COMPOUND

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of U.S. Provisional Application Nos.

62/190,924 and 62/190,928, both of which were filed on July 10, 2015, and both of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to a method for producing various aziridine or dihydrofuran compounds that can be used in synthesizing various natural products and pharmaceutically active compounds. In particular, the present invention relates to using an α,β- unsaturated compound to produce various aziridine compounds and dihydrofuran compounds. In particular, the present invention relates to a method for producing an aziridine compounds of the formula:

or a dihydrofuran compound of the formula: ⁰ by reacting an α,β-

R

unsaturated compound of the formula: with an appropriate starting material. In this manner a wide variety of aziridine compounds and dihydrofuran compounds can be produced using the method of the invention.

BACKGROUND OF THE INVENTION

[0003] Aziridine and dihydrofuran compounds are important intermediates in synthesis of natural products and pharmaceutically active compounds. While some methods are available for producing various aziridine and dihydrofuran compounds, they often require a circuitous synthetic route, require expensive reagents, require heavy metals that are toxic to mammals, require extensive protection/deprotection steps, do not provide chiral synthesis or provide a low enantiomeric selectivity, or result in only a moderate to low yield of aziridine compounds. [0004] In addition, conventional methods for producing dihydrofuran compounds also suffer from some of the limitation discussed above, including but not limited to, requiring a circuitous synthetic route, use of expensive reagents and/or heavy metals that are toxic to mammals. Furthermore, as with aziridine synthesis, conventional methods for producing dihydrofuran also often requires extensive protecti on/deprotecti on steps and often provide only a moderate to low overall yield of dihydrofuran compounds.

[0005] Therefore, there is a continuing need for a relatively efficient and inexpensive method for producing important aziridine and dihydrofuran compounds that can be used in synthesis of natural products and pharmaceutically active compounds.

SUMMARY OF THE INVENTION

[0006] One aspect of the invention provides a method for producing various aziridine compounds including, but not limited to, enantiomerically and/or diastereomerically enriched aziridine compounds. In some particular embodiments of the invention, chiral aziridine compounds are produced in a single step. The method of the invention provides easy access to various aziridine compounds including, but not limited to, chiral (i.e., enantiomerically and/or diastereomerically enriched) aziridine compounds.

[0007] Another aspect of the invention provides a method for producing various dihydrofuran compounds. In one particular embodiment, the invention provides a method or a process for producing 2, 5 -dihydrofuran compounds. Still in another embodiment of the invention, the method provides a synthesis of 2, 3 -di substituted 2, 5 -dihydrofuran compounds. In some embodiments of the invention, the method or process produces dihydrofuran compounds in a single step.

[0008] In general, the method of the invention utilizes an α,β-unsaturated compound of the formula: where R ¹ is hydrogen, alkyl, haloalkyl, aryl, aralkyl, alkenyl, aralkenyl, cycloalkyl, heteroalkyl, or heteroaryl; or R ¹ together with W form a heterocycloalkyl; X is a leaving group; andW is an electron withdrawing group. DETAILED DESCRIPTION OF THE INVENTION

[0009] Definitions:

[0010] "Alkyl" refers to a saturated linear monovalent hydrocarbon moiety of one to twelve, typically one to six, carbon atoms or a saturated branched monovalent hydrocarbon moiety of three to twelve, preferably three to six, carbon atoms. Exemplary alkyl group include, but are not limited to, methyl, ethyl, ^-propyl, 2-propyl, tert-butyl, pentyl, and the like.

[0011] "Alkylene" refers to a saturated linear divalent hydrocarbon moiety of one to twelve, typically one to six, carbon atoms or a branched saturated divalent hydrocarbon moiety of three to twelve, preferably three to six, carbon atoms. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, and the like.

[0012] "Aryl" refers to a monovalent mono-, bi- or tricyclic aromatic hydrocarbon moiety of 6 to 15 ring atoms which is optionally substituted with one or more, preferably one, two, or three substituents within the ring structure. When two or more substituents are present in an aryl group, each substituent is independently selected. Exemplary substituents for the aryl group include, but are not limited to, alkyl, haloalkyl, thioalkyl, heteroalkyl, halo, nitro, cyano, cycloalkyl, aryl, heteroaryl, heterocyclyl, haloalkoxy, aryloxy, heteroaryloxy, etc.

[0013] "Aralkyl" refers to a moiety of the formula -R ^b R ^c where R ^b is an alkylene group and R ^c is an aryl group as defined herein. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like.

