Organic & Biomolecular Chemistry (v.17, #19)

Front cover (4665-4665).

Inside front cover (4666-4666).

Contents list (4667-4675).

Chemical composition of DNA-encoded libraries, past present and future by Paige Dickson; Thomas Kodadek (4676-4688).
DNA-encoded libraries represent an exciting and powerful modality for high-throughput screening. In this article, we highlight recent important advances in this field and also suggest some important directions that would make the technology even more powerful.

Metal-catalysed reactions enabled by guanidine-type ligands by Xi-Yang Cui; Choon-Hong Tan; Dasheng Leow (4689-4699).
Guanidines, which exist widely in nature, have been frequently utilised as strong Brønsted bases in organic chemistry. As ligands, guanidines can have different coordination modes with the metal center. However, the exploitation of these guanidine complexes as catalysts has been much less successful. The anionic counterpart of guanidine, which is known as guanidinate, is also able to function as a ligand. The catalytic activities of metal-guanidinate complexes are of great interest to chemists. The potential of catalytic guanidine or guanidinate metal complexes to catalyse unique chemical transformations is immensely promising. This field is currently being pursued with great interest by synthetic organic chemists. In this review, the representative reactions enabled by guanidine and guanidinate metal complexes are highlighted.

N-Heterocyclic carbene (NHC)-catalyzed diastereoselective synthesis of multisubstituted sulfenylated indanes has been developed. In the presence of 1 mol% NHC, various thiols underwent the sulfa-Michael–Michael cascade reaction with benzenedi(enones) efficiently to form the carbon–sulfur bond and construct sulfenylated indanes in good to excellent yields with high diastereoselectivity. In addition, the NHC-catalyzed sulfa-Michael-aldol cascade reaction between o-formyl chalcone and thiols has also been demonstrated to afford sulfenylated indanes with a free hydroxyl group in moderate yields and good diastereoselectivity.

β-Glucuronidase triggers extracellular MMAE release from an integrin-targeted conjugate by Paula López Rivas; Christoph Müller; Christian Breunig; Torsten Hechler; Andreas Pahl; Daniela Arosio; Laura Belvisi; Luca Pignataro; Alberto Dal Corso; Cesare Gennari (4705-4710).
A non-internalizing αvβ3 integrin ligand was conjugated to the anticancer drug MMAE through a β-glucuronidase-responsive linker. In the presence of β-glucuronidase, only the conjugate bearing a PEG4 spacer inhibited the proliferation of integrin-expressing cancer cells at low nanomolar concentrations, indicating important structural requirements for the efficacy of these therapeutics.

Total synthesis of (±)-epi-stemodan-13α,17-diol by Song Chen; Ting Chen; Guanggen Liu; Xiao Wang; Guili Zhu; Yongjiang Liu; Shaomin Fu; Bo Liu (4711-4714).
Stemodan-13α,17-diol is a natural stemodane-type diterpenoid isolated from Stemodia chilensis. Herein we report the total synthesis of its epimer, stemodan-13β,17-diol, by applying titanium-mediated polyene cyclization and iron-catalyzed [5 + 2] cycloaddition as the key transformations to expeditiously install the molecular scaffold.

Acid catalysed rearrangement of isobenzofurans to angularly fused phthalides by Bhavani Shankar Chinta; Soniya Gandhi; Beeraiah Baire (4715-4719).
An acid catalysed, cascade process for the construction of angularly fused polycyclic phthalides from isobenzofurans under transition metal free conditions has been reported. This process is very general for diverse gem-disubstituted isobenzofuran substrates. Control experiments supported the mechanism as the nucleophilic attack of the carboxylate onto the acid activated furan ring for the simultaneous ring closing–ring opening cascade followed by dehydration. This method serves as a greener alternative for the synthesis of angularly fused polycyclic phthalides.

