THIOPHOSPHATE, AND PHOSPHONATE NUCLEOSIDE COMPOUNDS

PRIOR RELATED APPLICATION

[0001] This application claims the benefit of, and priority to, United States Provisional Patent Application No. 61/917,199 entitled "Production of Cyclic Phosphate, Phosphoramidate, Thiophosphate, and Phosphonate Nucleoside Compounds" filed 17 December 2013, which is hereby incorporated, in its entirety, by reference.

FIELD

[0002] Provided herein are methods for the production of cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds. Also provided herein are compounds useful in the production of cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds. The cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds are useful in the treatment of viral infections, including hepatitis C virus infections in hosts in need thereof.

BACKGROUND

[0003] The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. (Boyer, N. et al., J. Hepatol. 32:98-112, 2000). HCV causes a slow growing viral infection and is the major cause of cirrhosis and hepatocellular carcinoma (Di Besceglie, A. M. and Bacon, B. R., Scientific American, Oct.: 80-85, 1999; Boyer, N. et al., J. Hepatol. 32:98-112, 2000). It is estimated there are about 130-150 million people with chronic hepatitis C virus infection. Hepatitis C-related liver diseases cause approximately 350,000 to 500,000 deaths each year. HCV infection becomes chronic in about 55-85% of cases, with many patients initially being asymptomatic. About 15-30% of patients with chronic hepatitis due to HCV develop cirrhosis within about 20 years. (Hepatitis C Fact Sheet, World Health Organization Fact Sheet No. 164, April 2014). Development of cirrhosis due to HCV also increases the risk of hepatocellular cancer (The Merck Manual Online, Chronic Hepatitis, available at www.merckmanuals.com/professional/hepatic_and_biliary_disord ers/hepatitis/ chronic_hepatitis.html, last revision February 2014). [0004] In light of the fact that HCV infection has reached epidemic levels worldwide, and has tragic effects on the infected patient, there is a strong need to provide new methods of producing pharmaceutical agents to treat hepatitis C. Further, given the rising threat of other flaviviridae infections, there is a strong need to provide new methods of producing pharmaceutical agents that have low toxicity to the host.

SUMMARY

[0005] Provided herein are methods of producing cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds useful, for example, for the treatment of flavivirus infections such as HCV infections. Also provided herein are compounds useful in the preparation of cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds.

[0006] In certain embodiments, methods of producing cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds described herein produce the trans isomer of compound I (compound lb) as the major product. Without wishing to be bound by any theory, it is believed that employing a P(III) reagent (for example, compound A2) in the methods described herein, as opposed to a P(V) reagent, enables the preferential production of the trans isomer of compound I (compound lb). Prior methods report the production of the cis isomer of compound I (compound la) as the major product. See, Reddy et al., J. Org. Chem. 2011, 76, 3782-3790, Int. Pat. Appl. Pub. No. WO 2010/135520 Al, and Int. Pat. Appl. Pub. No. WO 2012/075140 Al . Prior methods employing a P(III) reagent report very low yields and poor production of the desired trans isomer of compound I (compound lb). The reported methods also employ tetrazole as a key reagent, which is explosive and is normally only available in small quantities. See, Reddy et al., J. Org. Chem. 2011, 76, 3782-3790. The methods described herein therefore provide a novel method to produce the desired trans isomer lb as the major product.

[0007] Provided herein are methods of producing cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds. In an aspect, provided herein are methods of producing a compound of Formula I:

comprising: (a) reacting a compound of Formula II with a compound of Formula III to form a compound of Formula IV:

III IV ; and

(b) contacting the compound of Formula IV with an intramolecular ring closure reagent and an oxidation reagent to form the compound of Formula I:

wherein: Base is a nucleobase; R ^A is hydrogen, methyl, or halo; R ^B is hydrogen, hydroxyl, or halo; X is -R ¹ , -OR ¹ , -SR ¹ , -NR ¹ R ² , or an O-linked or N-linked amino acid residue, or derivative thereof; each R ¹ is independently alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkylcarbonylthioalkyl, hydroxylalkylcarbonylthioalkyl, or alkylcarbonylthioalkyl; and each R is independently hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl.

[0008] In certain embodiments, provided herein are methods of producing a compound of Formula I, wherein the methods provide high yields of a compound of Formula lb:

wherein Base, R ^A , R ^B , and X are as described in the context of Formula I. In certain embodiments, provided herein are methods of producing a compound of Formula I, wherein the method further provides separating or purifying the compound of Formula lb from a reaction mixture comprising compounds of Formula lb and Formula la:

wherein Base, R ^A , R ^B , and X are as described in the context of Formula I.

[0009] Also provided herein are compounds useful in the preparation of cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleosides. In one aspect, provided herein are compounds according to Formula III:

III wherein: X is -R ¹ , -OR ¹ , -SR ¹ , -NR ¹ R ² , or an O-linked or N-linked amino acid residue, or derivative thereof; each R ¹ is independently alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkylcarbonylthioalkyl, hydroxylalkylcarbonylthioalkyl, or alkylcarbonylthioalkyl; and each R is independently hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl.

DESCRIPTION OF EXEMPLARY EMBODIMENTS

[0010] Provided herein are methods of producing cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds useful for treating liver disorders such as HCV infection in a subject.

Definitions

[0011] When referring to the methods and compounds described herein, the following terms have the following meanings unless indicated otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0012] The term "alkyl," as used herein, unless otherwise specified, refers to a saturated straight or branched hydrocarbon. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group includes one to ten carbon atoms, i.e., C\ to C ₁₀ alkyl. In certain embodiments, the alkyl group is methyl, CF ₃ , CCI ₃ , CFCI ₂ , CF ₂ C1, ethyl, CH ₂ CF ₃ , CF ₂ CF ₃ , propyl, isopropyl, butyl, isobutyl, secbutyl, t- butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, or 2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups, including halogenated alkyl groups. In certain embodiments, the alkyl group is a fluorinated alkyl group. Non-limiting examples of moieties with which the alkyl group can be substituted include halogen (fluoro, chloro, bromo or iodo), hydroxyl, carbonyl, cycloalkyl, aralkyl, sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al. , Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.

[0013] The term "lower alkyl," as used herein, and unless otherwise specified, refers to a saturated straight or branched hydrocarbon having one to six carbon atoms, i.e., C _\ to C ₆ alkyl. In certain embodiments, the lower alkyl group is a primary, secondary, or tertiary hydrocarbon. The term includes both substituted and unsubstituted moieties.

[0014] The term "upper alkyl," as used herein, and unless otherwise specified, refers to a saturated straight or branched hydrocarbon having seven to thirty carbon atoms, i.e., C ₇ to C30 alkyl. In certain embodiments, the upper alkyl group is a primary, secondary, or tertiary hydrocarbon. The term includes both substituted and unsubstituted moieties.

[0015] The term "cycloalkyl," as used herein, unless otherwise specified, refers to a saturated cyclic hydrocarbon. In certain embodiments, the cycloalkyl group may be a saturated, and/or bridged, and/or non-bridged, and/or a fused bicyclic group. In certain embodiments, the cycloalkyl group includes three to ten carbon atoms, i.e., C ₃ to C ₁₀ cycloalkyl. In some embodiments, the cycloalkyl has from 3 to 15 (C _3-15 ), from 3 to 10 (C ₃ _ 10), or from 3 to 7 (C ₃ _ ₇ ) carbon atoms. In certain embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl or adamantyl. The term includes both substituted and unsubstituted cycloalkyl groups, including halogenated cycloalkyl groups. In certain embodiments, the cycloalkyl group is a fluorinated cycloalkyl group. Non-limiting examples of moieties with which the cycloalkyl group can be substituted include halogen (fluoro, chloro, bromo or iodo), hydroxyl, carbonyl, sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary. [0016] "Alkylene" refers to divalent saturated aliphatic hydrocarbon groups, including those having from one to eleven carbon atoms which can be straight-chained or branched. In certain embodiments, the alkylene group contains 1 to 10 carbon atoms. The term includes both substituted and unsubstituted moieties. This term is exemplified by groups such as methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), the propylene isomers (e.g., -CH ₂ CH ₂ CH ₂ - and - CH(CH ₃ )CH ₂ -) and the like. The term includes halogenated alkylene groups. In certain embodiments, the alkylene group is a fluorinated alkylene group. Non- limiting examples of moieties with which the alkylene group can be substituted include halogen (fluoro, chloro, bromo or iodo), hydroxyl, carbonyl, sulfanyl, amino, alkylamino, alkylaryl, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected, or protected as necessary.

[0017] "Alkenyl" refers to monovalent olefmically unsaturated hydrocarbon groups, in certain embodiments, having up to about 11 carbon atoms, including from 2 to 8 carbon atoms, or from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1, including from 1 to 2, site of olefmic unsaturation. The term includes both substituted and unsubstituted moieties. Exemplary alkenyl groups include ethenyl (i.e., vinyl, or - CH=CH ₂ ), n-propenyl (-CH ₂ CH=CH ₂ ), isopropenyl (-C(CH ₃ )=CH ₂ ), and the like. The term includes halogenated alkenyl groups. In certain embodiments, the alkenyl group is a fluorinated alkenyl group. Non-limiting examples of moieties with which the alkenyl group can be substituted include halogen (fluoro, chloro, bromo or iodo), hydroxyl, carbonyl, sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary.

[0018] The term "cycloalkenyl," as used herein, unless otherwise specified, refers to an unsaturated cyclic hydrocarbon. In certain embodiments, cycloalkenyl refers to mono- or multicyclic ring systems that include at least one double bond. In certain embodiments, the cycloalkenyl group may be a bridged, non-bridged, and/or a fused bicyclic group. In certain embodiments, the cycloalkyl group includes at least three carbon atoms, including three to ten carbon atoms, i.e., C ₃ to Cio cycloalkyl. In some embodiments, the cycloalkenyl has from 3 to 10 (C ₃ _io), or from 4 to 7 (C ₄ _7) carbon atoms. The term includes both substituted and unsubstituted cycloalkenyl groups, including halogenated cycloalkenyl groups. In certain embodiments, the cycloalkenyl group is a fluorinated cycloalkenyl group. Non- limiting examples of moieties with which the cycloalkenyl group can be substituted include halogen (fluoro, chloro, bromo or iodo), hydroxyl, carbonyl, sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary.

[0019] "Alkenylene" refers to divalent olefinically unsaturated hydrocarbon groups, in certain embodiments, having up to about 11 carbon atoms or from 2 to 6 carbon atoms which can be straight-chained or branched and having at least 1 or from 1 to 2 sites of olefinic unsaturation. This term is exemplified by groups such as ethenylene (-CH=CH-), the propenylene isomers (e.g., -CH=CHCH ₂ - and -C(CH ₃ )=CH- and -CH=C(CH ₃ )-) and the like. The term includes both substituted and unsubstituted alkenylene groups, including halogenated alkenylene groups. In certain embodiments, the alkenylene group is a fluorinated alkenylene group. Non-limiting examples of moieties with which the alkenylene group can be substituted include halogen (fluoro, chloro, bromo or iodo), hydroxyl, carbonyl, sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary.

[0020] "Alkynyl" refers to acetylenically unsaturated hydrocarbon groups, in certain embodiments, having up to about 11 carbon atoms or from 2 to 6 carbon atoms which can be straight-chained or branched and having at least 1 or from 1 to 2 sites of alkynyl unsaturation. Non-limiting examples of alkynyl groups include acetylenic, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), and the like. The term includes both substituted and unsubstituted alkynyl groups, including halogenated alkynyl groups. In certain embodiments, the alkynyl group is a fluorinated alkynyl group. Non-limiting examples of moieties with which the alkynyl group can be substituted include halogen (fluoro, chloro, bromo or iodo), hydroxyl, carbonyl, sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary.

[0021] The term "aryl," as used herein, and unless otherwise specified, refers to a substituent derived from an aromatic ring. In an embodiment, an aryl group is a C ₆ -Ci ₂ aryl group. In an embodiment, an aryl group is phenyl, biphenyl or naphthyl. The term includes both substituted and unsubstituted moieties. An aryl group can be substituted with any described moiety, including, but not limited to, one or more moieties selected from the group halogen (fluoro, chloro, bromo or iodo), alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. [0022] "Alkoxy" and "alkoxyl" refer to the group -OR' where R' is alkyl or cycloalkyl as defined herein. In certain embodiments, the alkoxyl or alkoxy group is -OR', wherein R' is alkyl or cycloalkyl, and wherein alkyl is Ci to C ₁₀ alkyl, and cycloalkyl is C3 to C ₁₅ cycloalkyl. Alkoxy and alkoxyl groups include, by way of example, methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2- dimethylbutoxy, and the like.

[0023] "Alkoxycarbonyl" refers to a radical -C(0)-alkoxy where alkoxy is as defined herein.

[0024] "Alkoxyalkylcarbonyl" refers to a radical -C(0)-alkyl-alkoxy where alkoxy and alkyl are as defined herein.

[0025] "Alkoxycarbonylalkyl" refers to a radical -alkyl-C(0)-alkoxy where alkoxy and alkyl are as defined herein.

[0026] "Alkoxycarbonylamino" refers to a radical -amino-C(0)-alkoxy where alkoxy and amino are as defined herein.

[0027] "Arylalkoxycarbonylalkyl" refers to a radical -alkyl-C(0)-alkoxy-aryl, where alkyl, alkoxy, and aryl are as described herein.

[0028] As used herein, "alkylcarbonylthioalkyl" refers to a radical -alkyl-S-C(0)-alkyl, where alkyl is as defined herein.

[0029] "Alkylcarbonylalkoxy(arylalkyl)" refers to a radical -alkoxy(arylalkyl)-C(0)- alkyl, where alkyl, alkoxy, and arylalkyl are as described herein.

[0030] "Cycloalkylcarbonylalkoxyl" refers to a radical -alkoxyl-C(0)-cycloalkyl, where alkoxyl and cycloalkyl are as described herein.

[0031] "Alkylcarbonylalkoxyl" refers to a radical -alkoxy-C(0)-alkyl, where alkoxy and alkyl are as described herein.

[0032] As used herein, "hydroxyalkylenecarbonylthioalkyl" refers to a radical -alkyl-S- C(0)-alkylene-OH, where alkyl is as defined herein.

[0033] "Alkoxycarbonylaminoalkylcarbonylthioalkyl" refers to a radical -alkyl-S-C(O)- alkyl-amino-C(0)-alkoxy, where alkyl, amino and alkoxy are as defined herein.

[0034] "Hydroxylalkylcarbonylthioalkyl" refers to a radical -alkyl-S-C(0)-alkyl-OH, where alkyl is as defined herein. [0035] "Aminoalkylcarbonylalkoxycarbonylthioalkyl" refers to a radical -alkyl-S-C(O)- alkoxy-C(0)-alkyl-amino, where alkyl, alkoxy, and amino are as described herein.

