Peptide synthesis, using

Akaji K, Kiso Y, Carpino LA. Fmoc-based solid-phase peptide synthesis using a new t-alcohol type 4-(l, l -dimethyl-l -hydroxypropyl)phenoxyace-tyl handle (DHPP)-resin (Fmoc = 9-fluorenyloxycarbonyl). J Chem Soc Chem Comm 1990 584-586. 

Moser et al. (1968) (one of the co-authors was Clifford Matthews) reported a peptide synthesis using the HCN trimer aminomalonitrile, after pre-treatment in the form of a mild hydrolysis. IR spectra showed the typical nitrile bands (2,200 cm ) and imino-keto bands (1,650 cm ). Acid hydrolysis gave only glycine, while alkaline cleavage of the polymer afforded other amino acids, such as arginine, aspartic acid, threonine etc. The formation of the polymer could have occurred according to the scheme shown in Fig. 4.9. 

Fig. 5.2 Peptide synthesis using Leuchs anhydrides amino acid 1 (with residue Ri) is reacted with phosgene to give the Leuchs anhydride. This reacts with amino acid 2 (residue R2) to give the peptide carbamate. The dipeptide is obtained after cleavage of C02...

Tam, R, Lu, Y.-A., Liu, C.-F., and Shao, J. (1995) Peptide synthesis using unprotected peptides through orthogonal coupling methods. Proc. Natl. Acad. Sci. USA 92, 12485-12489. 

The synthesis of some multiblock copolymers was attempted by successive polymerization using this iniferter technique. However, pure tri- or tetrablock copolymers free from homopolymers were not isolated by solvent extraction because no suitable solvent was found for the separation. In 1963, Merrifield reported a brilliant solid-phase peptide synthesis using a reagent attached to the polymer support. If a similar idea can be applied to the iniferter technique, pure block copolymer could be synthesized by radical polymerization. The DC group attached to a polystyrene gel (PSG) through a hydrolyzable ester spacer was prepared and used as a PSG photoiniferter (Eq. 53) [186] ... 

GE Reid, RJ Simpson. Automated solid-phase peptide synthesis use of 2-(17f-ben-zotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate for coupling of tert-butyloxycarbonyl amino acids. Anal Biochem 200, 301, 1992. 

P Sieber, B Iselin. Peptide synthesis using the 2-(p-diphenyl)-isopropoxycarbonyl (Dpoc) amino protecting group. Helv Chim Acta 51, 622, 1968. 

A Atherton, H Fox, D Harkiss, CJ Logan, RC Sheppard, BJ Williams. A mild procedure for solid phase peptide synthesis Use of fluorenylmethoxycarbonylamino-acids. J Chem Soc Chem Commun 537, 1978. 

T Brown, JH Jones, JD Richards. Further studies on the protection of histidine side chains in peptide synthesis use of the jr-benzyloxymethyl group. J Chem Soc Perkin Trans 1, 1553, 1982. 

A Mehta, R Jaouhari, TJ Benson, KT Douglas. Improved efficiency and selectivity in peptide synthesis use of triethylsilane as a carbocation scavenger in deprotection of t-butyl and t-butoxycarbonyl-protected sites. Tetrahedron Lett 33, 5441, 1992. 

LA Carpino, A El-Faham, F Albericio. Racemization studies during solid-phase peptide synthesis using azabenzotriazole-based coupling reagents. Tetrahedron Lett... 

JC Hendrix, JT Jarrett, ST Anisfield, PT Lansbury. Studies related to a convergent fragment-coupling approach to peptide synthesis using the Kaiser oxime resin. J Org Chem 57, 3414, 1992. 

Stehle, P, Bahsitta, H. P., and Piirst, P. (1986). Analytical control of enzyme-catalyzed peptide-synthesis using capillary isotachophoresis.. Chromatogr. 370, 131—138. 

One of the very first papers reporting about endo-linkers was published by Elmore et al. (Scheme 10.4) [13]. They described a new linker containing a phos-phodiester group (19) for solid-phase peptide synthesis using a Pepsyn K (polyacrylamide) resin. After completion of coupling and deprotection cycles, the phos-phodiester (20) was cleaved with a phosphodiesterase. In this way / -casomorphin. Leu-enkephalin and a collagenase substrate (21) were synthesized in high yields. 

