Chemistry

New Life for Cyclopropanes

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Science  12 Jul 2013:
Vol. 341, Issue 6142, pp. 110
DOI: 10.1126/science.341.6142.110-b

Although the carbon bonds in triangular cyclopropane rings are strained, these substructures appear in numerous, reasonably stable natural and synthetic compounds. Biochemically, they tend to result from enzymatic coupling of olefins with stabilized cations. Chemists instead typically treat the olefins with transiently generated, metal-bound neutral carbenes, a strategy that broadens the versatility of substitution patterns around the ring. Mechanistically, metal activation of carbenes is loosely analogous to the pathway whereby cytochrome P450 enzymes activate oxygen, and this insight led recently to the preparation of engineered P450 variants active for synthetic cyclopropanation in aqueous solution (see Coelho et al., Reports, 18 January 2013, p. 307). Coelho et al. have now further engineered this class of enzymes to enable carbene-derived cyclopropanation in vivo in Escherichia coli cells, despite the complete absence of a native reaction in this vein. The key mutation was replacement of a cysteine residue with serine, leading to O (rather than S) coordination of the iron active site (confirmed crystallographically). This substitution facilitated catalyst activation using endogenous NADH as a reductant. Overall activity for styrene cyclopropanation, with ethyldiazoacetate as the carbene precursor, was even higher in vivo than in vitro, with no loss of enantio- or diastereoselectivity (favoring the cis product).

Nat. Chem. Biol. 9, 10.1038/NCHEMBIO.1278 (2013).

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