[0014] "Chiral center" (i.e., stereochemical center, stereocenter, or stereogenic center) refers to an asymmetrically substituted atom, e.g., a carbon atom to which four different groups are attached. The ultimate criterion of a chiral center, however, is nonsuperimposability of its mirror image.

[0015] "Cycloalkyl" refers to a non-aromatic, preferably saturated, monovalent mono- or bicyclic hydrocarbon moiety of three to ten ring carbons. The cycloalkyl can be optionally substituted with one or more, preferably one, two, or three, substituents within the ring structure. When two or more substituents are present in a cycloalkyl group, each substituent is

independently selected. Exemplary substituents for cycloalkyl group include, but are not limited to, alkyl, haloalkyl, halo, nitro, cyano, heteroalkyl, aryl, heteroaralkyl, etc. [0016] "Cycloalkylalkyl" refers to a moiety of the formula -R ^d R ^e where R ^d is an alkylene group and R ^e is a cycloalkyl group as defined herein. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, and the like. Similarly, terms heteroalkylalkyl, heteroaralkyl (or heteroaralkyl), aralkyl (or arylalkyl) refers to -R ^f R ^s where R ^f is an alkylene group and R ^s is a heteroalkyl, heteroaryl, and aryl, respectively, as defined herein

[0017] The terms "halo," "halogen" and "halide" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodo.

[0018] "Haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atom is replaced by same or different halo atoms. The term "haloalkyl" also includes perhalogenated alkyl groups in which all alkyl hydrogen atoms are replaced by halogen atoms. Exemplary haloalkyl groups include, but are not limited to, -CH ₂ C1, -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CC1 , and the like.

[0019] "Heteroalkyl" refers to a branched or unbranched, cyclic or preferably acyclic saturated alkyl moiety containing carbon, hydrogen and one or more heteroatoms in place of a carbon atom, or optionally one or more heteroatom-containing substituents independently selected from -OR ^a , -C(0)R ^a , - R ^b R ^c , -C(0)NR ^b R ^c and -S(0)„R ^d (where n is an integer from 0 to 2 ). R ^a is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,

heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl. R ^b is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,

heteroaralkyl, or acyl. R ^c is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, acyl, alkylsulfonyl, carboxamido, or mono- or di- alkylcarbomoyl. Optionally, R ^b and R ^c can be combined together with the nitrogen to which each is attached to form a four-, five-, six- or seven-membered heterocyclic ring (e.g., a pyrrolidinyl, piperidinyl or morpholinyl ring). R ^d is hydrogen (provided that n is 0), alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, amino, monsubstituted amino, disubstituted amino, or hydroxy alkyl.

Representative examples include, for example, 2-methoxyethyl, benzyloxymethyl, thiophen-2- ylthiomethyl, 2-hydroxyethyl, and 2,3-dihydroxypropyl. [0020] "Heterocyclyl" means a non-aromatic monocyclic moiety of three to eight ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0) _n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms can optionally be a carbonyl group. The heterocyclyl ring can be optionally substituted

independently with one or more, preferably one, two, or three, substituents. When two or more substituents are present in a heterocyclyl group, each substituent is independently selected. Exemplary substituents for heterocyclyl group include, but are not limited to, alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano, aryl, heteroaryl, aralkyl, heteroaralkyl, etc.

[0021] "Enantiomeric excess" refers to the difference between the amount of

enantiomers. The percentage of enantiomeric excess (% e.e, or %ee) can be calculated by subtracting the percentage of one enantiomer from the percentage of the other enantiomer. For example, if the %ee of (R)-enantiomer is 99% and %ee of (S)-enantiomer is 1%, the %ee of (R)- isomer is 99%-l% or 98%.

[0022] "Diastereomeric excess" refers to the difference between the amount of diastereomers. The percentage of diastereomeric excess (% d.e, or %de) can be calculated by subtracting the percentage of one diastereomer from the percentage of the other diastereomers. For example, if the %de of (R,R)-diastereomer is 99% and %de of all other diastereomers (e.g., (R,S)-, (S,S)- and (S,R)-diastereomers) is 1%, the %de of (R,R)-isomer is 99%-l% or 98%.

