Organic & Biomolecular Chemistry (v.12, #1)
Front cover (1-1).
Inside front cover (2-2).
Contents list (3-9).
To be or not to be metal-free: trends and advances in coupling chemistries by Rick Arneil D. Arancon; Carol Sze Ki Lin; Carolina Vargas; Rafael Luque (10-35).
Coupling reactions have been part of several extensive studies in order to develop innovative and greener protocols that can generate a wide range of compounds with applications in pharmaceuticals, agrochemicals and biologically active compounds. Metal-free couplings are an important and increasingly trendy field that has attracted a significant deal of interest in recent years, generating a lot of controversy on the issue of whether metal free is really free. Aside from focusing on such a controversial topic itself, this contribution aims to provide a brief introduction on coupling chemistry to point out the transition of this technology from metal-catalyzed to metal-free. This is followed by a range of key selected synthetically useful metal-free processes and a brief commentary on the current debate of whether metal-free reactions are really metal-free and the required experiments for a full understanding of a metal-free coupling process.
Chiral amides via copper-catalysed enantioselective conjugate addition by Anne K. Schoonen; M. Ángeles Fernández-Ibáñez; Martín Fañanás-Mastral; Johannes F. Teichert; Ben L. Feringa (36-41).
A highly enantioselective one pot procedure for the synthesis of β-substituted amides was developed starting from the corresponding α,β-unsaturated esters. This new methodology is based on the copper-catalysed enantioselective conjugate addition of Grignard reagents to α,β-unsaturated esters and subsequent direct formation of amides by quenching the corresponding enolates with different amines. Various primary and secondary amines bearing alkyl or aryl substituents can be used giving rise to a large variety of β-substituted amides with excellent enantioselectivities.
Copper-catalyzed redox-neutral C–H amination with amidoximes by Hui Chen; Shunsuke Chiba (42-46).
CuI-catalyzed reactions of N-alkylamidoximes afforded dihydroimidazoles via sp3 C–H amination. On the other hand, the reactions of N-benzoylamidoximes resulted in sp2 C–H amination to form quinazolinones. The reaction mechanisms could be characterized as a redox-neutral radical pathway including a Cu(i)–Cu(ii) redox catalytic cycle.
Silyl-protected dioxaborinanes: application in the Suzuki cross-coupling reaction by Sean Goggins; Eleanor Rosevere; Clément Bellini; Joseph C. Allen; Barrie J. Marsh; Mary F. Mahon; Christopher G. Frost (47-52).
The synthesis of a range of novel silyl-protected dioxaborinanes as a column- and bench-stable boron reagent were found to be advantageous to achieving good yields in palladium-catalysed cross-coupling reactions under standard conditions.
Synthesis of crambescin B carboxylic acid, a potent inhibitor of voltage-gated sodium channels by Atsuo Nakazaki; Yuki Ishikawa; Yusuke Sawayama; Mari Yotsu-Yamashita; Toshio Nishikawa (53-56).
The stereocontrolled synthesis of a racemic carboxylic acid of crambescin B, a marine alkaloid, is described. The synthesis features two highly stereoselective reactions: (i) palladium-catalyzed hydroxymethylation of an alkynyl aziridine having an N-guanidino group and (ii) cascade bromocyclization providing a spiro-hemiaminal structure. The cell-based colorimetric assay showed that the synthesized carboxylic acid exhibited a potent inhibitory activity on voltage-gated sodium channels.
FeCl3-catalyzed synthesis of functionally diverse dibenzo[b,f]oxepines and benzo[b]oxepines via alkyne–aldehyde metathesis by Krishnendu Bera; Swapnadeep Jalal; Soumen Sarkar; Umasish Jana (57-61).
An efficient synthesis of dibenzo[b,f]oxepines and benzo[b]oxepines via FeCl3-catalyzed alkyne–aldehyde metathesis reaction is described. Structurally diverse dibenzo[b,f]oxepines and benzo[b]oxepines have been achieved in good yields with high regio- and chemoselectivity under mild conditions. Notably, among the various catalysts such as Fe(iii), Au(iii), In(iii), Zn(ii), Ag(i) and triflic acid, the alkyne–aldehyde metathesis reaction of 2-(2′-phenylethynyl-phenyloxy)-benzaldehyde is only catalyzed by environmentally friendly and sustainable iron(iii) chloride.
