RuV -Acylimido Intermediate in [RuIV (Por)Cl2 ]-Catalyzed C-N Bond Formation: Spectroscopic Characterization, Reactivity, and Catalytic Reactions.

Metal-catalyzed C-N bond formation reactions via acylnitrene transfer have recently attracted much attention, but direct detection of the proposed acylnitrenoid/acylimido M(NCOR) (R=aryl or alkyl) species in these reactions poses a formidable challenge. Herein, we report on Ru(NCOR) intermediates in C-N bond formation catalyzed by [RuIV (Por)Cl2 ]/N3 COR, a catalytic method applicable to aziridine/oxazoline formation from alkenes, amination of substituted indoles, α-amino ketone formation from silyl enol ethers, amination of C(sp3 )-H bonds, and functionalization of natural products and carbohydrate derivatives (up to 99 % yield). Experimental studies, including HR-ESI-MS and EPR measurements, coupled with DFT calculations, lend evidence for the formulation of the Ru(NCOR) acylnitrenoids as a RuV -imido species.

Polyunsaturated fatty acid amides from the Zanthoxylum genus - from culinary curiosities to probes for chemical biology.

Covering up to February 2017The pericarps of several species from the Zanthoxylum genus, a.k.a. the "prickly ash", have long been used for culinary purposes throughout Asia, most notably in the Sichuan (previously Szechuan) cuisine of Southwestern China, due to the unique tingling and numbing orosensations arising from a collection of polyunsaturated fatty acid amide (alkamide) constituents. The past decade has experienced dramatically increased academic and industrial interest in these pungent Zanthoxylum-derived alkamides, with a concomitant explosion in studies aimed at elucidating the specific biochemical mechanisms behind several medically-relevant biological activities exhibited by the natural products. This rapid increase in interest is partially fueled by advances in organic synthesis reported within the past few years that finally have allowed for the production of diastereomerically-pure Zanthoxylum alkamides and related analogs in multigram quantities. Herein is a comprehensive review of the discovery, total synthesis, and biological evaluation of Zanthoxylum-derived polyunsaturated fatty acid amides and synthetic analogues. Critical insights into how chemical synthesis can further benefit future chemical biology efforts in the field are also provided.

Self-Supported N-Heterocyclic Carbenes and Their Use as Organocatalysts.

The study of N-heterocyclic carbenes (NHCs) as organocatalysts has proliferated in recent years, and they have been found to be useful in a variety of reactions. In an attempt to further expand their utility and to study their recyclability, we designed and synthesized a series of self-supported NHCs in which the catalytic carbene groups form part of a densely functionalized polymer backbone, and studied them as organocatalysts. Of the self-Supported NHCs examined, a benzimidazole derived polymer with flexible linkers connecting the catalytic groups was found to be the most efficient organocatalyst in a model benzoin condensation reaction, and thus it was used in a variety of such reactions, including some involving catalyst recycling. Furthermore, it was also used to catalyze a set of redox esterification reactions involving conjugated unsaturated aldehydes. In all of these reactions the catalyst afforded good yield of the desired product and its polymeric nature facilitated product purification.

Catalytic Wittig and aza-Wittig reactions.

This review surveys the literature regarding the development of catalytic versions of the Wittig and aza-Wittig reactions. The first section summarizes how arsenic and tellurium-based catalytic Wittig-type reaction systems were developed first due to the relatively easy reduction of the oxides involved. This is followed by a presentation of the current state of the art regarding phosphine-catalyzed Wittig reactions. The second section covers the field of related catalytic aza-Wittig reactions that are catalyzed by both phosphine oxides and phosphines.

Rasta resin-triphenylphosphine oxides and their use as recyclable heterogeneous reagent precursors in halogenation reactions.

Heterogeneous polymer-supported triphenylphosphine oxides based on the rasta resin architecture have been synthesized, and applied as reagent precursors in a wide range of halogenation reactions. The rasta resin-triphenylphosphine oxides were reacted with either oxalyl chloride or oxalyl bromide to form the corresponding halophosphonium salts, and these in turn were reacted with alcohols, aldehydes, aziridines and epoxides to form halogenated products in high yields after simple purification. The polymer-supported triphenylphosphine oxides formed as a byproduct during these reactions could be recovered and reused numerous times with no appreciable decrease in reactivity.

Metallo-sideromycin as a dual functional complex for combating antimicrobial resistance.