[0023] "Leaving group" has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or a group capable of being displaced by a nucleophile and includes halo (such as chloro, bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy,

trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy), methoxy, Ν,Ο- dimethylhydroxylamino, and the like. Specific examples of leaving groups include, but are not limited to, CI, Br, I and sulfonate esters such as OMs (mesylate), OTs (tosylate), ONs (nosylate), OTf (triflate) and any other sulfonate esters.

[0024] The term "electron withdrawing group" refers an atom or a functional group that removes electron density from a conjugated π system via resonance or inductive electron withdrawal, thus making the π system more electrophilic. Exemplary electron withdrawing groups that are useful in the invention include, but are not limited to, esters, sulfonyl (e.g., a moiety of the formula: -S0 ₂ R ^a , where R ^a is alkyl), alkylsulfates (e.g., a moiety of the formula: - OS(0) ₂ OR ^a , where R ^a is alkyl), aldehydes, nitro groups (-NO _n , where n is 1 or 2), nitriles, phosphonates (e.g., -OP0 R ^a or -P(=0)(OR ^a ) ₂ , where each R ^a is independently alkyl), amides (- CONR ^a R ^b , where each of R ^a and R ^b is independently alkyl, cycloalkyl, cycloalkylalkyl, or R ^a and R ^b together with the nitrogen atom to which they are attached form a nitrogen containing heterocyclyl), ketones, as well as other heteroatom containing functional groups.

[0025] The term "α,β-unsaturated compound" refers to any compound that has α,β- unsaturation near the electron withdrawing group. Such a compound can be generally represented as R ^a -CR ^b =CR ^c -Z, where Z is an electron withdrawing group as defined herein and each of R ^a , R ^b and R ^c is independently hydrogen or carbon atom containing group. The α,β- unsaturated compounds of the invention can also have other unsaturated bond(s) that is conjugated to the α,β-unsaturation. Thus, the term α,β-unsaturated compound includes other extended conjugated compounds, such as α,β- and ,d- unsaturated compounds as well as other more extended conjugated compounds.

[0026] "Protecting group" refers to a moiety, except alkyl groups, that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3 edition, John Wiley & Sons, New York, 1999, and Harrison and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996), which are incorporated herein by reference in their entirety. Representative hydroxy protecting groups include acyl groups, benzyl and trityl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers. Representative amino protecting groups include, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2- trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9- fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC), and the like.

[0027] "Corresponding protecting group" means an appropriate protecting group corresponding to the heteroatom (i.e., N, O, P or S) to which it is attached.

[0028] When describing a chemical reaction, the terms "treating", "contacting" and

"reacting" are used interchangeably herein, and refer to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.

[0029] As used herein, the terms "those defined above" and "those defined herein" when referring to a variable incorporates by reference the broad definition of the variable as well as any narrow and/or preferred, more preferred and most preferred definitions, if any.

[0030] Method for producing Aziridine Compounds : One particular aspect of the invention provides methods and processes for producing aziridine compounds. One particular aspect of the invention provides a method for producing an aziridine compound of the formula:

A-I

said method comprising:

deprotonating an α,β-unsaturated com ound of the formula:

with a base under condition sufficient to produce a deprotonated intermediate; and reacting said deprotonated intermediate an imine compound of the formula:

A-III

under conditions sufficient to produce said aziridine compound of Formula A-I, wherein

each of a and b is a chiral center;

R is alkyl, haloalkyl, aryl, aralkyl, alkenyl, aralkenyl, cycloalkyl, heteroalkyl, or

heteroaryl;

R ¹ is hydrogen, alkyl, haloalkyl, aryl, aralkyl, alkenyl, aralkenyl, cycloalkyl, heteroalkyl, or heteroaryl; or R ¹ together with W form a heterocycloalkyl X is a leaving group;

W is an electron withdrawing group; and

Y is an auxiliary group.

[0031] It should be appreciated that compound of Formula A-II can also include one or more substituents (e.g., alkyl, halo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl heterocycloalkyl, haloalkyl, etc.) on the a-position of the carbonyl group.

[0032] In some embodiments, R ¹ is hydrogen or alkyl or together with W form a heterocyclyl.

[0033] In another embodiment, the electron withdrawing group comprises -S0 ₂ R,

-COR, -N0 ₂ , -P=0(OR) ₂ or -C0 ₂ R, where each R is independently alkyl, typically Ci-Ci ₂ alkyl, and often Ci-C ₆ alkyl.

