Final Stages and Cyclization to Rapamycin

(a) Sonogashira, K. Tohda, Y. Hagihara, N. Tetrahedron Lett. 1975, 4467 (b) Sonogashira, K. In Comprehensive Organic Synthesis, Trost, B. M. Fleming, 

The Logic of Chemical Synthesis, John Wiley Sons New York, 1989. 

Greene, T. W. Wuts, P. G.M. Protective Groups in Organic Synthesis, John Wiley Sons New York, 1991, p. 329. 

The mechanism for the transformation of 5 to 4 was not addressed. However, it seems plausible that samarium diiodide accomplishes a reduction of the carbon-chlorine bond to give a transient, resonance-stabilized carbon radical which then adds to a Smni-activated ketone carbonyl or combines with a ketyl radical. Although some intramolecular samarium(n)-promoted Barbier reactions do appear to proceed through the intermediacy of an organo-samarium intermediate (i.e. a Smm carbanion),10 ibis probable that a -elimination pathway would lead to a rapid destruction of intermediate 5 if such a species were formed in this reaction. Nevertheless, the facile transformation of intermediate 5 to 4, attended by the formation of the strained four-membered ring of paeoniflorigenin, constitutes a very elegant example of an intramolecular samarium-mediated Barbier reaction. 

The completion of the synthesis of 1 only requires two deprotection steps. Hydrogenolysis of the four benzyl ethers, followed by cleavage of the triisopropylsilyl ether with hydrofluoric acid in acetonitrile, provides paeoniflorin (1) in an overall yield of 92 %. 

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