Synthesis of the northern sector (C8–C19) of rapamycin via Chan rearrangement and oxidation of an α-acyloxyacetate
Graphical abstract
Introduction
In 1975, a substance named rapamycin (1) was isolated from the soil fungus Streptomyces hygroscopicus during a search for naturally occurring antifungal agents.1, 1(a), 1(b) Although the antifungal properties of 1 were not particularly impressive, it later became apparent that rapamycin was a potent immunosuppressant2 with a mode of action similar to a related Streptomyces metabolite FK-506 (2).3, 3(a), 3(b) Both 1 and 2 were studied as prospective therapeutic agents for treatment of graph rejection that accompanies organ and tissue transplantation, and rapamycin is known to be particularly effective in suppressing the immune response with relatively few side effects. The ability of 1 to prevent the formation of antibodies against cell surface antigens of transplanted tissue has placed it at the forefront of medical practice in the area of organ transplantation and rapamycin is now a recognized drug in combination with cyclosporine A for treatment of host vs graft disease.4
The pipecolic keto amide sector of the rapamycin and FK-506 structures plays an important role as a peptidomimetic when these immunosuppressants are bound to certain cytosolic enzymes (immunophilins). Specifically, the rapamycin–immunophilin complex acts as a prolyl cis–trans isomerase5 in which the C1–C10 segment of 1 mimics the transition state of a bound proline-containing peptide.6 This results in inhibition of at least three protein kinases and interferes with a signaling pathway that originates in the interleukin-2 receptor.7 Thus, the functionality present in the terminal portion of this ‘northern’ domain of 1 is a pivotal component of the architecture of this macrolide.
In addition to efforts directed toward clarifying the mode of action of rapamycin and FK-506,8, 8(a), 8(b) a large number of synthetic studies on these immunosuppressive agents has been carried out. These investigations have resulted in five total syntheses of rapamycin9, 9(a), 9(b), 9(c), 9(d), 9(e), 9(f) and three of FK-506,10, 10(a), 10(b), 10(c), 10(d), 10(e), 10(f) as well as numerous publications reporting approaches to the tricarbonyl subunits of 1 and 2.11, 11(a), 11(b), 11(c), 11(d), 11(e), 11(f), 11(g), 11(h), 11(i), 11(j)
Integral to any strategy for assembling the ‘northern’ (C8–C19) subunit of 1 is the correct installation of stereocenters at C11, 14 and 16. Additionally, connection of this sector to a second major subunit at C19–C20 requires placement of a functionalized trisubstituted (E) alkene at C17–C18. With these prerequisites in mind, a plan was conceived for synthesis of the C8–C19 portion 3 of rapamycin that envisioned this segment of the molecule as the acylation–hydrolysis product from dithiane 4 and dimethyl oxalate (Scheme 1). Precedent for this strategy existed in Corey's synthesis of aplasmomycin,12 a macrolide that contains a borate-complexed 2,7-dihydroxy-3-ketolactone masked as a cyclic hemiketal. Dithiane 4 was foreseen as emanating from a 2,4,5-trihydroxypentanal 5 whose (2R,4S) configuration would originate in d-xylose (6). As it happened, this approach to 3 failed and a second generation plan was devised that employed 4 in a manner different from the approach projected in Scheme 1. Specifically, dithiane 4 was advanced to an α-acyloxy acetate designed to undergo base-mediated (Chan) rearrangement to a conjugated enediolate which, upon subsequent epoxidation, would yield an α,β-diketo ester.
Section snippets
First generation approach via acylation of a dithiane
The known diol 7, prepared in two steps from d-xylose (6),13 was selectively esterified at the primary alcohol with pivaloyl chloride14 to give 8 from which the residual secondary hydroxyl group was excised by reduction of xanthate 9 with tri-n-butylstannane (Scheme 2).15 Although hydrolysis of acetonide 10 proceeded cleanly to diol 11, attempts to homologate the open form of this cyclic hemiacetal by means of Wittig olefination were unsuccessful. The apparent sensitivity of 11 towards basic
Conclusion
We have shown that an α-acyloxy ester bearing the three stereocenters corresponding to C11, 14 and 16 of rapamycin undergoes rearrangement and subsequent oxidation to provide the masked tricarbonyl unit embedded in the C8–C19 portion of 1. The congested functional groupings in this sector of rapamycin limit practical approaches to its synthesis, but internal reorganization of a substrate such as 62 is a viable strategy for gaining access to this important domain of the immunosuppressant. The
Acknowledgements
We are indebted to Professor Steven Ley and Michael Willis, Cambridge University, for 1H and 13C NMR spectra of 37. This research was assisted financially by the National Institutes of Health through Grant No. GM50574.
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