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

Abstract

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.

Efficient one-pot green synthesis of tetrakis(acetonitrile)copper(i) complex in aqueous media

“…used in research laboratories and industrial processes as catalysts in cycloaddition 3,4 and Ullmann 5 reactions, intramolecular aromatic annulations, 6,7 oxidation of primary alcohols 8 and many other popular reactions of organic synthesis. [9][10][11][12][13] At the same time they serve as important precursors for the synthesis of overwhelming majority of mononuclear [14][15][16] and homo- 17 and hetero-polynuclear 18,19 copper(I) complexes, which also have numerous practical applications, [20][21][22] one of which is large-scale production of emitting materials for OLED fabrication. 23 Total number of references related to these compounds as reagents/reactants exceeds 3100 (over 100 of them during 2018 year), including the papers in journals of highest rank.…”

Asymmetric Vinylogous Aldol-type Reactions of Aldehydes with Allyl Phosphonate and Sulfone

“…In all cases with 4′ , the vinylogous product 5a′ was obtained with unsatisfactory regio- and enantioselectivities (entries 1–9). ( R )-DTBM-SEGPHOS, an effective bulky ligand, led to good control of the enantioselectivity in our previously reported catalytic asymmetric aldol reaction of unsaturated esters and aldehydes (Zhang and Yin, 2018) and gave excellent control of the regioselectivity. The enantioselectivity was improved from 43% to 76% by switching phenyl to 2-pyridinyl (entry 10).…”

Lewis acid-catalyzed asymmetric reactions of β,γ-unsaturated 2-acyl imidazoles

“…These compounds and their analogs bearing one potential enolization have been demonstrated as highly active nucleophiles in a number of catalytic asymmetric reactions for the synthesis of natural products and bioactive compounds [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] . Especially, γ-addition as dienolate pronucleophiles with either metal catalysis [17][18][19][20][21][22][23][24][25][26][27][28] or organocatalysis [29][30][31][32][33][34][35][36] has been widely documented during the past several years, and the maintained πconjugation of γ-addition process leading to thermodynamically stable conjugated products (Fig. 1a, A).…”