Enantioselective Synthesis and Biological Evaluation of Sanglifehrin A and B and Analogs

Abstract

Sanglifehrin Aa nd Ba re immunosuppressive macrocyclic natural products endowed with and differentiated by au nique spirocyclic lactam. Herein, we report an enantioselective total synthesis and biological evaluation of sanglifehrin Aand Band analogs.Access to the spirocyclic lactam was achieved through convergent assembly of ak ey pyranone intermediate followed by as tereo-controlled spirocyclization. The 22-membered macrocyclic core was synthesized by ringclosing metathesis in the presence of 2,6-bis(trifluoromethyl) benzeneboronic acid (BFBB). The spirocyclic lactam and macrocycle fragments were united by aS tille coupling to furnish sanglifehrin Aa nd B. Additional sanglifehrin B analogs with variation at the C40 position were additionally prepared. Biological evaluation revealed that the 2-CF 3 analog of sanglifehrin Be xhibited higher anti-proliferative activity than the natural products sanglifehrin Aand BinJ urkat cells. Both natural products induced higher-order homodimerization of cyclophilin A( CypA), but only sanglifehrin Ap romoted CypA complexation with inosine-5'-monophosphate dehydrogenase 2( IMPDH2). The synthesis reported herein will enable further evaluation of the spirolactam and its contribution to sanglifehrin-dependent immunosuppressive activity.