Organic & Biomolecular Chemistry (v.18, #3)

Front cover (355-356).

Contents list (357-364).

Recent developments in the chemistry of allenyl sulfones by Deepak Yadav; Rajeev S. Menon (365-378).
Allenyl sulfones are versatile building blocks that readily partake in a variety of transformations such as Michael additions, rearrangements, cycloadditions, electrophilic additions and redox reactions. Selected recent developments in the preparation and various reactions of allenyl sulfones are presented.

The accessory gene regulator (agr) quorum-sensing system is arguably the most important regulator of staphylococcus virulence and has been the focus of tremendous interest in the development of effective therapies for pathogenic bacterial infections. With regards to chemotherapeutic based strategies, the significant proportion of currently reported agr-system modulating molecules are mimics of the native ArgC substrate, which is a thioester-based macrocyclic peptide know as the auto-inducing peptide. Over the past two decades, more than two-hundred synthetic analogues have been reported. This review traces the development of the synthetic strategies employed to synthesise these analogues with a particular focus on macrocyclisation. At present these synthetic approaches can be clustered into five broad categories (1) solution-phase cyclisation, (2) immobilised carbodiimide assisted cyclisation, (3) concomitant on-resin cleavage and macrocyclisation, (4) Boc-compatible chemoselective thioesterification, and (5) Fmoc-compatible chemoselective thioesterification. The advantages and limitation provided by each of the approaches are compared and contrasted with a view towards potential reaction scale-up.

Hydrocyanation is a powerful method for the preparation of nitriles which are versatile building blocks for the synthesis of amines, acids and amides. This review summarizes the research on transition-metal-catalyzed (asymmetric) hydrocyanation of nonpolar (or non-activated) alkenes and alkynes in the last decade. These studies involve the extension of HCN surrogates and unsaturated substrates, catalyst development as well as the improvement of the activity and multiple selectivities. The remaining challenges and personal future perspectives are presented at the end.

Ag-Catalyzed minisci C–H difluoromethylarylation of N-heteroarenes by Xiaojuan Xie; Yifang Zhang; Jian Hao; Wen Wan (400-404).
A mild silver-catalyzed decarboxylative difluoromethylarylation of electron-deficient N-heteroarenes has been developed by using aryldifluoro acetic acid as difluoromethyl sources. This protocol provides an efficient and straightforward access to difluoromethylated heteroarenes in moderate to excellent yields with good selectivities. Furthermore, this reaction was applicable to bioactive heteroarenes, providing a straightforward approach for the late-stage C–H difluoromethylation of pharmacophores.

Enantioselective catalytic synthesis of α-aryl-α-SCF32,2-amino acids by Andreas Eitzinger; Jean-François Brière; Dominique Cahard; Mario Waser (405-408).
We herein report a novel entry towards chiral α-SCF32,2-amino acids by carrying out the ammonium salt-catalyzed α-trifluoromethylthiolation of isoxazolidin-5-ones. This approach allowed for high enantioselectivities and high yields and the obtained heterocycles proved to be versatile platforms to access other targets of potential interest.

An iron-catalyzed one-pot three-component reaction of 1-substituted benzimidazoles with diazoacetates and electron-deficient alkynes or alkenes has been reported. Mechanistically, the reaction goes through a 1,3-dipolar cycloaddition of catalytically generated benzimidazolium N-ylides with various activated alkynes or alkenes, leading to multi-substituted and polycyclic fused pyrrole derivatives, respectively.

Synthesis of substituted benzo[b][1,4]oxazepine derivatives by the reaction of 2-aminophenols with alkynones by Kohei Oshimoto; Biao Zhou; Hiroaki Tsuji; Motoi Kawatsura (415-419).
We have developed a novel synthetic method accessing benzo[b][1,4]oxazepines that are one of the rare classes of benzoxazepine derivatives by reaction of 2-aminophenols with alkynones in 1,4-dioxane at 100 °C. A series of benzo[b][1,4]oxazepine derivatives can be prepared by using this synthetic protocol. Mechanistic experiments indicated that the hydroxy proton of the aminophenol could play a crucial role in the formation of an alkynylketimine intermediate that undergoes 7-endo-dig cyclization.

