Total synthesis of auripyrone A using a tandem non-aldol aldol/Paterson aldol process as a key step.

Extensive NMR investigation of the compounds revealed a complex spiroketal core capped at one end by a tetrasubstituted g-pyrone, residing in an anomerically favored configuration wherein all but the substituents are positioned equatorially except for the C10 methyl and the C11 acyloxy groups. Auripyrones A (1) and B (2) showed cytotoxicity against HeLa S3 cells with IC50 values of 260 and 480 ngmL , respectively. To date one total synthesis of 1 has been reported by Perkins et al., which utilizes an elegant biomimetic cyclization of an acyclic triketone intermediate to generate the spiroketal moiety. The major drawback of this approach, however, is the late-stage formation of the g-pyrone in the presence of the sensitive spiroketal moiety, which proceeded with poor yield (39% based on recovered starting material). Nonetheless, Perkins convergent total synthesis of 1 constitutes the only established synthetic route, and led to the determination of the absolute stereochemistry of the natural product. Herein, we report our convergent approach for the total synthesis of auripyrone A (1) as a single diastereomer in high chemical yield. In our retrosynthetic analysis (Scheme 1), the sensitive spiroketal moiety of 1 could be derived from a late-stage cyclization of the C17 ketone onto the hemiketal 3, which should be available from the aldolate 4. The key intermediate 4 could be obtained from a fully matched double stereodifferentiating anti-aldol reaction of the boron enolate of the ketone 6 with the aldehyde 5. The g-pyrone moiety of 5 would result from the aldehyde 7 by using the protocol of Gillingham and Hoveyda. Finally, the stereopentad 7 was envisioned to arise from the known epoxide 8 by a novel tandem non-aldol aldol/Paterson-lactate-derived aldol reaction with the ketone 9. The synthesis commenced with the assembly of 7, using a highly convergent tandem non-aldol aldol/Paterson-lactatederived aldol reaction (Scheme 2). Epoxidation of the allylic alcohol 10 (synthesized in five steps from (S)-Roche ester), under either reagent controlled Sharpless conditions or substrate controlled reaction conditions with mCPBA, furnished the epoxide 8 in 85% yield and 20:1 diastereomeric ratio (d.r.), or 90% yield and 16:1 d.r., respectively. Protection of 8 with TESCl provided the corresponding silyl ether which was then treated with TESOTf at 45 8C to give, by the non-aldol aldol reaction, the syn-aldol adduct 11 in 86% yield and 20:1 d.r. Unlike conventional auxiliary-based aldol methods which require a protection step and subsequent removal of the chiral auxiliary to generate the protected aldehyde, the Figure 1.