Organic & Biomolecular Chemistry (v.17, #11)

Front cover (2829-2830).

Contents list (2831-2838).

Saturated bioisosteres of benzene: where to go next? by Pavel K. Mykhailiuk (2839-2849).
The replacement of para-substituted benzenes with saturated bi- and polycyclic bioisosteres – bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane and cubane, – often increases the potency, selectivity and metabolic stability of bioactive compounds. The currently remaining challenge for chemists, however, is to rationally design, synthesize and validate the saturated bioisosteres for ortho- and meta-substituted benzenes.

Recent advances in the synthesis of C2-spiropseudoindoxyls by Yanling Ji; Xianghong He; Cheng Peng; Wei Huang (2850-2864).
Compared with the numerous reviews on the construction of C3 spirooxindoles, few reviews have examined the synthesis of structurally analogous C2-spiropseudoindoxyl derivatives. This scaffold has attracted substantial attention from synthetic chemists because of its relevance to medicinal chemistry. This review summarizes the recent progress in the synthesis of many heterocycle and carbocycle fused spiropseudoindoxyl compounds. The article is divided into sections according to the type of catalysis, including metal catalysis, high-iodine reagent mediation, and organic catalysis. We also discuss challenges and future directions based on the progress in the field. We believe that this review will update researchers focused on the synthesis of C2-spiropseudoindoxyl compounds and will encourage further growth in this field.

Recent advances in metal-free aerobic C–H activation by André Shamsabadi; Vijay Chudasama (2865-2872).
Herein we describe recent developments in selective, metal-free, dioxygen-induced C–H activation. This method of activating C–H bonds is an attractive alternative to traditional methodologies as it uses dioxygen, an inherently sustainable and widely accessible oxidant, in place of expensive or toxic metals and/or hazardous peroxides. Reactions developed on the basis of using aerobic C–H activation are also discussed.

Photoredox-catalyzed cascade annulation of N-propargylindoles with sulfonyl chlorides: access to 2-sulfonated 9H-pyrrolo[1,2-a]indoles by Pengbo Zhang; Shanshan Shi; Xia Gao; Shuang Han; Jinming Lin; Yufen Zhao (2873-2876).
A photoredox-catalyzed cascade radical reaction of N-propargylindoles and sulfonyl chlorides to 2-sulfonated 9H-pyrrolo[1,2-a]indoles was described. By the direct use of commercially available sulfonyl chlorides as radical precursors, this transformation proceeded smoothly to afford the corresponding products in moderate to good yields under external oxidant-free conditions at room temperature.

Synthesis of trisaccharide repeating unit of fucosylated chondroitin sulfate by Haiqing He; Dong Chen; Xiaomei Li; Chengji Li; Jin-Hua Zhao; Hong-Bo Qin (2877-2882).
We described the chemical synthesis of a sulfated trisaccharide repeating unit of fucosylated chondroitin sulfate (FCS), which has significant anticoagulant activity. Well-functionalized monosaccharides were readily prepared, and highly efficient glycosylations using a common activator (NIS/TfOH) were also presented. The synthesized trisaccharide 4 could be used to extend oligosaccharide sequences.

Thiosquaramide-catalysed asymmetric double Michael addition of 2-(3H)-furanones to nitroolefines by Mengchen Yang; Chen Chen; Xing Yi; Yuan Li; Xiaoqin Wu; Qingshan Li; Shurong Ban (2883-2886).
New chiral thiosquaramides and their applications in catalytic asymmetric double addition of 5-methyl-2(3H)-furanones to nitroolefins were described. Enantiomerically enriched 2,4,4-trisubstituted butenolides bearing a quaternary stereogenic center could be smoothly constructed with high diastereoselectivities (up to >99 : 1 dr) and excellent enantioselectivities (up to 95% ee) under mild conditions.

Here, we report a facile permeability assay to quantitatively evaluate the membrane permeability of multiple peptides in parallel. With a fluorogenic click reaction between azidocoumarin and a terminal alkyne tag introduced on a peptide, the peptide that crossed an artificial membrane or a cell monolayer was quantitatively detected. The method allows a rapid measurement of the permeability of multiple compounds on a plate reader even in the presence of a complex mixture of biological molecules.

