Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-03-23
2002-05-07
Gitomer, Ralph (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S103000
Reexamination Certificate
active
06384265
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to kinetic resolution of enol ester epoxides and to production of &agr;-acyloxy carbonyl compounds from enol ester epoxides, in particular with inversion of stereochemistry.
BACKGROUND OF THE INVENTION
The stereochemistry of a molecule is important in many of the properties of the molecule. For example, it is well known that physiological properties of drugs having one or more chiral centers, i.e., stereochemical centers, depend on the stereochemistry of a drug's chiral center. In addition, properties of a polymer containing a chiral monomeric unit depend on the enantiomeric purity of the monomer. Thus, it is advantageous to be able to control the stereochemistry of a chemical reaction or to be able to separate or enrich stereoisomers of a compound from a mixture.
Epoxides are used in many industrial processes as chiral building blocks for the synthesis of enantiomerically pure complex molecules such as polymers, surfactants, pesticides, insecticides, insect hormones, insect repellants, pheromones, food flavoring, and drugs. One can stereoselectively synthesize a variety of chiral epoxides, for example, as disclosed in commonly assigned PCT Patent Application No. PCT/US97/18310, filed Oct. 8, 1997, which is incorporated herein by reference in their entirety. However, there are instances where such asymmetric synthesis of epoxides may not be possible or economically desirable or cost effective. Since an epoxide serves as an intermediate or a starting material for many chemical compounds, it is especially desirable to have a general method for resolving a racemic mixture of epoxides or be able to stereoselectively convert one particular stereoisomer of the epoxide to afford enantiomerically enriched products and/or unreacted epoxides.
One of the useful products derived from an enol ester epoxide is an &agr;-acyloxy carbonyl compound. Enol ester epoxides can rearrange to &agr;-acyloxy ketones or aldehydes under a variety of conditions, for example, thermal or acidic conditions. An &agr;-acyloxy carbonyl compound itself can be further used as a chiral building block in many industrial processes. While a variety of reagents are available for converting enol ester epoxides to &agr;-acyloxy carbonyl compound with retention of stereochemistry, currently no acid catalyzed method is available for stereoselectively converting enol ester epoxides to &agr;-acyloxy carbonyl compound with inversion of stereochemistry.
Therefore, there is a need for a method for converting enol ester epoxides to &agr;-acyloxy carbonyl compounds with inversion of stereochemistry. There is also a need for a method for resolving a racemic or stereoisomeric mixture of enol ester epoxides.
SUMMARY OF THE INVENTION
The present invention provides a method for stereoselectively producing an &agr;-acyloxy carbonyl compound from an enol ester epoxide comprising contacting the enol ester epoxide with an acid catalyst under a condition sufficient to stereoselectively produce the &agr;-acyloxy carbonyl compound. Preferably, the conversion of enol ester epoxide to the &agr;-acyloxy carbonyl compound includes an inversion of stereochemistry. When the enol ester epoxide is enantiomerically enriched, an achiral catalyst can be used to stereoselectively convert the enol ester epoxide to either of the desired &agr;-acyloxy carbonyl compound stereoisomers.
Alternatively, a chiral Lewis acid catalyst can be used to provide a kinetic resolution of the racemic mixture of enol ester epoxides. By combining these two processes (e.g., the use of a chiral Lewis acid followed by the use of an achiral acid catalyst), a stereoselective production of predominantly one stereoisomer of &agr;-acyloxy carbonyl compounds from both stereoisomers of enol ester epoxides can be achieved from a racemic mixture of enol ester epoxides.
Another embodiment of the present invention provides a kinetic resolution of a stereoisomeric mixture of an enol ester epoxide. Preferably, the kinetic resolution of enol ester epoxide involves contacting the stereochemical mixture (i.e., stereoisomeric mixture) of the enol ester epoxide with a chiral Lewis acid catalyst to convert predominantly one enantiomer of the enol ester epoxide to an &agr;-acyloxy carbonyl compound. Preferably, the chiral Lewis acid catalyst stereoselectively converts the enol ester epoxide to the &agr;-acyloxy carbonyl compound.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the terms “inversion” and “inversion of stereochemistry” are used interchangeably herein and refer to a process which results in the &agr;-acyloxy group of the &agr;-acyloxy carbonyl compound having an opposite stereochemical configuration relative to the stereochemistry of the starting epoxide group. This is generally illustrated in the conversion of compound 3 to compound 8 in Scheme 1 below. Preferably, when methods of the present invention result in inversion of stereochemistry at least about 75% of the product results from inversion of stereochemistry, more preferably at least about 80%, still more preferably at least about 90%, yet still more preferably at least about 95%, and most preferably substantially all of the product has inversion of stereochemistry.
The terms “retention” and “retention of stereochemistry” are used interchangeably herein and refer to a process which results in the &agr;-acyloxy group of the &agr;-acyloxy carbonyl compound having a same stereochemical configuration relative to the stereochemistry of the starting epoxide group. This is generally illustrated in the conversion of compound 3 to compound 6 in Scheme 1 below. Preferably, when methods of the present invention result in retention of stereochemistry at least about 75% of the product results from retention of stereochemistry, more preferably at least about 80%, still more preferably at least about 90%, yet still more preferably at least about 95%, and most preferably at least about 99%.
The terms “enantioselective” and “stereoselective” are used interchangeably herein and refer to a process which results in the production of an &agr;-acyloxy carbonyl compound having predominantly one particular stereochemistry of the &agr;-acyloxy group. It should be appreciated that while the enol ester epoxide may have other chiral centers other than the epoxide moiety, the terms “enantioselective” and “stereoselective” refer only to the &agr;-acyloxy stereochemical center resulting from the opening of the epoxide ring moiety.
The terms “enantiomeric excess” and “stereoisomeric excess” are used interchangeably herein and refer to a process which produces an &agr;-acyloxy carbonyl compound having predominantly one particular stereochemistry of the &agr;-acyloxy group. Preferably, methods of the present invention produce the &agr;-acyloxy carbonyl compound, with inversion of the stereochemistry, in an enantiomeric excess of at least about 12% ee, more preferably at least about 80% ee, still more preferably at least about 90% ee, and most preferably at least about 95% ee.
Unless the context requires otherwise, the terms “stereoisomeric mixture” and “stereochemical mixture” are used interchangeably herein and refer to a relative ratio of each stereoisomer or enantiomer present in the starting material, e.g., prior to a kinetic resolution. Furthermore, when these terms are used without any value, they refer to the fact that the starting material contains more than one stereoisomer or enantiomer.
The term “enantiomerically enriched mixture” of a compound refers to a stereoisomeric or enantiomeric mixture of a compound where the relative ratio of each stereoisomer or enantiomer is different than the starting material, e.g., prior to a kinetic resolution.
An “enol ester epoxide” refers to an epoxide compound having an acyloxy substituent on one of the carbon atoms of the epoxide ring, i.e., a compound having the formula:
An “&agr;-acyloxy carbonyl compound” refers to a carbonyl compound, e.g., a ketone or aldehyde, having an acyloxy substituent &agr; to the carbonyl functionality, i.e., a co
Colorado State University Research Foundation
Gitomer Ralph
Khare Devesh
Townsend and Townsend / and Crew LLP
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