Dipeptides acylations with

Similarly, acylation of the dipeptide 410 with bromoacetyl chloride followed by base-induced cyclization gives the pyrazinylacetate ester 411 <2001BML1251>. Compound 410 is itself cyclized with />-toluenesulfonic acid to give the (iV-alkylated indole) equivalent of 406 <200JME3518>. 

Piperazine-2,5-diones can be symmetric or asymmetric. Symmetric DKPs are readily obtained by heating amino acid esters,1179-181 whereas asymmetric DKPs are obtained directly from the related dipeptides under basic or, more properly, acid catalysis, or by cyclocondensation of dipeptide esters.1182-185 As an alternative procedure hexafluoroacetone can be used to protect/activate the amino acid for the synthesis of symmetric DKPs or of the second amino acid residue for synthesis of the dipeptide ester and subsequent direct cyclocondensation to DKPs.1186 The use of active esters for the cyclocondensation is less appropriate since it may lead to epimerization when a chiral amino acid is involved as the carboxy component in the cyclization reaction. Resin-bound DKPs as scaffolds for further on-resin transformations are readily prepared using the backbone amide linker (BAL) approach, where the amino acid ester is attached to the BAL resin by its a-amino group and then acylated with a Fmoc-protected amino acid by the HATU procedure, N -deprotection leads to on-resin DKP formation1172 (see Section 6.8.3.2.2.3). 

N-Trifluoroacetyl methyl esters were used by Weygand et al. [206] for the analysis of amino acids and dipeptides, their properties were described by Makisumi and Saroff [207] and the conditions for their quantitative preparation and analysis were investigated by various workers [197,208—211 ]. A common procedure for their preparation is the following. Esterification is accomplished by reaction with methanolic HC1 at 70°C for 30 min, and acylation with TFA anhydride at room temperature for 30 min Arg requires, however, a higher reaction temperature (140°C for 10 min) and His, even under these conditions, gives only low yields. A temperature of 120°C for 20 min was therefore recommended for acylation [212]. 

Multidimentional nonlinear infrared spectroscopy is used for identification of dynamic structures in liquids and conformational dynamics of molecules, peptides and, in principle, small proteins in solution (Asplund et al., 2000 and references herein). This spectroscopy incorporates the ability to control the responses of particular vibrational transitions depending on their couplings to one another. Two and three-pulse IR photon echo techniques were used to eliminate the inhomogeneous broadening in the IR spectrum. In the third-order IR echo methods, three phase-locked IR pulses with wave vectors kb k2, and k3 are focused on the sample at time intervals. The IR photon echo eventually emitted and the complex 2D IR spectrum is obtained with the use of Fourier transformation. The method was applied to the examination of vibrational properties of N-methyl acetamid and a dipeptide, acyl-proline-NH2.in D20. The 2D IR spectrum showed peaks at 1,610 and 1, 670 cm 1, the two frequencies ofthe acyl-proline dipeptide. Geometry and time-ordering of the incoming pulse sequence in fifth-order 2D spectroscopy is shown in Fig. 1.3. 

A remarkably simple one-step synthesis of a peptide receptor in 13% yield has been reported by Yoon and Still (Figure 69) [94], This molecule was shown to bind y-acylated amino acids and dipeptide amides with high enantioselectivity. For example, L- and D-enantiomers of N-Boc-Gly-Val-NHMe (Boc=t-butoxycarbonyl, Val = valine) showed complexation free energies of... 

To investigate the antifungal activity of cispentacin derivatives, six dipeptide derivatives of ( )-c -2-ACPC were synthetized. The syntheses were straightforward the Z-protected ( )-c -2-ACPC was activated with isobutyl chloroformate and treated with the corresponding amines, followed by deprotection to give the carboxamides 122 (R =Me, R2=H R =H, R2=Me R1=CH2Ph, R2=H) [167]. The A-acyl derivatives 2 (R =Me, R2=H R =H, R2=Me RI=CH2Ph, R2=H) were prepared from the methyl ester of ( )-ci s,-2-ACPC, which was acylated with Boc-amino acids, followed by hydrolysis and deprotection, to afford 123 [167]. 

