Synthesis of (2R, 5S)- and (2S, 5S)-2-carboxy-1,4-diaza-[4.3.0]bicyclononane as building blocks for the synthesis of new potential HIV protease inhibitors

A procedure for the preparation of optically active (2R,5S)- and (2S,5S)-2-Carboxy-1,4-diaza-[4.3.0]bicyclononane is described. The method is based on the reduction of diketopiperazines obtained from cyclization of Pro-L-Ser or Pro-D-Ser and occurs without loss of enantiomeric purity. The synthesis is based on readily available starting materials and can be easily arranged for multigram scale preparations.

Satisfactory multigram scale preparations can be arranged. The key step of the syntesis is the protection of the ternary nitrogen atom as methylammonium salt, during the oxidation process.Figure optionsDownload full-size imageDownload as PowerPoint slide

N-[1′-(Benzyloxycarbonyl)prolyl] serine methyl esterE.e. = ≥95%m.p. 103–107°C[α]D25−28.95(c 2, CHCI3)Source of chirality: (S)-proline, (S)-serineAbsolute configuration: 2S, 2′S

N-[1′-(Benzyloxycarbonyl)prolyl] serine methyl esterE.e. = ≥95%m.p. 123–125°C[α]D25−100.72(c 1.5, CHCI3)Source of chirality: (S)-proline, (R)-serineAbsolute configuration: 2R, 2′S

2-Hydroxymethyl-3,6-diketo-1,4-diaza[4.3.0]bicylononaneE.e. = ≥95%m.p. 134–136°C[α]D25−114.8(c 2, CMSO)Source of chirality: (S)-proline, (S)-serineAbsolute configuration: 2S, 5S

2-Hydroxymethyl-3,6-diketo-1,4-diaza[4.3.0]bicylononaneE.e. = ≥95%m.p. 248–250°C[α]D25−149.55(c 0.7, CMSO)Source of chirality: (S)-proline, (R)-serineAbsolute configuration: 2R, 5S

2-Hydroxymethyl-1,4-diaza[4.3.0]bicylononaneE.e. = ≥95%b.p. 125–130°C/0.5 mBar[α]D25+7.77(c 1.88, CHCI3)Source of chirality: (S)-proline, (S)-serineAbsolute configuration: 2R, 5S

2-Hydroxymethyl-1,4-diaza[4.3.0]bicylononaneE.e. = ≥95%b.p. 112°C/0.5 mBar[α]D25+14.56(c 1, CHCI3)Source of chirality: (S)-proline, (R)-serineAbsolute configuration: 2S, 5S

1-(Tert-butoxycarbonyl)-2-hydroxymethyl-1,4-diaza[4.3.0]bicyclononaneE.e. = ≥95%, D.e. = ≥95% (by 1H NMR)Waxy solid[α]D25+64.7(c 1, CHCI3)Source of chirality: (S)-proline, (S)-serineAbsolute configuration: 2R, 5S

1-(Tert-butoxycarbonyl)-2-hydroxymethyl-1,4-diaza[4.3.0]bicyclononaneE.e. = ≥95%, D.e. = ≥95% (by 1H NMR)Waxy solid[α]D25+66.1(c 2, CHCI3)Source of chirality: (S)-proline, (R)-serineAbsolute configuration: 2S, 5S

1-(Tert-butoxycarbonyl)-2-hydroxymethyl-1,4-diaza[4.3.0]bicyclononan-4-methylammonium iodideE.e. = ≥95%Waxy solid[α]D25+57.8(c 2.5, H2O)Source of chirality: (S)-proline, (S)-serineAbsolute configuration: 2R, 5S

1-(Tert-butoxycarbonyl)-2-hydroxymethyl-1,4-diaza[4.3.0]bicyclononan-4-methylammonium iodideE.e. = ≥95%Waxy solid[α]D25+60.9(c 1.5, H2O)Source of chirality: (S)-proline, (R)-serineAbsolute configuration: 2S, 5S

1-(Tert-butoxycarbonyl)-2-carboxy-1,4-diaza[4.3.0]bicyclononan-4-methylammonium acetateE.e. = ≥95%[α]D25−43.8(c 1.3, AcOH)Source of chirality: (S)-proline, (S)-serineAbsolute configuration: 2R, 5S

1-(Tert-butoxycarbonyl)-2-carboxy-1,4-diaza[4.3.0]bicyclononan-4-methylammonium acetateE.e. = ≥95%[α]D25+10.7(c 2.8, AcOH)Source of chirality: (S)-proline, (R)-serineAbsolute configuration: 2S, 5S

2-Carboxymethyl-1,4-diaza[4.3.0]bicyclononaneE.e. = ≥95%; D.e. = ≥ 95% (by 1H NMR)[α]D25−9.4(c 0.6, AcOH)Source of chirality: (S)-proline, (S)-serineAbsolute configuration: 2R, 5S

2-Carboxymethyl-1,4-diaza[4.3.0]bicyclononaneE.e. = ≥95% D.e. = ≥ 95% (by 1H NMR)[α]D25+3.5(c 0.5, AcOH)Source of chirality: (S)-proline, (R)-serineAbsolute configuration: 2S, 5S