Rapamycins

A number of fungal immunosuppressives have been isolated from fermentation broths and demonstrated to have immunotherapeutic efficacy. Other than cyclosporin (35), two fungal metaboHtes, sirolimus (36), previously known as rapamycin (80), and FK-506 (37) (81) are in various stages of development (see Antibiotics, macrolides). 

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... 

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. 

The X-ray crystal structure of rapamycin reveals the constitution of the major isomer, compound 1, although in solution at least four isomers are detectable. The most abundant isomers are 1 (major) and the isomeric seven-membered hemiketal (mixture of stereoisomers). For the purposes of this chapter, we will restrict ourselves to structure 1. 

The optically active iodide 153 (Scheme 43) can be conveniently prepared from commercially available methyl (S)-(+)-3-hydroxy-2-methylpropionate (154) (see Scheme 41). At this stage of the synthesis, our plan called for the conversion of 153 to a nucleophilic organometallic species, with the hope that the latter would combine with epoxide 152. As matters transpired, we found that the mixed higher order cuprate reagent derived from 153 reacts in the desired and expected way with epoxide 152, affording alcohol 180 in 88% yield this regioselective union creates the C12-C13 bond of rapamycin. 

The oxirane ring in 175 is a valuable function because it provides a means for the introduction of the -disposed C-39 methoxy group of rapamycin. Indeed, addition of CSA (0.2 equivalents) to a solution of epoxy benzyl ether 175 in methanol brings about a completely regioselective and stereospecific solvolysis of the oxirane ring, furnishing the desired hydroxy methyl ether 200 in 90 % yield. After protection of the newly formed C-40 hydroxyl in the form of a tert-butyldimethylsilyl (TBS) ether, hydrogenolysis of the benzyl ether provides alcohol 201 in 89 % overall yield. 

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