Rhodium-Mediated Enantioselective Cyclopropanation of Allenes

Reaction of monosubstituted allenes with aryldiazoacetate esters under dirhodium tetracarboxylate catalysis led to alkylidene cyclopropane products in 80−90% ee. Monosubstituted alkyl- and arylallene substrates gave 60−75% yield under standard conditions, while yields for 1,1-disubstituted allenes were significantly lower. Cyclopropanation of 1-methyl-1-(trimethylsilyl)allene proceeded in higher yield than other 1,1-disubstituted substrates, suggesting rate enhancement mediated by a significant β-silicon effect

Rhodium-Mediated Enantioselective Cyclopropanation of Allenes

Reaction of monosubstituted allenes with aryldiazoacetate esters under dirhodium tetracarboxylate catalysis led to alkylidene cyclopropane products in 80−90% ee. Monosubstituted alkyl- and arylallene substrates gave 60−75% yield under standard conditions, while yields for 1,1-disubstituted allenes were significantly lower. Cyclopropanation of 1-methyl-1-(trimethylsilyl)allene proceeded in higher yield than other 1,1-disubstituted substrates, suggesting rate enhancement mediated by a significant β-silicon effect

Synthesis of DNA-Encoded Macrocyclic Peptides via Nitrile-Aminothiol Click Reaction

DNA-encoded library (DEL) technology holds exciting potential for discovering novel therapeutic macrocyclic peptides (MPs). Herein, we describe the development of a DEL-compatible peptide macrocyclization method that proceeds via intramolecular click-condensation between 3-(2-cyano-4-pyridyl)-l-alanine (Cpa) and an N-terminal cysteine. Cyclization takes place spontaneously in a buffered aqueous solution and affords the cyclized products in excellent yields. The reaction exhibits a broad substrate scope and can be employed to generate MPs of variable ring size and amino acid composition

Development of Endocyclic Control Elements for Peptide Macrocycles

Synthetic methods that provide control over macrocycle conformation represent valuable tools for the discovery of bioactive molecules. Incorporation of heterocycles into cyclic peptides may offer a way to stabilize their solution conformations. Herein, we used N-(isocyanimino)­triphenylphosphorane (Pinc) to install an oxadiazole ring and an endocyclic amine into peptide macrocycles. To elucidate the conformational effect of this constellation of functionalities, we performed synthesis, variable temperature NMR analysis, and NOE-based molecular dynamics simulation of a range of macrocycles in DMSO. As part of this study, we conducted experiments to compare macrocycle conformation in aqueous and DMSO solutions. The obtained solution structures suggest that the reduced amide bond/heterocycle (RAH) motif can stabilize macrocycle conformations in both water and DMSO, which addresses an enduring challenge in molecular design. The conformational effect of the RAH was used in an effort to mimic the biologically relevant secondary structure of MAdCAM-1. This resulted in the discovery of a novel α4β7 integrin antagonist

Development of Endocyclic Control Elements for Peptide Macrocycles

Synthetic methods that provide control over macrocycle conformation represent valuable tools for the discovery of bioactive molecules. Incorporation of heterocycles into cyclic peptides may offer a way to stabilize their solution conformations. Herein, we used N-(isocyanimino)­triphenylphosphorane (Pinc) to install an oxadiazole ring and an endocyclic amine into peptide macrocycles. To elucidate the conformational effect of this constellation of functionalities, we performed synthesis, variable temperature NMR analysis, and NOE-based molecular dynamics simulation of a range of macrocycles in DMSO. As part of this study, we conducted experiments to compare macrocycle conformation in aqueous and DMSO solutions. The obtained solution structures suggest that the reduced amide bond/heterocycle (RAH) motif can stabilize macrocycle conformations in both water and DMSO, which addresses an enduring challenge in molecular design. The conformational effect of the RAH was used in an effort to mimic the biologically relevant secondary structure of MAdCAM-1. This resulted in the discovery of a novel α4β7 integrin antagonist

Development of Endocyclic Control Elements for Peptide Macrocycles

Synthetic methods that provide control over macrocycle conformation represent valuable tools for the discovery of bioactive molecules. Incorporation of heterocycles into cyclic peptides may offer a way to stabilize their solution conformations. Herein, we used N-(isocyanimino)­triphenylphosphorane (Pinc) to install an oxadiazole ring and an endocyclic amine into peptide macrocycles. To elucidate the conformational effect of this constellation of functionalities, we performed synthesis, variable temperature NMR analysis, and NOE-based molecular dynamics simulation of a range of macrocycles in DMSO. As part of this study, we conducted experiments to compare macrocycle conformation in aqueous and DMSO solutions. The obtained solution structures suggest that the reduced amide bond/heterocycle (RAH) motif can stabilize macrocycle conformations in both water and DMSO, which addresses an enduring challenge in molecular design. The conformational effect of the RAH was used in an effort to mimic the biologically relevant secondary structure of MAdCAM-1. This resulted in the discovery of a novel α4β7 integrin antagonist