Active site labeling of fatty acid and polyketide acyl-carrier protein transacylases by Tony D. Davis; Jennifer M. Michaud; Michael D. Burkart (4720-4724).
Metabolic engineering of fatty acids and polyketides remains challenging due to unresolved protein–protein interactions that are essential to synthase activity. While several chemical probes have been developed to capture and visualize protein interfaces in these systems, acyl carrier protein (ACP) transacylase (AT) domains remain elusive. Herein, we combine a mutational strategy with fluorescent probe design to expedite the study of AT domains from fatty acid and polyketide synthases. We describe the design and evaluation of inhibitor-inspired and substrate-mimetic reporters containing sulfonyl fluoride and β-lactone warheads. Moreover, specific active-site labeling occurs by optimizing pH, time, and probe concentration, and selective labeling is achieved in the presence of inhibitors of competing domains. These findings provide a panel of AT-targeting probes and set the stage for future combinatorial biosynthetic and drug discovery initiatives.

Synthesis of cyclic gem-dinitro compounds via radical nitration of 1,6-diynes with Fe(NO3)3·9H2O by Xiaofei Yi; Kai Chen; Wei Chen; Wanzhi Chen; Miaochang Liu; Huayue Wu (4725-4728).
Cyclic gem-dinitro compounds were obtained via nitration of 1,6-diynes using Fe(NO3)3·9H2O as the nitrating agent. The reaction proceeds at room temperature using a cheap nitrating agent. A number of gem-dinitro cyclic compounds were obtained in moderate to good yields. The reaction offers an easy and convenient protocol to prepare gem-dinitro compounds, which are not easily obtained via the known procedures.

Substituent-controlled racemization of dissymmetric coordination capsules by Kentaro Harada; Ryo Sekiya; Takeshi Maehara; Takeharu Haino (4729-4735).
We report the effect of substituents (methyl, isopropyl, methoxy, and methoxyphenyl) at the 6′-position of the 2,2′-bipyridyl arms on the racemization of dissymmetric coordination capsules 1a–d. When the capsules included (R)-4,4′-diacetoxy-2,2′-benzyloxycarboxyl-biphenyl ((R)-3), the (M)-helical conformer was enriched with a diastereomeric excess (de%) of >98% for 1a, 31% for 1b, 81% for 1c and 75% for 1d. The entrapped guests in 1a, 1c and 1d can be removed by washing the solid containing the host–guest complexes with diethyl ether. The rate of racemization in THF follows the order of 1c > 1d≫1a. X-ray crystal structural analysis and density functional theory calculation of model complex 4c indicate a distorted tetrahedral coordination of the Cu(i) center, and UV-vis absorption spectroscopy indicates similar coordination environments in 1c and 4c. A series of experiments demonstrates that the racemization rate depends on the dihedral angles of the bipyridyl arms, and the angles are regulated by the substituents. The methoxy and methoxyphenyl substituents in 1c and 1d enlarge the dihedral angles of the bipyridyl arms. This facilitates the access of solvent molecules to the Cu(i) centers and promotes racemization. The slower racemization of 1d can be ascribed to the steric protection of the Cu(i) centers from incoming solvent molecules by the p-methoxyphenyl group.

Late-stage C–H amination of abietane diterpenoids by María Ivana Lapuh; Alejandro Dana; Pablo H. Di Chenna; Benjamin Darses; Fernando J. Durán; Philippe Dauban (4736-4746).
This study aims at highlighting the synthetic versatility of the rhodium-catalyzed C–H amination reactions using iodine(iii) oxidants for the late-stage functionalization of natural products. Inter- and intramolecular nitrene insertions have been performed from various abietane diterpenoids, leading to the amination of the C-3, C-6, C-7, C-11 and C-15 positions. Ca. 20 aminated compounds have been isolated with yields of up to 86% and high levels of regio-, chemo- and stereoselectivities.

An evaluation of a range of aryl, alkyl and vinyl esters as prospective C(1)-ammonium enolate precursors in enantioselective Michael addition–lactonisation processes with (E)-trifluoromethylenones using isothiourea catalysis is reported. Electron deficient aryl esters are required for reactivity, with 2,4,6-trichlorophenyl esters providing optimal product yields. Catalyst screening showed that tetramisole was the most effective isothiourea catalyst, giving the desired dihydropyranone product in excellent yield and stereoselectivity (up to 90 : 10 dr and 98 : 2 er). The scope and limitations of this process have been evaluated, with a range of diester products being generated after ring-opening with MeOH to give stereodefined dihydropyranones with excellent stereocontrol (10 examples, typically ∼90 : 10 dr and >95 : 5 er).

