Organic & Biomolecular Chemistry (v.17, #6)
Front cover (1289-1289).
Inside front cover (1290-1290).
Contents list (1291-1300).
Applications of N′-monofunctionalised TsDPEN derivatives in asymmetric catalysis by Jonathan Barrios-Rivera; Yingjian Xu; Martin Wills (1301-1321).
This review contains an account of recent developments in the applications of N′-monoalkylated or N′-mono(thio)acylated(N-sulfonyl)-1,2-diphenylethylene-1,2-diamine (TsDPEN) derivatives to asymmetric catalysis. The coverage features examples of applications of derivatives as ligands in organometallic complexes for use in asymmetric reduction and oxidation reactions. The use of TsDPEN derivatives as catalysts in a diverse range of C–C and C–S bond formation reactions is also described in detail.
SuperQuat chiral auxiliaries: design, synthesis, and utility by Stephen G. Davies; Ai M. Fletcher; Paul M. Roberts; James E. Thomson (1322-1335).
The SuperQuat (4-substituted 5,5-dimethyloxazolidine-2-one) family of chiral auxiliaries was first developed by us in the 1990s to address the shortcomings of the Evans (4-substituted oxazolidin-2-one) family of chiral auxiliaries. The incorporation of geminal dimethyl substitution at C(5) has two effects: (i) it induces a conformational bias on an adjacent, otherwise conformationally labile C(4)-substituent so that it projects towards the N-acyl fragment, thus offering superior diastereofacial selectivity in a range of transformations; and (ii) it hinders nucleophilic attack at the endocyclic carbonyl group, facilitating recovery and recyclability of the auxiliary, with enhanced cleavage properties. This review summarises the development and some of the most common uses of the SuperQuat family of chiral auxiliaries, particularly in the synthesis of natural products or other targets having bioloigcal interest. Where possible, comparisons with the performances of the corresponding Evans auxiliaries are presented.
Supramolecular vesicles based on pillar[n]arenes: design, construction, and applications by Tangxin Xiao; Weiwei Zhong; Lixiang Xu; Xiao-Qiang Sun; Xiao-Yu Hu; Leyong Wang (1336-1350).
Supramolecular vesicles have attracted considerable attention due to their advantages of facile construction, high-cargo-loading capacity, and good biocompatibility. Pillar[n]arenes are a unique family of supramolecular macrocycles, exhibiting excellent features and broad applications due to their intrinsic topology and high functionality. In the past decade, the construction of pillar[n]arene-based supramolecular vesicles has been continuously attempted and developed rapidly. In this review, we mainly summarize the significant advancements of such supramolecular vesicles in the last three years. By showing some representative examples, the design strategies, construction methods, and potential applications of these dynamic nanocarriers are discussed in detail. In particular, the responsiveness of such vesicles to various external stimuli and their applications in drug delivery are highlighted. The outstanding performance of pillar[n]arene-based supramolecular vesicles would definitely enrich the family of supramolecular vesicles and promote the development of dynamic supramolecular materials.
Recent advances in transition metal-catalyzed C(sp2)–H nitration by Li-Rui Song; Zhoulong Fan; Ao Zhang (1351-1361).
Nitroaromatic compounds play an important role in organic synthesis, medicinal chemistry and chemical industry. Among the recently reported synthetic methods to access nitroarenes, transition metal-catalyzed C(sp2)–H activation/nitration has become one of the most attractive protocols, showing high regioselectivity, excellent functional group tolerance and step-economy. In this review, we discuss advances in direct C(sp2)–H nitration for the synthesis of nitroaromatic compounds and mechanistic insights over the past decade. We hope this will provide valuable information for researchers interested in the rapidly developing field of metal-catalyzed C(sp2)–H nitration.
Synthesis and biological evaluation of fluorinated analogues of ripostatin A by Vladyslav Shenderman; Evgeny V. Prusov (1362-1364).
Several monocyclic derivatives of 14,14′-difluororipostatin A were prepared using a catalytic Mukaiyama aldol reaction, a ring-closing metathesis reaction and a late stage click reaction as key steps. The biological activity of the produced compounds was assessed in vivo using a panel of pathogenic microorganisms. Moderate antibiotic activity was observed for 11-OMe-ripostatin A and 11-OMe-14,14′-difluororipostatin A.