[0036] As used herein, "(alkoxycarbonyl)(alkoxycarbonylamino)alkyl" refers to an alkyl radical substituted with both an alkoxycarbonyl and an alkoxycarbonylamino group, where "alkoxycarbonyl" and "alkoxycarbonylamino" are as described herein. In an embodiment, the

term refers to a radical of formula , wherein n is an integer selected from the range of 1-10, A ^A is -C(O)-O-R ¹⁰ °, A ^N is -NH-C(0)-0-R ¹⁰¹ , and each of R ¹⁰⁰ and R ¹⁰¹ is independently lower alkyl. In an embodiment, each of R ¹⁰⁰ and R ¹⁰¹ is independently C ₁ -C5 alkyl.

[0037] "Amino" refers to the group -NHR" or -NH-, wherein R" is selected from hydrogen, alkyl, aryl and cycloalkyl.

[0038] "Amino alcohol" refers to the radical -NHLOH, wherein L is alkylene. [0039] "Carboxyl" or "carboxy" refers to the radical -C(0)OH.

[0040] The term "alkylamino" or "arylamino" refers to an amino group that has one or two alkyl or aryl substituents, respectively. In certain embodiments, the alkyl substituent is upper alkyl. In certain embodiments, the alkyl substituent is lower alkyl. In another embodiment, the alkyl, upper alkyl, or lower alkyl is unsubstituted.

[0041] "Halogen" or "halo" refers to chloro, bromo, fluoro or iodo.

[0042] "Monoalkylamino" refers to the group alkyl-NR'-, wherein R' is selected from hydrogen, alkyl and cycloalkyl.

[0043] "Thioalkoxy" refers to the group -SR' where R' is alkyl or cycloalkyl.

[0044] The term "heterocyclo" or "heterocyclic" refers to a monovalent monocyclic non- aromatic ring system and/or multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclo or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. Heterocyclo groups are bonded to the rest of the molecule through the non-aromatic ring. In certain embodiments, the heterocyclo is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclo may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclic radicals include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4- dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, heterocyclic may also be optionally substituted as described herein. Non-limiting examples of moieties with which the heterocyclic group can be substituted include halogen (fluoro, chloro, bromo or iodo), hydroxyl, carbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, sulfanyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary.

[0045] The term "heteroaryl" refers to a monovalent monocyclic aromatic group and/or multicyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S and N in the ring. Heteroaryl groups are bonded to the rest of the molecule through the aromatic ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl and xanthenyl. In certain embodiments, heteroaryl may also be optionally substituted as described herein.

[0046] The term "alkylaryl" refers to an aryl group with an alkyl substituent. The term "aralkyl" or "arylalkyl" refers to an alkyl group with an aryl substituent.

[0047] The term "alkylheterocyclo" refers to a heterocyclo group with an alkyl substituent. The term "heterocycloalkyl" refers to an alkyl group with a heterocyclo substituent.

[0048] The term "alkylheteroaryl" refers to a heteroaryl group with an alkyl substituent. The term "heteroarylalkyl" refers to an alkyl group with a heteroaryl substituent.

[0049] As used herein, the term "hydantoinyl" refers to the group , where

R and R are each independently hydrogen or lower alkyl.

[0050] As used herein, the term "hydantoinylalkyl" refers to the group -alkyl- hydantoinyl, where alkyl and hydantoinyl are as described herein.

[0051] The term "protecting group" as used herein and unless otherwise defined refers to a group that is added to an oxygen, nitrogen or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.

[0052] "Pharmaceutically acceptable salt" refers to any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1 ,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-l- carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid and the like acids; or (2) base addition salts formed when an acidic proton present in the parent compound either (a) is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion or an aluminum ion, or alkali metal or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide, ammonia or (b) coordinates with an organic base, such as aliphatic, alicyclic, or aromatic organic amines, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

[0053] Pharmaceutically acceptable salts further include, by way of example only and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1 ,2-ethane-disulfonate, 2- hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2- naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4- methylbicyclo[2.2.2]-oct-2-ene- 1 -carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate and the like.

[0054] As used herein, the term "nucleobase" refers to the base portion of a nucleoside or nucleotide. In certain embodiments, a nucleobase is a purine or pyrimidine base, as defined herein.

[0055] The term "purine" or "pyrimidine" base refers to, but is not limited to, adenine, N ⁶ -alkylpurines, N ⁶ -acylpurines (wherein acyl is C(0)(alkyl, aryl, alkylaryl, or arylalkyl), N ⁶ - benzylpurine, N ⁶ -halopurine, N ⁶ -vinylpurine, N ⁶ -acetylenic purine, N ⁶ -acyl purine, N ⁶ -hydroxyalkyl purine, N ⁶ -alkylaminopurine, N ⁶ -thioalkyl purine, N ² -alkylpurines, N ² - alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, C ⁵ -alkylpyrimidines, C ⁵ -benzylpyrimidines, C ⁵ -halopyrimidines, C ⁵ -vinylpyrimidine, C ⁵ -acetylenic pyrimidine, C ⁵ -acyl pyrimidine, C ⁵ -hydroxyalkyl purine, C ⁵ -amidopyrimidine, C ⁵ -cyanopyrimidine, C ⁵ -iodopyrimidine, C ⁶ -iodo-pyrimidine, C ⁵ -Br- vinyl pyrimidine, C ⁶ -Br-vinyl pyrimidine, C ⁵ -nitropyrimidine, C ⁵ -amino-pyrimidine, N ² - alkylpurines, N -alkyl-6-thiopurines, 5-azacytidine, 5-azauracil, triazolopyridine, imidazolopyridine, pyrrolopyrimidine, and pyrazolopyrimidine. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 7-deazaguanine, 7-deazaadenine, 2,6- diaminopurine, and 6-chloropurine. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t- butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.

[0056] The term "acyl" or "O-linked ester" refers to a group of the formula C(0)R', wherein R' is alkyl or cycloalkyl (including lower alkyl), carboxylate residue of amino acid, aryl including phenyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl; or substituted alkyl (including lower alkyl), aryl including phenyl optionally substituted with chloro, bromo, fluoro, iodo, Ci to C ₄ alkyl or Ci to C ₄ alkoxy, sulfonate esters such as alkyl or arylalkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxy-trityl, substituted benzyl, alkaryl, arylalkyl including benzyl, alkoxyalkyl including methoxymethyl, aryloxyalkyl such as phenoxymethyl. Aryl groups in the esters optimally comprise a phenyl group. In particular, acyl groups include acetyl, trifluoroacetyl, methylacetyl, cyclpropylacetyl, propionyl, butyryl, hexanoyl, heptanoyl, octanoyl, neo-heptanoyl, phenylacetyl, 2-acetoxy-2-phenylacetyl, diphenylacetyl, a-methoxy-a-trifluoromethyl- phenylacetyl, bromoacetyl, 2-nitro-benzeneacetyl, 4-chloro-benzeneacetyl, 2-chloro-2,2- diphenylacetyl, 2-chloro-2-phenylacetyl, trimethylacetyl, chlorodifluoroacetyl, perfluoroacetyl, fluoroacetyl, bromodifluoroacetyl, methoxyacetyl, 2-thiopheneacetyl, chlorosulfonylacetyl, 3 -methoxyphenyl acetyl, phenoxyacetyl, tert-butyl acetyl, trichloroacetyl, monochloro-acetyl, dichloroacetyl, 7H-dodecafluoro-heptanoyl, perfluoro- heptanoyl, 7H-dodeca-fluoroheptanoyl, 7-chlorododecafluoro-heptanoyl, 7-chloro- dodecafluoro-heptanoyl, 7H-dodecafluoroheptanoyl, 7H-dodeca-fluoroheptanoyl, nona- fluoro-3 ,6-dioxa-heptanoyl, nonafluoro-3 ,6-dioxaheptanoyl, perfluoroheptanoyl, methoxybenzoyl, methyl 3-amino-5-phenylthiophene-2-carboxyl, 3,6-dichloro-2-methoxy- benzoyl, 4-(l,l,2,2-tetrafluoro-ethoxy)-benzoyl, 2-bromo-propionyl, omega-aminocapryl, decanoyl, n-pentadecanoyl, stearyl, 3-cyclopentyl-propionyl, 1-benzene-carboxyl, O- acetylmandelyl, pivaloyl acetyl, 1-adamantane-carboxyl, cyclohexane-carboxyl, 2,6- pyridinedicarboxyl, cyclopropane-carboxyl, cyclobutane-carboxyl, perfluorocyclohexyl carboxyl, 4-methylbenzoyl, chloromethyl isoxazolyl carbonyl, perfluorocyclohexyl carboxyl, crotonyl, 1 -methyl- lH-indazole-3 -carbonyl, 2-propenyl, isovaleryl, 1-pyrrolidinecarbonyl, 4- phenylbenzoyl.

[0057] The term "amino acid" refers to naturally occurring and synthetic α, β, γ, or δ amino acids, and includes but is not limited to, amino acids found in proteins, i.e. glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In certain embodiments, the amino acid is in the L-configuration. In certain embodiments, the amino acid is in the D-configuration. In certain embodiments, the amino acid is provided as a substituent of a compound described herein, wherein the amino acid is a residue selected from alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β- isoleuccinyl, β-prolinyl, β-phenylalaninyl, β -tryptophanyl, β-methioninyl, β-glycinyl, β- serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β- glutaroyl, β-lysinyl, β-argininyl, or β-histidinyl.

[0058] The term "amino acid derivative" refers to a group derivable from a naturally or non-naturally occurring amino acid, as described and exemplified herein. Amino acid derivatives are apparent to those of skill in the art and include, but are not limited to, ester, amino alcohol, amino aldehyde, amino lactone, and N-methyl derivatives of naturally and non-naturally occurring amino acids. In an embodiment, an amino acid derivative is provided as a substituent of a compound described herein, wherein the substituent is -NR ^x -Gl(Sci)- C(0)-Q ¹ , wherein Q ¹ is -SR ^Y , -NR ^Y R ^Y , or alkoxyl, R ^Y is hydrogen or alkyl, S _C i is a side chain of a naturally occurring or non-naturally occurring amino acid, Gl is C ₁ -C ₂ alkylene, and R ^x is hydrogen or R ^x and Sci, together with the atoms to which they are attached, combine to form a five-membered heterocyclic ring. Those of skill in the art will recognize that Gl forms bonds to NR and to Q , while Sci forms a single, branching bond to a carbon atom of Gl. In an embodiment, an amino acid derivative is provided as a substituent of a compound described herein, wherein the substituent is -0-C(0)-G2(Sc ₂ )-NH-Q , wherein Q is hydrogen or alkoxyl, Sc ₂ is a side chain of a naturally occurring or non-naturally occurring amino acid and G2 is C ₁ -C ₂ alkylene. In certain embodiments, Q and Sc ₂ , together with the atoms to which they are attached, combine to form a five-membered heterocyclic ring. In certain embodiments, each of G2 and G2 is independently Ci alkylene and each of Sci and Sc ₂ is independently hydrogen, alkyl, arylalkyl, heterocycloalkyl, carboxylalkyl, heteroarylalkyl, aminoalkyl, hydroxylalkyl, aminoiminoaminoalkyl, aminocarbonylalkyl, sulfanylalkyl, carbamoylalkyl, alkylsulfanylalkyl, or hydroxylarylalkyl. In an embodiment, an amino acid derivative is provided as a substituent of a compound described herein, wherein the amino acid derivative is in the D-configuration. In an embodiment, an amino acid derivative is provided as a substituent of a compound described herein, wherein the amino acid derivative is in the L-configuration.

[0059] As used herein, the term "aminoalkyl" refers to an alkyl group with an amino substituent, where alkyl and amino are as described herein.

[0060] As used herein, the term "carboxylalkyl" refers to the group -alkyl-C(0)OH, where alkyl is as described herein.

[0061] As used herein, the term "aminoiminoaminoalkyl" refers to the group -alkyl-amino- C(NH)-amino, where alkyl and amino are as described herein.

[0062] As used herein, the term "aminocarbonylalkyl" refers to the group -alkyl-C(O)- amino, where alkyl and amino are as described herein.

[0063] As used herein, the term "sulfanylalkyl" refers to the group -alkyl-SH, where alkyl is as described herein. [0064] As used herein, the term "carbamoylalkyl" refers to the group -alkyl-C(0)-amino, where alkyl and amino are as described herein.

[0065] As used herein, the term "alkylsulfanylalkyl" refers to the group -alkyl-S-alkyl, where alkyl is as described herein.

[0066] As used herein, the term "hydroxylalkyl" refers to the group -alkyl-OH, where alkyl is as described herein.

[0067] As used herein, the term "hydroxylarylalkyl" refers to the group -alkyl-aryl-OH, where alkyl and aryl are as described herein.

[0068] Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a chain or ring provided such substitution is chemically allowed and results in a stable compound. A "stable" compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0069] To the extent substituents and substituent patterns provide for the existence of tautomers (e.g., keto-enol tautomers) in the compounds described herein, all tautomeric forms of these compounds, whether present individually or in mixtures, are within the scope of the present disclosure. Compounds of the present disclosure having a hydroxy substituent on a carbon atom of a heteroaromatic ring are understood to include compounds in which only the hydroxy is present, compounds in which only the tautomeric keto form (i.e., an oxo substituent) is present, and compounds in which the keto and enol forms are both present.

[0070] The term "substantially free of or "substantially in the absence of with respect to a nucleoside composition refers to a nucleoside composition that includes at least 85% or 90% by weight, in certain embodiments 95%, 98%, 99%, or 100% by weight, of the designated stereoisomer of that nucleoside. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of other stereoisomers.

[0071] Similarly, the term "isolated" with respect to a nucleoside composition refers to a nucleoside composition that includes at least 85%, 90%, 95%, 98%, 99% to 100% by weight, of the nucleoside, the remainder comprising other chemical species or enantiomers.

[0072] As used herein, "alkyl," "cycloalkyl," "alkenyl," "cycloalkenyl," "alkynyl," "aryl," "alkoxy," "alkoxycarbonyl," "alkoxycarbonylalkyl," "amino," "carboxyl," "alkylamino," "arylamino," "thioalkyoxy," "heterocyclo," "heteroaryl," "alkylheterocyclo," "alkylheteroaryl," "acyl," "aralkyl," "alkaryl," "purine," "pyrimidine," "carboxyl" and "amino acid" groups optionally comprise deuterium at one or more positions where hydrogen atoms are present, and wherein the deuterium composition of the atom or atoms is other than the natural isotopic composition.

