Organic & Biomolecular Chemistry (v.15, #11)

Front cover (2271-2272).

Contents list (2273-2279).

In this review, the recent applications of a variety of chiral imino-containing ligands classified by different types of metal-catalyzed asymmetric reactions are summarized. The progress made in this area would encourage us to design and synthesize more novel chiral imino-containing ligands, and explore their applications in metal-catalyzed asymmetric transformations.

Recent advances in organocatalytic enantioselective transfer hydrogenation by Ana Maria Faísca Phillips; Armando J. L. Pombeiro (2307-2340).
The organocatalytic reduction of CC and CN double bonds with biomimetic reductants, e.g. Hantzsch 1,4-dihydropyridine esters and benzothiazolines, is reviewed. Very high yields and stereoselectivities have been achieved with a variety of catalysts, including chiral amines, thioureas and phosphoric acids, even with loadings equivalent to those of transition metal-catalyzed reactions in some cases. Reductive amination reactions and the dearomatization of heteroaromatic substrates are the subject of more than one half of the contributions. Of lately, methodologies based on kinetic resolution, cascade reactions involving transfer hydrogenation and the development of novel reductants have become prominent in an area which brings great prospects for the future of target oriented-synthesis.

Rapid chemoenzymatic route to glutamate transporter inhibitor l-TFB-TBOA and related amino acids by Haigen Fu; Sabry H. H. Younes; Mohammad Saifuddin; Pieter G. Tepper; Jielin Zhang; Erik Keller; André Heeres; Wiktor Szymanski; Gerrit J. Poelarends (2341-2344).
The complex amino acid (l-threo)-3-[3-[4-(trifluoromethyl)benzoylamino]benzyloxy]aspartate (l-TFB-TBOA) and its derivatives are privileged compounds for studying the roles of excitatory amino acid transporters (EAATs) in regulation of glutamatergic neurotransmission, animal behavior, and in the pathogenesis of neurological diseases. The wide-spread use of l-TFB-TBOA stems from its high potency of EAAT inhibition and the lack of off-target binding to glutamate receptors. However, one of the main challenges in the evaluation of l-TFB-TBOA and its derivatives is the laborious synthesis of these compounds in stereoisomerically pure form. Here, we report an efficient and step-economic chemoenzymatic route that gives access to enantio- and diastereopure l-TFB-TBOA and its derivatives at multigram scale.

Gold/silver-catalyzed controllable regioselective vinylcarbene insertion into O–H bonds by Guangyang Xu; Kai Liu; Zhenya Dai; Jiangtao Sun (2345-2348).
An unprecedented regioselective metallo-vinylcarbene insertion into O–H bonds has been achieved with vinyldiazoacetates and 2-pyridones/benzyl alcohols as ideal substrates, which displayed distinct regioselectivity by employing gold and silver catalytic systems.

A T4 DNA ligase-catalysed oligonucleotide polymerisation process has been recently developed to enable the incorporation of multiple functional groups throughout a nucleic acid polymer. T4 DNA ligase requires ATP as a cofactor to catalyse phosphodiester bond formation during the polymerisation process. Herein, we describe the structure–activity relationship of ATP within the context of T4 DNA ligase-catalyzed oligonucleotide polymerisation. Using high-throughput sequencing, we study not only the influence of ATP modification on polymerisation efficiency, but also on the fidelity and sequence bias of the polymerisation process.

Isoafricanol synthase from Streptomyces malaysiensis by Patrick Rabe; Markiyan Samborskyy; Peter F. Leadlay; Jeroen S. Dickschat (2353-2358).
Genome sequencing of Streptomyces malaysiensis DSM 4137 revealed the presence of four terpene cyclase genes, one of which was characterised as (+)-isoafricanol synthase. Its cyclisation mechanism was extensively studied using isotopically labelled precursors. Several enzymes with high homology that likely also function as (+)-isoafricanol synthases are encoded in a number of other genome sequenced streptomycetes.

Palladium/zinc co-catalyzed asymmetric transfer hydrogenation of oxabenzonorbornadienes with alcohols as hydrogen sources by Fujie Ma; Jingchao Chen; Fan Yang; Madhuri Vikas Shinde; Yongyun Zhou; Baomin Fan (2359-2362).
Asymmetric transfer hydrogenation of oxabenzonorbornadienes was realized by using alcohols as hydrogen sources under a co-catalytic system of palladium and zinc. Both primary and secondary alcohols could serve as reductants and afforded enantiomerically enriched 1,2-dihydronaphth-1-ol products with high optical purities.