Silver-mediated oxidative C–C bond sulfonylation/arylation of methylenecyclopropanes with sodium sulfinates: facile access to 3-sulfonyl-1,2-dihydronaphthalenes by Yu Liu; Qiao-Lin Wang; Zan Chen; Quan Zhou; Cong-Shan Zhou; Bi-Quan Xiong; Pan-Liang Zhang; Chang-An Yang; Ke-Wen Tang (1365-1369).
The novel AgNO3-mediated oxidative sulfonylation/arylation of a C–C σ-bond in methylenecyclopropanes with sodium sulfinates to synthesize various 3-sulfonylated 1,2-dihydronaphthalenes is reported. This sulfonylation/arylation transformation proceeds via a sequence of sulfonylation, C–C σ-bond cleavage and intramolecular cyclization, and the experimental results show that the C–C σ-bond difunctionalization reaction includes a radical process. This strategy provides a simple and convenient route for the difunctionalization of C–C bonds with a phenyl ring and a sulfonyl radical via the one-pot construction of a C–S bond and a new C–C bond.
Scalable electrochemical oxidant-and metal-free dehydrogenative coupling of S–H/N–H by Shanyu Tang; Yan Liu; Longjia Li; Xuanhe Ren; Jiao Li; Guanyu Yang; Heng Li; Bingxin Yuan (1370-1374).
A practical and scalable electrochemical oxidation of S–H and N–H was developed. This oxidant- and catalyst-free electrochemical process enables S–N bond formation with inexpensive nickel electrodes in an undivided cell. This procedure exhibits broad substrate scopes and good functional-group compatibility. A 50 g scale oxidative coupling augurs well for industrial applications.
Seven-enzyme in vitro cascade to (3R)-3-hydroxybutyryl-CoA by Luis E. Valencia; Zhicheng Zhang; Alexis J. Cepeda; Adrian T. Keatinge-Clay (1375-1378).
Economical and environmentally-friendly routes to convert feedstock chemicals like acetate into valuable chiral products such as (R)-3-hydroxybutyrate are in demand. Here, seven enzymes (CoaA, CoaD, CoaE, ACS, BktB, PhaB, and GDH) are employed in a one-pot, in vitro, biocatalytic synthesis of (3R)-3-hydroxybutyryl-CoA, which was readily isolated. This platform generates not only chiral diketide building blocks but also desirable CoA derivatives.
Imidazole carbamate probes for affinity guided azide-transfer to metal-binding proteins by Michael Rosholm Mortensen; Nanna Louise Nielsen; Johan Palmfeldt; Kurt Vesterager Gothelf (1379-1383).
Probes for affinity guided conjugation have shown great promise for the preparation of high-quality protein conjugates. However, such probes are often limited in their protein scope. Here, we demonstrate the synthesis and use of imidazole carbamate probes for affinity guided conjugation of an azide handle to a wide variety of metal binding proteins such as antibodies, enzymes, nanobodies and His6-tagged proteins. The azide handles were used to link dyes to the proteins for gel analysis and binding studies. In a comparative study we find that the probe containing three NTA groups show higher selectivity than the probe containing two. In a mixture of proteins, the probe shows preference for labelling His6-tagged proteins.
Photochemical benzylic bromination in continuous flow using BrCCl3 and its application to telescoped p-methoxybenzyl protection by Yuma Otake; Jason D. Williams; Juan A. Rincón; Oscar de Frutos; Carlos Mateos; C. Oliver Kappe (1384-1388).
BrCCl3 represents a rarely used benzylic brominating reagent with complementary reactivity to other reagents. Its reactivity has been revisited in continuous flow, revealing compatibility with electron-rich aromatic substrates. This has brought about the development of a p-methoxybenzyl bromide generator for PMB protection, which was successfully demonstrated on a pharmaceutically relevant intermediate on 11 g scale, giving 91% yield and a PMB-Br space–time-yield of 1.27 kg L−1 h−1.
Chemiluminescence molecular probe with a linear chain reaction amplification mechanism by Samer Gnaim; Doron Shabat (1389-1394).
