Organic & Biomolecular Chemistry (v.14, #27)

Front cover (6357-6357).

Inside front cover (6358-6358).

Contents list (6359-6367).

Our synthetic strategy for the hydrophobic glycoprotein is summarized. The reverse-polarity protection strategy, in which the side chain carboxy group is protected as a basic picolyl ester, combined with the O-acylisopeptide method proved to be efficient for the preparation of the hydrophobic glycoprotein by ligation methods, and would be applicable for the synthesis of membrane proteins in the future.

Enantioselective synthesis of cyanohydrins catalysed by hydroxynitrile lyases – a review by Paula Bracco; Hanna Busch; Jan von Langermann; Ulf Hanefeld (6375-6389).
The first enantioselective synthesis was the selective addition of cyanide to benzaldehyde catalysed by a hydroxynitrile lyase (HNL). Since then these enzymes have been developed into a reliable tool in organic synthesis. HNLs to prepare either the (R)- or the (S)-enantiomer of the desired cyanohydrin are available and a wide variety of reaction conditions can be applied. As a result of this, numerous applications of these enzymes in organic synthesis have been described. Here the examples of the last decade are summarised, the enzyme catalysed step is discussed and the follow-up chemistry is shown. This proves HNLs to be part of main stream organic synthesis. Additionally the newest approaches via immobilisation and reaction engineering are introduced.

Overproduction and identification of butyrolactones SCB1–8 in the antibiotic production superhost Streptomyces M1152 by John D. Sidda; Vincent Poon; Lijiang Song; Weishan Wang; Keqian Yang; Christophe Corre (6390-6393).
Gamma-butyrolactones (GBLs) are signalling molecules that control antibiotic production in Streptomyces bacteria. The genetically engineered strain S. coelicolor M1152 was found to overproduce GBLs SCB1–3 as well as five novel GBLs named SCB4–8. Incorporation experiments using isotopically-labelled precursors confirmed the chemical structures of SCB1–3 and established those of SCB4–8.

A prototype reversible polymersome-stabilized H2S photoejector operating under pseudophysiological conditions by A. Tron; A. Peyret; J. Thevenot; R. Bofinger; S. Lecommandoux; N. D. McClenaghan (6394-6397).
Persistent self-assembled polymersome capsules are shown to solubilise and stabilize a new hydrosulfide-containing (2), as well as hydroxylated (1), malachite green derivatives in their leuco-forms in aqueous buffer solution. Photoirradiation resulted in reversible hydroxide release/hydrogen sulfide generation. Notably, the efficient augmentation of H2S concentration to physiologically-relevant levels is shown.

Photooxygenation of an amino-thienopyridone yields a more potent PTP4A3 inhibitor by Joseph M. Salamoun; Kelley E. McQueeney; Kalyani Patil; Steven J. Geib; Elizabeth R. Sharlow; John S. Lazo; Peter Wipf (6398-6402).
The phosphatase PTP4A3 is an attractive anticancer target, but knowledge of its exact role in cells remains incomplete. A potent, structurally novel inhibitor of the PTP4A family was obtained by photooxygenation of a less active, electron-rich thienopyridone (1). Iminothienopyridinedione 13 displays increased solution stability and is readily obtained by two new synthetic routes that converge in the preparation of 1. The late-stage photooxygenation of 1 to give 13 in high yield highlights the potential of this reaction to modify the structure and properties of a biological lead compound and generate value for expanding the scope of an SAR investigation. Analog 13 should become a valuable tool for further exploration of the role of PTP4A3 in tumor progression.

2-Trifluoromethylthiolation of glycals by Yang Yu; De-Cai Xiong; Xin-Shan Ye (6403-6406).
Methods for trifluoromethylthiolation are very limited. To tackle this problem, a mild and efficient approach to the 2-trifluoromethylthiolation of glycals has been developed. This protocol employed N-trifluoromethylthiosaccharin as the trifluoromethylthiolating reagent, TMSCl as the activator, and DBU as the base, affording 2-trifluoromethylthioglycals in good yields. These trifluoromethylthiolated carbohydrates may benefit the development of carbohydrate-based drugs.

A facile and general procedure for the preparation of alkynyl C-nucleosides with varied fluorophores is presented. Sonogashira coupling was used as a key reaction to conjugate the dyes to an easily accessible ethynyl functionalized deoxyribose derivative. The new C-nucleosides were used for the preparation of DNA-based polyfluorophores.

