On the origins of diastereoselectivity in the alkylation of enolates derived from N-1-(1'-naphthyl)ethyl-O-tert-butylhydroxamates: chiral Weinreb amide equivalents.

The stereochemical outcome observed upon alkylation of enolates derived from N-1-(1'-naphthyl)ethyl-O-tert-butylhydroxamates (chiral Weinreb amide equivalents) may be rationalized by a chiral relay mechanism. Deprotonation with KHMDS leads to a nonchelated (Z)-enolate in which the oxygen atoms adopt an anti-periplanar conformation. The configuration of the N-1-(1'-naphthyl)ethyl group dictates the conformation of the O-tert-butyl group and the configuration adopted by the adjacent pyramidal nitrogen atom. Highly diastereoselective enolate alkylation then proceeds anti to both the bulky tert-butyl group (sterically driven) and the N-lone pair (stereoelectronically driven).

The chiral auxiliary N-1-(1'-naphthyl)ethyl-O-tert-butylhydroxylamine: a chiral Weinreb amide equivalent.

The chiral auxiliary N-1-(1'-naphthyl)ethyl-O-tert-butylhydroxylamine is readily prepared from N-hydroxyphthalimide in four steps, with resolution giving access to both enantiomers in > 98% ee, on a multigram (> 25 g) scale. Conversion to a range of N-acyl derivatives, followed by highly diastereoselective alkylation (> or = 94% de) gives the corresponding chiral, 2-substituted derivatives as single diastereoisomers (> 98% de) after chromatography. Reductive cleavage with LiAlH(4) allows direct access to chiral aldehydes, and treatment with MeLi gives chiral methyl ketones in excellent enantiopurity (> or = 94% ee). The auxiliary can be recovered in > 98% ee and recycled.