Rapamycin, total synthesis

The imposing structure and potential medicinal importance of rapamycin provide a strong impetus for the development of an efficient path by which a total synthesis can be achieved. At present, the chemical literature is replete with interesting synthetic studies that focus on various features of the rapamycin molecule. These undertakings provide salient testimony to the excitement that this natural product has generated. Rapamycin has already succumbed to four distinct and instructive total syntheses 5 8 this chapter will... 

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. 

The recently published total synthesis of rapamycin involves several steps in which TPAP was used under a variety of conditions [173]. 

Maddess Matthew L, Tackett Miles N et al (2007) Total synthesis of rapamycin. Angew Chem Int Ed 46 591-597... 

Hayward CM, Yohannes D et al (2002) Total synthesis of rapamycin via a novel titanium-mediated aldol macrocyclization reaction. J Am Chem Soc 115 9345-9346... 

Anderson JC, Ley SV et al (1994) Studies towards the total synthesis of rapamycin a convergent and stereoselective synthesis of the C22-C32 carbon framework. Tetrahedron Lett 35 2087-2090... 

One total synthesis of rapamycin has been mentioned above a second has been reported... 

S.L. Schreiber and co-workers accomplished the total synthesis of (-)-rapamycin. In their approach, they utilized an Evans-Tishchenko reaction of C22-C42 fragment and Boc pipecolinal. The reaction provided the product with excellent yield and as a >20 1 mixture of the anti and syn diastereomers. 

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

In Section II, the synthetic strategies for macrolide synthesis are introduced and focus in particular on asymmetric synthesis of 1,3-diol, synthetic methodology for macrolactone, and glycosidation. In Section III, the total synthesis of selected macrolide antibiotics is introduced FK506 (tacrolimus 1), rapamycin (sirolimus 2), avermectins (3), altohyrtins (spongistatins 4), and epothilones (5) (Fig. 1). Several other synthesized macrolides are also illustrated. 

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 total synthesis of rapamycin (2) by Schreiber et al. was accomplished via unique Sml2-mediated attachment of pipecolic acid to the C22-C42 segment, subsequent coupling with the C10-C21 segment, addition of a glycolate derivative at CIO, and macrolactamization. The C9 methylene was finally oxidized to ketone (Fig. 6). 

The completion of the total synthesis is described in Scheme 47. The HW reaction of phosphine oxide 320 and 314 efficiently afforded ( )-triene 321. After hydrolysis of dimethyl acetal in 321 followed by aldol reaction, macro-lactamization was carried out under Mukaiyama macrocyclization conditions to give an 1 1 mixture of diastereomers 322. Removal of three allylcarbonates followed by treatment with the Dess-Martin reagent resulted in oxidation of the three alcohols and subsequent oxidation of the C9 methylene. Final deprotection of the resulting tetraketone with HF-py completed the total synthesis of rapamycin (2). 

The Smith group has also achieved the total synthesis of rapamycin (2) and demethoxyrapamycin (Fig. 6). Their total synthesis of 2 features aldol reaction of acetylpipecolic acid and the C10-C20 segment, esterification with the C21-C42 segment, and final Stille macrocyclization at the C20 and C21 positions. 

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). 

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