Organic & Biomolecular Chemistry (v.15, #46)

Front cover (9737-9738).

Contents list (9739-9746).

Cooperative bimetallic catalysis in asymmetric allylic substitution by Jingke Fu; Xiaohong Huo; Bowen Li; Wanbin Zhang (9747-9759).
Synergistic catalysis is gaining increasing attention due to its advantages over traditional catalytic methodologies, such as improved catalytic activity, broader substrate scope, increased selectivity and lower cost. Methodologies involving the synergistic combination of metal catalysts and organocatalysts have been intensively studied. Given the clear benefits of bimetallic catalyst systems consisting of two distinct metal catalysts, cooperative bimetallic catalysis has proved to be successful for a number of difficult asymmetric transformations. This review highlights the recent advances in bimetallic systems for catalytic asymmetric allylic substitution reactions. Strategies using a chiral metal catalyst and the cooperative effect of a second achiral metal catalyst for asymmetric transformations are discussed. Additionally, several challenging asymmetric reactions realized by employing two different chiral metal catalysts in a synergistic manner are also covered.

Oligonucleotides (ONs) modified with 2′-O-(pyren-1-yl)methylribonucleotides have been explored for a range of applications in molecular biology, nucleic acid diagnostics, and materials science for more than 25 years. The first part of this review provides an overview of synthetic strategies toward 2′-O-(pyren-1-yl)methylribonucleotides and is followed by a summary of biophysical properties of nucleic acid duplexes modified with these building blocks. Insights from structural studies are then presented to rationalize the reported properties. In the second part, applications of ONs modified with 2′-O-(pyren-1-yl)methyl-RNA monomers are reviewed, which include detection of RNA targets, discrimination of single nucleotide polymorphisms, formation of self-assembled pyrene arrays on nucleic acid scaffolds, the study of charge transfer phenomena in nucleic acid duplexes, and sequence-unrestricted recognition of double-stranded DNA. The predictable binding mode of the pyrene moiety, coupled with the microenvironment-dependent properties and synthetic feasibility, render 2′-O-(pyren-1-yl)methyl-RNA monomers as a promising class of pyrene-functionalized nucleotide building blocks for new applications in molecular biology, nucleic acid diagnostics, and materials science.

Regioselective phosphinylation of coumarins under green LED irradiation and its mechanism by Qingrui Li; Xiuli Zhao; Yabo Li; Mengmeng Huang; Jung Keun Kim; Yangjie Wu (9775-9778).
The regioselective synthesis of 3-phosphinylated coumarins in moderate to excellent yields was developed via an EY/BPO-mediated cross-dehydrogenative coupling (CDC) reaction under green LED irradiation. The results of control experiments showed that the active intermediate, a P-centered radical, might be obtained through energy transfer and electron transfer processes.

Synthesis of 2,2-bis(pyridin-2-yl amino)cyclobutanols and their conversion into 5-(pyridin-2-ylamino)dihydrofuran-2(3H)-ones by Lorenza Ghisu; Nicola Melis; Francesco Secci; Pierluigi Caboni; Massimiliano Arca; Régis Guillot; Thomas Boddaert; David J. Aitken; Angelo Frongia (9779-9784).
A two-step protocol is presented for the preparation of 5-(pyridin-2-ylamino)dihydrofuran-2(3H)-ones from 2-hydroxycyclobutanone and some 2-aminopyridines via a catalyst-free synthesis of 2,2-bis(pyridin-2-ylamino)cyclobutanols followed by Dess–Martin periodinane mediated ring expansion.

Organocatalytic umpolung annulative dimerization of ynones for the synthesis of 5-alkylidene-2-cyclopentenones by Dhevalapally B. Ramachary; T. Prabhakar Reddy; A. Suresh Kumar (9785-9789).
A novel phosphine-catalyzed umpolung [3 + 2]-annulative dimerization of ynones was developed to furnish functionally rich 5-alkylidene-2-cyclopentenones. In this protocol, ynone acts as both C2 and C3 synthons, which undergo [3 + 2]-annulative dimerization.