Stereoselective synthesis of cyclopentanone-fused benzosultams through Tomita zipper cyclization by Dhevalapally B. Ramachary; Patoju M. Krishna; T. Prabhakar Reddy (6413-6416).
A powerful intermolecular version of the Tomita zipper-cyclization (TZC) reaction was developed to provide functionalized drug-like cyclopentanone-fused benzosultams in good yields with excellent stereoselectivities using organophosphine-catalysis.

This article describes an efficient method for the introduction of perfluoroalkyl groups into N-acrylamides, 2-isocyanides, olefins, and other heterocycles using perfluoroalkyl radicals that were generated from the reaction between sodium perfluoroalkanesulfinates and a hypervalent iodine(iii) reagent. This approach represents a simple, scalable perfluoroalkylation method under mild and metal-free conditions.

The enantioselective N-heterocyclic carbene-catalyzed [2 + 4] cyclocondensation of α-chloroaldehydes and saccharine-derived 1-azadienes was developed, giving the corresponding saccharine-derived dihydropyridinones in good yields with exclusive cis-selectivities and excellent enantioselectivities.

A divergent, new, and highly stereoselective synthesis of cis-2,6-disubstituted piperidine natural products including isosolenopsins, deoxocassine, and spectaline was achieved from chiral aziridine decorated with appropriate alkyl chains for isosolenopsins or alkynyl groups for deoxocassine and spectaline at C2. The characteristic feature of this synthesis is one-pot sequential reactions under atmospheric hydrogen including the reduction of alkyne (for deoxocassine and spectaline), reductive ring-opening of aziridine, debenzylation, and intramolecular reductive amination in high yields. The prerequisite aziridines were elaborated from commercially available (2S)-hydroxymethylaziridine through oxidation, Wittig olefination, and the Grignard reaction for isosolenopsins or substrate-controlled lithium alkynylate addition for deoxocassine and spectaline.

1,2-Diketones are employed, for the first time, as electrophiles in the vinylogous aldol reaction. With 5 mol% of chiral tertiary amine-thiourea C8, a direct vinylogous aldol-cyclization cascade reaction between β,γ-unsaturated amides and o-quinones has been achieved to produce spirocyclic dihydropyranones in 76–99% yield and 82–95% ee.

Competitive counterion complexation allows the true host : guest binding constants from a single titration by ionic receptors by Márcia Pessêgo; Nuno Basílio; M. Carmen Muñiz; Luis García-Río (6442-6448).
Counterion competitive complexation is a background process currently ignored by using ionic hosts. Consequently, guest binding constants are strongly affected by the design of the titration experiments in such a way that the results are dependent on the guest concentration and on the presence of added salts, usually buffers. In the present manuscript we show that these experimental difficulties can be overcome by just considering the counterion competitive complexation. Moreover a single titration allows us to obtain not only the true binding constants but also the stoichiometry of the complex showing the formation of 1 : 1 : 1 (host : guest : counterion) complexes. The detection of high stoichiometry complexes is not restricted to a single titration experiment but also to a displacement assay where both competitive and competitive-cooperative complexation models are taken into consideration.

Chemoenzymatic synthesis and pH-responsive properties of amphoteric block polysaccharides by Takuya Nakauchida; Yusei Takata; Kazuya Yamamoto; Jun-ichi Kadokawa (6449-6456).
Here, we investigated the chemoenzymatic synthesis of α(1→4)-linked amphoteric block polysaccharides. Amylouronic acid as an acidic block was first synthesized by 2,2,6,6-tetramethylpiperidine 1-oxyl-mediated oxidation of a water-soluble amylose (chemical reaction). A short maltooligosaccharide chain, serving as an initiating site for the following enzymatic polymerization, was then introduced at the nonreducing end of the product by thermostable α-glucan phosphorylase-catalyzed enzymatic oligomerization of α-d-glucose 1-phosphate. Finally, thermostable α-glucan phosphorylase-catalyzed enzymatic polymerization of α-d-glucosamine 1-phosphate from the produced primer provided a basic block at the nonreducing end, leading to the desired amphoteric block polysaccharides. The structures of the products at each step were determined by 1H NMR analysis. Furthermore, amphoteric products exhibited specific inherent isoelectric points (pIs). When the pH-responsive properties in aqueous solutions were evaluated using a divalent acid and base, similar hierarchical assembling/disassembling processes were observed by shifting the pH values from the pI to both the acidic and basic pH.

