Organic & Biomolecular Chemistry (v.16, #32)

Front cover (5723-5724).

Contents list (5725-5732).

Indium(iii) as π-acid catalyst for the electrophilic activation of carbon–carbon unsaturated systems by José Pérez Sestelo; Luis A. Sarandeses; M. Montserrat Martínez; Lorena Alonso-Marañón (5733-5747).
This review focuses on the utilization of indium(iii) as π-acid for the activation of C–C unsaturated bonds in organic synthesis. In addition to its well-known σ-coordination with carbonyl derivatives, indium(iii) undergoes efficient π-coordination with unsaturated systems to trigger nucleophilic addition. Accordingly, indium(iii) halides and salts (InX3, X = Cl, Br, I, OTf, ONf, NTf2) have been reported as useful catalysts for a broad range of carbon–carbon and carbon–heteroatom bond formation reactions, including hydrofunctionalization (hydroarylation, hydroamination, hydroalkoxylation, and hydrothiolation), enyne cycloisomerization, and related reactions. In these reactions the counterion has a significant effect on the catalytic activity, and the development of novel In(iii) complexes and the generation of highly electrophilic cationic indium(iii) species has increased its synthetic applications as a π-acid catalyst.

E-Selective synthesis of vinyl sulfones via silver-catalyzed sulfonylation of styrenes by Qingwen Gui; Kang Han; Zhuoliang Liu; Zhaohong Su; Xiaoli He; Hongmei Jiang; Bufan Tian; Yangyan Li (5748-5751).
An efficient and highly E-selective protocol for the synthesis of vinyl sulfones is described. This simple protocol demonstrates the first synthesis of vinyl sulfones via a silver-catalyzed C–S bond coupling reaction. In addition, the success of the reaction was found to be critically dependent on the use of TEMPO as the additive.

The di- and trichloromethylation of N-allyl anilines was developed under metal-free conditions, leading to a variety of di- and trichloromethylated indolines in moderate to good yields. This procedure used the commercially available chemical feedstocks CH2Cl2, CHCl3 and CCl4 as the di- and trichloromethyl sources.

Tracking down protein–protein interactions via a FRET-system using site-specific thiol-labeling by B. Söveges; T. Imre; Á. L. Póti; P. Sok; Zs. Kele; A. Alexa; P. Kele; K. Németh (5756-5763).
Förster resonance energy transfer is among the most popular tools to follow protein–protein interactions. Although limited to certain cases, site-specific fluorescent labeling of proteins via natural functions by means of chemical manipulations can redeem laborious protein engineering techniques. Herein we report on the synthesis of a heterobifunctional tag and its use in site-specific protein labeling studies aiming at exploring protein–protein interactions. The oxadiazole-methylsulfonyl functionality serves as a thiol specific warhead that enables easy and selective installation of fluorescent labels through a bioorthogonal motif. Mitogen activated protein kinase (MAPK14) and its substrate mitogen activated protein kinase activated kinase (MAPKAP2) or its docking motif, a 22 amino acid-long peptide fragment, were labeled with a donor and an acceptor, respectively. Evolution of strong FRET signals upon protein–protein interactions supported the specific communication between the partners. Using an efficient FRET pair allowed the estimation of dissociation constants for protein–protein and peptide–protein interactions (145 nM and 240 nM, respectively).

Evaluation of topologically distinct constrained antimicrobial peptides with broad-spectrum antimicrobial activity by Fang Yuan; Yuan Tian; Weirong Qin; Jingxu Li; Dan Yang; Bingchuan Zhao; Feng Yin; Zigang Li (5764-5770).
Antimicrobial peptides (AMPs) are short cationic peptides with a high affinity for membranes and emerged as a promising therapeutic approach with potential for treating infectious diseases. Chemical stabilization of short peptides proved to be a successful approach for enhancing their bio-physical properties. Herein, we designed and synthesized a panel of conformationally constrained antimicrobial peptides with either α-helical or β-hairpin conformation using templating strategies. These synthetic short constrained peptides possess different topological distributions of hydrophobic and hydrophilic residues and displayed distinct antimicrobial activity. Notably, the conformationally constrained α-helical peptides displayed a faster internalization into the bacteria cells compared to their β-hairpin analogues. These synthetic short constrained peptides showed killing effects on a broad spectrum of microorganisms mainly through pore formation and membrane damage which provided a potentially promising skeleton for the next generation of stabilized antimicrobial peptides.

