Peptides, coupling methods

JM Humphrey, AR Chamberlin. Chemical synthesis of natural product peptides coupling methods for the incorporation of noncoded amino acids into peptides. Chem Rev 97, 2243, 1997. 

In the dendritic [Co(salen)] complexes prepared by Breinbauer and Jacobsen the dendrimer again serves as - covalent - support material for the catalytic entities attached to the periphery [62]. These dendritic Jacobsen catalysts were obtained by reaction of the corresponding PAMAM dendrimers with active ester derivates of chiral ]Co(II)-(salen)] units according to standard peptide coupling methods. In hydrolytic kinetic resolution of vinylcyclohexane oxide the dendrimer 14 (Fig. 6.40) showed a dramatically increased reactivity compared to the commercially available monomeric Jacobsen catalyst [63-67]. Whereas the latter merely gave a conversion of less than 1% with an indeterminable ee, 14 afforded a conversion of 50% with an ee of 98 2. 

Scheme 1 Synthesis of Pyrphos-functionalized PPI and PAMAM dendrimers by peptide coupling methods...

In the future, the technique of solid-phase sequencing will be most aided by improved peptide coupling methods and a reduction in the side reactions of the Edman degradation. 

FIGURE 44.8. Bartlett s structure, an extended vinylo-gous amide which retains planarity, hence stabilizing the sheet form. This amino acid can be added by normal peptide coupling methods on solid phase [73]. 

The overall synthetic strategy toward the tetrapeptide scaffold of telaprevir requires four key amino acid building blocks (45-49, Scheme 8), which can be coupled using standard peptide coupling methods. As in the synthesis of boceprevir, the P2 domain (48), which contains the bicyclic proline mimic, is the most synthetically challenging fragment of telaprevir, particularly in the context of a scalable route for commercialization. Likewise, the synthesis of the PI ketoamide domain (49) has required significant revision and optimization in the transition from discovery to process scale. 

For the addition of the first amino acid to supports derivatized with peptide amide-forming linkers, such as trialkoxybenzhydrylamine 9, trialkoxybenzyl-amine 10, and aminoxanthenyl 11 resins, any of the standard peptide coupling methods described in Section 7 can be used. Since basic reagents such as 4-dimethylaminopyridine are not required to effect this transformation, there is no risk of enantiomerization or dipeptide formation. Many resins of this type are supplied Fmoc-protected and these should be treated with piperidine prior to the addition of the first amino acid. With automated peptide synthesizers, Fmoc removal and loading with the C-terminal residue can be programmed to occur as part of the normal coupling cycle. 

After chromatographic separation of the diastereomers (1 1) of the condensation product 121, facile deprotection of the amine with TFA liberates the secondary amide 122 in moderate yield (58%). The following amidation reaction was performed without prior activation of the ester by employing l,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). The resulting extensive racemization, however, indicated that the chiral center was rather acidic. Therefore, common peptide coupling methods were explored, which resulted in good yield and poor enantiomeric excess or vice versa. 

Racemization Suppression in Peptide Couplings. A mixture of copper(It) chloride and triethylamine catalyzes the formation of peptide bonds. Furthermore, when used as an additive, CuCl2 suppresses racemization in both the carbodiimide and mixed anhydride peptide coupling methods. Recently it was shown that a combination of 1-hydroxybenzotriazole and CuCl2 gives improved yields of peptides while eliminating racemization. ... 

The DCC peptide coupling method can be improved both in terms of yield and suppression of racemization by the addition of Lewis acids, especially zinc chloride. A promising pilot study on the use of polymer-bound carbonic-carboxylic anhydride functions for the preparation of amides has been reported. It has been suggested in two reports that peptide bond formation is more rapid when soluble polymers are used, specifically a, >-diaminopolyethyl-ene glycol ( amino PEG ) and chloromethylated polystyrene. ... 

Since the attack of a neighboring nucleophile to the diazoniiun moiety proceeds in an intramolecular coupling step and the compoimds produced are largely less acid sensitive than dialkyl-substituted triazenes, even the weak nucleophihcity of secondary amides or arenes can be used for the generation of heterocycles [240,241]. For example benzo[a][l,2,3]triazinones 296 can therefore be formed upon cychzation of suitable substituted benzamides. The latter ones are accessible from carboxylate resins and amines by peptide coupling methods. 

Humphrey, J. M. Chamberlin, A. R. Chemical Synthesis of Natural Product Peptides Coupling Methods for the Incorporation of Noncoded Amino Acids into Peptides. Chem. Rev. 1997, 97, 2243-2266. 

If an (i)-aminopyridinethiol ester is used, macrolactamization occurs. A method for the synthesis of p-Iactams from (3-amino acids has also been developed where the use of MeCN has been found to be critical (eq 2). The intermolecular version of this reaction is a powerful peptide coupling method. ... 

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