Reduced collagen cross links: the first synthesis of all the possible (2S,2′S)-stereoisomers of 5-hydroxylysinonorleucine and of 5,5′-dihydroxylysinonorleucine in enantiomerically pure form

The paper reports the first enantioselective synthesis of all the possible collagen reduced cross links as described: (2S,2′S,5R)- and (2S,2′S,5S)-5-hydroxylysinonorleucine 3a and 3b, (2S,2′S,5R,5′R)-5,5′-dihydroxylysinonorleucine 4a, (2S,2′S,5R,5′S)-5,5′-dihydroxylysinonorleucine 4b and (2S,2′S,5S,5′S)-5,5′-dihydroxylysinonorleucine 4c. The Williams’ glycine template methodology was used both for the introduction of a stereogenic at the α-position and for an easy protection of the amino acidic functionalities during the synthesis of the dimeric amino acids.

Figure optionsDownload as PowerPoint slide

tert-Butyl (3S,5S,6R)-3-[(3R)-4-bromo-3-hydroxybutyl]-2-oxo-5,6-diphenyl-1,4-oxazinane-4-carboxylateC25H30BrNO5[α]D25=-46.6 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5S,6R,3′R)

tert-Butyl (3S,5S,6R)-3-[(3S)-4-bromo-3-hydroxybutyl]-2-oxo-5,6-diphenyl-1,4-oxazinane-4-carboxylateC25H30BrNO5[α]D25=-45.7 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5S,6R,3′S)

tert-Butyl (3S,5S,6R)-3-[(3R)-3,4-epoxybutyl]-2-oxo-5,6-diphenyl-1,4-oxazinane-4-carboxylateC25H29NO5[α]D25=-48.0 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5S,6R,3′R)

tert-Butyl (3S,5S,6R)-3-[(3S)-3,4-epoxybutyl]-2-oxo-5,6-diphenyl-1,4-oxazinane-4-carboxylateC25H29NO5[α]D25=-71.0 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5S,6R,3′S)

tert-Butyl (3S,5S,6R)-3-{(R)-4-[(S)-5-(benzyloxycarbonylamino)-6-tert-butoxy-6-oxohexylamino]-3-hydroxybutyl}-2-oxo-5,6-diphenyl-1,4-oxazinane-4-carboxylateC43H57N3O9[α]D25=-23.5 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5S,6R,3′R,5′S)

tert-Butyl (3S,5S,6R)-3-{(S)-4-[(S)-5-(benzyloxycarbonylamino)-6-tert-butoxy-6-oxohexylamino]-3-hydroxybutyl}-2-oxo-5,6-diphenyl-1,4-oxazinane-4-carboxylateC43H57N3O9[α]D25=-21.1 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5S,6R,3′S,5′S)

tert-Butyl (3S,5S,6R)-3-((3R)-4-benzyl{(2R)-4-[(3S,5S,6R)-4-(tert-butyloxycarbonyl)-2-oxo-5,6-diphenyl-1,4-oxazinan-3-yl]-2-hydroxybutyl}amino-3-hydroxybutyl)-2-oxo-5,6-diphenyl-1,4-oxazinane-4-carboxylateC57H67N3O10[α]D25=-63.5 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S,5S,6R,3′S,5′S,6′R,3″R)

tert-Butyl(3S,5S,6R)-3-((3S)-4-benzyl{(2S)-4-[(3S,5S,6R)-4-(tert-butyloxycarbonyl)-2-oxo-5,6-diphenyl-1,4-oxazinan-3-yl]-2-hydroxybutyl}amino-3-hydroxybutyl)-2-oxo-5,6-diphenyl-1,4-oxazinane-4-carboxylateC57H67N3O10[α]D25=-21.4 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S,5S,6R,3′S,5′S,6′R,3″S)

tert-Butyl (3S,5S,6R)-3-((3R)-4-benzyl{(2S)-4-[(3S,5S,6R)-4-(tert-butyloxycarbonyl)-2-oxo-5,6-diphenyl-1,4-oxazinan-3-yl]-2-hydroxybutyl}amino-3-hydroxybutyl)-2-oxo-5,6-diphenyl-1,4-oxazinane-4-carboxylateC57H67N3O10[α]D25=-44.0 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S,5S,6R,3′S,5′S,6′R,3″R)

tert-Butyl (3S,5S,6R)-3-[(3R)-4-benzylamino-3-hydroxybutyl]-2-oxo-5,6-diphenyl-1,4-oxazinane-4-carboxylateC32H38N2O5[α]D25=-44.8 (c 1, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,5S,6R,3′R)

(2S,5R)-2-Amino-6-[(5S)-5-amino-5-carboxypentylamino]-5-hydroxyhexanoic acid 3aC12H28Cl3N3O5[α]D25=+4.4 (c 0.33, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,5R,5′S)

(2S,5S)-2-Amino-6-[(5S)-5-amino-5-carboxypentylamino]-5-hydroxyhexanoic acid 3aC12H28Cl3N3O5[α]D25=+8.7 (c 0.33, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,5S,5′S)

(2S,5R)-2-Amino-6-[(2R,5S)-5-amino-5-carboxy-2-hydroxypentylamino]-5-hydroxyhexanoic acidC12H25N3O6[α]D25=-3.4 (c 0.5, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,5R,2′R,5′S)

(2S,5S)-2-amino-6-[(2S,5S)-5-amino-5-carboxy-2-hydroxypentylamino]-5-hydroxyhexanoic acidC12H25N3O6[α]D25=+9.1 (c 0.5, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,5S,2′S,5′S)