DMF-dimethyl sulfate as a new reagent for the synthesis of β-lactams

A number of 2-azetidinones were synthesized in good to excellent yields by a novel reaction between Schiff bases, substituted acetic acids and alkoxymethylene-N,N-dimethyliminium salts, the adduct formed from DMF and O-alkylating agents. The advantages of this new method are mild reaction conditions, low cost, avoiding the use of chlorinating agents and easy purification of the products. The best results were obtained when DMF and dimethyl sulfate were used at room temperature.     

Discovery of potent inhibitors of human β-tryptase from pre-equilibrated dynamic combinatorial libraries

Pre-equilibrated dynamic combinatorial libraries based on acyl hydrazone interchange of peptide-derived hydrazides and di- and tri-aldehydes have been used to discover potent inhibitors with nanomolar affinities for β-tryptase. To identify potent inhibitors the activity of the full library containing 95 members was compared with those of sub-libraries in which individual building blocks were missing. The most active library members contain a rigid central aromatic scaffold with three cationic peptide arms. The arms of the best inhibitors also contained a tailor-made GCP oxoanion binding motif attached to a lysine side chain. The most potent tri-armed hydrazones with peptide arms GKWR or GKWK(GCP) were shown to inhibit β-tryptase (K _i ca. 10–20 nM) reversibly, non-competitively and selectively (compared to related serine proteases, e.g. trypsin and chymotrypsin), most likely by binding to the protein surface, also in agreement with molecular modelling calculations. These new inhibitors are one order of magnitude more efficient than related tetravalent inhibitors obtained from previous work on a split-mix-combinatorial library and were identified with significantly less effort, demonstrating the usefulness of this approach for the identification of enzyme inhibitors in general.     

Nucleophilic ring-opening of epoxide and aziridine acetates for the stereodivergent synthesis of β-hydroxy and β-amino γ-lactams

A highly regio- and stereoselective synthesis of novel β,γ-disubstituted γ-lactams with either an anti or syn relative configuration was developed from readily available epoxide and aziridine acetates. The key steps include the regio- and diastereocontrolled nucleophilic ring-opening of these three-membered heterocycles followed by mild reductive cyclization of the γ-azido ester intermediate. The method was also extended to an asymmetric synthesis of (4R,5S)-4-hydroxy-5-phenylpyrrolidin-2-one from a chiral epoxide acetate. The main features of this versatile synthesis of functionalized γ-lactams include the involvement of inexpensive reagents and mild conditions together with high chemical efficiency.     

Palladium-catalyzed cross-coupling of α-bromocarbonyls and allylic alcohols for the synthesis of α-aryl dicarbonyl compounds

The palladium-catalyzed coupling of olefins and organohalides is a versatile approach for synthesizing complex molecules from simple starting materials. We have developed a palladium-catalyzed coupling of α-bromocarbonyl compounds with allylic alcohols for the generation of acyclic aryl-substituted dicarbonyl compounds. The reaction proceeds via a tandem olefin insertion of an α-acyl radical followed by a 1,2-aryl migration. In addition to providing preliminary evidence for a free radical mediated mechanism, we demonstrate unprecedented levels of 1,3-stereoinduction for the 1,2-migration step.     

What causes extended layering of ionic liquids on the mica surface?

Extended layering of ionic liquids (ILs) on the mica surface has been reported by several groups previously and it is generally accepted that the electrostatic interaction at the IL/mica interface is critical to the observed extended layering. Here we report that, indeed, water adsorption on the mica surface is the key to the extended layering of ionic liquids. The atomic force microscopy (AFM), attenuated total reflectance-fourier transform infrared spectroscopy (ATR-FTIR) and contact angle (CA) results show that ionic liquids form extended layering on a mica surface under ambient conditions when water is adsorbed on the mica surface under such conditions. However, when airborne hydrocarbon contaminants replace the water on the mica surface at the elevated temperatures, instead of layering, ionic liquids exhibit droplet structure, i.e., dewetting. Based on the experimental results, we propose that water enables ion exchange between K+ and the cations of ILs on the mica surface and thus triggers the ordered packing of cations/anions in ILs, resulting in extended layering.     

Studying the active-site loop movement of the S?o Paolo metallo-β-lactamase-1

Metallo-β-lactamases (MBLs) catalyse the hydrolysis of almost all β-lactam antibiotics. We report biophysical and kinetic studies on the São Paulo MBL (SPM-1), which reveal its Zn(ii) ion usage and mechanism as characteristic of the clinically important di-Zn(ii) dependent B1 MBL subfamily. Biophysical analyses employing crystallography, dynamic ¹⁹F NMR and ion mobility mass spectrometry, however, reveal that SPM-1 possesses loop and mobile element regions characteristic of the B2 MBLs. These include a mobile α3 region which is important in catalysis and determining inhibitor selectivity. SPM-1 thus appears to be a hybrid B1/B2 MBL. The results have implications for MBL evolution and inhibitor design.     

