Organic & Biomolecular Chemistry (v.16, #44)

Front cover (8423-8423).

Inside front cover (8424-8424).

Contents list (8425-8433).

Molecular photoswitches are a class of chemical structures that can readily isomerize between distinct geometries upon irradiation with light. Molecular photoswitches are utilized to control protein structure and function with temporal and spatial precision. In this review, we summarize the recent progress in the development of azobenzene-based molecular photoswitches and their applications in the photocontrol of protein structure and function. For clarity of discussion, we divide the known photoswitchable proteins into different categories: protein motifs, ion channels, receptors, and enzymes. Basic approaches and considerations for the structure-guided design of photoswitchable ligands are discussed. The applications and limitations of current photoswitches are also discussed.

Metal-catalyzed 1,3-dipolar cycloaddition reactions of nitrile oxides by Silvia Roscales; Joaquín Plumet (8446-8461).
In the present review advances in the metal-catalyzed 1,3-dipolar cycloaddition reactions of nitrile oxides, mainly in the last decade, will be presented and discussed. An overview on the structure, preparation, dimerization and related reactions as well as the relevant aspects in the cycloaddition chemistry of nitrile oxides (including mechanistic aspects) have also been considered.

Electrolysis promoted reductive amination of electron-deficient aldehydes/ketones: a green route to the racemic clopidogrel by Qianyun Zhang; Wen Zhu; Jinzhong Yao; Xiaofang Li; Hongwei Zhou (8462-8466).
An electrocatalytic reductive amination of electron-deficient aldehydes/ketones was developed, which could be used in the synthesis of functionalized tertiary amines and large scale preparation of racemic clopidogrel. A plausible mechanism involving an iminium cation intermediate was proposed.

Base-catalyzed selective esterification of alcohols with unactivated esters by Chunyan Zhang; Guoying Zhang; Shizhong Luo; Chunfu Wang; Huiping Li (8467-8471).
A practical and efficient base-catalyzed esterification has been developed for the facile synthesis of a broad range of esters from simple alcohols with unactivated tert-butyl esters. This protocol could be conducted at mild conditions, providing esters in high to excellent yields with good functional tolerance. Mechanistic studies provided evidence of an exchange of the tert-butyl alkoxide metal with the alcohol, producing a new alkoxide to participate in the transesterification reaction.

A novel transition metal-free decarboxylative fluoroalkylation of activated alkenes and C–H functionalization cascade process has been developed. This approach provides an efficient way to construct valuable 1,1-dimethyl-2,2,2-trifluoroethyl substituted oxindoles.

Total synthesis of (±)-chondrosterin I using a desymmetric aldol reaction by Yuichiro Kawamoto; Daiki Ozone; Toyoharu Kobayashi; Hisanaka Ito (8477-8480).
The first total synthesis of racemic chondrosterin I was accomplished. The synthetic features include a Michael addition to incorporate a nitro alkane moiety, an oxidative Nef reaction, intramolecular cyclization of the γ-ketoester derivative, and a desymmetric intramolecular aldol reaction of the meso diketoester compound. The present strategy will be applicable to the synthesis of an optically active form by asymmetric desymmetrization.

A facile tandem decyanation/cyanation reaction of α-iminonitriles toward cyano-substituted amides by Zhengwang Chen; Pei Liang; Botao Liu; Haiqing Luo; Jing Zheng; Xiaowei Wen; Tanggao Liu; Min Ye (8481-8485).
A new tandem decyanation/cyanation reaction of α-iminonitriles has been developed. A variety of cyano-substituted aryl amides and heteroaryl amides are synthesized in good yields. Both electron-rich and electron-deficient groups are compatible with the standard conditions. This reaction features a nonmetallic cyano source, tandem decyanation and cyanation reaction, waste utilization of the HCN from the hydrolysis of α-iminonitriles, formation of two important functional groups in one-step operation, etc.

Reacting Wittig reagents and the hypervalent iodine reagent iodosotoluene, in the presence of 10 mol% Cu(tfacac)2 and 5 equiv. of alkene, results in a novel cyclopropanation reaction. The reagent combination is believed to generate a transient monocarbonyl iodonium ylide (MCIY) in situ, which can be intercepted by the copper catalyst to give a metallocarbene. Both ester and ketone derived phosphoranes can be used, as can styrenyl and non-styrenyl alkenes, which provides cyclopropanes in yields up to 81%.

