FILED OF THE INVENTION [02] The present invention is directed to a method for enantioselectively epoxidizing olefins having at least one electron withdrawing group attached to the olefinic moiety.

BACKGROUND OF THE INVENTION [03] Chiral epoxides having at least an electron withdrawing group attached to the epoxide carbon, such as a, (3-epoxy esters, are useful intermediates for the synthesis of a variety of enantiomerically enriched or enantiomerically pure complex molecules, including therapeutically useful compounds. Thus, asymmetric epoxidation of electron deficient olefins presents an attractive strategy for the synthesis of optically active corresponding epoxides, for example, producing glycidic esters from a, p-unsaturated esters.

[04] Currently, only a few methods are available for epoxidizing electron deficient olefins, such as a, p-unsaturated esters. Unfortunately, each of the currently available method has its own short comings, such as use of transition metal catalysts, low selectivity, low yield, as well as others. Therefore, there is still a need for a method for producing enantiomerically enriched epoxides from olefins.

SUMMARY OF THE INVENTION [05] One aspect of the present invention provides a method for producing an enantiomerically enriched epoxide from an electron deficient olefin, said method comprising admixing the olefin, an enantiomerically enriched chiral ketone, and an oxidizing agent under conditions sufficient to produce the enantiomeric enriched epoxide, wherein the yield and the enantiomeric excess of the epoxide is at least about 50% and at least about 80%, respectively.

[06] Preferably, the electron deficient olefin is selected from the group consisting of an a, p-unsaturated ester, an a, p-unsaturated ketone, a vinyl sulfone compound, a vinyl nitrile compound, and a vinyl nitro compound. More preferably, the electron deficient olefin is an a, p-unsaturated ester.

[07] In one embodiment, the chiral ketone is a cyclic chiral ketone of the formula: wherein bonds a, b and c are any combination of cis-or trans-configuration relative to one another ; X is hydrogen, halide, or alkoxide ; Y is-OR', hydrogen, or halide; Rl is selected from the group consisting of a carboxyl group, carbamate, carbonate, alkyl, and other hydroxy protecting group; R2 is selected from the group consisting of a carboxyl group, carbamate group and a carbonate group ; and each of R3 and R4 is independently a hydroxy protecting group or R3 and R4 together form a diol protecting group.

[08] Another aspect of the present invention provides, a method for producing an enantiomerically enriched a, (3-epoxy ester comprising admixing an oc, (3-unsaturated ester, an enantiomerically enriched cyclic chiral ketone, and an oxidizing agent under conditions sufficient to produce the a, p-epoxy ester at a yield of at least 50%.

[09] Preferably, the enantiomeric excess of the cyclic chiral ketone is at least about 90%.

[10] Yet another aspect of the present invention provides a compound of the formula :

where bonds a, b and c are any combination of cis-or trans-configuration relative to one another; X is hydrogen, halide, or alkoxide ; Y is-ORI, hydrogen, or halide; Rl is selected from the group consisting of a carboxyl group, carbamate, carbonate, alkyl, and other hydroxy protecting group; R2 is selected from the group consisting of a carboxyl group, carbamate group and a carbonate group; and each of R3 and R4 is independently a hydroxy protecting group or R3 and R4 together form a diol protecting group.

[11] In one particular embodiment, compound of Formula II is of the formula:

IIA where Rl, R2, R3, R4, a, b, and c are those defined herein. Preferably, Rl and R2 are independently a carboxyl group.

[12] In one embodiment, R3 and R4 together form a diol protecting group.

[13] hi one specific embodiment, chiral ketone of Formula II is of the formula:

[14] DETAILED DESCRIPTION OF THE INVENTION [15] As used herein, "electron withdrawing group"refers to a moiety whose electronegativity increases the nucleophilic attack of the olefinic moiety to which it is attached to. Preferably, the electron withdrawing group comprises an unsaturation which is conjugated with the olefinic moiety. Exemplary preferred electron withdrawing groups

include esters, ketone, sulfone, nitrile, and nitro. More preferably, the electron withdrawing group is an ester.

[16] The terms"ester"and"ester group"are used interchangeably herein and refer to a moiety of the formula-CO2R, where R is optionally substituted alicyclic, cyclic, aliphatic, aromatic hydrocarbon moiety or a combination thereof comprising at least one carbon atom.