[0073] Also as used herein, "alkyl," "cycloalkyl," "alkenyl," "cycloalkenyl," "alkynyl," "aryl," "alkoxy," "alkoxycarbonyl," "alkoxycarbonylalkyl," "carboxyl," "alkylamino," "arylamino," "thioalkyoxy," "heterocyclo," "heteroaryl," "alkylheterocyclo," "alkylheteroaryl," "acyl," "aralkyl," "alkaryl," "purine," "pyrimidine," "carboxyl" and "amino acid" groups optionally comprise carbon- 13 at an amount other than the natural isotopic composition.

Methods

[0074] Provided herein are methods of producing cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds. The cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds are useful for the treatment of Flaviviridae infections such as HCV infection. In certain embodiments, provided herein are methods of producing a compound of Formula IV:

IV comprising: (a) reacting a compound of Formula II with a compound of Formula III to form the compound of Formula IV:

II III wherein: Base is a nucleobase; R ^A is hydrogen, methyl, or halo; R ^B is hydrogen, hydroxyl, or halo; X is -R ¹ , -OR ¹ , -SR ¹ , -NR ¹ R ² , or an O-linked or N-linked amino acid residue, or derivative thereof; each R ¹ is independently alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkylcarbonylthioalkyl, hydroxylalkylcarbonylthioalkyl, or alkylcarbonylthioalkyl; and each R is independently hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl.

[0075] In certain embodiments, provided herein are methods of producing a compound of Formula I:

comprising: (b) contacting a compound of Formula IV with an intramolecular ring closure reagent and an oxidation reagent to form the compound of Formula I:

wherein: Base is a nucleobase; R ^A is hydrogen, methyl, or halo; R ^B is hydrogen, hydroxyl, or halo; X is -R ¹ , -OR ¹ , -SR ¹ , -NR ¹ R ² , or an O-linked or N-linked amino acid residue, or derivative thereof; each R ¹ is independently alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkylcarbonylthioalkyl, hydroxylalkylcarbonylthioalkyl, or alkylcarbonylthioalkyl; and each R is independently hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl. In certain embodiments, methods of producing a compound of Formula I are provided wherein in step (b) the compound of Formula IV is contacted with the ring closure reagent and then contacted with the oxidation reagent. In certain embodiments, methods of producing a compound of Formula I are provided wherein in step (b) the compound of Formula IV is contacted with the oxidation reagent and then contacted with the ring closure reagent. In certain embodiments, methods of producing a compound of Formula I are provided wherein in step (b) the compound of Formula IV is contacted with the oxidation reagent and the ring closure reagent at the same time. In certain embodiments, methods of producing a compound of Formula I are provided wherein in step (b) the compound of Formula IV is contacted with the oxidation reagent and the ring closure reagent at the same time and in the same pot. [0076] In certain embodiments, provided herein are methods of producing a compound of Formula I:

comprising: (a) reacting a compound of Formula II with a compound of Formula III to form a compound of Formula IV:

III IV ; and

(b) contacting the compound of Formula IV with an intramolecular ring closure reagent and an oxidation reagent to form the compound of Formula I:

wherein: Base is a nucleobase; R ^A is hydrogen, methyl, or halo; R ^B is hydrogen, hydroxyl, or halo; X is -R ¹ , -OR ¹ , -SR ¹ , -NR ¹ R ² , or an O-linked or N-linked amino acid residue, or derivative thereof; each R ¹ is independently alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkylcarbonylthioalkyl, hydroxylalkylcarbonylthioalkyl, or alkylcarbonylthioalkyl; and each R is independently hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl. In certain embodiments, methods of producing a compound of Formula I are provided wherein in step (b) the compound of Formula IV is contacted with the ring closure reagent and then contacted with the oxidation reagent. In certain embodiments, methods of producing a compound of Formula I are provided wherein in step (b) the compound of Formula IV is contacted with the oxidation reagent and then contacted with the ring closure reagent. In certain embodiments, methods of producing a compound of Formula I are provided wherein in step (b) the compound of Formula IV is contacted with the oxidation reagent and the ring closure reagent at the same time. In certain embodiments, methods of producing a compound of Formula I are provided wherein in step (b) the compound of Formula IV is contacted with the oxidation reagent and the ring closure reagent at the same time and in the same pot.

[0077] In certain embodiments, provided herein are methods of producing a compound of Formula I, wherein a compound of Formula IV is contacted with a ring closure reagent to form a compound of Formula il:

the compound of Formula il is contacted with an oxidation reagent to form the compound of Formula I:

wherein Base, R ^A , R ^B and X are as described in the context of Formula I.

[0078] In certain embodiments, provided herein are methods of producing a compound of Formula I, wherein a compound of Formula IV is contacted with an oxidation reagent to form a compound of Formula ill:

the compound of Formula ill is contacted with a ring closure reagent to form the compound of Formula I: wherein Base, R ^A , R ^B and X are as described in the context of Formula I.

[0079] In certain embodiments, provided herein are methods of producing a compound of Formula I, wherein the methods provide high yields of a compound of Formula lb:

wherein Base, R ^A , R ^B and X are as described in the context of Formula I. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide production of a compound of Formula lb:

from a compound of Formula II:

HO* RB

II in a yield selected from a range of 15% to 55%; wherein Base, R ^A , and R ^B are as described in the context of Formula I. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide production of a compound of Formula lb in a yield selected from a range of 17% to 51%. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide production of a compound of Formula lb in a yield selected from a range of 30% to 50%. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide production of a compound of Formula lb in a yield selected from a range of 40% to 50%. [0080] In certain embodiments, the methods provide production of a compound of Formula lb from a compound of Formula II wherein the compound of Formula lb is produced at a percent diastereomeric excess selected from a range of 10% to 80% with respect to a compound of Formula la:

wherein Base, R ^A , R ^B and X are as described in the context of Formula I. In certain embodiments, the methods provide production of a compound of Formula lb from a compound of Formula II wherein the compound of Formula lb is produced at a percent diastereomeric excess selected from a range of 20%> to 80%> with respect to a compound of Formula la. In certain embodiments, the methods provide production of a compound of Formula lb from a compound of Formula II wherein the compound of Formula lb is produced at a percent diastereomeric excess selected from a range of 40% to 80% with respect to a compound of Formula la. In certain embodiments, the methods provide production of a compound of Formula lb from a compound of Formula II wherein the compound of Formula lb is produced at a percent diastereomeric excess selected from a range of 40%> to 70%> with respect to a compound of Formula la.

[0081] In certain embodiments, provided herein are methods of producing a compound of Formula I, wherein the method further provides separating or purifying a compound of Formula lb from a reaction mixture comprising compounds of Formula lb and Formula la:

wherein Base, R ^A , R ^B and X are as described in the context of Formula I.

[0082] In certain embodiments, provided herein are methods of producing a compound of Formula I, wherein the methods provide high yields of a compound of Formula Vb:

wherein Base, R ^A , R ^B and R ¹ are as described in the context of Formula I. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide for production of a compound of Formula Vb:

from a compound of Formula II:

HO* RB

II in a yield selected from a range of 15% to 55%; wherein Base, R ^A , R ^B and R ¹ are as described in the context of Formula I. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide production of a compound of Formula Vb in a yield selected from a range of 17% to 51%. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide production of a compound of Formula Vb in a yield selected from a range of 30% to 50%. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide production of a compound of Formula Vb in a yield selected from a range of 40% to 50%.

[0083] In certain embodiments, the methods provide production of a compound of Formula Vb from a compound of Formula II wherein the compound of Formula Vb is produced at a percent diastereomeric excess selected from a range of 10%> to 80%> with respect to a compound of Formula Va:

wherein Base, R ^A , R ^B and X are as described in the context of Formula I. In certain embodiments, the methods provide production of a compound of Formula Vb from a compound of Formula II wherein the compound of Formula Vb is produced at a percent diastereomeric excess selected from a range of 20% to 80% with respect to a compound of Formula Va. In certain embodiments, the methods provide production of a compound of Formula Vb from a compound of Formula II wherein the compound of Formula Vb is produced at a percent diastereomeric excess selected from a range of 40%> to 80%> with respect to a compound of Formula Va. In certain embodiments, the methods provide production of a compound of Formula Vb from a compound of Formula II wherein the compound of Formula Vb is produced at a percent diastereomeric excess selected from a range of 40% to 70% with respect to a compound of Formula Va.

[0084] In certain embodiments, provided herein are methods of producing a compound of Formula I, wherein the method further provides separating or purifying a compound of Formula Vb from a reaction mixture comprising compounds of Formula Vb and Formula Va:

wherein Base, R ^A , R ^B and X are as described in the context of Formula I.

[0085] In certain embodiments, provided herein are methods of producing a compound of Formula I, wherein the methods provide high yields of a compound of Formula VIb:

wherein Base, R ^A , R ^B and R ¹ are as described in the context of Formula I. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide for production of a compound of Formula VIb:

from a compound of Formula II ,O _A Base

HO° R

II in yields selected from a range of 15% to 55%; wherein Base, R ^A , R ^B , R ¹ and R ² are as described in the context of Formula I. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide production of a compound of Formula VIb in a yield selected from a range of 17% to 51%. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide production of a compound of Formula VIb in a yield selected from a range of 30% to 50%. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide production of a compound of Formula VIb in a yield selected from a range of 40% to 50%.

[0086] In certain embodiments, the methods provide production of a compound of Formula VIb from a compound of Formula II wherein the compound of Formula lb is produced at a percent diastereomeric excess selected from a range of 10%> to 80%> with respect to a compound of Formula Via:

wherein Base, R ^A , R ^B and X are as described in the context of Formula I. In certain embodiments, the methods provide production of a compound of Formula VIb from a compound of Formula II wherein the compound of Formula VIb is produced at a percent diastereomeric excess selected from a range of 20%> to 80%> with respect to a compound of Formula Via. In certain embodiments, the methods provide production of a compound of Formula VIb from a compound of Formula II wherein the compound of Formula VIb is produced at a percent diastereomeric excess selected from a range of 40%> to 80%> with respect to a compound of Formula Via. In certain embodiments, the methods provide production of a compound of Formula VIb from a compound of Formula II wherein the compound of Formula VIb is produced at a percent diastereomeric excess selected from a range of 40% to 70% with respect to a compound of Formula Via. [0087] In certain embodiments, provided herein are methods of producing a compound of Formula I, wherein the method further provides separating or purifying a compound of Formula VIb from a reaction mixture comprising compounds of Formula VIb and Formula Via:

wherein Base, R ^A , R ^B and X are as described in the context of Formula I.

[0088] In certain embodiments, provided herein are methods of producing a compound of Formula I, wherein the methods provide high yields of a compound of Formula lb:

In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide for production of a compound of Formula lb:

from a compound of Formula Al :

Al in yields selected from a range of 15% to 55%. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide production of a compound of Formula lb in a yield selected from a range of 17% to 51%. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide production of a compound of Formula lb in a yield selected from a range of 30% to 50%. In an embodiment, provided herein are methods of producing a compound of Formula I, wherein the methods provide production of a compound of Formula lb in a yield selected from a range of 40% to 50%.

[0089] In certain embodiments, the methods provide production of a compound of Formula lb from a compound of Formula Al wherein the compound of Formula lb is produced at a percent diastereomeric excess selected from a range of 10%> to 80%> with respect to a compound of Formula la:

In certain embodiments, the methods provide production of a compound of Formula lb from a compound of Formula Al wherein the compound of Formula lb is produced at a percent diastereomeric excess selected from a range of 20%> to 80%> with respect to a compound of Formula la. In certain embodiments, the methods provide production of a compound of Formula lb from a compound of Formula Al wherein the compound of Formula lb is produced at a percent diastereomeric excess selected from a range of 40%> to 80%> with respect to a compound of Formula la. In certain embodiments, the methods provide production of a compound of Formula lb from a compound of Formula Al wherein the compound of Formula lb is produced at a percent diastereomeric excess selected from a range of 40% to 70% with respect to a compound of Formula la.

[0090] In certain embodiments, provided herein are methods of producing a compound of Formula I, wherein the method further provides separating or purifying a compound of Formula lb from a reaction mixture comprising compounds of Formula lb and Formula la:

[0091] In certain embodiments, a method for producing a compound of Formula I is provided wherein in step (a) the compound of Formula II is reacted at a concentration selected from the range of 0.2 M to 0.5 M, optionally 0.25 M to 0.45 M, optionally 0.3 M to 0.4 M, optionally about 0.35 M. In certain embodiments, a method for producing a compound of Formula I is provided wherein in step (a) the compound of Formula III is reacted at a concentration selected from the range of 0.2 M to 0.7 M, optionally 0.3 M to 0.6 M, optionally 0.4 M to 0.5 M, optionally about 0.45 M, optionally at about the same concentration as the compound of Formula II. In certain embodiments, a method for producing a compound of Formula I is provided wherein in step (a) the compound of Formula II is reacted at a concentration selected from the range of 0.2 M to 0.5 M, optionally 0.25 M to 0.45 M, optionally 0.3 M to 0.4 M, optionally about 0.35 M; and the compound of Formula III is reacted at a concentration selected from the range of 0.2 M to 0.7 M, optionally 0.3 M to 0.6 M, optionally 0.4 M to 0.5 M, optionally about 0.45 M, optionally at about the same concentration as the compound of Formula II.

[0092] The methods for producing cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds described herein can be carried out in the presence of additional reagents. In certain embodiments, for example, a method of producing a compound of Formula I is provided wherein the reactants in step (a) are contacted with an organic base. In certain embodiments, the organic base is triethylamine (Et ₃ N), pyridine, N, N-diisopropylethylamine, diisopropylamine, benzylamine, Ν,Ν,Ν',Ν'- tetramethylethylenediamine (TMEDA), pyrrolidine, diethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1-methylimidazole (NMI), 4- (dimethylamino)pyridine (DMAP), potassium carbonate, lithium diisopropylamide (LDA), sodium hexamethyldisilazane (NaHMDS), (+/-)-trans-l,2-cyclohexanediamine, or 1,4- Diazabicyclo[2.2.2]octane. In certain embodiments the organic base is contacted at a concentration selected from the range of 0.4 M to 0.9 M, optionally 0.5 M to 0.8 M, optionally 0.6 M to 0.7 M, optionally about 0.65 M, optionally at a concentration which is about twice the concentration of the compound of Formula II. [0093] In certain embodiments, a method of producing a compound of Formula I is provided wherein the reactants in step (a) are contacted with a solvent. In certain embodiments, the solvent is dichloromethane (DCM), tert-butyl methyl ether (TBME), tetrahydrofuran (THF), isopropylacetate, toluene, 2-methyl tetrahydrofuran (2-MeTHF), di- methoxyethane, di-ethoxyethane or combination thereof.

