P-peptide synthesis

Mergler M, Tanner R, Gosteli J, Grogg P. Peptide synthesis by a combination of solid-phase and solution methods. I A new very acid-labile... 

Mergler, M. Nyfeler, R. Tanner, R. Gosteli, J. Grogg, P. Peptide Synthesis by a Combination of Solid-Phase and Solution Methods. 11. Synthesis of Fully Protected Peptide Fragments on 2-Methoxy-4-alkoxybenzyl Alcohol Resin, Tetrahedron Lett. 1988, 29,4009. 

S. Abele, D. Seebach, Preparation of Achiral and of Enantiopure Geminally Disubstituted p-Amino Acids for P-Peptide Synthesis , Eur. J. Org. Chem. 2000, 1 - 15. 

Nelson, S. G., Spencer, K. L., Cheung, W. S. and Mamie, S. J. (2002) Divergent reaction pathways in amine additions to P-lactone electrophiles. An application to P-peptide synthesis. Tetrahedron, 58, 7081-7091. 

Seebach, D., Beck, A.K., Capone, S., Deniau, G., GroJelj, U., and Zass, E. (2009) Enantioselective preparation of P -amino acid derivatives for P-peptide synthesis. Synthesis, 1, 1-32. 

CF3CO2H. Colourless liquid, b.p. 72-5 C, fumes in air. Trifluoroacetic acid is the most important halogen-substituted acetic acid. It is a very strong acid (pK = o y) and used extensively for acid catalysed reactions, especially ester cleavage in peptide synthesis. 

In each step of the usual C-to-N peptide synthesis the N-protecting group of the newly coupled amino acid must be selectively removed under conditions that leave all side-chain pro-teaing groups of the peptide intact. The most common protecting groups of side-chains (p. 229) are all stable towards 50% trifluoroacetic acid in dichloromethane, and this reagent is most commonly used for N -deprotection. Only /ert-butyl esters and carbamates ( = Boc) are solvolyzed in this mixture. 

This reaction sequence is much less prone to difficulties with isomerizations since the pyridine-like carbons of dipyrromethenes do not add protons. Yields are often low, however, since the intermediates do not survive the high temperatures. The more reactive, faster but less reliable system is certainly provided by the dipyrromethanes, in which the reactivity of the pyrrole units is comparable to activated benzene derivatives such as phenol or aniline. The situation is comparable with that found in peptide synthesis where the slow azide method gives cleaner products than the fast DCC-promoted condensations (see p. 234). 

FIGURE 27 14 A section of polystyrene showing one of the benzene rings modified by chloromethylation Indi vidual polystyrene chains in the resin used in solid phase peptide synthesis are con nected to one another at various points (cross linked) by adding a small amount of p divinylbenzene to the styrene monomer The chloromethylation step is carried out under conditions such that only about 10% of the benzene rings bear —CH2CI groups... 

M. Bodansky, Peptide Synthesis, 2nd ed., John Wiley Sons, Inc., New York, 1976 J. Meinhofer in Ref. 1, Chapt. 9, p. 297 G. R. Pettit, Synthetic Peptides, Vols. 1—4, Van Nostrand Reinhold, New York, 1980, Vols. 5, 6, Elsevier New York, 1982 E. Shroeder and K. Luebke, The Peptide, Vol. 1, Methods of Peptide Synthesis, Academic Press, New York, 1965 N. Izumiya and co-workers. Fundamentals and Experiments of Peptide Synthesis (in Japanese), Mamzen, Tokyo, Japan, 1987 R. B. Merriheld,/ Mm. Chem. Soc. 85, 2149 (1963) G. Barany and R. B. Merriheld in E. Gross andj. Meinenhofer, eds.. The Peptides Mnalysis, Synthesis, Biology, Vol. 2, Academic Press, New York, 1980, pp. 1—284 G. R. Marshall, Peptides Chemistry and Biology, Escom, Leiden, The Netherlands, 1988. 

Nearly all of the benzyl chloride [100-44-7], henzal chloride [98-87-3], and hen zotrichl oride /P< -(97-i manufactured is converted to other chemical intermediates or products by reactions involving the chlorine substituents of the side chain. Each of the compounds has a single primary use that consumes a large portion of the compound produced. Benzyl chloride is utilized in the manufacture of benzyl butyl phthalate, a vinyl resin plasticizer benzal chloride is hydrolyzed to benzaldehyde hen zotrichl oride is converted to benzoyl chloride. Benzyl chloride is also hydrolyzed to benzyl alcohol, which is used in the photographic industry, in perfumes (as esters), and in peptide synthesis by conversion to benzyl chloroformate [501-53-1] (see Benzyl ALCOHOL AND p-PHENETHYL ALCOHOL CARBONIC AND CARBONOCm ORIDIC ESTERS). 