A rapid construction of the ABC tricyclic skeleton of malabanone A by Tao Li; Guangmiao Wu; Shangbiao Feng; Zemin Wang; Xingang Xie; Xuegong She (8491-8494).
The construction of the ABC tricyclic skeleton of malabanone A with the required 4 stereocenters was accomplished in a concise route starting from R-carvone. The synthesis featured an intramolecular [3 + 2] cycloaddition reaction to assemble its A ring and an intramolecular Diels–Alder reaction to construct its C ring.

Palladium-catalyzed cascade carboesterification of norbornene with alkynes by Wanqing Wu; Can Li; Jianxiao Li; Huanfeng Jiang (8495-8504).
An efficient and convenient palladium-catalyzed cascade carboesterification of norbornenes (NBE) with alkynes has been accomplished to afford functionalized α-methylene γ-lactone and tetrahydrofuran derivatives in good to excellent yields. This new strategy exhibits excellent atom- and step-economy, good functional group tolerance and broad substrate scope. In particular, NBE-palladium species was proposed to be the key intermediate in the catalytic cycle to suppress the β-H elimination process. Notably, the developed protocol provides a straightforward and practical tool for the construction of diverse oxygen-containing heterocycle frameworks, illustrating a promising application in synthetic and pharmaceutical chemistry.

Cyclic arylopeptoid oligomers: synthesis and conformational propensities of peptide-mimetic aromatic macrocycles by Masahide Hayakawa; Ayaka Ohsawa; Kumi Takeda; Ryo Torii; Yoshiaki Kitamura; Hiroshi Katagiri; Masato Ikeda (8505-8512).
Macrocyclic peptide-mimetic molecules are attracting renewed attention and have found widespread application in research fields ranging from biochemical science to materials science. Herein, we describe the synthesis and structural elucidation of cyclo[n]-p-arylopeptoids (classified into cyclic aromatic ε-amino acids) bearing various side chains, namely, C[n]pAP(Rn) (where n inside brackets denotes the number of main chain units and R inside parentheses represents side chains). We investigate the influence of n and R on the macrocyclization efficiency of linear p-arylopeptoid oligomers (n = 3, 4, 5) under high-dilution conditions with or without slow addition. The structures of the cyclo[4]-p-arylopeptoids (C[4]pAP(Rn)) and their conformational dynamics are disclosed on the basis of single-crystal X-ray analyses, viable-temperature (VT) 1H NMR studies, and density functional theory (DFT) calculations. We found two representative conformations (open and closed) of cyclo[4]-p-arylopeptoids (C[4]pAP(Rn)) in the solid state and whose preference in the solution state was most likely dependent on solvent polarity. We believe that this simple but dynamic macrocyclic peptide-mimetic molecular scaffold would be attractive for developing new functional molecular tools based on rational molecular design as well as molecular library screening strategies.

Atropisomeric meroterpenoids with rare triketone-phloroglucinol-terpene hybrids from Baeckea frutescens by Ji-Qin Hou; Bao-Lin Wang; Chao Han; Jian Xu; Zhe Wang; Qi-Wei He; Pei-Lin Zhang; Shu-Min Zhao; Xin Pei; Hao Wang (8513-8524).
Baefrutones A–F (1–6), six new meroterpenoids with rare triketone-phloroglucinol-monoterpene/sesquiterpene frameworks, together with their biosynthetically related intermediate (±)-baeckenon B (7), were isolated from the aerial part of Baeckea frutescens under the guidance of HPLC-Q/TOF-MS2 investigation. Compounds 1–4 represent the first examples of natural meroterpenoids existing as four pairs of inseparable diastereomeric atropisomers (2 : 1, 1H NMR integration) caused by the restricted rotation around the C-6–C-7–C-1′ bonds arising from the intramolecular hydrogen bond between C-1 carbonyl and 2′-OH. The discovery of these architectures not only largely enriched the chemodiversity of the meroterpenoid and atropisomer library, but also might be exciting and challenging for asymmetric organic synthesis. Their structures and absolute configurations were established by extensive spectroscopic analysis, X-ray diffraction, and ECD calculations. Compounds 5 and 6 were biomimetically synthesized from 7 and β-caryophyllene via a regioselective oxidative hetero-Diels–Alder reaction, thus providing access to the construction of the 6/6/9/4 tetracyclic ring system. The anti-inflammatory activities of these meroterpenoids were also discussed.

Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations by Guido J. Noguera; Lucas E. Fabian; Elisa Lombardo; Liliana M. Finkielsztein (8525-8536).
Chagas disease or American trypanosomiasis is a parasitic disease caused by the protozoan Trypanosoma cruzi. Its squalene epoxidase (SE) is a target for drug design and development because it is a key enzyme in the biosynthetic pathway of ergosterol, which is essential for the life cycle of the parasite. Previously, we reported that some 4-arylthiazolylhydrazones derived from 1-indanones (TZHs) active against T. cruzi are able to accumulate squalene probably by SE inhibition. In this work, we performed a series of theoretical studies to verify that TZHs act as inhibitors of this enzyme. Since the crystal structure of SE is unknown for all species, we built a 3D enzyme model of T. cruzi SE by homology modeling. Based on this model, we carried out docking, molecular dynamics, and MM/PBSA calculations and the results were compared with those found for the reference inhibitor compound terbinafine (Tbf). The binding free energy values allowed the discrimination between accumulators and non-accumulators of squalene compounds, in agreement with the experimental findings. Pairwise residue free energy decomposition showed that the key amino acids involved in inhibitor binding for TZHs and Tbf were the same. Also, molecular superposition analysis between these compounds revealed high structural similarity. In addition, we proposed a pharmacophore model for T. cruzi SE inhibitors, which confirmed that TZHs and Tbf share chemical features with respect to their biochemical interaction characteristics at similar positions in 3D space. All theoretical calculations suggest that the experimentally observed squalene accumulation is produced by T. cruzi SE inhibition.

One-pot synthesis of monodisperse dual-functionalized polyethylene glycols through macrocyclic sulfates by Xiaoyan Lv; Xing Zheng; Zhigang Yang; Zhong-Xing Jiang (8537-8545).
Dual-functionalization of monodisperse oligoethylene glycols, especially hetero-functionalization, provides a series of highly valuable intermediates for life and materials sciences. However, the existing methods for the preparation of these compounds suffer excessive protecting and activating group manipulation as well as tedious purification. Here, a one-pot dual-substitution strategy with macrocyclic sulfates of polyethylene glycols as the key intermediates was developed for the convenient and scalable preparation of a series of homo-functionalized and hetero-functionalized oligoethylene glycols in just 1 step. A high synthetic efficacy was achieved by avoiding the protecting and activating group manipulation and the intermediate purification.

A novel and efficient method for the synthesis of arylacetamides by the reactions of gem-difluoroalkenes with N,N-dialkylformamides, and primary and secondary amines with the assistance of KOtBu and water was developed.

Sulfinates and thiocyanates triggered 6-endo cyclization of o-alkynylisocyanobenzenes by Onnicha Khaikate; Jatuporn Meesin; Manat Pohmakotr; Vichai Reutrakul; Pawaret Leowanawat; Darunee Soorukram; Chutima Kuhakarn (8553-8558).
Diverse 2-sulfonyl- and 2-thiocyanato-3-substituted quinolines were synthesized from o-alkynylisocyanobenzenes by nucleophilic addition of the respective sulfinate sodium salts and ammonium thiocyanate to the isocyanide moiety followed by cyclization. The salient features of the methodology include metal-free, ambient temperature and mild reaction conditions, ease of reagent handling, and broad functional group tolerance.

Highly reactive bis-cyclooctyne-modified diarylethene for SPAAC-mediated cross-linking by Alexander V. Strizhak; Krishna Sharma; Oleg Babii; Sergii Afonin; Anne S. Ulrich; Igor V. Komarov; David R. Spring (8559-8564).
Photoisomerizable diarylethenes equipped with triple bonds are promising building blocks for constructing bistable photocontrollable systems. Here we report on the design, synthesis and application of a cross-linking reagent which is based on a diarylethene core and features two strained cyclooctynes. High reactivity of the cyclooctyne rings in catalyst-free 1,3-dipolar cycloaddition reactions was suggested to stem from the additional strain imposed by the fused thiophene rings. This hypothesis was confirmed by quantum chemical calculations.