An efficient Ugi-3CR/aza Diels–Alder/Pomeranz–Fritsch protocol towards novel aza-analogues of (±)-nuevamine, (±)-lennoxamine and magallanesine: a diversity oriented synthesis approach by Óscar Vázquez-Vera; Jorge S. Sánchez-Badillo; Alejandro Islas-Jácome; Manuel A. Rentería-Gómez; Shrikant G. Pharande; Carlos J. Cortes-García; Mónica A. Rincón-Guevara; Ilich A. Ibarra; Rocío Gámez-Montaño; Eduardo González-Zamora (2363-2369).
A rapid and efficient synthesis of a series of (±)-nuevamine, (±)-lennoxamine and magallanesine aza analogues is described. The synthetic strategy involves Ugi-3CR and two further condensation processes, aza-Diels–Alder cycloaddition and the Pomeranz–Fritsch reaction. The variation of the chain-size in aldehyde moieties provided structural diversity in only two operational reaction steps.

Efficient synthesis of 2-aryloxy-3-butenoic acid esters by allylic C–H bond carboxylation of allyl aryl ethers with CO2 has been achieved through deprotonative alumination with an aluminium ate compound (iBu3Al(TMP)Li) followed by NHC-copper-catalysed carboxylation of the resulting aryloxy allylaluminum species. Functional groups such as halogens (F, Cl, Br, I), CF3, amino, methylthio, silyloxy and hetero aromatic groups survived the reaction conditions. The regio- and stereoselective transformation (isomerization) of 2-aryloxy-3-butenoate products to (Z)-2-aryloxy-2-butenate isomers has also been achieved in the presence of a catalytic amount of DBU. These transformations thus constitute an efficient protocol for the divergent synthesis of both 2-aryloxy-3- and 2-butenonates from a single allyl aryl ether substrate using CO2 as a C1 building block.

The synthesis of monofluoroalkenes bearing a malonate or its derivatives at the β position is presented. The reaction can be performed with various 3,3-difluoropropenes. A preliminary result for an enantioselective variant is also reported. Further synthetic transformations of a monofluoroalkene were also accomplished.

An efficient Sn(ii)-catalyzed one-pot synthesis of a 3-substituted azetidine-2,4-dione framework by Santosh S. Chavan; Mrudul V. Supekar; Pralhad A. Burate; Bapurao D. Rupanwar; Anil M. Shelke; Gurunath Suryavanshi (2385-2391).
A novel Sn(ii)-catalyzed tandem cyclization reaction of aromatic aldehydes with ethyl cyanoacetate has been achieved to afford a series of 3-substituted azetidine-2,4-diones in good to excellent yields. This protocol provides straightforward access to construct the azetidine core through sequential Knoevenagel condensation, hydration and the C–N cyclization reaction.

Iridium catalyzed acceptor/acceptor carbene insertion into N–H bonds in water by Kankanala Ramakrishna; Chinnappan Sivasankar (2392-2396).
The chemistry of A and D/A carbenes (D and A are donor and acceptor groups, respectively) is known to a great extent in the literature. Nevertheless the chemistry of the A/A class of carbenes is less explored, although the A/A class of carbenes is more important in natural product synthesis. The known catalysts for A/A carbene chemistry are also less in number and are found to be efficient only in typical organic solvents. These limitations prompted us to search for new catalysts and environmentally benign reaction conditions for the A/A class of carbenes. The present study reveals that [(COD)IrCl]2 is found to be an efficient catalyst for the A/A class of carbenes, and Pd2(dba)3 for the D/A class of carbenes, for insertion into N–H bonds in water under mild reaction conditions. A reactivity comparison study with different classes of carbenes revealed that silver based catalysts are the right choice for the D/D class of carbenes for insertion into N–H bonds in water. A large number of α-amino malonates and amino esters, which are important for the synthesis of heterocycles and several natural products, have been synthesized by following the current methodology, and characterized using standard analytical and spectroscopic techniques.

A carbanion of tert-butyl 3-(1-pyrrolidinyl)crotonate adds to nitrobenzenes to form σH-adducts, which in the presence of pivaloyl chloride and triethylamine are converted into 3-(1-pyrrolidinyl)quinolines or 3-(1-pyrrolidinyl)quinoline 1-oxides depending on the nitrobenzene structure. This is the first methodology in which a quinoline ring is constructed from a substrate bearing a pyrrolidinyl ring. Starting from optically pure enamines, the method allows synthesis of the corresponding chiral products without racemisation.

