T1 - Synthesis and chemical properties of tetrazole peptide analogues

Traditional approaches to peptide synthesis were based on solution methods using convergent synthetic schemes, with isolation and characterization of each intermediate. This provided well-defined products with confidence in their final structures, but at the price of increased labor and losses at each synthetic step in separating product from reagents and byproducts. Until recently, the synthesis of small proteins (60 to 100 residues) has been dominated by fragment condensation in solution with maximal protection of side chains. The desired protein sequence is divided into peptide segments of about 10 residues, which is about the maximum length of peptide readily prepared by stepwise addition in solution. After each reaction, the product is isolated and fully characterized before proceeding with the next reaction. Once the set of fragments has been prepared, they are combined pairwise to generate segments of approximately 20 residues. These are then combined pairwise to generate fragments of approximately 40 residues, and this fragment condensation continues until the desired sequence is obtained. The protecting groups on side chains are then removed to give the fully unprotected peptide chain, which is allowed to fold, resulting in the desired protein. First, the 80-residue protein is divided into eight 10-residue segments that are prepared by stepwise elongation requiring nine coupling and nine deprotection steps, with isolation of each intermediate to give a completely protected fragment with both amino and carboxyl termini protected. Depending on the role of the segment, either its N- or C-terminus is deprotected and reacted with its adjacent fragment. This process is continued until the entire protein is assembled, deprotected, purified, and allowed to fold.

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Figure 1. A common implementation of the BOC strategy for peptide synthesis.
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Peptides & Proteins - Michigan State University

The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam 2 was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an optimized transaminase providing the desired configuration in >60:1 /. The final chiral center was set via a crystallization induced diastereomeric transformation. The asymmetric spirocyclization to form the second fragment, chiral spiro acid intermediate 3, was catalyzed by a novel doubly quaternized phase transfer catalyst and provided optically pure material on isolation. With the two fragments in hand, development of their final union by amide bond formation and subsequent direct isolation is described. The described chemistry has been used to deliver over 100 kg of our desired target, ubrogepant.

Chemical Synthesis of Peptide Natural ..

Chemoselective reactions for amide bond formation have transformed the ability to access synthetic proteins and other bioconjugates through ligation of fragments. In these ligations, amide bond formation is accelerated by transient enforcement of an intramolecular reaction between the carboxyl and the amine termini of two fragments. Building on this principle, we introduce an aldehyde capture ligation that parlays the high chemoselective reactivity of aldehydes and amines to enforce amide bond formation between amino acid residues and peptides that are difficult to ligate by existing technologies.

This modified amino acid is obtained when synthesizing peptides with C-terminal Cys.
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Peptide bonds: Formation and cleavage | Chemical …

Figure 4. Native chemical ligation of two unprotected peptide fragment using thiol-thioester exchange with ligation at the N-terminal cysteine residue (9).

Chemical ligation approach to form a peptide bond …

Prewash with DMF (2x)
Treat with piperidine/DMF (1:4), 5 and 10 minutes, 10 ml of reagent/g peptide-resin.
Wash alternately with DMF and IPA until neutral pH.

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Certain groups of chemical functionality have exceptional affinities for selective reaction, particularly in the formation of small rings. Recent developments have led to the synthesis of large peptide fragments by solid-phase synthesis, removal from the polymeric support and of most, if not all, side-chain protecting groups, and then selective coupling of the unprotected fragments based on chemical ligation. The most developed strategy for this approach is the use of an N-terminal cysteine residue with a special reactive C-terminal group on the other peptide. This approach was initially conceived by Kemp in his thiol capture strategy (7) and was reduced to a practically successful general approach by the groups of Kent (8-10) and Tam (11-13). For illustrative purposes, the native chemical ligation procedure of Dawson et al. (9) is described (Fig. 4), because it seems to have had the most practical impact. In this case, solid-phase synthesis is used to prepare two unprotected peptide segments that are combined in aqueous solution. The C-terminal fragment contains an N-terminal cysteine residue, and the C-terminal peptide fragment is prepared as the thioester. The thioester is displaced by the thiolate anion of a Cys residue. If the Cys is N-terminal, an acyl migration through formation of a five-membered ring occurs to generate the desired stable amide bond. If the sulfur atom of a Cys residue within the peptide chain is involved, then the thioether formed is capable of being displaced by other thiols, until the fragment migrates to the N-terminal Cys, when the stable rearrangement can occur. An alternative strategy, using an N-terminal b-bromoalanine of fragment two and the C-terminal thioester of fragment one to give the same covalent thioester intermediate by thioesterification, has been explored by Tam et al. (12)