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CuH-Catalyzed Enantioselective Ketone Allylation with 1,3-Dienes: Scope, Mechanism, and Applications

preprint
submitted on 13.12.2018 and posted on 14.12.2018 by Chengxi Li, Richard Liu, Luke T. Jesikiewicz, Yang Yang, Peng Liu, Stephen L. Buchwald

Chiral tertiary alcohols are important building blocks for the synthesis of pharmaceutical agents and biologically active natural products. The addition of carbon nucleophiles to ketones is the most common approach to tertiary alcohol synthesis, but traditionally relies on stoichiometric organometallic reagents that are difficult to prepare, sensitive, and uneconomical. We describe a mild and efficient method for the copper-catalyzed allylation of ketones, using widely available 1,3-dienes as allylmetal surrogates. Homoallylic alcohols bearing a wide range of functional groups are obtained in high yield and with good regio-, diastereo-, and enantioselectivity. Mechanistic investigations using density functional theory (DFT) implicate the in situ formation of a rapidly equilibrating mixture of isomeric copper(I) allyl complexes, from which Curtin-Hammett kinetics determine the major isomer of product. A stereochemical model is provided to explain the high diastereo- and enantioselectivity of this process. Finally, this method was applied toward the preparation of an important drug, (R)-Procyclidine, and a key intermediate in the synthesis of several pharmaceuticals.


History

Email Address of Submitting Author

ryl@mit.edu

Institution

MIT

Country

USA

ORCID For Submitting Author

0000-0003-0951-6487

Declaration of Conflict of Interest

None

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