Acylthioureas as anion transporters: the effect of intramolecular hydrogen bonding by Cally J. E. Haynes; Nathalie Busschaert; Isabelle L. Kirby; Julie Herniman; Mark E. Light; Neil J. Wells; Igor Marques; Vítor Félix; Philip A. Gale (62-72).
Small molecule synthetic anion transporters may have potential application as therapeutic agents for the treatment of diseases including cystic fibrosis and cancer. Understanding the factors that can dictate the anion transport activity of such transporters is a crucial step towards their application in biological systems. In this study a series of acylthiourea anion transporters were synthesised and their anion binding and transport properties in POPC bilayers have been investigated. The transport activity of these receptors is dominated by their lipophilicity, which is in turn dependent on both substituent effects and the formation and strength of an intramolecular hydrogen bond as inferred from DFT calculations. This is in contrast to simpler thiourea systems, in which the lipophilicity depends predominantly on substituent effects alone.
Design, synthesis and characterization of novel inhibitors against mycobacterial β-ketoacyl CoA reductase FabG4 by Deb Ranjan Banerjee; Debajyoti Dutta; Baisakhee Saha; Sudipta Bhattacharyya; Kalyan Senapati; Amit K. Das; Amit Basak (73-85).
We report the design and synthesis of triazole-polyphenol hybrid compounds 1 and 2 as inhibitors of the FabG4 (Rv0242c) enzyme of Mycobacterium tuberculosis for the first time. A major advance in this field occurred only a couple of years ago with the X-ray crystal structure of FabG4, which has helped us to design these inhibitors by the computational fragment-based drug design (FBDD) approach. Compound 1 has shown competitive inhibition with an inhibition constant (Ki) value of 3.97 ± 0.02 μM. On the other hand, compound 2 has been found to be a mixed type inhibitor with a Ki value of 0.88 ± 0.01 μM. Thermodynamic analysis using isothermal titration calorimetry (ITC) reveals that both inhibitors bind at the NADH co-factor binding domain. Their MIC values, as determined by resazurin assay against M. smegmatis, indicated their good anti-mycobacterial properties. A preliminary structure–activity relationship (SAR) study supports the design of these inhibitors. These compounds may be possible candidates as lead compounds for alternate anti-tubercular drugs. All of the reductase enzymes of the Mycobacterium family have a similar ketoacyl reductase (KAR) domain. Hence, this work may be extrapolated to find structure-based inhibitors of other reductase enzymes.
Hydrophilic tetracarboxy bacteriochlorins for photonics applications by Jianbing Jiang; Pothiappan Vairaprakash; Kanumuri Ramesh Reddy; Tuba Sahin; M. Phani Pavan; Elisa Lubian; Jonathan S. Lindsey (86-103).
Bacteriochlorins absorb strongly in the near-infrared (NIR, 700–900 nm) region and hence are well suited for photophysical studies and photomedical applications, yet such endeavors heretofore have been largely limited by the intrinsic lipophilicity of the bacteriochlorin macrocycle. Here, a new molecular design is investigated wherein 3,5-dicarboxyphenyl units are appended to the β-pyrrolic positions of the bacteriochlorin. Use of the 3,5-aryl substitution motif places the carboxylic acid groups, which are anionic at neutral pH, above and below the plane of the bacteriochlorin macrocycle. A de novo synthesis has been employed to create five such bacteriochlorins, which uses as intermediates two new 2,12-dibromobacteriochlorin building blocks and a known 3,13-dibromobacteriochlorin. The aryl groups with protected carboxylate moieties were introduced by Suzuki coupling; subsequent deprotection afforded the hydrophilic bacteriochlorins. The latter were characterized by absorption and fluorescence spectroscopy in DMF and in aqueous phosphate buffer (pH 7). In most cases, comparable sharp emission (FWHM of ∼25 nm) and modest fluorescence yields (0.060–0.11) were observed in aqueous phosphate buffer medium and in DMF. Aqueous solubility was examined by absorption spectral interrogation of samples over a 1000-fold concentration range with reciprocal change in pathlength (∼0.5, 5, 50, and 500 μM; 10, 1, 0.1, and 0.01 cm pathlength cuvettes). One hydrophilic bacteriochlorin was prepared that contains a single maleimido-terminated tether for bioconjugation; the tether was installed by the sequence of 15-bromination of the bacteriochlorin, Suzuki coupling, and DCC-mediated amide formation. The maleimido-bacteriochlorin was conjugated to a 48-residue cysteine-containing peptide analogue of a constituent from a bacterial photosynthetic light-harvesting complex. Taken together, the results show a new molecular design and facile de novo synthetic route for obtaining hydrophilic bacteriochlorins including a bioconjugatable group if desired.