Visible light-promoted difluoromethylthiolation of aryldiazonium salts by Wengui Wang; Shuxiang Zhang; Huaiqing Zhao; Shoufeng Wang (8565-8568).
Difluoromethylthiolation of aryldiazonium salts under photocatalytic conditions with a shelf-stable, easily prepared and inexpensive reagent, PhSO2SCF2H was described. A variety of difluoromethylthioethers were obtained utilizing aryldiazonium salts containing different functional groups. Aryldiazonium salts with a heteroarene moiety were tolerated. Fluorescence quenching experiments indicated that both oxidative and reductive quenching cycles occurred during this process.

Understanding coordination equilibria in solution and gel-phase [2]rotaxanes by Sean W. Hewson; Kathleen M. Mullen (8569-8578).
This paper describes the use of the copper(i)-catalysed azide–alkyne cycloaddition reaction in an active metal template methodology for the synthesis of [2]rotaxanes both in solution and on polymer resins. The use of TentaGel resin beads has allowed the rotaxane functionalised solid supports to be characterized by 1H HR MAS NMR. Whereas previous research in the assembly of interlocked architectures on surfaces are complicated by the concurrent attachment of large proportions of non-interlocked byproducts, in this example over 80% of the functionalization is the desired interlocked rotaxane. The inclusion of zinc metalloporphyrins in the structure of the [2]rotaxane thread allowed the position of the macrocycle to be ‘switched’ upon the addition of competing base, removal of the metal or appropriate choice of solvent. Investigations into the pseudocooperative effect the mechanical bond has on the metalloporphyrin-macrocycle coordination equilibrium were performed and the associated effective molarity in this [2]rotaxane was calculated to be 120 mM.

Expedient synthesis of trifunctional oligoethyleneglycol-amine linkers and their use in the preparation of PEG-based branched platforms by Sylvain Ursuegui; Jérémy P. Schneider; Claire Imbs; Florian Lauvoisard; Marta Dudek; Michel Mosser; Alain Wagner (8579-8584).
We designed a convergent synthesis pathway that provides access to trifunctional oligoethyleneglycol-amine (OEG-amine) linkers. By applying the reductive coupling of a primary azide to bifunctional OEG-azide precursors, the corresponding symmetrical dialkylamine bearing two homo-functional end chain groups and a central nitrogen was obtained. These building blocks bear minimal structural perturbation compared to the native OEG backbone which makes them attractive for biomedical applications. The NMR investigations of the mechanism process reveal the formation of nitrile and imine intermediates which can react with the reduced free amine form. Additionally, these trifunctional OEG-amine linkers were employed in a coupling reaction to afford branched multifunctional PEG dendrons which are molecularly defined. These discrete PEG-based dendrons (n = 16, 18 and 36) could be useful for numerous applications where multivalency is required.

Iridium-catalyzed [4 + 2] annulation of 1-arylindazolones with α-diazo carbonyl compounds: access to indazolone-fused cinnolines by Chikkagundagal K. Mahesha; Devesh S. Agarwal; Pidiyara Karishma; Datta Markad; Sanjay K. Mandal; Rajeev Sakhuja (8585-8595).
An efficient one-pot Ir-catalyzed method was developed for the synthesis of indazolone-fused cinnolines by [4 + 2] annulation of 1-arylindazolones with α-diazo carbonyl compounds via sequential C–H activation/carbene insertion/cyclization in a tandem manner. This method has excellent tolerance towards electron-withdrawing and electron-donating functional groups on 1-arylindazolone. This method was also found to be applicable to cyclic α-diazo carbonyl compounds.

Pd-Catalyzed tandem reaction of N-(2-cyanoaryl)benzamides with arylboronic acids: synthesis of quinazolines by Jianghe Zhu; Yinlin Shao; Kun Hu; Linjun Qi; Tianxing Cheng; Jiuxi Chen (8596-8603).
The synthesis of 2,4-disubstituted quinazolines by a palladium-catalyzed reaction of arylboronic acids with N-(2-cyanoaryl)benzamides has been developed with moderate to excellent yields. The method shows good functional group tolerance. In particular, halogen and hydroxyl substituents, which are amenable for further synthetic elaborations, are well tolerated. Moreover, the present synthetic route could be readily scaled up to gram quantity without difficulty. The mechanism possibly involves nucleophilic addition to the nitrile function, forming an imine intermediate followed by an intramolecular addition to the amide and dehydration to the quinazoline ring.

