Solid phase submonomer azapeptide synthesis

Late-Stage N-Alkylation of Azapeptides

“…Reduction of 3 to give 4 was accomplished with 1% TFA and NaBH 3 CN (25 equiv), which was followed by peptide elongation to afford azapeptoid 2a . Conversely, 2b was accessed via chemoselective alkylation of semicarbazone 3 and orthogonal deprotection to give 5 , using established azapeptide submonomer synthesis procedures . Co-injection of these control peptides with our late-stage monoalkylation reaction product confirmed the identity of the major product ( 2a ) by LCMS analysis (Figure b).…”

Constrained Dipeptide Surrogates: 5- and 7-Hydroxy Indolizidin-2-one Amino Acid Synthesis from Iodolactonization of Dehydro-2,8-diamino Azelates

“…In peptide science, conformationally constrained dipeptides serve effectively as tools for structure–activity relationship studies to identify biologically active conformers [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Among approaches for creating constrained dipeptides that employ steric [ 2 , 3 ], stereo-electronic [ 4 , 5 ], and covalent constraints [ 1 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], the use of azabicyclo[X.Y.0]alkanone amino acids offers unique potential for locking the polyamide backbone into specific orientations that may mimic natural secondary structures such as β-turns.…”

“…In peptide science, conformationally constrained dipeptides serve effectively as tools for structure–activity relationship studies to identify biologically active conformers [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Among approaches for creating constrained dipeptides that employ steric [ 2 , 3 ], stereo-electronic [ 4 , 5 ], and covalent constraints [ 1 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], the use of azabicyclo[X.Y.0]alkanone amino acids offers unique potential for locking the polyamide backbone into specific orientations that may mimic natural secondary structures such as β-turns. Among such bicyclic systems, the azabicyclo[4.3.0]alkanone amino acids, so-called indolizidine-2-one amino acid (I 2 aa) analogs and their ring-substituted derivatives (e.g., 1 – 3 , Figure 1 ), are among the most studied for utility in dissecting the backbone geometry and side chain alignment responsible for peptide activity towards the development of receptor ligands (e.g., 4 ) and enzyme inhibitors (e.g., 5 – 7 ) [ …”

Diversity-Oriented Synthesis of ERα Modulators via Mitsunobu Macrocyclization

“…Compared with the synthetic methods of azacyclopeptides, this new method provides selective nitrogen functionalization and cyclization, which can overcome the problem of excessive alkylation with reactive dielectrics, which is of great significance for further applications. 17 Initially, we used nitrobenzylidene-protected azaGly-Lys(2hydroxyacetyl)-NHBn 1a to verify our hypothesis that the introduction of extended carbon chains could synthesize cyclic azadipeptide employing the Mitsunobu reaction. We found that using typical Mitsunobu conditions of PBu 3 (2 equiv), DTBAD (2 equiv), and THF as the solvent for 3 h provided the desired cyclic azadipeptide 2a with isolated yields of 58%.…”

“…Here, we provide a convenient method for synthesizing azacyclopeptides through intramolecular Mitsunobu macrocyclization (Figure ). Compared with the synthetic methods of azacyclopeptides, this new method provides selective nitrogen functionalization and cyclization, which can overcome the problem of excessive alkylation with reactive dielectrics, which is of great significance for further applications …”