[0034] Yet in other embodiments, Y is a chiral auxiliary group. By using the chiral auxiliary group, methods of the invention provide a diastereomerically and/or enantiomerically enriched aziridine compound. In one particular embodiment, the chiral auxiliary group is a moiety of the formula: where

* denotes a chiral center; and

R ^a is alkyl, cycloalkyl, aralkyl, alkenyl, aralkenyl, heteroalkyl, or heteroaryl.

[0035] As would be expected, the enantiomeric excess of starting material has a great influence on the diastereomeric and/or enantiomeric excess of the product (i.e., aziridine compound of Formula A-I). Accordingly, in one particular embodiment, imine compound of Formula A-III that is used in the method of invention has enantiomeric excess of at least 99 % e.e. In this manner, the aziridine compound that is produced using the method of the invention is diastereomerically enriched. It should be appreciated that diastereomeric excess and

enantiomeric excess described herein refer to diastereomeric excess and enantiomeric excess, respectively, prior to any separation step or stereoisomer enrichment step. [0036] In one particular embodiment, the diastereomeric excess of aziridine compound of

Formula A is at least 95% d.e.

[0037] One specific example of the imine compound that is used in the method of invention has the following formula:

O II

'

where R and R ^a are those defined herein. Within this example, in one instance, R ^a is tert-butyl.

[0038] In one particular aspect of the invention, the method of the invention provides an aziridine substituted furanone of the formula:

Al-I

In this aspect of the invention, a typical reaction involves deprotonating an α,β-unsaturated furanone compound of the formula:

Al-II

with a base under condition sufficient to produce a deprotonated intermediate; and reacting said deprotonated intermediate an imine compound of the formula:

R N

A-III

to produce an aziridine substituted furanone compound of the formula:

Al-I

where

each of a and b is a chiral center;

R is alkyl, haloalkyl, aryl, aralkyl, alkenyl, aralkenyl, cycloalkyl, heteroalkyl, or

heteroaryl;

X is a leaving group; and

Y is an auxiliary group.

[0039] It should be appreciated that compound of Formula Al-II can also include one or more substituents (e.g., alkyl, halo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl heterocycloalkyl, haloalkyl, etc.) on the a-position of the carbonyl group.

[0040] In some embodiments, Y is a chiral auxiliary group. One skilled in the art having read the present disclosure can envision and utilize a variety of chiral auxiliary groups. In one particular embodiment, said chiral auxiliary group is a moiety of the formula: where

the squiggly line indicates the point of attachment of the chiral auxiliary group to the nitrogen atom;

* denotes a chiral center; and

R ^a is alkyl, cycloalkyl, aralkyl, alkenyl, aralkenyl, heteroalkyl, or heteroaryl.

[0041] Typically, the imine compound A-III has enantiomeric excess of at least 90 %ee, typically at least 95 %ee, and often at least 99 %e.e. Accordingly, in some instances, the aziridine substituted furanone compound that is produced by the method of the invention is diastereomerically enriched. In some embodiments, the method of invention produces the aziridine substituted furanone compound of Formula Al-I in a diastereomeric excess of at least 90% de, typically at least 95% de, and often at least 98% de.

[0042] In some embodiments, the method of invention includes a step of removing the chiral auxiliary group. Removal of the chiral auxiliary group Y provides an aziridine substituted furanone compound in which only the chiral centers "a" and "b" are present.

[0043] Yet in other embodiments, the method provides an aziridine substituted compound whose enantiomerically enrichment is at least about 90%, typically at least about 95%), and often at least about 98%>.

[0044] A wide variety of methods are known to one skilled in the organic chemistry for removing the chiral auxiliary group. Such methods depend on the nature of the chiral auxiliary group that is used in the initial reaction. For example, for a chiral auxiliary group of formula A- IV, one of the method for removing the chiral auxiliary group is illustrated in the Examples section as well as on the commonly assigned U.S. Provisional Patent Application No.

62/027,209, filed on July 21, 2014, which is incorporated herein by reference in its entirety.

[0045] Method for producing Dihydrofuran Compounds : Another aspect of the invention provides a method for producing a dihydrofuran compound. In one particular embodiment of the invention, the reaction involves deprotonating an α,β-unsaturated compound of the formula:

B-2

with a base under condition sufficient to produce a deprotonated intermediate; and reacting said deprotonated intermediate an aldehyde compound of the formula:

B-III

a dihydrofuran compound of the formula:

B-I

where

W is an electron withdrawing group;

X is a leaving group; and

R is alkyl, haloalkyl, heteroalkyl, aryl, aralkyl, alkenyl, aralkenyl, cycloalkyl, heteroalkyl, or heteroaryl.