Palladium-catalyzed intermolecular tandem cyclization reaction: a highly regioselective synthesis of functionalized 3H-spiro[isobenzofuran-1,3′-isochroman] scaffolds by Liang Wang; Xuehu Li; Hua Tao; Xiang Zhou; Xihong Lu; Wenyue Du; Tingting Jiang; Zhijun Xin; Jianping Liang (2403-2410).
A highly regioselective synthesis of functionalized 3H-spiro[isobenzofuran-1,3′-isochroman] scaffolds using a novel palladium-catalyzed tandem cyclization reaction is explored. During the reaction process, C–O, C–C and C–O bonds are sequentially formed in one pot via decarboxylative allenylpalladium formation, nucleophilic attack, arylpalladium addition and intramolecular nucleophilic attack.

Intramolecular macrolactonization, photophysical and biological studies of new class of polycyclic pyrrole derivatives by Suresh Kumar Mondal; Arabinda Mandal; Susanta Kumar Manna; Sk Asraf Ali; Maidul Hossain; Vangala Venugopal; Avijit Jana; Shubhankar Samanta (2411-2421).
Herein, we report an efficient synthesis of N-substituted pyrrole derivatives and their application to construct macrocyclic oxazocinone via a two-component coupling reaction followed by base mediated intramolecular cyclization. This methodology provides an easy two-step approach to constitute a library of fused pyrrolo-oxazocinone derivatives in good yields under mild reaction conditions. The present methodology offers an easy access to the synthesis of a library of fluorescent pyrole derivatives. Among them, tert-butyl 2-(2-(3-hydroxypropyl)-7-methoxy-4,5-dihydro-2H-benzo[e]isoindol-1-yl)acetate has been employed in bio-analytical imaging which shows efficient cellular internalization along with no obvious cellular toxicity.

Structural probes used to help elucidate mechanistic information of the organocatalyzed asymmetric ketimine hydrosilylation have revealed a new catalyst with unprecedented catalytic activity, maintaining adequate performance at 0.01 mol% loading. A new ‘dual activation’ model has been proposed that relies on the presence of both a Lewis basic and Brønsted acidic site within the catalyst architecture.

A novel and effective method for the construction of highly functionalized aminothiophenes via the cyclization of gem-difluoroalkenes with β-keto tertiary thioamides is described. The reactions proceed smoothly with the assistance of K2CO3 under transition-metal-free conditions, affording a variety of valuable N,N-disubstituted 2-aminothiophenes in moderate to good yields.

Multi-substituted trans-dihydronaphthalenes were obtained in high enantiomeric excess from a TiCl4-mediated cyclization of enantioenriched donor–acceptor cyclopropanes, followed by a triflation of the hydroxy groups. The C–OTf bond in these multi-substituted trans-dihydronaphthalenes is susceptible to further Pd-catalyzed hydrogenations and coupling reactions, which afforded the corresponding C–H or C–C bonded products.

Diversity-oriented synthesis and cytotoxic activity evaluation of biaryl-containing macrocycles by Karell Pérez-Labrada; Marco A. Cruz-Mendoza; Alejandra Chávez-Riveros; Eduardo Hernández-Vázquez; Tomás Torroba; Luis D. Miranda (2450-2458).
Synthesis of biaryl-containing macrocycles has been carried out through a four-step approach comprising two Ugi four component reactions and a Suzuki–Miyaura macrocyclization. This protocol allowed the synthesis of 12- and 14-membered macrocycles. Cytotoxic activity evaluation showed that some of the molecules were effective against leukemia, glioblastoma and lung cancer cell lines (IC50 = 4.0, 5.9 and 7.6, respectively).

Ratiometric electrochemical detection of hydrogen peroxide and glucose by Sean Goggins; Ellen A. Apsey; Mary F. Mahon; Christopher G. Frost (2459-2466).
Hydrogen peroxide (H2O2) detection is of high importance as it is a versatile (bio)marker whose detection can indicate the presence of explosives, enzyme activity and cell signalling pathways. Herein, we demonstrate the rapid and accurate ratiometric electrochemical detection of H2O2 using disposable screen-printed electrodes through a reaction-based indicator assay. Ferrocene derivatives equipped with self-immolative linkers and boronic acid ester moieties were synthesised and tested, and, through a thorough assay optimisation, the optimum probe showed good stability, sensitivity and selectivity towards H2O2. The optimised conditions were then applied to the indirect detection of glucose via an enzymatic assay, capable of distinguishing 10 μM from the background within minutes.

Back cover (2467-2468).