美国普渡大学Mingji Dai团队报道了催化作用下三环前列腺素D2代谢物甲酯的简洁立体选择性全合成策略。相关研究成果于2021年12月6日发表于国际一流学术期刊《德国应用化学》。

该文报告了从现成的已知环戊烯二醇衍生物经8个步骤完成临床相关的外消旋形式三环前列腺素D 2代谢物（三环PGDM）甲酯的简明和立体选择性全合成。该合成具有镍催化的Ueno-Stork型二碳官能化以生成两个连续的立体中心，钯催化的羰基螺内酯化以构建核心恶烷吡咯内酯，以及Z-选择性交叉复分解以引入（Z）-3-丁烯酸酯侧链，通过传统的Wittig协议引入的团队具有挑战性，并且对于之前的两次全合成来说很麻烦。

该文还开发了一种通用的Z-选择交叉复分解方案来构建（Z）-β，γ-不饱和酯，其具有广泛的官能团耐受性和高立体选择性。此外，该合成已经积累了75 mg有价值的材料，用于临床炎症的¹⁸O三环-PGDM分析。

附：英文原文

Title: Catalysis-Enabled Concise and Stereoselective Total Synthesis of the Tricyclic Prostaglandin D2 Metabolite Methyl Ester

Author: Mingji Dai, Hunter S. Sims, Pedro de Andrade Horn, Ryota Isshiki, Melissa Lim, Yan Xu, Robert H. Grubbs

Issue&Volume: 2021-12-06

Abstract: A concise and stereoselective total synthesis of the clinically relevant tricyclic prostaglandin D  2  metabolite (tricyclic-PGDM) methyl ester in racemic form was accomplished in 8 steps from a readily available known cyclopentene-diol derivative. The synthesis features a nickel-catalyzed Ueno-Stork-type dicarbofunctionalization to generate two consecutive stereocenters, a palladium-catalyzed carbonylative spirolactonization to build the core oxaspirolactone, and a  Z  -selective cross metathesis to introduce the (  Z  )-3-butenoate side chain, a group challenging to introduce through traditional Wittig protocols and troublesome for the two previous total syntheses. A general  Z  -selective cross metathesis protocol to construct (  Z  )-β,γ-unsaturated esters was also developed that has broad functional group tolerance and high stereoselectivity. Additionally, our synthesis already accumulated 75 mg of valuable material for an  18  O tricyclic-PGDM based assay used in clinical settings for inflammation.

DOI: 10.1002/anie.202115633

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202115633