The rapid emergence of antimicrobial resistance (AMR) pathogens highlights the urgent need to approach this global burden with alternative strategies. Cefiderocol (Fetroja®) is a clinically-used sideromycin, that is utilized for the treatment of severe drug-resistant infections, caused by Gram-negative bacteria; there is evidence of cefiderocol-resistance occurring in bacterial strains however. To increase the efficacy and extend the life-span of sideromycins, we demonstrate strong synergisms between cefiderocol and metallodrugs (e.g., colloidal bismuth citrate (CBS)), against Pseudomonas aeruginosa and Burkholderia cepacia. Moreover, CBS enhances cefiderocol efficacy against biofilm formation, suppresses the resistance development in P. aeruginosa and resensitizes clinically isolated resistant P. aeruginosa to cefiderocol. Notably, the co-therapy of CBS and cefiderocol significantly increases the survival rate of mice and decreases bacterial loads in the lung in a murine acute pneumonia model. The observed phenomena are partially attributable to the competitive binding of Bi3+ to cefiderocol with Fe3+, leading to enhanced uptake of Bi3+ and reduced levels of Fe3+ in cells. Our studies provide insight into the antimicrobial potential of metallo-sideromycins.

Time-resolved resonance Raman and computational investigation of the influence of 4-acetamido and 4-N-methylacetamido substituents on the chemistry of phenylnitrene.

A time-resolved resonance Raman (TR(3)) and computational investigation of the photochemistry of 4-acetamidophenyl azide and 4-N-methylacetamidophenyl azide in acetonitrile is presented. Photolysis of 4-acetamidophenyl azide appears to initially produce singlet 4-acetamidophenylnitrene which undergoes fast intersystem crossing (ISC) to form triplet 4-acetamidophenylnitrene. The latter species formally produces 4,4'-bisacetamidoazobenzene. RI-CC2/TZVP and TD-B3LYP/TZVP calculations predict the formation of the singlet nitrene from the photogenerated S(1) surface of the azide excited state. The triplet 4-acetamidophenylnitrene and 4,4'-bisacetamidoazobenzene species are both clearly observed on the nanosecond to microsecond time-scale in TR(3) experiments. In contrast, only one species can be observed in analogous TR(3) experiments after photolysis of 4-N-methylacetamidophenyl azide in acetonitrile, and this species is tentatively assigned to the compound resulting from dimerization of a 1,2-didehydroazepine. The different photochemical reaction outcomes for the photolysis of 4-acetamidophenyl azide and 4-N-methylacetamidophenyl azide molecules indicate that the 4-acetamido group has a substantial influence on the ISC rate of the corresponding substituted singlet phenylnitrene, but the 4-N-methylacetamido group does not. CASSCF analyses predict that both singlet nitrenes have open-shell electronic configurations and concluded that the dissimilarity in the photochemistry is probably due to differential geometrical distortions between the states. We briefly discuss the probable implications of this intriguing substitution effect on the photochemistry of phenyl azides and the chemistry of the related nitrenes.

A time-resolved spectroscopic study of the bichromophoric phototrigger 3',5'-dimethoxybenzoin diethyl phosphate: interaction between the two chromophores determines the reaction pathway.

3',5'-Dimethoxybenzoin (DMB) is a bichromophoric system that has widespread application as a highly efficient photoremovable protecting group (PRPG) for the release of diverse functional groups. The photodeprotection of DMB phototriggers is remarkably clean, and is accompanied by the formation of a biologically benign cyclization product, 3',5'-dimethoxybenzofuran (DMBF). The underlying mechanism of the DMB deprotection and cyclization has, however, until now remained unclear. Femtosecond transient absorption (fs-TA) spectroscopy and nanosecond time-resolved resonance Raman (ns-TR(3)) spectroscopy were employed to detect the transient species directly, and examine the dynamic transformations involved in the primary photoreactions for DMB diethyl phosphate (DMBDP) in acetonitrile (CH(3)CN). To assess the electronic character and the role played by the individual sub-chromophore, that is, the benzoyl, and the di-meta-methoxybenzylic moieties, for the DMBDP deprotection, comparative fs-TA measurements were also carried out for the reference compounds diethyl phosphate acetophenone (DPAP), and 3',5'-dimethoxybenzylic diethyl phosphate (DMBnDP) in the same solvent. Comparison of the fs-TA spectra reveals that the photoexcited DMBDP exhibits distinctly different spectral character and dynamic evolution from those of the reference compounds. This fact, combined with the related steady-state spectral and density functional theoretical results, strongly suggests the presence in DMBDP of a significant interaction between the two sub-chromophores, and that this interaction plays a governing role in determining the nature of the photoexcitation and the reaction channel of the subsequent photophysical and photochemical transformations. The ns-TR(3) results and their correlation with the fs-TA spectra and dynamics provide evidence for a novel concerted deprotection-cyclization mechanism for DMBDP in CH(3)CN. By monitoring the direct generation of the transient DMBF product, the cyclization time constant was determined unequivocally to be approximately 1 ns. This indicates that there is little relevance for the long-lived intermediates (>10 ns) in giving the DMBF product, and excludes the stepwise mechanism proposed in the literature as the major pathway for the DMB cyclization reaction. This work provides important new insights into the origin of the 3',5'-dimethoxy substitution effect for the DMB photodeprotection. It also helps to clarify the many different views presented in previous mechanistic studies of the DMB PRPGs. In addition to this, our fs-TA results on the reference compound DMBnDP in CH(3)CN provide the first direct observation (to the best of our knowledge) showing the predominance of a prompt (approximately 2 ps) heterolytic bond cleavage after photoexcitation of meta-methoxybenzylic compounds. This provides insight into the long-term controversies about the photoinitiated dissociation mode of related substituted benzylic compounds.