[0094] In certain embodiments, a method for producing a compound of Formula I is provided wherein in step (b) the compound of Formula IV is contacted at a concentration selected from the range of 0.01 M to 0.15 M, optionally 0.04 M to 0.12 M, optionally 0.07 M to 0.09 M, optionally about 0.08 M.

[0095] In certain embodiments, a method of producing a compound of Formula I is provided wherein in step (b) the ring closure reagent is pyridinium trifluoromethanesulfonate, 3-pyridinesulfonic acid, triflic acid, pyridine tosylate, or an acid-base system. In certain embodiments, a method of producing a compound of Formula I is provided wherein a base in the acid-base system is pyridine, 2,6-lutidine, 2,2-bypyridyl, 1,10-phenanthroline, quinoline, 5-bromoquinoline, 4-dimethylaminopyridine (DMAP), 2,6-di-fert-butylpyridine, dioxane, 1- methylimidazole (NMI), potassium carbonate, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), methylmorpholine, aniline, benzylamine, bipyridyl, or imidazole. In certain embodiments, a method of producing a compound of Formula I is provided wherein an acid in the acid-base system is trifluoromethanesulfonic acid, hydrochloric acid, oxalic acid, (lR)-(-)-10- camphorsulfonic acid, (lS)-(+)-10-camphorsulfonic acid, benzenesulfonic acid, trifluoroacetic acid, acetic acid, citric acid, methanesulfonic acid, triflic acid, 3- pyridinesulfonic acid, or p-toluenesulfonic acid. In certain embodiments, a method of producing a compound of Formula I is provided wherein in step (b) the ring closure reagent is contacted at a concentration selected from the range of 0.08 M to 0.24 M, optionally 0.12 M to 0.2 M, optionally 0.15 M to 0.17 M, optionally at about 0.16 M, optionally at about twice the concentration of the compound of Formula IV.

[0096] In certain embodiments, a method of producing a compound of Formula I is provided wherein the in step (b) the oxidation reagent is contacted under anhydrous conditions. In certain embodiments, a method of producing a compound of Formula I is provided wherein in step (b) the oxidation agent is a peroxide. In certain embodiments, a method of producing a compound of Formula I is provided wherein the peroxide is tert-butyl hydroperoxide, urea hydrogen peroxide, or meta-chloroperoxybenzoic acid (mCPBA). In certain embodiments, a method of producing a compound of Formula I is provided wherein in step (b) the oxidation agent is iodine. In certain embodiments, a method of producing a compound of Formula I is provided wherein in step (b) the oxidation agent is contacted at a concentration selected from the range of 0.08 M to 0.24 M, optionally 0.12 M to 0.2 M, optionally 0.15 M to 0.17 M, optionally at about 0.15 M, optionally at about twice the concentration of the compound of Formula IV.

[0097] In certain embodiments a method of producing a compound of Formula I is provided wherein in step (b) the ring closure reagent is provided in a solvent. In certain embodiments a method of producing a compound of Formula I is provided wherein in step (b) the ring closure reagent is provided in a solvent under anhydrous conditions. In certain embodiments, a method of producing a compound of Formula I is provided wherein in step (b) the ring closure reagent is provided in a solvent selected from dichloromethane (DCM), toluene, tetrahydrofuran (THF), acetonitrile (ACN), 2-methyl tetrahydrofuran, and a combination thereof.

[0098] In certain embodiments a method of producing a compound of Formula I is provided wherein in step (b) the oxidation reagent is provided in a solvent. In certain embodiments a method of producing a compound of Formula I is provided wherein in step (b) the oxidation reagent is provided in a solvent under anhydrous conditions. In certain embodiments, a method of producing a compound of Formula I is provided wherein in step (b) the oxidation reagent is provided in a solvent selected from dichloromethane (DCM), toluene, decane, tetrahydrofuran (THF), water, acetonitrile (ACN), 2-methyl tetrahydrofuran, di-methoxyethane, di-ethoxyethane and a combination thereof.

[0099] The methods for producing cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds described herein can be conducted over a range of temperatures. In certain embodiments, for example, a method of producing a compound of Formula I is provided wherein the temperature in step (a) is kept below about 30 °C, optionally below about 25 °C, optionally below about 20 °C. In certain embodiments, for example, a method of producing a compound of Formula I is provided wherein the temperature in step (a) is kept in the range of about 10 °C to 30 °C, optionally 15 °C to 25 °C, optionally 15 °C to 20 °C. In certain embodiments, for example, a method of producing a compound of Formula I is provided wherein the temperature in step (b) is kept below about 40 °C, optionally below about 30 °C, optionally below about 25 °C. In certain embodiments, for example, a method of producing a compound of Formula I is provided wherein the temperature in step (b) is kept in the range of about 10 °C to 40 °C, optionally 15 °C to 25 °C, optionally 18 °C to 23 °C.

[00100] The methods for producing cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds described herein can be conducted over a range of reaction times. In certain embodiments, for example, a method of producing a cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, or cyclic phosphonate nucleoside compound is provided wherein the reaction in step (a) is conducted for 15 minutes to 150 minutes, optionally from 30 minutes to 120 minutes, optionally from 30 minutes to 60 minutes, optionally for about 60 minutes. In certain embodiments, for example, a method of producing cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds is provided wherein in step (b) the compound of Formula IV is contacted with a ring closure reagent from 20 minutes to 3 hours, optionally from 20 minutes to 75 minutes, optionally from 30 minutes to 60 minutes, optionally for about 60 minutes. In certain embodiments, for example, a method of producing cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds is provided wherein in step (b) the compound of Formula ill is contacted with a ring closure reagent from 20 minutes to 3 hours, optionally from 20 minutes to 75 minutes, optionally from 30 minutes to 60 minutes, optionally for about 60 minutes.

[00101] In certain embodiments, for example, a method of producing cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds is provided wherein in step (b) the compound of Formula IV is contacted with an oxidation reagent from 15 minutes to 120 minutes, optionally from 30 minutes to 120 minutes, optionally from 30 minutes to 60 minutes, optionally for about 45 minutes. In certain embodiments, for example, a method of producing cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds is provided wherein in step (b) the compound of Formula il is contacted with an oxidation reagent from 15 minutes to 120 minutes, optionally from 30 minutes to 120 minutes, optionally from 30 minutes to 60 minutes, optionally for about 45 minutes.

[00102] In an embodiment, a method of producing a compound of Formula I is provided as described herein, wherein: , or a tautomeric form thereof;

R ^A is hydrogen, methyl, chloro, bromo, fluoro, or iodo; R ^B is hydrogen, hydroxyl, chloro, bromo, fluoro, or iodo;

X is -R ¹ , -OR ¹ , -SR ¹ , -NR ¹ R ² , or -0-C(0)-G2(S _C2 )-NH-Q ² ;

R ¹ is alkyl, aryl, aryl-alkyl, cycloalkyl, heterocyclo-alkyl, alkoxyl-carbonyl-alkyl, alkoxyl- carbonyl-amino-alkyl-carbonyl-thio-alkyl, hydroxyl-alkyl-carbonyl-thio-alkyl, or alkyl- carbonyl-thio-alkyl;

R is hydrogen, alkyl, cycloalkyl, aryl, or aryl-alkyl.

R ⁴ is hydrogen, hydroxyl, alkoxyl, amino, or alkylamino;

R ⁵ is hydrogen, hydroxyl, amino, or alkoxyl;

R ⁶ is hydrogen, chloro, bromo, fluoro, iodo, or alkyl;

R ⁷ is hydrogen, hydroxyl, or -NH ₂ ;

Q ¹ is -SR ^Y , -NR ^Y R ^Y , or alkoxyl;

2 2

Q is hydrogen or alkoxyl; or Q and Sc ₂ , together with the atoms to which they are attached, combine to form a five-membered heterocyclic ring;

R ^x is hydrogen or R ^x and Sci, together with the atoms to which they are attached, combine to form a five-membered heterocyclic ring;

R ^Y is hydrogen or alkyl;

Sci and Sc ₂ are hydrogen, alkyl, aryl-alkyl, heterocyclo-alkyl, -alkyl-C(0)OH, heteroaryl-alkyl, aminoalkyl, hydroxyl-alkyl, -alkyl-amino-C(NH)-amino, -alkyl-C(O)- amino, -alkyl-SH, -alkyl-C(0)-amino, -alkyl-S-alkyl, or -alkyl-aryl-OH;

Gl and G2 are C ₁ -C ₂ alkylene; alkyl at each occurrence is Ci to C ₁₀ unsubstituted alkyl or Ci to C ₁₀ alkyl substituted with one or more fluoro, chloro, bromo, iodo, hydroxyl, carbonyl, cycloalkyl, sulfanyl, amino, -0-(Ci to C ₁₀ unsubstituted alkyl), aryl-oxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate; alkoxyl at each occurrence is -OR' where R' is alkyl or cycloalkyl; aryl at each occurrence is C ₆ -Ci2 unsubstituted aryl or C ₆ -Ci2 aryl substituted with one or more fluoro, chloro, bromo, iodo, alkyl, hydroxyl, amino, alkoxy, aryl-oxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate; heteroaryl at each occurrence is a C5-C20 monovalent monocyclic aromatic group and/or multicyclic aromatic group that contains at least one aromatic ring having one or more O, S and N in the ring; heteroaryl groups are bonded to the rest of the molecule through the aromatic ring; wherein each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom; cycloalkyl at each occurrence is a C3-C15 unsubstituted cycloalkyl or C3-C15 cycloalkyl substituted with one or more fluoro, chloro, bromo, iodo, alkyl, hydroxyl, amino, alkoxy, aryl-oxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate; heterocyclo at each occurrence is a C3-C20 monovalent monocyclic non-aromatic and/or multicyclic non-aromatic that contains at least one non-aromatic ring having one or more O, S and N in the ring; heterocyclo groups are bonded to the rest of the molecule through the non-aromatic ring; and amino at each occurrence is -NHR" or -NH-, wherein R" is hydrogen, Ci to C ₁₀ unsubstituted alkyl, C ₆ -Ci2 unsubstituted aryl, or C3-C15 unsubstituted cycloalkyl.

[00103] In an embodiment, a method of producing a compound of Formula I is provided as described herein, wherein R ¹ is alkyl. In an embodiment, a method of producing a compound of Formula I is provided as described herein, wherein R ¹ is aryl. In an embodiment, a method of producing a compound of Formula I is provided as described herein, wherein R ¹ is arylalkyl. In an embodiment, a method of producing a compound of Formula I is provided as described herein, wherein R ¹ is cycloalkyl. In an embodiment, a method of producing a compound of Formula I is provided as described herein, wherein R ¹ is heterocycloalkyl. In an embodiment, a method of producing a compound of Formula I is provided as described herein, wherein R ¹ is alkoxycarbonylalkyl. In an embodiment, a method of producing a compound of Formula I is provided as described herein, wherein R ¹ is alkoxycarbonylaminoalkylcarbonylthioalkyl. In an embodiment, a method of producing a compound of Formula I is provided as described herein, wherein R ¹ is hydroxylalkylcarbonylthioalkyl. In an embodiment, a method of producing a compound of Formula I is provided as described herein, wherein R ¹ is alkylcarbonylthioalkyl.

[00104] In an embodiment, a method of producing a compound of Formula I is provided

as described herein, wherein Base , or a tautomeric form thereof, wherein: R ⁴ is hydrogen, hydroxyl, alkoxyl, amino or alkylamino; R ⁵ is hydrogen, hydroxyl, amino, or alkoxyl; R is hydrogen, halogen, or alkyl; and R is hydrogen, hydroxyl, or -NH ₂ . In an embodiment, a method of producing a compound of Formula I is provided,

wherein Base is ; · a anndd R R ⁶ is hydrogen, halogen, or alkyl; and R ⁷ is hydrogen, hydroxyl or -NH ₂ . In an embodiment, a

method of producing a compound of Formula I is provided, wherein Base

Formula I is provided, wherein Base is uracil, 5-fluorouracil, 2,6-diaminopurine, thymine, cytosine, guanine, or 6-ethoxypurine. In an embodiment, a method of producing a compound of Formula I is provided, wherein Base is 5-fluorouracil, 2,6-diaminopurine or 6- ethoxypurine. In an embodiment, a method of producing a compound of Formula I is provided, wherein R ⁶ is halo. In an embodiment, a method of producing a compound of Formula I is provided, wherein R ⁶ is fluoro. In an embodiment, a method of producing a compound of Formula I is provided, wherein Base is 5-fluorouracil. [00105] In an embodiment, a method of producing a compound of Formula I is provided, wherein R ^A is hydrogen or methyl. In an embodiment, a method of producing a compound of Formula I is provided, wherein R ^B is hydroxyl. In an embodiment, a method of producing a compound of Formula I is provided, wherein R ^B is halo. In an embodiment, a method of producing a compound of Formula I is provided, wherein R ^B is chloro. In an embodiment, a method of producing a compound of Formula I is provided, wherein R ^A is hydrogen or methyl and R ^B is halo. In an embodiment, a method of producing a compound of Formula I is provided, wherein R ^A is methyl and R ^B is chloro.

[00106] In certain embodiments, provided herein is a method of producing a compound of Formula I wherein the compound according to Formula I is of Formula lb:

wherein Base, X, R ^A , R ^B , and R ¹ are as described in the context of Formula I.

[00107] In certain embodiments, provided herein is a method of producing a compound of Formula I wherein the compound according to Formula I is of Formula V:

wherein Base, R ^A , R ^B , and R ¹ are as described in the context of Formula I.

[00108] In certain embodiments, provided herein is a method of producing a compound of Formula I wherein the compound according to Formula I is of Formula VI:

wherein Base, R ^A , R ^B , R ¹ and R ² are as described in the context of Formula I.

[00109] In certain embodiments, provided herein is a method of producing a compound of Formula I wherein the compound according to Formula I is of Formula Vb: wherein Base, R ^A , R ^B , and R ¹ are as described in the context of Formula I.

[00110] In certain embodiments, provided herein is a method of producing a compound of Formula I wherein the compound according to Formula I is of Formula VIb:

wherein Base, R ^A , R ^B , R ¹ and R ² are as described in the context of Formula I.

