Application of the N-hydroxymethyl group to the stereoselective synthesis of (3S,4S)-3-aminodeoxystatine derivatives

Stereoselective synthesis of two 3-aminodeoxystatine derivatives was achieved. Chiral γ-amino-α,β-unsaturated esters containing an N-aminomethyl group undergo the stereoselective conjugate addition with an internal carbamate or amide nitrogen nucleophile. The diastereoselectivity was about 10:1 by 1H NMR. Thus, the 3-aminodeoxystatine derivatives were prepared from commercially available N-Boc-l-leucine in nine steps in overall yields of 26% and 20% for the benzyl carbamate and the acetamide derivatives, respectively.

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Methyl (E)-(4S)-4-(N-acetoxymethyl-N-tert-butoxycarbonyl)amino-6-methylhept-2-enoateC17H29NO6[α]D25=-15 (c 0.76, CHCl3)Source of chirality: l-leucine (99% ee)Absolute configuration: (S)

Methyl (E)-(4S)-4-(N-benzyloxycarbonylaminomethyl-N-tert-butoxycarbonyl)amino-6-methylhept-2-enoateC23H34N2O6[α]D26=-34 (c 0.94, CHCl3)Source of chirality: l-leucine (99% ee)Absolute configuration: (S)

Methyl (3S,4S)-3-(benzyloxycarbonyl)amino-4-(tert-butoxycarbonyl)amino-6-methylheptanoateC22H34N2O6[α]D25=-40 (c 0.6, MeOH)Source of chirality: l-leucine (99% ee)Absolute configuration: (3S,4S)