Among the numerous variations made around the a-methyl-DOPA molecule, acylation with a glycyl-glycyl residue was claimed to improve oral bioavailability. For a series of anticandidal di- and tripeptides containing m-fluorophenylalanine (m-FPhe), competitive antagonism studies supported peptide transport-mediated entry of the warhead m-FPhe inside the cell. Dipeptides derived from a-methyldopa (Fig. 33.9) show a 10 to 20-fold better penetration of the intestinal wall than a-methyldopa itself. 

Tiyptophan-isoleucine dipeptide linked to PEGA resin was acylated with Boc-protected 3-(l,3-oxazinyl)propanoic acid. Exposure of the material to TEA generates acyliminium ions that cyclize to p-carbolines, with a preference for the traws-stereoisomer [355], The modified dipeptides were cleaved firom the resin with a base. 

The initially planned 2 + 3 combination (linking the N-terminal dipeptide segment with the central tripeptide) ran into technical difficulties and therefore the plan was changed and the central portion of the molecule attached to the C-terminal tetrapeptide segment to give a heptapeptide derivative. The heptapep-tide amide was partially deblocked and acylated with the N-terminal dipeptide. 

Acid catalyzed hydrolysis followed by the identification of D-amino acids in the hydrolysate is equally useful. To make this possible the amino acids in the mixture are acylated with an enantiomerically pure amino acid, for instance with the N-carboxyanhydride of L-leucine. In the resulting mixture of dipeptides any racemized residue is revealed by the formation of two dipeptides that are diastereoisomers of each other, for instance L-leucyl-L-phenylalanine and L-leucyl-D-phenylalanine. Since these are compounds with different physical properties they are separable and appear as a doublet on recordings of an amino acid analzyer. In recent years the conversion to diastereoisomers became unnecessary because the availability of chiral supports now permits separation of enantiomers by high pressure liquid chromatography (HPLC) and also by thin layer chromatography on plates covered with a chiral layer. 

It has been shown that glyeine amides of aminobenzophenones are readily converted to the corresponding benzodiazepines in vivo. Peptides which terminate in such a moiety should thus serve as a benzodiazepine prodrug after hydrolysis by peptidases. One of the glycine residues in lorzafone (194)is presumably removed metabolicaUy in this manner to give a benzodiazepine precursor which spontaneously cyclizes. Acylation of benzophenone 190 with the trityl protected dipeptide 191, as its acid chloride 192, affords the amide 193. Removal of the trityl protecting group with acid yields lorzafone (194) [50]. 

A comparison of the structures of penicillin and Dalanyl-Dalanine (cf. structures 41 and 42) shows that there is a great deal of similarity between the two molecules. Penicillin is essentially an acylated cyclic dipeptide of Dcysteine and Dvaline (84). As such, it contains a peptide bond, that of the /3-lactam ring, that can acylate the enzyme. Labeling studies of the peptidoglycan transpeptidase of Bacillus subtilis indicate that radioactive penicillin reacts with a sulfhydryl group of a cysteine residue of the enzyme (86). 

Racemization studies in the synthesis of the tripeptide Z-Gly-Phe-Gly from Z-Gly-Phe and Gly-OC2H5 revealed that in THF at room temperature such racemization occurred to the extent of about 5%, in DMF at -10 °C, however, less than 0.5%. 53 103 In the synthesis of Boc-Val-Tyr-OC2H5 (50%) from Boc-Val and Tyr-OC2H5 with CDI, a small amount of 0-acylation of tyrosine (4%) also occurred in the dipeptide. 11] A V -Carbonyldibenzimidazole was found inferior to CDI in the synthesis of peptides because of poorer yields and more rigorous reaction conditions needed. 53... 

Another -activation of amino acids for peptide synthesis is achieved by preparing sulfenamides from sulfenylimidazoles. A sulfenylimidazole is formed in situ from the sulfenyl chloride (prepared from the disulfide and chlorine) and imidazole, which reacts further with an amino acid ester to give a sulfenamide in high yield. Conversion of such sulfenamides with IV-acyl amino acids by means of triphenylphosphine affords dipeptides with racemization of less than 0.5%.[481... 

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