Introduction [17] Asymmetric epoxidation of olefins using a chiral ketone and an oxidizing agent is generally disclosed in commonly assigned U. S. Patent Application No. 09/284,054, filed April 6,1999, which is a U. S. National Phase Patent Application of PCT Patent Application No. PCT/US97/18310, filed October 8,1997, U. S. Patent Application No.

09/673,335, filed October 13,2000, which is a U. S. National Phase Patent Application of PCT Patent Application No. PCT/US99/08418, filed April 16,1999, U. S. Patent Application Nos. 09/663,390, filed August 10,2000 and 09/534,419, filed March 23,2000. All of the above patent applications are incorporated herein by reference in their entirety.

[18] While the enantioselective epoxidation reaction described in the above incorporated patent applications are useful for a variety of olefins, high yielding and highly enantioselective epoxidation of electron deficient olefins, e. g., a, 3-unsaturated esters, using a mixture of a chiral ketone and an oxidizing agent still remains a challenging problem. For example, the epoxidation of cinnamates by various chiral dioxiranes provide only moderate to good enantioselectivites. In addition to the selectivity, the low reactivity of these reactions have also been a major obstacle for achieving efficient epoxidation.

[19] The present invention provides a method for producing an enantiomerically enriched epoxide from an electron deficient olefin.

[20] Methods of the present invention can also be used for kinetic resolution of the electron deficient olefins. In this aspect, the method generally involves converting one of the stereoisomer of the electron deficient olefin to an epoxide at a higher rate than the other isomer, which results in a relative enrichment of the other stereoisomer. The terms "enrichment"and"relative enrichment"are used herein interchangeably to describe an increase of one stereoisomer relative to the other. It should be appreciated that enrichment of an electron deficient olefin is a result of a decrease in the amount of one stereoisomer by conversion to an epoxide.

Olefin [21] As used herein an"electron deficient olefin"refers to an olefin having at least one electron withdrawing group bonded directly to the olefinic moiety. Suitable olefins of the present invention can be generally represented by a formula: RaRbC=CR°Rd where each of Ra, Rb, Rc and Rd is independently any substituent known to one skilled in the art, including, but not limited to, hydrogen, halide, and optionally substituted alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy and a mixture thereof, provided that at least one of Ra, Rb, R° and Rd is an electron withdrawing group as defined herein. Preferably, the olefin is an a, (3-unsaturated ester, i. e. , where at least one of Ra, Rb, Rc and Rd is an ester group.

[22] Typically, the initial concentration of the olefin is from about 0.001 mole/liter (M) to about 10 M. Preferably, the initial concentration of the olefin is from about 0.02 M to about 1 M.

[23] Methods of the present invention generally comprises admixing the olefin, an enantiomerically enriched chiral ketone, and an oxidizing agent under conditions sufficient to produce the enantiomeric enriched epoxide. It should be appreciated that asymmetric epoxidation of the present invention can be performed in a variety of different sequences.

For example, the addition sequences of the olefin, the chiral ketone, and the oxidizing agent can be interchanged. Typically, however, the oxidizing agent is added to a reaction mixture comprising the chiral ketone and the olefin. A reverse-addition technique can also be used depending upon the reactivity of each component.

Chiral Ketone [24] Without being bound by a theory, it is believed that contacting an oxidizing agent with a chiral ketone produces a chiral dioxirane, which is believed to be the active species in generating the epoxide from the olefin. In general, the chiral dioxirane is generated and used in situ by contacting (i. e. , reacting) a chiral ketone with an oxidizing agent in the presence of the olefin. Although potentially the actual epoxidizing agent (e. g., dioxirane) may be generated in a separate reaction prior to contacting with an olefin, it is more advantageous to combine the chiral ketone and the olefin in a single reaction mixture and generate the dioxirane in situ by adding an oxidizing agent to the reaction mixture.

[25] While the present invention is described in reference to dioxirane as being the actual epoxidizing agent, the scope of the present invention is not limited to such. Generally, any reactive species which stereoselectively generates the epoxide from the reaction mixture

provided herein is within the scope of the present invention. However, for brevity and consistancy throughout this disclosure, the reactive species is described as being a dioxirane of the chiral ketone.