CGmCGCG is a versatile substrate with which to evaluate Tet protein activity by Seiichiro Kizaki; Hiroshi Sugiyama (104-107).
Tet family proteins have the ability to convert 5-methylcytosine (mC) to 5-hydroxymethylcytosine, and further to 5-formylcytosine and 5-carboxycytosine. We found that CGmCGCG can be the substrate of Tet protein, and observed iterative oxidation of mC by HPLC analysis. We also demonstrated that Tet protein favours single-stranded DNA over double-stranded DNA.
A step toward polytwistane: synthesis and characterization of C2-symmetric tritwistane by Martin Olbrich; Peter Mayer; Dirk Trauner (108-112).
Twistane is a classic hydrocarbon with fascinating stereochemical properties. Herein we describe a series of oligomers of twistane that converges on a chiral nanorod, which we term polytwistane. A member of this series, C2-symmetric tritwistane, has been synthesized for the first time.
Precursor-directed biosynthesis of micacocidin derivatives with activity against Mycoplasma pneumoniae by Martin F. Kreutzer; Hirokazu Kage; Jennifer Herrmann; Julia Pauly; Ron Hermenau; Rolf Müller; Dirk Hoffmeister; Markus Nett (113-118).
Micacocidin is a promising natural product for the treatment of Mycoplasma pneumoniae infections. In the biosynthesis of this antibiotic, a fatty acid-AMP ligase (FAAL) activates the starter unit hexanoic acid as acyl-adenylate and forwards it to an iteratively acting polyketide synthase. Biochemical analysis of the FAAL revealed an extended substrate tolerance, thereby opening the door for the modification of a micacocidin residue that is barely accessible via semisynthesis. A total of six new analogues were generated by precursor-directed biosynthesis in this study and profiled against M. pneumoniae.
Asymmetric chroman synthesis via an intramolecular oxy-Michael addition by bifunctional organocatalysts by Ryota Miyaji; Keisuke Asano; Seijiro Matsubara (119-122).
Cinchona-alkaloid-urea-based bifunctional organocatalysts facilitate the catalytic asymmetric synthesis of chroman derivatives via an intramolecular oxy-Michael addition reaction. Phenol derivatives bearing an easily available (E)-α,β-unsaturated ketone or a thioester moiety are useful substrates for the title transformation. This method represents a facile synthesis of various optically active 2-substituted chromans in high yield.
N-Heterocyclic carbene-catalyzed cascade reaction of 2-aroylvinylcinnamaldehydes with 2-aroylvinylchalcones: rapid assembly of six contiguous stereogenic centers with high diastereoselectivity by Xing-Wen Fan; Ying Cheng (123-131).
N-Heterocyclic carbene-catalyzed reaction of 2-aroylvinylcinnamaldehydes with 2-aroylvinylchalcones proceeded via a triple Michael addition and intramolecular lactonization cascade to produce novel 9-(2-aroyl-3-aroylmethyl-1-indanyl)-3-arylindeno[2,1-c]pyran-1-ones in good yields with high diastereoselectivity. This reaction constructed six contiguous stereogenic centers in a single reactive event. Among 32 possible diastereoisomers that contain six stereocenters, only two diastereoisomers were detected with diastereomeric ratios being 10 : 1–28 : 1. This work opens up a new avenue for the synthesis of complex indane derivatives, a type of compound that has been reported to possess various biological and pharmaceutical activities.
