Total synthesis of (-)-Crinipellin A

Abstract

Crinipellins are presently the only group of natural products having unique tetraquinane framework, a combination of linear and angular triquinane moieties, isolated from cultures of the basidiomycete Crinipellis stipitaria in 1985. Each of these highly oxygenated substances contains at least eight contiguous stereogenic centers, three of which are quaternary chiral carbon atoms. Three members of this group, Crinipellin A, O-Acetylcrinipellin A, and Crinipellin B, each of which contains an α-methylidenecyclopentanone moiety, exhibit strong antibiotic activity. The structural uniqueness and interesting biological activity make crinipellins attractive target for synthesis. Although there have been a lot of synthetic approaches to crinipellins, because of its unprecedented structural features, there has been only one report of the total synthesis and one formal synthesis of crinipellin B in racemic form. Recently, we developed a tandem reaction strategy for forming triquinanes from linear allenyl diazo compounds through an intramolecular 1,3-dipolar cycloaddition reaction of an allenyl diazo group that generates a trimethylenemethane (TMM) diyl followed by an intramolecular [2+3] TMM diyl cycloaddition reaction. The intramolecular cycloaddition reaction of TMM diyl was successfully utilized in construction of unique tetraquinane core structure of crinipellins, which extended the scope of the tandem cycloaddition reaction via TMM diyl to more complex and more challenging structures. Application of extended TMM cycloaddition strategy to the assembly of natural products was also successful. Formal asymmetric synthesis of crinipellin B and the first asymmetric total synthesis of crinipellin A have been accomplished. The unique tetraquinane structure of crinipellins was constructed efficiently through cycloaddition reaction of TMM diyl. For asymmetric synthesis, we developed the several methods to prepare the chiral intermediates for cycloaddition reaction through ...