Fully regiocontrolled synthesis of deacetamidoisocolchicine: formal total synthesis of colchicine

Abstract

A 19-step synthesis of deacetamidoisocolchicine 4 has been developed starting from commercially available benzaldehyde 10. Key elements of the strategy used include Robinson annulation of the benzosuberone 15 to produce the tricyclic enone 18 and elaboration of this latter compound to the tetracyclic α-methoxy enone 7a. Base-promoted ring-expansion of 7a then provided the title compound 4, the acquisition of which constitutes a formal total synthesis of the alkaloid colchicine 1. In connection with efforts to optimise the yield of 4, the novel acid-catalysed conversion of 32 into dibenzocyclooctene 35 has been observed. The X-ray crystal structures of compound 35 and the novel dichlorocarbene insertion product 24 are reported.