Stereoselective Organocatalytic Approach to α,β-Disubstituted-β-amino Acids: A Short Enantioselective Synthesis of Cispentacin

alpha-Branched alpha,beta-unsaturated aldehydes have been tested in the organocatalytic tandem Michael addition/cyclization with N-(benzyloxycarbonyl) hydroxylamine, a reaction which until now has been restricted to alpha-unsubstituted enals. Starting from cyclopentene-2-carbaldehyde, and using diphenylprolinol trimethylsilyl ether as a chiral amine catalyst, this approach has led to the development of a practical, high yielding (93-98% overall yield, three steps), and highly enantioselective (up to 98:2 er) route to the cyclic beta-amino acid cispentacin, which compares favourably with previously described asymmetric syntheses of this biologically active natural product. When using acyclic alpha-branched alpha,beta-unsaturated aldehydes as substrates, the reaction yields depend on the substitution pattern of the aldehydes, and mixtures of cis- and trans-isomers are obtained. Nevertheless, this strategy has proved to be successful in some instances, and (3R, 4R)-benzyl 3-ethyl-4-methyl-5-oxoisoxazolidin-2-carboxylate could be obtained in 70% overall yield (two steps) from the reaction of 2-ethylcrotonaldehyde and N-(benzyloxycarbonyl) hydroxylamine under catalysis with diphenylprolinol trimethylsilyl ether, and with high enantiomeric purity (99:1 er).