A biocatalytic cascade for the amination of unfunctionalised cycloalkanes by Michele Tavanti; Juan Mangas-Sanchez; Sarah L. Montgomery; Matthew P. Thompson; Nicholas J. Turner (9790-9793).
Here we describe a one-pot, three-enzyme, cascade involving a cytochrome P450 monooxygenase, an alcohol dehydrogenase and a reductive aminase for the synthesis of secondary amines from cycloalkanes. Amine product concentrations of up to 19.6 mM were achieved. The preparative scale amination of cyclohexane was also demonstrated with a space–time yield of 2 g L−1 d−1.

Regioselective and enantiospecific synthesis of the HSP co-inducer arimoclomol from chiral glycidyl derivatives by Benjamin N. Atkinson; Hannah L. Woodward; James Sipthorp; Paul V. Fish (9794-9799).
A new efficient chiral synthesis of enantiopure arimoclomol (2) is reported from (R)-(−)-glycidyl nosylate (11) with complete retention of chiral integrity. Off-target pharmacology of arimoclomol (2) was evaluated against a representative set of drug targets and showed modest binding to a few kinases. Pharmacokinetic data was generated in vivo in mouse and showed a low brain : plasma ratio. These studies will be helpful towards a better understanding of the PK-PD relationship of 2 in disease models.

Co(ii) induces a large VCD signal enhancement, which overcomes the low sensitivity of VCD and opens new perspectives in quantitative VCD. We used a stereodynamic system, where the analyte determines the chirality of the Co(ii) coordination sphere. The strong VCD signals stand out the baseline, which allows for their rapid and accurate quantitation. This lends itself to the first general method for the ee determination of α-amino acids based on vibrational circular dichroism and constitutes a model for the design of sensitive quantitative assays based on VCD.

An efficient and practical procedure for the synthesis of 2-benzyl- and 2-benzylidene-substituted benzo[b]thiazinones from easily available 2-iodophenylcinnamamides and potassium sulfide has been developed. In the presence of DBU, the reaction proceeds via electrophilic addition, followed by dehydrogenation and reduction to give 2-benzyl benzo[b]thiazinones. Furthermore, 2-benzylidenebenzo[b]thiazinones were obtained in moderate to good yields without the addition of DBU.

Acetylenic scaffolding with subphthalocyanines – synthetic scope and elucidation of electronic interactions in dimeric structures by Henrik Gotfredsen; Line Broløs; Thomas Holmstrøm; Jacob Sørensen; Alberto Viñas Muñoz; Martin Drøhse Kilde; Anders B. Skov; Marco Santella; Ole Hammerich; Mogens Brøndsted Nielsen (9809-9823).
Boron subphthalocyanines (SubPcs) are powerful chromophoric heterocycles that can be synthetically modified at both axial and peripheral positions. Acetylenic scaffolding offers the possibility of building large, unsaturated carbon-rich frameworks that can exhibit excellent electron-accepting properties, and when combined with SubPcs it presents a convenient method for preparing interesting chromophore–acceptor architectures. Here we present synthetic methodologies for the post-functionalization of the relatively sensitive SubPc chromophore via acetylenic coupling reactions. By gentle AlCl3-mediated alkynylation at the axial boron position, we managed to anchor two SubPcs to the geminal positions of a tetraethynylethene (TEE) acceptor. Convenient conditions that allow for stepwise desilylations of trimethylsilyl (TMS) and triisopropylsilyl (TIPS) protected SubPc-decorated acetylenes using silver(i) fluoride were developed. The resulting terminal alkynes were successfully used as coupling partners in metal-catalyzed couplings, providing access to larger acetylenic SubPc scaffolds and multiple chromophore systems. Moreover, conditions allowing for the conversion of a terminal alkyne into an iodoalkyne in the presence of SubPc were developed, and the product was subjected to cross-coupling reactions affording unsymmetrical 1,3-butadiynes. The degree of interactions between two SubPc units as a function of the acetylenic bridge was studied by UV-Vis absorption spectroscopy and cyclic voltammetry. A TEE bridging unit was found to strongly influence the reductions and oxidations of the two SubPc units, while a more flexible bridge had no influence.

