Chemistry

Small Yet Selective

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Science  04 Aug 2006:
Vol. 313, Issue 5787, pp. 593
DOI: 10.1126/science.313.5787.593c

Structural diversification of complex molecular frameworks, for example to combat antibiotic resistance, would benefit from an often elusive catalytic combination of specificity (to leave intact biochemically critical functional groups) and versatility (to offer as wide a range of functionality as possible in the components varied for screening). Enzymes have evolved to achieve remarkable selectivity in modifying the structures of intricate organic molecules. The price of this function, however, is a comparatively narrow substrate scope and range of transformations relative to inherently less selective small-molecule catalysts.

Regioselective acylation is a common example of a reaction traditionally left to enzymes. In the absence of a chiral catalyst, acylation of the antibiotic erythromycin A is known to occur preferentially at the 2′ and 4″ hydroxyl sites. Lewis and Miller show that a pentapeptide catalyst overcomes this kinetic selectivity to acetylate a third site, the 11-OH, with 5:1 selectivity; the same site preference is also observed for the catalyzed addition of longer-chain acyl groups, with selectivities ranging from 3.5 to >10:1. Moreover, an accompanying tautomerization further modifies the adjacent molecular framework. The results suggest that small-molecule catalysts may have unexpected promise for direct functionalization of complex molecules with high regio- and stereoselectivity. — JSY

Angew. Chem. Int. Ed. 45, 10.1002/anie.200601490 (2006).

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