Jaroslav Šavrda

Activation of N,N-bis(alkoxycarbonyl) amino acids. Synthesis of N-alkoxycarbonyl amino acid N-carboxyanhydrides and N,N-dialkoxycarbonyl amino acid fluorides, and the behavior of these amino acid derivatives.

Abstract Series of Boc- and Cbz-NCAs ( 2 ), and of N,N- bis (alkoxycarbonyl) amino acid fluorides U 2 AAFs ( 3 ) have been prepared by activation of N,N- bis -Boc- and N-Cbz,N-Boc-α-amino acids ( 1 ) with the Vilsmeier reagent or cyanuric fluoride. The absence of epimerization of 2 and 3 during both their formation and their coupling under standard conditions of peptide synthesis had been demonstrated by optical purity Youngs tests. In other activated derivatives of bis -urethane protected activated amino acids, the exchangeability of the α-H is shown by the considerable racemization of Boc 2 Phe-OSu ( 8 ) in the presence of base, and by the formation of a Dakin-West type product 11 from the dipeptide Boc 2 Phe-Leu-OBn.

Novel α,α-disubstituted α-aminoacids with axial dissymmetry and their N- or C-protected derivatives

Abstract Racemic as well as enantiomerically pure 1,1′-binaphthyl-substituted α-aminoisobutyric acid (Bin), a new chiral atropoisomeric α,α-disubstituted glycine, and its biphenyl analogue (Bip), have been prepared with good yields by bis-alkylation of a glycine tert-butyl ester Schiff base with 2,2′-bis(bromomethyl)-1,1′-binaphthyl and 2,2′-bis(bromomethyl)-1,1′-biphenyl, respectively, under phase transfer conditions. The free aminoacids Bin and Bip, as well as their N-protected (Z, Boc, Fmoc) and/or C-protected (ethyl or tert-butyl esters) derivatives, useful for the incorporation of these new aminoacids into peptides, have been obtained. A slow interconversion between the two enantiomers of the Bip derivatives is generally observed in 1H NMR at room temperature, with a rotational energy barrier of 59 kJ mol−1.

N-t-Boc 6-amino-1,11-(20-crown-6)-6,7-dihydro-5H-dibenzo[a,c] cycloheptene-6-carboxylic acid methyl ester, the first prototype of a crown-carrier-axially dissymmetric-α,α-disubstituted glycine

Abstract N-t-Boc 6-amino-1,11-(20-crown-6)-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-6-carboxylic acid methyl ester: Boc-[20-C-6]-Bip-OMe 1 , a new crown-carrier-α,α-disubstituted glycine with axial dissymmetry and a potential building block for the synthesis of polypeptide supramolecular devices, has been synthesized at the racemic state by phase transfer bis-alkylation of a glycine tert -butyl ester Schiff base with 2,2′- bis -(bromomethyl)-6,6′-dimethoxy-1,1′-diphenyl, followed by demethylation, esterification, N-protection and crown formation upon cyclization of the di-cesium salt of the resulting diphenol with pentaethyleneglycol ditosylate.

Synthesis, conformational study, and spectroscopic characterization of the cyclic Cα,α‐disubstituted glycine 9‐amino‐9‐fluorenecarboxylic acid

A series of terminally blocked peptides (to the pentamer level) from l‐Ala and the cyclic Cα,α‐disubstituted Gly residue Afc and one Gly/Afc dipeptide have been synthesized by solution method and fully characterized. The molecular structure of the amino acid derivative Boc‐Afc‐OMe and the dipeptide Boc‐Afc‐Gly‐OMe were determined in the crystal state by X‐ray diffraction. In addition, the preferred conformation of all of the model peptides was assessed in deuterochloroform solution by FT‐IR absorption and 1H‐NMR. The experimental data favour the conclusion that the Afc residue tends to adopt either the fully‐extended (C5) or a folded/helical structure. In particular, the former conformation is highly populated in solution and is also that found in the crystal state in the two compounds investigated. A comparison with the structural propensities of the strictly related Cα,α‐disubstituted Gly residues Ac5c and Dϕg is made and the implications for the use of the Afc residue in conformationally constrained analogues of bioactive peptides are briefly examined. A spectroscopic (UV absorption, fluorescence, CD) characterization of this novel aromatic Cα,α‐disubstituted Gly residue is also reported. Copyright

Synthesis of a potential “suicide substrate” of the HIV-1 protease, incorporating A 3-acetoxy-Δ-4,5-(L)-pipecolic acid as proline substitute.

