Organic & Biomolecular Chemistry (v.17, #26)

Front cover (6307-6308).

Contents list (6309-6316).

Organoboron synthesis via ring opening coupling reactions by Riccardo Gava; Elena Fernández (6317-6325).
One of the most atom economical synthesis reactions of organoboron compounds can be achieved by addition reactions of boron reagents to unsaturated substrates. However, when the addition reaction takes place via carbanions promoting ring opening coupling reactions, the selective cleavage of the inherent bonds and the generation of new C–C bonds warrant the selective synthesis of organoboron systems with total efficiency. Here we describe new trends towards the selective synthesis of organoboron compounds where boron reagents and cyclic substrates participate in the generation of carbanions, in the presence of stoichiometric amounts of main-group metals or catalytic amounts of transition metal complexes, via ring opening coupling transformations. The generality and limitations of these new protocols are discussed.

Late stage functionalization of heterocycles using hypervalent iodine(iii) reagents by Rajnish Budhwan; Suman Yadav; Sandip Murarka (6326-6341).
Late stage functionalization (LSF) through direct X–H manipulations (X = C, N) enables synthetic chemists to accelerate the diversification of natural products, agrochemicals and pharmaceuticals allowing rapid access to novel bioactive molecules without resorting to arduous de novo synthesis. LSF does not only allow tapping of the hitherto unexplored chemical space but also renders the synthetic sequence more straightforward, atom economical and cost-effective. In this regard, the recent decade has witnessed the emergence of hypervalent iodine(iii) reagents as a powerful synthetic tool owing to their easy availability, mild reaction conditions, remarkable oxidizing properties and high functional group tolerance. Iodine(iii) reagents have tremendous applications in the regio- and chemo-selective late-stage functionalization of a diverse variety of heterocycles through an exciting range of transformations, such as oxidative amination, cross-dehydrogenative coupling (CDC), fluoroalkylation, azidation, halogenation and oxidation. The present review, classified according to the types of synthetic methods involved, encompasses all these recent developments in the field of transition-metal-free iodine(iii)-catalyzed/mediated direct functionalizations of heterocycles with representative examples and insightful mechanistic discussions.

Using LiCl as a chlorine source, the chlorination of 2-aminopyridines or 2-aminodiazines in the presence of Selectfluor and DMF is established under mild conditions. This method gives chlorinated pyridines or diazines in good to high yields with high regioselectivities. Also, this method is extended to the bromination of 2-aminopyridines or 2-aminodiazines by using LiBr. The regioselectivity of the chlorination reaction is strongly dependent upon the substituent pattern in either the 2-aminopyridines or 2-aminodiazines. The synthesis of Buparlisib from chlorinated pyridines was explored. A study of the mechanism revealed that this chlorination occurs via either a pyridine or diazine radical process.

A transition metal free approach for the synthesis of methyl/ethyl aryl ether via oxidative C–H etherification of acylanilines with alcohols has been developed. Various acylanilines are compatible under standard conditions, giving the corresponding products in moderate to good yields. This strategy avoids transition-metal catalyst and excessive alcohol, providing a simple and reliable alternative method for the synthesis of methyl/ethyl aryl ether. Control experiments reveal that a radical mechanism is involved in this transformation.

A range of 3,3-disubstituted oxindoles accessed using para-quinone methides derived from isatins with thiols were used for the formation of unsymmetrical disulfides, and 3,3-disubstituted oxindoles with a chiral quaternary carbon center and unsymmetric disulfides could also be directly obtained with high selectivities catalyzed by chiral phosphines in one step.

Convenient one-pot access to 2H-3-nitrothiochromenes from 2-bromobenzaldehydes, sodium sulfide and β-nitrostyrenes by Thi Thu Huong Le; Chitose Youhei; Quy Hien Le; Thanh Binh Nguyen; Dinh Hung Mac (6355-6358).
An efficient synthesis of 2H-3-nitrothiochromenes via a cascade reaction was established. Starting from commercially available o-bromobenzaldehydes and β-nitrostyrenes with sodium sulfide nonahydrate as an inexpensive sulfur source, various substituted thiochromenes were synthesized with high functional group tolerance without any added transition metal catalyst or additive.

