Nα-Aroyl-N-Aryl-Phenylalanine Amides: A Promising Class of Antimycobacterial Agents Targeting the RNA Polymerase.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains the leading cause of death from a bacterium in the world. The global prevalence of clinically relevant infections with opportunistically pathogenic non-tuberculous mycobacteria (NTM) has also been on the rise. Pharmacological treatment of both TB and NTM infections usually requires prolonged regimens of drug combinations, and is often challenging because of developed or inherent resistance to common antibiotic drugs. Medicinal chemistry efforts are thus needed to improve treatment options and therapeutic outcomes. Nα-aroyl-N-aryl-phenylalanine amides (AAPs) have been identified as potent antimycobacterial agents that target the RNA polymerase with a low probability of cross resistance to rifamycins, the clinically most important class of antibiotics known to inhibit the bacterial RNA polymerase. In this review, we describe recent developments in the field of AAPs, including synthesis, structural characterization, in vitro microbiological profiling, structure-activity relationships, physicochemical properties, pharmacokinetics and early cytotoxicity assessment.

Strain-Release Pentafluorosulfanylation and Tetrafluoro(aryl)sulfanylation of [1.1.1]Propellane: Reactivity and Structural Insight.

We leveraged the recent increase in synthetic accessibility of SF5 Cl and Ar-SF4 Cl compounds to combine chemistry of the SF5 and SF4 Ar groups with strain-release functionalization. By effectively adding SF5 and SF4 Ar radicals across [1.1.1]propellane, we accessed structurally unique bicyclopentanes, bearing two distinct elements of bioisosterism. Upon evaluating these "hybrid isostere" motifs in the solid state, we measured exceptionally short transannular distances; in one case, the distance rivals the shortest nonbonding C⋅⋅⋅C contact reported to date. This prompted SC-XRD and DFT analyses that support the notion that a donor-acceptor interaction involving the "wing" C-C bonds is playing an important role in stabilization. Thus, these heretofore unknown structures expand the palette for highly coveted three-dimensional fluorinated building blocks and provide insight to a more general effect observed in bicyclopentanes.

A New Ligand Design Based on London Dispersion Empowers Chiral Bismuth-Rhodium Paddlewheel Catalysts.

Heterobimetallic bismuth-rhodium paddlewheel complexes with phenylglycine ligands carrying TIPS-groups at the meta-positions of the aromatic ring exhibit outstanding levels of selectivity in reactions of donor/acceptor and donor/donor carbenes; at the same time, the reaction rates are much faster and the substrate scope is considerably wider than those of previous generations of chiral [BiRh] catalysts. As shown by a combined experimental, crystallographic, and computational study, the new catalysts draw their excellent application profile largely from the stabilization of the chiral ligand sphere by London dispersion (LD) interactions of the peripheral silyl substituents.

Synthesis, structural characterization and antimycobacterial evaluation of several halogenated non-nitro benzothiazinones.

8-Nitro-1,3-benzothiazin-4-ones (BTZs), with BTZ043 and PBTZ169 as the most advanced compounds, represent a new class of potent antitubercular agents, which irreversibly inhibit decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1), an enzyme crucial for cell wall synthesis in the pathogen Mycobacterium tuberculosis. Synthesis, structural characterization and in vitro testing against Mycobacterium aurum DSM 43999 and M. tuberculosis H37Rv of halogenated 2-(4-ethoxycarbonylpiperazin-1-yl)-1,3-benzothiazin-4-ones lacking a nitro group are reported. X-ray crystallography reveals that the structure of the BTZ scaffold can significantly deviate from planarity. In contrast to recent reports, the results of the present study indicate that further investigation of halogenated non-nitro BTZs for antitubercular activity is less than a promising approach.

Hydrogenative Metathesis of Enynes via Piano-Stool Ruthenium Carbene Complexes Formed by Alkyne gem-Hydrogenation.

The only recently discovered gem-hydrogenation of internal alkynes is a fundamentally new transformation, in which both H atoms of dihydrogen are transferred to the same C atom of a triple bond while the other position transforms into a discrete metal carbene complex. [Cp*RuCl]4 is presently the catalyst of choice: the resulting piano-stool ruthenium carbenes can engage a tethered alkene into either cyclopropanation or metathesis, and a prototypical example of such a reactive intermediate with an olefin ligated to the ruthenium center has been isolated and characterized by X-ray diffraction. It is the substitution pattern of the olefin that determines whether metathesis or cyclopropanation takes place: a systematic survey using alkenes of largely different character in combination with a computational study of the mechanism at the local coupled cluster level of theory allowed the preparative results to be sorted and an intuitive model with predictive power to be proposed. This model links the course of the reaction to the polarization of the double bond as well as to the stability of the secondary carbene complex formed, if metathesis were to take place. The first application of "hydrogenative metathesis" to the total synthesis of sinularones E and F concurred with this interpretation and allowed the proposed structure of these marine natural products to be confirmed. During this synthesis, it was found that gem-hydrogenation also provides opportunities for C-H functionalization. Moreover, silylated alkynes are shown to participate well in hydrogenative metathesis, which opens a new entry into valuable allylsilane building blocks. Crystallographic evidence suggests that the polarized [Ru-Cl] bond of the catalyst interacts with the neighboring R3Si group. Since attractive interligand Cl/R3Si contacts had already previously been invoked to explain the outcome of various ruthenium-catalyzed reactions, including trans-hydrosilylation, the experimental confirmation provided herein has implications beyond the present case.

