Novel approach to the zaragozic acids. Enantioselective total synthesis of 6,7-dideoxysqualestatin H5

The total synthesis of 6,7-dideoxysqualestatin H5 (3) has been completed by a concise approach that features the stereoselective intramolecular vinylogous aldol reaction of the furoic ester 25a to give 30 or its trimethylsilyl ether derivative 34, which possess the requisite absolute stereochemistry at C(3)-C(5) of 3. Compound 34 was reduced to the saturated bislactone 39, and the C(1) side chain subunit 47 was introduced leading to a mixture of the hemiacetals 48 and the corresponding ketone 49. When this mixture was stirred with methanolic acid, transketalization occurred to give a mixture of 50 and the spirocyclic methyl acetals 51a,b. Oxidation of the primary alcohol group in 50 followed by saponification of the two remaining ester groups gave 3. The longest linear sequence in the synthesis commences with commercially available erythronolactone (26) and requires 17 chemical steps with only 10 isolated intermediates.     

Synthesis,metal-exchange kinetics and X-ray structure of the nickel(II) complex of the diazacyclam ligand 1,3,6,10,12,15-hexa-azatricyclo [13.3.1.16,10]eicosane, [NiL] (ClO4)2

The preparation of the nickel(II) complex of the diazacyclam ligand 1,3,6,10,12,15-hexaazatricyclo [13.3.1.16,10]eicosane (2) by the reaction of the nickel(II) complex of N-(2-aminoethyl)-1,3-diaminopropane with formaldehyde in MeOH solution is described. The crystal structure of [NiL](ClO4)2 has been determined. The nickel atom is four coordinate and planar with Ni-N bond lengths of 1.969(4) and 1.928(3)Å in a centrosymmetric structure. The basic diazacyclam ring system has a trans III configuration with the two additional six-membered rings fused in a chair conformation.The kinetics of the metal exchange:for the nickel complexes (1) and (2) have been studied in detail. Under the experimental conditions employed, with copper(II) in at least a tenfold excess, the reaction is independent of the copper(II) concentration. The copper(II) effectively scavenges the free ligand as the nickel(II) complex dissociates. For the nickel complex (1) k = 2 × 10–4 s–1 at 60°C and H = 126 ± 5 kJmol–1 and S298 = 61 ± 15 JK–1mol–1. For the complex (2), k = 1.8 × 10–4 s–1 at 60°C and H = 99 ± 6 kJmol–1 and S298 = –21 ± 10 JK–1 mol–1.     

2-Mercaptomethyl-thiazolidines use conserved aromatic–S interactions to achieve broad-range inhibition of metallo-β-lactamases

Infections caused by multidrug resistant (MDR) bacteria are a major public health threat. Carbapenems are among the most potent antimicrobial agents that are commercially available to treat MDR bacteria. Bacterial production of carbapenem-hydrolysing metallo-β-lactamases (MBLs) challenges their safety and efficacy, with subclass B1 MBLs hydrolysing almost all β-lactam antibiotics. MBL inhibitors would fulfil an urgent clinical need by prolonging the lifetime of these life-saving drugs. Here we report the synthesis and activity of a series of 2-mercaptomethyl-thiazolidines (MMTZs), designed to replicate MBL interactions with reaction intermediates or hydrolysis products. MMTZs are potent competitive inhibitors of B1 MBLs in vitro (e.g., K_i = 0.44 μM vs. NDM-1). Crystal structures of MMTZ complexes reveal similar binding patterns to the most clinically important B1 MBLs (NDM-1, VIM-2 and IMP-1), contrasting with previously studied thiol-based MBL inhibitors, such as bisthiazolidines (BTZs) or captopril stereoisomers, which exhibit lower, more variable potencies and multiple binding modes. MMTZ binding involves thiol coordination to the Zn(ii) site and extensive hydrophobic interactions, burying the inhibitor more deeply within the active site than d/l-captopril. Unexpectedly, MMTZ binding features a thioether–π interaction with a conserved active-site aromatic residue, consistent with their equipotent inhibition and similar binding to multiple MBLs. MMTZs penetrate multiple Enterobacterales, inhibit NDM-1 in situ, and restore carbapenem potency against clinical isolates expressing B1 MBLs. Based on their inhibitory profile and lack of eukaryotic cell toxicity, MMTZs represent a promising scaffold for MBL inhibitor development. These results also suggest sulphur–π interactions can be exploited for general ligand design in medicinal chemistry.

Metallo-β-lactamases (MBLs) are major culprits of resistance to carbapenems in bacteria. A series of thiazolidines are potent MBL inhibitors, restoring the activity of carbapenems. Metal binding and sulphur–π interactions are key to inhibition.     