The aim of this work is to show that by increasing the number of donor substituents in a donor/acceptor system, the sensitivity of the azobenzene linkage towards a reductive cleavage reaction can be enhanced to unprecedented high levels. For instance, in a triple-donor system, less than a second constitutes the half-life of the azo (NN) bond. Synthetic access to such redox active scaffolds is highly practical and requires only 1–2 synthetic steps. The fundamental molecular design is also adaptable. This is demonstrated through scaffold functionalization by azide, tetraethylene glycol, and biotin groups. The availability of the azide group is shown in a copper-free ‘click’ reaction suitable in context with protein conjugation and proteomics application. Finally, the clean nature of the scission process is demonstrated with the help of liquid chromatography coupled with mass analysis. This work, therefore, describes development of cleavable azobenzene linkers that can be accessed with synthetic ease, can be multiply functionalized, and show a clean and rapid response to mild reducing conditions.

Stereochemistry, lipid length and branching influences Mincle agonist activity of monoacylglycerides by Ayesha Khan; Chriselle D. Braganza; Kristel Kodar; Mattie S. M. Timmer; Bridget L. Stocker (425-430).
Herein, we report on the synthesis of a series of enantiomerically pure linear, iso-branched, and α-branched monoacyl glycerides (MAGs) in 63–72% overall yield. The ability of the MAGs to signal through human macrophage inducible C-type lectin (hMincle) using NFAT-GFP reporter cells was explored, as was the ability of the compounds to activate human monocytes. From these studies, MAGs with an acyl chain length ≥C22 were required for Mincle activation and the production of interleukin-8 (IL-8) by human monocytes. Moreover, the iso-branched MAGs led to a more pronounced immune response compared to linear MAGs, while an α-branched MAG containing a C-32 acyl chain activated cells to a higher degree than trehalose dibehenate (TDB), the prototypical Mincle agonist. Across the compound classes, the activity of the sn-1 substituted isomers was greater than the sn-3 counterparts. None of the representative compounds were cytotoxic, thus mitigating cytotoxicity as a potential mediator of cellular activity. Taken together, 6h (sn-1, iC26+1), 8a (sn-1, C32) and 8b (sn-3, C32) exhibited the best immunostimulatory properties and thus, have potential as vaccine adjuvants.

Multi-state amine sensing by electron transfers in a BODIPY probe by Katherine L. VanDenburgh; Yun Liu; Tumpa Sadhukhan; Christopher R. Benson; Natalie M. Cox; Sundus Erbas-Cakmak; Bo Qiao; Xinfeng Gao; Maren Pink; Krishnan Raghavachari; Amar H. Flood (431-440).
Amines are ubiquitous in the chemical industry and are present in a wide range of biological processes, motivating the development of amine-sensitive sensors. There are many turn-on amine sensors, however there are no examples of turn-on sensors that utilize the amine's ability to react by single electron transfer (SET). We investigated a new turn-on amine probe with a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophore. BODIPY fluorescence is first preprogrammed into an off state by internal photoinduced electron transfer (PET) to an electron-deficient quinolinium ring, resulting in fluorescence quenching. At low concentrations of aliphatic amine (0 to 10 mM), this PET pathway is shut down by external SET from the amine to the photoexcited charge-transfer state of the probe and the fluorescence is turned on. At high concentrations of amine (50 mM to 1 M), we observed collisional quenching of the BODIPY fluorescence. The probe is selective for aliphatic amines over aromatic amines, and aliphatic thiols or alcohols. The three molecular processes modulate the BODIPY fluorescence in a multi-mechanistic way with two of them producing a direct response to amine concentrations. The totality of the three molecular processes produced the first example of a multi-state and dose-responsive amine sensor.