We report a diastereoselective Mannich-type reaction of α-alkyl, α-aryl, and α-vinyl fluoroacetates with N-tert-butylsulfinyl imines. This method provides a powerful means to access a broad range of highly functionalized β-amino acids containing α-fluorinated quaternary stereogenic carbon centers. We also show that the stereochemical outcome of the present reaction is highly dependent on the steric and electronic properties of the fluorocarbon nucleophiles. This protocol uses readily available starting materials, tolerates a variety of functional groups, and is operationally simple.

N-Heterocyclic carbene-triggered transition-metal-free synthesis of 2,3-disubstituted benzofuran derivatives by Yuanwei Xie; Chenxia Yu; Yonglei Que; Tuanjie Li; Yuhong Wang; Yinan Lu; Wenjing Wang; Shide Shen; Changsheng Yao (6463-6469).
An NHC-triggered, transition-metal-free strategy for the efficient synthesis of 2,3-disubstituted benzofuran derivatives in moderate to excellent yields from aryl or alkyl aldehydes and o-quinone methides has been developed. This method features mild reaction conditions, operational simplicity, broad substrate scope and convergent assembly.

Bio-reducible polycations from ring-opening polymerization as potential gene delivery vehicles by Qing-Ying Yu; Yan-Hong Liu; Zheng Huang; Ji Zhang; Chao-Ran Luan; Qin-Fang Zhang; Xiao-Qi Yu (6470-6478).
Synthetic polycations show great potential for the construction of ideal non-viral gene delivery systems. Several cationic polymers were synthesized by the epoxide ring-opening polymerization between diepoxide and various polyamines. Disulfide bonds were introduced to afford the polymers bio-reducibility, while the oxygen-rich structure might enhance the serum tolerance and biocompatibility. The polycations have much lower molecular weights than PEI 25 kDa, but still could well bind and condense DNA into nano-sized particles. DNA could be released from the polyplexes by addition of reductive DTT. Compared to PEI, the polycations have less cytotoxicity possibly due to their lower molecular weights and oxygen-rich structure. More significantly, these materials exhibit excellent serum tolerance than PEI, and up to 6 times higher transfection efficiency than PEI could be obtained in the presence of serum. The transfection mediated by TETA-SS was seldom affected even at a high concentration of serum. Much lower protein adsorption of polycations than PEI was proved by bovine serum albumin adsorption experiments. Flow cytometry also demonstrates their good serum resistance ability.

A reactivity and selectivity study of O,O-diethyl 2,4-dinitrophenyl phosphate (1) and O,O-diethyl 2,4-dinitrophenyl thionophosphate (2) with a series of thiols of low molecular weight: N-acetyl cysteine (NAC), l-cysteine (Cys), homocysteine (Hcys), glutathione (GSH), and d-penicillamine (Pen) was conducted. Results show that (i) these nucleophiles only attack at the aromatic moiety of both triester derivatives, (ii) a kinetic control product by sulfhydryl attack of thiols was observed in the reactions of both triesters with Cys and Hcys, followed by an intramolecular amine attack leading to a thermodynamic control product. The kinetic study leads to the proposal of Meisenheimer complex formation and then proton transfer to the reaction media as the mechanism of these reactions.

Pd-catalyzed one-pot sequential unsymmetrical cross-coupling reactions of aryl/heteroaryl 1,2-dihalides by Abhinandan K. Danodia; Rakesh K. Saunthwal; Monika Patel; Rakesh K. Tiwari; Akhilesh K. Verma (6487-6496).
Efficient, step-economic, Pd(ii)-catalyzed one-pot sequential Sonogashira/Sonogashira, Sonogashira/Suzuki, Sonogashira/Heck, Suzuki/Sonogashira, Suzuki/Suzuki, Suzuki/Heck, Heck/Sonogashira, Heck/Suzuki and Heck/Heck cross coupling reactions of sterically hindered aryl/heteroaryl 1,2-dihalides have been developed. The present methodology allows the conversion of easily available aryl/heteroaryl 1,2-dihalides into synthetically useful unsymmetrically substituted arenes/heteroarenes in good to excellent yields under mild reaction conditions. This methodology is a powerful tool for building a versatile substrate which can be utilized for the synthesis of various organic scaffolds.