Photophysics and photodeprotection reactions of p-methoxyphenacyl phototriggers: an ultrafast and nanosecond time-resolved spectroscopic and density functional theory study.

Time-resolved spectroscopic experiments were performed to investigate the kinetics and mechanisms of the photodeprotection reactions for p-methoxyphenacyl (pMP) compounds, p-methoxyphenacyl diethyl phosphate (MPEP) and diphenyl phosphate (MPPP). The experimental results reveal that compared to the previous reports for the counterpart p-hydroxyphenacyl (pHP) phosphates, the (3)npi*/pipi* mixed character triplet of pMP acts as a reactive precursor that leads to the subsequent solvent and leaving group dependent chemical reactions and further affects the formation of photoproducts. The MPPP triplet in H(2)O/CH(3)CN and in fluorinated alcohols shows a rapid heterolytic cleavage (tau approximately 5.4 ns) that results in deprotection and formation of a solvolytic rearrangement product, whereas the MPPP triplet in CH(3)CN and the MPEP triplet in CH(3)CN and H(2)O/CH(3)CN and fluorinated alcohols decay on a much longer time scale (tau approximately 100 ns) with little observation of the rearrangement product. The density functional theory (DFT) calculations reveal a substantial solvation effect that is connected with the methoxy versus hydroxyl substitution in accounting for the different deprotection reactivity of pMP and pHP compounds. The results reported here provide new insight in elucidating the solvent and leaving group dependent dual reactivity of pMP compounds on the formation of the rearrangement versus reductive photoproduct.

Halogen Bond-Catalyzed Friedel-Crafts Reactions of Aldehydes and Ketones Using a Bidentate Halogen Bond Donor Catalyst: Synthesis of Symmetrical Bis(indolyl)methanes.

The use of a halogen bond donor to catalyze Friedel-Crafts reactions of indoles with a range of aldehydes and ketones to directly produce bis(indolyl)methanes, including the natural products arsindoline A, arundine, trisindoline, and vibrindole A, is reported. The bidentate catalyst used in these reactions proved to be more effective than a monondentate analogue, a thiourea commonly used as an organocatalyst, and even a trityl cation that has been used previously in the synthesis of bis(indolyl)methanes.

Reductive Halogenation Reactions: Selective Synthesis of Unsymmetrical α-Haloketones.

A method for the selective synthesis of unsymmetrical α-haloketones has been developed. The key transformation is a triphenylphosphine oxide catalyzed reductive halogenation of an α,ß-unsaturated ketone in which trichlorosilane is the reducing reagent and an N-halosuccinimide is the electrophilic halogen source. This method allows for a halogen atom to be installed selectively at either of two very similarly substituted sites adjacent to a ketone group.

S-Dimethylarsino-glutathione (darinaparsin®) targets histone H3.3, leading to TRAIL-induced apoptosis in leukemia cells.

Histone H3.3 was identified as an arsenic-binding protein of S-dimethylarsino-glutathione (ZIO-101, darinaparsin®) in leukemia cells by GE-ICP-MS. Such a binding results in TRAIL-induced apoptosis. We further validate histone H3.3 as a vital target for ZIO-101, offering new information on the mode of action of arsenic-based anticancer agents.

Highly Enantioselective Synthesis Using Prolinol as a Chiral Auxiliary: Silver-Mediated Synthesis of Axially Chiral Vinylallenes and Subsequent (Hetero)-Diels-Alder Reactions.

