Chapter 4 Total synthesis of kainoids by dearomatizing anionic cyclization

Abstract

This chapter discusses the use of cyclization in the synthesis of the members of the kainoid family. The kainoids are pyrrolidine-dicarboxylic acids. The parent member of the family is kainic acid. One of their most important features that has made them more of a synthetic challenge than they would otherwise have been is the cis relative stereochemistry of the two substituents. Several previous syntheses of kainoids incorporate this cis stereochemistry by tying the two groups into a ring during the synthesis. The chapter details the structural and mechanistic features of cyclization. Best yields are obtained from benzamides when the organolithium is formed under the conditions that promote cyclization, because then the anion forms trans to oxygen by translocation from the ortho position cyclizes before it has an opportunity to translocate a second time to the position syn to oxygen. The initial product of the cyclization reaction is an extended enolate from the naphthamides and from the benzamides. The chapter details the reasons for avoiding hexamethylphosphoramide (HMPA)—lithium diisopropylamide (LDA)—as a cyclization promote. It also discusses asymmetric cyclization with chiral lithium amides and stereospecific cyclization of chiral benzamides.