Zhang Hai-Jun, Yin Liang
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis , Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences , 345 Lingling Road , Shanghai 200032 , China.
J Am Chem Soc. 2018 Sep 26;140(38):12270-12279. doi: 10.1021/jacs.8b07929. Epub 2018 Sep 11.
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.
通过铜（I）催化的β，γ-不饱和酯与各种醛（包括芳族醛、杂芳族醛、α，β-不饱和醛和脂肪族醛）的直接烯醇型羟醛反应（DVAR），实现了一种用于手性α，β-不饱和δ-内酯不对称合成的简单方法。对于芳族和杂芳族醛，需要一锅法反应，该反应由DVAR、不饱和碳-碳双键从（E）-型异构化为（Z）-型以及随后的分子内酯交换组成，以中等至高收率和高对映选择性得到内酯。对于α，β-不饱和醛和脂肪族醛，DVAR直接进行，以中等收率和高对映选择性得到内酯。在DVAR中，各种官能团具有良好的耐受性。此外，该方法很好地适用于分布在天然产物、天然产物衍生物和药物分子（阿托西汀和萘普生）衍生物中的醛基。机理研究表明，α-加成是可逆的且不利，这解释了DVAR中优异的区域选择性。通过去质子化生成的铜（I）-二烯醇盐物种被认为与烯丙基铜（I）物种形成平衡，后者与醛反应，通过醛的催化不对称烯丙基化得到DVAR产物。最后，通过克级反应证明了本反应的稳健性，并通过依折麦布和福司曲星的形式不对称合成展示了本方法的实用性。
