One After Another

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Science  21 Oct 2005:
Vol. 310, Issue 5747, pp. 409
DOI: 10.1126/science.310.5747.409b

Multistep synthesis is more efficient when two or more reactions are run consecutively in the same flask, thereby eliminating isolation and purification steps. Huang et al. show that a single catalyst can sequentially facilitate nucleophilic and electrophilic additions to α,β-unsaturated aldehydes (compounds with adjacent C=C and C=O groups), with both steps proceeding in high enantioselectivity. Initial reaction of the chiral imidazolidinone catalyst at the C=O group yields an iminium intermediate that adds furan, indole, and thiophene-derived nucleophiles at the β-carbon of the C=C group. The product then remains activated toward addition of electrophilic chlorine at the α-carbon. Moreover, the catalyst- reagent interactions dominate the reaction kinetics, selecting for a syn addition geometry in which both nucleophile and electrophile bond to the same face of the olefin, despite the unfavorable sterics of this arrangement. Overall yields are in the 60 to 90% range, with 9 to 1 or greater syn selectivities, and 99% enantiomeric excess of the major product. Hydride nucleophiles can be added as well, and a fluorine electrophile substituted for the chloro compound. Selectivity switches with hydride to favor the anti product, although a syn geometry can still be induced by addition of an alternate catalyst after the nucleophilic step. — JSY

J. Am. Chem. Soc. 10.1021/ja055545d (2005).

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