Z-dipeptides

Peptides with C-terminal diphenyl 1-aminoalkylphosphonates can also be used as a starting material for the synthesis of peptides with free C-terminal 1-aminoalkylphosphonic acids. In the earlier attempts, 45 diphenyl esters of Z-dipeptides 24 were transesterified to dimethyl esters 25 and these were hydrolyzed simultaneously with the Z group by HBr/ AcOH, to give the dipeptides of 1-aminoalkylphosphonic acids 26 (Scheme 17).[451 The overall yields are quite good. It is worth mentioning that diphenyl 1-aminomethylphos-... 

Fig. 3 Chromatograms obtained by pH zone-refining CCC. (A) Separation of CBZ(Z) dipeptides. Experimental conditions are as follows apparatus type-J multilayer CPC (PC Inc., Potomac, MD, USA) with a 10-cm revolution radius column multilayer coil, 1.6-mm ID, 325 mL capacity solvent system methyl tert-h xiy ether/acetonitrile/water (2 2 3), 16 mM TEA in organic phase (pH 1.83), and 5.5 mM NH3 in aqueous phase (pH 10.62) sample eight CBZ(carbobenzyloxy) dipeptides as indicated in the chromatogram, each 100 mg in 50 mL of solvent (25 mL in each phase) flow rate 3.3 mL/hr in head-to-tail elution mode detection 206 nm revolution 800 rpm retention of stationary phase 65.1%. (B) Separation of bacitracin complex. High-performance liquid chromatography (HPLC) analysis indicated that two major components, bacitracins A and B, were isolated in peaks 3 and 5, respectively. Experimental conditions are as follows apparatus and column same as above solvent system methyl r -butyl ether/ acetonitrile/water (4 1 5), 40 mM triethylamine, 10% DEHPA in the organic stationary phase, and 20 mM HCl in aqueous mobile phase flow rate 3 mL/min sample 5 g of bacitracin dissolved in 40 mL of solvent (20 mL in each phase) revolution 800 rpm detection 280 nm.

The octadecylamide of N-benzyloxycarbonyl-L-isoleucine 79 and N-benzyloxycarbonyl-L-Val-L-Val alkylamide 80, as well as some other N-Z-dipeptide alkylamides [60], exhibited excellent gelation properties toward many organic solvents of low, medium, and high polarity at mgc values in the range of 5-40 g L The compound was used for the preparation of organogel electrolytes and porous titania with fibrous structure by sol-gel transcription of gel fibers using polymerization of titanium tetraisopropoxide [61,62]. 

As a second example, proteinase activities in soils have been measured using proteins, protein and peptide derivatives, and substituted amides and esters as assay substrates. Ladd and Butler tested a range of N-benzyloxycarbonyl (Z) dipeptide derivatives, including those with amino acid residues with either aromatic, acidic, or non-polar aliphatic (long or... 

Soil differed in their relative activities towards ZPL and BAA the enzymes involved were extracted from a soil with different efficiencies. Extracted ZPL-hydrolysing enzymes retained complete activity when freeze-dried, or dried at 30°C (90 min), or when incubated under bacteriostatic conditions for 10 days at 25°C. Incubation of the extracts for 1 day at 30°C with or without the addition of microbial proteinases, thermolysin or subtilisin decreased activities towards ZPL by about 10% only. The extracted enzyme, in regard to its specificity of hydrolysis of Z-dipeptides and its response to inhibitors, exhibited some of the properties of carboxypeptidase. 

The first two entries in Table 9 illustrate the above principle. Both tripeptide Boc—Cys(SBzl)—D-vai-OBzi and dipeptide Z—Tyr—D-Arg-OMe are... 

In the first publication describing the preparative use of an enzymatic reaction in ionic liquids, Erbeldinger et al. reported the use of the protease thermolysin for the synthesis of the dipeptide Z-aspartame (Entry 6) [34]. The reaction rates were comparable to those found in conventional organic solvents such as ethyl acetate. Additionally, the enzyme stability was increased in the ionic liquid. The ionic liquid was recycled several times after the removal of non-converted substrates by extraction with water and product precipitation. Recycling of the enzyme has not been reported. It should be noted, however, that according to the log P concept described in the previous section, ethyl acetate - with a value of 0.68 - may interfere with the pro-... 