A new signal amplification probe with a linear chain reaction amplification mechanism and distinct chemiluminescence output was developed. The probe is composed of a unique structural motif that combines a chemiexcitation mechanism with an intramolecular transesterification into a single molecular structure. As demonstrated with a probe designed to detect hydrogen peroxide, an auto-inductive chemiluminescence signal amplification was obtained through methanol release by an intramolecular transesterification of the generated 2-hydroxymethylbenzoate derivative. The methanol was then oxidized by alcohol oxidase to regenerate the analyte of interest, hydrogen peroxide. Our probe enabled direct measurement of light emission with a limit of detection of 2.5 μM, whilst the assay was rapidly completed within 14 to 150 minutes. Such molecular probes with chemiluminescence signal enhancement through analyte amplification could be used for the detection of other chemical and biological analytes.
A new trifluoromethylated sulfonamide phosphine ligand for Ag(i)-catalyzed enantioselective [3 + 2] cycloaddition of azomethine ylides by Yuanqi Wu; Bing Xu; Bing Liu; Zhan-Ming Zhang; Yu Liu (1395-1401).
A newly developed Ming-Phos ligand with a 3,5-bis(trifluoromethyl)phenyl substituent was demonstrated to be highly efficient for Ag-catalyzed asymmetric [3 + 2] cycloaddition reactions of azomethine ylides with maleimides, cyclopentene-1,3-diones, and N-(2-t-butylphenyl)maleimide. Being easily prepared on the gram scale in one step, the ligand in combination with a Ag catalyst enables the synthesis of a variety of highly functionalized bicyclic pyrrolidine derivatives in good yields and excellent enantioselectivities under mild conditions.
Direct synthesis of 2,4,5-trisubstituted imidazoles from primary alcohols by diruthenium(ii) catalysts under aerobic conditions by Saranya Sundar; Ramesh Rengan (1402-1409).
Herein we report a straightforward synthetic approach to 2,4,5-trisubstituted imidazoles from readily available primary alcohols using arene diruthenium(ii) catalysts. Dinuclear arene ruthenium complexes have been synthesized and structurally characterized with the aid of analytical and spectral techniques. A library of 2,4,5-trisubstituted imidazoles was achieved with a yield up to 95% by loading 0.25 mol% of the catalyst. The present protocol is environmentally benign, which is performed under aerobic conditions and liberates water as the sole by-product.
Tandem synthesis of 4-aminoxanthones is controlled by a water-assisted tautomerization: a general straightforward reaction by Ana Bornadiego; Jesús Díaz; Carlos F. Marcos (1410-1422).
Aminoxanthones constitute a group of therapeutically promising compounds that so far have been synthetically challenging. Here, we report the synthesis of both aminodihydroxanthones and fully aromatized aminoxanthones by an easy to perform, one-step multicomponent reaction of isocyanides, 3-carbonylchromones and dienophiles. The mechanism of the reaction involves a sequence of a [4 + 1] cycloaddition, iminolactone-aminofuran tautomerization, [4 + 2] cycloaddition, oxygen ring opening and aromatization. Remarkably, DFT quantum chemical computations revealed that the iminolactone-aminofuran tautomerization requires the assistance of a water molecule and, contrary to intuition, it is the rate-determining step. Conversely, both the [4 + 1] and the [4 + 2] cycloadditions have relatively low calculated energy barriers, regardless the substituents on the starting materials. Thus, we have stablished a straightforward and a wide-ranging synthesis of diversely substituted xanthones. This highly convergent process has also been applied to the synthesis of biologically important chromenophenantridines and secalonic acid related xanthone dimers.
Synthesis of diphenylamine macrocycles and their anti-inflammatory effects by Alejandra Chávez-Riveros; Eduardo Hernández-Vázquez; Antonio Nieto-Camacho; Teresa Ramírez-Apan; Luis D. Miranda (1423-1435).
A collection of fourteen diphenylamine macrocyclic derivatives containing a peptide chain with different substituents was synthesized using a protocol of two Ugi four component reactions (Ugi-4CR) and a Buchwald–Hartwig macrocyclization. Their anti-inflammatory effects were assayed with an ear edema model using 12-O-tetradecanoylphorbol-13-acetate, while the activity of myeloperoxidase was determined to evaluate the index of leukocyte infiltration. Compound 5e had an ID50 of 0.18 μM per ear with a potency higher than that of the reference drugs indomethacin and celecoxib (0.24 and 0.91 μM per ear, respectively). Moreover, the cytotoxicity of the macrocycles was determined in two healthy cell lines, showing a low percentage of toxicity.