Synthetic route for the novel pyrimidine-substituted alkanoate,acetohydrazide, and imines: Synthon for β-lactams

A simple and efficient synthesis of novel pyrimidine-substituted alkanoate, acetohydrazide, and imines is described. The synthesis of novel ethyl 2-(2,6-dimethylpyrimidin-4-yloxy)acetate (EDMPyA) 2 was performed through S_N2 O-alkylation of 2,6-dimethyl-4-hydroxypyrimidine 1 with ethyl haloacetate. The compound EDMPyA 2 was subjected to nucleophilic substitution reaction with hydrazine hydrate to afford novel 2-(2,6-dimethylpyrimidin-4-yloxy)acetohydrazide (DMPyAH) 3. This DMPyAH 3 upon condensation with differently substituted carbonyl compounds (aldehydes/ketones) furnished DMPyAH imines (DMPyAH-I) 4a–d. These imines can be used for the preparation of unique β-lactams. The structure elucidation of all the newly synthesized compounds was performed using spectroscopy (FT-IR, ¹H and ¹³C NMR) and elemental analysis (C, H, N).     

Bypassing the lack of reactivity of endo-substituted norbornenes with the catalytic rectification–insertion mechanism

The catalytic 1,2-insertion polymerization of polar norbornenes (NBEs) leads to the formation of functional rigid macromolecules with exceptional thermal, optical and mechanical properties. However, this remarkable reaction is plagued by the low reactivity of the polar monomers, and most notably of those bearing a functional group in endo position. We have examined the polymerization mechanism of NBEs bearing one or two CO₂Me groups either in exo or endo position catalyzed by the so-called naked allyl Pd⁺ SbF₆^– catalyst (1). Although endo dimethyl ester of 5-norbornene-2,3-dicarboxylic acid (NBE(CO₂Me)₂) is polymerized by 1, two endo units are never inserted consecutively along the polymer chain. Indeed, 1 is a tandem catalyst which not only catalyzes the insertion of the monomer but also the isomerization of endo and exo isomers. Thus, the polymerization of endo monomers proceeds via a novel mechanism, coined rectification–insertion mechanism, whereby half of the endo monomers are rectified into exo ones prior insertion, leading to the formation of an alternating endo–exo copolymer using an endo only feedstock. With this mechanism, the lack of reactivity of endo norbornenes is bypassed, and the polymerization of predominantly endo polar NBEs bearing a variety of functionalities such as esters, imides, acids, aldehydes, alcohols, anhydrides, or alkyl bromides proceeds with catalyst loadings as low as 0.002 mol%.     

Structure–activity relationship studies of cyclopropenimines as enantioselective Br?nsted base catalysts

We recently demonstrated that chiral cyclopropenimines are viable Brønsted base catalysts in enantioselective Michael and Mannich reactions. Herein, we describe a series of structure–activity relationship studies that provide an enhanced understanding of the effectiveness of certain cyclopropenimines as enantioselective Brønsted base catalysts. These studies underscore the crucial importance of dicyclohexylamino substituents in mediating both reaction rate and enantioselectivity. In addition, an unusual catalyst CH···O interaction, which provides both ground state and transition state organization, is discussed. Cyclopropenimine stability studies have led to the identification of new catalysts with greatly improved stability. Finally, additional demonstrations of substrate scope and current limitations are provided herein.     

Consecutive C–F bond activation and C–F bond formation of heteroaromatics at rhodium: the peculiar role of FSi(OEt)3

C–F activation of 2,3,5,6-tetrafluoropyridine at [Rh{Si(OEt)₃}(PEt₃)₃] (1) yields [Rh{2-(3,5,6-C₅F₃HN)}(PEt₃)₃] (2) and FSi(OEt)₃, but in an unprecedented consecutive reaction FSi(OEt)₃ acts as a fluoride source to give [Rh(4-C₅F₄N)(PEt₃)₃] (4) by regeneration of the C–F bond and C–H activation. Analogous refluorination steps were observed for other 2-pyridyl rhodium complexes. NMR spectroscopic studies revealed a delicate balance between the feasibility for C–F bond formation accompanied by a C–H activation and the occurrence of competing reactions such as hydrodefluorinations induced by the intermediary presence of H₂.     

