Total synthesis of (+)-calyculin A and (-)-calyculin B: Cyanotetraene construction, asymmetric synthesis of the C(26-37) oxazole, fragment assembly, and final elaboration

A convergent total synthesis leading to (+)-calyculin A and (-)-calyculin B (1 and 2), antipodes of the potent, highly selective and remarkably cell-p ermeable phosphatase inhibitors calyculins A and B, has been achieved. In t he preceding paper we outlined the asymmetric synthesis of the C(9-25) spir oketal dipropionate subunit (+)-BC; herein we describe construction of the C(1-8) cyanotetraene, an asymmetric synthesis of the C(26-37) oxazole, frag ment assembly and final elaboration to (+)-l and (-)-2. Highlights of the s ynthesis include: application of a one-pot three-component Suzuki reaction for the construction of phosphonate A, a bifunctional triene precursor of t he Light sensitive C(1-8) cyanotetraene subunit, on asymmetric synthesis of the C(26-32) oxazole (-)-D, exploiting the Silks-Odom Se-77 NMR protocol t o assess enantiomeric purity, construction of the C(33-37) subtarget (-)-E in a highly stereocontrolled fashion via an acyliminium ion, and a concise, highly efficient sequence for fragment assembly and elaboration to (+)-cal yculin A and (-)-calyculin B. The synthesis of (-)-2 also confirms the stru cture of calyculin B, previously based only on spectral comparison with cal yculin A.