 Hz, 1 H), 6.66 (ddt, 7= 11.4, 4.8, 1.3 Hz, l H), 6.20 (dd, 7=6.1, 1.9 Hz, 1 H), 5.20-5.08 (m, 3 H), 3.22 -3.20 (m, 1 H), 2.43 (ddd, 7= 14.5, 9.2, 5.7 Hz, 1 H), 2.37 - 2.31 (m, 1 H), 2.26 (ddd, 7= 15.1, 11.4, 9.5 Hz, 1 H), 2.15 -2.07 (m, 2 H), 2.04 - 1.96 (m, 2 H), 1.86 - 1.81 (m, 1 H), 1.56- 1.46 (m, 1 H), 1.41 - 1.08 (m, 9 H), 0.87 (t, 7= 7.2 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 194.69, 172.42, 159.56, 140.28, 135.60, 131.83, 130.91, 125.53, 73.20, 43.47, 34.40, 34.14, 32.75, 31.90, 28.45, 26.06, 25.51, 24.64, 22.92, 14.22 ppm; HR-MS (ESI-TOF): calcd for C2oH2 ₈ 0 ₃ Na [M+Na] ⁺ : 339.1931, found: 339.1925. [00268] A ¹² -PGJ ₂ Macrolactones (172, 175 and 178): To a stirred solution of A ¹² -PGJ ₂

(168) (49 mg, 150 μπιοΐ, 1.0 equiv) of in CH ₂ C1 ₂ (10 mL) at 25 °C was added seqentially NEt ₃ (42 pL, 300 μηιοΐ, 2.0 equiv) dimethylaminopyridine (1.8 mg, 15 pmol, 0.1 equiv) and 2-methyl-6- nitrobenzoic anhydride (77 mg, 230 pmol, 1.5 equiv). After stirring for an additional 12 h, the reaction mixture was washed sequentially with sat. aqueous NaHCOs-solution (10 mL), sat. aqueous NH4CI (10 mL), and brine (10 mL). The organic layer was dried (Na ₂ S0 ₄ ), filtered, and concentrated under reduced pressure. The resulting residue was purified by PTLC (silica gel, hexanes:EtOAc= 3: 1) to give dimer 172 (13 mg, 20 μιηοΐ, 27 %), trimer 175 (5.1 mg, 5.3 μπιοΐ, 10 %) and tetramer 178 (4.6 mg, 3.6 μπιοΐ, 9 %) as colorless oils.

[00269] (3aZ,6S,12Z,14aS,17a£,20S,26Z,28aS)-6,20-Dipentyl- 5,10,ll,14,14a,19,20,23,24,25,28,28a-dodecahydro-3H,8H- dicyclopenta[e^][l,14]dioxacyclohexacosine-3,8,17,22(6H,9H)- tetrone (172): Rf=0.40 (silica gel, hexanes:EtOAc, 3: 1); [a]j¾ ⁵ =+59 (c= 1.2 in C ₆ H ₆ ); IR (film): v _ma* 3010, 2954, 2931, 2860, 1732, 1705,

1657, 1581, 1457, 1343, 1240, 1178, 1088, 823 cm ^"1 ; Ή-NMR (600 MHz, CDCh) δ 7.52 (dd, 7=6.0, 2.5 Hz, 2 H), 6.49-6.46 (m, 2 H), 6.33 (dd, 7=6.0, 1.8 Hz, 2 H), 5.49-5.44 (m, 2 H), 5.41 -5.36 (m, 2 H), 5.04-5.00 (m, 2H), 3.43-3.41 (m, 2 H), 2.75-2.70 (m, 2H), 2.61 (ddd, 7= 14.6, 9.6, 7.9 Hz, 2H), 2.42 (dt, 7= 14.6, 6.0 Hz, 2 H), 2.28-2.18 (m, 4H), 2.13- 1.99 (m, 6 H), 1.68- 1.58 (m, 8 H), 1.37- 1.23 (m, 12 H), 0.87 (t, 7=6.7 Hz, 6H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.04, 172.75, 161.50, 139.78, 135.02, 131.60, 130.78, 126.13, 72.91, 43.38, 34.47, 34.30, 33.84, 31.66, 30.66, 26.91, 24.98, 24.75, 22.59, 14.06 ppm, due to the inherent symmetry of the molecule each ¹³ C NMR resonance represents two equivalent C atoms; HR-MS (ESI-TOF): calcd for C ₄ oH ₅ 60 ₆ Na ⁺ [M+Na] ⁺ : 655.3969, found: 655.3966.

[00270] (3a£,6S,12Z,14a5,17a£,20S,26Z,28aS,31a£,34S,40Z,42aS)-6,2 0,34-Tripentyl- 5,10,H,14,14a,19,20,24,25,28,28a,33,34,37,38,39,42,42a-octad ecahydro-3H,8H,22H-tricyclo- penta[e^,ei][l,14,27]trioxacyclononatriacontine-3,8,17,22,31 ,36(6i/,9 /,23H)-hexone (175): R _f = 0.30 (silica gel, hexanes:EtOAc, 3:1); [αβ ⁵ = +87 (c=0.7 in C ₆ H ₆ ); IR (film): v _max 3010, 2961, 2926,