Synthesis of multisubstituted arylsulfones via a one-pot, three-component [3 + 3] benzannulation reaction by Xiang-Zheng Tang; Jie Liang; Xue-Jing Zhang; Raymond Wai-Yin Sun; Ming Yan; Albert S. C. Chan (4753-4760).
A one-pot, three-component [3 + 3] benzannulation reaction of α,β-unsaturated carbonyl compounds, bromoallylic sulfones, and sodium sulfinates had been developed. A series of multisubstituted arylsulfones were prepared with moderate to good yields. This method has the advantages of good step-economy, broad substrate scope and operational simplicity.

We disclose herein the first transition-metal- and external oxidant/reductant-free visible-light-mediated synthesis of (un)symmetrical diaryl/alkyl aryl sulfones from arenediazonium tetrafluoroborates and sodium sulfinates using eosin Y as an organic photoredox catalyst. The utilization of visible light as an inexpensive and ecosustainable energy source, operational simplicity, ambient temperature and clean reaction in aqueous acetonitrile are the salient features of the developed protocol. The desired sulfones were also synthesized via a one-pot, two-step process directly from anilines and sulfinate salts in good to excellent yields.

A catalyst- and solvent-free intramolecular rearrangement sequence leading towards benzimidazole-tethered tetrasubstituted olefins through a solid-state melt reaction (SSMR) involving imine formation, cyclization, N-allylation and isomerization has been realized for the first time. Interestingly, only water is the byproduct in this novel quadruple domino reaction. Furthermore, the reaction is highly stereoselective, atom economical and environmentally benign in nature.

Copper-catalyzed oxidative amination of methanol to access quinazolines by Gandhesiri Satish; Ashok Polu; Laxman Kota; Andivelu Ilangovan (4774-4782).
A novel method for the copper-catalyzed oxidative amination of 2′-aminoarylketones with methanol as a C1 carbon source and ammonium acetate as an amine source to construct quinazolines was established in a one-pot manner. The reaction conditions are straightforward and highly atom economic to deliver the corresponding quinazolines in high yields with wide functional group tolerance. Importantly, the present method is applicable on a multigram scale and its synthetic utility is demonstrated by synthesizing quazodine, a muscle-relaxing drug in high yields.

Cobalt-catalyzed cyclization with the introduction of cyano, acyl and aminoalkyl groups by Hiroto Hori; Shigeru Arai; Atsushi Nishida (4783-4788).
An efficient synthesis of carbo- and heterocycles using CC, CO and CN bonds under cobalt catalysis is described. The substituents on olefins are key for controlling the regio- and chemoselectivity in the initial hydrogen atom transfer step and quaternary carbons are efficiently constructed under mild conditions. Cyclopropane cleavage and tandem cyclization give highly functionalized bicyclic skeletons in a single operation.

Regioselective and oxidant-free sulfinylation of indoles and pyrroles with sulfinamides by Yuan-Zhao Ji; Jin-Yu Zhang; Hui-Jing Li; Chunguang Han; Yi-Kun Yang; Yan-Chao Wu (4789-4800).
An unexpected time-controlled highly selective C3- or C2-sulfinylation of pyrroles with sulfinamides is reported for the first time. The sulfinylation of indoles with sulfinamides using this protocol is oxidant-free and can be performed under obviously more feasible conditions (1.2 equiv. of indoles, 10 min) in comparison with the precedent procedure (3–20 equiv. of indoles, 16–18 h, ammonium persulfate as oxidant, hv). A variety of functional groups were tolerated, and various C2-thioindoles and C2/3-thiopyrroles were obtained in moderate to excellent yields.

