Chiral iron porphyrin (+)-D4-(por)FeCl catalyzes highly enantioselective cyclopropanation of alkenes using in situ generated diazoacetonitrile with up to 35 000 product turnover†

Abstract

Transition metal-catalyzed asymmetric cyclopropanation of alkenes is an important strategy to construct chiral cyclopropane skeletons of pharmaceutical interest, but highly enantioselective and practical carbene transfer reactions based on Earth abundant and bio-compatible metals are still a difficult challenge. In this work, we use a chiral iron porphyrin (+)-D₄-(por)FeCl catalyst and in situ generated α-diazoacetonitrile for highly enantioselective cyclopropanation of arylalkene. This reaction is applicable to a wide range of arylalkenes (44 examples) with yield up to 99%, diastereomeric ratio (dr) up to 93 : 7, and enantiomeric excess (ee) values up to 98%. Importantly, for the cyclopropanation reaction of 3,4-difluorostyrene (1.40 g, 10.0 mmol) with α-diazoacetonitrile in the presence of 0.002 mol% of (+)-D₄-(por)FeCl as a catalyst, the turnover number and enantioselectivity of the cyclopropyl nitrile product reached 31 000 and 88% ee, respectively. Using cyclopropyl nitriles as a starting material, downstream functionalization derivatives including cyclopropyl carboxylic acids, cyclopropylamines, and cyclopropylmethanamines can be produced as key intermediates for the preparation of a series of bioactive or drug-like molecules. In addition, the chiral Fe(II)porphyrin–cyanocarbene intermediate [(−)-D₄-(por)Fe^II(:CHCN)], which is directly responsible for the carbene transfer reaction, has been characterized by ¹H NMR, HR ESI-MS, UV-vis and ATR-FTIR spectroscopy.