The first radiosynthesis of 2-amino-5-[18F]fluoropyridines via a “minimalist” radiofluorination/palladium-catalyzed amination sequence from anisyl(2-bromopyridinyl)iodonium triflate by Mathilde Pauton; Raphaël Gillet; Catherine Aubert; Guillaume Bluet; Florence Gruss-Leleu; Sébastien Roy; Cécile Perrio (6359-6363).
The synthesis of 2-amino-5-[18F]fluoropyridines was achieved in 8–85% yields by palladium-catalyzed reaction of 2-bromo-5-[18F]fluoropyridine with piperidine, dimethylamine, butylamine, methylpiperazine, benzylamine, aniline and 3-aminopyridine. 2-Bromo-5-[18F]fluoropyridine was obtained by radiofluorination of anisyl(2-bromopyridinyl-5)iodonium triflate (88% yield). The radiofluorination step was performed under “minimalist” conditions to guarantee a successful subsequent amination reaction.

Facile synthesis of chiral ε-sultams via an organocatalytic aza-Friedel–Crafts reaction by Zi-Biao Zhao; Lei Shi; Yaming Li; Fan-Jie Meng; Yong-Gui Zhou (6364-6368).
Chiral ε-sultams, with their unique strain cyclic structure, are a type of molecule with important biological activities. A facile enantioselective aza-Friedel–Crafts reaction of seven-membered cyclic N-sulfonylimines with naphthols was developed with a cinchona alkaloid-based bifunctional organocatalyst, giving chiral ε-sultams with an enantiomeric excess of up to 92%.

Photoaffinity palladium reagents for capture of protein–protein interactions by Qizhen Zheng; Zhengyuan Pang; Jingwei Liu; Yi Zhou; Yang Sun; Zheng Yin; Zhiyong Lou (6369-6373).
Protein–protein interactions (PPIs) are indispensable in almost all cellular processes. Probing of complex PPIs provides new insights into the biological system of interest and paves the way for the development of therapeutics. Herein, we report a strategy for the capture of protein–protein interactions using photoaffinity palladium reagents. First, the palladium-mediated reagent site specifically transferred a photoaffinity modified aryl group to the designated cysteine residue. Next, the photoaffinity group was activated by UV radiation to trap the proximal protein residue for the formation of a crosslink. This strategy was used to capture the PYL-ABA-PP2C interaction, which is at the core of the abscisic acid (ABA) signalling pathway. Our results indicated that this palladium-mediated strategy can serve as an alternative for incorporating an increasing number of diverse substrates for protein crosslinking through cysteine modifications and can be explored for use in mapping protein–peptide or protein–protein interaction surfaces and in trapping potential interacting partners.

Identification of crucial bottlenecks in engineered polyketide biosynthesis by Marius Grote; Susanna Kushnir; Niclas Pryk; David Möller; Julian Erver; Ahmed Ismail-Ali; Frank Schulz (6374-6385).
The concept of combinatorial biosynthesis promises access to compound libraries based on privileged natural scaffolds. Ever since the elucidation of the biosynthetic pathway towards the antibiotic erythromycin A in 1990, the predictable manipulation of type I polyketide synthase megaenzymes was investigated. However, this goal was rarely reached beyond simplified model systems. In this study, we identify the intermediates in the biosynthesis of the polyether monensin and numerous mutated variants using a targeted metabolomics approach. We investigate the biosynthetic flow of intermediates and use the experimental setup to reveal the presence of selectivity filters in polyketide synthases. These obstruct the processing of non-native intermediates in the enzymatic assembly line. Thereby we question the concept of a truly modular organization of polyketide synthases and highlight obstacles in substrate channeling along the cascade. In the search for the molecular origin of a selectivity filter, we investigate the role of different thioesterases in the monensin gene cluster and the connection between ketosynthase sequence motifs and incoming substrate structures. Furthermore, we demonstrate that the selectivity filters do not apply to new-to-nature side-chains in nascent polyketides, showing that the acceptance of these is not generally limited by downstream modules.

Convertible and conformationally constrained nucleic acids (C2NAs) by Jean-Marc Escudier; Corinne Payrastre; Béatrice Gerland; Nathalie Tarrat (6386-6397).
We introduce the concept of Convertible and Constrained Nucleic Acids (C2NAs). By means of the synthesis of a stereocontrolled N-propargyl dioxo-1,3,2-oxaza-phosphorinane as an internucleotidic linkage, the torsional angles α and β can adopt either the canonical (g, t) set of values able to increase DNA duplex stability or the non-canonical (g+, t) set that stabilized the hairpin structure when installed within the loop moiety. With an appended propargyl function on the nitrogen atom of the six-membered ring, the copper catalysed Huisgen's cycloaddition (CuAAC click chemistry) allows for the introduction of new functionalities at any location on the nucleic acid chain while maintaining the properties brought by the geometrical constraint and the neutral internucleotidic linkage.

