Interphylal Product Splicing:  The First Total Syntheses of Cephalostatin 1, the North Hemisphere of Ritterazine G, and the Highly Active Hybrid Analogue, Ritterostatin G_N1_N¹

Abstract

Convergent total syntheses of the extremely potent cell growth inhibitor cephalostatin 1 and two hybrid analogues, ritterostatins G N 1 N and G N 1 S, have been achieved. Ritterostatin G N 1 N displays sub-nanomolar activity in the 60 cell line human tumor panel of the National Cancer Institute. The North hemisphere of ritterazine G was efficiently constructed from hecogenin acetate in 15% yield over 13 steps. Extension of a key photolysis/Prins sequence to intermediates 19 and 32 proceeded in excellent yield, leading to installation of the Δ 14 moiety in the North G and South 1 steroidal subunits. Application of a method for directed unsymmetrical coupling furnished the natural and analogue pyrazines in good yield from the cephalostatin and ritterazine components.