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Totally Synthetic by Paul H. Docherty, 28 September 2006

Total Synthesis of Guanacastepene N


S. Iimura, L. E. Overman, R. Paulini, A. Zakarian, J. Am. Chem. Soc. 2006, 128, 13095-13101.

DOI: 10.1021/ja0650504

This is a really nice total synthesis of the popular guanacastapene targets (see this smart synthesis by Sorensen), using a unusual Heck cyclisation. This reaction forms the main unifying transformation of the separate fragments, along with an organocuparate 1,4-addition. On with the synthesis!

I really liked this smart use of a Ireland-Claisen rearrangement to set the stereochemistry about the quaternary centre in this transformation. The chiral acetate was received from a resolution, and with three neat steps they have already set a stereochemistry of a complex centre. Conversion of the alcohol to an iodide left them with a coupling partner for the 5-member ring in 69% over four steps, and into the raison d’etre:

Doing an unusal 7-endo-Heck reaction, through an eclipsed insertion topography, allowed then to access the 7-member ring in a good yield. The 6-exo process is stereochemically impossible, as the required geometry forces the methyl group into the five-member ring, so the desired product and process prevails completely, completing the carbocyclic skeleton of the natural product. Interestingly, they achieved a better yield of the methyl ester analogue, but were unable to cleave the ester, so had to resort to the benzyl ester shown.

Elaboration of this structure was completed in a fashion similar to that used by Danishefsky in his total synthesis of guanacastepene A, leaving the group with a intermediate which could lead to many members of the guanacastapene family.