2861, 1731, 1704, 1656, 1536, 1456, 1345, 1207, 1033, 808 cm ^"1 ; >H-NMR (600 MHz, CDC1 ₃ ) δ 7.50 (dd, 7=6.0, 2.5 Hz, 3 H), 6.51 (t, 7=7.6 Hz, 3H), 6.33 (dd, 7=6.0, 1.8 Hz, 3 H), 5.47-5.43 (dt, 7= 10.8, 7.4 Hz, 3H), 5.36-5.32 (dt, 7= 11.0, 7.1 Hz, 3 H), 5.00-4.96 (m, 3 H), 3.47-3.44 (m, 3 H), 2.66-2.56 (m, 6 H), 2.49 (ddd, 7= 14.8, 7.9, 6.1 Hz, 3 H), 2.26 (td, 7=7.8, 3.3 Hz, 6 H), 2.19 (dt, 7= 15.6, 8.2 Hz, 3 H), 2.02 (q, 7=7.4 Hz, 6 H), 1.70- 1.54 (m, 12H), 1.38- 1.24 (m, 18 H), 0.87 (t, 7= 6.7 Hz, 9 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 196.09, 172.90, 161.65, 139.63, 135.02, 131.65, 130.36, 125.87, 72.96, 43.30, 33.92, 33.87, 31.65, 30.29, 26.80, 25.10, 24.82, 22.61, 14.08 ppm, due to the inherent symmetry of the molecule each ¹³ C NMR resonance represents three equivalent C atoms [exception: the signal at 33.87 ppm represents six C atoms]; HR-MS (ESI-TOF): calcd for C6oH ₈₄ 0 ₉ Na ⁺ [M+Na] ⁺ : 971.6008, found: 971.6014.

[00271] (3a£,6S,12Z,14a5,17a£,20S,26Z,28aS,31a£,34S,40Z,42aS,45a� �,48S,54Z)- 6,20,34,48-Tetrapentyl-

5,10,ll,14,14a,19,20,24,25,28,28a,33,34,38,39,42,42a,47,4 8,51,52,53,56,56a-tetracosahydro- 3H,8H,22H,36H-tetracyclopenta[e^",ei i][l,14,27,40]tetraoxacyclo-dopentacontine-

3,8,17,22,31,36,45,50(6H,9H,23H,37H)-octone (178): R _f =0.10 (silica gel, hexanes:EtOAc, 3: 1); [a]¾ ⁵ =+110 (c =0.4 in C ₆ H ₆ ); IR (film): v _max 3010, 2961, 2927, 2861, 1731, 1704, 1656, 1535, 1456,

1346, 1207, 1033, 810 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 7.50 (dd, 7= 6.1, 2.6 Hz, 4 H), 6.52 (t, 7= 7.6 Hz, 4 H), 6.32 (dd, 7= 6.0, 1.8 Hz, 4 H), 5.47 -5.43 (m, 4 H), 5.35 -5.31 (m, 4 H), 5.02 -4.95 (m, 4 H), 3.48 -3.46 (m, 4 H), 2.64-2.49 (m, 12 H), 2.28 -2.18 (m, 12 H), 2.02 (q, 7= 7.4 Hz, 8 H), 1.68 - 1.53 (m, 16 H), 1.37 - 1.25 (m, 24 H), 0.87 (t, 7= 6.6 Hz, 12 H) ppm; ¹³ C-NMR (151 MHz, CDCI ₃ ) δ 196.12, 172.96, 161.74, 139.59, 134.99, 131.66, 130.27, 125.80, 72.89, 43.25, 33.92, 33.89, 33.72, 31.64, 30.26, 26.80, 25.12, 24.84, 22.61, 14.08 ppm, due to the inherent symmetry of the molecule each ¹³ C NMR resonance represents four equivalent C atoms; HR-MS (ESI-TOF): calcd for C ₈ oHn ₂ Oi ₂ Na ⁺ [M+Na] ⁺ : 1287.8046, found: 1287.8052.

[00272] (5Z,12£',15S)-10-Chloro-l,15-epoxyprosta-5,9,12-triene-l,ll -dione (170): To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (16 mg, 45 μιηοΐ, 1.5 equiv) and 4-dimethyl- aminopyridine (11 mg, 90 μηιοΐ, 3.0 equiv) in CH ₂ CI ₂ (20 mL) was added a solution of lO-chloro-Δ ¹² - PGJ2 (166) (12 mg, 30.0 μηιοΐ, 1.0 equiv) in CH2CI2 (10 mL) at 25 °C dropwise via syringe pump over 15 h. After stirring for an additional 2 h, the reaction mixture was washed sequentially with sat. aqueous NaHC0 ₃ -solution (10 mL), aqueous HCl (0.2 M; 10 mL), and brine (10 mL). The organic layer was dried (Na ₂ S04) _: filtered, and concentrated under reduced pressure. Flash column chromatography (Si0 ₂ ; hexanes:EtOAc, 4: 1) yielded pure title compound (170, 7.3 mg, 24 μιηοΐ, 69 %) as a white solid. 170: Rf=0.60 (silica gel, hexanes:EtOAc, 4: 1); m.p. = 91-92°C; [α ⁵ =-44 (c=0.4 in C ₆ ¾); IR (film): v _max 3010, 2955, 2929, 2859, 1716, 1703, 1659, 1279, 1163, 939 cm ^"1 ; 'H-NMR (600 MHz, CDCb) δ 7.41 (d, 7=2.9 Hz, 1 H), 6.67 (dd, 7= 11.6, 4.6 Hz, 1 H), 5.41 (td, 7= 10.4, 5.8 Hz, 1 H), 5.27-5.18 (m, 2 H), 3.72-3.69 (m, 1 H), 2.74-2.66 (m, 2 H), 2.54-2.43 (m, 3 H), 2.32 (ddd, 7= 15.5, 9.1, 2.9 Hz, 1 H), 2.25 (ddd, 7= 15.5, 9.1, 2.6 Hz, 1 H), 2.01 - 1.95 (m, 1 H), 1.65 -1.45 (m, 5 H), 1.31 - 1.20 (m, 5 H), 0.89 (t, 7=6.7 Hz, 3 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 188.25, 173.06, 153.51, 137.85, 137.25, 134.26, 132.52, 124.63, 73.16, 41.58, 34.32, 34.14, 32.78, 31.65, 28.52, 25.86, 25.14, 24.38, 22.58, 14.06 ppm; HR-MS (ESI-TOF): calcd for C2oH ₂ 70 ₃ ClNa ⁺ [M+Na] ⁺ : 373.1541, found: 373.1545.