Chemoenzymatic macrocycle synthesis using resorcylic acid lactone thioesterase domains by Graham W. Heberlig; Jesse T. C. Brown; Ryan D. Simard; Monica Wirz; Wei Zhang; Meng Wang; Leah I. Susser; Mark E. Horsman; Christopher N. Boddy (5771-5779).
A key missing tool in the chemist's toolbox is an effective biocatalyst for macrocyclization. Macrocycles limit the conformational flexibility of small molecules, often improving their ability to bind selectively and with high affinity to a target, making them a privileged structure in drug discovery. Macrocyclic natural product biosynthesis offers an obvious starting point for biocatalyst discovery via the native macrocycle forming biosynthetic mechanism. Herein we demonstrate that the thioesterase domains (TEs) responsible for macrocyclization of resorcylic acid lactones are promising catalysts for the chemoenzymatic synthesis of 12- to 18-member ring macrolactones and macrolactams. The TE domains responsible for zearalenone and radicicol biosynthesis successfully generate resorcylate-like 12- to 18-member macrolactones and a 14-member macrolactam. In addition these enzymes can also macrolactonize a non-resorcylate containing depsipeptide, suggesting they are versatile biocatalysts. Simple saturated omega-hydroxy acyl chains are not macrocyclized, nor are the alpha-beta unsaturated derivatives, clearly outlining the scope of the substrate tolerance. These data dramatically expand our understanding of substrate tolerance of these enzymes and are consistent with our understanding of the role of TEs in iterative polyketide biosynthesis. In addition this work shows these TEs to be the most substrate tolerant polyketide macrocyclizing enzymes known, accessing resorcylate lactone and lactams as well as cyclicdepsipeptides, which are highly biologically relevant frameworks.

An organocatalytic enantioselective Mannich reaction between rhodanines and isatin-derived ketimines was developed. With 2 mol% of a quinine-based tertiary amine-thiourea catalyst C2, 3,3-disubstituted oxindoles with vicinal tetrasubstituted stereocenters were obtained in moderate-to-excellent yields (43–99%) with excellent diastereoselectivities (98 : 2–99 : 1 dr) and good-to-excellent enantioselectivities (up to 97% ee). The readily available substrates, low catalyst loading and high stereoselectivity are the major features.

Synthesis of 3-cyanomethylated coumarins by a visible-light-mediated direct cyanomethylation of aryl alkynoates by Wei Zhang; Chen Yang; Yu-Liang Pan; Xin Li; Jin-Pei Cheng (5788-5792).
A visible-light-promoted, mild, and direct cyanomethylation of aryl alkynoates has been developed. This method provides a new strategy toward the synthesis of 3-cyanomethylated coumarins via a domino radical addition/5-exo cyclization/ester migration cascade reaction in moderate to good yields at room temperature. Converting the resulting products into various molecules exhibited the synthetic utility of the present methodology.

Synthesis of 6-SF5-indazoles and an SF5-analog of gamendazole by Oleksandr S. Kanishchev; William R. Dolbier (5793-5799).
This work describes an efficient synthetic approach for a new type of SF5-substituted heterocyclic system, namely 6-SF5-indazoles. During this study, various derivatives of 6-SF5-indazoles such as bromo, iodo, nitro, N-acetyl and N-benzyl substituted compounds were synthesized and characterized. In addition, the utility of the synthetic methodology was demonstrated via the synthesis of 6-SF5-gamendazole – a fully matched analog of the experimental male contraceptive gamendazole, which has a 6-CF3-substituted indazole core.

We synthesized a small library of eighteen 5-substituted pyrimidine or 7-substituted 7-deazapurine nucleoside triphosphates bearing methyl, ethynyl, phenyl, benzofuryl or dibenzofuryl groups through cross-coupling reactions of nucleosides followed by triphosphorylation or through direct cross-coupling reactions of halogenated nucleoside triphosphates. We systematically studied the influence of the modification on the efficiency of T7 RNA polymerase catalyzed synthesis of modified RNA and found that modified ATP, UTP and CTP analogues bearing smaller modifications were good substrates and building blocks for the RNA synthesis even in difficult sequences incorporating multiple modified nucleotides. Bulky dibenzofuryl derivatives of ATP and GTP were not substrates for the RNA polymerase. In the case of modified GTP analogues, a modified procedure using a special promoter and GMP as initiator needed to be used to obtain efficient RNA synthesis. The T7 RNA polymerase synthesis of modified RNA can be very efficiently used for synthesis of modified RNA but the method has constraints in the sequence of the first three nucleotides of the transcript, which must contain a non-modified G in the +1 position.