[26] It is also believed that the reaction between an olefin and the dioxirane provides an epoxide and regenerates the chiral ketone ; therefore, the chiral ketone can be used as a catalyst. Thus, less than one equivalent of the chiral ketone, relative to the olefin, can be used in the present invention, i. e. , the same molecule of chiral ketone can be used more than once in epoxidizing an olefin. The average number of epoxidation of olefins produced by a ketone molecule is known as a catalytic turn-over number, or simply a turn- over number. Preferably, the ketones of the present invention have a turn-over number of at least about 3, more preferably at least about 50 and most preferably at least about 100.

Moreover, since the ketones have such a high turn-over number, the amount of the ketones required to epoxidize a given amount of olefin can be less than the stoichiometric amount, i. e. , one equivalent, of the olefin. Preferably no more than about 0.3 equivalents of ketone is used to epoxidize olefins, more preferably no more than about 0.05 equivalents, and most preferably no more than about 0.01 equivalents.

[27] In one embodiment, the chiral ketone is a cyclic chiral ketone. Preferably, the cyclic chiral ketone is of the formula : I where bonds a, b and c are any combination of cis-or trans-configuration relative to one another; X is hydrogen, halide, or alkoxide; Y is-OR', hydrogen, or halide; Rl is selected from the group consisting of a carboxyl group, carbamate, carbonate, alkyl, and other hydroxy protecting group; R is selected from the group consisting of a carboxyl group, carbamate group and a carbonate group; and each of R3 and R4 is independently a hydroxy protecting group or R3 and R4 together form a diol protecting group. Suitable hydroxy protecting groups are well known to one skilled in the art. See, for example, Protective Groups in Organic Synthesis, 3rd edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, 1999, pp. 23-245, which is incorporated herein by reference.

formula-C (=O) R', where R'is hydrogen or optionally substituted alicyclic, cyclic, aliphatic, aromatic hydrocarbon moiety or a combination thereof. In one particular embodiment, Ri and R2 are acetyl group, i. e. , a moiety of the formula-C (=O) CH3.

[29] Suitable hydroxy protecting group for R3 and R4 include, carboxyl groups, silyl ethers, carbonates (e. g.,-C (=O) OR" where R"is optionally substituted alicyclic, cyclic, aliphatic, aromatic hydrocarbon moiety or a combination thereof comprising at least one carbon atom), ethers and the like.

[30] In one embodiment, R3 and R4 together form a dial protecting group. Such diol protection groups are well known to one skilled in the art. See, for example, Protective Groups in Organic Synthesis, 3rd edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, 1999, pp. 201-245, which is incorporated herein by reference. Preferably, R3 and R4 together with atoms to which they are attached to form a cyclic acetal or a cyclic ketal.

[31] Bonds a, b, and c can be any combination of cis-or trans-configuration relative to one another. Preferably, bonds a and b are of cis-configuration relative to each other. More preferably, bonds a, b and c are of cis-configuration relative to each other.

[32] One of the advantages of the present invention is availability of relatively inexpensive starting materials for producing chiral ketones. For example, chiral ketones of Formula I can be synthesized in high overall yield from readily available carbohydrates, such as fructose and sorbose.

[33] In one particular embodiment of the present invention, the chiral ketone of Formula I is derived from a carbohydrate. Preferably, the chiral ketone is derived from an oxidation of an unprotected hydroxy group of a carbohydrate compound having at least one protected hydroxy group. Preferably, the protecting groups for protected hydroxy groups are selected from the group consisting of silyl ethers, ethers, acetals, ketals, esters, ortho esters, sulfonates, phosphates and mixtures thereof. The protecting groups for two or more hydroxy groups of the carbohydrate or its derivative can be interconnected. For example, an acetonide group protecting 4,5-hydroxy groups of fructose can be considered to be"two interconnected acetal protecting groups"since they protect two hydroxy groups on the fructose. The oxidation of a hydroxy group of a carbohydrate to form a carbonyl group is well known to one skilled in the art. See Mio et al. Tetrahedron 1991, 47, 2133-2144. For example, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Swern oxidation condition or other oxidizing conditions can be used to oxidize a hydroxy group of a carbohydrate or its

derivative to a ketone compound of the present invention. Preferably, the carbohydrate is selected from the group consisting of fructose, sorbose, arabinose, mannose, and glucose. <BR> <BR> <P>More preferably, the carbohydrate is selected from the group consisting of (D)-fructose, (L) -<BR> fructose, (L) -sorbose, (L) -arabinose, and (D)-arabinose.