A NIR fluorescent probe for detection of viscosity and lysosome imaging in live cells by Tong Chen; Zikang Chen; Ruiyuan Liu; Shaobing Zheng (6398-6403).
Lysosomes, as the cellular recycling center, are filled with numerous hydrolases that can degrade most cellular macromolecules. Studies have shown that the abnormality of viscosity in lysosomes will disrupt the normal function of lysosomes. Herein, a D–π-A structure near-infrared fluorescent probe containing N,N-dimethylamino benzene as an electron donor, benzothiozole as an electron acceptor, and a vinyl group as a π unit, Lyso-BTC, is explored for fluorescence imaging of lysosomes and detection of lysosomal viscosity changes. Lyso-BTC exhibits a large Stokes shift (∼180 nm), NIR emission (685 nm), good biocompatibility, excellent photostability, and fluorescence response to viscosity. Moreover, the results of in vitro studies reveal that Lyso-BTC is lysosome-targeted and could be applied for the detection of viscosity changes in lysosomes caused by chloroquine treatment. These results confirm that Lys-BTC could be employed to monitor lysosomal viscosity changes in living cells.

The known azastilbene (E)-1,2-di(quinolin-3-yl)ethane (2a) and the novel azoniastilbene derivatives (E)-2-(2-(naphthalen-2-yl)vinyl)quinolizinium (2b) and (E)-3,3′-(ethane-1,2-diyl)bis(1-methylquinolinin-1-ium) (2c) were synthesized. Their interactions with duplex and quadruplex DNA (G4-DNA) were studied by photometric, fluorimetric, polarimetric and flow-LD analysis, and by thermal DNA denaturation studies, as well as by 1H-NMR spectroscopy. The main goal of this study was a comparison of these conformationally flexible compounds with the known G4-DNA-binding diazoniadibenzo[b,k]chrysenes, that have a comparable π-system extent, but a rigid structure. We have observed that the aza- and azoniastilbene derivatives 2a–c, i.e. compounds with almost the same spatial dimensions and steric demand, bind to DNA with an affinity and selectivity that depends significantly on the number of positive charges. Whereas the charge neutral derivative 2a binds unspecifically to the DNA backbone of duplex DNA, the ionic compounds 2b and 2c are typical DNA intercalators. Notably, the bis-quinolinium derivative 2c binds to G4-DNA with moderate affinity (Kb = 4.8 × 105 M−1) and also stabilizes the G4-DNA towards thermal denaturation (ΔTm = 11 °C at ligand–DNA ratio = 5.0). Strikingly, the corresponding rigid counterpart, 4a,12a-diazonia-8,16-dimethyldibenzo[b,k]chrysene, stabilizes the G4-DNA to an even greater extent under identical conditions (ΔTm = 27 °C). These results indicate that the increased flexibility of a G4-DNA ligand does not necessarily lead to stronger interactions with the G4-DNA as compared with rigid ligands that have essentially the same size and π system extent.

The role of olefin geometry in the activity of hydrocarbon stapled peptides targeting eukaryotic translation initiation factor 4E (eIF4E) by James M. Song; Erin E. Gallagher; Arya Menon; Lauren D. Mishra; Amanda L. Garner (6414-6419).
Hydrocarbon stapled (HCS) peptides are a class of cross-linked α-helix mimetics. The technology relies on the use of α,α′-disubstituted alkenyl amino acids, which fully contrain the helical region to typically yield peptides with enhanced structural ordering and biological activity. Recently, monosubstituted alkenyl amino acids were disclosed for peptide stapling; however, the impact that this tether has on HCS peptide structure and activity has not yet been fully explored. By applying this HCS to the disordered peptide eIF4E-binding protein 1 (4E-BP1), we discovered that this type of tethering has a dramatic effect on olefin geometry and activity of the resultant stapled peptides, where the putative trans isomer was found to exhibit enhanced in vitro and cellular inhibitory activity against eIF4E protein–protein interactions. We further demonstrated that the metathesis catalyst used for ring-closing metathesis can influence monosubstituted HCS peptide activity, presumably through alteration of the cis/trans olefin ratio. This study represents one of the first in-depth analyses of olefin isomers of a stapled peptide and highlights an additional feature for medicinal chemistry optimization of this class of peptide-based probes.

