Enantioselective synthesis of beta-amino acids using hexahydrobenzoxazolidinones as chiral auxiliaries

A practical synthetic route for the asymmetric synthesis of β2-amino acids is described. In the first step, the procedure involves the N-acylation of readily available, enantiopure hexahydrobenzoxazolidinone (4R,5R)-1 with 3-methylbutanoyl chloride 2, 4-methylpentanoic acid 3, and 3-(1-tert-butoxycarbonyl)-1H-indol-3-yl)propanoic acid 4 to afford derivatives 5a, 5b, and 5c, respectively, which were alkylated with high diastereoselectivity by means of reaction between their sodium enolates and benzyl bromoacetate. Removal of the chiral auxiliary from the alkylated products followed by hydrogenation and hydrolysis gave β2-amino acids (S)-10a, (S)-10b, and (S)-10c, which were N-protected with Fmoc. Enantiomeric (R)-10a–c were similarly prepared from the isomeric hexahydrobenzoxazolidinone (4S,5S)-1; thus, the route presented here provides access to both enantiomers of valuable highly enantioenriched β2-amino acids.

An efficient asymmetric synthetic route that provides both enantiomers of β2-homovaline, β2-homoleucine, and β2-homotryptophan from chiral hexahydrobenzoxazolidinones is described.Figure optionsDownload as PowerPoint slide

(4R,5R)-3-(3-Methylbutanoyl)hexahydrobenzoxazolidin-2-oneC12H19NO3[α]D25=-72 (c 1.02, CHCl3)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (4R,5R)

(4R,5R)-3-(4-Methylpentanoyl)hexahydrobenzoxazolidin-2-oneC13H21NO3[α]D25=-74 (c 1.0, CHCl3)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (4R,5R)

(4R,5R)-3-{1-[(tert-Butoxy)carbonyl]-1H-indol-3-yl}-1-oxopropyl-hexahydrobenzoxazolidin-2-oneC23H28N2O5[α]D25=-28 (c 1.0, CHCl3)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (4R,5R)

Benzyl-3(R)-(isopropyl)-4-[(4R,5R)-2-oxo-hexahydrobenzoxazolidin-3-yl]-4-oxobutanoateC21H27NO5[α]D25=-5.6 (c 1.0, CHCl3)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (4R,5R,3R)

Benzyl-3(S)-(isobutyl)-4-[(4R,5R)-2-oxo-hexahydrobenzoxazolidin-3-yl]-4-oxobutanoateC22H29NO5[α]D25=+11 (c 1.0, MeOH)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (4R,5R,3S)

Benzyl-3(S)-({1-[(tert-butoxy)carbonyl]-1H-indol-3-yl}methyl)-4-[(4R,5R)-2-oxohexahydrobenzoxazoli-din-3-yl]-4-oxobutanoateC32H36N2O7[α]D25=-31.7 (c 1.0, CHCl3)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (4R,5R,3S)

3(R)-(Isopropyl)-4-[(4R,5R)-2-oxo-hexahydrobenzoxazolidin-3-yl]-4-oxobutanoic acidC14H21NO5[α]D25=-25.4 (c 1.0, CHCl3)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (4R,5R,3R)

3(S)-(Isobutyl)-4-[(4R,5R)-2-oxo-hexahydrobenzoxazolidin-3-yl]-4-oxobutanoic acidC15H23NO5[α]D25=+6 (c 1.0, MeOH)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (4R,5R,3S)

3(S)-({1-[(tert-Butoxy)carbonyl]-1H-indol-3-yl}methyl)-4-[(4R,5R)-2-oxohexahydro-benzoxazolidin-3-yl]-4-oxobutanoic acidC25H30N2O7[α]D25=-49 (c 1.0, CHCl3)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (4R,5R,3S)

(4R,5R)-3-[2(S)-({[(Benzyloxy)carbonyl]amino}methyl)-3-methyl-butanoyl]hexahydrobenzoxazolidin-2-oneC21H28N2O5[α]D25=-8 (c 1.0, CHCl3)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (4R,5R,3S)

(4R,5R)-3-[2(S)-({[(Benzyloxy)carbonyl]amino}methyl)-4-methyl-pentanoyl] hexahydrobenzoxazolidin-2-oneC22H30N2O5[α]D25=+24 (c 1.0, MeOH)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (4R,5R,3S)

(4R,5R)-3-[2(S)-({[(Benzyloxy)carbonyl]amino}methyl)-3-({1-[(tert-Butoxy)carbonyl]-1H-indol-3-yl}-1oxo-propyl)-hexahydrobenzoxazolidin-2-oneC32H37N3O7[α]D25=+7.4 (c 1.01, acetone)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (4R,5R,3S)

2(S)-([{(Benzyloxy)carbonyl}amino]methyl)-3-methylbutanoic acidC14H19NO4[α]D25=+18 (c 1.0, CHCl3)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (2S)

2(S)-([{(Benzyloxy)carbonyl}amino]methyl)-4-methylpentanoic acidC15H21NO4[α]D25=+12.5 (c 1.0, MeOH)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (2S)

Benzyl-2(S)-({[(Benzyloxy)carbonyl]amino}methyl)-3-{1-[(tert-Butoxy)carbonyl]-1H-indol-3yl}-propanoateC33H37N2O6[α]D25=+6.5 (c 1.85, MeOH)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (2S)

2(S)-[(Amino)methyl]-3-methylbutanoic acidC6H13NO2ee = 98% (HPLC analysis)[α]D25=+13 (c 1.0, H2O)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (2S)

2(S)-[(Amino)methyl]-4-methylpentanoic acidC7H15NO2ee = 94% (by análisis HPLC)[α]D25=-4 (c 1.0, H2O)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (2S)

2(S)-([Amino]methyl)-3-{1-[(tert-Butoxy)carbonyl]-1H-indol-3-yl}propionic acidC17H22N2O4ee = 82% (by análisis HPLC)[α]D25=+7.4 (c 0.95, MeOH)Source of chirality: (4R,5R)-3H-hexahydrobenzoxazo-lidin-2-one)Absolute configuration: (2S)