Stereospecific Synthesis of cis-2,5-Disubstituted Pyrrolidines via N,O‑Acetals Formed by Hydroamination Cyclization–Hydroalkoxylation of Homopropargylic Sulfonamides in HFIP

We reported a novel two-step stereoselective synthesis of functionalized pyrrolidines from homopropargylic sulfonamides and nucleophiles via an isolable N,O-acetal intermediates. This reaction features mild conditions and good scope of substrates. In addition, the use of hexafluoroisopropanol, acting as a solvent, an additive, a weak nucleophile, and a good leaving group, is pivotal to the success of the method. Moreover, reactions of chiral homopropargylic sulfonamides afford only 2,5-cis-disubstituted pyrrolidines with high diastereoselectivity (up to >99:1 dr) and enantioselectivity (up to >99% ee). The overall reaction constitutes a formal 1,1-bifunctionalization of terminal alkynes, which has hitherto been reported only rarely. Additionally, this method provides efficient access to pharmaceutical intermediate and to carry out postmodification of natural products.