[00273] 10-Chloro-A ¹² -PGJ ₂ Macrolactones (173, 176 and 179): To a stirred solution of 10-chloro-PGJ ₂ (166) (30 mg, 82 μπιοΐ, 1.0 equiv) of in CH ₂ C1 ₂ (10 mL) at 25 °C was added seqentially NEt3 (23 pL, 160 pmol, 2.0 equiv), dimethylaminopyridine (1.0 mg, 8.2 pmol, 0.1 equiv) and 2- methyl-6-nitrobenzoic anhydride (42 mg, 120 pmol, 1.5 equiv). After stirring for an additional 12 h, the reaction mixture was washed sequentially with sat. aqueous aHC0 ₃ solution (3 mL), sat. aqueous NH ₄ CI (3 mL), and brine (10 mL). The organic layer was dried (Na ₂ S0 ₄ ), filtered, and concentrated under reduced pressure. The resulting residue was purified by PTLC (silica gel, hexanes:EtOAc = 3: l) to give dimer 173 (6.2 mg, 3.0 pmol, 20 %), trimer 176 (2.8 mg, 2.7 pmol, 8 %) and tetramer 179 (1.4 mg, 1.0 pmol, 4 %) as colorless oils.

[00274] (3aZ,65,12Z,14aS,17a£,20S,26Z,28aS)-2,16-Dichloro-6,20-dipe ntyl- 5,10,ll,14,14a,19,20,23,24,25,28,28a-dodecahydro-3H,8H-dicyc lopenta[c r][l,14]dioxacyclo- hexacosine-3,8,17,22(6H,9H)-tetrone (173): R _f =0.50 (silica gel, hexanes:EtOAc, 4: 1); [αβ ⁵ = +21 (c=0.6 in C ₆ ¾); IR (film): v _ma x 3011, 2954, 2930, 2859, 1731, 1715, 1662, 1589, 1457, 1378, 1284, 1148, 1042, 763 cm ^"1 ; ¹ H-NMR (600 MHz, C ₆ D ₆ ) δ 6.82 (d, 7=2.9 Hz, 2 H), 6.72-6.63 (m, 2H), 5.26-5.22 (m, 2 H), 5.09-5.05 (m, 2 H), 5.00-4.96 (m, 2H), 2.91 -2.88 (m, 2H), 2.52-2.47 (m, 2H), 2.35 (ddd, 7= 14.6, 9.5, 7.3 Hz, 2 H), 2.12-2.03 (m, 6H), 1.88- 1.84 (m, 6H), 1.58- 1.10 (m, 20 H), 0.88 (t, 7=7.2 Hz, 6 H) ppm; ¹³ C-NMR (151 MHz, C ₆ D ₆ ) δ 185.17, 170.52, 151.33, 136.14, 135.87, 130.59, 130.19, 123.96, 70.78, 39.74, 32.40, 31.84, 29.97, 28.76, 25.13, 23.48, 23.12, 21.06, 12.33 ppm, due to the inherent symmetry of the molecule each C NMR resonance represents two equivalent C atoms; HR-MS (ESI-TOF): calcd for [M+Na] ⁺ : 723.3190, found: 723.3162.

[00275] (3a£,65,12Z,14aS,17a£,205,26Z,28aS,31a£,34S,40Z,42aS)-2,1 6,30-Trichloro- 6,20,34-tripentyl-5,10,ll,14,14a,19,20,24,25,28,28a,33,34,37 ,38,39,42,42a-octadecahydro- 3H,8H,22H-tricyclopenta[e ,ei][l,14,27]trioxacyclononatriacontine-

3,8,17,22,31,36(6H,9H,23H)-hexone (176): R _f = 0.40 (silica gel, hexanes:EtOAc, 4: 1); [αβ ⁵ = +103

(c = 0.2 in C ₆ H ₆ ); IR (film): v _max 3011, 2954, 2928, 2858, 1730, 1716, 1662, 1589, 1457, 1377, 1284, 1147, 1033, 737 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 7.37 (d, 7= 2.9 Hz, 3 H), 6.65 (t, 7=7.6 Hz, 3 H), 5.50-5.46 (m, 3 H), 5.35 -5.30 (m, 3 H), 5.00-4.96 (m, 3 H), 3.49-3.46 (m, 3 H), 2.67 -2.51 (m, 9 H), 2.31 -2.19 (m, 9H), 2.03 (q, 7= 7.1 Hz, 6 H), 1.70- 1.54 (m, 12 H), 1.38 - 1.22 (m, 18 H), 0.88 (t, 7= 6.7 Hz, 9 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 188.17, 172.87, 154.12, 137.43, 137.16, 133.05, 132.26, 125.26, 72.76, 41.44, 33.90, 33.81, 33.72, 31.62, 30.27, 26.78, 25.12, 24.74, 22.60, 14.07 ppm, due to the inherent symmetry of the molecule each ¹³ C NMR resonance represents three equivalent C atoms; HR-MS (ESI-TOF): calcd for C6oH8i0 ₉ Cl ₃ Na ⁺ [M+Na] ⁺ : 1073.4838, found: 1073.4848.