[00111] In certain embodiments, provided herein is a method of producing a compound of Formula I wherein the compound according to Formula I is of Formula lb:

[00112] In certain embodiments, provided herein is a method of producing a compound of Formula I wherein the compound according to Formula II is of Formula Al :

Al

[00113] In certain embodiments, provided herein is a method of producing a compound of Formula I wherein the compound according to Formula III is of Formula A2:

A2

[00114] In certain embodiments, provided herein is a method of producing a compound of Formula A3 :

A3 comprising: (a) reacting a compound of Formula Al with a compound of Formula A2 to form the compound of Formula A3:

A3

[00115] In certain embodiments, provided herein is a method of producing a compound of Formula lb:

comprising: (b) contacting a compound of Formula A3 with an intramolecular ring closure reactant and an oxidation reactant to form the compound of Formula lb:

In certain embodiments, methods of producing a compound of Formula lb are provided wherein in step (b) the compound of Formula A3 is contacted with the ring closure reagent and then contacted with the oxidation reagent. In certain embodiments, methods of producing a compound of Formula lb are provided wherein in step (b) the compound of Formula A3 is contacted with the oxidation reagent and then contacted with the ring closure reagent. In certain embodiments, methods of producing a compound of Formula lb are provided wherein in step (b) the compound of Formula A3 is contacted with the oxidation reagent and the ring closure reagent at the same time. In certain embodiments, methods of producing a compound of Formula lb are provided wherein in step (b) the compound of Formula A3 is contacted with the oxidation reagent and the ring closure reagent at the same time and in the same pot.

[00116] In certain embodiments, provided herein is a method of producing a compound of Formula lb:

comprising: (a) reacting a compound of Formula Al with a compound of Formula A2 to form a compound of Formula A3:

^{A2 A3} ; and

(b) contacting the compound of Formula A3 with an intramolecular ring closure reagent and an oxidation reagent to form the compound of Formula lb:

In certain embodiments, methods of producing a compound of Formula lb are provided wherein in step (b) the compound of Formula A3 is contacted with the ring closure reagent and then contacted with the oxidation reagent. In certain embodiments, methods of producing a compound of Formula lb are provided wherein in step (b) the compound of Formula A3 is contacted with the oxidation reagent and then contacted with the ring closure reagent. In certain embodiments, methods of producing a compound of Formula lb are provided wherein in step (b) the compound of Formula A3 is contacted with the oxidation reagent and the ring closure reagent at the same time. In certain embodiments, methods of producing a compound of Formula lb are provided wherein in step (b) the compound of Formula A3 is contacted with the oxidation reagent and the ring closure reagent at the same time and in the same pot.

[00117] In certain embodiments, provided herein is a method of producing a compound of Formula lb wherein in step (b) the compound of Formula A3 is contacted with a ring closure reagent to form a compound of Formula A4:

the compound of Formula A4 is contacted with an oxidation reagent to form the compound of Formula lb:

[00118] In certain embodiments, provided herein is a method of producing a compound of Formula lb wherein in step (b) the compound of Formula A3 is contacted with an oxidation reagent to form a compound of Formula A5:

the compound of Formula A5 is contacted with a ring closure reagent to form the compound of Formula lb:

Compounds

[00119] Provided herein are compounds useful in the preparation of cyclic phosphate, cyclic phosphoramidate, cyclic thiophosphate, and cyclic phosphonate nucleoside compounds. In certain embodiments, provided herein are compounds according to Formula III:

III wherein X is -R ¹ , -OR ¹ , -SR ¹ , -NR ¹ R ² , or an O-linked or N-linked amino acid residue, or derivative thereof; each R ¹ is independently alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkylcarbonylthioalkyl, hydroxylalkylcarbonylthioalkyl, or alkylcarbonylthioalkyl; and each R is independently hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl. [00120] In certain embodiments, provided herein are compounds according to Formula III, wherein:

X is -R ¹ , -OR ¹ , -SR ¹ , -NR ¹ R ² , or -0-C(0)-G2(S _C 2)- NH-Q ² ;

R ¹ is alkyl, aryl, aryl-alkyl, cycloalkyl, heterocyclo-alkyl, alkoxyl-carbonyl-alkyl, alkoxyl-carbonyl-amino-alkyl-carbonyl-thio-alkyl, hydroxyl-alkyl-carbonyl-thio-alkyl, or alkyl-carbonyl-thio-alkyl;

R is hydrogen, alkyl, cycloalkyl, aryl, or aryl-alkyl.

Q ¹ is -SR ^Y , -NR ^Y R ^Y , or alkoxyl;

2 2

Q is hydrogen or alkoxyl; or Q and Sc ₂ , together with the atoms to which they are attached, combine to form a five-membered heterocyclic ring;

R ^x is hydrogen or R ^x and Sci, together with the atoms to which they are attached, combine to form a five-membered heterocyclic ring;

R ^Y is hydrogen or alkyl;

Sci and Sc ₂ are hydrogen, alkyl, aryl-alkyl, heterocyclo-alkyl, -alkyl-C(0)OH, heteroaryl-alkyl, aminoalkyl, hydroxyl-alkyl, -alkyl-amino-C(NH)-amino, -alkyl-C(O)- amino, -alkyl-SH, -alkyl-C(0)-amino, -alkyl-S-alkyl, or -alkyl-aryl-OH;

Gl and G2 are C ₁ -C ₂ alkylene; alkyl at each occurrence is Ci to C ₁₀ unsubstituted alkyl or Ci to C ₁₀ alkyl substituted with one or more fluoro, chloro, bromo, iodo, hydroxyl, carbonyl, cycloalkyl, sulfanyl, amino, -0-(Ci to C ₁₀ unsubstituted alkyl), aryl-oxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate; alkoxyl at each occurrence is -OR' where R' is alkyl or cycloalkyl; aryl at each occurrence is C ₆ -Ci ₂ unsubstituted aryl or C ₆ -Ci ₂ aryl substituted with one or more fluoro, chloro, bromo, iodo, alkyl, hydroxyl, amino, alkoxy, aryl-oxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate; heteroaryl at each occurrence is a C5-C ₂₀ monovalent monocyclic aromatic group and/or multicyclic aromatic group that contains at least one aromatic ring having one or more O, S and N in the ring; heteroaryl groups are bonded to the rest of the molecule through the aromatic ring; wherein each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom; cycloalkyl at each occurrence is a C3-C15 unsubstituted cycloalkyl or C3-C15 cycloalkyl substituted with one or more fluoro, chloro, bromo, iodo, alkyl, hydroxyl, amino, alkoxy, aryl-oxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate; heterocyclo at each occurrence is a C3-C ₂₀ monovalent monocyclic non-aromatic and/or multicyclic non-aromatic that contains at least one non-aromatic ring having one or more O, S and N in the ring; heterocyclo groups are bonded to the rest of the molecule through the non-aromatic ring; and amino at each occurrence is -NHR" or -NH-, wherein R" is hydrogen, Ci to C ₁₀ unsubstituted alkyl, C ₆ -Ci ₂ unsubstituted aryl, or C3-C15 unsubstituted cycloalkyl.

[00121] In certain embodiments, provided herein are compounds according to Formula VII:

wherein R is defined as described in the context of Formula III.

[00122] In certain embodiments, provided herein are compounds according to Formula VIII:

VIII wherein R 1 and R 2 are as described in the context of Formula III.

[00123] In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R ¹ is alkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R ¹ is aryl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R is arylalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R ¹ is cycloalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R ¹ is heterocycloalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R ¹ is alkoxycarbonylalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R ¹ is alkoxycarbonylaminoalkylcarbonylthioalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R ¹ is hydroxylalkylcarbonylthioalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R ¹ is alkylcarbonylthioalkyl.

[00124] In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R is hydrogen. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is hydrogen and R 1 is alkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is hydrogen and R 1 is aryl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is hydrogen and R 1 is arylalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or

VIII, wherein R 2 is hydrogen and R 1 is cycloalkyl. In an embodiment, provided herein are

2 1 compounds according to any of Formulas III, VII or VIII, wherein R is hydrogen and R is heterocycloalkyl. In an embodiment, provided herein are compounds according to any of

Formulas III, VII or VIII, wherein R 2 is hydrogen and R 1 is alkoxycarbonylalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is hydrogen and R 1 is alkoxycarbonylaminoalkylcarbonylthioalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is hydrogen and R 1 is hydroxylalkylcarbonylthioalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R is hydrogen and R ¹ is alkylcarbonylthioalkyl.

[00125] In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R is alkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is alkyl and R 1 is alkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is alkyl and R 1 is aryl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is alkyl and R 1 is arylalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is alkyl and R 1 is cycloalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is alkyl and R 1 is heterocycloalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or

VIII, wherein R 2 is alkyl and R 1 is alkoxycarbonylalkyl. In an embodiment, provided herein

2 1 are compounds according to any of Formulas III, VII or VIII, wherein R is alkyl and R is alkoxycarbonylaminoalkylcarbonylthioalkyl. In an embodiment, provided herein are

2 1 compounds according to any of Formulas III, VII or VIII, wherein R is alkyl and R is hydroxylalkylcarbonylthioalkyl. In an embodiment, provided herein are compounds

2 1 according to any of Formulas III, VII or VIII, wherein R is alkyl and R is alkylcarbonylthioalkyl.

[00126] In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R is cycloalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is cycloalkyl and R 1 is alkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is cycloalkyl and R 1 is aryl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is cycloalkyl and R 1 is arylalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or

VIII, wherein R 2 is cycloalkyl and R 1 is cycloalkyl. In an embodiment, provided herein are

2 1 compounds according to any of Formulas III, VII or VIII, wherein R is cycloalkyl and R is heterocycloalkyl. In an embodiment, provided herein are compounds according to any of

Formulas III, VII or VIII, wherein R 2 is cycloalkyl and R 1 is alkoxycarbonylalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is cycloalkyl and R 1 is alkoxycarbonylaminoalkylcarbonylthioalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is cycloalkyl and R 1 is hydroxylalkylcarbonylthioalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R is cycloalkyl and R ¹ is alkylcarbonylthioalkyl.

[00127] In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R is aryl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is aryl and R 1 is alkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is aryl and R 1 is aryl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is aryl and R 1 is arylalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is aryl and R 1 is cycloalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is aryl and R 1 is heterocycloalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or

VIII, wherein R 2 is aryl and R 1 is alkoxycarbonylalkyl. In an embodiment, provided herein

2 1 are compounds according to any of Formulas III, VII or VIII, wherein R is aryl and R is alkoxycarbonylaminoalkylcarbonylthioalkyl. In an embodiment, provided herein are

2 1 compounds according to any of Formulas III, VII or VIII, wherein R is aryl and R is hydroxylalkylcarbonylthioalkyl. In an embodiment, provided herein are compounds

2 1 according to any of Formulas III, VII or VIII, wherein R is aryl and R is alkylcarbonylthioalkyl.

[00128] In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R is arylalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is arylalkyl and R 1 is alkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is arylalkyl and R 1 is aryl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is arylalkyl and R 1 is arylalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or

VIII, wherein R 2 is arylalkyl and R 1 is cycloalkyl. In an embodiment, provided herein are

2 1 compounds according to any of Formulas III, VII or VIII, wherein R is arylalkyl and R is heterocycloalkyl. In an embodiment, provided herein are compounds according to any of

Formulas III, VII or VIII, wherein R 2 is arylalkyl and R 1 is alkoxycarbonylalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is arylalkyl and R 1 is alkoxycarbonylaminoalkylcarbonylthioalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R 2 is arylalkyl and R 1 is hydroxylalkylcarbonylthioalkyl. In an embodiment, provided herein are compounds according to any of Formulas III, VII or VIII, wherein R is hydrogen and R ¹ is alkylcarbonylthioalkyl.

[00129] In certain embodiments, provided herein are compounds according to Formula A2:

A2

EXAMPLES

[00130] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); (microliters); mM (millimolar); μΜ (micromolar); Hz (Hertz); MHz (megahertz); mmol (millimoles); hr or hrs (hours); min (minutes); MS (mass spectrometry); ESI (electrospray ionization); TLC (thin layer chromatography); HPLC (high pressure liquid chromatography); THF (tetrahydrofuran); CDCI ₃ (deuterated chloroform); AcOH (acetic acid); DCM (dichloromethane); DMSO (dimethylsulfoxide); OMSO-d^ (deuterated dimethylsulfoxide); EtOAc (ethyl acetate); MeOH (methanol); and BOC (t-butyloxycarbonyl).

[00131] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions are conducted at room temperature unless otherwise noted. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure.

Example la

Preparation of Compound lb Scheme 1

Preparation of P(III) reagent, l-chloro-l-isopropoxy-N,N-diisopropylphosphinamine

(A2)

1 ) i-PrOH in THF

O

2) i-Pr ₂ NEt in THF I

PC

3) i-Pr ₂ NH in DCM N' ^P "CI

A2

Table 1 - Compounds Used in the Preparation of A2

[00132] Compound A2 was prepared as follows.

[00133] A reaction vessel was charged with Anhydr. THF (380 mL) and PC1 ₃ (21.8 mL). The PCI3 solution was cooled to -50 °C (MeOH/dry ice). Anhydrous 2-Propanol (19.2 mL) in THF (30 mL) was added using an addition funnel to maintain the internal temperature below -40 °C over about 40 minutes. The reaction mixture was stirred for additional 1 h at the same temperature. An aliquot was pulled from the reaction mixture for in-process testing and examined by 31 P NMR in either CDCI3 or THF-d8. The reaction was done without adding a base. A list of chemical shifts is provided in Table 2.

[00134] N,N-diisopropylethylamine (87 mL) in Anhydr. THF (lOOmL) was charged using an addition funnel to maintain the internal temperature below -40 °C. The mixture was stirred for additional lh at the same temperature. The clear solution turned to cloudy slurry as i- Pr ₂ NEt-HCl precipitated out. Diisopropylamine (35 mL) in anhydrous DCM (100 mL) was charged using an addition funnel to maintain the temperature below -40 °C. The cooling bath was removed and the solution stirred at room temperature for 15 h (overnight). A sample was pulled and checked using ³¹ P NMR in THF-d8.

[00135] The reaction mixture was concentrated in vacuo to near dryness at a bath temperature below 40 °C. TBME (680 mL) was charged and the mixture stirred for 1 h. The white precipitates were filtered off and the solid washed with TBME (200 mL). The filtrate was concentrated in vacuo to give the product as a yellow liquid (52.6 g, 93%). The product yellow liquid was used for the next step without further purification. The purity was not

31

directly determined but appeared to be -86% based on P NMR.

Table 2 - Chemical Shifts of Selected Compounds

Preparation of crude A3 from Al

Table 3 - Compounds Used in the Preparation of A3

[00136] A3 was prepared as follows.

[00137] Al (2.0 g) was charged, then anhydrous DCM (20 mL) was charged, then triethylamine (2.2 mL) was charged at room temperature. Next, A2 (2.15 g) in DCM (4 mL) was charged using an addition funnel to maintain temperature below 20 °C over about 5 minutes. The mixture was stirred for 30 minutes at room temperature. A sample was pulled for in-process testing and checked by HPLC. Table 4 provides a list of the HPLC retention times.

Table 4 - HPLC Retention Times

*3.0 min peak in Table 4 is for a hydro lyzed A3 using reverse phase HPLC. This did not impact in-process monitoring.

