Asymmetric
Synthesis of α,β-Unsaturated
δ‑Lactones through Copper(I)-Catalyzed Direct Vinylogous
Aldol Reaction
Version 2 2018-09-14, 15:50
Version 1 2018-09-11, 16:19
Posted on 2018-09-14 - 15:50
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 (E)-form to (Z)-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.
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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. https://doi.org/10.1021/jacs.8b07929
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