Caspase-3 probes for PET imaging of apoptotic tumor response to anticancer therapy by Filipe Elvas; Tom Vanden Berghe; Yves Adriaenssens; Peter Vandenabeele; Koen Augustyns; Steven Staelens; Sigrid Stroobants; Pieter Van der Veken; Leonie wyffels (4801-4824).
Apoptosis is a highly regulated process involved in the normal organism development and homeostasis. In the context of anticancer therapy, apoptosis is also studied intensively in an attempt to induce cell death in cancer cells. Caspase activation is a known key event in the apoptotic process. In particular, active caspase-3 and -7 are the common effectors in several apoptotic pathways, therefore effector caspase activation may be a promising biomarker for response evaluation to anticancer therapy. Quantitative imaging of apoptosis in vivo could provide early assessment of therapeutic effectiveness and could also be used in drug development to evaluate the efficacy as well as potential toxicity of novel treatments. Positron Emission Tomography (PET) is a highly sensitive molecular imaging modality that allows non-invasive in vivo imaging of biological processes such as apoptosis by using radiolabeled probes. Here we describe the development and evaluation of fluorine-18-labeled caspase-3 activity-based probes (ABPs) for PET imaging of apoptosis. ABPs were selected by screening of a small library of fluorine-19-labeled DEVD peptides containing different electrophilic warhead groups. An acyloxymethyl ketone was identified with low nanomolar affinity for caspase-3 and was radiolabeled with fluorine-18. The resulting radiotracer, [18F]MICA-302, showed good labeling of active caspase-3 in vitro and favorable pharmacokinetic properties. A μPET imaging experiment in colorectal tumor xenografts demonstrated an increased tumor accumulation of [18F]MICA-302 in drug-treated versus control animals. Therefore, our data suggest this radiotracer may be useful for clinical PET imaging of response to anticancer therapy.

To inform the design of future merocyanine-based sensors for nucleophilic analytes, a range of model styrylindolium salts were synthesised, and their behaviour towards cyanide, methanethiolate and sulfide was examined using spectroscopic techniques. In the majority of cases, standard 1,2- and 1,4-nucleophilic additions predominated; however, 4-nitrostyrylindolium salts underwent an unexpected dearomatising 1,8-addition with sulfur-centred nucleophiles. The enamine triene products thus produced display useful optical properties and provide a platform for novel sensor design, and the unusual 1,8-reaction pathway enables synthesis of novel molecular architecture.

Modification of oligonucleotides with weak basic residues via the 2′-O-carbamoylethyl linker for improving nuclease resistance without loss of duplex stability and antisense activity by Yoshiaki Masaki; Keishi Yamamoto; Keita Yoshida; Atsuya Maruyama; Takahito Tomori; Yusuke Iriyama; Hiroyuki Nakajima; Tatsuro Kanaki; Kohji Seio (4835-4842).
For the improvement of nuclease resistance, four kinds of new modifications through a carbamoylethyl linker were designed. Among them, the 2′-O-[2-N-{2-(benzimidazol-1-yl)ethyl}carbamoylethyl] modification showed 20-fold longer half-life when treated with a 3′ to 5′ exonuclease compared to the 2′-O-methoxyethyl (MOE) modification, which is used in approved drugs. In addition, this large modification did not disturb the binding affinity or RNase H-dependent antisense activity. From these findings, it could be concluded that an adequate linker, such as carbamoylethyl in this study, could extend the utility of 2′-O-modification without loss of the properties of nucleic acids. This strategy would be useful for the development of nucleic acid therapeutics.

Silver-mediated three-component cycloaddition reaction for direct synthesis of 1-N-vinyl-substituted 1,2,3-triazoles by Jinpeng Chen; Taoyuan Liang; He Zhao; Chuyuan Lin; Lu Chen; Min Zhang (4843-4849).
Herein, we report direct synthesis of 1-N-vinyl-1,2,3-triazoles via silver-mediated three-component cycloaddition reaction of phenylacetylenes, trimethylsilylazide, and 1,3-dicarbonyl compounds. The synthetic protocol proceeds with operational simplicity, good substrate and functional group compatibility, and easily available feedstocks, and without the need for pre-installation of vinylazide precursors, and offers a practical method for the efficient elaboration of triazole derivatives.