[00138] Additional A2 (200mg in 0.5 mL of DCM) was charged as the starting material was remaining. The mixture was stirred for 30 minutes. A sample was pulled for in-process testing and checked by HPLC. The reaction mixture was concentrated in vacuo at a bath temperature below 30 °C to near dryness. 20mL of TBME was charged and the filter cake washed with TBME (lOmL). The filtrate was concentrated in vacuo at a bath temperature below 30 °C to give the crude product as off-white solid (4g, not fully dried). The crude product was used for the next step without further purification.

[00139] Test 20: As used herein, "test 20" refers to the HPLC method summarized as follows. Column: Zorbax Eclipse XDB-C8; 4.6x75mm 3.5-Micron. Mobile Phase A:

Acetonitrile. Mobile Phase B: 0.01M ammonium acetate buffer, PH=4.4. Column

Temperature: 28°C. Flow Rate: 1.4ml/min. Detection: UV 254nm, UV272nm. Injection volume: 8μ1. Sample: about lmg/ml in methanol. Gradient: see Table 5. Equilibration: 4 minutes.

Table 5 - Gradient for HPLC method Test20

Preparation of Compound lb

Table 6 - Compounds Used in the Preparation of Compound lb Reagent

Compound MW Amount mmol Equiv.

Grade

7.2

Crude ~ 4g, not

- 465.91 Based on 1.0 A3 fully dried previous step

Anhydrous,

DCM 30 mL

ACS

Anhydrous,

Toluene 60 mL

ACS

Pyridinium

ACS 229.18 3.2 g 14.4 2.0 trifluoromethanesulfonate

t-BuOOH

ACS 2.6 mL 14.3 2.0 ~5.5M in decane

DCM for work-up 30 + 30 mL

IN aqueous HC1 for work¬

60 mL

up

Compound lb 380.72

[00140] Compound lb was prepared as follows.

[00141] Crude A3 from the previous step was charged. Anhydrous DCM (30 mL) was charged. Anhydrous toluene (60 mL) was charged. Pyridinium trifluoromethanesulfonate (3.2 g) was charged portion-wise at room temperature. The mixture was stirred for 3 hrs. A sample for in-process testing was pulled and checked by HPLC to ensure A3 was completely converted to A4. Table 7 provides a list of HPLC retention times. As soon as the reaction was complete, tert-butyl hydroperoxide solution (2.6mL) was charged slowly using a syringe to maintain the internal temperature below 30 °C over 30 minutes. The mixture was stirred for 2 h at room temperature. A sample for in-process testing was pulled and checked by HPLC.

[00142] Additional DCM (30 mL) was charged. The organic reaction mixture was washed with IN aqueous HC1 (60 mL). DCM-toluene (v/v, 1/1) became the lower layer during the extraction process. The two layers were separated. DCM (30 mL) was charged to the aqueous layer, and the two layers separated. The two organic layers were combined and washed with water (30 mL). The two layers were separated and the organic layer dried (MgS0 ₄ ). The filtrate was filtered and concentrated in vacuo to obtain the crude product as an off-white solid (3g, slightly wet). The product was purified using normal silica gel column chromatography to give pure compound lb as a white solid (1.2g, 44% from Al). Column size: 40g silica, eluent A: 30% EtOAc in DCM, eluent B: 3% MeOH in Eluent B. The product came out at ~40 min in 50% of eluent B.

Table 7 - HPLC Retention Times

[00143] Analytical data for Compound lb is provided below. [00144] Ή NMR (400 MHz, DMSO-d6): δ 11.65 (1H, s), 7.82 (1H, d, J=8.1 Hz), 6.44 (1H, s), 5.68 (1H, d, J=8.1 Hz), 4.84 (1H, d, J=9.5 Hz), 4.75 - 4.62 (3H, m), 4.36 (1H, dd, J=9.4, 15.8 Hz), 1.52 (3H, s), 1.31 (6H, t, J=5.8 Hz).

[00145] ¹³ C NMR (101 MHz, DMSO-d6): δ 23.1, 23.6, 23.8, 68.5, 70.8, 72.7, 75.0, 80.5, 94.2, 103.0, 140.4, 150.9, 163.1.

[00146] ³¹ P NMR (162 MHz, DMSO-d6): -6.31.

[00147] LC-MS: 381.1 ([M+l] ⁺ ).

[00148] HPLC (Method: Test 20): retention time: 3.7 min. Retention time of Compound la: 3.4 min.

Example lb

First Alternative Preparation of Compound lb

Scheme 2

[00149] Preparation of Intermediate A3

[00150] A nitrogen purged reactor was charged with Al (1.0 eq) and anhydrous DCM (10 vol). To the stirred suspension, TEA (2.0 eq) was added and stirred for 10 min at 18-23 °C. A solution of Reagent A2 (1.1 eq) in anhydrous DCM (2 vol) was added over 30 to 60 min, while maintaining the temperature below 25 °C. The solution was analyzed by normal phase HPLC after 30 to 60 min. The reaction is deemed complete when the amount of Al is less than 5%. One deemed complete, the reaction mixture was concentrated to a residue (bath at 25 to 30 °C). The solids were slurried in MTBE (10 vol) and re-concentrated to a residue. MTBE (10 vol) was added and the slurry stirred at 18-23 °C for 30 min. The slurry was filtered through a pad of Solka Floe and washed with MTBE (5 vol). The filtrate was concentrated to a foam, dissolved in toluene (10 vol) and silica gel (2 g/g input Al) added. The solution was stirred for 30 min and filtered through a pad of Solka Floe. The filtrate was washed with toluene (5 vol) and concentrated to a glassy foam. The product was analyzed by 1H NMR (CDCI ₃ ) to make sure TEA and TEA-HC1 was removed. Material was used in the next step without further purification.

[00151] Preparation of Compound lb

[00152] Step 1: Pre-formation of Pyridine-Benzenesulfonate. A reactor was charged with toluene (8.8 vol). To the stirred solvent, BSA (2.0 eq) and add excess pyridine (10 eq) were added. The suspension was stirred for 10 min, then concentrated to a residue (bath at 40 to 45 °C). Toluene (8.8 vol) was added and re-concentrated to a residue. Toluene (8.8 vol) was added and re-concentrate to a residue a third time.

[00153] Step 2: Cyclization. A nitrogen purged reactor was charged with the pyridine - BSA salt prepared above. THF (10 vol) was charged and the suspension stirred at 18-23 °C. A solution of A3 (23 g) in THF (10 vol) was added at a rate such that the temperature remained below 25 °C. The reaction mixture was assayed after 30 min by normal phase HPLC. The reaction was deemed complete when the two peaks for A3 were less than 1%.

[00154] Step 3: Oxidation. A solution of t-BuOOH in decane (5-6 M, 2.0 eq) was added over 5 to 10 min while maintaining the temperature below 25 °C. After 30 to 60 min, the reaction was assayed by reverse phase HPLC to determine consumption of the cyclized A4. The reaction as deemed complete when A4 was less than 5%.

[00155] Work-up. The reaction mixture was concentrated to 50% of the original volume and diluted with DCM (15 vol). It was then washed with 1 N HC1 (15 vol), the phases separated and the aqueous phase back-extracted with DCM (7.5 vol). The combined organic phases were washed with a mixture of brine (5 vol), water (5 vol) and saturated aqueous sodium thiosulfate (5 vol). The solution was assayed to determine the absence of peroxides. The phases were separated and the organic phase concentrated to a residue.

[00156] Purification. The crude material was purified via flash column chromatography. A pack silica gel (10 g/g crude) was wetted with DCM. The crude material was dissolved in minimal DCM, loaded onto a column and eluted with DCM (20 vol based on crude weight), followed by 2% MeOH/DCM until all lb eluted. The pure fractions were concentrated to obtain pure lb. [00157] Characterization Assays. The formation of A3 was deemed complete after 30 minutes by HPLC with 84.3% product (1.2: 1.0 isomer ratio), containing 0.35% Al. The material was isolated in 79.5% AUC by HPLC, with a potency of 79.5% as determined by 1H NMR (1,4-dimethoxybenzene internal standard). Analysis by chiral HPLC indicated an

31

isomer ratio of 1.0: 1.0; P NMR analysis also showed a 1.0: 1.0 ratio, with various small phosphorus impurities. A3 was converted to A4, the reaction was deemed complete after 30 minutes with no detectable starting material, as determined via normal phase HPLC. A4 was then converted to product. This reaction was deemed complete after 30 minutes with 2.6% A4 remaining (85: 15 isomer ratio). The crude compound lb was isolated in 86.6% chemical purity (AUC) by HPLC, having an isomer ratio of 78:22. After column purification, compound lb was isolated in 97.2% AUC (1.0:0.02).

Example lc

Second Alternative Preparation of Compound lb

[00158] Preparation of P(III) Reagent (A2)

[00159] A2 lot A2L1: The preparation of A2 was scaled to 200 g. It had been observed that in previous experiments, degradation of the product was seen during work up. The reaction was set up as follows. A flask was charged with THF (11 vol), PC1 ₃ (200 g) and cooled to -30 to -20 °C. The batch was charged with IPA (111.4 mL, 1.0 eq) and held at the same temperature for 15 minutes. The batch was added with a solution of

diisopropylethylamine (508 mL, 2.0 eq) in THF (1 L) over 45 minutes. After being held for 30 minutes at same temperature the batch was added with a solution of diisopropylamine (204 mL, 1.0 eq) in DCM (600 mL) over 15 minutes. Several aliquots were removed and subjected to different work up conditions to ascertain the effect on product purity.

[00160] A2 lot A2L2: An aliquot of A2 was concentrated, dissolved in MTBE, stirred for

31

30 min at 15 to 20 °C, filtered and re-concentrated. Prior to work up, P NMR indicated two minor impurities. After initial concentration, 31 P NMR indicated several additional impurities, totaling -10%. After addition of MTBE and filtration, NMR indicated there was ~4% oxidized A2, bringing the total impurities to 15%.

[00161] A2 lot A2L3: A second aliquot of A2 was first diluted with MTBE, stirred for 45

31

min at 15 to 20 °C, then concentrated. Analysis by P NMR indicated 15% impurities, but no oxidation of A2. [00162] A2 lot A2L4: A third aliquot of A2 was treated with silica gel, stirred for 10 min,

31

filtered and concentrated. Analysis by P NMR indicated significant degradation of the product.

[00163] A2 lot A2L5: The purpose of this experiment was to investigate replacement of DCM / THF with 2-MeTHF. A flask was charged with 2-MeTHF (11 vol), PC1 ₃ (50 g) and cooled to -20 to -10 °C. The batch was charged with IPA (28 mL, 1.0 eq) and held at same temperature for 15 minutes. The batch was combined with a solution of

diisopropylethylamine (508 mL, 2.0 eq) in 2-MeTHF (250 mL) over 20 minutes. After being held for 60 minutes at same temperature the batch was added with a solution of

diisopropylamine (51 mL, 1.0 eq) in 2-MeTHF (150 mL) over 15 minutes. Formation of A2 proceeded typically. After work up, analysis by 31 P NMR indicated significant

decomposition.

[00164] Formation of A3

[00165] Several screening reactions have been performed in the synthesis of A3. Several solvents and bases have been investigated. A summary of the results are shown below in Table 8. Unless otherwise noted, all reactions were performed at ambient conditions (15 to 20 °C), 2 equivalents of base were used, and 1.1 equivalents of A2 were used.

Table 8: Preparation of A3

Base 1 = (+/-)-trans-l,2-cyclohexanediamine

Base 2 = l,4-Diazabicyclo[2.2.2]octane

[00166] The above table indicates that diisopropylethylamine and diisopropylamine were similar to triethylamine with respect to the ratio of product to starting material and A4. The reaction mixture was a slurry in the solvents other than DCM.

[00167] Standard Conditions / Standard Workup: A N ₂ purged reactor is charged with Al (1.0 eq) and anhydrous DCM (10 vol). To the stirred suspension, TEA is added (2.0 eq) and stirred for 10 min at 18-23 °C. A solution of A2 is slowly added (1.1 eq) in anhydrous DCM (2 vol) over 30 to 60 min, while maintaining the temperature below 25 °C. The reaction is analyzed by normal phase HPLC after 30 to 60 min. The reaction is typically deemed complete when the amount of Al is less than 5%. Once deemed complete, the reaction mixture is concentrated to a residue (bath at 25 to 30 °C). The solids are slurried in MTBE (10 vol) and re-concentrated to a residue. MTBE (10 vol) is added and the slurry stirred at 18-23 °C for 30 min. The slurry is filtered through a pad of Solka Floe and washed with MTBE (5 vol). The filtrate is concentrated to a foam, dissolved in toluene (10 vol) and silica gel (2 g/g input Al) is added. The mixture is stirred for 30 min and filtered through a pad of Solka Floe. The filtrated is washed with toluene (5 vol) and concentrated to a glassy foam. Analysis is by 1H NMR (CDC1 ₃ ) to confirm TEA and TEA-HC1 has been removed.

[00168] Al lot A1L1 : A jacketed reactor was charged with Acetyl-Al (210 g), MeOH (2.1 L) and added with sodium methoxide (102 g, 30 wt% in MeOH). The batch was stirred for 2 hours at 20 to 25 °C. A separate reactor was charged with Dowex 50WX4 resin (315), MeOH (3.2 L), stirred for 30 minutes, filtered, and dried under nitrogen for 15 minutes. Upon completion of the reaction as verified by HPLC, the batch was charged with the resin and stirred for 1 hour. The batch was filtered over Celite, the solids washed with MeOH, filtrates combined, and concentrated at 40 to 45 °C. EtOAc (3.2 L) was added to the concentrated batch, stirred at 40 to 45 °C until fully dissolved and transferred to a jacketed reactor. Heptane (1.1 L) was slowly added forming a slurry. The batch was cooled to 10 to 15 °C, stirred for 1.5 hours, filtered, the solids washed with heptane (500 mL), dried under hot nitrogen at 45 to 50 °C to afford Al (95 g, 59% yield).

[00169] Al lot A1L2: A jacketed reactor was charged with Acetyl-Al (320 g), MeOH (3.2 L) and added with sodium methoxide (150 g, 30 wt% in MeOH). The batch was stirred for 2 hours at 20 to 25 °C. A separate reactor was charged with Dowex 50WX4 resin (480 g), MeOH (4.8 L), stirred for 30 minutes, filtered, and dried under nitrogen for 15 minutes. Upon completion of the reaction as verified by HPLC, the batch was charged with the resin and stirred for 1 hour. The batch was filtered over Celite, the solids washed with MeOH, filtrates combined, and concentrated at 40 to 45 °C. EtOAc (4.8 L) was added to the concentrated batch, stirred at 40 to 45 °C until fully dissolved and transferred to a jacketed reactor. Heptane (1.6 L) was slowly added forming a slurry. The batch was cooled to 10 to 15 °C, stirred for 1.5 hours, filtered, the solids washed with heptane (500 mL), dried under hot nitrogen at 45 to 50 °C to afford Al (175 g, 71% yield).

