Overman, Limura, Paulini and Zakarian. JACS, 2006, ASAP. DOI: 10.1021/ja0650504.
I seemed to miss this one somewhere, probably in the move from my placement back to Cambridge. Anyway, this is a really nice synthesis of the popular guanacastapene targets (see this smart synthesis by Sorensen), using a unusual and funky Heck cyclisation. This reaction forms the main unifying transformation of the separate fragments, along with a 1,4 organocuparate addition. On with the synthesis!
I really liked this smart use of a Ireland claisen to set the stereochemistry about the quaternary centre in this transformation. The chiral acetate was recieved from a resolution, and with three neat steps they’ve 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, 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 acheived 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 synthesis of guanacastepene A, leaving the group with a intermediate which could lead to many mambers of the guanacastapene family.