Hypervalent molecule | EPFL Graph Search

In chemistry, a hypervalent molecule (the phenomenon is sometimes colloquially known as expanded octet) is a molecule that contains one or more main group elements apparently bearing more than eight electrons in their valence shells. Phosphorus pentachloride (), sulfur hexafluoride (), chlorine trifluoride (), the chlorite () ion, and the triiodide () ion are examples of hypervalent molecules. Definitions and nomenclature Hypervalent molecules were first formally defined by Jeremy I. Musher in 1969 as molecules having central atoms of group 15–18 in any valence other than the lowest (i.e. 3, 2, 1, 0 for Groups 15, 16, 17, 18 respectively, based on the octet rule). Several specific classes of hypervalent molecules exist:

Hypervalent iodine compounds are useful reagents in organic chemistry (e.g. Dess–Martin periodinane)
Tetra-, penta- and hexavalent phosphorus, silicon, and sulfur compounds (e.g. PCl5, PF5, SF6, sulfuranes and persulfuranes)
Noble gas compounds (ex. x

Application of Hypervalent Iodine Reagents for Novel Cysteine Labeling

Romain Gaëtan Tessier

Selective functionalization of peptides and proteins has always been a valuable tool for the study and manipulation of biological processes. In this context, cysteines are of particular interest. Their intrinsic high nucleophilicity makes these amino acids excellent targets for peptides and proteins modification. As a result, cysteine labeling techniques have been extensively investigated. Nevertheless, while bioconjugation requires high efficiency, selectivity and kinetic under mild and aqueous conditions, most of the reported methodologies exhibit significant limitations. For instance, lack of chemoselectivity, as well as low or uncontrolled reactivity, are frequently reported. Furthermore, many of these methods rely on reagents challenging to prepare, store and use. In this regard, hypervalent iodine reagents are attractive. Heterocyclic Î»3-iodanes demonstrated high reactivity and selectivity, together with great stability and low toxicity. Nevertheless, applications to peptides and proteins modification remain rare. Employing ethynylbenziodoxolone reagents (EBXs), we previously described an efficient and chemoselective alkynylation of organosulfur compounds. The process was performed under âopen-flaskâ conditions, at room temperature, without any metal- or additive-assistance. In collaboration with Dr. Adibekian and co-workers, we then employed this methodology to intracellular proteomic profiling of cysteine residues. Nevertheless, only the most reactive cysteines were efficiently labeled. Accordingly, the goal of my thesis was to investigate the reactivity between any cysteine residues and EBX reagents, under mild and aqueous conditions. We started our investigations with treatment of glutathione, a naturally occurring tripeptide, with an azide-containing EBX reagent. Although a complete conversion of the starting material was observed, the corresponding thioalkyne product was not formed. Instead, we observed thiol-yne reactivity and selective thiol trans-addition in Î²-position of the EBX reagent, leading to vinylbenziodoxolone product (VBX). This efficient cysteine labeling exhibited high selectivity, fast kinetic and great robustness. Various cysteine-containing peptides and proteins, along with diverse EBX reagents, were well tolerated. When an azide-containing EBX reagent was employed, strain-promoted azide-alkyne cycloadditions (SPAAC) were successfully achieved. Alternatively, the hypervalent iodine function was engaged in aqueous Suzuki-Miyaura cross-couplings. Various boronic acids, containing electron-rich and âdeficient aryls, heteroaryls and vinyls, were successfully subjected to this palladium-promoted process. Remarkably, both SPAAC and cross-coupling were orthogonal to each other. We then investigated the singular reactivity of the TMS-EBX reagent. Under basic aqueous conditions, we observed fast desilylation of the hypervalent iodine reagent. Upon glutathione treatment, the resulting EBX substrate was engaged in a thiol-yne reaction. Nevertheless, the corresponding VBX product exhibited a low stability and led to alkynylated glutathione. Further optimization furnished an efficient, selective and rapid ethynylation of numerous cysteine-containing peptides.

EPFL2019

Hypervalent Iodine-Mediated Late-Stage Peptide and Protein Functionalization

Emmanuelle Madeline Dominique Allouche, Elija Grinhagena, Jérôme Waser

Hypervalent iodine compounds are powerful reagents for the development of novel transformations. As they exhibit low toxicity, high functional group tolerance, and stability in biocompatible media, they have been used for the functionalization of biomolecules. Herein, we report recent advances up to June 2021 in peptide and protein modification using hypervalent iodine reagents. Their use as group transfer or oxidizing reagents is discussed in this Minireview, including methods targeting polar, aromatic, or aliphatic amino acids and peptide termini.

WILEY-V C H VERLAG GMBH2021

Ethynyl benziodoxolones: functional terminators for cell-penetrating poly(disulfide)s

Stefan Matile, Romain Gaëtan Tessier, Jérôme Waser

Outperforming cell-penetrating peptides (CPPs), cell-penetrating poly(disulfide)s (CPDs) are attracting increasing interest. CPDs are accessible by ring-opening disulfide-exchange polymerization under mild conditions in neutral water. Initiation of the polymerization with thiols results in quantitative labeling of one CPD terminus with initiators of free choice. In contrast, labeling of the other terminus with iodoacet-amides has so far been ineffective because of poor yields and the high excess of reagents needed. In this report, we introduce hypervalent iodine reagents as operational terminators of the synthesis of CPDs, also at high dilution. The power of the approach is exemplified with green-fluorescent initiators and ethynyl benziodoxolone terminators containing additional azides for CuAAC with red-fluorescent alkynes. The absorption spectra of the resulting CPDs demonstrate that stoichiometric application of ethynyl benziodoxolone terminators results in 46% incorporation. FRET between green-fluorescent initiators and red-fluorescent terminators demonstrates significant folding of CPDs in solution; it disappears upon reductive depolymerization. Substrates attached to the new termini are shown to enter into HeLa cells. Moreover, disappearance of FRET in the cytosol corroborated the reductive cleavage of CPDs upon internalization. Beyond the introduction of enthynyl benziodoxolones as operational terminators, these findings thus demonstrate also the compatibility of CuAAC with poly(disulfide) s and the usefulness of doubly-labeled CPDs for structural and mechanistic studies.

Royal Society of Chemistry2016

Application of Hypervalent Iodine Reagents for Novel Cysteine Labeling

Romain Gaëtan Tessier

EPFL2019