Manipulating the stereoselectivity of the thermostable Baeyer–Villiger monooxygenase TmCHMO by directed evolution by Guangyue Li; Maximilian J. L. J. Fürst; Hamid Reza Mansouri; Anna K. Ressmann; Adriana Ilie; Florian Rudroff; Marko D. Mihovilovic; Marco W. Fraaije; Manfred T. Reetz (9824-9829).
Baeyer–Villiger monooxygenases (BVMOs) and evolved mutants have been shown to be excellent biocatalysts in many stereoselective Baeyer–Villiger transformations, but industrial applications are rare which is partly due to the insufficient thermostability of BVMOs under operating conditions. In the present study, the substrate scope of the recently discovered thermally stable BVMO, TmCHMO from Thermocrispum municipale, was studied. This revealed that the wild-type (WT) enzyme catalyzes the oxidation of a variety of structurally different ketones with notable activity and enantioselectivity, including the desymmetrization of 4-methylcyclohexanone (99% ee, S). In order to induce the reversal of enantioselectivity of this reaction as well as the transformations of other substrates, directed evolution based on iterative saturation mutagenesis (ISM) was applied, leading to (R)-selectivity (94% ee) without affecting the thermostability of the biocatalyst.

Highly regioselective gold-catalyzed formal hydration of propargylic gem-difluorides by Jean-Denys Hamel; Tatsuru Hayashi; Mélissa Cloutier; Paul R. Savoie; Olivier Thibeault; Meggan Beaudoin; Jean-François Paquin (9830-9836).
Herein, we report a highly regioselective gold-catalyzed formal hydration of propargylic gem-difluorides. Not only does this transformation provide access to versatile fluorinated building blocks that were difficult or hardly possible to access beforehand, but it also represents a rare case of a highly regioselective gold-catalyzed hydroalkoxylation of internal alkynes and puts forward the utility of the difluoromethylene unit as a directing group in catalysis.

A copper-catalyzed asymmetric Friedel–Crafts propargylic alkylation of electron-rich phenol derivatives with a variety of propargylic esters has been described. With Cu(OTf)2 decorated with a chiral tridentate ketimine P,N,N-ligand as the catalyst, asymmetric Friedel–Crafts propargylic alkylation of 3,5-dialkoxyphenol derivatives proceeded smoothly in high yields and with good to excellent enantioselectivities. The present study suggested that the presence of an electron-rich substituent on the meta-position of phenol is essential for the promotion of Friedel–Crafts propargylic alkylation, and the substrate bearing two electron-rich groups on both the 3,5-positions of phenol tends to give a satisfactory performance.

Metal-free oxidative para-acylation of unprotected anilines with N-heteroarylmethanes by Min Liu; Xue Chen; Tieqiao Chen; Qing Xu; Shuang-Feng Yin (9845-9854).
A selective oxidative para-acylation of unprotected anilines with methyl groups in N-heteroarylmethanes was achieved. This transformation proceeds under mild metal-free reaction conditions to produce the corresponding valuable diarylmethanones in good to high yields, featuring high site-selectivity, high functional-group-tolerance, gram-scale synthesis and easy product-derivation. Preliminary mechanistic studies revealed that the present oxidative para-acylation would take place via a Friedel–Crafts-type process of in situ imines and the steric hindrance might be the key issue for the high regio-selectivity.

Dissociative reactions of benzonorbornadienes with tetrazines: scope of leaving groups and mechanistic insights by M. Xu; R. Galindo-Murillo; T. E. Cheatham; R. M. Franzini (9855-9865).
Bioorthogonal dissociative reactions boast diverse potential applications in chemical biology and drug delivery. The reaction of benzonorbornadienes with tetrazines to release amines from carbamate leaving groups was recently introduced as a bioorthogonal bond-cleavage reaction. The present study aimed at investigating the scope of leaving groups that are compatible with benzonorbornadienes. Synthesis of several benzonorbornadienes with different releasable groups is reported, and the reaction of these molecules with tetrazine was found to be rapid and afforded high release yields. The tetrazine-induced release of molecules proceeds in a cascade of steps including inverse-electron demand cycloaddition and cycloreversion reactions that form unstable isoindoles/isobenzofuran intermediates and spontaneously eliminate a leaving group of interest. In the case of oxygen-bridged BNBDs at room temperature, we observed the formation of an unproductive byproduct.

