Synthesis of the Tricyclic Core of Colchicine via a Dienyne Tandem Ring-Closing Metathesis Reaction

Link: Org Lett ASAP

François-Didier Boyer and Issam Hanna*

Unité de Chimie Biologique, AgroParisTech, INRA, F-78026 Versailles, and Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France

This paper presented a very neat use of RCM and quite clever strategy to construct the 7,7-fused core of colchicine. For the first time, the 7,7-fused bicyclic system could be accessed very quickly in a single step. This main strategy is summarized in the retrosynthetic analysis below.

Therefore, substrate 4 was needed for the RCM step and it was constructed according to the following scheme.

The key reactions were formylation of 6 mediated by SnCl4 to give 7 and the synthesis of propargylic alcohol 14 which was achieved in three steps from 5, using the Ohira-Bestman reagent in the last step.

Next, sequential RCM reactions were performed on 14 using Grubbs' second generation catalyst (15) after the protection of the OH group with TMS. The reaction proved to be very efficient, providing the desired 16 in 74% yield from 14.

This intermediate 16 was further elaborated as shown in Scheme 4 via oxidative rearrangement. Compound 18 could be obtained in high yield. However, going along a more well-known route of previous total syntheses of colchicine, intermediate 19 could be obtained in modest yield, along with 20, from 17. This latter route effectively constituted a formal synthesis of colchicine. The final completion of this molecule by a novel sequence is currently under investigation.

Overall, the double RCM (enyne RCM and RCM) in constructing the 7,7-core of colchicine presented in this paper is quite ingenius.