Peptide coupling reactions

Activated esters for use in peptide-coupling reactions were produced by photolysis of optically active chromium aminocarbenes with alcohols which are good leaving groups, such as phenol, pentafluorophenol, 2,4,5-trichlorophenol, and N-hydroxysuccinimide (Table 17) [ 109]. Since arylcarbenes bearing the op-... 

Twenty one rhena-/3-ketoimine derivatives of 14 different amino acids and one dipeptide have also been synthesized (37,38). The amino acid derivatives are prepared according to Eq. (3) in which the primary amine is an amino acid ester. A dipeptide derivative is formed via normal peptide coupling reactions, as shown in Eq. (4). In this reaction sequence, the ethyl... 

SS Wang, JP Tam, BSH Wang, RB Merrifield. Enhancement of peptide coupling reactions by 4-dimethylaminopyridine. Int J Pept Prot Res 18, 459, 1981. 

An alternative approach is the cleavage of a UV-active protecting group from the resin, such as the widely used Fmoc Test. The quantitation of the 9-fluorenyl-methyloxycarbonyl (Fmoc) protecting group for amines is used in SPPS as an indirect method to determine the extent of a peptide coupling reaction. Similar approaches have also been recently reported for the quantitation of supported thiols [151, 154] and have also been the subject of an excellent review [148]. 

Isoxazolium salts, such as the well-known Woodward s Reagent K , have found significant use as reagents in the preparation of activated enol esters suitable for peptide coupling reactions. Since this aspect of isoxazole chemistry has been extensively surveyed, this topic will not be treated in further detail here (B-74MI11601). 

Exercise 25-21 How could an optically pure W-acylamino acid racemize and lead to racemic W-acylpeptides as the result of a peptide coupling reaction wherein the carboxyl group of the amino acid was converted to an anhydride group (Review Section 25-5A.)... 

Protection of peptide aldehydes as semicarbazones serves two purposes (1) it reduces or eliminates racemization during chromatographic separation, and (2) the semicarbazone protects the aldehyde functional group during subsequent peptide coupling reactions. Crude aldehydes can be immediately reacted with semicarbazide hydrochloride to give the corresponding semicarbazones. The semicarbazones are purified on a silica gel column and are subsequently deprotected with 37% formaldehyde/HCl. To determine the optical purity, the aldehydes are immediately reduced with sodium borohydride followed by determination of the optical rotation of the alcohol (Table 3).[5]... 

CHClj, and subsequent peptide coupling reaction using TATU, HOAT,188 DIPEA and Boc-(S)-Phe-OH in DMF, and cleavage of the O-benzoyl group using NaCN in MeOH. This reaction sequence shows that the succinimide ring is fully compatible with the mild reaction conditions required for the incorporation of this Asp-Ser- a-chimera into a peptide sequence. CD measurements confirmed the P-turn type II conformation in solution. 

E.C. 3.5.1.4) used to prepare amino acids, usually through resolution, and also penicillin G acylase (penicillin G amidohydrolase) (E.C. 3.5.1.11), used in the manufacture of semisynthetic penicillins.152 153 Immobilized penicillin G acylase has most recently been used to catalyze the formation of. V-a-phenylacetyl amino acids, which can then be used in peptide coupling reactions (see Section 19.2.3.2).154 Bacterial aminoacylase I (.V-acyl-i.-amino acid amidohydrolase, E.C. 3.5.1.14) has also been used to acylate chiral amines with poor to moderate enantioselectively.155... 

TABLE 19.2 Peptide Coupling Reactions Using Unnatural Amino Acids in Both the Acyl Donor and Acceptor Sites (the Arrow Indicates the Peptide Bond That Was Synthesized) ... 

The Schmidt group reported another synthesis of rat brain Thy-1 GPI in 1999 [52], In 2003, they reported a rather similar synthesis [53] that involved differentially protected phosphoethanolamine groups useful for future regioselective protein/ peptide coupling reactions. This differentiation was made possible by using Cbz and te/t-butoxycarbonyl (Boc)-protected phosphoramidite reagents that could be... 

Due to its wide application in peptide synthesis, 1-hydroxybenzotriazole 849 is the most commonly used benzo-triazole derivative with hundreds of references in Chemical Abstracts each year. The utility of 849 (Scheme 183) rests essentially on its readiness to form esters with carboxylic acids in the presence of dehydrating agents. l-Hydroxy-7-azabenzotriazole 847 is also used in peptide coupling reactions, especially with sterically encumbered amines. The faster reaction rates and reduced racemization is attributed to base catalysis by the adjacent pyridine nitrogen 848 during the coupling reactions. 

Figure 3 Biosynthetic pathways. (A) In the terpenoid coupling reaction, isomers of isopentenyl pyrophosphate are joined with the loss of pyrophosphate, leading to a linear intermediate that is cyclized to a terpenoid skeleton, as shown for the diterpene taxol. (B) In the polysaccharide coupling reaction, hexose and pentose monomers are joined with the loss of a nucleoside diphosphate, as shown for the epivancosaminyl-glucose disaccharide of vancomycin. (C) In the first step of the nonribosomal peptide coupling reaction, an aminoacyl adenylate is transferred to a carrier protein or thiolation domain (denoted T ) with loss of adenosine monophosphate. In the second step, this carrier protein-tethered aminoacyl group is coupled to the amine of an aminoacyl cosubstrate, forming a peptide bond, as shown for two residues in backbone of vancomycin. (D) In the polyketide coupling reaction, the loss of carbon dioxide from a two or three-carbon monomer yields a thioester enolate that attacks a carrier protein-tethered intermediate, forming a carbon-carbon bond as shown for the polyketone precursor of enterocin.

The resulting free NH2 group could be used for further peptide coupling reactions. 

N-oxide salts (HBTU and TBTU, respectively) [39], or from l-hydroxy-7-azabenzotriazole (HOAt) such as N-[(dimethylamino)-lH-l,2,3-triazolo[4,5-fe] pyridino-l-y]methylene]-N-methy]methanaminium tetrafluoroborate N-oxide (HATU) [40], are well established reagents. They are especially devoted to peptide coupling reactions due to their efficiency and the low degree of undesirable race-mization produced in the final peptide compared to the use of classical carbodi-imide-coupling methods. Therefore, as the polystyrene-supported HOBt is an often used polymeric reagent (Section 7.6.3) [41], its transformation in a supported HOBt and tetramethylurea-derived aminium salt analog to HBTU and TBTU resulted directly. Thus, the reaction of polystyrene-2% divinylbenzene copolymer resin P-HOBt (20) with tetramethylchloroformamidinium tetrafluoroborate (21) (4 equivalents) in the presence of triethylamine gave polymeric N-[(lH-benzotriazol-l-yl)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate N-oxide (P-TBTU, 22) (Scheme 7.6) [42],... 

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