Synthetic studies towards diazepanone scaffolds

The synthesis of new enantiopure polyfunctionalised diazepanone scaffolds is described. The key steps involve the opening of an azido-epoxide C4 building block derived from l-ascorbic or d-isoascorbic acid by a l-serine derivative followed by a lactonisation–lactamisation two-step sequence.

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(2R,3R)-3-[(N-Fluorenylmethoxycarbonyl-O-benzyl-l-serinyl)amino]-4-tert-butyldiphenylsilyloxy-1,2-epoxybutaneC45H48N2O6SiDe >95% (by 1H NMR)[α]D = +16 (c 1.0, CH2Cl2)Source of chirality: l-ascorbic acid and O-benzyl-N-Fmoc-l-serineAbsolute configuration: (2R,3R)

(3S,6S,7R)-3-Benzyloxymethyl-7-tert-butyldiphenylsilyloxymethyl-6-hydroxy-1,4-diazepan-2-oneC30H38N2O4SiDe >95% (by 1H NMR)[α]365 = −2.5 (c 1.0, CH2Cl2)Source of chirality: l-ascorbic acid and O-benzyl-N-Fmoc-l-serineAbsolute configuration: (3S,6S,7R)

(3R,6S,7R)-3-Benzyloxymethyl-7-tert-butyldiphenylsilyloxymethyl-6-hydroxy-1,4-diazepan-2-oneC30H38N2O4SiDe > 95% (by 1H NMR)[α]D = +32 (c 1.0, CH2Cl2)Source of chirality: l-ascorbic acid and O-benzyl-N-Fmoc-l-serineAbsolute configuration: (3R,6S,7R)

tert-Butyl (2S,3R)-N-(3-azido-2,4-di-tert-butyldiphenylsilyloxy-butyl)-O-benzyl-l-serine esterC50H64N4O5Si2De >95% (by 1H NMR)[α]D = +4 (c 1.0, CH2Cl2)Source of chirality: l-ascorbic acid and O-benzyl-N-Fmoc-l-serineAbsolute configuration: (2S,3R)

tert-Butyl N-[(2S,3R)-3-azido-4-tert-butyldiphenylsilyloxy-2-hydroxybutyl]-N′-methyl-O-benzyl-l-serine esterC35H48N4O5SiDe >95% (by 1H NMR)[α]D = −29 (c 1.0, CH2Cl2)Source of chirality: l-ascorbic acid and O-benzyl-N-Fmoc-N-methyl-l-serineAbsolute configuration: (2S,3R)

tert-Butyl (2S,3R)-N-(3-amino-4-tert-butyldiphenylsilyloxy-2-hydroxy-butyl)-N′-methyl-O-benzyl-l-serine esterC35H50N2O5SiDe >95% (by 1H NMR)[α]D = −19 (c 1.0, CH2Cl2)Source of chirality: l-ascorbic acid and O-benzyl-N-Fmoc-N-methyl-l-serineAbsolute configuration: (2S,3R)

(3S,6S,7R)-3-Benzyloxymethyl-7-tert-butyldiphenylsilyloxymethyl-6-hydroxy-4-N-methyl-1,4-diazepan-2-oneC31H40N2O4SiDe >95% (by 1H NMR)[α]D = +20 (c 1.0, CH2Cl2)Source of chirality: l-ascorbic acid and O-benzyl-N-Fmoc-N-methyl-l-serineAbsolute configuration: (3S,6S,7R)

(1′R,3S,6S)-6-[(1′-Azido-2′-tert-butyldiphenylsilyloxy)-ethyl]-3-benyloxymethyl-morpholin-2-oneC30H36N4O4SiDe >95% (by 1H NMR)[α]D = −10 (c 1.0, CH2Cl2)Source of chirality: l-ascorbic acid and O-benzyl-N-Fmoc-l-serineAbsolute configuration: (1′R,3S,6S)

(1′R,3S,6S)-6-[(1′-Azido-2′-tert-butyldiphenylsilyloxy)-ethyl]-3-benzyloxymethyl-4-methyl-morpholin-2-oneC31H38N4O4SiDe >95% (by 1H NMR)[α]D = −2 (c 1.0, CH2Cl2)Source of chirality: l-ascorbic acid and O-benzyl-N-Fmoc-N-methyl-l-serineAbsolute configuration: (1′R,3S,6S)

(3S,6S,7R)-3-(Benzyloxymethyl)-7-((tert-butyldiphenylsilyloxy)methyl)-4-N-(5″-(uracil-1′-yl)pentyl)-6-hydroxy-1,4-diazepan-2-oneC39H50N4O6SiDe >95% (by 1H NMR)[α]D = +17.0 (c 1.0, CH2Cl2)Source of chirality: l-ascorbic acid and O-benzyl-N-Fmoc-l-serineAbsolute configuration: (3S,6S,7R)

(2R,3S)-3-Azido-4-tert-butyldiphenylsilyloxy-1,2-epoxybutaneC20H25N3O2SiDe >95% (by 1H NMR)[α]D = −24 (c 1.0, CH2Cl2)Source of chirality: d-isoascorbic acidAbsolute configuration: (2R,3S)

tert-Butyl N-[(2R,3R)-3-azido-4-tert-butyldiphenylsilyloxy-2-hydroxybutyl]-N′-methyl-O-benzyl-l-serineC35H48N4O5SiDe >95% (by 1H NMR)[α]D = −10 (c 1.0, CH2Cl2)Source of chirality: d-isoascorbic acid and O-benzyl-N-Fmoc-N-methyl-l-serineAbsolute configuration: (2R,3R)

(1′R,3S,6R)-6-[(1′-Azido-2′-tert-butyldiphenylsilyloxy)-ethyl]-3-benzyloxymethyl-4-methyl-morpholin-2-oneC31H38N4O4SiDe >95% (by 1H NMR)[α]D = −29 (c 1.0, CH2Cl2)Source of chirality: d-isoascorbic acid and O-benzyl-N-Fmoc-N-methyl-l-serineAbsolute configuration: (1′R,3S,6R)

(3S,6R,7R)-3-Benzyloxymethyl-7-tert-butyldiphenylsilyloxymethyl-6-hydroxy-4-N-methyl-1,4-diazepan-2-oneC31H40N2O4SiDe >95% (by 1H NMR)[α]D = +24 (c 1.0, CH2Cl2)Source of chirality: d-isoascorbic acid and O-benzyl-N-Fmoc-N-methyl-l-serineAbsolute configuration: (3S,6R,7R)