An endoplasmic reticulum-targetable fluorescent probe for highly selective detection of hydrogen sulfide by Hui Zhang; Jiali Chen; Haiqing Xiong; Yun Zhang; Wenqiang Chen; Jiarong Sheng; Xiangzhi Song (1436-1441).
Hydrogen sulfide (H2S), a critical endogenous signaling molecule, is widely involved in many physiological processes. Endoplasmic reticulum, an important organelle with a sac-like structure, plays crucial roles in maintaining the normal function of cells. Accordingly, monitoring the H2S levels in endoplasmic reticulum is of great importance. Herein, we have developed an endoplasmic reticulum-targetable fluorescent probe, ER-CN, for H2S detection. ER-CN features excellent sensing properties, such as high sensitivity and selectivity. In addition, ER-CN exhibits low cytotoxicity and a fine endoplasmic reticulum targeting property (with a Pearson's colocalization coefficient of 0.95). Significantly, visualization of H2S in the endoplasmic reticulum of living HeLa cells by using ER-CN was successfully realized.
Copper-mediated oxidative [3 + 2]-annulation of nitroalkenes and pyridinium ylides: general access to functionalized indolizines and efficient synthesis of 1-fluoroindolizines by Vladimir A. Motornov; Andrey A. Tabolin; Yulia V. Nelyubina; Valentine G. Nenajdenko; Sema L. Ioffe (1442-1454).
A general method for the synthesis of substituted indolizines by copper(ii) acetate-promoted oxidative [3 + 2]-annulation of α-fluoronitroalkenes with in situ generated pyridinium ylides was developed. Application of the copper(ii) acetate–2,6-lutidine system provides efficient access to various 1-fluoroindolizines in up to 81% yield. Both electron-rich and electron-deficient nitroalkenes as well as different pyridinium and isoquinolinium salts can be involved in the reaction. Moreover, it was found that copper-mediated annulation is applicable for other α-substituted (alkyl, chloro, and ester) nitroalkenes giving rise to the corresponding indolizines. First synthesis of monofluorinated [3,2,2]cyclazines was demonstrated via oxidative annulation of 3-unsubstituted fluoroindolizines with diethyl acetylene dicarboxylate.
Synthesis and application of P,olefin type axially chiral ligands with sec-alkyl groups by Takashi Mino; Daiki Yamaguchi; Chihiro Masuda; Junpei Youda; Toshibumi Ebisawa; Yasushi Yoshida; Masami Sakamoto (1455-1465).
We synthesized N-trans-cinnamyl-N-cyclohexylaniline type aminophosphine 2 and a series of N-2-adamantyl-N-trans-cinnamylaniline type aminophosphines 3. Although aminophosphine 2 failed to find the existence of axial chirality, aminophosphines 3, which exist in the axial chirality in a C(aryl)–N(amine) bond by chiral HPLC analysis as 1-adamantyl type chiral ligands 1. Enantiomeric isomers of 3b, 3c, and 3d were obtained in an enantiomerically pure form. We also identified the palladium-catalyzed asymmetric allylic substitution of 1,3-diphenyl-2-propenyl acetate with indoles using aminophosphines 3b–d as effective chiral ligands in high enantioselectivities (up to 96% ee).
Enantiomeric NMR discrimination of carboxylic acids using actinomycin D as a chiral solvating agent by Liwen Bai; Pian Chen; Jiangxia Xiang; Jiarui Sun; Xinxiang Lei (1466-1470).
Actinomycin D (Act-D) is a biologically important polypeptide antibiotic clinically used to treat several malignant tumors. Herein, we extended its hitherto-unexplored application as an applicable chiral solvating agent (CSA) for the rapid enantiomeric determination of different chiral carboxylic acids in deuterated chloroform by 1H NMR spectroscopy. Notable enantiodiscrimination with well-splitting α-H or α-CH3 resonance signals of the enantiomers of carboxylic acids were achieved without significant interference from Act-D. To check its applicability for the determination of enantiomeric excess (ee) values, various mandelic acid (MA) samples were determined and compared with the observed ones, resulting in an excellent linear relationship. To our knowledge, this is the first example of using a natural antibiotic compound as a CSA to achieve chiral recognition for carboxylic acids.