[00170] A3 lot A3L1: Following standard conditions, 20 g of Al (lot A1L1) was converted to A3 using A2. HPLC analysis at 30 min indicated 1% Al remaining. Standard workup was performed, followed by the toluene / silica gel treatment previously described. Analysis by Q 1H NMR indicated 76% potency, with no detectable TEA or TEA-HCl, and 10% toluene. Analysis by normal phase HPLC indicated no detectable Al and reverse phase HPLC indicated 5%> oxidized A3, and 9%> bis-phosphorylated impurity.

[00171] A3 lot A3L2: Following standard conditions, 20 g of Al (lot A1L2) was converted to A3 using A2. In an attempt to reduce the bis-phosphorylated impurity, only 1.0 equiv. of A2 was added and HPLC analysis at 30 min indicated 11% Al remaining. An additional charge of 0.1 equiv. of A2 was made and HPLC analysis at 30 min indicated 3% Al remaining. Standard workup was performed, followed by the toluene/ silica gel treatment previously described. Analysis by Q 1H NMR indicated 83%> potency, with no detectable TEA or TEA-HCl, and 6% toluene. Analysis by normal phase HPLC indicated no detectable Al and reverse phase HPLC indicated 2%> oxidized A3, and 7%> bis-phosphorylated impurity.

[00172] A3 lot A3L3: Use of 2-MeTHF as solvent for the preparation of A3. Following standard conditions, except 2-MeTHF as solvent, 2 g of Al (lot A1L1) was converted to A3 using A2. HPLC analysis at 30 min indicated 26% Al remaining. HPLC analysis at 130 min indicated 8.5% Al remaining. An additional charge of 0.1 equiv. of A2 was made and HPLC analysis at 30 min indicated 4% Al remaining with 86% A3, 2% bis-phosphorylated impurity and 3% A4. The reaction mixture was filtered and concentrated to a foam (3.4 g, 100%). 1H NMR analysis indicated no residual Et ₃ N.HCl. The material was used without purification in the next step.

[00173] A3 lot A3L4: Use of non-distilled A2 as solvent for the preparation of A3. Following standard conditions, except 2-MeTHF as solvent, 2 g of Al (lot A1L1) was converted to A3 using crude A2 (A2L1). HPLC analysis at 90 min indicated 15.4% Al remaining. HPLC analysis at 130 min indicated 10.8% Al remaining. An additional charge of 0.1 equiv. of A2 was made and HPLC analysis at 90 min indicated 2.8% Al remaining with 87% A3, 2.6% bis-phosphorylated impurity and 4% A4. The reaction mixture was filtered and concentrated to a foam (drying). 1H NMR analysis indicated no residual Et ₃ N.HCl. The material can be used without purification in the next step.

[00174] Preparation of lb

[00175] A series of reactions have been run exploring different conditions for the formation of lb. The results are provided in the tables below.

[00176] General Conditions: To a solution of A3 (1 equiv.) in the appropriate solvent was added pyridine triflate (2 equiv. unless stated) and the solution stirred for a minimum of 5 minutes. To this was added 5M t-BuOOH in decane or I ₂ as a solution in THF/Water (1 equiv.). The reaction was stirred for a further 30 min and analyzed by HPLC.

Table 9: Results Prior to Normal Phase IPC

[00177] Alternate synthesis: A use-test (10 g scale) was performed with diacetyl-Al obtained from the above 1 kg batch with 5.4 M sodium methoxide in methanol at 20-25 °C: Diacetyl-Al (10.0 g, 27.7 mmol) (purity: >97 %, AUC at 254 nm) was taken in methanol (10 vol, 100 mL) under nitrogen in an oven-dried RBF. The reaction mixture at this time was a suspension. To this was added 0.95 equiv. of 5.4 M sodium methoxide in methanol (4.9 mL, 26.33 mmol) drop wise. The reaction mixture was a clear solution once the addition was complete. IPC at 1 h 20 min deemed the reaction to be complete. At this time, MeOH pre- treated resins were poured into the reaction mixture and were allowed to stir at ambient temperature for 1 h. The reaction mixture was filtered and filter bed was washed with 3-4 bed volumes of methanol. The combined organics were concentrated in vacuo to obtain Al as an off-white /pale-yellow solid [7.4 g, yield: 96.4%; purity: 98.1% (AUC at 254 nm)], KF = 2.25 %.

[00178] Anhydrous Conditions: A N ₂ purged reactor was charged with Al (1.0 eq) and anhydrous DCM (10 vol). To the stirred suspension, TEA (2.0 eq) was added and stirred for 10 min at 18-23 °C. A solution of A2 (1.1 eq) in anhydrous DCM (2 vol) was slowly added over 30 to 60 min, while maintaining the temperature below 25 °C. Analysis is by normal phase HPLC after 30 to 60 min. Reaction is typically deemed complete when the amount of Al is less than 5%. Once deemed complete, the reaction mixture is concentrated to a residue (bath at 25 to 30 °C). The solids are slurried in MTBE (10 vol) and re-concentrated to a residue. MTBE (10 vol) is added and the slurry stirred at 18-23 °C for 30 min. The slurry is filtered through a pad of Solka Floe and washed with MTBE (5 vol). The filtrate is concentrated to a foam, dissolved in toluene (10 vol) and silica gel (2 g/g input Al) is added. The mixture is stirred for 30 min and filtered through a pad of Solka Floe. The filtrated is washed with toluene (5 vol) and concentrated to a glassy foam. Analysis is by 1H NMR (CDCI ₃ ) to confirm TEA and TEA-HC1 have been removed.

Table 10: Effect of Moisture on the Conversion of A3 to lb

[00179] Hydrolyzed Impurities:

[00180] In Table 11 , pyridine was used as the base unless otherwise stated. Table 11: Effect of Acid on the Conversion of A3 to lb

A3 %AUC Quant.

%AUC

Reaction Lot # Solvent lb/la A3 HPLC Comments

Hydrolysis

(g) oxidation Yield

11-14 A3L15 2: 1 75:25 51% 7% NA Standard conditions, at

0.25 tol/ 18-23 °C, except:

DCM Added 2 equiv. Pyridine followed by 2 equiv. (1S)- (+)-10-CSA. A3 consumed after 30 min.

11-15 A3L15 2: 1 NA 100% NA NA Standard conditions, at

0.25 tol/ 18-23 °C, except:

DCM Added 2 equiv. Pyridine followed by 2 equiv. (lR)-(+)-10-CSA (old bottle). A3 consumed but no A4 formed.

11-16 A3L15 2: 1 75:25 66% 4% NA Standard conditions, at

0.25 tol/ 18-23 °C, except:

DCM Added 2 equiv. Pyridine followed by 2 equiv. (lR)-(+)-10-CSA (new bottle). A3 consumed but little A4 formed.

11-17 A3L15 2: 1 74:26 4.6% 11% NA Standard conditions, at

0.25 tol/ 18-23 °C, except:

DCM Added 2 equiv. pyridine tosylate. A3 consumed after 30 min

11-18 A3L15 2: 1 78:22 6.6% 14% 20% Scale up of 11-17

2.5 tol/

DCM

9-27 A3L9 2: 1 65:35 7% 4% 31% Standard conditions

9.0 tol/ From t-BuOOH Oxidation DCM A3

11-1 A3L10 2: 1 70:30 8.5% 2% 37% Added 2 equiv. Pyridine

0.25 tol/ from A3 followed by 2 equiv.

DCM triflic acid. t-BuOOH

Oxidation

11-19 A3L15 2: 1 53:47 84% NA NA Used 2 equiv. of 3- 0.25 tol/ pyridinesulfonic acid. No DCM base. Adding DMF (1.5 mL) allowed A4 formation to progress

11-20 A3L10 DMF 66:34 31% 6.5% NA Used 2 equiv. of 3- 0.25 pyridinesulfonic acid. No base. A3 consumed after 20 min

[00181] In Table 12, benzenesulfonic acid was used as aci d unless otherwise stated. Table 12: Effect of base on the Conversion of A3 to lb

A3 %AUC Quant.

%AUC

Reaction Lot # Solvent lb/la A3 HPLC Comments

Hydrolysis

(g) oxidation Yield

9-27 A3L9 2: 1 65:35 7% 4% 31% Standard conditions

9.0 tol/ From

DCM A3 A3 %AUC Quant.

%AUC

Reaction Lot # Solvent lb/la A3 HPLC Comments

Hydrolysis

(g) oxidation Yield

11-1 A3L10 2: 1 70:30 8.5% 2% 37% Added 2 equiv. Pyridine

0.25 tol/ from A3 followed by 2 equiv.

DCM triflic acid

12-1 A3L15 2: 1 75:25 23% 11% NA Standard conditions, at

0.25 tol/ 18-23 °C, except:

DCM Added 2 equiv. 2,6- lutidine followed by 2 equiv. benzenesulfonic acid. A3 consumed after 30 min.

12-2 A3L15 2: 1 45:55 17% 23% NA Standard conditions, at

0.25 tol/ 18-23 °C, except:

DCM Added 2 equiv. imidazole

followed by 2 equiv. benzenesulfonic acid. A3 consumed after 30 min.

12-3 A3L15 2: 1 79:21 18% 12% NA Standard conditions, at

0.25 tol/ 18-23 °C, except:

DCM Added 2 equiv. quinoline

followed by 2 equiv. benzenesulfonic acid. A3 consumed after 30 min.

12-4 A3L15 2: 1 55:45 30% 4% NA Standard conditions, at

0.25 tol/ 18-23 °C, except:

DCM Added 2 equiv. NMI

followed by 2 equiv. benzenesulfonic acid. A3 consumed after 30 min.

12-5 A3L15 2: 1 NA NA NA NA Standard conditions, at

0.25 tol/ 18-23 °C, except:

DCM Added 2 equiv. K ₂ C0 ₃

followed by 2 equiv. benzenesulfonic acid. A3 unreacted.

12-6 A3L15 2: 1 NA 27% in NA NA Standard conditions, at

0.25 tol/ cyclization 18-23 °C, except:

DCM Used DBU and

azeotropically dried Benzenesulfonic acid. Little A4

12-7 A3L15 2: 1 NA 35% in NA NA Standard conditions, at

0.25 tol/ cyclization 18-23 °C, except:

DCM Used 4-

Methylmorpholine and azeotropically dried Benzenesulfonic acid.

Little A4

12-8 A3L15 2: 1 NA 75% in NA NA Standard conditions, at

0.25 tol/ cyclization 18-23 °C, except:

DCM Used Aniline and

azeotropically dried Benzenesulfonic acid. Little A4 A3 %AUC Quant.

%AUC

Reaction Lot # Solvent lb/la A3 HPLC Comments

Hydrolysis

(g) oxidation Yield

12-9 A3L15 2: 1 NA 26% in NA NA Standard conditions, at

0.25 tol/ cyclization 18-23 °C, except:

DCM Used Benzylamine and azeotropically dried Benzenesulfonic acid. Little A4

12-10 A3L15 2: 1 73:27 11% 38% NA Standard conditions, at

1.0 tol/ 18-23 °C, except:

DCM Used Quinoline and 3- Pyridinesulfonic acid.

A3 consumed after 30 min. Oxidation with t- BuOOH clean at 60 min.

12-11 A3L15 2: 1 70:30 9.8% 10% NA Standard conditions, at

0.25 tol/ 18-23 °C, except:

DCM Added 2 equiv. 2,2- Bypyridyl followed by 2 equiv. benzenesulfonic acid (azeotropically dried). A3 consumed after 30 min.

12-12 A3L15 2: 1 NA NA NA NA Standard conditions, at

0.25 tol/ 18-23 °C, except:

DCM Added 2 equiv. 1,10- phenanthroline followed by 2 equiv.

benzenesulfonic acid (azeotropically dried).

12-13 A3L15 2: 1 76:24 25% 12% NA Standard conditions, at

0.25 tol/ 18-23 °C, except:

DCM Added 2 equiv. 5- bromoquinoline followed by 2 equiv. benzenesulfonic acid (azeotropically dried). A3 consumed after 30 min.

12-14 A3L15 2: 1 NA 55% NA NA Standard conditions, at

0.25 tol/ 18-23 °C, except:

DCM Added 2 equiv. DMAP

followed by 2 equiv. benzenesulfonic acid (azeotropically dried). Some A3 remaining.

[00182] Re-worked: A2 was dissolved in toluene (10 vol) and treated with silica gel (lg/g) with stirring for 30 min. The suspension was filtered through a pad of Solka floe. The filtrate was concentrated to a foam, dissolved in toluene (10 vol) and re-concentrated to a foam. Analysis by Q 1H NMR indicated there was no trace of TEA-HCl. Analysis by NP HPLC indicated no detectable Al .

Table 13: Suppression of the Effect of Water on the Conversion of A3 to lb A3 %AUC Quant.

%AUC

Reaction Lot # Solvent lb/la A3 HPLC Comments

Hydrolysis

(g) oxidation Yield

13-3 A3L15 2: 1 NA 92% in NA NA Standard conditions, at 18- 0.25 tol/ cyclization 23 °C, except:

DCM Used 2,6-di-t-

Butylpyridine

and azeotropically dried

Benzenesulfonic acid.

13-4 A3L15 2: 1 19:81 17% 16% NA Repeat 13-3 except

0.25 tol/ Reverse addition and used DCM preformed 2,6-di-t- Butylpyridine-BSA

(azeotropically dried with toluene). A3 soln. added to above.

13-5 A3L15 Anhydr. 82: 18 13% NA NA Reverse addition. Pyridine - 0.5 THF BSA preformed and

azeotropically dried with toluene, A3 soln. added to above in THF.

13-6 A3L15 Anhydr. 82: 18 9% 5% 40% Reverse addition at 18-23

0.5 THF °C. Pyridine-BSA

preformed and azeotropically dried with toluene, A3 azeotropically dried with toluene, then added to above in THF. Standard i-BuOOH oxidation, at 18-23 °C.

13-7 8.4 Anhydr. NA 78% NA NA Scale-up of 13-6

THF Reverse addition at 0-5 °C.

Pyridine-BSA preformed and azeotropically dried with toluene, A3

azeotropically dried with toluene, then added to above in THF. Standard t- BuOOH oxidation at 0-5 °C .

13-8 A3L15 Anhydr. 76:24 12% 10% 51% Repeat of 13-6 at 0-5 °C

1.0 THF using stock lot of A3.

Reverse addition. Pyridine- BSA preformed and azeotropically dried with toluene, A3 added to above in THF. Standard t- BuOOH oxidation at 0-5 °C.

