An environmentally friendly and safe approach towards a stereoselective, enzyme catalyzed synthesis of cyclopropanes was investigated. Cyclopropanes represent an interesting moiety in drug development, due to their biological activity in combination with good metabolic stability. Since enantiomers may exhibit widely differing pharmacological and DMPK properties, stereoselective cyclopropanations are of high interest. However, cyclopropanation procedures often require expensive chiral ligands and/or chiral (metal) catalysts to obtain high stereoselectivity. Cis-selective CYP450-enzymes were used for the cyclopropanation of functionalized styrenes with ethyl diazoacetate to afford arylcyclopropanes in moderate yield with varying diastereoselectivities and moderate to high enantioselectivities. Ethyl diazoacetate is a good reagent for carbon-isotope incorporation since it can be derived from a readily available labeled precursor (glycine) and is a two carbon synthon. In addition, the metabolic stability of cyclopropanes make labeling the ring attractive for metabolism studies. Several labeled arylcyclopropanes were synthesized as a proof of concept. It was envisaged that the enzymatic cyclopropanation could be utilized for large-scale syntheses (multikilogram), but ethyl diazoacetate is a highly energetic compound requiring careful control measures for use on a large scale. In an effort to reduce the energetic nature of the compound, several higher molecular weight esters were synthesized. N-Hexyl diazoacetate significantly reduced the hazard associated with the compound and was successfully utilized as a substrate in the reaction albeit with loss of diastereocontrol.

Enzymatic cyclopropanation optimization study using safer diazoacetate analogs

ACS Spring Meeting 2021

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