The asymmetric construction of CF3-containing spiro-thiazolone-pyrrolidine compounds via [3 + 2] cycloaddition by Boyu Li; Jikun Liu; Fengyun Gao; Mengmeng Sun; Yifei Guo; Yuan Zhou; Dongwa Wen; Yabo Deng; Hui Chen; Kairong Wang; Wenjin Yan (2892-2895).
The first organocatalytic method for the asymmetric construction of CF3-containing spiro-thiazolone-pyrrolidine compounds has been developed. This is one of the very few methods to reach spiro-thiazolones, and afforded the products in excellent yields and stereoselectivities catalysed by only 1 mol% cinchona alkaloid-derived catalyst.

Many pyridine syntheses have been developed to date. In this study, we focused on pyridine synthesis with 1,5-diketone derivatives and hydroxylamine. Treatment of simple 1,5-diketoalkanes and hydroxylamine in basic or acidic conditions gave aldol adducts without any pyridine compounds. However, by screening the reaction conditions, we found that acidic conditions produced via the formation of oxime intermediates derived from 1,5-diketoalkanes allowed the formation of the corresponding pyridine derivatives. This is the first example of 2,4,6-trialkylpyridine synthesis from quite simple 1,5-diketoalkanes. In order to demonstrate the utility of the reaction, we demonstrated the synthesis of pyridine derivatives and the total synthesis of a 6-substituted pyridyl-natural product, anibamine. This was achieved by following the above methodology using a reported compound as the starting material to give the product in 12% yield.

Modular synthesis and modification of novel bifunctional dendrons by Ludovico G. Tulli; Daniela Miranda; Cameron C. Lee; Yang Sullivan; Robert Grotzfeld; Gregory Hollingworth; Rainer Kneuer; Alexei S. Karpov (2906-2912).
Herein, we report the design and synthesis of two novel bifunctional dendrons bearing multiple amine termini at the periphery and an azide at the focal point. Copper-catalyzed alkyne–azide cycloaddition enabled modular dendritic scaffold assembly resulting in a first generation dendron carrying six amines and a second generation dendron carrying eighteen amines. Peripheral amines were labeled with multiple copies of a metal isotope, whereas the azide functionality at the focal point was employed in conjugation to a single anti-human CD4 antibody. We demonstrated that the highly monomeric first generation dendron–antibody conjugate selectively detected CD4+ T cells in the PMBC culture.

Tetrahydroquinolines by the multicomponent Povarov reaction in water: calix[n]arene-catalysed cascade process and mechanistic insights by Terezinha Ruth Marques Rezende; Jodieh Oliveira Santana Varejão; Anna Luísa Lacerda de Almeida Sousa; Sandra Milena Bonilla Castañeda; Sergio Antonio Fernandes (2913-2922).
The catalyst p-sulfonic acid calix[4]arene was effectively used in the three-component Povarov reaction between aromatic anilines and two equivalents of 2,3-dihydrofuran to obtain furano[3,2-c]-1,2,3,4-tetrahydroquinolines. These reactions proceeded efficiently using water as a green solvent and nontoxic catalysts that could be efficiently reused; the reactions were metal-free and used only inexpensive and easily available compounds. Together with a simple workup procedure, these advantages make this protocol a very efficient and green alternative to the traditional methods for constructing tetrahydroquinoline structures, through the formation of two new C–C bonds and one C–N bond. Isotopic labelling experiments revealed the mechanism for the Povarov reactions, showing that the reaction proceeds through a sequence of steps via ionic intermediates, and the proposed reaction mechanism was validated.

Synthesis and antitubercular activity of 1- and 3-substituted benzo[g]isoquinoline-5,10-diones by Robert J. Smets; Eveline Torfs; Filip Lemière; Paul Cos; Davie Cappoen; Kourosch Abbaspour Tehrani (2923-2939).
In this study, a small library of twenty benzo[g]isoquinoline-5,10-diones were synthesized in a novel straightforward approach, starting from 2-methyl-1,4-naphthoquinone (vitamin K). An intramolecular Heck reaction of a N-vinylacetamide was a crucial step in the synthetic route, at which the combination of cesium carbonate and a bulky, electron rich trialkylphosphine (tBuCy2P.HBF4) provided high 6-endo-trig selectivity. The anti-tubercular activity against Mycobacterium tuberculosis H37Ra and acute cytotoxicity against J774 A.1 macrophages were studied. From the structure activity relationship, it could be derived that in general the substitution of position 3 yielded analogs with a higher antitubercular potency. Among these, two analogs, 27a and 27b, showed remarkable activity with minimal inhibition concentrations of respectively 28.92 μM and 1.05 μM, and acute cytotoxic concentrations of >128 μM and 34.85 μM. In addition, the analogs and their possible metabolites were evaluated using a Vitotox™ assay to study the possibility of genotoxicity. Results indicated that none of the evaluated analogs and their possible metabolites showed early signs of genotoxicity.

