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Method for preparing a biologically active 2-substituted succinic acid derivative involving asymmetrically catalytically hydrogenating the corresponding 2(E)-alkylidene succinate derivative in the presence of a rhodium complexed (R,R)-bisphosphine compound.
The present invention is directed to a method of preparing (R)-succinic acid derivatives represented by the formula: ##STR4## wherein R1and R2 independently represent substituted and unsubstituted alkyl radicals having from 1 to about 20 carbon atoms, substituted and unsubstituted cycloalkyl radicals having from about 4 to about 10 carbon atoms and substituted and unsubstituted aryl radicals; provided that R2 is not a strong electron withdrawing radical, i.e., electron withdrawing capability (sigma value) is less than about 0.27, i.e., less than that of a COOCH3 ; [for example, see March, Advanced Organic Chemistry, 2 ed., p. 253 (1977)], and R3 represents --OH, --OR--O--, O--M+, HN? (R1)3, --NHR1, --N(R1)2 and the like, wherein R1 represents radicals as defined above for R1, and M represents a Group IIA metal.
The present invention is directed to asymmetric homogeneous hydrogenation of certain 2(E)-alkylidene mono-substituted succinic acid(cas:110-15-6) derivatives to produce the corresponding (R)-succinic acid(cas:110-15-6) derivatives which are useful for synthesizing certain enzyme inhibitors.
The 2(E)-alkylidene succinic acid(cas:110-15-6) derivatives can be obtained by any one of a variety of methods including by a Stobbe condensation of an aldehyde or a ketone with a dialkyl succinate ester; by a Wittig reaction of a phosphorane (also called a phosphorus ylide) succinate with an aldehyde; by a Heck reaction of a dialkyl itaconate with a halogen compound, such as iodobenzene or iodonaphthalene, in the presence of palladium diacetate; and other methods as exemplified herein.
The subject method involves asymmetric reduction of 2(E)-alkylidene mono-substituted succinates represented by the formula: ##STR5## wherein R1, R2 and R3 represent the same radicals as defined above, utilizing as catalyst a rhodium complex of an optically active bisphosphine compound represented by the formula: ##STR6## wherein A and B each independently represent substituted and unsubstituted alkyl radicals having from 1 to about 12 carbon atoms, substituted and unsubstituted cycloalkyl radicals having from about 4 to about 7 carbon atoms and substituted and unsubstituted aryl radicals; provided that such radicals provide no significant interference with the steric requirements around the phosphorus atom, and A and B are different.
The (R)-succinates, which are produced according to the subject method with high optical purities and in high yields, are useful for preparing various potent enzyme inhibitors. For example, the activity of carboxypeptidase A has been found to be strongly inhibited by 2(R)-benzyl succinic acid (Byres et al., J. Biol. Chem., 247, 606 (1977).
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