Chiral Heterobimetallic Bismuth-Rhodium Paddlewheel Catalysts: A Conceptually New Approach to Asymmetric Cyclopropanation.

Cyclopropanation reactions of styrene derivatives with donor-acceptor carbenes formed in situ are significantly more enantioselective when catalyzed by the heterobimetallic bismuth-rhodium complex 5 a endowed with N-phthalimido tert-leucine paddlewheel ligands rather than by its homobimetallic dirhodium analogue 1 a. This virtue is likely the result of two synergizing factors: the conical shape of 5 a translates into a narrower calyx-like chiral binding site about the catalytically active Rh center; the Bi atom, although fully solvent exposed, does not decompose aryl diazoacetates and is hence incapable of promoting a racemic background reaction. Moreover, ligand variation proved that successful catalyst design mandates that the anisotropy of the conical heterobimetallic core be matched by proper directionality of the ligand sphere.

A Highly Reduced Ni-Li-Olefin Complex for Catalytic Kumada-Corriu Cross-Couplings.

The catalytic activity of a highly reduced Ni catalyst in the context of a Kumada-Corriu cross-coupling has been studied. This nickel complex is characterized by its high electron density, stabilized by simple olefin ligands in combination with two Li ions. Landmark reactivity has been found with this precatalyst which operates at cryogenic temperatures, thus allowing the presence of sensitive functionalities. Structural elucidation of oxidative addition intermediates and their reactivity suggest highly reduced species being operative in the C-C bond forming event.

Structure and Reactivity of Half-Sandwich Rh(+3) and Ir(+3) Carbene Complexes. Catalytic Metathesis of Azobenzene Derivatives.

Traditional rhodium carbene chemistry relies on the controlled decomposition of diazo derivatives with [Rh2(OAc)4] or related dinuclear Rh(+2) complexes, whereas the use of other rhodium sources is much less developed. It is now shown that half-sandwich carbene species derived from [Cp*MX2]2 (M = Rh, Ir; X = Cl, Br, I, Cp* = pentamethylcyclopentadienyl) also exhibit favorable application profiles. Interestingly, the anionic ligand X proved to be a critical determinant of reactivity in the case of cyclopropanation, epoxide formation and the previously unknown catalytic metathesis of azobenzene derivatives, whereas the nature of X does not play any significant role in -OH insertion reactions. This perplexing disparity can be explained on the basis of spectral and crystallographic data of a representative set of carbene complexes of this type, which could be isolated despite their pronounced electrophilicity. Specifically, the donor/acceptor carbene 10a derived from ArC(═N2)COOMe and [Cp*RhCl2]2 undergoes spontaneous 1,2-migratory insertion of the emerging carbene unit into the Rh-Cl bond with formation of the C-metalated rhodium enolate 11. In contrast, the analogous complexes 10b,c derived from [Cp*RhX2]2 (X = Br, I) as well as the iridium species 13 and 14 derived from [Cp*IrCl2]2 are sufficiently stable and allow true carbene reactivity to be harnessed. These complexes are competent intermediates for the catalytic metathesis of azobenzene derivatives, which provides access to α-imino esters that would be difficult to make otherwise. Rather than involving metal nitrenes, the reaction proceeds via aza-ylides that evolve into diaziridines; a metastable compound of this type has been fully characterized.

Half-Sandwich Ruthenium Carbene Complexes Link trans-Hydrogenation and gem-Hydrogenation of Internal Alkynes.

