TY - JOUR
T1 - Cyclopropanations via Heme Carbenes
T2 - Basic Mechanism and Effects of Carbene Substituent, Protein Axial Ligand, and Porphyrin Substitution
AU - Wei, Yang
AU - Tinoco, Antonio
AU - Steck, Viktoria
AU - Fasan, Rudi
AU - Zhang, Yong
N1 - Publisher Copyright:
© 2017 American Chemical Society.
PY - 2018/2/7
Y1 - 2018/2/7
N2 - Catalytic carbene transfer to olefins is a useful approach to synthesize cyclopropanes, which are key structural motifs in many drugs and biologically active natural products. While catalytic methods for olefin cyclopropanation have largely relied on rare transition-metal-based catalysts, recent studies have demonstrated the promise and synthetic value of iron-based heme-containing proteins for promoting these reactions with excellent catalytic activity and selectivity. Despite this progress, the mechanism of iron-porphyrin and hemoprotein-catalyzed olefin cyclopropanation has remained largely unknown. Using a combination of quantum chemical calculations and experimental mechanistic analyses, the present study shows for the first time that the increasingly useful C-C functionalizations mediated by heme carbenes feature an FeII-based, nonradical, concerted nonsynchronous mechanism, with early transition state character. This mechanism differs from the FeIV-based, radical, stepwise mechanism of heme-dependent monooxygenases. Furthermore, the effects of the carbene substituent, metal coordinating axial ligand, and porphyrin substituent on the reactivity of the heme carbenes was systematically investigated, providing a basis for explaining experimental reactivity results and defining strategies for future catalyst development. Our results especially suggest the potential value of electron-deficient porphyrin ligands for increasing the electrophilicity and thus the reactivity of the heme carbene. Metal-free reactions were also studied to reveal temperature and carbene substituent effects on catalytic vs noncatalytic reactions. This study sheds new light into the mechanism of iron-porphyrin and hemoprotein-catalyzed cyclopropanation reactions and it is expected to facilitate future efforts toward sustainable carbene transfer catalysis using these systems.
AB - Catalytic carbene transfer to olefins is a useful approach to synthesize cyclopropanes, which are key structural motifs in many drugs and biologically active natural products. While catalytic methods for olefin cyclopropanation have largely relied on rare transition-metal-based catalysts, recent studies have demonstrated the promise and synthetic value of iron-based heme-containing proteins for promoting these reactions with excellent catalytic activity and selectivity. Despite this progress, the mechanism of iron-porphyrin and hemoprotein-catalyzed olefin cyclopropanation has remained largely unknown. Using a combination of quantum chemical calculations and experimental mechanistic analyses, the present study shows for the first time that the increasingly useful C-C functionalizations mediated by heme carbenes feature an FeII-based, nonradical, concerted nonsynchronous mechanism, with early transition state character. This mechanism differs from the FeIV-based, radical, stepwise mechanism of heme-dependent monooxygenases. Furthermore, the effects of the carbene substituent, metal coordinating axial ligand, and porphyrin substituent on the reactivity of the heme carbenes was systematically investigated, providing a basis for explaining experimental reactivity results and defining strategies for future catalyst development. Our results especially suggest the potential value of electron-deficient porphyrin ligands for increasing the electrophilicity and thus the reactivity of the heme carbene. Metal-free reactions were also studied to reveal temperature and carbene substituent effects on catalytic vs noncatalytic reactions. This study sheds new light into the mechanism of iron-porphyrin and hemoprotein-catalyzed cyclopropanation reactions and it is expected to facilitate future efforts toward sustainable carbene transfer catalysis using these systems.
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U2 - 10.1021/jacs.7b09171
DO - 10.1021/jacs.7b09171
M3 - Article
C2 - 29268614
AN - SCOPUS:85041930852
SN - 0002-7863
VL - 140
SP - 1649
EP - 1662
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 5
ER -