A surprising mechanistic "switch" in Lewis acid activation: a bifunctional, asymmetric approach to alpha-hydroxy acid derivatives.
We report a detailed synthetic and mechanistic study of an unusual bifunctional, sequential hetero-Diels-Alder/ring-opening reaction in which chiral, metal complexed ketene enolates react with o-quinones to afford highly enantioenriched, alpha-hydroxylated carbonyl derivatives in excellent yield. A number of Lewis acids were screened in tandem with cinchona alkaloid derivatives; surprisingly, trans-(Ph(3)P)(2)PdCl(2) was found to afford the most dramatic increase in yield and rate of reaction. A series of Lewis acid binding motifs were explored through molecular modeling, as well as IR, UV, and NMR spectroscopy. Our observations document a fundamental mechanistic "switch", namely the formation of a tandem Lewis base/Lewis acid activated metal enolate in preference to a metal-coordinated quinone species (as observed in other reactions of o-quinone derivatives). This new method was applied to the syntheses of several pharmaceutical targets, each of which was obtained in high yield and enantioselectivity.
Abraham
Ciby J
CJ
Department of Chemistry, New Chemistry Building, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, USA.
Paull
Daniel H
DH
Bekele
Tefsit
T
Scerba
Michael T
MT
Dudding
Travis
T
Lectka
Thomas
T
D000143:Acids / Q000737:chemistry*; D002384:Catalysis; D002703:Chloranil / Q000737:chemistry; D006880:Hydroxy Acids / Q000737:chemistry*; D008953:Models, Anatomic; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry; D017905:Phosphites / Q000737:chemistry; D013053:Spectrophotometry; D013237:Stereoisomerism
D000143:Acids; D006880:Hydroxy Acids; D017905:Phosphites; D002703:Chloranil; D010165:Palladium; C013318:triphenyl phosphite