Aziridine ring opening as regio- and stereoselective access to O-glycosyl amino acids and their transformation into O-glycopeptide mimetics

Glycosyl amino acid mimetics of the typical GalNAc-(1→O)-Ser/Thr motif of O-glycopeptides were synthesised. Starting from galactose a 1,5-anhydro derivative could be obtained and regio- and stereoselectively coupled to serine- or threonine-derived aziridine compounds, respectively. The corresponding Fmoc derivatives could be used to prepare two 13-mer glycopeptides of the mucin MUC1 carrying instead of Ser-2 or Th-5, the corresponding O-glcycosyl amino acid mimetics.

Figure optionsDownload as PowerPoint slide

1,5-Anhydro-6-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-d-galactitolEe = 100%[α]D20=+26.1 (c 1,CH2Cl2)Source of chirality: synthesis from d-galactoseAbsolute configuration (d-galacto)

(2S)-Benzyl-1-trityl-aziridine-2-carboxylateEe = 100%[α]D20=-92.3 (c 1, THF)Source of chirality: from l-serineAbsolute configuration (2S)

(2S,3S)-Benzyl-3-methyl-1-trityl-aziridine-2-carboxylateEe = 100%[α]D20=-74.5 (c 1, CHCl3)Source of chirality: from l-threonineAbsolute configuration (2S,3S)

(2S)-Benzyl-1-benzyloxycarbonyl-aziridine-2-carboxylateEe = 100%[α]D20=-18.6 (c 1, CH2Cl2)Source of chirality: from l-serineAbsolute configuration (2S)

(2S,3S)-Benzyl-1-benzyloxycarbonyl-3-methyl-aziridine-2-carboxylateEe = 100%[α]D20=-67.1 (c 1, MeOH)Source of chirality: from l-threonineAbsolute configuration (2S,3S)

Nα-Benzyloxycarbonyl-3-O-[1,5-anhydro-6-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-d-galactitol-2]-l-serine benzylesterEe = 100%[α]D20=+9.7 (c 1, CH2C12)Source of chirality: from d-galactose and l-serineAbsolute configuration (d-galacto and l-serine)

Nα-Benzyloxycarbonyl-3-O-[1,5-anhydro-6-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-d-galactitol-2]-l-threonine benzylesterEe = 100%[α]D20=+0.4 (c 1, CH2C12)Source of chirality: from d-galactose and l-threonineAbsolute configuration (d-galacto and l-threonine)

3-O-[1,5-Anhydro-6-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-d-galactitol-2]-l-serineEe = 100%[α]D20=+3.7 (c 0.5, MeOH)Source of chirality: from d-galactose and l-serineAbsolute configuration (d-galacto and l-serine)

3-O-[1,5-Anhydro-6-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-d-galactitol-2]-l-threonineEe = 100%[α]D20=-0.7 (c 0.5, MeOH)Source of chirality: from d-galactose and l-threonineAbsolute configuration (d-galacto and l-threonine)

3′-O-[1,5-Anhydro-d-galactitol-2]-l-serine trifluoroacetateEe = 100%[α]D20=+17.4 (c 1, H2O)Source of chirality: from d-galactose and l-serineAbsolute configuration (d-galacto and l-serine)

3′-O-[1,5-Anhydro-d-galactitol-2]-l-threonine trifluoroacetateEe = 100%[α]D20=+18.6 (c 1, H2O)Source of chirality: from d-galactose and l-threonineAbsolute configuration (d-galacto and l-threonine)

Nα-Fluorenylmethoxycarbonyl-3-O-[1,5-anhydro-6-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-galactitol-2]-l-serineEe = 100%[α]D20=+19.7 (c 1.0, MeOH)Source of chirality: from d-galactose and l-serineAbsolute configuration (d-galacto and l-serine)

Nα-Fluorenylmethoxycarbonyl-3-O-[1,5-anhydro-6-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-galactitol-2]-l-threonineEe = 100%[α]D20=+22.9 (c 1, MeOH)Mp 75 °CSource of chirality: from d-galactose and l-threonineAbsolute configuration (d-galacto and l-threonine)