Overcoming Difficulties in Total Synthesis of (+)-Cotylenin A

Abstract

The total synthesis of the natural product cotelynin A, which exhibits promising anti-cancer activity, is urgently required, as its source, Cladosporium sp. 501-7W, has lost its proliferative ability. Herein, we report the first total synthesis of cotelynin A. Contiguous asymmetric carbons at the C8 and C9 positions in the B-ring of the aglycon moiety of cotylenin A are difficult to construct after the formation of the B-ring via pinacol coupling. The revised synthesis of the aglycon moiety involved the alkenylation of a methyl ketone to construct the B-ring; for this convergent synthesis, one fragment was prepared using our catalytic asymmetric intramolecular cyclopropanation, and the other fragment was obtained via the acyl radical cyclization of a known aldehyde, which was prepared by sharpless asymmetric epoxidation of geraniol and subsequent rearrangement. Radical generation using a copper catalyst and TBHP was effective for an acyl radical cyclization. The two prepared fragments were then assembled via Utimoto coupling. The α-hydroxyketone at the C8-C9 position was stereoselectively reduced with Me4NBH(O2CiPr)3, which was newly prepared in this study, and led to the successful construction of the C8-C9 1,2-diol. A structurally unprecedented sugar moiety was synthesized for the first time by terminating successive reversible acetalizations with an irreversible epoxide ring-opening reaction. Although the glycosylation of the synthesized fragments proceeded with difficulty owing to steric hindrance around the C9 hydroxy group of the aglycone, the desired product was successfully obtained under the reaction conditions reported by Wan et al.