N-Arylations of trifluoromethylated N-acylhydrazones with diaryliodonium salts as arylation reagents by Huaiyuan Zhang; Ke-Hu Wang; Junjiao Wang; Yingpeng Su; Danfeng Huang; Yulai Hu (2940-2947).
A novel and efficient N-arylation of trifluoromethylated N-acylhydrazones is described by using diaryliodonium salts as arylation reagents in the presence of copper salts. A wide variety of N-aryl acylhydrazones are obtained with good to excellent yields under mild reaction conditions.

Rhodium-catalyzed direct C–H bond alkynylation of aryl sulfonamides with bromoalkynes by Hongcen Hou; Yongli Zhao; Shouzhi Pu; Junmin Chen (2948-2953).
Herein we report a novel rhodium-catalyzed ortho-mono-alkynylation of aryl sulfonamides. The reactions of N-tosylacetamides with triisopropylsilyl (TIPS)-substituted bromoalkyne are catalyzed by a [(Cp*RhCl2)2] complex without cyclization, forming ortho-(1-alkynyl) benzenesulfonamides. While triethylsilyl or trimethylsilyl (TES or TMS)-substituted bromoalkyne was also amenable to the alkynylation, affording six-membered benzosultams via the alkynylation/intramolecular cyclization cascade reaction. The present protocol displays high functional group tolerance and broad substrate scope under an air atmosphere in good to high yields. Mechanistic studies indicate that the reaction proceeds by a turnover limiting C–H activation step and a plausible mechanism was proposed.

Structure elucidation and biosynthetic gene cluster analysis of caniferolides A–D, new bioactive 36-membered macrolides from the marine-derived Streptomyces caniferus CA-271066 by Ignacio Pérez-Victoria; Daniel Oves-Costales; Rodney Lacret; Jesús Martín; Marina Sánchez-Hidalgo; Caridad Díaz; Bastien Cautain; Francisca Vicente; Olga Genilloud; Fernando Reyes (2954-2971).
Bioassay-guided isolation based on the antifungal activity of a culture broth of the marine-derived actinomycete Streptomyces caniferus CA-271066 led to the discovery of new 36-membered polyol macrolides, caniferolides A–D (1–4). Their connectivity was determined by spectroscopic methods including ESITOF-MS and 1D/2D NMR. The relative stereochemistry of each stereocluster in these compounds was established using NOE analysis, the universal database method and J-based configuration analysis, further assisted by comparisons with NMR data of structurally related macrolides. Genome sequencing followed by detailed bioinformatics analysis led to the identification of the corresponding biosynthetic gene cluster and allowed the prediction of the stereochemical outcome of their biosynthesis, confirming the relative stereochemistry of each stereocluster already determined by NMR and establishing their stereochemical relationship, ultimately rendering the absolute configuration of all chiral centers. Furthermore, based on our results and already published data, it has been possible to derive the complete absolute configuration of the related macrolides PM100117 and PM100118, astolides A and B, and deplelides A and B. Caniferolides A–D have shown pronounced antifungal activity against Candida albicans and Aspergillus fumigatus alongside antiproliferative activity against five human tumoral cell lines.

Zinc-catalyzed regioselective C–P coupling of p-quinol ethers with secondary phosphine oxides to afford 2-phosphinylphenols by Ming Zhang; Xiaoyu Jia; Haowei Zhu; Xutong Fang; Chenyi Ji; Sizhuo Zhao; Li-Biao Han; Ruwei Shen (2972-2984).
The zinc triflate-catalyzed highly regioselective C–P cross coupling reaction of p-quinol ethers with secondary phosphine oxides is reported. The reaction provides a facile alternative method for the synthesis of 2-phosphinylphenols in good to high yields. Mechanistically, zinc triflate may serve as an oxophilic σ-Lewis acid to activate the C–O bond in p-quinol ether first. Then the regioselective attack of the phosphorus nucleophile at the α-carbon position takes place to form the C–P bond and give the product. In addition, α-alkynyl substituted p-quinol ethers also react with secondary phosphine oxides in the same reaction mode to give 6-alkynyl 2-phosphinylphenols in the presence of the zinc catalyst.

