Synthesis of β-Substituted α-Amino Acids via Lewis Acid Promoted Enantioselective Radical Conjugate Additions
2005-09-30T00:00:00Z (GMT) by
Lewis acid promoted radical conjugate additions to β-substituted α,β-unsaturated α-nitro esters and amides were investigated. With achiral Lewis acids, there was competition between the desired radical conjugate addition and undesired alkene reduction mediated by Bu<sub>3</sub>SnH. Zinc Lewis acids provided the greatest amounts of addition products with both substrate classes. Studies with Bu<sub>3</sub>SnD indicated that the acidic α-stereocenter of the α-nitro ester products does not racemize under controlled workup conditions. The corresponding α-nitro amides racemized significantly during chromatography, but this problem could be greatly minimized by subjecting the crude adducts to subsequent transformations. Indium-mediated reduction of the nitro group followed by acylation of the resulting amine provided good yields of β-substituted α-amino acid derivatives with mimimal levels of racemization. Attempts to use chiral Lewis acids in a stereoselective variant of this process revealed that Kanemasa's DBFOX/Ph ligand (<b>14a</b>) was uniquely effective. Moderate to good ee's and low dr's were obtained with amide substrates. Determination of the absolute configurations of the <i>syn</i> and <i>anti</i> isomers of adduct <b>7b</b> showed that the hydrogen atom abstraction step was significantly more stereoselective than the radical conjugate addition step. A model for substrate binding to the chiral Lewis acid is presented.