[00276] (3aE,6S,12Z,14aS,17a£,20S,26Z,28aS,31a£,34S,40Z,42aS,45a£ ,48S,54Z,56aS )-2,16,30,44-Tetrachloro-6,20,34,48-tetrapentyl-

5,10,ll,14,14a,19,20,24,25,28,28a,33,34,38,39,42,42a,47,4 8,51,52,53,56,56a-tetracosahydro- 3H,8H,22H,36H-tetracyclopenta[e^,ei i][l,14,27,40]tetraoxacyclodopentacontine-

3,8,17,22,31,36,45,50(6H,9H,23H,37H)-octone (179): R _f =0.30 (silica gel, hexanes:EtOAc, 4: 1); [αβ =+147 (c =0.1 in C ₆ H ₆ ); IR (film): v _mi » 2952, 2930, 1730, 1717, 1662, 1589, 1458, 1285, 1174,

1040, 867, 761 cm ^"1 ; Ή-NMR (600 MHz, CDC1 ₃ ) δ 7.38 (dd, J =2.9, 0.9 Hz, 4 H), 6.66 (t, =7.7 Hz, 4 H), 5.50-5.45 (m, 4 H), 5.34-5.30 (m, 4 H), 5.01 -4.97 (m, 4 H), 3.51 -3.49 (m, 4 H), 2.63 (dt, /= 11.8, 5.0 Hz, 4 H), 2.60-2.54 (m, 8 H), 2.28 -2.20 (m, 12 H), 2.02 (q, 7=7.3 Hz, 8 H), 1.71 - 1.49 (m, 16 H), 1.37- 1.22 (m, 24 H), 0.87 (t, /= 6.9 Hz, 12 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 188.20, 172.92, 154.23, 137.38, 137.11, 133.03, 132.27, 125.20, 72.68, 41.39, 33.92, 33.85, 33.63, 31.62, 30.23, 26.78, 25.14, 24.76, 22.61, 14.08 ppm, due to the inherent symmetry of the molecule each ¹³ C NMR resonance represents four equivalent C atoms; HR-MS (ESI-TOF): calcd for

[M+Na] ⁺ : 1423.6487, found: 1423.6504.

[00277] (5Z,12£',15S)-10-Chloro-20,20,20-trifluoro-l,15-epoxyprosta -5,9,12-triene- 1,11-dione (171): To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (9.8 mg, 29 μιηοΐ, 1.5 equiv) and 4-dimethylaminopyridine (6.9 mg, 57 μιηοΐ, 3.0 equiv) in CH2CI2 (20 mL) was added a solution of A ¹² -PGJ ₃ (167) (8.0 mg, 19 μπιο1, 1.0 equiv) in CH2CI2 (10 mL) at 25 °C dropwise via syringe pump over 15 h. After stirring for an additional 2 h, the reaction mixture was washed sequentially with sat. aqueous NaHCC -solution (10 mL), aqueous HQ (0.2 M; 10 mL), and brine (10 mL). The organic layer was dried (Na2S04), filtered, and concentrated under reduced pressure. Flash column chromatography (S1O ₂ ; hexanes:EtOAc, 3:1) yielded pure title compound (171, 5.6 mg, 14 μπιο1, 73 %) as a white solid. 171: R _f =0.60 (silica gel, hexanes:EtOAc, 3: 1); m.p. = 92-93 °C; [αβ ⁵ =-14 (c=0.5 in C ₆ H ₆ ); IR (film): v _ma x 3010, 2954, 2928, 2858, 1729, 1713, 1661, 1589, 1456,

1436, 1377, 1239, 1172, 109, 801 cm ^"1 ; Ή-NMR (600 MHz, CDCL) δ 7.41 (dd, 7=3.0, 0.9 Hz, 1 H), 6.65 (dd, 7= 11.5, 4.8 Hz, 1 H), 5.42 (td, 7= 10.3, 5.7 Hz, 1 H), 5.27 -5.21 (m, 2H), 3.71 -3.69 (m, 1 H), 2.74-2.68 (m, 2 H), 2.54-2.43 (m, 3 H), 2.26 (ddd, 7= 15.5, 9.1, 2.6 Hz, 1 H), 2.12-2.04 (m, 2H), 2.01 - 1.95 (m, 1 H), 1.76-1.50 (m, 7 H), 1.48- 1.38 (m, 2 H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 188.22, 173.08, 153.51, 138.04, 137.29, 133.71, 132.51, 127.18 (q, 7=281.9 Hz), 124.59, 72.67, 41.54, 34.18, 34.04, 33.64 (q, 7=29.2 Hz), 32.74, 28.51, 25.87, 24.68, 24.37, 21.87 (q, 7= 3.2 Hz) ppm; HR- MS (ESI-TOF): calcd for C2oH ₂ 5Q3F ₃ Cl ⁺ [M+H] ⁺ : 405.1439, found: 405.1429.

