Rapamycin Nicolaou

Scheme 5.3.6 Approach to the total synthesis of Rapamycin Nicolaou s stitching cyclization ...

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). 

Our general survey of palladium in organic synthesis must now come to an end. At the very least, we hope that our brief foray into this fascinating area conveys some of the vitality that characterizes research in this area. The remainder of this chapter will address the first total synthesis of rapamycin by the Nicolaou group. This work is predicated on a novel variant of the Stille reaction. 

Even if the only difference between the two alkenes is the number of substituents, that can be enough for some reactions. If the substituents are simple alkyl or aryl groups, then the more highly substituted alkene will be the more nucleophilic. This is enough to allow the epoxidation of the trisubstituted alkene in citronellene2 28 while leaving the monosubstituted alkene intact and provide a source of the optically active acid 31 for Nicolaou s synthesis of rapamycin.3... 

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 total synthesis of rapamycin (2) has been accomplished by the Nicolaou [129], Schreiber [130], Danishefsky [131], and Smith [132] groups. 

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). 

The Eschenmoser-Claisen rearrangement has found applications in the synthesis of polyketides as well. Eor instance, in Nicolaou s synthesis of rapamycin, a building block 90 corresponding to the functionalized cyclohexane ring of the nat-... 

Scheme 7.31 The Eschenmoser-Claisen rearrangement in Nicolaou s synthesis of rapamycin.

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... 

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