Syntheses of enantiomerically pure 2-substituted pyrrolidin-3-ones via lithiated alkoxyallenes - An auxiliary-based synthesis of both enantiomers of the antibiotic anisomycin

Abstract

The hydrochlorides of both enantiomers of the antibiotic anisomycin were prepared starting with the 'diacetone-fructose'-substituted allene 1 and the N-Boc-protected imine precursor 2a. Addition of an excess of lithiated 1 to 2a provided a 2:1 mixture 3a of diastereoisomers, which were cyclized to 4a under base promotion (Scheme 2). The two diastereoisomers of 4a were separated and converted into enantiomerically pure pyrrolidin-3-ones (2R)-5a and (2S)-5a. A similar sequence yielded the N-Tos-protected compounds (2R)-5b and (2S)-5b. Compounds 5a were converted into silyl enol ethers 6 and by subsequent regio- and stereoselective hydroboration into pyrrolidine derivatives 7 (Scheme 3). Straightforward functional-group transformations led to the hydrochlorides 9 of anisomycin (Scheme 3). The (2R) series provided the hydrochloride (2R)-9 of the natural occurring enantiomer, whereas the (25) series furnished the antipode (2S)-9. The overall sequence to the natural product involved ten steps with eight purified intermediates and afforded an overall yield of 8%. Our stereochemically divergent approach to this type of hydroxylated pyrrolidines is highly flexible and should easily allow preparation of many analogues. © 2005 Verlag Helvetica Chimica Acta AG.