Synthesis of pyrazolylvinyl ketones from furan derivatives by Nattawut Sawengngen; Petrakis N. Chalikidi; Sara Araby; Frank Hampel; Peter Gmeiner; Olga V. Serdyuk (4850-4855).
A new protocol for the synthesis of pyrazol-5-ylvinyl ketones, e.g. pyrazole-chalcones, employing furfuryl ketones as a triketone equivalent, has been developed. The reaction occurs under mild conditions and does not require the use of expensive materials. Other important benefits include the simplicity and atom efficiency of this approach.

Gold–carbene assisted formation of tetraarylmethane derivatives: double X–H activation by gold by Dalovai Purnachandar; Kanaparthy Suneel; Sridhar Balasubramanian; Galla V. Karunakar (4856-4864).
An efficient gold–carbene promoted generation of tetraarylmethane derivatives from enynones and indoles was accomplished by the formation of a new C–O bond and two C–C bonds. It is significant that (2-furyl) gold–carbene assisted addition of two nucleophiles resulted in the formation of tetraarylmethane derivatives with a quaternary centre in moderate to good yields in one pot.

Pd(ii)-Catalyzed C8–H alkoxycarbonylmethylation of 1-naphthylamides with α-chloroalkyl esters by Xiaolong Wang; Cancan Feng; Fan Yang; Yangjie Wu (4865-4868).
An efficient protocol for palladium-catalyzed picolinamide directed C8–H alkoxycarbonylmethylation of 1-naphthylamine derivatives with α-chloroalkyl esters has been developed. The reaction exhibited a broad substrate scope and good functional group tolerance with high isolated yields. Note that α-chloroalkyl esters as a new type of alkylating reagent could be easily functionalized further due to their pending an ester group.

Oxidative sulfonamidomethylation of imidazopyridines utilizing methanol as the main C1 source by Xue-Mei Zhao; En-Ling Huang; Yu-Shen Zhu; Jing Li; Bing Song; Xinju Zhu; Xin-Qi Hao (4869-4878).
An efficient one pot, three component synthesis of C3 sulfonamidomethylated imidazopyridines has been disclosed under metal-free conditions, which utilized the commercially available and renewable reagent methanol as the main methylene source. A wide range of substituted imidazopyridines and sulfamides/amines were well tolerated to afford the corresponding products in up to 92% yield. In the isotopic labelling experiment, it was found that a minor part of the methylene also originated from DTBP. Moreover, the radical scavenger reactions were conducted, which suggested that a free-radical mechanism was probably not involved. The current methodology featured several advantages, including broad substrate scope, good functional group tolerance and high reaction efficiency.

Diversity of mechanisms in Ras–GAP catalysis of guanosine triphosphate hydrolysis revealed by molecular modeling by Bella L. Grigorenko; Ekaterina D. Kots; Alexander V. Nemukhin (4879-4891).
The mechanism of the deceptively simple reaction of guanosine triphosphate (GTP) hydrolysis catalyzed by the cellular protein Ras in complex with the activating protein GAP is an important issue because of the significance of this reaction in cancer research. We show that molecular modeling of GTP hydrolysis in the Ras–GAP active site reveals a diversity of mechanisms of the intrinsic chemical reaction depending on molecular groups at position 61 in Ras occupied by glutamine in the wild-type enzyme. First, a comparison of reaction energy profiles computed at the quantum mechanics/molecular mechanics (QM/MM) level shows that an assignment of the Gln61 side chain in the wild-type Ras either to QM or to MM parts leads to different scenarios corresponding to the glutamine-assisted or the substrate-assisted mechanisms. Second, replacement of Gln61 by the nitro-analog of glutamine (NGln) or by Glu, applied in experimental studies, results in two more scenarios featuring the so-called two-water and the concerted-type mechanisms. The glutamine-assisted mechanism in the wild-type Ras–GAP, in which the conserved Gln61 plays a decisive role, switching between the amide and imide tautomer forms, is consistent with the known experimental results of structural, kinetic and spectroscopy studies. The results emphasize the role of the Ras residue Gln61 in Ras–GAP catalysis and explain the retained catalytic activity of the Ras–GAP complex towards GTP hydrolysis in the Gln61NGln and Gln61Glu mutants of Ras.