Multimerization of DAB-1 onto Au GNPs affords new potent and selective N-acetylgalactosamine-6-sulfatase (GALNS) inhibitors by C. Matassini; C. Vanni; A. Goti; A. Morrone; M. Marradi; F. Cardona (8604-8612).
Gold glyconanoparticles (Au GNPs) decorated with the natural iminosugar DAB-1 at different densities are reported. These new multivalent iminosugar architectures strongly and selectively inhibit N-acetylgalactosamine-6-sulfatase (GALNS), whose deficiency is connected to the lysosomal storage disease Morquio A. The combination of the dendrimeric technique with the synthetic strategy employed for Au GNP preparation allowed the enhancement of the multivalent presentation of the iminosugar onto the surface of gold nanoparticles, which resulted in the best GALNS inhibitor reported to date (IC50 = 520 nM).

Porphyrin–ferrocene conjugates for photodynamic and chemodynamic therapy by Zhitao Lei; Xiaoyu Zhang; Xiaohua Zheng; Shi Liu; Zhigang Xie (8613-8619).
Chemodynamic therapy can convert endogenous hydrogen peroxide (H2O2) at tumor localization into the toxic hydroxyl radical (˙OH) destroying tumor cells. Photodynamic therapy as a noninvasive method utilizes photosensitizers (PSs) to convert O2 into cytotoxic reactive oxygen species (e.g., 1O2) upon laser irradiation, which is dependent on the content of oxygen. The combination of the two therapeutic strategies on a single platform can enhance the anticancer effect. Herein, we report a porphyrin–ferrocene theranostic agent for combined photodynamic and chemodynamic therapy. Compared to monotherapy, the as-prepared porphyrin–ferrocene conjugates exhibit superior efficiency and potency in killing cancer cells at low drug doses. This study suggests the rational design of molecular structures as multifunctional therapeutics for potential clinic application.

A novel and efficient aminomethylation approach has been developed for the regioselective functionalization of imidazoheterocycles under metal-free conditions. A wide range of imidazoheterocycles and 2/4-aminoazaheterocycles successfully provided corresponding aminomethylated imidazoheterocycles in moderate to excellent (33–80%) yields. The isotopic labelling study suggested that TBHP played a dual role as both an oxidant and a methylene source in this transformation. The developed protocol follows a radical pathway which is supported by radical trapping experiments.

Pd(ii) catalyzed direct C–H carbonylative annulation of N,1-diaryl-1H-tetrazol-5-amines and N,4-diaryl-4H-1,2,4-triazol-3-amines gave the corresponding triazole and tetrazole fused quinazolinones in good yields. This methodology offers a convenient method for the synthesis of these important heterocyclic scaffolds in a highly atom economical process. On the mechanistic aspect weakly nucleophilic triazole and tetrazole moieties function as both directing as well as intramolecular nucleophiles. The catalytically active C–H activated intermediate dimeric Pd complex was isolated and characterized which on exposure to CO gas gave the corresponding tetrazole fused quinazolinone derivative. On the basis of isolation of the intermediate and observed kinetic isotope effects, a mechanism has been proposed for the C–H activated direct carbonylative annulation reaction.

Accessing 4-oxy-substituted isoquinolinones via C–H activation and regioselective migratory insertion with electronically biased ynol ethers by Brandon L. Coles-Taylor; Maximilian S. McCallum; J. Scott Lee; Brian W. Michel (8639-8646).
The rhodium-catalyzed C–H activation and annulation with ynol ethers to directly provide 4-oxy substituted isoquinolinones is reported. The polarized nature of ynol ethers provides an electronic bias for controlling the regioselectivity of the migratory insertion process. While the highly reactive nature of ynol ethers presents a challenge, mild conditions were found to provide product in moderate to good yield. Utility was demonstrated by application in the synthesis of a prolyl-4-hydroxylase inhibitor framework.

Correction: An unprecedented tandem synthesis of fluorescent coumarin-fused pyrimidines via copper-catalyzed cross-dehydrogenative C(sp3)–N bond coupling by Santosh Kumari; S. M. Abdul Shakoor; Sadhika Khullar; Sanjay K. Mandal; Rajeev Sakhuja (8647-8648).
Correction for ‘An unprecedented tandem synthesis of fluorescent coumarin-fused pyrimidines via copper-catalyzed cross-dehydrogenative C(sp3)–N bond coupling’ by Santosh Kumari et al., Org. Biomol. Chem., 2018, 16, 3220–3228.

Back cover (8649-8650).