The hydrogenation of internal alkynes with [Cp*Ru]-based catalysts is distinguished by an unorthodox stereochemical course in that E-alkenes are formed by trans-delivery of the two H atoms of H2. A combined experimental and computational study now provides a comprehensive mechanistic picture: a metallacyclopropene (η2-vinyl complex) is primarily formed, which either evolves into the E-alkene via a concerted process or reacts to give a half-sandwich ruthenium carbene; in this case, one of the C atoms of the starting alkyne is converted into a methylene group. This transformation represents a formal gem-hydrogenation of a π-bond, which has hardly any precedent. The barriers for trans-hydrogenation and gem-hydrogenation are similar: whereas DFT predicts a preference for trans-hydrogenation, CCSD(T) finds gem-hydrogenation slightly more facile. The carbene, once formed, will bind a second H2 molecule and evolve to the desired E-alkene, a positional alkene isomer or the corresponding alkane; this associative pathway explains why double bond isomerization and over-reduction compete with trans-hydrogenation. The computed scenario concurs with para-hydrogen-induced polarization transfer (PHIP) NMR data, which confirm direct trans-delivery of H2, the formation of carbene intermediates by gem-hydrogenation, and their evolution into product and side products alike. Propargylic -OR (R = H, Me) groups exert a strong directing and stabilizing effect, such that several carbene intermediates could be isolated and characterized by X-ray diffraction. The gathered information spurred significant preparative advances: specifically, highly selective trans-hydrogenations of propargylic alcohols are reported, which are compatible with many other reducible functional groups. Moreover, the ability to generate metal carbenes by gem-hydrogenation paved the way for noncanonical hydrogenative cyclopropanations, ring expansions, and cycloadditions.

Palladium(II)-Stabilized Pyridine-2-Diazotates: Synthesis, Structural Characterization, and Cytotoxicity Studies.

Well-defined diazotates are scarce. Here we report the synthesis of unprecedented homoleptic palladium(II) diazotate complexes. The palladium(II)-mediated nitrosylation of 2-aminopyridines with NaNO2 results in the formation of metal-stabilized diazotates, which were found to be cytotoxic to human ovarian cancer cells.

Two Amphoteric Silver Carbene Clusters.

Two highly labile silver carbene cluster complexes are described, which are unique in that they mark the transition point at which the carbene center transmutes from a fairly common NHC-like nucleophilic behavior to an electrophilic character befitting reactive silver carbene intermediates of relevance in various catalytic transformations. This amphoteric character is the distinguishing attribute of a µ-bridged donor/donor carbene entity that connects two silver atoms of triangular or tetrahedral metallic core units.

A Purely Organic Tricarbanion.

How many carbanions can an organic molecule accommodate? The formation of purely organic carbanions with multiple charges is challenging as charge stabilization cannot be achieved through metal coordination. Previously, only quaternary ammonium dicarbanion salts had been reported. By using highly electron-deficient trifluoromethanesulfonyl (triflyl or Tf) groups, the formation of a purely organic tricarbanion has been realized for the first time.

The Catalytic Asymmetric Mukaiyama-Michael Reaction of Silyl Ketene Acetals with α,ß-Unsaturated Methyl Esters.

α,ß-Unsaturated esters are readily available but challenging substrates to activate in asymmetric catalysis. We now describe an efficient, general, and highly enantioselective Mukaiyama-Michael reaction of silyl ketene acetals with α,ß-unsaturated methyl esters that is catalyzed by a silylium imidodiphosphorimidate (IDPi) Lewis acid.

Ruthenium-Catalyzed Alkyne trans-Hydrometalation: Mechanistic Insights and Preparative Implications.

[Cp*RuCl]4 (1) has previously been shown to be the precatalyst of choice for stereochemically unorthodox trans-hydrometalations of internal alkynes. Experimental and computational data now prove that the alkyne primarily acts as a four-electron donor ligand to the catalytically active metal fragment [Cp*RuCl] but switches to adopt a two-electron donor character once the reagent R3MH (M = Si, Ge, Sn) enters the ligand sphere. In the stereodetermining step the resulting loaded complex evolves via an inner-sphere mechanism into a ruthenacyclopropene which swiftly transforms into the product. In accord with the low computed barriers, spectral and preparative data show that the reaction is not only possible but sometimes even favored at low temperatures. Importantly, such trans-hydrometalations are distinguished by excellent levels of regioselectivity when unsymmetrical alkynes are used that carry an -OH or -NHR group in vicinity of the triple bond. A nascent hydrogen bridge between the protic substituent and the polarized [Ru-Cl] unit imposes directionality onto the ligand sphere of the relevant intermediates, which ultimately accounts for the selective delivery of the R3M- group to the acetylene C-atom proximal to the steering substituent. The interligand hydrogen bonding also allows site-selectivity to be harnessed in reactions of polyunsaturated compounds, since propargylic substrates bind more tightly than ordinary alkynes; even the electronically coupled triple bonds of conjugated 1,3-diynes can be faithfully discriminated as long as one of them is propargylic. Finally, properly positioned protic sites lead to a substantially increased substrate scope in that they render even 1,3-enynes, arylalkynes, and electron-rich alkynylated heterocycles amenable to trans-hydrometalation which are otherwise catalyst poisons.

Catalytic Asymmetric [4+2]-Cycloaddition of Dienes with Aldehydes.

