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
Alkene metathesis with directly fluorinated alkenes is challenging, limiting its application in the burgeoning field of fluoro‐organic chemistry. A new nickel tris(phosphite) fluoro(trifluoromethyl)carbene complex ([P3Ni]=CFCF3) reacts with CF2=CF2(TFE) or CF2=CH2(VDF) to yield both metallacyclobutane and perfluorocarbene metathesis products, [P3Ni]=CF2and CR2=CFCF3(R=F, H). The reaction of [P3Ni]=CFCF3with trifluoroethylene also yields metathesis products, [P3Ni]=CF2and
- NSF-PAR ID:
- 10067016
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Angewandte Chemie
- Volume:
- 130
- Issue:
- 20
- ISSN:
- 0044-8249
- Page Range / eLocation ID:
- p. 5874-5878
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract 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. -
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t BuSO2)C6H4I) attached in solution and reveal a thus far unknown role of the ArIO oxidant. The HAT reactivity of [(TPA)FeO(X)]+/2+decreases in the order of X: ArIO > MeCN > ArI ≈ TfO−. Hence, ArIO is not just a mere oxidant of the iron(II) complex, but it can also increase the reactivity of the iron(IV)‐oxo complex as a labile ligand. The detected HAT reactivities of the [(TPA)FeO(X)]+/2+complexes correlate with the Fe=O and FeO−H stretching vibrations of the reactants and the respective products as determined by infrared photodissociation spectroscopy. Hence, the most reactive [(TPA)FeO(ArIO)]2+adduct in the series has the weakest Fe=O bond and forms the strongest FeO−H bond in the HAT reaction. -
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t BuSO2)C6H4I) attached in solution and reveal a thus far unknown role of the ArIO oxidant. The HAT reactivity of [(TPA)FeO(X)]+/2+decreases in the order of X: ArIO > MeCN > ArI ≈ TfO−. Hence, ArIO is not just a mere oxidant of the iron(II) complex, but it can also increase the reactivity of the iron(IV)‐oxo complex as a labile ligand. The detected HAT reactivities of the [(TPA)FeO(X)]+/2+complexes correlate with the Fe=O and FeO−H stretching vibrations of the reactants and the respective products as determined by infrared photodissociation spectroscopy. Hence, the most reactive [(TPA)FeO(ArIO)]2+adduct in the series has the weakest Fe=O bond and forms the strongest FeO−H bond in the HAT reaction. -
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