Understanding exo-selective Diels–Alder reactions involving Fischer-type carbene complexes by Jorge Juan Cabrera-Trujillo; Israel Fernández (2985-2991).
The factors controlling the selectivity of the Diels–Alder cycloaddition reactions involving Fischer-type carbene complexes and cyclopentadiene have been explored computationally by means of density functional theory calculations. To this end, the influence of the substituents directly attached to the carbene ligand on the endo : exo ratio has been compared to the available experimental data and quantitatively analysed in detail by means of the combination of the activation strain model of reactivity and energy decomposition analysis methods. The insight gained in this computational study may be important for the rational design of exo-selective Diels–Alder reactions.

Aptamer-guided acridine derivatives for cervical cancer by Josué Carvalho; Jéssica Lopes-Nunes; Ana Catarina Lopes; Maria Paula Cabral Campello; António Paulo; João A. Queiroz; Carla Cruz (2992-3002).
DNA aptamers represent a way to target cancer cells at a molecular level and continue to be developed with a view to improve treatment and imaging in cancer medicine. AT11-L0, derived from the DNA sequence AT11, forms a single major parallel G-quadruplex (G4) conformation and exhibits an anti-proliferative activity similar to that of AT11 and AS1411 aptamers. On the other side, acridine orange derivatives represent a valuable class of G4 ligands. Herein, we evaluate AT11-L0 G4 as a supramolecular carrier for the delivery of acridine ligands C3, C5 and C8 to HeLa cancer cells. The CD titrations suggest no changes in the chiroptical signal upon addition of an excess of ligands maintaining the parallel G4 topology and C8 stabilizes the structure for more than 20 °C. All the ligands exhibit high affinity (micromolar range) towards AT11-L0 G4, and the respective complexes against nucleolin (nanomolar range) suggesting that the ligands do not negatively affect the recognition of the nucleolin by AT11-L0 G4. NMR studies showed that AT11-L0 forms a G4 containing four G-tetrad layers. Ligand C8 binds AT11-L0 G4 through π–π stacking of the acridine moiety onto the top-tetrad with the involvement of additional interactions with the ligand's side chain and iodobenzene ring. In vitro, the complexes lowered the ligand's cytotoxicity towards non-malignant cells but have a weak inhibitory effect in HeLa cancer cells, except for the AT11-L0-C5 complex. All complexes are efficiently internalized into nucleolin-positive HeLa cells. Overall, these results suggest that AT11-L0 can act as an aptamer by targeting nucleolin and a delivery system of cytotoxic ligands for cervical cancer.

An efficient preparation of β-ketophosphine oxides from alkynylphosphine oxides with benzaldehyde oxime as a hydroxide source by Lu-Lu Chen; Jing-Wen Zhang; Wan-Wan Yang; Pei Chen; Dan-Yun Chen; Yan-Bo Wang (3003-3009).
An effective and facile transition-metal-free method has been developed for the synthesis of β-ketophosphine oxides from alkynylphosphine oxides with benzaldehyde oxime as a hydroxide surrogate. The current methodology provides simple access to various β-ketophosphine oxides in moderate to excellent yields with a broad substrate scope.

Expanding the “minimalist” small molecule tagging approach to different bioactive compounds by Wenjie Lang; Chaonan Yuan; Biwei Zhu; Sijun Pan; Jian Liu; Jie Luo; Shikun Nie; Qing Zhu; Jun-Seok Lee; Jingyan Ge (3010-3017).
“Minimalist” small molecule tagging (MSMT) is a promising approach that easily converts bioactive compounds into affinity-based probes (AfBPs) for proteomic studies. In this work, seven bioactive compounds targeting diversified protein classes were installed with “minimalist” linkers through common reactions to generate the corresponding AfBPs. These probes were evaluated for cell-based protein profiling and target validation. Among them, the entinostat-derived probe EN and the camptothecin-derived probe CA were further utilized in cellular imaging and SILAC-based large-scale target identification. Our extensive studies suggest that the “minimalist” small molecule tagging approach could be expanded to different classes of bioactive compounds for modification into AfBPs as a dual functional tool for both proteomics and cellular imaging.

Synthesis and characterization of new D–π-A and A–π-D–π-A type oligothiophene derivatives by Fabiana Pandolfi; Daniele Rocco; Leonardo Mattiello (3018-3025).
In this work, we present a series of newly synthesized conjugated oligothiophene derivatives, with different numbers of central thiophene units, and different donor/acceptor architectures. Electrochemical and spectroscopic data have also been reported. We used thiophene or bithiophene as central donor core units, 3-octylthiophenes as π-bridge and solubilizing sub-units, and ethyl cyanoacetate or rhodanine moieties as acceptor end groups, in order to get D–π-A and A–π-D–π-A molecular architectures. The length of the synthesized oligothiophenes ranges from three to eight thiophene units, a variety that is sufficient to put in evidence different optical and electrochemical characteristics as well as semiconducting characteristics. Oligothiophene compounds can be regarded not only as models for the study of structure–property relationships relative to polythiophenes, but also they present a large number of applications in the field of organic electronics (i.e.: as donors in bulk-heterojunction solar cells and hole-transporting layer materials in perovskite solar cells, among others).

