Enantioselective Synthesis of Borrelidin

There are two criteria forjudging any total synthesis the importance of the molecule that has been prepared, and the creativity evidenced in the synthetic route. When the natural product has Only two rings, as with borrelidin 1, the standards are even higher. The enantioselective total synthesis of borrelidin by Jim Morken of the University of North Carolina (J. Am. Chem. Soc. 125 1458, 2003) more than exceeds those standards. 

Borrelidin 1 has attracted attention because it inhibits angiogenesis, and so potentially blocks tumor growth, with an IC., of 0.8 nM. Retro.synthetic analysis of 1 led the investigators to the prospective intermediates 2 and 3. To assemble these two fragments, they interatively deployed the elegant enantio- and diastereoselective intermolecular reductive ester aldol condensation that they had recently developed. This transformation is exemplified by the homologation of 4 to 6 catalyzed by the enantiomerically-pure Ir complex 5. 

The final stages of the synthesis illustrate both the power and the current limitations of transition-metal mediated C-C bond formation. Coupling of 2 and 3 led to the ene-yne 7. Pd-mediated hydrostannylation of the alkyne proceeded with high geometric control, but tended to 

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