Rapamycin, synthesis

Gu J, Ruppen ME, Cai P. (2005) Lipase-catalyzed regioselective esterification of rapamycin Synthesis of temsirolimus (CCl-779). Org Lett 7 3945-3948. 

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 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. 

White and Deerberg explored this reaction system in connection with the synthesis of a portion of the structure of rapamycin.165 Better yields were observed from benzyloxy than for a methoxy substituent, and there was a slight enhancement of stereoselectivity with the addition of ERG substituents to the benzyloxy group. 

A striking example of a macrocyclic closure is found in the double stitching done in the final step of the synthesis of the immunosuppressant rapamycin. Bis-1,2-(tri-n-butylstannyl)ethene reacted with the diiodide to close a 31-membered ring in 28% yield at 70% conversion. The intermediate iodostannane (from a single coupling) was also isolated in about 30% yield and could be cyclized in a second step.210... 

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

Many antibiotics, which inhibit protein synthesis, do not bind to ribosomes but block any of a variety of vital chemical processes needed for growth. Among them are pseudomonic acid, which inhibits isoleucyl-tRNA synthetase from many gram-positive bacteria.1111/VV Rapamycin, best known as an immunosuppressant (Box 9-F), inhibits phosphoinositide-3-kinase and also phosphorylation of the cap-binding protein 4G, a component of the eukaryotic initiation factor complex (Fig. 29-11 ).ww The bacterial enzyme peptide deformylase, which is absent from the human body, has been suggested as a target for design of synthetic antibiotics. 01... 

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... 

Cao W, Mohacsi B Shorthouse R, Pratt R, Morris RE. Effects of rapamycin on growth factor-stimulated vascular smooth muscle cell DNA synthesis, Inhibition of basic fibroblast growth factor and platelet-derived growth factor action and antagonism of rapamycin by FK506, Transplantation 1995 3 390-395. 

Morris RE, Cao W, Huang X, et al, Rapamycin (Sirolimus) inhibits vascular smooth muscle DNA synthesis in vitro and... 

Studies on the exact mode of action of the unmodified sanglifehrin A (1) by Liu et al. found that 1 inhibits the T cell cycle (G1 phase), mediated by activation of the tumor suppressor gene p53 [21]. Sanglifehrin A (1) is a novel immunosuppressant, which, in addition to CsA, FK506, and rapamycin, represents a fourth class of immunophilin-binding metabolites with a new, as yet undefined mechanism of action [22]. The structural variation now accessible through total and partial synthesis should contribute to understanding of its bio-... 

Sadoshima, J.-I., and Izumo, S. 1995. Rapamycin selectively inhibits angiotensin Il-induced increase in protein synthesis in cardiac myocytes in vitro potential role of 70-kD S6 kinase in angiotensin Il-induced cardiac hypertrophy. Circ. Res. 77 1040-1052. 

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