Catalytic Intramolecular Conjugate Additions of Aldehyde-Derived Enamines to α,β-Unsaturated Esters

Abstract

We report a pairing of known catalysts that enables intramolecular conjugate additions of aldehyde-derived enamines to α,β-unsaturated esters. Despite extensive prior exploration of conjugate additions of aldehyde-derived enamines, catalytic conjugate additions to unactivated enoate esters are unprecedented. Achieving enantioselective and diastereoselective six-membered ring formation requires the coordinated action of a chiral pyrrolidine, for nucleophilic activation of the aldehyde via enamine formation, and a hydrogen bond donor, for electrophilic activation of the enoate ester. Proper selection of the hydrogen bond donor is essential for chemoselectivity, which requires minimizing competition from homoaldol reaction. Utility is demonstrated in a six-step synthesis of (−)-yohimbane from cycloheptene.Letter pubs.acs.org/OrgLett

Enantioselective Syntheses of Yohimbine Alkaloids: Proving Grounds for New Catalytic Transformations

“…A recent enantioselective synthesis of (-)-yohimbane was reported by Gellman and co-workers in 2020. 58 They employ a traditional E-ring first approach, but rather than desymmetrize a pre-formed cyclohexane or cyclohexene system like Riva, Katsuki, or Ghosh, they construct the ring from an acyclic precursor using a catalytic asymmetric Stork enamine reaction (similar to Momose's yohimbine synthesis). Like Hong's synthesis, Gellman's synthesis is impressively concise and highlights the power of asymmetric enamine catalysis for the construction of enantioenriched yohimbine-type alkaloids.…”

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