The one-pot three-component reaction of secondary α-amino acids, including proline, thiazolidine-4-carboxylic acid, and piperidine-2-carboxylic acid sarcosine with dialkyl acetylenedicarboxylate and N-substituted maleimides in refluxing ethanol afforded functionalized pyrrolo[3,4-a]pyrrolizines, pyrrolo[3′,4′:3,4]pyrrolo[1,2-c]thiazoles, pyrrolo[3,4-a]indolizines and octahydropyrrolo[3,4-c]pyrroles in good yields and with high diastereoselectivity. On the other hand, the similar three-component reaction containing primary α-amino acids, such as glycine, alanine, phenylalanine and leucine, with N-substituted maleimides and two molecules of dialkyl acetylenedicarboxylate obtained the corresponding hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)maleates.

The mechanism and regioselectivity of the intramolecular hydroarylation of phenyl propargyl ether catalyzed by indium in gas and solvent phases were investigated by means of the density functional theory method. The computed results revealed that the reaction proceeds through initial π-coordination of the propargyl moiety to the catalyst, which triggers the nucleophilic attack of the phenyl ring via an exo- or endo-dig pathway in a Friedel–Crafts type mechanism. Calculation results obtained employing InI2+ as the possible catalyst show similar activation energies for the 5-exo-dig and 6-endo-dig pathways. In contrast, the neural catalyst InI3 shows a kinetic preference for 6-endo-dig versus 5-exo-dig cyclizations leading to the experimentally observed product, 2H-chromene. The calculation results suggest that InI3 could be the real catalytic species for this reaction as it shows regioselectivity in agreement with the experimental observation. Furthermore, the 6-endo-dig cyclization through deprotonation/protonation steps is kinetically more favored than the stepwise two consecutive [1,2]-H shift steps. The rate determining step of the whole catalytic cycle is the deprotonation step with an energy barrier of 18.9 kcal mol−1 in toluene solvent. The effects of substituents on both the phenyl ring and the propargyl moiety on the selectivity and elementary steps of the hydroarylation process were investigated. A methoxy group, particularly at the meta-position, on the phenyl ring largely decreases the energy barrier of the first step for the 6-endo path, though it shows little effect on the activation energies of the second and third steps. Our calculation results are in good agreement with the experimental results.

In search of developing new useful “click reactions”, herein we report the organocatalytic azomethine imine-olefin [3 + 2]-cycloaddition as a new click reaction for the synthesis of drug-like spiroindane-1,3-dione-pyrazolidinones from indane-1,3-diones, aldehydes and N,N-cyclic azomethine imines through amino acid-catalysis. The scope of this new click reaction is demonstrated using many examples with high reactivity, selectivity and yields.

A facile H3PO4-promoted bridging methylenation of imidazopyridines or similar heterocycles has been described for the synthesis of symmetrical methylene-bridged imidazoheterocycles, in which DMSO was used as the carbon source. The reaction obtained good yields for most substrates with high C3-regioselectivity. This method also features metal-free, practicability and low cost.

Effect of an N-substituent in sulfonamide-bridged nucleic acid (SuNA) on hybridization ability and duplex structure by Yasunori Mitsuoka; Hiroshi Aoyama; Akira Kugimiya; Yuko Fujimura; Tsuyoshi Yamamoto; Reiko Waki; Fumito Wada; Saori Tahara; Motoki Sawamura; Mio Noda; Yoshiyuki Hari; Satoshi Obika (6531-6538).
A sulfonamide-bridged nucleic acid without an N-substituent (SuNA[NH]) was successfully synthesized. A comparison of the SuNA[NMe]- and SuNA[NH]-modified oligonucleotides revealed that the duplex-forming abilities of the SuNA[NMe]-modified oligonucleotides with complementary DNA and RNA were higher than those of the SuNA[NH]-modified oligonucleotides. The crystal structures of DNA duplexes containing a SuNA[NR] revealed that the helical structures of the two duplexes and hydration patterns around the bridge moiety were different. These results provide insights into hydration patterns and rationale for the high RNA affinity of SuNA-modified oligonucleotides.

Synthesis and evaluation of influenza A viral neuraminidase candidate inhibitors based on a bicyclo[3.1.0]hexane scaffold by Cinzia Colombo; B. Mario Pinto; Anna Bernardi; Andrew J. Bennet (6539-6553).
This manuscript describes a novel class of derivatives based on a bicyclo[3.1.0]hexane scaffold, proposed as mimics of sialic acid in a distorted boat conformation that is on the catalytic pathway of neuraminidases (sialidases). A general synthetic route for these constrained-ring molecules was developed using a photochemical reaction followed by a Johnson–Corey–Chaykovsky cyclopropanation. Functionalization with the goal of occupying the 150-cavity was also exploited. Inhibition assays demonstrated low micromolar inhibition against both group-1 (H5N1) and group-2 (H9N2) influenza neuraminidase subtypes, indicating good affinity for the alpha and beta sialic acid mimics and 150-cavity-targeted derivatives. These results provide a validation of a bicyclo[3.1.0]hexane scaffold as a mimic of a distorted sialic acid bound in the neuraminidase active site during catalysis.