Computational study of the mechanism of amide bond formation via CS2-releasing 1,3-acyl transfer by Yuan-Ye Jiang; Tian-Tian Liu; Xue Sun; Zhong-Yan Xu; Xia Fan; Ling Zhu; Siwei Bi (5808-5815).
Reactions of thiocarboxylic acids and dithiocarbamate-terminal amines provide a linker-traceless method for amide bond formation under mild conditions, whereas the reaction mechanism is not clear. A systematic study was performed herein with density functional theory (DFT) calculations to elucidate the detailed mechanism, the substitution effect on the proposed CS2-releasing 1,3-acyl transfer and the differences between CS2- and CO2-releasing 1,3-acyl transfer. Relevant results indicate that this type of reaction proceeds via the nucleophilic addition of an in situ generated dithiocarbamic acid on thiocarboxylic acid, H2S elimination, rate-determining 1,3-acyl transfer and CS2 release. For the generation of secondary amides via the 1,3-acyl transfer, a thiocarboxylic acid- or dithiocarbamic acid-assisted pathway, in which both the carbonyl group and amide nitrogen are activated, is the most favored. For the generation of tertiary amides, MeOH-assisted carbonyl-activation is the most favorable pathway. N,N-Dialkyl substitution of the mixed anhydride intermediate promotes the 1,3-acyl transfer by the steric effect. In contrast, N-phenyl substitution and using thiobenzoic acid as a substrate slow down 1,3-acyl transfer by both the conjugation effect and steric effect. Furthermore, CS2-releasing 1,3-acyl transfer was found to be favored over CO2-releasing 1,3-acyl transfer in the aspects of both kinetics and thermodynamics mainly because the S–COR bond is weaker than the O–COR bond.

In the presence of triethylamine, the domino annulation reaction of two molecules of pivaloylacetonitrile with one molecule of 2-aryl-3-nitrochromene in tetrahydrofuran resulted in the unprecedented imino-substituted dihydrofuro[2,3-c]chromene derivatives in high yields. More importantly, the above domino reaction in refluxing methanol or ethanol afforded alkoxy-substituted chromeno[3,4-b]pyridines in satisfactory yields. However, a similar reaction of benzoylacetonitrile with 2-aryl-3-nitrochromenes in basic medium gave the expected furo[2,3-c]chromene derivatives in moderate yields.

(−)-Cytisine: Access to a stereochemically defined and functionally flexible piperidine scaffold by Worawat Niwetmarin; Hugo Rego Campello; Hazel A. Sparkes; Varinder K. Aggarwal; Timothy Gallagher (5823-5832).
N-Benzyl cytisine undergoes an efficient C(6)–N(7) cleavage via directed C(6) lithiation, borylation and oxidation to provide a “privileged” heterocyclic core unit comprising a highly functionalised, cis-3,5-disubstituted piperidine in enantiomerically pure form. The potential offered by this unit as a means to explore chemical space has been evaluated and methods have been defined (and illustrated) that allow for selective manipulation of N(1), C(3′), and the pyridone N. The pyridone core can also be diversified via bromination (at C(3′′) and C(5′′)) which is complementary to direct C–H activation based on Ir-catalyzed borylation to provide access to C(4′′). The use of a boronate-based 1,2-migration as an alternative trigger to mediate C(6)–N(7) cleavage of cytisine was evaluated but failed. However, the stability of the intermediate boronate opens a new pathway for the elaboration of cytisine itself using both Matteson homologation and Zweifel olefination.

The base-promoted α-alkylation of N-((S)-1-phenylethyl)azetidine-2-carboxylic acid esters 1 was investigated. The use of diastereomerically pure borane complexes 3 as substrates, which are easily prepared from 1, dramatically improved the yields and diastereoselectivities of α-alkylated products 2. For example, the treatment of tert-butyl ester (1S,2S,1′S)-3a with 2.4 equivalents of lithium bis(trimethysilyl)amide (LiHMDS) at 0 °C followed by 2.6 equivalents of benzyl bromide afforded α-benzylated (2S,1′S)-2aa in 90% yield as almost a single diastereomer. Our method enables the production of optically active α-substituted azetidine-2-carboxylic acid esters starting from commercially available (S)-1-phenylethylamine, which is one of the least expensive chiral compounds.