A base-mediated dinucleophilic cyclization of readily accessible 2,3-epoxy tosylates with 2-mercaptobenzimidazole has been developed for the one-pot diastereoselective synthesis of benzimidazole-based tricyclic compounds equipped with two stereogenic centres. With trans-substrates bearing an aryl or alkyl substituent at the C3 position, the reaction involves an initial S–C1 bond-forming intermolecular alkylation followed by an N–C3 bond-forming, endo-selective intramolecular epoxide ring-opening cyclization reaction. A spectacular regioselectivity switching (tandem S–C3 and N–C1 bond formation reactions) was observed with related trans-N-tosylaziridine substrates. Wide substrate scope, complete diastereoselectivity, high to complete regioselectivity and mild transition metal-free conditions render this protocol particularly efficient and practical.

Metal-free consecutive C(sp2)–X (X = Cl, Br, S, N) bond formations of N-aryl amines (cyclic, fused, carbamate, and aminium radicals) were achieved under mild conditions using [bis(trifluoroacetoxy)iodo]benzene (PIFA) and simple nonharmful sodium salts. This direct and selective C(sp2)–H functionalization showed excellent functional group compatibility, cost effectiveness, and late-stage applicability for the synthesis of biologically active natural products. Two mechanisms were proposed to explain the ortho- or para-preference, as well as the accelerating effect of CH3NO2.

Wagner–Meerwein type rearrangement in 5-oxohomoadamantane series by Ilya M. Tkachenko; Polina A. Mankova; Victor B. Rybakov; Evgeniy V. Golovin; Yuri N. Klimochkin (465-478).
Efficient methods for introducing various substituents into the α-position of ethyl 5-oxohomoadamantyl-4-carboxylate are reported. An unexpected acid-catalysed 1,2-alkyl shift in the series of synthesized α,α-bis-substituted 5-oxohomoadamantanes, and also in the hydroxy derivatives of homoadamantane was found. Such a retropinacol-like rearrangement leads to tetra- or pentacyclic mono- or bis-lactones containing a homoadamantane moiety. This new transformation opens access to the synthesis of previously unknown 2,4-di and 2,3,4-trisubstituted derivatives of homoadamantane. The resulting caged γ-butyro- and δ-valerolactones could be considered as potential synthetic or metabolic precursors of conformationally restricted GABA and δ-aminovaleric acid analogues.

Asymmetric organocatalytic Mannich reaction of α-azido ketones and N-Boc protected isatin-derived ketimines were investigated for the first time. Examination of both 2-adamantyl and 3,5-bis(trifluoromethyl)aniline substituted quinine-based squaramides afforded chiral Mannich bases with two contiguous stereogenic centers in high yields (up to 97%) and stereoselectivity (up to dr = 24 : 1 syn : anti and 96% ee). Azido and masked amino functionalities of the potent heterocycle precursor adducts were utilized in representative examples.

Tandem addition/cyclization for synthesis of 2-aroyl benzofurans and 2-aroyl indoles by carbopalladation of nitriles by Julin Gong; Kun Hu; Yinlin Shao; Renhao Li; Yetong Zhang; Maolin Hu; Jiuxi Chen (488-494).
The first example of the palladium-catalyzed tandem addition/cyclization of 2-(2-acylphenoxy)acetonitriles with arylboronic acids has been developed, providing a new strategy for the synthesis of 2-aroyl benzofurans with excellent chemoselectivity and wide functional group compatibility. Preliminary mechanistic experiments indicate that this tandem process involves sequential nucleophilic addition generating 2-(2-acylphenoxy)-1-phenylethan-1-one followed by an intramolecular cyclization. This methodology has also been applied to the synthesis of 2-aroyl indoles and the potent CYP19 inhibitor 1-(benzofuran-2-yl(phenyl)methyl)-1H-1,2,4-triazole.