[00278] A ¹² -PGJ ₂ Macrolactones (174, 177 and 180): To a stirred solution of A ¹² -PGJ ₂ (167) (40 mg, 100 μπιοΐ, 1.0 equiv) of in CH2CI2 (10 mL) at 25 °C was added seqentially NEt ₃ (28 μί, 200 μιηοΐ, 1.0 equiv) dimethylaminopyridine (1.2 mg, ΙΟ μπιοΙ, 0.1 equiv) and 2-methyl-6- nitrobenzoic anhydride (52 mg, 150 μπιοΐ, 1.5 equiv). After stirring for an additional 12 h, the reaction mixture was washed sequentially with sat. aqueous NaHC0 ₃ -solution (10 mL), sat. aqueous NH ₄ CI (10 mL), and brine (10 mL). The organic layer was dried (Na2S04), filtered, and concentrated under reduced pressure. The resulting residue was purified by PTLC (silica gel, hexanes:EtOAc= 3:1) to give dimer 174 (7.6 mg, 9.4 μπιοΐ, 19 %), trimer 177 (3.7 mg, 3.0 μιηοΐ, 9 %) and tetramer 180 (3.0 mg, 1.9 μηιοΐ, 8 %) as colorless oils.

[00279] (3aZ,6S,12Z,14aS,17a£,20S,26Z,28aS)-2,16-Dichloro-6,20-bis( 5,5,5- trifluoropentyl)-5,10,ll,14,14a,19,20,23,24,25,28,28a-dodeca hydro-3H,8H- dicyclopenta[e ][l,14]dioxacyclohexacosine-3,8,17,22(6i/,9iT)-tetrone (174): R _f =0.40 (silica gel, hexanes:EtOAc, 3: 1); [αβ ⁵ =+10 (c=0.6 in C ₆ ¾); IR (film): v _max 2947, 2873, 1732, 1662, 1589, 1256,

1143, 1044 cm ^"1 ; 'H-NMR (600 MHz, CDC1 ₃ ) δ 7.40 (d, 7=2.8 Hz, 2 H), 6.61 (t, 7=7.7 Hz, 2H), 5.52-5.48 (m, 2 H), 5.40-5.36 (m, 2 H), 5.04-5.00 (m, 2H), 3.45-3.42 (m, 2H), 2.76-2.72 (m, 2H), 2.65 (ddd, 7= 14.6, 9.5, 7.4 Hz, 2H), 2.45 (dt, 7= 14.7, 6.2 Hz, 2 H), 2.31 -2.19 (m, 4 H), 2.17-2.03 (m, lOH), 1.68 - 1.36 (m, 16H) ppm; ¹ C-NMR (151 MHz, CDC1 ₃ ) δ 188.08, 172.71, 153.88, 137.84, 137.32, 132.82, 132.21, 127.16 (q, 7=281.9 Hz), 125.53, 72.37, 41.53, 34.19, 33.80, 33.69, 33.67 (q, 7= 31.2 Hz), 30.59, 26.87, 24.63, 24.54, 21.83 (q, 7= 3.2 Hz) ppm, due to the inherent symmetry of the molecule each ¹³ C NMR resonance represents two equivalent C atoms; HR-MS (ESI-TOF): calcd for C ₄ oH4906F ₆ Cl2 ⁺ [M+H] ⁺ : 809.2805, found: 809.2780.

[00280] (3a£,6S,12Z,14a5,17a£,20S,26Z,28a5,31a£,345,40Z,42aS)-2,1 6,30-Trichloro- 6,20,34- tris(5,5,5-trifluoropentyl)-5,10,ll,14,14a,19,20,24,25,28,28 a,33,34,37,38,39,42,42a- octadecahydro-3H,8H22H-tricyclopenta[e^,ei][l,14,27]trioxacy clononatriacontine- 3,8,17,22,31,36 (6H,9H,23H)-hexone (177): R _f =0.30 (silica gel, hexanes:EtOAc, 3: 1); [a]¾ ⁵ = +40 (c=0.3 in C ₆ H ₆ ); IR (film): v _ma* 2922, 2927, 2852, 1733, 1661, 1589, 1440, 1258, 1143, 1033 cm ^"1 ; Ή- NMR (600 MHz, CDC1 ₃ ) δ 7.38 (t, 7=2.6 Hz, 3 H), 6.63 (t, 7=7.6 Hz, 3 H), 5.50-5.46 (m, 3 H), 5.35 -5.30 (m, 3 H), 5.00-4.96 (m, 3 H), 3.49-3.46 (m, 3 H), 2.66-2.50 (m, 9H), 2.30-2.19 (m, 9H), 2.11 -2.01 (m, 12H), 1.70- 1.35 (m, 24H) ppm; ¹³ C-NMR (151 MHz, CDCI3) δ 188.13, 172.87, 154.18, 137.62, 137.17, 132.50, 132.26, 127.20 (q, 7=281.9 Hz), 125.23, 72.33, 41.39, 33.73, 33.64 (q, 7= 31.2 Hz), 33.60, 33.54, 30.25, 26.74, 24.69, 24.64, 21.82 (q, 7= 3.2 Hz) ppm, due to the inherent symmetry of the molecule each ¹³ C NMR resonance represents three equivalent C atoms; HR-MS (ESI- TOF): calcd for [M+H] ⁺ : 1213.4171, found: 1213.4179.

