Rapamycin, Stille coupling

A distinguishing feature of the Nicolaou synthesis of rapamycin is the use of a palladium-mediated tandem inter-/intramolecular Stille coupling to construct rapamycin s 31-membered macrolide ring and conjugated triene moiety. This maneuver was unprecedented in the macrolide field,9 and it can be applied to a fully deprotected seco substrate (vide infra). 

The most spectacular application of the Stille reaction is represented by the final step of Nicolaou s elegant total synthesis of rapamycin (2) (see Section III.B), in which a tandem Stille coupling is carried out on the fully functionalized skeleton. 

The first total synthesis of rapamycin (2) was accomplished by Nicolaou et al. in 1993. The synthetic feature includes esterification of the C34 hydroxyl group of the C21-C42 segment with pipecolic acid, amide formation with the C8-C18 segment, and extremely novel macrocyclization by double Stille coupling using vinyl stannane at the Cl8 and C21 positions (Fig. 6). 

Coupling of two segments 360 and 367 by EDC-DMAP-induced esterification gave 368 (Scheme 53). The macrocyclization of 368 was effectively achieved by intramolecular Pd-mediated Stille coupling in 74% yield. Final desilylation completed the total synthesis of rapamycin (2). 

This tremendous substrate tolerance is very significant for natural-product synthesis. In a synthesis of rapamycin 2.160, a double Stille coupling was used to close the macrocycle in the last step after all of the deprotections had been carried out (Scheme 2.51). Other no protecting group Stille couplings are in syntheses of manumycin 2.163 (Scheme 2.52) " and indanomycin (Scheme 2.53). ... 

SCHEME 1 Last step of a total synthesis of rapamycin by Nicolaou et al7 It features sequential Stille couplings of the frara-configured ethene-l,2-distannane trans-9. Its coupling partners are two constitutionally different iodoalkene moieties of substrate 12. 

As mentioned already in the description, the Stille coupling is one of the most powerful and reliable tool available to synthetic chemists to form a sigma carbon carbon bond (C(Sp ) C(sp ) or C(sp ) C(Sp )). There are countless examples reported in literature over the past 30 years. Not only this reaction found an abundant application in the synthesis of small molecules but it has also been widely used in total syntheses of complex natural products sometimes as a key step The stitching approaches used by the Nicolaou and Danishefsky groups to respectively close at a late stage of the synthesis the 29-membered ring macrocycle found in rapamycin, and to... 

---