Catalytic enantioselective 1,6-conjugate additions of propargyl and allyl groups

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 known chiral catalysts that facilitate the catalytic enantioselective additions of nucleophiles to enoates(1). However, catalytic enantioselective 1,6-conjugate additions are uncommon, and ones that are able to incorporate readily functionalizable moieties, such as propargyl or allyl groups, into acyclic α,β,γ,δ-doubly unsaturated acceptors are unknown(2). Chemical transformations that could generate a new bond at the C6 position of a dienoate are particularly desirable, as the resulting products would be subjected to further modifications; such reactions, especially when dienoates contain two equally substituted olefins, are scarce(3) and are confined to reactions promoted by a phosphine–copper (with alkyl Grignard(4,5), dialkylzinc or trialkylaluminum compounds(6,7)), a diene–iridium (with arylboroxines)(8,9), and a bisphosphine–cobalt catalyst (with monosilyl-acetylenes)(10). 1,6-conjugate additions are otherwise limited to substrates where there is full substitution at C4(11). It is not clear why certain catalysts favor bond formation at C6, and – while there are a small number of catalytic enantioselective conjugate allyl additions(12,13,14,15) – related 1,6-additions and processes involving a propargyl unit are non-existent. In this manuscript, 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 allenylboron compound or a monosubstituted allene may be used. Products can be obtained in up to 83 percent yield, >98 percent diastereo- (for allyl additions) and 99:1 enantiomeric ratio. Mechanistic details, including the origins of high site- (1,6- versus 1,4-) and enantioselectivity as a function of the catalyst structure and reaction type, have been elucidated by means of density functional theory (DFT) calculations.