[00281] (3a£,65,12Z,14aS,17a£,205,26Z,28aS,31a£,34S,40Z,42aS,45a� �,48S,54Z,56aS )-2,16,30,44-Tetrachloro-6,20,34,48-tetrakis(5,5,5-trifluoro pentyl)- 5,10,H,14,14a,19,20,24,25,28,28a,33,34,38,39,42,42a,47,48,51 ,52,53,56,56a-tetracosahydro- 3H,8H,22H,36H-tetracyclopenta[e ,ei i][l,14,27,40]tetraoxacyclodopentacontine-

3,8,17,22,31,36,45,50(6H9H,23H,37H)-octone (180): R _f =0.20 (silica gel, hexanes:EtOAc, 3: 1); [a]¾ ⁵ =+13 (c =0.3 in C6H ₆ ); IR (film): vmax 2945, 1731, 1661, 1541, 1440, 1257, 1142, 1033 cm ^"1 ; Ή-

NMR (600 MHz, CDC1 ₃ ) δ 7.38 (d, 7=2.6 Hz, 4 H), 6.64 (t, 7= 7.6 Hz, 4 H), 5.50-5.46 (m, 4 H), 5.34 -5.29 (m, 4 H), 5.01 -4.97 (m, 4 H), 3.59 -3.49 (m, 4 H), 2.64-2.50 (m, 12 H), 2.29 -2.21 (m, 12H), 2.12-2.00 (m, 16 H), 1.70- 1.34 (m, 32 H) ppm; ¹³ C-NMR (151 MHz, CDC1 ₃ ) δ 188.16, 172.90, 154.30, 137.55, 137.10, 132.53, 132.26, 127.13 (q, 7= 281.9 Hz), 125.16, 72.24, 41.34, 33.76, 33.61 (q, 7= 29.2 Hz), 33.59, 30.22, 26.75, 24.70, 24.63, 21.81 (q, 7= 3.2 Hz) ppm, due to the inherent symmetry of the molecule each ¹ C NMR resonance represents four equivalent C atoms; HR-MS (ESI-TOF) : calcd for C.80H96O12F12CI [M+Na] ⁺ : 1639.5357, found: 1639.5395. Example 4 - Biological Activity

[00282] The synthesized A ¹² -PGJ ₃ (1) and A ¹² -PGJ ₃ analogs (2-44, ent-l, ent-2, and ent-11) were evaluated for their cytotoxicities against the NIH-60 Screen panel of human cancer cell lines, including leukemia, non-small cell lung, colon, central nervous system, melanoma, ovarian, renal, breast, and prostate cancer cell lines. Selected data are shown in Table 1 (For full data, see FIGS. 1A- 1Z). Compounds 1, 5, ent-l, 13, 17, 19, 22, 31, 34- 36, and 40-43 did not advance beyond the one- dose assay (10 μΜ) as they did not show significant cytotoxicities (see Table 1), whereas the remaining compounds, having exhibited promising potencies, were tested at lower concentrations. As shown in Table 1, among the most potent of these analogs against the tested cell lines were: dimethyl amide 9 (leukemia: GI50 = 0.376 μΜ; non-small cell lung cancer: GI50 = 1.33 μΜ; colon cancer: GI50 = 0.440 μΜ; CNS cancer: GI50 = 1.32 μΜ; melanoma: GI50 = 0.356 μΜ; ovarian cancer: GI50 = 0.471 μΜ; renal cancer: GI50 = 0.504 μΜ; breast cancer: GI50 = 0.368 μΜ; prostate cancer: GI50 = 1.78 μΜ); methyl esters 29 (leukemia: GI50 = 0.281 μΜ; non-small cell lung cancer: GI50 = 1 -03 μΜ; colon cancer: GI50 = 0.494 μΜ; CNS cancer: GI50 = 1.45 μΜ; melanoma: GI50 = 0.210 μΜ; ovarian cancer: GI50 = 0.774 μΜ; renal cancer: GI50 = 1.55 μΜ; breast cancer: GI50 = 0.329 μΜ; prostate cancer: GI50 = 2.53 μΜ), and 32 (leukemia: GI50 = 0.0893 μΜ; non-small cell lung cancer: GI50 = 0.271 μΜ; colon cancer: GI50 = 0.275 μΜ; CNS cancer: GI50 = 0.339 μΜ; melanoma: GI50 = 0.258 μΜ; ovarian cancer: GI50 = 0.347 μΜ; renal cancer: GI50 = 0.378 μΜ; breast cancer: GI50 = 0.185 μΜ; prostate cancer: GI50 = 0.539 μΜ); lactones 11 (leukemia: GI50 = 0.309 μΜ; non-small cell lung cancer: GI50 = 0.415 μΜ; colon cancer: GI50 = 0.201 μΜ; CNS cancer: GI50 = 0.773 μΜ; melanoma: GI50 = 0.219 μΜ; ovarian cancer: GI50 = 0.343 μΜ; renal cancer: GI50 = 0.206 μΜ; breast cancer: GI50 = 0.387 μΜ; prostate cancer: GI50 = 1.42 μΜ), ent-11 (leukemia: GI50 = 0.170 μΜ; non-small cell lung cancer: GI50 = 0.231 μΜ; colon cancer: GI50 = 0.133 μΜ; CNS cancer: GI50 = 0.365 μΜ; melanoma: GI50 = 0.145 μΜ; ovarian cancer: GI50 = 0.342 μΜ; renal cancer: GI50 = 0.183 μΜ; breast cancer: GI50 = 0.356 μΜ; prostate cancer: GI50 = 0.362 μΜ), 24 (leukemia: GI50 = 0.275 μΜ; non-small cell lung cancer: GI50 = 0.663 μΜ; colon cancer: GI50 = 0.430 μΜ; CNS cancer: GI50 = 0.706 μΜ; melanoma: GI50 = 0.559 μΜ; ovarian cancer: GI50 = 0.568 μΜ; renal cancer: GI50 = 0.730 μΜ; breast cancer: GI50 = 0.203 μΜ; prostate cancer: GI50 = 1.35 μΜ), 33 (leukemia: GI ₅₀ = 0.0753 μΜ; non-small cell lung cancer: GI50 = 0.156 μΜ; colon cancer: GI50 = 0.0995 μΜ; CNS cancer: GI50 = 0.214 μΜ; melanoma: GI50 = 0.159 μΜ; ovarian cancer: GI50 = 0.143 μΜ; renal cancer: GI50 = 0.300 μΜ; breast cancer: GI50 = 0.0836 μΜ; prostate cancer: GI50 = 0.346 μΜ), and 44 (leukemia: GI50 = 0.106 μΜ; non-small cell lung cancer: GI50 = 0.090 μΜ; colon cancer: GI50 = 0.091 μΜ; CNS cancer: GI50 = 0.116 μΜ; melanoma: GI50 = 0.084 μΜ; ovarian cancer: GI50 = 0.149 μΜ; renal cancer: GI50 = 0.090 μΜ; breast cancer: GI50 = 0.165 μΜ; prostate cancer: GI50 = 0.088 μΜ). Interestingly, Δ ¹² - PGJ ₃ macrolactone 11 demonstrated no toxicity in athymic nude mice up to 200 mg/kg/dose (intraperitoneally administered), a promising result that allowed it to advance to in vivo efficacy studies in mice (Table 1, FIGS. 1A-1TT).