Oxidizing agent [34] Depending on the nature of the oxidizing agent, it is added as a solution or a solid to the reaction mixture comprising the chiral ketone and the olefin. In this manner, the chiral ketone can be used in an amount less than the stoichiometric amount relative to the amount of the olefin. It should be appreciated that in situ generation of dioxirane from a ketone generally requires the oxidizing agent to be more reactive towards the ketone than the olefin to avoid competing oxidation of olefin by the oxidizing agent. However, when the reactivity of the oxidizing agent with the olefin is similar or greater than with the ketone then one method of providing a higher amount of reaction between the oxidizing agent and the ketone to generate the dioxirane is to use the ketone in an amount substantially more than the amount of the olefin. In these cases, preferably the amount of ketone used is at least about 3 times more than the amount olefin, more preferably at least about 5 times, and most preferably at least about 10 times.

[35] When a solution comprising an oxidizing agent is used, preferably the initial concentration of the oxidizing agent is from about 0.1 M to about 1 M, more preferably from about 0.2 M to about 0.5 M. The rate of addition of the oxidizing agent to the reaction mixture will vary depending on a various factors, such as the reaction temperature, the size of the reaction, and the olefin substrates.

[36] In general, any oxidizing agent capable of providing dioxiranes from a corresponding ketone can be used in the present invention. However, for economic reasons a relatively inexpensive oxidizing agents such as peracids, hydrogen peroxide, sodium <BR> <BR> hypochlorite, peroxomonosulfate (e. g. , potassium peroxomonosulfate), sodium perborate and<BR> hypofluoride (HOF) are preferred. Non-organic oxidizing agents (i. e. , a compound that does not contain any carbon atom) are particularly preferred as these oxidizing agents and their reaction products can be easily removed from the reaction mixture by a simple aqueous extraction.

[37] The amount of oxidizing agent used in the present invention depends on a variety of factors including the reactivity of the ketone, olefin, and the decomposition rate of . the oxidizing agent. Typically, the amount of an oxidizing agent used is at least about 1

times the amount of the ketone, preferably at least about 9 times, and more preferably at least about 100 times. In another embodiment of the present invention, the amount of an oxidizing agent used is less than about 10 times the amount of the olefin, and more preferably less than about 3 times. However, it should be appreciated that the present invention is not limited to these particular amounts of the oxidizing agent.

[38] In one embodiment, the oxidizing agent is potassium peroxomonosulfate.

[39] However, the scope of the present invention is not limited to any particular oxidizing agent. Any suitable oxidizing agents known to one skilled in the art can be used.

Exemplary suitable oxidizing agents include, but are not limited to, peracids (e. g., mCPBA), hydrogen peroxide and a mixture of hydrogen peroxide and a nitrile compound.

Epoxidation Reaction [40] A longer reaction period generally provides higher yield of the epoxide.

However, there is a potential for decreased enantiomeric excess as the reaction time is prolonged. Typically, the reaction time is from about 5 h to about 48 h, preferably from about 10 h to about 36 h, and more preferably from about 20 h to about 30 h. However, it should be appreciated that the present invention is not limited to these particular reaction times.

[41] In some embodiment, methods of the present invention can also comprise adjusting the pH of the reaction mixture. The useful pH range is broad. Typically, however, the pH is preferably at least about pH 5. Because the pH can fluctuate during the course of reaction, the reaction pH referred to herein refers to an apparent pH. Preferably, the pH of the reaction is from about pH 5 to about pH 14, more preferably from about pH 5 to about pH 10, and most preferably from about pH 7 to about pH 9.

