Synthesis and application of methyleneoxy pseudodipeptide building blocks in biologically active peptides

Pseudodipeptides H-Phepsi[CH2O]Phe-OH, H-Tyrpsi[CH2O]Asp-OH and H-Propsi[CH2O]-D-Thr-OH were synthesized using the intramolecular Williamson reaction via substituted morpholin-3-one ring with the nitrogen atom protected with bulky Boc group. This protection and the substituent at C5 position induced...

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Bibliographic Details
Published in:Amino acids 2004-08, Vol.27 (1), p.19-27
Main Authors: Hlavácek, J, Marík, J, Konvalinka, J, Bennettová, B, Tykva, R
Format: Article
Language:English
Subjects:
Acetaldehyde
Acetaldehyde - chemistry
Acetates - chemistry
Alkylation
Amino acids
Amino Acids - chemistry
Animals
Benzaldehyde
Bonding
Carbon - chemistry
Dipeptides - chemical synthesis
Dipeptides - chemistry
Diptera
Female
HIV Protease - chemistry
HIV Protease Inhibitors - pharmacology
Hydrocarbons
Hydrolysis
Industrial gases
Magnetic Resonance Spectroscopy
Male
Methane - analogs & derivatives
Methane - chemistry
Models, Chemical
Nitrogen - chemistry
Oocytes - drug effects
Oocytes - ultrastructure
Peptides
Protein Structure, Tertiary
Quenching
Stereoisomerism
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Summary:Pseudodipeptides H-Phepsi[CH2O]Phe-OH, H-Tyrpsi[CH2O]Asp-OH and H-Propsi[CH2O]-D-Thr-OH were synthesized using the intramolecular Williamson reaction via substituted morpholin-3-one ring with the nitrogen atom protected with bulky Boc group. This protection and the substituent at C5 position induced the stereospecific alkylation at the C2 position introducing the side chain of the C-terminal amino acid mimetic. In the first pseudodipeptide a quenching of the enolate with benzaldehyde was followed by dehydration and corresponding double bond was hydrogenated with high stereospecific purity. In the other pseudodipeptides, this alkylation was carried out directly by tert-butyl 2-bromoacetate or acetaldehyde. However, in the latter reaction an R configuration of C3 substituent in conjugated lactame ring was determined using a NOE NMR. Consequently, after opening this ring by acidic hydrolysis, the C-terminal part of corresponding pseudodipeptide possessed the side-chain of D-Thr mimetic, contrary to former one. Synthesized pseudodipeptides were introduced into HIV protease inhibitors and into peptides with oostatic activity.
ISSN:0939-4451
1438-2199
DOI:10.1007/s00726-004-0099-z