Asymmetric synthesis of N-substituted N-hydroxyureas

Asymmetric synthesis of (S)-N-(1-arylethyl)-N-hydroxyureas, (S)-N-(6-methoxy)- and (S)-N-(6-benzyloxy-2,3-dihydrobenzofuran-3-yl)-N-hydroxyurea— lipoxygenase inhibitor, is described. Three approaches to the formation of the N-hydroxyurea moiety at the stereogenic center have been used. The first one, via the reaction of (R)-6-benzyloxy-2,3-dihydrobenzofuran-3-ol with N,O-bis(phenoxycarbonyl)hydroxylamine under Mitsunobu conditions, leads to a partially racemized product. Alternatively, the enantioselective reduction of oximes O-benzyl ethers of acetophenone, 4-methoxy- and 4-benzyloxyacetophenone, 6-methoxy- and 6-benzyloxy-2,3-dihydrobenzofuran-3-one with borane/oxazaborolidines can be controlled to produce either the corresponding hydroxylamine O-benzyl ethers or primary amines which have been transformed into N-substituted N-hydroxyureas in 57% to 99% ee.

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(R)-6-Benzyloxy-2,3-dihydrobenzofuran-3-olC15H14O3Ee = 87%[α]D20=-48.9 (c 1.5, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R), chemical correlation

(S)-3-Amino-6-benzyloxy-2,3-dihydrobenzofuranC15H15NO2Ee = 62%[α]D20=+22.0 (c 1.5, CHCl3)Absolute configuration: (S), chemical correlation

(S)-N-(6-Methoxy-2,3-dihydrobenzofuran-3-yl)-N-hydroxyureaC10H12N2O4Ee = 57%[α]D20=+72.6 (c 1.5, DMSO)Source of chirality: asymmetric synthesisAbsolute configuration: (S), chemical correlation

(S)-N-1-(4-Methoxyphenyl)ethyl-N-hydroxyureaC10H14NO3Ee = 98%[α]D20=-41.1 (c 1.2, DMSO)Source of chirality: asymmetric synthesisAbsolute configuration: (S), chemical correlation