内酸酐去对称化方法合成多羟基环己基β-氨基酸手性中间体

A Desymmetrization Approach for the Synthesis of a Key Chiral Intermediate for Polyhydroxy Cyclohexyl β-amino Acid Derivatives

多羟基环己基手性β-氨基酸及其衍生物具有重要的药物、生物和合成用途.本文报道以廉价的内消旋cis-1,2,3,6-四氢邻苯二甲酸酐为起始原料,以奎宁为手性试剂,通过去对称化、Curtius重排和醇解以及分子内立体选择性碘内酯化和消除反应等五步反应,以近40%的总产率简捷地合成光学活性多羟基环己基β-氨基酸的关键中间体.

Carboxycyclic polyhydroxy β-amino acids are a group of both naturally occurring and synthetic compounds with interesting biological and pharmacological activities. They have also been widely used as starting materials or intermediates for the preparation of heterocycles,natural products or their analogues and for drug development. Therefore the synthesis and biological studies of carbocyclic polyhydroxy β-amino acids have attracted increasing attention in recent years. Optical active cyclohexenyl（or dienyl）β-amino acids are important chiral intermediates for the synthesis of cyclohexyl polyhydroxy β-amino acids. This paper describes the synthesis of a key chiral cyclohexenyl β-amino acid derivative（9）for this purpose. The synthesis of the intermediate was achieved by quinine induced desymmetrization of cis-1, 2,3,6-tetrahydrophthalic acid to give the monoester（5）in 93 % yield and 〉 93 % ee. One pot Curtius rearrangement followed by alcoholysis with benzyl alcohol afforded the carbamate（6）in 83 % yield. Saponification of the methyl ester in（7） ,followed by iodo-lactonization and final elimination gave the desired cyclohexenyl β-amino acid derivative（9）in 40% overall yield in 5 steps. This intermediate has been converted into a few cyclohexyl polyhydroxy β-amino acids,which will be reported in due course.