Phenolate-induced, diastereo- and regioselective intramolecular exo-tet ring-opening cyclization of N-tosylaziridines has been achieved for the first time. The N-tosylaziridine substrates bearing a tethered (ortho-(tert-butyldimethylsiloxy))aryl substituent, prepared directly from the corresponding olefins under Sharpless aziridination conditions, furnished functionalized 2,3-dihydrobenzofuran, chroman, and 1-benzoxepane derivatives in excellent yields when treated with tetrabutylammonium fluoride (TBAF) at room temperature. Our ability to synthesize benzoxacycle-based N-tosyl-protected amino alcohols, that are otherwise difficult to obtain by traditional synthetic routes, has opened the door to diversify the chemistry of β-amino alcohols. We also succesfully performed the Baeyer–Villiger oxidation of a salicylaldehyde ether bearing a tethered N-tosylaziridine moiety with m-CPBA followed by tandem saponification and 6-exo-tet aziridine ring-opening cyclization, furnishing the corresponding trans-3,4-disubstituted-1,4-benzodioxane derivative. Overall, the study has unveiled a new entry to the synthesis of benzoxacycles and has also broadened the impact of aziridines as synthetic building blocks.

Synthesis and biological evaluation of cyclic derivatives of combretastatin A-4 containing group 14 elements by Víctor Blasco; Juan Murga; Eva Falomir; Miguel Carda; Santiago Royo; Ana C. Cuñat; Juan F. Sanz-Cervera; J. Alberto Marco (5859-5870).
Several tricyclic compounds inspired by the structure of combretastatin A-4 and bearing group 14 elements have been synthesized by homocoupling lithiated aryl fragments followed by ring-closing metathesis. These tricyclic compounds and their diolefin precursors were evaluated for their antiproliferative action on the tumor cell lines HT-29, MCF-7, HeLa and A-549 and on the non-tumor cell line HEK-293. In addition, their effects on the cell cycle were also measured. The tricyclic compounds show antiproliferative activity similar to that of combretastatin A-4, even though they are not so active in arresting the cell cycle. However, some diolefin precursors are able to cause accumulation of cells in the G2/M phase in a higher percentage than combretastatin A-4 itself. Inhibition of endothelial tube formation and VEGFR-2 phosphorylation of some selected compounds is comparable to that of combretastatin A-4, particularly those of tin-containing compounds 23c and 26c, whose actions exceed those of sorafenib, a clinically used VEGFR-2 inhibitor.

Guanidine functionalized anthranilamides as effective antibacterials with biofilm disruption activity by Rajesh Kuppusamy; Muhammad Yasir; Eugene Yee; Mark Willcox; David StC. Black; Naresh Kumar (5871-5888).
We describe a library of amphiphilic anthranilamide compounds as antimicrobial peptide (AMP) mimics. These contain a hydrophobic naphthoyl side chain and different hydrophilic cationic groups such as amino, quaternary ammonium and guanidino groups. These are prepared via the ring-opening of different isatoic anhydrides. The antibacterial activity against S. aureus and E. coli of compounds containing guanidino cationic groups was greater than that for amino and quaternary ammonium cationic groups. The fluoro-substituted guanidinium compound 9b showed a minimum inhibitory concentration (MIC) of 2.0 μM against S. aureus, and reduced established biofilms of S. aureus by 92% at 64 μM concentration. The bromo-substituted guanidinium compound 9d exhibited good MIC against S. aureus (3.9 μM) and E. coli (15.6 μM) and disrupted established biofilms of S. aureus by 83% at 62.4 μM concentration. Cytoplasmic membrane permeability studies suggested that depolarization and disruption of the bacterial cell membrane could be a possible mechanism for antibacterial activity and the in vitro toxicity studies against MRC-5 human lung fibroblast cells showed that the potent compounds are non-toxic against mammalian cells.

Ru(ii)-Catalyzed C7-acyloxylation of indolines with carboxylic acids by Pinaki Bhusan De; Sonbidya Banerjee; Sourav Pradhan; Tharmalingam Punniyamurthy (5889-5898).
Ruthenium(ii)-catalyzed site-selective C7-acyloxylation of indolines with carboxylic acids is presented. The substrate scope and functional group tolerance are important practical features. The kinetic isotope studies suggest that C–H bond activation may be the rate-determining step.