The organocatalyzed Mannich reaction of unsubstituted and N-aryl-substituted tetrahydroisoquinolines (THIQs) and the Strecker reaction of several N-aryl-substituted THIQs through dehydrogenative C(sp3)–H bond functionalization (cross-dehydrogenative coupling) promoted by organic single electron oxidants DDQ and IBX are presented. The C–H oxidation/Mannich reaction of less reactive N-aryl substituted pyrrolidines is achieved via metal catalyzed photoredox catalysis. Operationally simple procedures provide desired products in an effective and time preserving manner.

Copper-mediated cascade radical cyclization of olefins with naphthalenyl iododifluoromethyl ketones by Peng Peng; Guo-zhi Huang; Ying-xin Sun; Xing Wang; Jing-jing Wu; Fan-hong Wu (6426-6431).
Copper-mediated radical cyclization of naphthalenyl iododifluoromethyl ketones with olefins was successfully developed to generate a series of unprecedented gem-difluorodihydrophenanthrenones, especially 2,2-difluoro-3,4-dihydrophenanthren-1(2H)-one derivatives. This strategy features the use of cheap copper powder and excellent regioselectivity and diastereoselectivity, thus providing a facile approach for application in drug discovery and development. Preliminary mechanistic studies indicate the involvement of difluorinated radical intermediates. Density functional theory (DFT) calculation was performed to provide further evidence for regioselectivity.

Metal-free regioselective direct thiolation of 2-pyridones by Kunita Phakdeeyothin; Sirilata Yotphan (6432-6440).
A highly regioselective metal-free direct C–H thiolation of 2-pyridones with disulfides or thiols has been developed. A combination of persulfate and a commercially available halide source such as LiCl, NCS or I2 enables the successful direct incorporation of a sulfide moiety into the 5-position of pyridone under mild conditions, providing a useful and convenient approach for the preparation of a diverse array of 5-thio-substituted pyridones in moderate to excellent yields.

A novel, transition-metal free route leading to imidazo[1,2-a]pyridine derivatives via iodine mediated oxidative coupling between 2-aminopyridine and aromatic terminal alkyne has been demonstrated. This newly developed method discloses an operationally simple way for the construction of imidazoheterocycles. Commercially available antiulcer drug zolimidine may readily be synthesized employing this method.

Aryne insertion into the PO bond: one-pot synthesis of quaternary phosphonium triflates by Kashmiri Neog; Dhiraj Dutta; Babulal Das; Pranjal Gogoi (6450-6460).
A novel transition-metal free synthetic strategy has been developed for the direct synthesis of quaternary phosphonium triflates via insertion of aryne into phosphine oxide. This methodology provides good yields of quaternary phosphonium salts and one of the synthesized phosphonium salts has been unambiguously established by single crystal XRD study. Preliminary mechanistic studies suggest that the reaction proceeds via a sequential [2 + 2] cycloaddition followed by the o-arylation and protonation pathway.

Iridium-catalyzed intramolecular enantioselective allylation of quinazolin-4(3H)-one derivatives by Fei Peng; Hua Tian; Pengxiang Zhang; Haijun Yang; Hua Fu (6461-6464).
An efficient iridium-catalyzed intramolecular enantioselective allylation of quinazolin-4(3H)-one derivatives has been developed, and the corresponding products were obtained with high reactivity and high to excellent enantioselectivity with tolerance of some functional groups, in which our developed chiral cyclic phosphoramidite ligands greatly promoted the iridium-catalyzed reactivity and enantioselectivity.

Catalytic direct amidations in tert-butyl acetate using B(OCH2CF3)3 by Charlotte E. Coomber; Victor Laserna; Liam T. Martin; Peter D. Smith; Helen C. Hailes; Michael J. Porter; Tom D. Sheppard (6465-6469).
Catalytic direct amidation reactions have been the focus of considerable recent research effort, due to the widespread use of amide formation processes in pharmaceutical synthesis. However, the vast majority of catalytic amidations are performed in non-polar solvents (aromatic hydrocarbons, ethers) which are typically undesirable from a sustainability perspective, and are often poor at solubilising polar carboxylic acid and amine substrates. As a consequence, most catalytic amidation protocols are unsuccessful when applied to polar and/or functionalised substrates of the kind commonly used in medicinal chemistry. In this paper we report a practical and useful catalytic direct amidation reaction using tert-butyl acetate as the reaction solvent. The use of an ester solvent offers improvements in terms of safety and sustainability, but also leads to an improved reaction scope with regard to polar substrates and less nucleophilic anilines, both of which are important components of amides used in medicinal chemistry. An amidation reaction was scaled up to 100 mmol and proceeded with excellent yield and efficiency, with a measured process mass intensity of 8.

