Synthesis of beta-substituted alpha-amino acids via Lewis acid promoted enantioselective radical conjugate additions.
[Chemical reaction: See text] Lewis acid promoted radical conjugate additions to beta-substituted alpha,beta-unsaturated alpha-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 Bu3nH. Zinc Lewis acids provided the greatest amounts of addition products with both substrate classes. Studies with Bu3nD indicated that the acidic alpha-stereocenter of the alpha-nitro ester products does not racemize under controlled workup conditions. The corresponding alpha-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 beta-substituted alpha-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 (14a) was uniquely effective. Moderate to good ee's and low dr's were obtained with amide substrates. Determination of the absolute configurations of the syn and anti isomers of adduct 7b 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.
He
Liwen
L
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, USA
Srikanth
G S C
GS
Castle
Steven L
SL
D000596:Amino Acids / Q000138:chemical synthesis*; D002264:Carboxylic Acids / Q000737:chemistry*; D007204:Indium; D008958:Models, Molecular; D009574:Nitro Compounds / Q000737:chemistry; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D014961:X-Ray Diffraction
D000596:Amino Acids; D002264:Carboxylic Acids; D009574:Nitro Compounds; D007204:Indium