Intramolecular ester enolate-imine cyclization reactions for the asymmetric synthesis of polycyclic β-lactams and cyclic β-amino acid derivatives

Enolates of chiral N-(α-methyl-p-methoxybenzyl)-ω-imino-esters undergo intramolecular cyclization reactions to afford (syn)-aza-anions of β-amino esters in high dr that cyclize to afford N-(α-methyl-p-methoxybenzyl)-β-lactams that can be readily deprotected to afford their corresponding cyclic NH-β-lactams, β-amino esters, or β-amino acids.     

N,N-Dimethylphosphoramidic dichloride: a convenient reagent for the preparation of β-lactams from acetic acids and imines

A convenient reagent for the preparation of β-lactams from acetic acids and imines is described. A new route to α-keto-β-lactams from 3-bis(ethylthio)β-lactams is also reported. Reaction of 4-acethyl-β-lactams with diazomethane is also made.     

Well-defined silica supported aluminum hydride: another step towards the utopian single site dream?

Reaction of triisobutylaluminum with SBA15₇₀₀ at room temperature occurs by two parallel pathways involving either silanol or siloxane bridges. It leads to the formation of a well-defined bipodal [(SiO)₂Al–CH₂CH(CH₃)₂] 1a, silicon isobutyl [Si–CH₂CH(CH₃)₂] 1b and a silicon hydride [Si–H] 1c. Their structural identity was characterized by FT-IR and advanced solid-state NMR spectroscopies (¹H, ¹³C, ²⁹Si, ²⁷Al and 2D multiple quantum), elemental and gas phase analysis, and DFT calculations. The reaction involves the formation of a highly reactive monopodal intermediate: [SiO–Al–[CH₂CH(CH₃)₂]₂], with evolution of isobutane. This intermediate undergoes two parallel routes: transfer of either one isobutyl fragment or of one hydride to an adjacent silicon atom. Both processes occur by opening of a strained siloxane bridge, Si–O–Si but with two different mechanisms, showing that the reality of “single site” catalyst may be an utopia: DFT calculations indicate that isobutyl transfer occurs via a simple metathesis between the Al-isobutyl and O–Si bonds, while hydride transfer occurs via a two steps mechanism, the first one is a β-H elimination to Al with elimination of isobutene, whereas the second is a metathesis step between the formed Al–H bond and a O–Si bond. Thermal treatment of 1a (at 250 °C) under high vacuum (10^–5 mbar) generates Al–H through a β-H elimination of isobutyl fragment. These supported well-defined Al–H which are highly stable with time, are tetra, penta and octa coordinated as demonstrated by IR and ²⁷Al–¹H J-HMQC NMR spectroscopy. All these observations indicate that surfaces atoms around the site of grafting play a considerable role in the reactivity of a single site system.     

Stereospecific novel glycosylation of hydroxy β-lactams via iodine-catalyzed reaction: a new method for optical resolution

Glycosylation of racemic and optically active α-hydroxy β-lactams by reaction with a few glycal derivatives in the presence of catalytic amounts of iodine has provided stereospecific formation of α-glycosides. This method has been extended for the preparation of optically active hydroxy β-lactams in excellent yields. The stereochemistry and nature of the glycals as well as the stereochemistry of the β-lactam ring has a profound influence for effective glycosylation.     

Spectroscopic studies of the Ã-X̃ electronic spectrum of the β-hydroxyethylperoxy radical: structure and dynamics

The jet-cooled A?-X? near IR origin band spectra of the G(1)G(2)G(3) conformer of four β-hydroxyethylperoxy isotopologues, β-HEP (HOCH(2)CH(2)OO), β-DHEP (DOCH(2)CH(2)OO), β-HEP-d(4) (HOCD(2)CD(2)OO), and β-DHEP-d(4) (DOCD(2)CD(2)OO), have been recorded by a cavity ringdown spectrometer with a laser source linewidth of ~70 MHz. The spectra of all four isotopologues have been analyzed and successfully simulated with an evolutionary algorithm, confirming the cyclic structure of the molecule responsible for the observed origin band. The analysis also provides experimental A? and X? state rotational constants and the orientation of the transition dipole moment in the inertial axis system; these quantities are compared to results from electronic structure calculations. The observed, broad linewidth (Δν > 2 GHz) is attributed to a shortened lifetime of the A? state associated with dynamics along the reaction path for hydrogen transfer from the OH to OO group.     

Enantioselective and diastereoselective azo-coupling/iminium-cyclizations: a unified strategy for the total syntheses of (–)-psychotriasine and (+)-pestalazine B

We report a unified strategy for the total syntheses of (–)-psychotriasine and (+)-pestalazine B based on the advanced intermediates of 3α-amino-hexahydropyrrolo[2,3-b]indole. To construct these structural motifs, a cascade reaction involving a BINOL-derived phosphoric anion-paired catalyst for enantioselective or diastereoselective azo-coupling/iminium-cyclizations was developed. The remaining key steps of the synthesis involve a sterically hindered amination via hypervalent iodine reagents and the Larock annulation. These transformations enable a general approach to the syntheses of indole alkaloids containing a 3α-amino-hexahydropyrrolo[2,3-b]indole motif and could be further applied to build a natural product-based library.     

