Immobilized <i>N</i>‑Chlorosuccinimide as a Friendly Peptide Disulfide-Forming Reagent

A novel immobilized <i>N</i>-chlorosuccinimide resin was developed for peptide disulfide bond formation in combinatorial libraries. The resin is prepared in a simple two-step process from commercial starting materials. Disulfide formation is initiated by adding a peptide solution to the resin, and excess reagent is removed by a convenient filtration upon completion of disulfide formation. Completion of disulfide formation is rapid and clean, as demonstrated by the oxidation of a small nonapeptide library. This immobilized reagent allows a wider scope for the use of <i>N</i>-chlorosuccinimide-based disulfide formation in combinatorial chemistry

<i>N</i>‑Chlorosuccinimide, an Efficient Reagent for On-Resin Disulfide Formation in Solid-Phase Peptide Synthesis

<i>N</i>-Chlorosuccinimide is described as a widely applicable on-resin disulfide-forming reagent. Disulfide bond formation was completed within 15 min in DMF. This strategy was successfully used in the synthesis of oxytocin and a regioselective synthesis of an α-conotoxin. Moreover, disulfide formation with <i>N</i>-chlorosuccinimide was found to be compatible with oxidation-prone methionine and tryptophan

Cysteine Pseudoprolines for Thiol Protection and Peptide Macrocyclization Enhancement in Fmoc-Based Solid-Phase Peptide Synthesis

Contrary to other studies, here we describe cysteine (Cys) pseudoproline-containing peptides with short deprotection times in TFA. The deprotection times fell in the same range as other protecting groups commonly used in SPPS (e.g., 1–3 h). Moreover, when using Cys pseudoprolines as peptide macrocyclization-enhancing moieties a considerable reduction in reaction time was observed compared to a peptide containing trityl protected Cys

Controlling Multivalency and Multimodality: Up to Pentamodal Dendritic Platforms Based on Diethylenetriaminepentaacetic Acid Cores

A highly versatile synthetic strategy is described to generate multimodal and multivalent platforms based on a diethylenetriaminepentaacetic (DTPA) core. Compounds with different functionalization patterns, from mono- to pentamodal, have been prepared using robust and simple chemistry

Wang Linker Free of Side Reactions

A new resin for the solid-phase synthesis of peptide acids was developed. It was based on a linker with two unique features: methoxy groups as the only activating groups of the phenyl ring and a copper(I)-catalyzed Click chemistry reaction to anchor it to the solid support. The efficiency of this new resin in solid phase peptide synthesis was compared with that of Wang resin

Selective Formation of a <i>Z</i>‑Trisubstituted Double Bond Using a 1‑(<i>tert</i>-Butyl)tetrazolyl Sulfone

In our effort to gain further insight into the enantioselective synthesis of the structural core of phormidolides B and C, we have discovered the formation of a <i>Z</i>-trisubstituted double bond. Here, we describe a highly selective process that can be applied to our target following a strategy that is based on Julia–Kocienski olefination. The use of 1-(<i>tert</i>-butyl)­tetrazolyl sulfone affords the construction of the <i>Z</i>-trisubstituted alkene with high efficiency and stereoselectivity

Controlling Multivalency and Multimodality: Up to Pentamodal Dendritic Platforms Based on Diethylenetriaminepentaacetic Acid Cores

A highly versatile synthetic strategy is described to generate multimodal and multivalent platforms based on a diethylenetriaminepentaacetic (DTPA) core. Compounds with different functionalization patterns, from mono- to pentamodal, have been prepared using robust and simple chemistry

Tetrahydropyranyl, a Nonaromatic Acid-Labile Cys Protecting Group for Fmoc Peptide Chemistry

Tetrahydropyranyl (Thp), which exploits the concept of being an <i>S</i>,<i>O</i>-acetal nonaromatic protecting group for cysteine, has been shown to be superior to Trt, Dpm, Acm, and S<i>t</i>Bu in solid-phase peptide synthesis using the Fmoc/<i>t</i>Bu strategy. Thus, Cys racemization and C-terminal 3-(1-piperidinyl)­alanine formation were minimized when the Cys was protected with Thp. This nonaromatic protecting group also improved the solubility of Cys-containing protected peptides

Solid-Phase Synthesis of <i>N</i>Me-IB-01212, a Highly <i>N</i>-Methylated Cyclic Peptide

<i>N</i>-Methylation of peptides is an important synthetic tool in peptide-based medicinal chemistry. Herein, an optimized strategy for solid-phase synthesis of small but highly <i>N</i>-methylated cyclic peptides is described. The proposed route addresses several problems associated with the synthesis of peptides containing several sequential <i>N</i>-methyl-amino acids, such as in situ <i>N</i>-methylation, difficulty of acylation, epimerization, diketopiperazine formation, and stability at the <i>N</i>Me sites under trifluoroacetic acid exposure. The resulting <i>N</i>Me-IB-01212 exhibits micromolar activity and considerable stability

Semipermanent <i>C</i>‑Terminal Carboxylic Acid Protecting Group: Application to Solubilizing Peptides and Fragment Condensation

The 2-methoxy-4-methyl­sulfinyl­benzyl alcohol (Mmsb-OH) safety-catch linker has been described as a useful tool to overcome two obstacles in peptide synthesis: the solubility and fragment condensation of peptides. The incorporation of the linker into an insoluble peptide target, thereby allowing the conjugation of a poly-Lys as a “solubilizing tag”, notably enhanced the solubility of the peptide. The selective conditions that remove that linker favored its incorporation as a semipermanent <i>C</i>-terminal protecting group, thereby allowing fragment condensation of peptides