The Ley Synthesis of Rapamycin

Rapamycin 3 is used clinically as an immimosuppressive agent. The synthesis of 3 (Angew. Chem. Int. Ed. 2007, 591) by Steven V. Ley of the University of Cambridge was based 

The lactone of 1 was prepared by Fe-mediated cyclocarbonylation of the alkenyl epoxide 

The cyclohexane of 2 was constructed by SnCl -mediated cyclization of the allyl stan-nane 9, again employing a procedure developed in the Ley group. Hydroboration delivered the aldehyde 11, which was crotylated with 12, following the H. C. Brown method. The alcohol so produced (not illustrated) was used to direct the diastereoselectivity of epoxida-tion, then removed, to give 13. Coupling with 14 then led to 2. 

Combination of 1 with 2 led to 15, which was condensed with catechol to give the macrocycle 16. Exposure of 16 to base effected Dieckmann cyclization, to deliver the ring-contracted macrolactone 17, which was carried on to (-)-rapamycin 3. 

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