[42] The pH of the reaction solution can be conveniently achieved by adding sufficient amount of base to maintain the pH at the desired level. The base can be added separately, it can be added to the solution containing the ketone, or it can be added to the solution containing the oxidizing agent. Alternatively, a solid mixture of the base and oxidizing agent can be added to the reaction mixture. When a base is used to control the reaction pH, preferably the base is selected from the group consisting of hydroxides, carbonates, bicarbonates, borates and phosphates. More preferably the base is selected from the group consisting of potassium carbonate, potassium bicarbonate, lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, calcium carbonate, sodium borate, sodium phosphate, potassium phosphate, lithium hydroxide, sodium hydroxide,

potassium hydroxide, magnesium hydroxide and calcium hydroxide, most preferably the base is selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium borate, sodium phosphate, potassium phosphate and potassium hydroxide. Alternatively, the desire pH of the reaction can be more easily maintained by using a buffer solution.

[43] Another factor that can determine the yield of the epoxide and/or enantioselectivity of the reaction is the solvent system used. Typically, any relatively inert organic solvent can be used for the present invention. Exemplary solvents include, nitriles such as acetonitrile and propionitrile, dimethoxymethane (DMM), dimethoxyethane (DME), ethers such as tetrahydrofuran (THF), dichloromethane, chloroform, ethyl acetate, hexane, benzene, toluene, xylenes, dioxane, dimethyl formamide (DMF), pentane, alcohols including, but not limited to, methanol, ethanol and i-propyl alcohol, and mixtures thereof.

[44] Preferably, the solvent is selected from the group consisting of acetonitrile, DMM, DME, DMF, dioxane and mixtures thereof. In certain cases, a mixture of solvents provides higher yield and/or enantioselectivity.

[45] The temperature of the reaction can also affect the yield of the reaction and enantioselectivity of the epoxide. Generally, a lower reaction temperature requires a longer reaction time but results in higher enantioselectivity. Preferably, the reaction temperature is about 50 °C or less, more preferably about 30 °C or less, and most preferably from about 0 °C to about room temperature. However, the scope of the present invention is not limited to these particular reaction temperatures.

[46] Preferably, methods of the present invention results in the yield of the epoxide being at least about 50%, more preferably at least about 60% and most preferably at least about 70%.

[47] Typically, the enantiomeric excess of the resulting epoxide is at least about 70%. Preferably, the enantiomeric excess of the resulting epoxide is at least about 80%, more preferably at least about 85%, and most preferably at least about 90%.

[48] Through out this disclosure, combinations of the preferred embodiments of any particular characteristics or properties described herein form other preferred embodiments. Thus, for example, in one particularly preferred embodiment, methods of the present invention provides an enantiomerically enriched epoxide at a yield of at least about 50% and enantiomeric excess of at least about 80%.

[49] 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.

EXAMPLES [50] The results of asymmetric epoxidation with a number of substituted cinnamates using methods of the present invention are shown in the table below.

Table. Asymmetric Epoxidation oiS Olefins Catalyzed by Ketonea

entry substrate yield Ee Config. r, CO2Et 69 96 1 0-(2S, 3R) i 2d C02Et 87 94f 3c 02Et 65 919 ()- (2S, 3R) Mu0 4c C02Et 64 97g (+) c 5c C02Et 77 96 h 6c 02Et 40 95' F 7° 93 96' ()- (2S, 3R) \ C02Et Et 91 93 h C02Et 9° 64 2 (+)- \ covet COzEt "HP. coEt77) tic 94 90 COzEt zu TMS a. All reactions were carried out at 0"C to rt with substrate (1 eq. ), ketone (0.20-0. 30<BR> eq. ), Oxone (5 eq. ), and NaHCO3 (15.5 eq. ) in CH3CN-aq. EDTA (4 x 10-4 M) (-1. 5: 1). The reactions were stopped after 24 h. The chemical structure of the chiral ketone catalyst used in all of the examples in the table is: b. The epoxides were purified by flash chromatography and gave satisfactory spectroscopic characterization. c. 0.30 eq. Ketone used. d. 0.25 eq. ketone used.

e. 0.20 eq. ketone used.

[51] As shown in the Table above, methods of the present invention provide a high yield and enantiomeric excesses of the epoxide. Generally, the substrate with an electron- donating group showed higher reactivity but with slightly lower ee. Trisubstituted cinnamates were also effective substrates, giving high yields and ee's (Table 1, entries 7 & 8). Further studies showed this epoxidation could also be extended to a number of trisubstituted a, (3-unsaturated esters containing no phenyl groups, giving the epoxides with good yields and high ee's.

[52] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.