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

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.本研究开发了一种用于手性α,β-不饱和δ-内酯不对称合成的简便方法：通过铜(I)催化β,γ-不饱和酯与各类醛（包括芳香醛、杂芳醛、α,β-不饱和醛及脂肪醛）的直接乙烯基羟醛缩合反应（direct vinylogous aldol reaction, DVAR）实现目标转化。针对芳香醛与杂芳醛底物，需通过一锅法依次完成DVAR、不饱和碳碳双键的E式到Z式异构化以及后续分子内酯交换步骤，方可获得中等至较高产率且具有高对映选择性的内酯产物。而对于α,β-不饱和醛与脂肪醛，仅需直接进行DVAR反应即可得到中等产率且高对映选择性的内酯产物。该DVAR反应对多种官能团均具有良好的兼容性。此外，该方法可很好地应用于天然产物、天然产物衍生物以及药物分子（阿托西汀（atomoxetine）与萘普生（naproxen））中含有的醛基底物。机理研究表明，α-加成过程可逆且不利于目标反应，这正是DVAR反应具备优异区域选择性的原因。研究提出，经去质子化生成的铜(I)-二烯醇负离子物种可与烯丙基铜(I)物种形成动态平衡，后者通过醛的催化不对称烯丙基化反应与醛类底物结合，生成DVAR产物。最后，本反应的鲁棒性通过克级规模反应得到验证，而该方法的应用价值则通过依泽替米贝（ezetimibe）与福司曲星（fostriecin）的形式不对称合成得到了充分展示。