Using (S)-prolinol as a chiral auxiliary, axially chiral vinylallenes with excellent enantiopurity (up to >99% enantiomeric excess (ee)) were readily prepared from optically pure propargylamines in the presence of AgNO3 under microwave irradiation. Subsequent (hetero)-Diels-Alder reaction of these axially chiral vinylallenes with azodicarboxylates or maleimides on water demonstrates excellent axial-to-point chirality transfer (up to 99% ee).

Time-resolved resonance Raman investigation of the 2-fluorenylnitrenium ion reactions with C8 guanosine derivatives.

A nanosecond time-resolved resonance Raman (ns-TR3) spectroscopic study of the reactions of the 2-fluorenylnitrenium ion with several C8-substituted guanosine derivatives is reported. The TR3 spectra show that the 2-fluorenylnitrenium ion reacts with the C8-substituted guanosine derivatives (C8-methylguanosine and C8-bromoguanosine) to produce C8 intermediates with the methyl and bromine moieties still attached to the intermediate species at the C8 position. The C8-bromoguanosine species was observed to be less reactive toward the 2-fluorenylnitrenium ion compared to the guanosine and C8-methylguanosine species. Comparison of the TR3 spectra to the results obtained from density functional theory calculations was used to characterize the C8 intermediates observed to learn more about their structure and properties. The implications of these results for the chemical reactivity of arylnitrenium ions toward substituted guanosine derivatives are briefly discussed.

Modular functionalized polyphosphines for supported materials: previously unobserved (31)P-NMR «through-space¼ ABCD spin systems and heterogeneous palladium-catalysed C-C and C-H arylation.

The modular design of polyphosphines, diversely functionalized for facile immobilization on virtually any kind of support, is reported. Previously unobserved ABCD (31)P NMR spin-spin systems evidence the control exercised on the polyphosphines conformation. We illustrate the catalytic performance at low Pd loading of the recyclable immobilized polyphosphines in C-C bond formation reactions.

Rasta resin-PPh3-NBniPr2 and its use in one-pot Wittig reaction cascades.

A new triarylphosphine-tertiary amine bifunctional polymeric reagent has been prepared and used effectively in a variety of one-pot Wittig reactions. The design of this reagent resolved a deficiency of a previously reported related material, and allowed it to perform more efficiently in such reactions. Furthermore, it was readily recyclable, and was also successfully applied in cascade processes involving one-pot Wittig reactions followed by either a conjugate reduction or a reductive aldol reaction. In these reaction cascades, the phosphine oxide groups generated in the Wittig reaction served as the catalyst for the subsequent reaction.

Chromatography-free Wittig reactions using a bifunctional polymeric reagent.

The first example of a polystyrene bearing two distinct reagent groups has been prepared. This phosphine and amine functionalized material was used in one-pot Wittig reactions with an aldehyde and either an α-halo-ester, -ketone, or -amide. Due to the heterogeneous nature of the polymer, the desired alkene product of these reactions could be isolated in excellent yield in essentially pure form after only filtration and solvent removal.

Multipolymer reaction system for selective aerobic alcohol oxidation: simultaneous use of multiple different polymer-supported ligands.

A multipolymer reaction system has been developed in which a water-soluble polymer-supported 2,2'-bipyridine group and a similarly immobilized TEMPO derivative are used as ligands for copper to effect the mild and selective aerobic oxidation of primary alcohols in acetonitrile-water solvent. In this reaction system, poly(ethylene glycol) monomethyl ether (molecular weight = 5000 Da) was used as the support for both the 2,2'-bipyridine and TEMPO moieties because of its solubility properties. The use of these functionalized polymers simultaneously in catalytic quantities allows for primary alcohols to be oxidized selectively to the corresponding aldehydes in an environmentally friendly manner. This is the first reported example of using two different polymer-supported ligands together to form an organometallic species capable of catalyzing an organic reaction.

The Mitsunobu reaction: origin, mechanism, improvements, and applications.

The Mitsunobu reaction is a widely used and versatile method for the dehydrative oxidation-reduction condensation of an acid/pronucleophile usually with a primary or secondary alcohol that requires the combination of a reducing phosphine reagent together with an oxidizing azo reagent. The utility of this reaction stems from the fact that it is generally highly stereoselective and occurs with inversion of the stereochemical configuration of the alcohol starting material. Furthermore, as carboxylic acids, phenols, imides, sulfonamides, and other compounds can be used as the acid/pronucleophile, this reaction is useful for the preparation of a wide variety of functional groups. This Focus Review of the Mitsunobu reaction summarizes its origins, the current understanding of its mechanism, and recent improvements and applications.