Racemization of oxazepam and chiral 1,4-benzodiazepines. DFT study of the reaction mechanism in aqueous solution by Lucija Hok; Lucija Božičević; Helena Sremec; Davor Šakić; Valerije Vrček (1471-1479).
The tranquilizer and hypnotic drug oxazepam undergoes the racemization process in aqueous medium, which is relevant for its pharmacological profile. The experimental barrier value (ΔG‡298≈ 91 kJ mol−1) was determined earlier, but the exact mechanism of enantiomerization is not known. Four different mechanisms have been proposed in the literature: C3–H/H exchange reaction, keto–enol tautomerization, solvolytic identity reaction, and ring-chain tautomerization. However, none of the reported reactions has been confirmed as the main pathway for racemization. In this work, all these mechanisms were subjected to comprehensive analysis performed by high-level quantum-chemical models. Two density functionals (B3LYP and M062X) were employed for geometry optimization of all stationary points at the corresponding potential surfaces, and the double-hybrid model (B2PLYP) was used for improved energy calculations. Out of all the tested mechanisms, only the ring-chain tautomerism fits the two experimental targets: the measured energy barrier and the pH-rate profile of racemization. The latter reveals that no acid/base catalysis is required for racemization to occur. The ring-chain tautomerism is initiated by intramolecular proton transfer from the C3-hydroxyl group to the imine nitrogen, which triggers the benzodiazepine ring opening and the formation of the achiral aldehyde intermediate. The latter undergoes ring closure which results in the inverted configuration at the C3-chiral atom of oxazepam. Our computational results suggest that the same mechanism is operative in the fast racemization of different 1,4-benzodiazepines, which posses the hydroxyl group at the stereogenic C3-centre (e.g. lorazepam or temazepam). In other benzodiazepine members (e.g. cinazepam or camazepam) the keto–enol tautomerization and/or the C3–H/H exchange mechanism may become relevant for their much slower racemization. This computational study is not only revealing in terms of mechanistic details, but also has predictive power for optical stability estimates in the family of benzodiazepines and similar heterocycles.
Enzymatic radiosynthesis of a 18F-Glu-Ureido-Lys ligand for the prostate-specific membrane antigen (PSMA) by Phillip T. Lowe; Sergio Dall'Angelo; Ian N. Fleming; Monica Piras; Matteo Zanda; David O'Hagan (1480-1486).
Prostate cancer represents a major public health threat as it is one of the most common male cancers worldwide. The prostate-specific membrane antigen (PSMA) is highly over-expressed in prostatic cancer cells in a manner that correlates with both tumour stage and clinical outcome. As such, PSMA has been identified as an attractive target for both imaging and treatment of prostate cancer. In recent years the focus on urea-based peptidomimetic inhibitors of the PSMA (representing low molecular weight/high affinity binders) has intensified as they have found use in the clinical imaging of prostate tumours. Reported herein are the design, synthesis and evaluation of a new fluorinated PSMA targeting small-molecule, FDA-PEG-GUL, which possesses the Glu-NH-CO-NH-Lys pharmacophore conjugated to a 5′-fluorodeoxy-adenosine unit. Inhibition assays were performed with FDA-PEG-GUL which revealed that it inhibits the PSMA in the nanomolar range. Additionally, it has been purposely designed so that it can be produced using the fluorinase enzyme from its chlorinated precursor, allowing for the enzymatic synthesis of radiolabelled [18F]FDA-PEG-GUL via a nucleophilic reaction that takes place in experimentally advantageous conditions (in water at neutral pH and at ambient temperature). Specific binding of [18F]FDA-PEG-GUL to PSMA expressing cancer cells was demonstrated, validating it as a promising PSMA diagnostic tool. This work establishes a successful substrate scope expansion for the fluorinase and demonstrates its first application towards targeting the PSMA.
Towards 20,20-difluorinated bryostatin: synthesis and biological evaluation of C17,C27-fragments by Paul R. Mears; Steven Hoekman; Claire E. Rye; Fiona P. Bailey; Dominic P. Byrne; Patrick A. Eyers; Eric J. Thomas (1487-1505).
