jo051334f_si_001.cif (14.15 kB)
Synthesis of β-Substituted α-Amino Acids via Lewis Acid Promoted Enantioselective Radical Conjugate Additions
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posted on 2005-09-30, 00:00 authored by Liwen He, G. S. C. Srikanth, Steven L. CastleLewis 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 Bu3SnH. Zinc Lewis acids
provided the greatest amounts of addition products with both substrate classes. Studies with Bu3SnD 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 (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.
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nitro groupuse chiral Lewis acidsaddition productssubstrate bindingmimimal levelssubstrate classescrude adductshydrogen atom abstraction stepstereoselective variantDBFOXBu 3 SnDconjugate additionBu 3 SnHconjugate addition stepamide substratesachiral Lewis acidsZinc Lewis acidsadduct 7 bconjugate additionsacid derivativeschiral Lewis acidPromoted Enantioselective Radical Conjugate Additions Lewis acidundesired alkene reductionworkup conditions
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