In an attempt to identify new, biocompatible diphenols for the synthesis of polyiminocarbonates and polycarbonates, we considered derivatives of tyrosine dipeptide as potential monomers. Our experimental rationale was based on the assumption that a diphenol derived from natural amino acids may be less toxic than many of the industrial diphenols. After protection of the amino and carboxylic acid groups, we expected the dipeptide to be chemically equivalent to conventional diphenols. In preliminary studies (14) this hypothesis was confirmed by the successful preparation of poly(Z-Tyr-Tyr-Et iminocarbonate) from the protected tyrosine dipeptide Z-Tyr-Tyr-Et (Figure 3). Unfortunately, poly (Z-Tyr-Tyr-Et iminocarbonate) was an insoluble, nonprocessible material for which no practical applications could be identified. This result illustrated the difficulty of balancing the requirement for biocompatibility with the need to obtain a material with suitable "engineering" properties. 

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... 

The synthesis of the octapeptide isoleucine-5-angiotensin Z-Asp(NH2)-Arg(N02)-Val-Tyr-Ile-His-Pro-Phe-OCH3 using CDI as condensing agent was achieved by preparing the four required dipeptides (1—2), (3-4), (5-6), (7-8), two tetrapeptides (1-4) and (5-8), and finally the octapeptide itself. 123... 

The thermal [1] or photochemical [5] isomerization of N-silylated allylamine in the presence of Fe(CO)5 provides the corresponding N-silylated enamines 7a and 7b. Z-enamine 7b does not react in any of the examined cycloadditions. The cyclopropanation of E-enamine 7a with methyl diazoacetate under copper(I) catalysis provides the donor-acceptor-substituted cyclopropane 9 [1], which can be converted in good yield into the interesting dipeptide 10 [6]. 

Once it is part of a cyclic dipeptide, the prolyl residue becomes susceptible to enantiomerization by base (see Section 7.22). The implication of the tendency of dipeptide esters to form piperazine-2,5-diones is that their amino groups cannot be left unprotonated for any length of time. The problem arises during neutralization after acidolysis of a Boc-dipeptide ester and after removal of an Fmoc group from an Fmoc-dipeptide ester by piperidine or other secondary amine. The problem is so severe with proline that a synthesis involving deprotection of Fmoc-Lys(Z)-Pro-OBzl produced only the cyclic dipeptide and no linear tripeptide. The problem surfaces in solid-phase synthesis after incorporation of the second residue of a chain that is bound to the support by a benzyl-ester type linkage. There is also the added difficulty that hydroxymethyl groups are liberated, and they can be the source of other side reactions. 

The unusual amino acid (S)-2-amino-(Z)-3,5-hexadienoic acid (269), which is a component of the toxic y-glutamyl dipeptide isolated from the defensive glands of the Colorado beetle [209], has been synthesized along Scheme 17, after two initial attempts had proved unsuccessful due to the instability of 269 towards various oxidation conditions [210]. Scheme 17 relies on the hydrolysis of an ortho ester to generate the required carboxylic acid. Thus, the L-serine aldehyde equivalent 270 was treated with ( )-l-trimethylsilyl-l-propene-3-boronate to give the addition product 271. Reaction of 271 with KH gave the stereochemically pure (Z)-diene 272. Mild acid treatment of 272 followed by... 

FIGURE 1.28 Chromatograms of the HPLC enantiomer separation of Z-protected a-aminophosphinic acids (a,b) and phosphinic acid-ilr-dipeptide (c) on (a and b) a 0-9-(tert-butylcarbamoyl)quinidine CSP and (c) corresponding 0-9-(fcrr-butylcarbamoyl)qninine-CSP, respectively. Experimental conditions Column dimensions, 150 mm x 4 mm ID mobile phase, methanol-50 mM sodium phosphate buffer (80 20 v/v) (pHa 5.6) temperature, 40°C flow rate, 1 mLmin detection, UV at 250 nm and optical rotation detection (ORD). (Reproduced from M. Lammerhofer et ah, Tetrahedron Asymmetry, 14 2557 (2003). With permission.)... 

Synthesis of funtionalized (Z)-fluoroalkene-type dipeptide isosteres (36) via Sml2-mediated reduction of y,y-difluoro-ot, -enoates 2.3.19. Reductive formation of fluoroolefins and subsequent conversion to diketopiperazine mimics (71). Nonpeptidic amide bond replacement... 

The Phe-Gly isostere (Z)-5 was prepared starting with the aldehyde (7b) (Scheme 2). The A/-Boc protected dipeptide isostere (Z)-5 was obtained as a racemate. 

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