The effect of a coriolis force on Taylor-Couette flow

Taylor-Couette flow subject to a Coriolis force is studied experimentally and numerically. In the experiment, the Couette apparatus is mounted on a turntable with the axis of the cylinders orthogonal to the rotation vector of the turntable. The Coriolis force stabilizes the fluid against the onset of Taylor vortices and alters the velocity fields, both above and below the transition from the initial flow. At small dimensionless turntable frequencies, the transition yields time-independent Taylor vortices which are tilted with respect to the cylinder axis. At larger there is a direct transition to turbulence. We determine the first-order correction to the classical Couette initial flow, to account for the effects of the Coriolis force, by expanding in powers of. We present numerical results for the axial velocity (the only nonvanishing correction term to order) in the infinite-cylinder approximation.     

Ion/molecule reactions of ammonia and methylamine with chloro- and nitrobenzene. A comparison of chemical ionization and ion cyclotron resonance experiments

It is shown by ion cyclotron resonance measurements that ion/molecule reactions, leading to substitution or reduction product ions from chloro- and nitrobenzene with the title amines, are those between the molecular ions [RNH₂]⁺ or [C₆H₅X]⁺˙ and their respective counterparts C₆H₅X or RNH₂. The protonated reagent gas ions [RNH₃]⁺ are not involved in these reactions. In the case of nitrobenzene, adduct ions [C₆H₅NO₂·RNH₃]⁺ do not decompose within the time scale of the measurements. The results obtained are compared with those found under chemical ionization conditions.     

Determination of lead in rocks by radiometric isotope dilution and substoichiometric extraction

A rapid procedure is described for the determination of lead in rocks by an isotope-dilution substoichiometric method. After the sample has been digested with acid in the presence of ²¹⁰Pb tracer, the lead is separated by dithizone extractions. After the lead has been back-extracted into aqueous solution, it is reacted with a substoichiometric amount of EDTA. Excess of unreacted lead is removed by extraction with dithizone in carbon tetrachloride, and the specific activity of the aqueous complex is determined by counting ²¹⁰Pb. The standard deviation of the method is less than 10 % for replicate determinations of lead in several U.S. Geological Survey standard rocks. The agreement with literature values indicates that the method is accurate.     

Dichloro and alkylchloro gallium derivatives of dichalcogenoimidodiphosphinate ligands: isolation of a spirogallium cation

Dichloro and chloromethyl Ga(III) complexes of general formulae [XClGa-eta2-{R2P(E)NP(E'R'2-E,E'}](X = Cl, R, R'= Ph, E, E'= O (1), S (2), Se (3); R = Ph, R'= OEt, E = O, E'= S (4); R = Me, R'= Ph, E, E'= S (5) and X = Me, E, E'= O (6), S (7), Se (8)) were synthesised by either metathesis reactions between GaCl3 and the potassium salt of the ligand (X = Cl) or by methane eliminations from in situ prepared GaMe2Cl and the protonated ligands LH (X = Me). Redistribution reaction of (3) in either CDCl3 or THF afforded the solvent-free tetracoordinate gallium spirocycle cation [Ga-{eta2-{Ph2P(Se)NP(Se)Ph2-Se,Se'})2]+ (9+). The molecular structures of complexes 2, 4, 5, 7 and 9(+) show non-planar gallacycle rings.     

Nonclassical titanocene silyl hydrides

The titanocene silyl hydride complexes [Ti(Cp)2(PMe3)(H)(SiR3)] [SiR3=SiMePhCl (6), SiPh2Cl (7), SiMeCl2 (8), SiCl3 (9)] were prepared by HSiR3 addition to [Ti(Cp)2(PMe3)2] and were studied by NMR and IR spectroscopy, X-ray diffraction (for 6, 8, and 9), and DFT calculations. Spectroscopic and structural data established that these complexes exhibit nonclassical Ti-H-Si-Cl interligand hypervalent interactions. In particular, the observation of silicon-hydride coupling constants J(Si,H) in 6-9 in the range 22-40 Hz, the signs of which we found to be negative for 8 and 9, is conclusive evidence of the presence of a direct Si-H bond. The analogous reaction of [Ti(Cp)2(PMe3)2] with HSi(OEt)3 does not afford the expected classical silyl hydride complex [Ti(Cp)2(PMe3)(H)[Si(OEt)3]], and instead NMR-silent titanium (apparently TiIII) complex(es) and the silane redistribution product Si(OEt)4 are formed. The structural data and DFT calculations for the compounds [Ti(Cp)2(PMe3)(H)(SiR3)] show that the strength of interligand hypervalent interactions in the chlorosilyl complexes decreases as the number of chloro groups on silicon increases. However, in the absence of an Si-bound electron-withdrawing group trans to the Si-H moiety, a silane sigma complex is formed, characterized by a long Ti-Si bond of 2.658 A and short Si-H contact of 1.840 A in the model complex [Ti(Cp)2(PMe3)(H)(SiMe3)]. Both the silane sigma complexes and silyl hydride complexes with interligand hypervalent interactions exhibit bond paths between the silicon and hydride atoms in Atoms in Molecules (AIM) studies. To date a classical titanocene phosphane silyl hydride complex without any Si-H interaction has not been observed, and therefore titanocene silyl hydrides are, depending on the nature of the R groups on Si, either silane sigma complexes or compounds with an interligand hypervalent interaction.