Highly selective staining and quantification of intracellular lipid droplets with a compact push–pull fluorophore based on benzothiadiazole by S. Israel Suarez; Caroline C. Warner; Heather Brown-Harding; Andrea M. Thooft; Brett VanVeller; John C. Lukesh (495-499).
A robust lipophilic dye, based on the structures of the benzothiadiazole heterocycle, was shown to be a potent fluorescent stain for the selective imaging of lipid droplets (LDs) within both live and fixed human cells. Its small molecular framework, large Stokes shift, and vastly improved photostability over that of the current status quo, Nile Red, highlight its tremendous potential as a versatile chemical tool for facilitating LD imaging and research.

Ruthenium(ii)-catalyzed oxidative coupling by C2-alkenylation of N-acyl pyrroles with alkenes has been described. The acyl unit was found to be an effective chelating group for the activation of aryl C–H bonds ortho to the directing group. The alkenylation reaction of benzoyl pyrroles occurred regioselectively at the C2-position of the pyrrole ring, without touching the benzene ring. The reaction provides exclusively monosubstituted pyrroles under the optimized conditions. Disubstituted pyrroles could be obtained using higher loadings of the ruthenium(ii)-catalyst and the additives.

The contribution of achiral residues in the laspartomycin family of calcium-dependent lipopeptide antibiotics by Thomas M. Wood; Kristine Bertheussen; Nathaniel I. Martin (514-517).
The growing threat of antibacterial resistance is a global concern. The so-called calcium-dependent lipopeptide antibiotics (CDAs) have emerged as a promising source of new antibiotic agents that are rich in structural and mechanistic diversity. Over forty unique CDAs have been identified to date and share a number of common features. Recent efforts in our group have provided new mechanistic and structural insights into the laspartomycin family of CDAs. We here describe investigations aimed at probing the role of the three glycine residues found in the laspartomycin peptide macrocycle. In doing so laspartomycin analogues containing the achiral 2-aminoisobutyric acid (AIB) as well as l- or d-alanine in place of glycine were prepared and their antibacterial activities evaluated.

The phosphorylation mechanism of mevalonate diphosphate decarboxylase: a QM/MM study by James McClory; Chenggong Hui; Jian Zhang; Meilan Huang (518-529).
Mevalonate diphosphate decarboxylase (MDD) catalyses a crucial step of the mevalonate pathway via Mg2+-ATP-dependent phosphorylation and decarboxylation reactions to ultimately produce isopentenyl diphosphate, the precursor of isoprenoids, which is essential to bacterial functions and provides ideal building blocks for the biosynthesis of isopentenols. However, the metal ion(s) in MDD has not been unambiguously resolved, which limits the understanding of the catalytic mechanism and the exploitation of enzymes for the development of antibacterial therapies or the mevalonate metabolic pathway for the biosynthesis of biofuels. Here by analogizing structurally related kinases and molecular dynamics simulations, we constructed a model of the MDD–substrate–ATP-Mg2+ complex and proposed that MDD requires two Mg2+ ions for maintaining a catalytically active conformation. Subsequent QM/MM studies indicate that MDD catalyses the phosphorylation of its substrate mevalonate diphosphate (MVAPP) via a direct phosphorylation reaction, instead of the previously assumed catalytic base mechanism. The results here would shed light on the active conformation of MDD-related enzymes and their catalytic mechanisms and therefore be useful for developing novel antimicrobial therapies or reconstructing mevalonate metabolic pathways for the biosynthesis of biofuels.

Condensation of 1,2-dicarbonyl compounds with modified Huisgen zwitterions: synthesis of N-aryl–N-acyl hydrazones by Jialin Liu; Jilei Cao; Rongfang Liu; Ruifeng Li; Yan Qiao; Rong Zhou (530-537).
A phosphine-mediated deoxygenative condensation of 1,2-dicarbonyl compounds such as aroylformates, α-diketones, and isatins with arylazocarboxylates has been developed for a facile synthesis of N-aryl–N-acyl hydrazones in moderate to excellent yields under very mild conditions. Mechanistic investigation based on 31P NMR tracking experiments unveils that the reaction is initiated with the in situ formation of the modified Huisgen zwitterions from arylazocarboxylates and PPh3 and proceeds via a nitrogen to nitrogen ester group migration process. This study also represents the first exploration of the reactivity patterns of the modified Huisgen zwitterions derived from arylazocarboxylates toward electrophiles such as 1,2-dicarbonyl compounds.

