Asymmetric Synthesis of α,β-Unsaturated δ‑Lactones through Copper(I)-Catalyzed Direct Vinylogous Aldol Reaction

Published on 2018-09-14T15:50:49Z (GMT) by
A simple methodology for the asymmetric synthesis of chiral α,β-unsaturated δ-lactones was achieved by copper­(I)-catalyzed direct vinylogous aldol reaction (DVAR) of β,γ-unsaturated esters and various aldehydes, including aromatic aldehydes, hetero­aromatic aldehydes, α,β-unsaturated aldehydes, and aliphatic aldehydes. For aromatic and hetero­aromatic aldehydes, a one-pot reaction consisting of DVAR, isomerization of the unsaturated carbon–carbon double bond from (<i>E</i>)-form to (<i>Z</i>)-form, and subsequent intra­molecular trans­esterification was required to get the lactones in moderate to high yields with high enantio­selectivity. For α,β-unsaturated and aliphatic aldehydes, the DVAR proceeded directly to afford the lactones in moderate yields with high enantio­selectivity. In the DVAR, various functional groups were well tolerated. Moreover, the methodology was nicely applicable to the aldehyde group distributed in natural products, derivatives of natural product, and derivatives of drug molecules (atomoxetine and naproxen). The mechanism studies revealed that α-addition was reversible and not favored, which accounted for the excellent regio­selectivity in the DVAR. The copper­(I)–dienolate species generated through deprotonation was proposed to form an equilibrium with an allyl­copper­(I) species, which reacted with aldehydes to afford the DVAR products through a catalytic asymmetric allylation of aldehydes. Finally, the robustness of the present reaction was demonstrated by a gram-scale reaction, and the utility of the present methodology was showcased by the formal asymmetric synthesis of ezetimibe and fostriecin.

Cite this collection

Zhang, Hai-Jun; Yin, Liang (2018): Asymmetric

Synthesis of α,β-Unsaturated

δ‑Lactones through Copper(I)-Catalyzed Direct Vinylogous

Aldol Reaction. ACS Publications. Collection.