A General, Catalytic, and Enantioselective Synthesis of (S)-γ-[(S)-1-Aminoalkyl]-γ-lactones

Abstract

A catalytic asymmetric synthesis of N-phthaloyl (S)-γ-[(S)-1-aminoalkyl]-γ-lactones, widely used intermediates in the preparation of hydroxyethylene dipeptide isosteres, is described. The highly enantiopure epoxy alcohols arising from the Sharpless epoxidation of (E)-allyl alcohols are first converted to (S)-N-phthaloyl-[(S)-1-aminoalkyl]oxiranes by means of an efficient four-step sequence involving the regio- and stereoselective ring opening of the starting epoxide by azide, reduction, phthaloylation, and intramolecular Mitsunobu cyclization of the intermediate phthalimido diol. Treatment of the resulting oxirane with lithium (1R)-menthyloxyacetylide in the presence of boron trifluoride etherate, followed by in situ hydrolysis of the ynol ether, leads to a (4R,5S)-5-phthalimido-4-hydroxy ester. A Mitsunobu reaction with p-nitrobenzoic acid (which establishes the correct (S)-configuration at C-4) and subsequent selective saponification of the benzoate and cyclization of the inverted hydroxy ester afford the target N-protected (S)-γ-[(S)-1-aminoalkyl]-γ-lactones. Using this methodology, lactones 19 and 26 were obtained in seven steps from the readily available epoxy alcohols 5 and 20, respectively, in high enantiomeric purity.