A silver catalyzed domino reaction of N-cyanamide alkenes and 1,3-dicarbonyls including 1,3-diketones and ethyl acetoacetate has been developed for the facile synthesis of quinazolinones. In the presence of AgNO3/K2S2O8, the diketones could be converted to radicals and coupled with N-cyanamide alkenes to undergo a cyclization cascade for accessing quinazolinones. This method features mild reaction conditions, readily available starting materials, and valuable synthetic utility. Moreover, the products could be further transformed into various heterocycles.

An inorganic base-promoted domino reaction with organophosphites and acyl cyclopropane derivatives is developed and proved to provide an efficient access to functionalized enol phosphates. Unlike the well-known Perkow reaction, which employs trialkyl phosphite as the nucleophile, dialkyl phosphite is the key to the success of our transformation. This method is compatible with a series of dialkyl phosphites and acyl cyclopropanes possessing electron-withdrawing substituents, and an array of functionalized enol phosphates are successfully prepared. Based on the results of isotope-labeling and control experiments, this transformation is presumably initiated by the deprotonation of dialkyl phosphite and the following nucleophilic addition/anion shift/ring opening sequence leads to the formation of enol phosphates. Both the strain release of a three-membered ring and the formation of a relatively stable anion are indispensable driving forces for this process.

Tsavoenones A–C: unprecedented polyketides with a 1,7-dioxadispiro[]tetradecane core from the lichen Parmotrema tsavoense by Thuc-Huy Duong; Mehdi A. Beniddir; Grégory Genta-Jouve; Thammarat Aree; Marylène Chollet-Krugler; Joël Boustie; Solenn Ferron; Aurélie Sauvager; Huu-Hung Nguyen; Kim-Phi-Phung Nguyen; Warinthorn Chavasiri; Pierre Le Pogam (5913-5919).
New racemic dispiranic polyketides, tsavoenones A (1), B (2) and C (3), having a novel 1,7-dioxadispiro[]tetradecane scaffold were isolated from the foliose lichen Parmotrema tsavoense. These compounds were structurally elucidated by extensive NMR analyses, comparison between experimental and theoretical 13C NMR data and X-ray crystallography. A putative biosynthetic scenario for the formation of 1–3 from parmosidone D, a meta-depsidone previously isolated from the same lichen material, was proposed. Tested for its cytotoxicity, 1 displayed a moderate activity against human myelogenous leukemia K562 cell line with an IC50 value of 66 μg mL−1.

Dihydroindeno[1,2-b]pyrroles: new Al3+ selective off–on chemosensors for bio-imaging in living HepG2 cells by Kajal Mal; Barnali Naskar; Animesh Mondal; Sanchita Goswami; Chandraday Prodhan; Keya Chaudhuri; Chhanda Mukhopadhyay (5920-5931).
In this study, a new molecular organic probe has been designed and synthesized by using recyclable, inexpensive and non-toxic polyethylene glycol (PEG-400) as a promoting reaction medium in water under environmentally benevolent conditions. The probe has been explored as a potential chemosensor to detect Al3+ ions using a HEPES buffer (pH = 7.4) solution. Investigations of the fluorescence behaviour of this sensor in DMSO/H2O (2 : 8, v/v) solution displayed a dramatic switch-on response only in the presence of Al3+, while other metal ions, like Li+, Na+, K+, Ag+, Ca2+, Mg2+, Mn2+, Ba2+, Cu2+, Ni2+, Co2+, Fe2+, Zn2+, Cd2+, Hg2+, Pb2+, Sr2+, Fe3+ or Cr3+, have almost no influence on the fluorescence behaviour. Various common anions, such as ClO4, Cl, or NO3 in the form of Al3+ salts [e.g. Al(ClO4)3, AlCl3 or Al(NO3)3], had no influence on the fluorescence behaviour of the sensors. The detection limit for Al3+ is in the order of 10−6 M in DMSO/H2O (2 : 8, v/v) HEPES buffer (pH = 7.4) solution. Notably, this is the first report of a dihydroindeno[1,2-b]pyrrole moiety acting as a sensor for the selective detection of Al3+ ions through an off–on fluorescence response. The potential of the probe was also confirmed by employing it for fluorescence bio-imaging with Al3+ on HepG2 cells.

Correction for ‘Chiral NHC-catalyzed 1,3-dipolar [3 + 2] cycloaddition of azomethine imines with α-chloroaldehydes for the synthesis of bicyclic pyrazolidinones’ by Limin Yang, et al., Org. Biomol. Chem., 2018, 16, 4433–4438.

Back cover (5933-5934).