Table 1. Selected NCI-60 Cytotoxicity Screen Human Cancer Cell Line Panel Data (GIso in μΜ)" for A ¹² -PGJ ₃ (1) and Analogs 2-44, ent-l, ent-2, and ent-\l ^b

non-small

colon CNS ovarian renal breast prostate compound one dose ^c leukemia cell lung melanoma

cancer cancer cancer cancer cancer cancer cancer

1 58.29 - - - - - - - - -

2 - 0.368 1.03 0.538 1.63 0.237 0.692 1.75 0.376 2.70

3 - 0.371 1.25 0.572 0.480 0.180 0.483 1.76 0.372 1.58

4 - 0.534 0.753 0.590 0.581 0.536 0.671 0 827 0.750 0.836

5 98.69 - - - - - - - - -

6 - 1.14 1.30 1.02 1.50 0.350 1.26 1.62 0.626 2.15

7 - 0.957 1.54 0.612 1.30 0.317 1.20 1.52 0.455 1.95

8 - 2.09 1.59 1.73 2.61 1.06 2.63 1.94 1.67 2.52

9 - 0.376 1.33 0.440 1.32 0.356 0.471 0.504 0.368 1.78

10 - 2.44 1.76 1.99 3.35 1.44 3.19 2.37 2.28 3.83

11 - 0.309 0.415 0.201 0.773 0.219 0.343 0 206 0.387 1.42

12 - 1.97 1.74 1.58 2.03 1.34 3.22 1.63 0.544 3.32 enf-1 90.92 - - - - - - - - - ent-2 - 0.461 1.65 0.498 3.18 0.329 3.10 1.16 2.12 3.20 enf-11 - 0.170 0.231 0.133 0.365 0.145 0.342 0.183 0.356 0.362

13 98.44 - - - - - - - - -

14 - 0.398 1.78 0.631 2.35 0.417 1.54 1.64 0.500 2.44

15 - 1.92 2.02 1.80 3.52 1.46 2.96 1.89 3.07 3.64

16 - 2.43 1.91 2.10 3.10 1.59 3.30 2.04 2.69 3.14

17 78.37 - - - - - - - - -

18 - 0.519 1.56 0.447 2.60 0.505 2.88 2.03 1.21 3.02

19 93.39 - - - - - - - - -

20 - 0.345 1.06 1.07 1.79 0.243 1.31 1.70 0.393 2.79

21 - 0.267 0.257 0.299 0.401 0.280 0.423 0 298 0.292 0.574

22 100.62 - - - - - - - - -

23 - 0.278 0.673 0.235 0.695 0.754 1.16 0.864 1.43 0.297

24 - 0.275 0.663 0.430 0.706 0.559 0.568 0.730 0.203 1.35

25 - 0.465 1.35 1.27 1.55 1 29 1.99 1.65 0.444 2.43

26 - 0.975 1.95 1.67 2.06 0.955 1.97 1.73 0.775 2.59

27 - 0.397 1.23 0.326 1.26 0.439 0.495 1.19 0.287 1.66

28 - 2.17 1.71 2.08 3.54 1.74 3.23 2.47 2.32 5.17

29 - 0.281 1.03 0.494 1.45 0.210 0.774 1.55 0.329 2.53

30 - 0.847 0.524 0.634 0.995 0.563 0.747 0 686 1.18 0.837

31 49.47 - - - - - - - - -

32 - 0.0893 0.271 0.275 0.339 0.258 0.347 0.378 0.185 0.539

33 - 0.0753 0.156 0.0995 0.214 0.159 0.143 0 300 0.0836 0.346

34 100.52 - - - - - - - - -

35 93.16 - - - - - - - - -

36 101.45 - - - - - - - - -

37 ^d

38 - 1.04 4.58 1.34 4.01 3.77 1.21 4.99 1.32 6.09

39 - 1.06 1.32 0.880 1.86 0.854 1.71 1.25 1.02 1.74

40 100.98 - - - - - - - - -

41 100.84 - - - - - - - - -

42 96.77 - - - - - - - - -

43 94.50 - - - - - - - - -

44 - 0.106 0.090 0.091 0.116 0.084 0.149 0.090 0.165 0.088

'GIso = Concentration of compound required to inhibit growth by 50%; ^fe see Figures for complete