Computational study of diastereoselective ortho-lithiations of chiral ferrocenes by Andrea Škvorcová; Radovan Šebesta (132-140).
Diastereoselective ortho-lithiations serve for the preparation of many important chiral ferrocenes, however diastereoselections of these lithiations are explained only by simple steric models. We elucidated ortho-lithiations of three important ferrocenes based on DFT calculations. The calculations showed that simple models of transition states involving ferrocenyl substrates and lithium bases can only in some cases account for the experimental results. Transition state models, which include solvent or coordinating additives as distinct entities bound to lithium, can satisfactorily explain diastereoselection of the ortho-lithiations of chiral ferrocenes.
Model system for irreversible inhibition of Nek2: thiol addition to ethynylpurines and related substituted heterocycles by Honorine Lebraud; Christopher R. Coxon; Victoria S. Archard; Carlo M. Bawn; Benoit Carbain; Christopher J. Matheson; David M. Turner; Celine Cano; Roger J. Griffin; Ian R. Hardcastle; Ulrich Baisch; Ross W. Harrington; Bernard T. Golding (141-148).
Recent studies have shown that irreversible inhibition of Nek2 kinase [(Never in mitosis gene a)-related kinase 2], overexpression of which is observed in several cancers, can be achieved using Michael acceptors containing an ethynyl group, which target the enzyme's cysteine 22 residue lying near the catalytic site. The model studies described herein demonstrate an analogous capture of the ethynyl moiety in a series of ethynyl-heterocycles (e.g. 6-ethynyl-N-phenyl-9H-purin-2-amine) by N-acetylcysteine methyl ester in the presence of 1,4-diazabicyclo[2.2.2]octane in either dimethyl sulfoxide or N,N-dimethylformamide. Kinetic studies showed a 50-fold range in reactivity with 7-ethynyl-N-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine being the most reactive compound, whereas 4-ethynyl-N-phenyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine was the least reactive. Studies of the isomeric compounds, 2-(3-((6-ethynyl-7-methyl-7H-purin-2-yl)amino)phenyl)acetamide and 2-(3-((6-ethynyl-9-methyl-9H-purin-2-yl)amino)phenyl)acetamide, revealed the N7-methyl isomer to be 5-fold more reactive than the 9-methyl isomer, which is ascribed to a buttressing effect in the N7-methyl compound. Comparison of the crystal structures of these isomers showed that the ethynyl group is significantly displaced away from the methyl group exclusively in the N7-methyl isomer with an sp2 bond angle of 124°, whereas the corresponding angle in the N9-methyl isomer was the expected 120°. The results of this study indicate heterocyclic scaffolds that are likely to be more promising for inhibition of Nek2 and other kinases containing a reactive cysteine.
Synthesis of benzosultams via an intramolecular sp2 C–H bond amination reaction of o-arylbenzenesulfonamides under metal-free conditions by Yuewen Li; Qiuping Ding; Guanyinsheng Qiu; Jie Wu (149-155).
A practical synthetic method for the generation of benzosultams via an intramolecular sp2 C–H bond amination reaction of o-arylbenzenesulfonamides with PhI(OAc)2–I2 under metal-free conditions is developed. A broad range of substrates are tolerated under mild reaction conditions, affording bioactive benzosultams in good to excellent yields. The resulting benzothiazines could be conveniently transformed into their corresponding iodinated derivatives via electrophilic substitution reactions.
Reaction site-driven regioselective synthesis of AChE inhibitors by Emilia Oueis; Gianluca Santoni; Cyril Ronco; Olga Syzgantseva; Vincent Tognetti; Laurent Joubert; Anthony Romieu; Martin Weik; Ludovic Jean; Cyrille Sabot; Florian Nachon; Pierre-Yves Renard (156-161).