Bryostatins with modified C17–C27 fragments have not been widely studied. The synthesis of 20,20-difluorinated analogues was therefore investigated. Such substitution would inhibit dehydration involving the C19-hydroxyl group and stabilise the ring-closed hemiacetal tautomers. Following preliminary studies, allyldifluorination was used to prepare difluorinated alkenols. Oxidation followed by stereoselective Wittig reactions of the resulting α,α-difluorinated ketones gave (E)-α,β-unsaturated esters that were taken through to complete syntheses of 2-hydroxytetrahydropyrans corresponding to C17–C27 fragments of 20,20-difluorinated bryostatin. These compounds showed modest binding to protein kinase Cα isozyme. Attempts were also undertaken to synthesise macrocyclic 20,20-difluorinated analogues. During preliminary studies, allyldifluorination was carried out using a 2-alkyl-3-bromo-1,1-difluoropropene.
Characterization of the flavin monooxygenase involved in biosynthesis of the antimalarial FR-900098 by Kim Nguyen; Matthew A. DeSieno; Brian Bae; Tyler W. Johannes; Ryan E. Cobb; Huimin Zhao; Satish K. Nair (1506-1518).
The latter steps in this biosynthetic pathway for the antimalarial phosphonic acid FR-900098 include the installation of a hydroxamate onto 3-aminopropylphosphonate, which is catalyzed by the consecutive actions of an acetyltransferase and an amine hydroxylase. Here, we present the 1.6 Å resolution co-crystal structure and accompanying biochemical characterization of FrbG, which catalyzes the hydroxylation of aminopropylphosphonate. We show that FrbG is a flavin-dependent N-hydroxylating monooxygenase (NMO), which shares a similar overall structure with flavin-containing monooxygenases (FMOs). Notably, we also show that the cytidine-5′-monophosphate moiety of the substrate is a critical determinant of specificity, distinguishing FrbG from other FMOs in that the nucleotide cofactor-binding domain also serves in conferring substrate recognition. In the FrbG-FAD+-NADPH co-crystal structure, the C4 of the NADPH nicotinamide is situated near the N5 of the FAD isoalloxazine, and is oriented with a distance and stereochemistry to facilitate hydride transfer.
Identifying a novel anticancer agent with microtubule-stabilizing effects through computational cell-based bioactivity prediction models and bioassays by Yao Luo; Ranran Zeng; Qingqing Guo; Jianrong Xu; Xiaoou Sun; Ling Wang (1519-1530).
We report the identification of 14 novel anticancer agents through established computational anticancer cell-based models. Among these novel hits, the compound G03 exhibits stronger inhibitory effects on the proliferation of MCF-7, HepG2, MDA-MB-231, HCTT116, and HeLa as compared with the FDA-approved sorafenib, with IC50 values of 4.61, 3.20, 2.82, 2.98, and 2.90 μM, respectively. The tubulin protein was validated to be a target of G03 using SPR, tubulin polymerization, immunofluorescence, and western blot assays. G03 is a novel structurally simple anticancer agent with unusual microtubule-stabilizing effects. Our study demonstrated the identification of bioactive small molecules by computational phenotypic modeling, which represents a feasible route toward innovative leads for chemical biology and medicinal chemistry.
Radical alkylation of isocyanides with amino acid-/peptide-derived Katritzky salts via photoredox catalysis by Ze-Fan Zhu; Miao-Miao Zhang; Feng Liu (1531-1534).
An efficient and mild method was developed for the synthesis of 6-alkylated phenanthridines upon visible light irradiation. Bench-stable and easily handled redox-active Katritzky pyridinium salts derived from abundant amino acids/peptides were used as radical precursors for the alkylation of isocyanobiphenyl species. The reaction displays an excellent functional group tolerance and a potential utility for peptide functionalization, allowing access to desired products in good to excellent yields.
I2/DMSO-mediated multicomponent reaction of o-hydroxyaryl methyl ketones, rongalite, and DMSO: access to C3-sulfenylated chromones by Miao Wang; Bo-Cheng Tang; Jin-Tian Ma; Zi-Xuan Wang; Jia-Chen Xiang; Yan-Dong Wu; Jun-Gang Wang; An-Xin Wu (1535-1541).
An efficient I2–DMSO reagent system-mediated multicomponent reaction strategy for the synthesis of C3-sulfenylated chromones from o-hydroxyaryl methyl ketones, rongalite, and dimethyl sulfoxide has been developed. Notably, the double C–S bond cleavages of rongalite and dimethyl sulfoxide served as key steps in this smooth transformation, affording the C1 unit and sulfur source for the assembly of C3-sulfenylated chromones. Preliminary mechanistic studies indicated that in situ generated HCHO and (2-(2-hydroxyphenyl)-2-oxoethyl)dimethylsulfonium iodine were probably the key intermediates in this transformation.
