Significance of C-11 Methoxylation in desymmetrization of Cephalostatins

Aiming on targeting cephalostatin 1, a potentially active anti-tumor marine natural product structured as a bis-steroidal pyrazine BSP, significant efforts invested to synthesize a closed structure. Herein, the effect of introducing α-configurated methoxy group at C-11 on the chemistry of symmetrical BSP system is under focus. The significance of directing various reagents either to the methoxy half or to the methoxy-free half of this complicated BSP is highlighted. Several nucleophilic additions as sodium borohydride reduction, carbonyl oximation, nucleophilic addition of hydrazine derivatives and the reaction with Wittig-ylid were directed specifically to the methoxy-free half. However, F-ring opening process as well as hydroboration of ring-D double bond was directed selectively toward the methoxy half. In both cases, these processes led to a chemoselective/specific product. Moreover, the development of a mild demethoxylation reaction to remove the methoxy group, whenever wanted, gives us more ability and flexibility in controlling successive reactions and hence to play in any part of the playground . Both methoxylation and demethoxylation of C-11 are novel approaches applied in the cephalostatin research area. Thus, building up of a multi-step synthetic strategy to achieve the targeted molecule is now more possible.