Graduate School of Pharmaceutical Sciences and Research Center for Materials Science, Nagoya University, Chikusa, Nagoya, 464-8601, Japan.
Interdisciplinary Research Center for Catalytic Chemistry, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, 305-8565, Japan.
Nat Commun. 2022 Oct 12;13(1):5876. doi: 10.1038/s41467-022-33432-4.
α-Alkylation of a β-keto ester is a frequently used reaction for carbon-carbon bond formation. However, extension to a stereoselective reaction remains a significant challenge, because the product easily racemizes under acidic or basic conditions. Here, we report a hybrid system consisting of Pd and Ru complexes that catalyzes the asymmetric dehydrative condensation between cinnamyl-type allylic alcohols and β-keto esters. α-Non-substituted β-keto ester can be allylated to afford an α-mono-substituted product with high regio-, diastereo-, and enantioselectivity. No epimerization occurs owing to the nearly neutral conditions, which is achieved by a rapid proton transfer from Pd-enolate formation to Ru π-allyl complex formation. Four diastereomers can be synthesized on demand by changing the stereochemistry of the Pd or Ru complex. Eight stereoisomers with three adjacent stereogenic centers can be synthesized by employing diastereoselective reduction of the ketone in the products. The formal synthesis of (+)-pancratistatin demonstrates the utility of the reaction.
α-酮酯的α-烷基化反应是一种常用的碳-碳键形成反应。然而,将其扩展为立体选择性反应仍然是一个重大挑战,因为在酸性或碱性条件下,产物很容易外消旋化。在这里,我们报告了一种由 Pd 和 Ru 配合物组成的杂化体系,该体系可以催化肉桂型烯丙醇与β-酮酯之间的不对称脱水缩合反应。α-未取代的β-酮酯可以进行烯丙基化反应,以高区域选择性、非对映选择性和对映选择性得到α-单取代产物。由于反应条件接近中性,不会发生外消旋化,这是通过 Pd-烯醇化物形成到 Ru π-烯丙基配合物形成的快速质子转移来实现的。通过改变 Pd 或 Ru 配合物的立体化学,可以按需合成四种非对映异构体。通过对产物中酮的立体选择性还原,可以合成具有三个相邻手性中心的 8 个立体异构体。(+)-pancratistatin 的形式合成证明了该反应的实用性。