The enzyme-directed synthesis is an emerging fragment-based lead discovery approach in which the biological target is able to assemble its own multidentate ligands from a pool of building blocks. Here, we report for the first time the use of the human acetylcholinesterase (AChE) as an enzyme for the design and synthesis of new potent heterodimeric huprine-based inhibitors. Both the specific click chemistry site within the protein and the regioselectivity of the Huisgen cycloaddition observed suggest promising alternatives in the design of efficient mono- and dimeric ligands of AChE. Finally, a detailed computational modelling of the click reaction was conducted to further understand the origin of this TGS selectivity.
One-pot formation of fluorescent γ-lactams having an α-phosphorus ylide moiety through three-component α(δ′)-Michael reactions of phosphines with an enyne and N-tosyl aldimines by Yu-Wei Lin; Jie-Cheng Deng; You-Zung Hsieh; Shih-Ching Chuang (162-170).
We demonstrate a straightforward synthesis of γ-lactams possessing an α-phosphorus ylide moiety from assembly of phosphines, N-tosyl aldimines and an enyne through an initial α(δ′)-attack of phosphines to an enyne in up to 79% yield. The investigated multicomponent reaction tolerates a variety of triarylphosphines and electron-poor aldimines to give γ-lactams in one pot. One of the lactams, with the tri(p-tol)phosphine and 4-cyanophenyl moiety, exhibits fluorescence emission at 447 nm with a quantum yield of 0.11.
Exploring O-stannyl ketyl and acyl radical cyclizations for the synthesis of γ-lactone-fused benzopyrans and benzofurans by Helen Santoso; Myriam I. Casana; Christopher D. Donner (171-176).
The synthesis of a series of γ-lactone-fused benzopyrans and benzofurans, analogues of the pyranonaphthoquinone antibiotics, is reported. Preparation of the heterocycles was achieved by either O-stannyl ketyl or acyl radical cyclization of benzaldehyde precursors followed by oxidation to give the pyrano- and furanobenzoquinone systems. The observed diastereoselectivity during O-stannyl ketyl radical cyclization is influenced by aromatic substitution ortho to the aldehyde, whilst acyl radical cyclization followed by stereoselective reduction of the resulting pyranones provides a complimentary approach to forming the required γ-lactone-fused benzopyran systems.
Diverse modifications of the 4-methylphenyl moiety of TAK-779 by late-stage Suzuki–Miyaura cross-coupling by Anna Junker; Dirk Schepmann; Junichiro Yamaguchi; Kenichiro Itami; Andreas Faust; Klaus Kopka; Stefan Wagner; Bernhard Wünsch (177-186).
Chemokine receptor 5 (CCR5) antagonists provide a new therapeutic approach in the treatment of HIV-1 (AIDS). TAK-779 displays high affinity and selectivity for the CCR5 receptor and serves as a lead compound for the development of further antagonists. In order to increase the oral bioavailability replacement of the quaternary ammonium structure by a tertiary amine and modification of the 4-methylphenyl moiety were envisaged. Herein, a new synthetic strategy for the development of TAK-779 analogs by late stage diversification is reported. The Suzuki–Miyaura cross-coupling reactions allowed various modifications of the central amide building block 3 at the end of the synthesis leading to compounds 2f and 2h with a promising CCR5 binding affinity.
Unraveling polar Diels–Alder reactions with conceptual DFT analysis and the distortion/interaction model by Ariel M. Sarotti (187-199).
The reaction energetics of 280 polar Diels–Alder (DA) reactions between 70 dienophiles and 4 dienes have been studied in detail using the B3LYP/6-31G* level of theory, combining conceptual density functional theory (DFT) analysis and the distortion/interaction model. The barrier heights are governed by a fine balance between the energy required to distort the reactants from their initial to their transition state geometries (ΔE‡d) and the binding energy between the deformed reactants in the TS (ΔE‡i). The ΔE‡i values strongly correlate with the electrophilicity index, ω, which measures the stabilization energy when the system acquires an additional electronic charge from the environment, whereas the ΔE‡d was found to depend mainly on the nature of the diene, structural parameters of the dienophile (degree of substitution and ring size) and the asynchronicity of the TS. A detailed analysis to account for the geometrical parameters of the strained diene and dienophile moieties that influence the energy strain of the distorted fragments is also reported.
Back cover (201-202).