Conjugate addition of lithium N-tert-butyldimethylsilyloxy-N-(α-methylbenzyl)amide: asymmetric synthesis of β2,2,3-trisubstituted amino acids

Conjugate addition of the homochiral ammonia equivalent lithium N-tert-butyldimethylsilyloxy-N-(α-methylbenzyl)amide to a range of α,β-unsaturated esters gives the corresponding β-amino esters in moderate to good levels of diastereoselectivity. O-Desilylation and cyclisation furnishes homochiral isoxazolidin-5-ones in >99:1 dr after purification. Sequential alkylation of these templates proceeds to give the corresponding 3,4-anti-disubstituted and 3,4,4-trisubstituted derivatives as single diastereoisomers after purification. The first alkylation occurs with high levels of diastereoselectivity on the face of the enolate anti to the C(3)-substituent, whereas the facial selectivity of the second alkylation is governed by a chiral relay effect, which depends upon the relative steric bulk of both the C(3)- and C(4)-substituents. Subsequent hydrogenolysis promotes cleavage of both the N-α-methylbenzyl group and the N–O bond within the isoxazolidin-5-one ring in one pot to give the corresponding β2,2,3-trisubstituted amino acids directly.

Graphical abstractConjugate addition of the homochiral ammonia equivalent lithium N-tert-butyldimethylsilyloxy-N-(α-methylbenzyl)amide to α,β-unsaturated esters coupled with O-deprotection and cyclisation gives isoxazolidin-5-ones in high diastereoisomeric ratios. Diastereoselective alkylation reactions of these templates facilitate the synthesis of β2,2,3-trisubstituted amino acids.Figure optionsDownload full-size imageDownload as PowerPoint slide