Dicyclohexylurea derivatives of amino acids as dye absorbent organogels and anion sensors by Karabi Roy; Suvankar Ghosh; Monikha Chetia; Priyadarshi Satpati; Sunanda Chatterjee (3026-3039).
Dicyclohexyl urea (DCU) derivatives of amino acids Fmoc-Phe-DCU (M1), Fmoc-Phg-DCU (M2) and Fmoc-Gaba-DCU (M3) have been shown to form phase selective, thermoreversible and mechanically robust gels in a large range of organic solvents. This is the first report of low molecular weight gelators (LMWG) from DCU derivatives of amino acids. The self-assembly mechanism of the organogels has been probed using concentration dependent 1H NMR, DMSO titration 1H NMR, fluorescence, FTIR, PXRD and FESEM techniques. Self-assembly leading to gelation process is mainly driven by hydrophobicity and π–π stacking interactions in between Fmoc groups. Interestingly, the gels can absorb several kinds of organic dyes efficiently and can be reused for dye absorption for multiple cycles. Additionally, M1–M3 act as sensors for anions like fluoride, acetate and hydroxide, for which they have specific fluorescence response. Gel formation by M1–M3 is completely arrested in the presence of fluoride. The possible binding mode of fluoride has been delineated using DFT studies. Calculations suggest, involvement of urea NH in a six membered intramolecular hydrogen bond, rendering it unavailable for fluoride binding. Backbone –NH of the amino acids of M1–M3 is responsible for fluoride binding. The reported small, economically viable, synthetically facile molecules not only enrich the repertoire of LMWG molecules, but can have multifaceted applications.

A simple and new multicomponent reaction for the one-pot synthesis of substituted 4-arylidene imidazolin-5-ones from l-amino acid methyl esters, iso-, isothio- or isoselenocyanates, and α-bromoketones is demonstrated. Isolation of thiohydantoin and 5-benzylidene 2-thioxoimidazolidin-4-one intermediates revealed a possible reaction mechanism. The strategy was further extended to the synthesis of 2-iminothiazolines and 2-thioxoimidazolin-4-ones.

Synthesis and nano-Pd catalyzed chemoselective oxidation of symmetrical and unsymmetrical sulfides by Xing Li; Jia Du; Yongli Zhang; Honghong Chang; Wenchao Gao; Wenlong Wei (3048-3055).
A highly chemoselective, efficient and nano-Pd catalyzed protocol for the rapid construction of sulfoxides and sulfones via the oxidation of symmetrical and unsymmetrical sulfides using H2O2 as an oxidant has been developed, respectively. The ready availability of starting materials, easy recovery and reutilization of the catalyst, wide substrate scope, and high yields make this protocol an attractive alternative. The process also involves the metal-free and microwave-promoted synthesis of symmetrical diarylsulfides, and FeCl3-mediated preparation of symmetrical diaryldisulfides through the reaction of arenediazonium tetrafluoroborates with Na2S·9H2O as a sulfur source. In addition, unsymmetrical sulfides were generated via the K2CO3-mediated reaction of arenediazonium tetrafluoroborates with symmetrical disulfides.

Facile synthesis of 2-azaspiro[3.4]octane by Subbiah Ramesh; Ramadas Balakumar; John R. Rizzo; Tony Y. Zhang (3056-3065).
Our annulation strategy utilized for the synthesis of 2-azaspiro[3.4]octane is explained. Three successful routes for the synthesis were developed. One of the approaches involved annulation of the cyclopentane ring and the remaining two approaches involved annulation of the four membered ring. All three approaches employ readily available starting materials with conventional chemical transformations and minimal chromatographic purifications to afford the title compound. The merits and limitations of the three approaches are also discussed.

Correction for ‘The expanding spectrum of diketopiperazine natural product biosynthetic pathways containing cyclodipeptide synthases’ by Paul Borgman et al., Org. Biomol. Chem., 2019, DOI: 10.1039/c8ob03063d.

Back cover (3067-3068).