Discovery of a novel ligand that modulates the protein–protein interactions of the AAA+ superfamily oncoprotein reptin

Developing approaches to discover protein–protein interactions (PPIs) remains a fundamental challenge. A chemical biology platform is applied here to identify novel PPIs for the AAA+ superfamily oncoprotein reptin. An in silico screen coupled with chemical optimization provided Liddean, a nucleotide-mimetic which modulates reptin''s oligomerization status, protein-binding activity and global conformation. Combinatorial peptide phage library screening of Liddean-bound reptin with next generation sequencing identified interaction motifs including a novel reptin docking site on the p53 tumor suppressor protein. Proximity ligation assays demonstrated that endogenous reptin forms a predominantly cytoplasmic complex with its paralog pontin in cancer cells and Liddean promotes a shift of this complex to the nucleus. An emerging view of PPIs in higher eukaryotes is that they occur through a striking diversity of linear peptide motifs. The discovery of a compound that alters reptin''s protein interaction landscape potentially leads to novel avenues for therapeutic development.     

Pd-η 3-C6H9 complexes of the Trost modular ligand: high nuclearity columnar aggregation controlled by concentration,solvent and counterion

Under optimised conditions, the Trost modular ligand (TML) series induces high levels of asymmetric induction in an extraordinarily wide range of reactions involving palladium π-allyl intermediates. Prior mechanistic investigations into reactions involving Pd-η ³-C₆H₉ intermediates have focussed on the monomeric 13-membered ring formed via P,P-chelation of the ligand to Pd. However, it is also recognised that ring-opening oligomerisation provides a pool of high nuclearity Pd-η ³-C₆H₉ species that, by affording a low level, or even the opposite sense, of asymmetric induction relative to the mononuclear species, are responsible for a reduction in selectivity under non-optimised conditions. Herein we describe an investigation by NMR spectroscopy, molecular mechanics, molecular dynamics, and small-angle neutron scattering (SANS), of a Pd-η ³-C₆H₉ cation bearing the 1,2-diaminocyclohexane TML ligand (2). Using both nondeuterated and perdeuterated (D₄₇) isotopologues of the resulting complexes ([1]⁺), we show that a two-stage oligomerisation-aggregation process forms self assembled cylindrical aggregates of very high nuclearity (up to 56 Pd centres). We also investigate how concentration, solvent and counter-anion all modulate the extent of oligomerisation.     

An improved method for determination of the activity of β-galactosidase in yoghurt by high-performance liquid chromatography

Summary A new method has been developed for the HPLC determination of the activity of lactase from the microorganisms in yoghurt. The method is based upon the ability of -galactosidase to hydrolyze lactose bonds in glucose and galactose. To determine such activity in yoghurt, 1 mL of yoghurt was diluted 110 with 0.1 M phosphate buffer (pH 7) containing 2 % (w/v) lactose and 5 mM dithioerythritol as reducing agent; the mixture was the incubated and injected into the HPLC. Lactase activity remained high as long as the number of viable microorganisms did not fall below the minimum CFU·mL^–1 (10⁷). This method is more repeatable than conventional colorimetric determination, and may also be automated for routine analysis.     

Effect of phenolic glycolipids from Mycobacterium kansasii on proinflammatory cytokine release. A structure–activity relationship study

The cell wall of pathogenic mycobacteria is abundant with virulence factors, among which phenolic glycolipids (PGLs) are prominent examples. Mycobacterium kansasii, an important opportunistic pathogen, produces seven PGLs and their effect on the release of important proinflammatory cytokines that mediate disease progression has not been investigated. We previously showed that proinflammatory cytokines are modulated by PGLs from M. tuberculosis, M. leprae and M. bovis. In this paper we describe the synthesis of a series of 17 analogs of M. kansasii PGLs containing a truncated aglycone. Subsequently, the effect of these compounds on the release of proinflammatory cytokines (TNF-α, IL-6, IL-1β, MCP-1) and nitric oxide (NO) was evaluated. These compounds exerted an immunoinhibitory effect on the release of the tested cytokines. The concentration-dependent inhibitory profile of the tested molecules was also found to be dependent on the methylation pattern of the molecule and was mediated via toll-like receptor (TLR)-2. This study led to the discovery of a glycolipid (18) that shows promising potent anti-inflammatory properties making it a potential candidate for further optimization of its anti-inflammatory profile.