Solid phase synthesis of constrained 13-membered peptide macrocycles employing Fukuyama–Mitsunobu alkylations

Trimodular Solution‐Phase Protocol for Rapid Large‐Scale Synthesis of Hydrogen Bond Surrogate‐Constrained α‐Helicomimics

“…In comparison, 10 eq. of both the diol and reagents were needed over ∼14 h in the SPPS protocol, in 0.1 mmol scale [1d] . We investigated the reason for this, by replicating the SPPS substrate in the model peptide 1 c , which showed a lack of initiation of reaction even after 24 h under these conditions, while both models 1 a and 1 d gave quantitative products (Scheme 2).…”

“…), DIAD (1.5 eq. ), (compared to 10 equivalents of the same in SPPS) [1d] in dry THF (0.3 M), to yield 5 a – d in quantitative yields (5×20 mmol). Alanine (Ala) is representative of all C α ‐substituted α‐amino acids.…”

“…These yielded the hydrazone, [1a] olefin, [1b] disulfide, [3] alkane, [4] and thioether [5] HBS models, among which the olefin models have been most efficient for enforcing α‐helical surfaces in C‐terminal extended medium length (≥7 residues) peptides and have been used to perturb protein‐protein, [6] protein‐DNA [7] and other biologically active [8] interfaces. In the later HBS models (model 2) however, exclusively the i+4→i peptide hydrogen bond was replaced by a propyl [N i+n −C 1 H 2 −C 2 H 2 −C 3 HR−N 4 i+1 <] group (Figure 1c) and have been efficient in enforcing both classical α‐helical [1d,f, 9] and 3 10 ‐helical [1e] (or β‐turn) conformations in shorter peptides (≤5 residues) and involve transition metal‐free synthetic protocols. All residues in the constrained sequence and hence the entire molecular recognition surfaces are retained in these HBS α‐helicomimics.…”

Combinatorial Chemistry Online Volume 17, Issue 7, July 2015

“…The protein arginine deiminases (PADs) are enzymes that catalyse the hydrolytic deimination of peptidic arginine guanidine groups (1) to generate ureas (2). There are several functionally distinct PAD subtypes identified that exhibit tissue-specific occurrence.…”

“…For these purposes, a straightforward synthetic pathway has been developed, employing natural amino acids bearing usual protecting groups and mediated through two Fukuyama-Mitsunobu alkylation reactions on unprotected 1,3-propanediol on solid phase. The linear precursors were obtained in good purity and moderate yields, and the final cyclisation step was carried out in solution [2]. An efficient protocol for the solid-phase synthesis of 2,4-disubstituted 5-carbamoyl-thiazole derivatives has been developed.…”