Stereoselective Synthesis of 2,6-Cis-Substituted Tetrahydropyrans: Bronsted Acid-Catalyzed Intramolecular Oxa-Conjugate Cyclization of α,β-Unsaturated Ester Surrogates

Intramolecular oxa-conjugate cyclization (IOCC) of alpha,beta-unsaturated carbonyl compounds, triggered by deprotonation with a base, represents a straightforward method for the synthesis of tetrahydropyrans. However, it has been known that stereochemical outcome of IOCC depends on the local structure substrates and sometimes requires harsh reaction conditions and/or prolonged reaction times for selective formation of 2,6-cis-substituted tetrahydropyrans. These shortcomings limit the feasibility of IOCC in the context of complex natural product synthesis. In this paper, we describe Bronsted acid-catalyzed IOCC of alpha,beta-unsaturated ester surrogates (e.g., alpha,beta-unsaturated thioesters, oxazolidinone imides, and pyrrole amides) under mild reaction conditions, which affords a series of synthetically versatile 2,6-cis-substituted tetrahydropyran derivatives with good to excellent stereoselectivity (dr from 7:1 to >20:1). These alpha,beta-unsaturated carbonyl compounds were found to be more reactive than the corresponding oxoesters that are generally unreactive toward Bronsted acid-catalyzed intramolecular oxa-conjugate additions. The product tetrahydropyrans could be transformed into various derivatives in an efficient manner, highlighting the usefulness of our methodology.