Push–pull isomers of indolizino[6,5,4,3-def]phenanthridine decorated with a triarylboron moiety by Lei Dong; Felix Saraci; Kang Yuan; Xiang Wang; Suning Wang (6470-6477).
1,3-Dipolar cycloaddition reactions between a new azomethine ylide and three BPhMes2-functionalized internal alkynes produced three pairs of fluorescent push–pull regioisomers, which show distinct electronic and photophysical properties. All the six compounds are found to exhibit charge-transfer (CT) fluorescence, and some of which show rare and interesting temperature “turn-on” fluorescence.

The structural features of a series of organic molecular complexes formed between the strong electrophilic tetracyanoethylene and twelve benzene derivatives with increased nucleophilic character, herein called Electron Density Transfer Complexes (EDTCs), have been studied using Molecular Electron Density Theory. The favourable nucleophilic/electrophilic interactions, which favour the global electron density transfer (GEDT) towards the electrophile, are responsible for the formation of these species. Molecular complexes presenting a GEDT above 0.05e are classified as EDTCs. Analysis of the Parr functions of the separated reagents and the topological analysis of the electron density of the EDTCs allow the understanding of the subtle changes in the electronic structure of this significant class of molecular complexes, and consequently, their physical properties.

Total syntheses of the bilirubin oxidation end product Z-BOX C and its isomeric form Z-BOX D by Daniel Schulze; Juliane Traber; Marcel Ritter; Helmar Görls; Georg Pohnert; Matthias Westerhausen (6489-6496).
Oxidative degradation products of bilirubin (BOXes) are biologically highly active and certain BOXes cause long-lasting narrowing of cerebral blood vessels presumably with a significant role in subarachnoid hemorrhage. Due to the fact that mode of action as well as fate of these BOXes is widely unknown, larger amounts of these bilirubin degradation end products are required. The total synthesis of colorless (Z)-3-(5-(2-amino-2-oxoethylidene)-4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)propanoic acid (BOX C) succeeds via a seven-step procedure with a total yield of 20%. Its isomeric form (Z)-3-(2-(2-amino-2-oxoethylidene)-4-methyl-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)propanoic acid (BOX D) can be prepared via a five-step protocol with a yield of 30%. NMR and crystallographic studies reveal that charge delocalization within the conjugated π-systems of BOXes C and D is negligible. Exposure of solutions of Z-BOX C and Z-BOX D to bright sunlight leads to Z/E-isomerization and mixtures of the respective E/Z-BOXes C and D.

Boron-dipyrromethene (BODIPY) fluorophore derivatives were prepared from a Pyrromethene scaffold and di-fluoroboron. To add to the range of biocompatible fluorophores, this report describes the synthesis and photophysical studies of carboxylate-functionalized BODIPY analogues from natural products, Tropolone and α-amino acids, through N,O-chelation. The structure of a few derivatives was confirmed by single crystal X-ray studies. UV/fluorescence studies revealed their fluorescence behaviors in organic solvents with a quantum yield of ∼0–15%, which varied based on the structure of amino acids. Further, electrochemical studies were accomplished by cyclic voltammetry, which confirm only one irreversible reduction reaction with Epc = −1.3 (V). Finally, their HOMO and LUMO molecular orbitals/energy differences were calculated from a theoretically (DFT) optimized structure, which also supported the role of amino group residues in the enhancement of the fluorescence. The glycinate derivative exhibited the greatest quantum yield compared to the other amino groups. Hence, 2-aminotropone containing BODIPY analogues are potential candidates for the development of various types of functionalized fluorophores as BODIPY analogues.

Correction for ‘Ring closing metathesis (RCM) approach to the synthesis of conduramine B-2, ent-conduramine F-2, aminocyclopentitol and trihydroxyazepane’ by Vimal Kant Harit et al., Org. Biomol. Chem., 2019, 17, 5951–5961.

Back cover (6507-6508).