1,2,4-Oxadiazole-5-ones as analogues of tamoxifen: synthesis and biological evaluation by Maria A. Chiacchio; Laura Legnani; Agata Campisi; Bottino Paola; Lanza Giuseppe; Daniela Iannazzo; Lucia Veltri; Salvatore Giofrè; Roberto Romeo (4892-4905).
A series of 2,3,4-triaryl-substituted 1,2,4-oxadiazole-5-ones have been prepared as fixed-ring analogues of tamoxifen (TAM), a drug inhibitor of Estradiol Receptor (ER) used in breast cancer therapy, by an efficient synthetic protocol based on a 1,3-dipolar cycloaddition of nitrones to isocyanates. Some of the newly synthesized compounds (14d–f, 14h and 14k) show a significant cytotoxic effect in a human breast cancer cell line (MCF-7) possessing IC50 values between 15.63 and 31.82 μM. In addition, compounds 14d–f, 14h and 14k are able to increase the p53 expression levels, activating also the apoptotic pathway. Molecular modeling studies of novel compounds performed on the crystal structure of ER reveal the presence of strong hydrophobic interactions with the aromatic rings of the ligands similar to TAM. These data suggest that 1,2,4-oxadiazole-5-ones can be considered analogues of TAM, and that their anticancer activity might be partially due to ER inhibition.

Melleolides impact fungal translation via elongation factor 2 by Maximilian Dörfer; Daniel Heine; Stefanie König; Sagar Gore; Oliver Werz; Christian Hertweck; Markus Gressler; Dirk Hoffmeister (4906-4916).
Melleolides from the honey mushroom Armillaria mellea represent a structurally diverse group of polyketide-sesquiterpene hybrids. Among various bioactivites, melleolides show antifungal effects against Aspergillus and other fungi. This bioactivity depends on a Δ2,4-double bond present in dihydroarmillylorsellinate (DAO) or arnamial, for example. Yet, the mode of action of Δ2,4-unsaturated, antifungal melleolides has been unknown. Here, we report on the molecular target of DAO in the fungus Aspergillus nidulans. Using a combination of synthetic chemistry to create a DAO-labelled probe, protein pulldown assays, MALDI-TOF-based peptide analysis and western blotting, we identify the eukaryotic translation elongation factor 2 (eEF2) as a binding partner of DAO. We confirm the inhibition of protein biosynthesis in vivo with an engineered A. nidulans strain producing the red fluorescent protein mCherry. Our work suggests a binding site dissimilar from that of the protein biosynthesis inhibitor sordarin, and highlights translational elongation as a valid antifungal drug target.

Correction: Substituent-controlled racemization of dissymmetric coordination capsules by Kentaro Harada; Ryo Sekiya; Takeshi Maehara; Takeharu Haino (4917-4918).
Correction for ‘Substituent-controlled racemization of dissymmetric coordination capsules’ by Kentaro Harada et al., Org. Biomol. Chem., 2019, DOI: 10.1039/c9ob00388f.

Correction: Trehalose-cored amphiphiles for membrane protein stabilization: importance of the detergent micelle size in GPCR stability by Manabendra Das; Yang Du; Jonas S. Mortensen; Manuel Ramos; Lubna Ghani; Ho Jin Lee; Hyoung Eun Bae; Bernadette Byrne; Lan Guan; Claus J. Loland; Brian K. Kobilka; Pil Seok Chae (4919-4920).
Correction for ‘Trehalose-cored amphiphiles for membrane protein stabilization: importance of the detergent micelle size in GPCR stability’ by Manabendra Das et al., Org. Biomol. Chem., 2019, 17, 3249–3257.

Back cover (4921-4922).