SN1 reactions in supercritical carbon dioxide in the presence of alcohols: the role of preferential solvation by Thais Delgado-Abad; Jaime Martínez-Ferrer; Rafael Acerete; Gregorio Asensio; Rossella Mello; María Elena González-Núñez (6554-6560).
Ethanol (3b) inhibits SN1 reactions of alkyl halides 1 in supercritical carbon dioxide (scCO2) and gives no ethers as products. The unexpected behaviour of alcohols 3 in the reaction of alkyl halides 1 with 1,3-dimethoxybenzene (2) in scCO2 under different conditions is rationalised in terms of Brønsted and Lewis acid–base equilibria of reagents, intermediates, additives and products in a singular solvent characterised by: (i) the strong quadrupole and Lewis acid character of carbon dioxide, which hinders SN2 paths by strongly solvating basic solutes; (ii) the weak Lewis base character of carbon dioxide, which prevents it from behaving as a proton sink; (iii) the compressible nature of scCO2, which enhances the impact of preferential solvation on carbon dioxide availability for the solvent-demanding rate determining step.

One-pot three-component synthesis of quinazolines via a copper-catalysed oxidative amination reaction by Tiantian Duan; Tianran Zhai; Huanhuan Liu; Zilong Yan; Yue Zhao; Lei Feng; Chen Ma (6561-6567).
A copper-catalysed three-component reaction for constructing a series of quinazoline derivatives has been developed. In this system, solvents act as the reactants and different functional groups are well tolerated to obtain corresponding products in moderate to good yields.

An organocatalyzed direct asymmetric vinylogous Michael addition reaction of α,β-unsaturated γ-butyrolactam to 2-enoylpyridines has been developed with a chiral bifunctional amine-squaramide as the catalyst. This approach provides easy access to a series of optically active α,β-unsaturated γ-substituted butyrolactams in high yields (up to 99%) with excellent diastereoselectivities (up to >99 : 1) and enantioselectivities (up to >99% ee).

A systematic theoretical study has been carried out to understand the mechanism and stereoselectivity of N-heterocyclic carbene (NHC)-catalyzed intramolecular crossed-benzoin reaction of enolizable keto-aldehyde using density functional theory (DFT) calculations. The calculated results reveal that the most favorable pathway contains four steps, i.e., the nucleophilic attack of NHC on the carbonyl carbon atom of a formyl group, the formation of a Breslow intermediate, a ring-closure process coupled with proton transfer, and regeneration of the catalyst. For the formation of the Breslow intermediate via the [1,2]-proton transfer process, apart from the direct proton transfer mechanism, the base Et3N and the in situ generated Brønsted acid Et3N·H+ mediated proton transfer mechanisms have also been investigated; the free energy barriers for the crucial proton transfer steps are found to be significantly lowered by explicit inclusion of the Brønsted acid Et3N·H+. The computational results show that the ring-closure process is the stereoselectivity-determining step, in which two chirality centers assigned on the coupling carbon atoms are formed, and the S-configured diastereomer is the predominant product, which is in good agreement with the experimental observations. NCI and NBO analyses are employed to disclose the origin of stereoselectivity and regioselectivity. Moreover, a global reaction index (GRI) analysis has been performed to confirm that NHC mainly plays the role of a Lewis base. The mechanistic insights obtained in the present study should be valuable for the rational design of an effective organocatalyst for this kind of reaction with high stereoselectivity and regioselectivity.

Automated library synthesis of cyclopropyl boronic esters employing diazomethane in a tube-in-tube flow reactor by Hannes F. Koolman; Stanislaw Kantor; Andrew R. Bogdan; Ying Wang; Jeffrey Y. Pan; Stevan W. Djuric (6591-6595).
The efficient synthesis of cyclopropyl boronic esters in library format using a diazomethane flow reactor has been achieved. A pivotal component of the system is a fully automated tube-in-tube reactor allowing for safe handling of hazardous diazomethane on repeated small scale and for the generation of larger quantities of product. The setup enables the repeated execution of Pd-catalyzed cyclopropanation reactions without compromising its operation over time.

Back cover (6597-6598).