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

Journal of the American Chemical Society
Chengxi LiStephen L Buchwald

Abstract

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 the product. A stereochemical model is provided to explain the high diastereo- and enantioselectivity of this process. Finally, this method was applied to the preparation of an important drug, ( R)-procyclidine, and a key intermediate in the synthesis of several pharmaceuticals.

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Citations

Jun 20, 2019·Angewandte Chemie·Christopher CoozeRylan J Lundgren
Sep 19, 2019·Chemistry : a European Journal·Liangliang Zhang, Martin Oestreich
Apr 10, 2020·Chemical Communications : Chem Comm·Yuki MatsudaTetsuaki Fujihara
May 7, 2020·Angewandte Chemie·Addison Nole DesnoyerT Don Tilley
Aug 29, 2020·Chemical Communications : Chem Comm·Penglin ZhangChun Zhang
Mar 2, 2021·Organic Letters·James Levi KnippelStephen L Buchwald
Mar 19, 2021·Journal of the American Chemical Society·Feng ZhongLiang Yin
Apr 17, 2021·Israel Journal of Chemistry·Allison M BergmannM Kevin Brown
Mar 30, 2021·Chemistry : a European Journal·Baptiste LecacheyJean-Marc Campagne
Jun 30, 2021·The Journal of Organic Chemistry·Kazutaka KanayamaTetsuaki Fujihara
May 16, 2020·Journal of the American Chemical Society·Yuxuan YeStephen L Buchwald
May 8, 2020·Journal of the American Chemical Society·Huan-Ming HuangFrank Glorius
Aug 23, 2019·Journal of the American Chemical Society·Gaël TranClément Mazet
May 13, 2020·Journal of the American Chemical Society·Yujing ZhouStephen L Buchwald
Dec 2, 2020·Journal of the American Chemical Society·Pengfei HuPhil S Baran
May 14, 2020·Accounts of Chemical Research·Richard Y Liu, Stephen L Buchwald

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