ABSTRACT
Acylation of tetra-O-pivaloyl-beta-D-galactopyranosylamine 2 by readily available N- (Cbz or Fmoc-alpha-aminoacyl) benzotriazoles under microwave irradiation proceeded diastereoselectively to give beta-N-glycoaminoacids 3a-d, (3c+3c') (compound numbers written within brackets represent a racemate or a diastereomeric mixture; compound numbers without brackets represent a single enantiomer) (83-92%), and glycosylated asparagine building block 9 (65%). N-Cbz-Protected peptidoylbenzotriazoles 4a-c similarly afforded beta-N-glycodipeptides 5a-c (76-81%). Regiospecific beta-N-linkage formation was established by 1D and 2D NMR techniques for 3b.
Subject(s)
Amino Acids/chemical synthesis , Glycopeptides/chemical synthesis , Amino Acids/chemistry , Amino Acids/radiation effects , Glycopeptides/chemistry , Glycopeptides/radiation effects , Magnetic Resonance Spectroscopy/methods , Microwaves , Molecular Structure , StereoisomerismABSTRACT
N-Z-pyroglutamyl pseudopeptides 3a-c are shown to be conveniently prepared from glutamyl-bis-Bt 1a by cyclization of an N-terminal glutamic acid residue. Structures are supported by 2D NMR studies and by comparison with the same products prepared by direct coupling of the C-terminus activated N-pGlu 1b and free amino acids 2a-c.
Subject(s)
Amino Acids/chemical synthesis , Pyrrolidonecarboxylic Acid/chemistry , Magnetic Resonance SpectroscopyABSTRACT
Hindered amino acids have been introduced into peptide chains by coupling N-(Cbz- and Fmoc-alpha-aminoacyl)benzotriazoles with amino acids, wherein at least one of the components was sterically hindered, to provide compounds 3a-e, (3c +3 c'), 5a-d, (5a + 5a'), 6a-c, (6b + 6b'), 8a-c, 9a-e, 10a-d, and (10a + 10a') in isolated yields of 41-95% with complete retention of chirality as evidenced by NMR and HPLC analysis. The benzotriazole activation methodology is a new route for the synthesis of sterically hindered peptides. (Note: compound numbers written within brackets represent diastereomeric mixtures or racemates; compound numbers without brackets represent enantiomers.).
Subject(s)
Amino Acids/chemistry , Peptides/chemistry , Magnetic Resonance Spectroscopy , Protein ConformationABSTRACT
1,2:3,4-Di-O-isopropylidene-alpha-D-galactopyranose (2), 1,2:5,6-di-O-isopropylidene-d-glucose (5), and 2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranose (7) are efficiently O-acylated in 78-96% yields with readily available N-(Z-alpha-aminoacyl)benzotriazoles 1a-e, 1d+1d' under microwave irradiation to give chiral 3a-d, 4, 6a-d, 8a,b and diastereomeric mixtures (3d+3d'), (6a+6a'), and (6d+6d'). The original chirality was retained as evidenced by HPLC. The diisopropylidene protecting groups were removed from compounds 3a,d, 6d to give the free O-(Z-alpha-aminoacyl) sugars 9a,b, 10.
Subject(s)
Carbamates/chemistry , Glycopeptides/chemistry , Hexoses/chemistry , Peptide Library , Carbamates/chemical synthesis , Glycopeptides/chemical synthesis , Hexoses/chemical synthesis , StereoisomerismABSTRACT
Dipeptides 3a-g, (3a + 3a'), (3d + 3d'), (3l + 3l')a and tripeptides 6a-e, (6b + 6b'), (6e + 6e') incorporating Z(epsilon)-Lys were prepared in high yields (70-95%) and enantiopurity (> or =97%) in partially aqueous acetonitrile solution by coupling using (i) Z(epsilon)-Lys with N-(Z- and Fmoc-aminoacyl)benzotriazoles 1a-g, (ii) Z(epsilon)-Lys with N-Z-dipeptidoylbenzotriazoles 5a-c, and (iii) N-Fmoc(alpha)-Z(epsilon)-l-Lys-Bt 1h and amino acids 2a,c-e. Unnatural dipeptides 3h-j, (3h + 3h') and tripeptides 6f were similarly prepared from Z(alpha)-Lys. Retention of chirality was demonstrated by parallel experiments involving l-Ala, dl-Ala, l-Met, and dl-Met by NMR and HPLC analysis.
Subject(s)
Dipeptides/chemical synthesis , Lysine/chemistry , Oligopeptides/chemical synthesis , Acetonitriles/chemistry , Dipeptides/chemistry , Oligopeptides/chemistry , Solutions/chemistry , StereoisomerismABSTRACT
Diverse N-protected di-(3a-d, 3a + a', 5a-d, 5d + d', and 7a-g) and tripeptides (10a-h) were synthesized under mild reaction conditions in good yields (65-97%) by acylation with 1-(N-protected-alpha-aminoacyl)benzotriazoles of the amino groups of free aspartic and glutamic acids. Complete retention of chirality was demonstrated by parallel experiments involving D-Ala, L-Ala, and DL-Ala for the preparation of dipeptides and tripeptides, and supported by NMR and HPLC analyses.
Subject(s)
Aspartic Acid/chemistry , Glutamic Acid/chemistry , Oligopeptides/chemical synthesis , Triazoles/chemistry , Aminoacylation , Aspartic Acid/chemical synthesis , Chromatography, High Pressure Liquid , Glutamic Acid/chemical synthesis , Magnetic Resonance Spectroscopy , Oligopeptides/chemistry , Stereoisomerism , Triazoles/chemical synthesisABSTRACT
Aspartic and glutamic acids were selectively extended at each of the alternative C-terminals under mild conditions to afford diverse natural and unnatural N-protected dipeptides and tripeptides in yields of 73-96%. The reactions between N-protected (alpha-aminoacyl)benzotriazoles and free amino acids or dipeptides proceeded with complete retention of chirality as supported by parallel experiments involving D-Ala, L-Ala, and DL-Ala in the preparation of dipeptides and tripeptides, monitored by NMR and HPLC analyses.
Subject(s)
Aspartic Acid/chemistry , Glutamic Acid/chemistry , Oligopeptides/chemical synthesis , Triazoles/chemistry , Aminoacylation , Aspartic Acid/chemical synthesis , Chromatography, High Pressure Liquid , Glutamic Acid/chemical synthesis , Magnetic Resonance Spectroscopy , Oligopeptides/chemistry , Stereoisomerism , Triazoles/chemical synthesisABSTRACT
Chiral O-(alpha-protected-aminoacyl)steroids 4a-f, 6a-b, 8 and 4a+4d and O-(alpha-protected-dipeptidoyl)steroids 12a,b are conveniently prepared under microwave irradiation in isolated yields of 65-96%, with complete chirality retention. The reaction utilized readily available N-(Z-alpha-aminoacyl)benzotriazoles 2a-f and Z-dipeptidoylbenzotriazole 11, with naturally occurring steroidal alcohols 3,5,7,9.