The / -(methylmercapto)phenyl ester has been prepared from an /-protected amino acid and 4-tH3SC6H40H (DCC, CH2CI2, 0°, 1 h 20°, 12 h, 60-70% yield). The p-(methylmercapto)phenyl ester serves as an unactivated ester that is activated on oxidation to the sulfone (H2O2, AcOH, 20°, 12 h, 60-80% yield) which then serves as an activated ester in peptide synthesis. ... 

Alkyldithio carbamates are prepared from the acid chloride (Et N, EtOAc, 0°) and amino acid, either free or as the O-silyl derivatives (70-88% yield). The N- i-propyldithio) carbamate has been used in the protection of proline during peptide synthesis. Alkyldithio carbamates can be cleaved with thiols, NaOH, Ph P/TsOH. They are stable to acid. Cleavage rates are a function of the size of the alkyl group as illustrated in the table below. 

In the second major method of peptide synthesis the carboxyl group is activated by converting it to an active ester, usually a p-nitrophenyl ester. Recall from Section 20.12 that esters react with ammonia and amines to give fflnides. p-Nitrophenyl esters are much more reactive than methyl and ethyl esters in these reactions because p-nitrophenoxide is a better (less basic) leaving group than methoxide and ethoxide. Simply allowing the active ester and a C-protected amino acid to stand in a suitable solvent is sufficient to bring about peptide bond formation by nucleophilic acyl substitution. 

The Phacm group is stable to the following conditions DIEA-CH2CI2, TFA-CH2CI2, piperidine-DMF, 0.1 M TBAF-DMF, and DBU-DMF for 24 h at It to HF-anisole or / -cresol (9 1) at 0° for 1 h and to TFA-scavengers (phenol, HSCH2CH2SH, p-cresol, anisole) for 2 h at 25°. It is partially stable (>80%) to TFMSA-TFA-/ -cresol for 2 h at 25°. These stability characteristics make the group compatible with BOC- or Fmoc-based peptide synthesis. ... 

This isoxazolium salt (10 g.) (obtained from the Aldrich Chemical Company, Inc.) was dissolved in 45 ml. of aqueous 1 M hydrochloric acid and reprecipitated by the slow addition with swirling of 400 ml. of acetone. The salt was collected, washed with 300 ml. of acetone, and dried overnight at 25° under reduced pressure (< 1 min.) to give a fluffy product, m.p. 206-208° (decomp.). An isomeric salt, A-ethyl-5-phenylisoxazolium-4 -sulfonate, which may be obtained by the usual synthetic procedure,2 is also useful in peptide synthesis. 

Recently, a very interesting preparation of P-peptides has been carried out by Kanerva and coworkers through a two-step lipase-catalyzed reactions in which N-acetylated P-amino esters were first activated as 2,2,2-trifluoroethyl esters with CALB [55]. The activated esters were then used to react with a P-aminoester in the presence of CALA in dry diethylether or diisopropylether (Scheme 7.31). In this peptide synthesis, the aminoester was used in excess and the unreacted counterpart was easily separated and later recyded. 

The charging of the tRNA molecule with the aminoacyl moiety requires the hydrolysis of an ATP to an AMP, equivalent to the hydrolysis of two ATPs to two ADPs and phosphates. The entry of the aminoacyl-tRNA into the A site results in the hydrolysis of one GTP to GDP. Translocation of the newly formed pep-tidyl-tRNA in the A site into the P site by EF2 similarly results in hydrolysis of GTP to GDP and phosphate. Thus, the energy requirements for the formation of one peptide bond include the equivalent of the hydrolysis of two ATP molecules to ADP and of two GTP molecules to GDP, or the hydrolysis of four high-energy phosphate bonds. A eukaryotic ribosome can incorporate as many as six amino acids per second prokaryotic ribosomes incorporate as many as 18 per second. Thus, the process of peptide synthesis occurs with great speed and accuracy until a termination codon is reached. 

OS 25] [R 4] [P 17] For dipeptide formation from the pentafluorophenyl ester of (J )-2-phenylbutyric acid and (S)-a-methylbenzylamine an extent of racemization of 4.2% was found [86]. At higher concentration (0.5 instead of 0.1 M), a higher degree of racemization was found (7.8%). This experiment also served to demonstrate monitoring of the racemization of a simple carboxylic acid used in peptide synthesis. 

Watts, P., Wiles, C., Haswell, S. )., PoMBO-ViLLAR, E., Investigation of racemization in peptide synthesis within a micro reactor. Lab. Chip 2 (2002) 141-144. 

M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 2nd Edition, Springer Verlag, Berlin, 1994 V. J. Hruby, and J.-P. Mayer, in Bioorganic Chemistry Peptides and Proteins, S. Hecht, ed. Oxford University Press, Oxford, 1998, pp. 27—64. 

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