Chemoenzymatic synthesis and application of a new, easily chiral auxiliary for the synthesis of peptidomimetics via an Ugi reaction

A new chiral auxiliary derived from α-phenylethylamine, α-(2,4-dimethoxyphenyl)ethylamine is presented. It significantly expands upon the application of α-phenylethylamine derivatives used as chiral auxiliaries. A straightforward, chemoenzymatic synthesis of non-racemic α-(2,4-dimethoxyphenyl)ethylamine is described and the new chiral auxiliary applied to an asymmetric Ugi reaction. The mild conditions used for the cleavage of the auxiliary allowed to obtain chiral, non-racemic peptidomimetics possessing reactive α,β-unsaturated double bonds.

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(S)-α-(2,4-Dimethoxyphenyl)ethyl amineC10H15NO2[α]D20 = −17 (c 0.85, CHCl3)Absolute configuration: (S)Source of chirality: enzymatic resolution

N-[1-(2,4-Dimethoxyphenyl)ethyl]-2-methoxyacetamideC13H19NO4[α]D20 = +111 (c 0.50, CHCl3); ee >99%Absolute configuration:(R)Source of chirality: enzymatic resolution

N-[1-(Cyclohexylamino)-4-methyl-1-oxopentan-2-yl]benzamideC19H28N2O2[α]D20 = +23 (c 0.65, CHCl3)Absolute configuration:(R)Source of chirality: enzymatic resolution

2,6-Bis-trifluoromethylobenzoic acid 2-[1-(ethoxycabonylmethylcarbamoyl)-3-methylbutylcarbamoyl]-allyl esterC23H26F6N2O6[α]D20 = +23 (c 0.9, CHCl3), ee = 92%Absolute configuration:(R)Source of chirality: enzymatic resolution