[0046] It should be appreciated that the compound B-2, can also include one or more substituents (e.g., alkyl, halo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl heterocycloalkyl, haloalkyl, etc.) on the α, β and/or γ-position of the electron withdrawing group, W.

[0047] The method of the invention provides a dihydrofuran compound in a yield of at least about 50%, typically at least about 60%, and often at least about 75%.

[0048] Additional objects, advantages, and novel features of this invention will become apparent to those skilled in the art upon examination of the following examples thereof, which are not intended to be limiting. In the Examples, procedures that are constructively reduced to practice are described in the present tense, and procedures that have been carried out in the laboratory are set forth in the past tense.

EXAMPLES

[0049] Example 1: General Procedure for the Synthesis of aziridine substituted fur anone compounds: To a flask equipped with magnetic stir bar and diisopropyl amine (2.0 eq. in THF, - 78 °C) was added «-butyl lithium (2.0 eq.) after which the solution was warmed to 0 °C and allowed to stir for 15 minutes. The resulting lithium diisopropyl amide (LDA) solution was then cooled to -78 °C and additional THF was added to reach an overall concentration of 0.1 M based on the sulfinimine. To the LDA solution, O. IM THF solution of 3-bromomethyl-2-buten-4-olide (1.2 eq.) was added, stirred for 30 minutes then solution of the respective sulfinimine (1.0 eq., 1M in THF) was then added using a syringe pump (0.5 mL/h) while the reaction temperature was maintained at -78 °C and allowed to stir for additional 3 hours after addition was complete. The reaction was then quenched with saturated ammonium chloride and allowed to warm to room temperature, extracted using ethyl acetate (3 times) and washed with brine. The combined organic extracts were dried using anhydrous sodium sulfate (Na ₂ S0 ₄ ) and solvent evaporated. Crude material was purified by flash column chromatography (silica gel, 20-50% EtOAc in hexanes) to afford the respective compound, which are shown below:

R

) {

)

(3:1 cis/trans)

(3:1 cis/trans) 44% 53%

[0050] Example 2: Using the corresponding enantiomer of the imine compound, a similar yield of the an enantiomer of compounds produced in Example 1 were also obtained as illustrated below.

R -

(3:1 ds/trans)

[0051] Example 3: General Procedure for the Synthesis of dihydrofuran compounds: To a flask equipped with magnetic stir bar and diisopropyl amine (3.0 eq. in THF, -78 °C) was added «-butyl lithium (2.0 eq.) after which the solution was warmed to 0 °C and allowed to stir for 15 minutes. The resulting lithium diisopropyl amide (LDA) solution was then cooled to -78 °C and additional THF was added to reach an overall concentration of 0.1 M based on the sulfinimine. To the LDA solution, neat ethyl-4-bromocrotonate (1.2 eq.) was added, stirred for 30 minutes then solution of the aldehyde (1.0 eq., 1M in THF) was then added using a syringe pump (0.5 mL/h) while the reaction temperature was maintained at -78 °C and allowed to stir for additional 4 hours after addition was complete. The reaction was then quenched with saturated ammonium chloride and allowed to warm to room temperature, extracted using ethyl acetate (3 times) and washed with brine. The combined organic extracts were dried using anhydrous sodium sulfate (Na ₂ S0 ₄ ) and solvent evaporated. Crude material was purified by flash column chromatography (silica gel, 10-15 % EtOAc in hexanes).

[0052] Some of the representative compounds produced using the method of the invention are shown below:

^Br ^^s^ ^C °2 ^Et

[0053] The foregoing discussion of the invention has been presented for purposes of illustration and description. The foregoing is not intended to limit the invention to the form or forms disclosed herein. Although the description of the invention has included description of one or more embodiments and certain variations and modifications, other variations and modifications are within the scope of the invention, e.g., as may be within the skill and knowledge of those in the art, after understanding the present disclosure. It is intended to obtain rights which include alternative embodiments to the extent permitted, including alternate, interchangeable and/or equivalent structures, functions, ranges or steps to those claimed, whether or not such alternate, interchangeable and/or equivalent structures, functions, ranges or steps are disclosed herein, and without intending to publicly dedicate any patentable subject matter. All references cited herein are incorporated by reference in their entirety.