A bridged backbone strategy enables collective synthesis of strychnan alkaloids

Abstract

Bridged frameworks are of high chemical and biological significance, being ubiquitous in pharmaceutical molecules and natural products. Specific structures are usually preformed to build these rigid segments at the middle or late stage in the synthesis of polycyclic molecules, resulting in decreased synthetic efficiency and target-specific syntheses. As a logically distinct synthetic strategy, we constructed an allene/ketone-equipped morphan core at the outset through an enantioselective α-allenylation of ketones. Experimental and theoretical results revealed that the high reactivity and enantioselectivity of this reaction are attributed to the cooperative effects of the organocatalyst and metal catalyst. The bridged backbone generated was employed as a structural platform to guide and facilitate the assembly of up to five fusing rings, and the allene and ketone groups thereon were used to precisely install various functionalities at C16 and C20 at the late stage, leading to a concise, collective total synthesis of nine strychnan alkaloids.