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Abstract Sanglifehrin A and B are immunosuppressive macrocyclic natural products endowed with and differentiated by a unique spirocyclic lactam. Herein, we report an enantioselective total synthesis and biological evaluation of sanglifehrin A and B and analogs. Access to the spirocyclic lactam was achieved through convergent assembly of a key pyranone intermediate followed by a stereo‐controlled spirocyclization. The 22‐membered macrocyclic core was synthesized by ring‐closing metathesis in the presence of 2,6‐bis(trifluoromethyl) benzeneboronic acid (BFBB). The spirocyclic lactam and macrocycle fragments were united by a Stille coupling to furnish sanglifehrin A and B. Additional sanglifehrin B analogs with variation at the C40 position were additionally prepared. Biological evaluation revealed that the
2‐CF3 analog of sanglifehrin B exhibited higher anti‐proliferative activity than the natural products sanglifehrin A and B in Jurkat cells. Both natural products induced higher‐order homodimerization of cyclophilin A (CypA), but only sanglifehrin A promoted 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. -
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Abstract Sanglifehrin A and B are immunosuppressive macrocyclic natural products endowed with and differentiated by a unique spirocyclic lactam. Herein, we report an enantioselective total synthesis and biological evaluation of sanglifehrin A and B and analogs. Access to the spirocyclic lactam was achieved through convergent assembly of a key pyranone intermediate followed by a stereo‐controlled spirocyclization. The 22‐membered macrocyclic core was synthesized by ring‐closing metathesis in the presence of 2,6‐bis(trifluoromethyl) benzeneboronic acid (BFBB). The spirocyclic lactam and macrocycle fragments were united by a Stille coupling to furnish sanglifehrin A and B. Additional sanglifehrin B analogs with variation at the C40 position were additionally prepared. Biological evaluation revealed that the
2‐CF3 analog of sanglifehrin B exhibited higher anti‐proliferative activity than the natural products sanglifehrin A and B in Jurkat cells. Both natural products induced higher‐order homodimerization of cyclophilin A (CypA), but only sanglifehrin A promoted 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.