NCI-60 screen data; mean growth % at 10 μΜ;

[00283] A selected number of compounds were also assayed for their cytotoxicities against cancer cell lines HEK 293T (human embryonic kidney cell line), MES SA (uterine sarcoma cell line), and MES SA DX (MES SA cell line with marked multi-drug resistance). The results are summarized in Table 2. The most potent proved to be 10-chloro-A ¹² -PGJ3 derivatives 32 (IC50 = 0.262 μΜ against HEK 293T; IC50 = 0.428 μΜ against MES SA; IC50 = 0.381 μΜ against MES SA DX) and 33 (IC50 = 0.370 μΜ against HEK 293T; IC50 = 0.410 μΜ against MES SA; IC50 = 0.316 μΜ against MES SA DX); lactones 11 (IC50 = 0.08 μΜ against HEK 293T; IC50 = 0.11 μΜ against MES S A; IC50 = 0.07 μΜ against MES SA DX) and 24 (IC50 = 0.418 μΜ against HEK 293T; IC50 = 0.468 μΜ against MES SA; IC50 = 0.314 μΜ against MES SA DX); amides 7 (IC50 = 0.56 μΜ against HEK 293T; IC50 = 0.57 μΜ against MES SA; IC50 = 0.81 μΜ against MES SA DX) and 9 (IC50 = 0.32 μΜ against HEK 293T; IC50 = 0.48 μΜ against MES SA; IC50 = 0.53 μΜ against MES SA DX), and methyl ester 2 (IC50 = 0.58 μΜ against HEK 293T; IC50 = 0.57 μΜ against MES SA; IC50 = 0.62 μΜ against MES SA DX) (Table 2 and 3, FIG. 2A-3C). Table 2. Cytotoxicity Data Against Cancer Cell Lines HEK 293T, MES SA, and MES SA DX" for A ¹² -PGJ3 and Selected Analogs (IC50 Values in μΜ) compound HE 293T MES SA MES SA DX

1 >5 >5 >5

2 0.583 0.569 0.615

3 -0.955 1.288 1.014

7 0.559 0.571 0.806

8 2.080 2.608 4.045

9 0.323 0.484 0.531

10 2.902 22.150 67.950

11 0.080 0.113 0.074

enf-11 0.490 0.435 0.346

15 >5 >5 >5

16 1.243 1.654 1.760

17 >5 >5 >5

18 0.734 0.681 0.698

21 0.660 1.458 0.861

24 0.418 0.468 0.314

27 -0.945 1.450 1.105

30 0.778 1.438 1.430

32 0.262 0.428 0.381

33 0.370 0.410 0.316

35 >10 >10 >10

37 81.500 >10 >10

40 >25 >25 >25

"ICso = 50% inhibitory concentration of compound against cell growth; MES SA = uterine sarcoma cell line; MES SA DX = MES SA cell line with marked multi-drug resistance; HEK 293T = human embryonic kidney cell line

[00284] The analysis for HEK 293T, MES SA, and MES SA DX were carried out using the following methods:

• Cytotoxity Assay: Cells were cultured in a T75 flask to ~ 50-80 % confluency and harvested with trypsin into a single cell suspension. Five hundred (500) cells per well were seeded in tissue culture plates in 50 μΕΛνε11 culture media and incubated at 37 °C for 18-24 hours. Compounds were diluted as 400x final desired concentrations in DMSO. Serial dilutions in DMSO were then diluted in culture media for a final DMSO concentration of 0.25 % and 50 μίΛνεΙΙ of the final dilution was added to the cells (Vf = 100 μί). Upon plating and treatment, cells were returned to the incubator for an additional 72 hours. CellTiter-Glo reagent was prepared per manufacturer's instructions and added at ΙΟΟ ίΛνεΙΙ to the cultures. CellTiter-Glo allows for relative enumeration of metabolically active cells by quantifying intracellular ATP concentrations. After 5 minutes of incubation with CellTiter-Glo at room temperature, 125 μίΛνεΙΙ of the Cell Titer Glo/cell lysate solution was transferred into black assay plates, which were then read in a luminometer within 30 minutes. Luminescence readings obtained from cultures that did not receive any treatment (cell culture media only) were set as 100 % control and all other luminescence values were normalized to these controls (e.g., Normalized RLU, relative luminescence unit).

• Cell lines used in the assay: MES SA and MES SA/Dx cells are uterine sarcoma. MES SA Dx cell line was generated from MES SA to achieve upregulation of MDR1. MES-SA/Dx cells exhibit marked cross-resistance to a number of chemotherapeutic agents (including daunorubicin, dactinomycin, vincristine, taxol, colchicine) and moderate cross-resistance to mitomycin C and melphalan. 293T cells are human embryonic kidney cell line.

[00285] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims. REFERENCES

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