Selective synthesis of trisubstituted pyrroles through the reactions of alkynyl Fischer carbene complexes with oxazolones by Julio López; Iván Velazco-Cabral; Eloy Rodríguez-deLeón; Clarisa Villegas Gómez; Francisco Delgado; Joaquín Tamariz; Ana Arrieta; Fernando P. Cossío; Miguel A. Vázquez (538-550).
An efficient and simple synthesis of novel trisubstituted 1H-pyrroles 4a–qvia 1,3-dipolar cycloaddition of Δ3-trifluoromethyloxazolones 2a–d with both chromium and tungsten alkynyl Fischer carbene complexes (1a–h) is described. An unexpected and unreported –CF3 group elimination process was observed in the pyrrole structure. Our experimental and theoretical data suggested that the metal fragment may be responsible for this phenomenon. The dipolar cycloaddition proceeded efficiently to produce a single regioisomer, which was unambiguously established through NMR and single-crystal X-ray diffraction studies. Nevertheless, the reaction of alkynyl carbenes bearing an α,β,γ,δ-unsaturated moiety with excess oxazolone 2a produced a polycyclic compound 6 speculatively formed through a cascade reaction involving 1,6-, 1,4- and 1,2-nucleophilic addition steps.

An efficient and new approach has been developed to synthesize bis(β,β′-dialkoxy carbonyl) derivatives through the reaction between N-tosylaziridines and malonate esters under ambient air using tBuOK in DMSO solvent. A plausible reaction pathway has been predicted. Control experiments suggested that the reactions proceed through the formation of α-aminoketones. This reaction offers a broad substrate scope, metal-free synthesis, excellent regioselectivity, easily accessible reactants, and simple operation. A gram-scale synthesis demonstrates the potential applications of the present method.

Isoquinolinequinone N-oxides as anticancer agents effective against drug resistant cell lines by Ryan D. Kruschel; Alyah Buzid; Udaya B. Rao Khandavilli; Simon E. Lawrence; Jeremy D. Glennon; Florence O. McCarthy (557-568).
The isoquinolinequinone (IQQ) pharmacophore is a privileged framework in known cytotoxic natural product families, caulibugulones and mansouramycins. Exploiting both families as a chemical starting point, we report on the structured development of an IQQ N-oxide anticancer framework which exhibits growth inhibition in the nM range across melanoma, ovarian and leukaemia cancer cell lines. A new lead compound (16, R6 = benzyl, R7 = H) exhibits nM GI50 values against 31/57 human tumour cell lines screened as part of the NCI60 panel and shows activity against doxorubicin resistant tumour cell lines. An electrochemical study highlights a correlation between electropositivity of the IQQ N-oxide framework and cytotoxicity. Adduct binding to sulfur based biological nucleophiles glutathione and cysteine was observed in vitro. This new framework possesses significant anticancer potential.

Correction: A folate-conjugated platinum porphyrin complex as a new cancer-targeting photosensitizer for photodynamic therapy by Mengqian Yang; Jingran Deng; Ding Guo; Jie Zhang; Lixia Yang; Fengshou Wu (569-569).
Correction for ‘A folate-conjugated platinum porphyrin complex as a new cancer-targeting photosensitizer for photodynamic therapy’ by Mengqian Yang et al., Org. Biomol. Chem., 2019, 17, 5367–5374.

Correction for ‘Preparation of 2-arylquinolines from β-arylpropionitriles with aryllithiums and NIS through iminyl radical-mediated cyclization’ by Hiroki Naruto, et al., Org. Biomol. Chem., 2019, 17, 5760–5770.

Back cover (571-572).