Despite its significant potential, a general catalytic asymmetric [4+2]-cycloaddition of simple and electronically unbiased dienes with any type of aldehyde has long been unknown. Previously developed methodologies invariably require activated, electronically engineered substrates. We now provide a general solution to this problem. We show that highly acidic and confined imidodiphosphorimidates (IDPis) are extremely effective Brønsted acid catalysts of the hetero-Diels-Alder reaction of a wide variety of aldehydes and dienes to give enantiomerically enriched dihydropyrans. Excellent stereoselectivity is generally observed and a variety of scents and natural products can be easily accessed.

9,9-Difluorobispidine Analogues of Cisplatin, Carboplatin, and Oxaliplatin.

As part of a comprehensive study of N-unsubstituted bispidines, the novel 9,9-difluorobispidine (D) has been synthesized. The compound crystallizes from pentane below 0 °C in the ordered-crystalline phase D-II and undergoes at 0-30 °C a stepwise endothermic phase transition to a dynamically disordered crystalline phase D-I; melting occurs at 227 °C. Single crystalline D-II has been subjected to X-ray structure analysis, revealing association of the molecules to form chains. Reaction of (1,5-hexadiene)PtCl2 with D affords {C7H10F2(NH)2}PtCl2 (D1), which can be converted by conventional routes to {C7H10F2(NH)2}Pt(cbdca)·5H2O (D2) and {C7H10F2(NH)2}Pt(C2O4) (D3). Compound D1 crystallizes solvent-free from water and is isomorphous to the solvent-free parent bispidine analogue (A1). The pentahydrate D2 is isomorphous to the bispidine and 9-oxabispidine homologues (A2 and C2), as shown by X-ray structure analyses. An increased polarity of the bispidine skeleton as a consequence of the high electronegativity of fluorine is seen as the reason for low cytotoxic potency of D1-D3.

Regio- and Stereoselective Chlorocyanation of Alkynes.

A variety of terminal and internal alkynes were converted regio- and stereoselectively into (Z)-3-chloroacrylonitriles by treatment with BCl3 in the presence of stoichiometric amounts of imidazolium thiocyanates. These products could be readily functionalized to provide useful building blocks, thus demonstrating the synthetic value of the method. Preliminary mechanistic studies suggest initial activation of the cationic thiocyanate by the Lewis acid, followed by electrophilic attack of the alkyne. The syn addition of a chloride to the vinyl cation intermediate and final elimination of the thiourea unit afford the desired chloroacrylonitriles.

Two Exceptional Homoleptic Iron(IV) Tetraalkyl Complexes.

The formation of the high-valent iron complex [Fe(cyclohexyl)4 ] from FeII under reducing conditions is best explained by disproportionation of a transient organoiron intermediate which is driven by dispersive forces between the cyclohexyl ligands and the formation of short and strong Fe-C bonds. The (meta)stability of this diamagnetic complex (S=0) is striking if one considers that it has empty d-orbitals at its disposal and contains, at the same time, no less than twenty H-atoms available for either α- or ß-hydride elimination.

α-Radical Phosphines: Synthesis, Structure, and Reactivity.

A series of phosphines featuring a persistent radical were synthesized in two steps by condensation of dialkyl-/diarylchlorophosphines with stable cyclic (alkyl)(amino)carbenes (cAACs) followed by one-electron reduction of the corresponding cationic intermediates. Structural, spectroscopic, and computational data indicate that the spin density in these phosphines is mainly localized on the original carbene carbon from the cAAC fragment; thus, it remains in the α-position with respect to the central phosphorus atom. The potential of these α-radical phosphines to serve as spin-labeled ligands is demonstrated through the preparation of several AuI derivatives, which were also structurally characterized by single-crystal X-ray diffraction.

Cs[H2NB2(C6F5)6] Featuring an Unequivocal 16-Coordinate Cation.

Cesium bis(perfluoro-triphenylborane)amide, Cs[H2NB2(C6F5)6] (1), has been prepared by the reaction of sodium salt and CsF in dichloromethane and water. The compound is exceptional for a [H2NB2(C6F5)6](-) salt in that it contains a monatomic solute-free cation. Determination of the molecular structure revealed a novel C2 symmetrical conformation of the weakly coordinating [H2NB2(C6F5)6](-) anion, which gives rise to an unprecedented 16-coordinate (CN 16) Cs(+) cation in a likewise unprecedented tetracosahedral arrangement of F atoms. The poor solubility of 1 allows nearly quantitative separation of Cs(+) from water, which suggests potential applications as an effective (134/137)Cs remover from nuclear waste solutions, administration as an antidote for (134/137)Cs poisoning, and use for (131/137)Cs radiotherapy (brachytherapy). Rb[H2NB2(C6F5)6]·CH2Cl2 (2) has also been characterized, featuring two inequivalent Rb(+) cations having CN 10, one of which involves Rb(+)(η(2)-Cl2CH2)2 coordination.