Use of Proteases in Peptide Synthesis. Typically peptides are synthesized the standard solid or liquid phase methodologies (56, 57). However, both of these techniques require harsh chemical reactions which are detrimental to certain amino acids. Furthermore, in practical terms most peptide syntheses are limited to the range of 30 to 50 amino acid residues. Hence, peptide synthesis is still somewhat problematic in many cases. In certain situations, the alternative method of peptide synthesis using proteases is an attractive choice. With this form of synthesis, one can avoid the use of the noxious and hazardous chemicals used in solid or liquid phase peptide synthesis. Since the reactions are enzyme catalyzed, racemization of the peptide bond does not occur. This technique has been used with success in the synthesis and semisynthesis of several important peptides including human insulin (55,59). 

Since the thioester linkage is susceptible to nucleophilic attack but stable to TEA treatment during solid-phase peptide synthesis (using standard Boc protection), Weigel and colleagues " have envisioned that hydroxylamine derivatives could directly cleave resin-bound peptide thioesters 201 or 202 to form the corresponding peptide hydroxamates 203 (Scheme 88). 

Chemical ligation methods for peptide synthesis using thioester chemistry in solution have been previously documented (see Vol. E 22a, Section 4.1.5). Generalized procedures for solid-phase ligation have been developed that simplify the overall procedure. One method uses a safety-catch acid labile linker at the C-terminus and was used for the synthesis of a 71-amino acid chemokine, vMIP I (Section 5.3.2.1). Another procedure uses a selectively cleavable glycolate ester linkage (Section 5.3.2.2). 

Scheme 19 Solid-Phase (S-Peptide Synthesis Using Amdt-Eistert Homologation1401...

Boc-o-Ampa-OH (40) was used in solution or solid-phase peptide synthesis using the usual coupling conditions without any difficulty 2,88,90 ... 

Esters of the PAM linker are slightly more resistant towards acids than the corresponding 4-alkylbenzyl esters [5,25-27] (Table 3.1). The PAM linker is particularly well suited for solid-phase peptide synthesis using A-Boc amino acids because less than 0.02% cleavage of the peptide from the support occurs during the acidolytic deprotection steps [27], Esters of both the 4-alkylbenzyl alcohol and PAM linkers can also be cleaved by nucleophiles (see Sections 3.1.2 and 3.3.3). 

The two most commonly used types of allyl alcohol linker are 4-hydroxycrotonic acid derivatives (Entry 1, Table 3.7) and (Z)- or ( )-2-butene-l, 4-diol derivatives (Entries 2 and 3, Table 3.7). The former are well suited for solid-phase peptide synthesis using Boc methodology, but give poor results when using the Fmoc technique, probably because of Michael addition of piperidine to the a, 3-unsaturated carbonyl compound [167]. Butene-l,4-diol derivatives, however, are tolerant to acids, bases, and weak nucleophiles, and are therefore suitable linkers for a broad range of solid-phase chemistry. 

Support-bound triacylmethanes (e.g. 2-acetyldimedone) readily react with primary aliphatic amines to yield enamines. These are stable towards weak acids and bases, and can be used as linkers for solid-phase peptide synthesis using either the Boc or Fmoc methodologies, as well as for the solid-phase synthesis of oligosaccharides [456]. Cleavage of these enamines can be achieved by treatment with primary amines or hydrazine (Entries 2 and 3, Table 3.23 see also Section 10.1.10.4). 

Figure 16.3. Solid-phase peptide synthesis using the Boc strategy [18,24]. All reactions, except the final cleavage, are performed at room temperature.

Figure 16.4. Solid-phase peptide synthesis using the Fmoc strategy.

A. Fischer, A. S. Bommarius, K. Drauz, and C. Wandrey, A novel approach to enzymatic peptide synthesis using highly solubilizing N -protecting groups of amino adds, Biocatalysis 1994, 8, 289-307. 

Proceed with the rest of the peptide synthesis using standard Fmoc chemistry. 

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