Coupling of (D,L)-baikiain methyl ester with Boc-(L)-phenylalanine, followed by saponification, idolactonization and aminolysis of the diastereoisomeric iodolactones by (L)-isoleucyl-(L)-valine methyl ester gave two diastereoisomeric peptides incorporating either a 3S-hydroxy-4S-iodo-(L)-pipecolic acid or a 3R-hydroxy-4R-iodo-(D)-pipecolic acid residue, which were separated by thin layer chromatography. Assignment of configuration was unambiguous when the synthesis was repeated with (L)-baikiain as starting material. All compounds exhibited conformational isomerism in their1H NMR spectra, attributed to the existence of boths-cis ands-trans configurations of the Phe-NR2 peptide bond. Acetylation of each of the two separated diastereoisomers gave Boc-(L)-Phe-3S-OAc-4S-I-(L)-Pip-(L)-Ile-(L)-Val-OMe and Boc-(L)-Phe-3R-OAc-4R-I-(D)-Pip-(L)-Ile-(L)-Val-OMe. N-deprotection and coupling of the former with Boc-(L)-Ser-(L)-Ala-(L)-Ala-OH by the DCC/HOBt method or stepwise elongation of the peptidic chain, gave Boc-(L)-Ser-(L)-Ala-(L)-Ala-(L)-Phe-3S-OAc-4S-I-(L)-Pip-(L)-Ile-(L)-Val-OMe. Dehydroiodination of this compound on treatment with DBU gave Boc-(L)-Ser-(L)-Ala-(L)-Ala-(L)-Phe-3S-OAc-Δ-4,5-(L)-Pip-(L)-Ile-(L)-Val-OMe, a potential “suicide substrate” of the HIV-1 protease.

Afc can adopt either the fully extended or a turn conformation

We have synthesized by solution methods and fully characterized two sets of terminally protected peptides based on the tricyclic Cα,α-disubstituted glycine Afc. The conformational preferences of the Afc/Gly peptides were examined by FT-IR absorption and1H NMR techniques, while those of the Afc/TOAC peptides were primarily investigated by using fluorescence spectroscopy. The X-ray diffraction structure of an Afc derivative was also analyzed. The body of solution and crystal-state experimental data conclusively confirms previous findings that the Afc residue may either adopt the fully extended (C5) or a turn conformation.

Peptoid mimics of a C2-symmetric inhibitor of the HIV-1 protease

Abstract Compounds II , designed as retro peptoid mimics of a known potent C 2 -symmetric inhibitor I of the HIV protease, were synthesized in solution, using BOP as coupling reagent. They showed no significant inhibitory activity with respect to the HIV-1 protease.

Urethane protected amino acid N-carboxyanhydrides and fluorides (U-NCAs and U2AAFs).

SummaryIn order to obtain peptide analogues containing a central pyrrolide bond, as potential mechanism-based inhibitors of the HIV-1 proteinase, activated derivatives of amino acids were required. Treatment of a N,N-bis(Boc) amino acid pyridinium salt with cyanuric fluoride in dichloromethane furnished the correspondingbis(Boc) amino acid fluoride (Boc2AAF). Use of the Vilsmeier reagent in acetonitrile, instead of the cyanuric fluoride, led to a N-Boc amino acid N-carboxyanhydride (Boc-NCA). From a mixed N-Z,N-Boc amino acid salt a N-Z,N-Boc amino acid fluoride and a Z-NCA were respectively obtained. The very sensitive Young test showed that during the coupling of the N-benzoyl-L-Leucine N-carboxyanhydride or the N-benzoyl N-Boc-L-leucyl fluoride with ethyl glycinate the degrees of racemization were weak. Owing to the electronegativity and the small size of the fluorine atom, thebis(urethane) amino acid fluorides are efficient acylating agents for amines and pyrrole anions.

Synthesis of C2-symmetric inhibitors of the HIV-1 protease, with N,N′-substituted ethylenediamide and ethylenediamine linkers.

Abstract Coupling of Z-(L)-phenylalanine with either ethylenediamine or N,N′-dimethylethylenediamine, followed by N-deprotection and either direct coupling with Z-(L)-valine or amide reduction prior to coupling, gave C2-symmetric compounds [Z-Val-Phe-(N(R)CH2-]2 (R = H, CH3) and [Z-Val-Phe(ΨCH2-N)-N(R)CH2-]2 (R= H, CH3, CH2COOH, CH2CH2OH) which were moderately active inhibitors of the HIV-1 protease.