13-9 A3L15 2: 1 tol/ 75:25 8% 11% 30% Reverse addition. Pyridine - 1.0 DCM Triflate

azeotropically dried with toluene, A3 added to above in 2: 1 tol/ DCM. Standard i-BuOOH oxidation at 0-5 °C. A3 %AUC Quant.

%AUC

Reaction Lot # Solvent lb/la A3 HPLC Comments

Hydrolysis

(g) oxidation Yield

13-10 2: 1 75:25 None 5% NA Standard conditions, at 18-

0.25 tol/ detected 23 °C, except: Used reDCM worked A3. Standard t- BuOOH oxidation, at 18- 23 °C.

13-11 2: 1 77:23 None 8% 43% Scale up of 13-10.

3.0 tol/ detected Standard conditions, at 0-5 DCM °C, except: Used reworked A3. Standard t- BuOOH oxidation at 0-5 °C.

13-12 A3L15 Toluene NA >90% NA NA Reverse addition. Pyridine - 1.0 BSA preformed and

azeotropically dried with toluene, A3 added to above in Toluene.

13-14 A3L15 2: 1 73:27 22% 8% NA Reverse addition. Pyridine - 0.5 tol/ 3-pyridinesulfonic acid DCM preformed and

azeotropically dried with toluene, A3 added to above in Toluene. Addition of DMF allowed complete conversion of A3

13-15 Anhyd. 78:22 3% 6% 42% 18-23 °C using Re -worked

0.5 THF A3. Reverse addition.

Pyridine-BSA preformed and azeotropically dried with toluene, A3 added to above in THF. Standard t- BuOOH oxidation at 18- 23 °C.

13-16 Toluene 72:28 ND 7% 38% Standard addition at 18-23

0.25 °C. Pyridine -triflate added as solid, to A3 in Toluene. Standard i-BuOOH oxidation at 18-23 °C.

13-17 2: 1 76:24 4% 19% NA 0-5 °C using Re -worked

1.0 Toluene A3. Reverse addition.

/DCM Pyridine-BSA preformed and azeotropically dried with toluene. Standard t- BuOOH oxidation at 0-5 °C.

13-18 2: 1 82: 18 1.5% 21% NA Standard addition at 0-5

1.0 Toluene °C. Pyridine -p- /DCM toluenesulfonate added as solid, to A3. Standard t- BuOOH oxidation at 0-5 °C.

13-19 10: 1 70:30 ND 4.5% NA Standard addition at 18-23

0.25 Toluene °C. Pyridine -triflate added /DMF as solid, to A3 in

Toluene/DMF. Standard t- BuOOH oxidation at 18- 23 °C. A3 %AUC Quant.

%AUC

Reaction Lot # Solvent lb/la A3 HPLC Comments

Hydrolysis

(g) oxidation Yield

13-20 10: 1 80:20 ND 12% NA Standard addition at 18-23

0.25 Toluene °C. Pyridine -p- /DMF toluenesulfonate added as solid, to A3 in Toluene/ DMF. Standard i-BuOOH oxidation at 18-23 °C.

13-21 2: 1 NA 12% NA NA Standard addition at 0-5

1.0 Toluene °C. 3-Pyridinesulfonic acid /DCM added as solid, to A3.

Solubility issues led to addition of 0.5 mL DMF. A3 not consumed.

13-22 Anhyd. 89: 11 5% 7% Standard addition of

1.0 THF 72:28 ND 3% Pyridine -triflate at 0-5 ° to

Re-worked A3 in THF Standard i-BuOOH oxidation at 0-5 °C. After 45 min, still A4 remaining. Added more i-BuOOH (20% extra).

13-23 THF IPC 1% 3% NA Reverse addition at 18-23

23.0 85: 15 °C using Re -worked A3.

Foam ND 1% NA Pyridine-BSA preformed

78:22 and azeotropically dried with toluene, A3 added to above in THF. Standard t- BuOOH oxidation at 18- 23 °C. Chromatography using standard conditions: Pure fractions: (7.92 isolated, 98.5: 1.5 ratio, 97.2% AUC) (82.5% potency (6.5 g), 35% activity yield)

Mixed fractions: (7.12 isolated, 55:45 ratio, 50.7% AUC), (43% potency (3.1 g), 16% activity yield,) 51%Total overall yield

Table 14: Further Suppression of the Effect of Water on the Conversion of A3 to lb

Table 15: Effect of Solvents on the Conversion of A3 to lb A3 %AUC

%AUC

Reaction Lot # Solvent lb/la A3 Comments

Hydrolysis

(g) oxidation

15-6 A3L15 2: 1 80:20 21% 7% Standard conditions, at 18-23 °C,

0.25 MTBE/ except: Used pyridine and DCM azeotropically dried benzenesulfonic acid in 2: 1 MTBE/DCM. Sticky, gummy solids observed. A3 consumed after 30 min. Oxidation with t-BuOOH clean at 30 min.

15-7 A3L15 DMF 60:40 28% 5% Standard conditions

0.25 t-BuOOH Oxidation

Example Id

Third Alternative Preparation of Compound lb

[00183] Preparation of A2

[00184] Preparation 1: Previously prepared crude A2 (104.5 g, >100%, 79.2% purity by

31

P NMR) was purified by vacuum distillation to afford two fractions of product as clear oils (32.5 g, 31.1% and 25.9 g, 24.8%). ³¹ P NMR indicated 88% and 92% purity, respectively.

[00185] Preparation 2: Previously prepared crude A2 (A2L1) was subjected to solvent exchange with MTBE and filtration. Mother liquor concentrated to provide 200.7 g crude

31

yellow oil with solids ( P NMR 90.2%> purity). This material was purified by vacuum distillation to afford one fraction of product as clear oil (151.0 g, 75%, ³¹ P NMR 91.7% purity).

[00186] Preparation 3: A2 was prepared on a 500 g scale using THF as the solvent. The batch was isolated in MTBE by concentration at 45 °C, added with MTBE (5 L), stirred for 1 hour, filtered, and the filtrate concentrated to provide 976 g (>100%>) of crude product (92.5%> by 31 P NMR). A portion of the crude material (280.5 g) was purified by vacuum distillation to

31

afford two fractions of product as clear oil (13.9 g, 4.9%>, 87.3%> purity by P NMR and

31

160.8 g, 57.3%), 90.5%) purity by P NMR respectively). The remaining portion of the crude material (695.5 g) was purified by vacuum distillation to afford two fractions of product as clear oil (26.2 g, 3.8%, 76.7% purity by ³¹ P NMR and 305.5 g, 43.9%,. 95.7% purity by ³¹ P NMR respectively).

[00187] Formation of A3

[00188] A3 lot A3L16: The purpose of this experiment was to scale up the preparation of A3 in 2-MeTHF, leading to telescoping through formation of lb. Using the standard procedure, a slurry of Al (20 g) in 2-MeTHF (10 vol) was treated with TEA (2.0 eq), followed by a solution of A2 (1.1 eq) in 2-MeTHF (2 vol). After 1 h, HPLC indicated 11% (AUC) Al remaining. After 2 h, HPLC indicated 16% remaining. A second charge of A2 (0.05 eq) in 2-MeTHF was made and after 45 min, HPLC indicated 3% Al remaining. The TEA salts were filtered off through a 2 cm pad of silica gel. This material was taken on to the next step without further purification.

[00189] A3 lot A3L17: The purpose of this experiment was the preparation of A3 in 2- MeTHF. Using the standard procedure, a slurry of Al (25 g) in 2-MeTHF (10 vol) was treated with TEA (2.0 eq), followed by a solution of A2 (1.1 eq) in 2-MeTHF (2 vol). After 1 h, HPLC indicated 6.9% (AUC) Al remaining. After 2 h, HPLC indicated 3.7% remaining. The TEA salts were filtered off through a 2 cm pad of silica gel, the solvent was swapped into MTBE and A3 isolated as a foam. The material was taken on without further purification into experiment 16-6.

[00190] A3 lot A3L18: The purpose of this experiment was the preparation of A3 in 2- MeTHF, with a final solvent swap into THF. Using the standard procedure, 20 g of Al was converted to A3, and isolated as a THF solution.

[00191] A3 lot A3L19: The purpose of this experiment was to repeat the preparation of A3 in 2-MeTHF and carry material over to the next step in THF. Using the standard procedure, 5 g of Al was converted to A3, and isolated as a THF solution.

Table 16: Preparation of Compound lb

A3 %AUC Quant.

%AUC

Reaction Lot # Solvent lb/la A3 HPLC Comments

Hydrolysis

(g) oxidation Yield

16-1 33.6 g THF IPC 10% 3.6% 41% Repeat of 13-27. THF

84: 16 from Al solution of preformed pyridine -BSA (2.0 eq) treated with A3 in THF at 18-23 °C. Oxidation using a solution of 1 eq iodine in 7 vol THF, 2.8 vol pyridine and 0.2 vol water at 18-23 °C. No detected 13.3 min peak. Work up modified to use EtOAc as extraction solvent and for final precipitation of lb. No Column.

16-2 33.6 g THF IPC ND ND NA Reverse addition at 18- 81 : 19 23 °C. THF solution of preformed pyridine -BSA treated with A3 in THF at 18 -23 °C. Oxidation using a solution of 1 eq iodine in THF, pyridine, water at 18 23 °C. Precipitation for EtOAc (15.1 g, 99.7% AUC by HPLC, 12.0 g activity, 44% from Al)

16-3 8.4 g THF 80:20 ND 0.8% 39% Reverse addition at 18- 23 °C. THF solution of preformed pyridine -BSA treated with A3 in THF at 18 -23 °C. Oxidation using a solution of 1 eq iodine, 5 eq pyridine, in THF water at 18-23 °C. Precipitation from EtOAc (3.65 g, 97.1% AUC by HPLC, 2.7 g activity, 39% from Al). Q HPLC indicated 146 mg lb lost to the mother liquor (2%).

A3 %AUC Quant.

%AUC

Reaction Lot # Solvent lb/la A3 HPLC Comments

Hydrolysis

(g) oxidation Yield

16-4 8.4 g 2- 85: 15 ND 0.7% 29% A3 prepared in 2- MeTHF MeTHF and telescoped into the cyclization. Reverse addition at 18- 23 °C. THF solution of preformed pyridine -BSA treated with the above, un-isolated A3 solution in 2-MeTHF at 18-23 °C. Oxidation using a solution of 1 eq iodine, 5 eq pyridine, in THF water at 18-23 °C. Precipitation from EtOAc (2.4 g, 98.3% AUC by HPLC, 2.0 g activity, 29% from Al). Q HPLC indicated 690 mg lb lost to the mother liquor (10%).

16-5 A3L16 2- 85: 15 5.2% 3.6% Isolated A3 prepared in 2- 33.6 g MeTHF 26% MeTHF and telescoped (theo.) into the cyclization.

Reverse addition at 18- 23 °C. 2-MeTHF solution of preformed pyridine -BSA treated with the above, un- isolated A3 solution in 2- MeTHF at 18-23 °C. Oxidation using a solution of 1 eq iodine, 5 eq pyridine, in 2- MeTHF water at 18-23 °C. Precipitation from EtOAc (8.4 g, 98.5% AUC by HPLC, 7.1 g activity, 26% from Al). Q HPLC indicated 900 mg lb lost to the mother liquor (3.3%).

A3 %AUC Quant.

%AUC

Reaction Lot # Solvent lb/la A3 HPLC Comments

Hydrolysis

(g) oxidation Yield

16-6 A3L17 THF 82: 18 ND ND Isolated A3 prepared in 2- 42.1 g 34% MeTHF. Reverse (theo.) from addition at 18-23 °C.

EtOAc THF solution of

preformed pyridine -BSA

Isolated treated THF solution of 28% A3 at 18-23 °C.

from Oxidation using a

IPA RX solution of 1 eq iodine,

16 eq pyridine, in THF water at 18-23 °C. Precipitation from EtOAc (14.4 g, 98.5% AUC by HPLC, 11.7 g activity, 34% from Al). Q HPLC indicated 935 mg lb lost to the mother liquor (2.7%).

Recrystallization from IPA (9.5 g, 100% AUC by HPLC, 100% potency, 28% from Al). Q HPLC indicated 2.18 g lb lost to the mother liquor (6.3%).

16-7 A3L18 THF 82: 18 ND ND Isolated A3 prepared in 2- 8.4 g 40% MeTHF. Reverse (theo.) from addition at 18-23 °C.

EtOAc THF solution of

preformed pyridine -BSA (Note: Pyr-BSA prepared and stored at 18-23 °C for 19 days) treated THF solution of A3 at 18-23 °C.

Oxidation using a solution of 1 eq iodine, 16 eq pyridine, in THF/ water at 18-23 °C. Precipitation from EtOAc (3.4 g, 98.3% AUC by HPLC, 2.76 g activity, 40% from Al). Q HPLC indicated 225 mg lb lost to the mother liquor (3.3%). A3 %AUC Quant.

%AUC

Reaction Lot # Solvent lb/la A3 HPLC Comments

Hydrolysis

(g) oxidation Yield

16-8 A3L17 THF 80:20 ND ND Isolated A3 prepared in 2- 25.2 g 34% MeTHF. Reverse (theo.) from addition at 18-23 °C.

EtOAc THF solution of

preformed pyridine -BSA treated THF solution of A3 at 18-23 °C.

Oxidation using a solution of 1 eq iodine, 16 eq pyridine, in THF/ water at 18-23 °C. Precipitation from EtOAc (8.1 g, 98.0% AUC by HPLC, 6.7 g activity, 33% from Al). Q HPLC indicated 1.14 g lb lost to the mother liquor (5.5%).

16-9 A3L19 THF 84: 16 ND ND Isolated See 16-9 notes, below.

8.4 g 7%

(theo.) from

EtOAc

00192] 16-9 Notes: A3 prepared in 2-MeTHF. Reverse addition at 18-23 °C. THF solution of preformed pyridine-BSA treated THF solution of A3 at 18-23 °C. Oxidation using a solution of 1 eq iodine, 16 eq pyridine, in THF/ water at 18-23 °C. Diluted 126 mL EtOAc. Washed with 2 portions 126 m IN aq. HC1 which were separated and back extracted with 63 mL EtOAc. Combined organics then subsequently washed with 84 mL 10% aq. sodium thiosulfate then 84 mL water. Organic layer dried with anhydrous sodium sulfate and filtered. Filtrate removed in vacuo and solvent exchanged with 50 mL EtOAc then 42 mL EtOAc. Repeat solvent exchanges to yield 5.09 g crude foam. Diluted in 25 mL EtOAc and stirred 16 hr. at 15 to 25 °C. Cooled to 5 to 10 °C for 1 hr. and filtered to yield tan solid (0.49 g, 7% from Al).

[00193] While the claimed subject matter has been described in terms of various embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the claimed subject matter is limited solely by the scope of the following claims, including equivalents thereof.