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 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.
Hlavácek
J
J
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic. honzah@uochb.cas.cz
Marík
J
J
Konvalinka
J
J
Bennettová
B
B
Tykva
R
R
D000079:Acetaldehyde / Q000737:chemistry; D000085:Acetates / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D002244:Carbon / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry*; D004175:Diptera; D005260:Female; D016333:HIV Protease / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006838:Hydrocarbons; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry*; D008956:Models, Chemical; D009584:Nitrogen / Q000737:chemistry; D009865:Oocytes / Q000187:drug effects / Q000648:ultrastructure; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism
D000085:Acetates; D000596:Amino Acids; D004151:Dipeptides; D017320:HIV Protease Inhibitors; D006838:Hydrocarbons; C030011:carbene; C016274:bromoacetate; D002244:Carbon; D016333:HIV Protease; D000079:Acetaldehyde; D009584:Nitrogen; D008697:Methane