Total Synthesis of (+)-Calyculin A and (−)-Calyculin B: Cyanotetraene Construction, Asymmetric Synthesis of the C(26−37) Oxazole, Fragment Assembly, and Final Elaboration

Abstract

A convergent total synthesis leading to (+)-calyculin A and (−)-calyculin B (1 and 2), antipodes of the potent, highly selective and remarkably cell-permeable phosphatase inhibitors calyculins A and B, has been achieved. In the preceding paper we outlined the asymmetric synthesis of the C(9−25) spiroketal dipropionate subunit (+)-BC; herein we describe construction of the C(1−8) cyanotetraene, an asymmetric synthesis of the C(26−37) oxazole, fragment assembly and final elaboration to (+)-1 and (−)-2. Highlights of the synthesis include: application of a one-pot three-component Suzuki reaction for the construction of phosphonate A, a bifunctional triene precursor of the light sensitive C(1−8) cyanotetraene subunit, an asymmetric synthesis of the C(26−32) oxazole (−)-D, exploiting the Silks−Odom 77Se NMR protocol to 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 (+)-calyculin A and (−)-calyculin B. The synthesis of (−)-2 also confirms the structure of calyculin B, previously based only on spectral comparison with calyculin A.