Zinc-bound thiolate-disulfide exchange: a strategy for inhibiting metallo-beta-lactamases

The mononuclear zinc thiolate complexes [(Tp(PhMe))Zn(S-R)], where Tp(PhMe) is hydrotris((3-methyl-5-phenyl)pyrazolyl)borate and (S-R) is benzyl thiolate, 4-nitrophenylthiolate, 4-trifluoromethylphenylthiolate, 4-chlorophenylthiolate, phenylthiolate, 2-methylphenylthiolate, 4-methylphenylthiolate, 4-methoxyphenylthiolate, or 4-hydroxyphenylthiolate, were synthesized. Representative members of the class were also characterized structurally. The benzyl thiolate complex undergoes a thiolate-disulfide exchange reaction with a variety of diphenyl and dipyridyl disulfides. Kinetic studies revealed that the reaction shows saturation behavior in both complex and disulfide for most of the disulfides studied. Combined with studies of the lability of the coordinated thiolate, a mechanism is proposed where the reactive species is the zinc-coordinated thiolate. When the free benzyl thiol was allowed to react with the same disulfides, the reaction was slower by a factor of 20-200 than that for the zinc-thiolate complex, depending on the particular disulfide employed. Since most metallo-beta-lactamases contain one or more cysteine residues, the one in the active site being coordinated to zinc, the present study was extended to examine whether disulfides can be used as inhibitors of these enzymes by selective oxidation of the metal-bound cysteine. Several disulfides allowed to react with metallo-beta-lactamase CcrA from Bacteroides fragilis were moderate to potent irreversible inhibitors of the enzyme.     

Water as the reaction medium in organic chemistry: from our worst enemy to our best friend

A review presenting water as the logical reaction medium for the future of organic chemistry. A discussion is offered that covers both the “on water” and “in water” phenomena, and how water is playing unique roles in each, specifically with regard to its use in organic synthesis.

A review that highlights water as the logical reaction medium in which organic chemistry can be practiced. The key roles that water can play in directing reaction outcomes, including impacting mechanistic features, are discussed using selected examples.     

N2Phos – an easily made,highly effective ligand designed for ppm level Pd-catalyzed Suzuki–Miyaura cross couplings in water

A new biaryl phosphine-containing ligand from an active palladium catalyst for ppm level Suzuki–Miyaura couplings, enabled by an aqueous micellar reaction medium. A wide array of functionalized substrates including aryl/heteroaryl bromides are amenable, as are, notably, chlorides. The catalytic system is both general and highly effective at low palladium loadings (1000–2500 ppm or 0.10–0.25 mol%). Density functional theory calculations suggest that greater steric congestion in N₂Phos induces increased steric crowding around the Pd center, helping to destabilize the 2 : 1 ligand–Pd(0) complex more for N₂Phos than for EvanPhos (and less bulky ligands), and thereby favoring formation of the 1 : 1 ligand–Pd^o complex that is more reactive in oxidative addition to aryl chlorides.

A new, biaryl phosphine-containing ligand, N₂Phos, forms a 1 : 1 complex with Pd resulting in an active catalyst at the ppm level for Suzuki–Miyaura couplings in water, enabled by an aqueous micellar medium. Notably, aryl chlorides are shown to be amenable substrates.     

Lipase-catalyzed esterification in water enabled by nanomicelles. Applications to 1-pot multi-step sequences

Esterification in an aqueous micellar medium is catalyzed by a commercially available lipase in the absence of any co-factors. The presence of only 2 wt% designer surfactant, TPGS-750-M, assists in a 100% selective enzymatic process in which only primary alcohols participate (in a 1 : 1 ratio with carboxylic acid). An unexpected finding is also disclosed where the simple additive, PhCF₃ (1 equiv. vs. substrate), appears to significantly extend the scope of usable acid/alcohol combinations. Taken together, several chemo- and bio-catalyzed 1-pot, multi-step reactions can now be performed in water.

Esterification in an aqueous micellar medium is catalyzed by a commercially available lipase in the absence of any co-factors.     

Aminopeptidase B,a glucagon-processing enzyme: site directed mutagenesis of the Zn<Superscript>2+</Superscript>-binding motif and molecular modelling

Background  

Aminopeptidase B (Ap-B; EC 3.4.11.6) catalyzes the cleavage of basic residues at the N-terminus of peptides and processes glucagon into miniglucagon. The enzyme exhibits, in vitro, a residual ability to hydrolyze leukotriene A₄ into the pro-inflammatory lipid mediator leukotriene B₄. The potential bi-functional nature of Ap-B is supported by close structural relationships with LTA₄ hydrolase (LTA₄H ; EC 3.3.2.6). A structure-function analysis is necessary for the detailed understanding of the enzymatic mechanisms of Ap-B and to design inhibitors, which could be used to determine the complete in vivo functions of the enzyme.     

Nickel Nanoparticle Catalyzed Mono- and Di-Reductions of gem-Dibromocyclopropanes Under Mild,Aqueous Micellar Conditions

Mild mono- and di-hydrodehalogenative reductions of gem-dibromocyclopropanes are described, providing an easy and green approach towards the synthesis of cyclopropanes. The methodology utilizes 0.5–5 mol % TMPhen-nickel as the catalyst, which, when activated with a hydride source such as sodium borohydride, cleanly and selectively dehalogenates dibromocyclopropanes. Double reduction proceeds in a single operation at temperatures between 20–45 °C and at atmospheric pressure in an aqueous designer surfactant medium. At lower loading and either in the absence of ligand or in the presence of 2,2′-bipyridine, this new technology can also be used to gain access to not only monobrominated cyclopropanes, interesting building blocks for further use in synthesis, but also mono- or di-deuterated analogues. Taken together, this base-metal-catalyzed process provides access to cyclopropyl-containing products and is achieved under environmentally responsible conditions.     

Nickel Nanoparticle Catalyzed Mono‐ and Di‐Reductions of gem‐Dibromocyclopropanes Under Mild,Aqueous Micellar Conditions

Mild mono‐ and di‐hydrodehalogenative reductions of gem‐dibromocyclopropanes are described, providing an easy and green approach towards the synthesis of cyclopropanes. The methodology utilizes 0.5–5 mol % TMPhen‐nickel as the catalyst, which, when activated with a hydride source such as sodium borohydride, cleanly and selectively dehalogenates dibromocyclopropanes. Double reduction proceeds in a single operation at temperatures between 20–45 °C and at atmospheric pressure in an aqueous designer surfactant medium. At lower loading and either in the absence of ligand or in the presence of 2,2′‐bipyridine, this new technology can also be used to gain access to not only monobrominated cyclopropanes, interesting building blocks for further use in synthesis, but also mono‐ or di‐deuterated analogues. Taken together, this base‐metal‐catalyzed process provides access to cyclopropyl‐containing products and is achieved under environmentally responsible conditions.