Asymmetric Schmidt reaction of hydroxyalkyl azides with ketones |
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Authors: | Sahasrabudhe Kiran Gracias Vijaya Furness Kelly Smith Brenton T Katz Christopher E Reddy D Srinivasa Aubé Jeffrey |
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Institution: | Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott Hall, Room 4070, University of Kansas, Lawrence, KS 66045-2506, USA. |
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Abstract: | An asymmetric equivalent of the Schmidt reaction permits stereocontrol in ring expansions of symmetrical cyclohexanones. The procedure involves the reaction of chiral 1,2- and 1,3-hydroxyalkyl azides with ketones under acid catalysis; the initial reaction affords an iminium ether that can be subsequently opened with base. A systematic study of this reaction is reported, in which ketone substrates, chiral hydroxyalkyl azides, and reaction conditions are varied. Selectivities as high as ca. 98:2 are possible for the synthesis of substituted caprolactams, with up to 1,7-stereoselection involved in the overall process. The fact that either possible migrating carbon is electronically identical provides an unusual opportunity to study a ring-expansion reaction controlled entirely by stereoelectronic factors. The mechanism of the reaction and the source of its stereoselectivity are also discussed. |
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