Ribosomal Synthesis of Macrocyclic Peptides <i>in Vitro</i> and <i>in Vivo</i> Mediated by Genetically Encoded Aminothiol Unnatural Amino Acids

A versatile method for orchestrating the formation of side chain-to-tail cyclic peptides from ribosomally derived polypeptide precursors is reported. Upon ribosomal incorporation into intein-containing precursor proteins, designer unnatural amino acids bearing side chain 1,3- or 1,2-aminothiol functionalities are able to promote the cyclization of a downstream target peptide sequence via a C-terminal ligation/ring contraction mechanism. Using this approach, peptide macrocycles of variable size and composition could be generated in a pH-triggered manner <i>in vitro</i> or directly in living bacterial cells. This methodology furnishes a new platform for the creation and screening of genetically encoded libraries of conformationally constrained peptides. This strategy was applied to identify and isolate a low-micromolar streptavidin binder (<i>K</i>_D = 1.1 μM) from a library of cyclic peptides produced in Escherichia coli, thereby illustrating its potential toward aiding the discovery of functional peptide macrocycles

Development of Endocyclic Control Elements for Peptide Macrocycles

Synthetic methods that provide control over macrocycle conformation represent valuable tools for the discovery of bioactive molecules. Incorporation of heterocycles into cyclic peptides may offer a way to stabilize their solution conformations. Herein, we used <i>N</i>-(isocyanimino)­triphenylphosphorane (Pinc) to install an oxadiazole ring and an endocyclic amine into peptide macrocycles. To elucidate the conformational effect of this constellation of functionalities, we performed synthesis, variable temperature NMR analysis, and NOE-based molecular dynamics simulation of a range of macrocycles in DMSO. As part of this study, we conducted experiments to compare macrocycle conformation in aqueous and DMSO solutions. The obtained solution structures suggest that the reduced amide bond/heterocycle (RAH) motif can stabilize macrocycle conformations in both water and DMSO, which addresses an enduring challenge in molecular design. The conformational effect of the RAH was used in an effort to mimic the biologically relevant secondary structure of MAdCAM-1. This resulted in the discovery of a novel α₄β₇ integrin antagonist

Development of Endocyclic Control Elements for Peptide Macrocycles

Synthetic methods that provide control over macrocycle conformation represent valuable tools for the discovery of bioactive molecules. Incorporation of heterocycles into cyclic peptides may offer a way to stabilize their solution conformations. Herein, we used <i>N</i>-(isocyanimino)­triphenylphosphorane (Pinc) to install an oxadiazole ring and an endocyclic amine into peptide macrocycles. To elucidate the conformational effect of this constellation of functionalities, we performed synthesis, variable temperature NMR analysis, and NOE-based molecular dynamics simulation of a range of macrocycles in DMSO. As part of this study, we conducted experiments to compare macrocycle conformation in aqueous and DMSO solutions. The obtained solution structures suggest that the reduced amide bond/heterocycle (RAH) motif can stabilize macrocycle conformations in both water and DMSO, which addresses an enduring challenge in molecular design. The conformational effect of the RAH was used in an effort to mimic the biologically relevant secondary structure of MAdCAM-1. This resulted in the discovery of a novel α₄β₇ integrin antagonist

Development of Endocyclic Control Elements for Peptide Macrocycles

Synthetic methods that provide control over macrocycle conformation represent valuable tools for the discovery of bioactive molecules. Incorporation of heterocycles into cyclic peptides may offer a way to stabilize their solution conformations. Herein, we used <i>N</i>-(isocyanimino)­triphenylphosphorane (Pinc) to install an oxadiazole ring and an endocyclic amine into peptide macrocycles. To elucidate the conformational effect of this constellation of functionalities, we performed synthesis, variable temperature NMR analysis, and NOE-based molecular dynamics simulation of a range of macrocycles in DMSO. As part of this study, we conducted experiments to compare macrocycle conformation in aqueous and DMSO solutions. The obtained solution structures suggest that the reduced amide bond/heterocycle (RAH) motif can stabilize macrocycle conformations in both water and DMSO, which addresses an enduring challenge in molecular design. The conformational effect of the RAH was used in an effort to mimic the biologically relevant secondary structure of MAdCAM-1. This resulted in the discovery of a novel α₄β₇ integrin antagonist