Stereoselective synthesis of all-cis boryl tetrahydroquinolines via copper-catalyzed regioselective addition/cyclization of o-aldiminyl cinnamate with B2Pin2 by Ya-Ping Bi; He-Min Wang; Hong-Yu Qu; Xian-Chen Liang; Ying Zhou; Xue-Ying Li; Defeng Xu; Mei-Hua Shen; Hua-Dong Xu (1542-1546).
A copper catalyzed intramolecular 1,2-carboboration of o-aldiminyl cinnamate has been realized in both regio- and stereoselective fashions. This reaction provides a convenient entry to highly valuable and otherwise challenging cis-2,3,4-trisubstituted tetrahydroquinolines carrying a 4-boryl group. An unusual non-Michael addition intermediate or alternatively, a cyclic enolate is proposed to account for the intriguing all-cis configuration in the final products.
Phosphine- and water-promoted pentannulative aldol reaction by Bishnupada Satpathi; Lona Dutta; S. S. V. Ramasastry (1547-1551).
Herein, an efficient metal-free intramolecular aldol reaction for the synthesis of an unusual class of cyclopentanoids is described. The reaction of α-substituted dienones tethered with ketones in the presence of tributylphosphine and water provided aldols. The role of water was realised to be crucial for this transformation. Furthermore, isotopic labeling experiments provided vital information about the reaction mechanism.
Continuous-flow protocol for the synthesis of enantiomerically pure intermediates of anti epilepsy and anti tuberculosis active pharmaceutical ingredients by Renata M. Aguiar; Raquel A. C. Leão; Alejandro Mata; David Cantillo; C. Oliver Kappe; Leandro S. M. Miranda; Rodrigo O. M. A. de Souza (1552-1557).
Continuous-flow production of chiral intermediates plays an important role in the development of building blocks for Active Pharmaceutical Ingredients (APIs), being α-amino acids and their derivatives widely applied as building blocks. In this work we developed two different strategies for the synthesis of intermediates used on the synthesis of levetiracetam/brivaracetam and ethambutol. The results obtained show that methionine methyl ester can be continuously converted to the desired ethambutol intermediate by RANEY® Nickel dessulfurization/reduction strategy whereas levetiracetam/brivaracetam intermediates could be synthesized by both RANEY® Nickel (without H2) and Pd/C–H2 approach or by photochemical desulfurization.
Fluorinated bisbenzimidazoles: a new class of drug-like anion transporters with chloride-mediated, cell apoptosis-inducing activity by Xi-Hui Yu; Xiao-Qiao Hong; Wen-Hua Chen (1558-1571).
Anion transporters have attracted substantial interest due to their ability to induce cell apoptosis by disrupting cellular anion homeostasis. In this paper we describe the synthesis, anion recognition, transmembrane anion transport and cell apoptosis-inducing activity of a series of fluorinated 1,3-bis(benzimidazol-2-yl)benzene derivatives. These compounds were synthesized from the condensation of 1,3-benzenedialdehyde or 5-fluoro-1,3-benzenedialdehyde with the corresponding 1,2-benzenediamines and fully characterized. They are able to form stable complexes with chloride anions, and exhibit potent liposomal and in vitro anionophoric activity. Their anion transport efficiency may be ameliorated by the total number of fluorine atoms, and the enhanced anionophoric activity was a likely consequence of the increased lipophilicity induced by fluorination. Most of these fluorinated bisbenzimidazoles exhibit potent cytotoxicity toward the selected cancer cells. Mechanistic investigations suggest that these compounds are able to trigger cell apoptosis probably by disrupting the homeostasis of chloride anions.
Correction: Ionic-liquid supported rapid synthesis of an N-glycan core pentasaccharide on a 10 g scale by Wei Li; Yu Gao; Qing Li; Zhong-Jun Li (1572-1572).
Correction for ‘Ionic-liquid supported rapid synthesis of an N-glycan core pentasaccharide on a 10 g scale’ by Wei Li et al., Org. Biomol. Chem., 2018, 16, 4720–4727.
Back cover (1573-1574).