Synthesis of unnatural homologues of deoxypyridinoline as possible internal standards in analytical detection of pyridinolinic cross-links of collagen

Three homologues of the collagen cross-links deoxypyridinoline, differing in the length of the side chain at the aromatic nitrogen, have been efficiently synthesized as possible internal standards in the quantitative analyses of pyridinolines. The first has a one-carbon shorter N-chain, while other two have a one-carbon and a two-carbon longer N-chain. The stereogenic centers are introduced stereoselectively using Williams’ glycine template methodology and oxazinones to generate chirality and to suitably protect the amino acid functionality during assembly of the pyridinoline nucleus.

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1-[(4S)-4-Benzyloxycarbonylamino-4-tert-butoxycarbonylbutyl]-4-[(2S)-2-benzyloxycarbonylamino-2-tert-butoxycarbonylethyl]-5-[(3S)-3-benzyloxycarbonylamino-3-tert-butoxycarbonylpropyl] pyridinium-3-olateC53H69N4O13[α]D20=+4.5 (c 1, CHCl3)Source of chirality: l-glutamic acidAbsolute configuration: (2S,3′S,4″S)

1-[(4S)-4-Amino-4-carboxylbutyl]-4-[(2S)-2-amino-2-carboxyethyl]-5-[(3S)-3-amino-3-carboxypropyl] pyridinium-3-olateC19H29F3N4O10[α]D20=+22.2 (c 0.9, H2O)Source of chirality: l-glutamic acidAbsolute configuration: (2S,3′S,4″S)

1-Benzyl-4-[(2S)-2-bis(tert-butoxycarbonylamino)-2-tert-butoxycarbonylethyl]-5-[(3S)-3-bis(tert-butoxycarbonylamino)-3-tert-butoxycarbonylpropyl] pyridinium-3-olateC47H71N3O13[α]D20=-34.0 (c 1, CHCl3)Source of chirality: l-glutamic acidAbsolute configuration: (2S,3′S)

4-[(2S)-2-Bis(tert-butoxycarbonylamino)-2-tert-butoxycarbonylethyl]-5-[(3S)-3-bis(tert-butoxycarbonylamino)-3-tert-butoxycarbonylpropyl]-3-hydroxypyridineC40H65N3O13[α]D20=-11.3 (c 1, CHCl3)Source of chirality: l-glutamic acidAbsolute configuration: (2S,3′S)

tert-Butyl (3S,5S,6R)-3-(5-azidopentyl)-2-oxo-5,6-diphenylmorpholine-4-carboxylateC26H32N4O4[α]D20=-61.2 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5S,6R)

tert-Butyl (3S,5S,6R)-3-(5-aminopentyl)-2-oxo-5,6-diphenylmorpholine-4-carboxylateC26H34N2O4[α]D20=-54.9 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5S,6R)

tert-Butyl (3S,5S,6R)-3-(6-iodohexyl)-2-oxo-5,6-diphenylmorpholine-4-carboxylateC27H34INO4[α]D20=-46.7 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5S,6R)

1-[(3S,5S,6R)-5-(5,6-Dibenzyl-4-tert-butoxycarbonyl-2-oxomorpholin-3-yl)pentyl]-4-[(2S)-2-bis(tert-butoxycarbonylamino)-2-tert-butoxycarbonylethyl]-5-[(3S)-3-bis(tert-butoxycarbonylamino)-3-tert-butoxycarbonylpropyl] pyridinium-3-olateC66H96N4O17[α]D20=-26.7 (c 1, CHCl3)Source of chirality: l-glutamic acid, Williams glycine templateAbsolute configuration: (2S,3′S,3″S,5″S,6″R)

1-[(3S,5S,6R)-6-(5,6-Dibenzyl-4-tert-butoxycarbonyl-2-oxomorpholin-3-yl)hexyl]-4-[(2S)-2-bis(tert-butoxycarbonylamino)-2-tert-butoxycarbonylethyl]-5-[(3S)-3-bis(tert-butoxycarbonylamino)-3-tert-butoxycarbonylpropyl] pyridinium-3-olateC67H98N4O17[α]D20=-30.6 (c 1, CHCl3)Source of chirality: l-glutamic acid, Williams glycine templateAbsolute configuration: (2S,3′S,3″S,5″S,6″R)

1-[(3S,5S,6R)-5-(5,6-Dibenzyl-2-oxomorpholin-3-yl)pentyl]-4-[(2S)-2-amino-2-carboxyethyl]-5-[(3S)-3-amino-3-carboxypropyl] pyridinium-3-olateC41H44F12N4O15[α]D20=-10.6 (c 1, CD3OD)Source of chirality: l-glutamic acid, Williams glycine templateAbsolute configuration: (2S,3′S,3″S,5″S,6″R)

1-[(3S,5S,6R)-6-(5,6-Dibenzyl-2-oxomorpholin-3-yl)hexyl]-4-[(2S)-2-amino-2-carboxyethyl]-5-[(3S)-3-amino-3-carboxypropyl] pyridinium-3-olateC42H46F12N4O15[α]D20=-10.5 (c 1, CH3OH)Source of chirality: l-glutamic acid, Williams glycine templateAbsolute configuration: (2S,3′S,3″S,5″S,6″R)

1-[(6S)-6-Amino-6-carboxylhexyl]-4-[(2S)-2-amino-2-carboxyethyl]-5-[(3S)-3-amino-3-carboxypropyl] pyridinium-3-olateC19H30N4O7[α]D20=+15.2 (c 0.5, H2O)Source of chirality: l-glutamic acid, Williams glycine templateAbsolute configuration: (2S,3′S,6″S)