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Catalytic Enantioselective Ynamide Additions to Isatins: Concise Access to Oxindole Alkaloids.

ABSTRACT: The highly enantioselective addition of terminal ynamides to a variety of isatins, catalyzed by a bisoxazolidine copper complex under mild, base-free reaction conditions, is described. The reaction is broad in scope, scalable, applicable to unprotected isatins, and provides efficient access to 3-hydroxyoxindoles carrying a tetrasubstituted chiral center with excellent yields and enantioselectivities. Synthetically versatile, multifunctional 3-hydroxyindolinones are obtained by hydration, partial hydrogenation, or hydroxyacyloxylation of the ynamide moiety at room temperature and exhaustive hydrogenation followed by reductive detosylation and spontaneous cyclization affords cinchonamidine alkaloids.

SUBMITTER: Moskowitz M

PROVIDER: S-EPMC6444906 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Project description:Conjugate (or 1,4-) additions of carbanionic species to α,β-unsaturated carbonyl compounds are vital to research in organic and medicinal chemistry, and there are several chiral catalysts that facilitate the catalytic enantioselective additions of nucleophiles to enoates. Nonetheless, catalytic enantioselective 1,6-conjugate additions are uncommon, and ones that incorporate readily functionalizable moieties, such as propargyl or allyl groups, into acyclic α,β,γ,δ-doubly unsaturated acceptors are unknown. Chemical transformations that could generate a new bond at the C6 position of a dienoate are particularly desirable because the resulting products could then be subjected to further modifications. However, such reactions, especially when dienoates contain two equally substituted olefins, are scarce and are confined to reactions promoted by a phosphine-copper catalyst (with an alkyl Grignard reagent, dialkylzinc or trialkylaluminium compounds), a diene-iridium catalyst (with arylboroxines), or a bisphosphine-cobalt catalyst (with monosilyl-acetylenes). 1,6-Conjugate additions are otherwise limited to substrates where there is full substitution at the C4 position. It is unclear why certain catalysts favour bond formation at C6, and-although there are a small number of catalytic enantioselective conjugate allyl additions-related 1,6-additions and processes involving a propargyl unit are non-existent. Here we show that an easily accessible organocopper catalyst can promote 1,6-conjugate additions of propargyl and 2-boryl-substituted allyl groups to acyclic dienoates with high selectivity. A commercially available allenyl-boron compound or a monosubstituted allene may be used. Products can be obtained in up to 83 per cent yield, >98:2 diastereomeric ratio (for allyl additions) and 99:1 enantiomeric ratio. We elucidate the mechanistic details, including the origins of high site selectivity (1,6- versus 1,4-) and enantioselectivity as a function of the catalyst structure and reaction type, by means of density functional theory calculations. The utility of the approach is highlighted by an application towards enantioselective synthesis of the anti-HIV agent (-)-equisetin.

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Catalytic Enantioselective Ynamide Additions to Isatins: Concise Access to Oxindole Alkaloids.

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