Differential array sensing for cancer cell classification and novelty detection by Alexandra M. Gade; Margaret K. Meadows; Andrew D. Ellington; Eric V. Anslyn (9866-9874).
A series of semi-specific peptides reported in the literature to bind various epitopes on cell surfaces were used in a differential sensing array to pattern cell line identity. The peptides were conjugated to thiazole orange to act as both a fluorescence reporter and a DNA intercalator. Fluorescence data for the peptides exposed to cells, with and without exogenous double stranded DNA (dsDNA), led to chemometric fingerprints for eight cancer cell lines. In contrast to the use of structures meant to act in completely non-specific ways, the use of a limited level of specificity generated linear discriminant score plots with high dimensionality, i.e. several principle components carrying significant variance. The arrays were found to correctly classify the cell lines from 60% to 100% depending upon the cell line. Due to the high dimensionality score plots, the identification of cell lines that were not part of the training set was examined. Support vector machines were used as a novelty detection routine and showed that a cancer line not part of the original training set could be correctly identified as being novel.

Copper nitrate-catalyzed oxidative coupling of unactivated C(sp3)–H bonds of ethers and alkanes with N-hydroxyphthalimide: synthesis of N-hydroxyimide esters by Xiaohe Xu; Jian Sun; Yuyan Lin; Jingya Cheng; Pingping Li; Yiyan Yan; Qi Shuai; Yuanyuan Xie (9875-9879).
A copper nitrate-catalyzed cross-dehydrogenative coupling reaction between N-hydroxyphthalimide (NHPI) and ethers/alkanes has been described. The reaction is accomplished smoothly by using simple and green molecular oxygen as the oxidant, providing an alternative for the efficient synthesis of N-alkoxyphthalimides. In addition, it was found that when tert-butyl ethers were used as substrates, unexpected N-hydroxyimide ester derivatives were obtained in moderate to excellent yields. To further understand this unusual transformation, control experiments were performed and a plausible mechanism was proposed.

β-Alanine and N-terminal cationic substituents affect polyamide–DNA binding by Beibei Liu; Shuo Wang; Karl Aston; Kevin J. Koeller; Shahrzad Fanny Hakami Kermani; Carlos H. Castañeda; M. José Scuderi; Rensheng Luo; James K. Bashkin; W. David Wilson (9880-9888).
Minor-groove binding hairpin polyamides (PAs) bind specific DNA sequences. Synthetic modifications can improve PA–DNA binding affinity and include flexible modules, such as β-alanine (β) motifs to replace pyrroles (Py), and increasing compound charge using N-terminal cationic substituents. To better understand the variations in kinetics and affinities caused by these modifications on PA–DNA interactions, a comprehensive set of PAs with different numbers and positions of β and different types of N-cationic groups was systematically designed and synthesized to bind their cognate sequence, the λB motif. The λB motif is also a strong binding promoter site of the major groove targeting transcription factor PU.1. The PA binding affinities and kinetics were evaluated using a spectrum of powerful biophysical methods: thermal melting, biosensor surface plasmon resonance and circular dichroism. The results show that β inserts affect PA–DNA interactions in a number and position dependent manner. Specifically, a β replacement between two imidazole heterocycles (ImβIm) generally strengthens binding. In addition, N-terminal cationic groups can accelerate the association between PA and DNA, but the bulky size of TMG can cause steric hindrance and unfavourable repulsive electrostatic interactions in some PAs. The future design of stronger binding PA requires careful combination of βs and cationic substituents.

1,3-Dibromo-5,5-dimethylhydantoin mediated oxidative amidation of terminal alkenes in water by Chunhua Ma; Guojie Fan; Ping Wu; Zhi Li; Yang Zhou; Qingjie Ding; Wei Zhang (9889-9894).
A variety of terminal alkenes were converted to the corresponding amides in yields of 25 to 86% in water via treatment with 1,3-dibromo-5,5-dimethylhydantoin, followed by reaction with molecular iodine and aq. NH3 (or amine) in one pot. This metal- and organic solvent-free protocol is not only suitable for styrene derivatives, but also, for the first time, works well on terminal aliphatic alkenes.

A novel sulfonamide non-classical carbenoid: a mechanistic study for the synthesis of enediynes by Theodore O. P. Hayes; Ben Slater; Richard A. J. Horan; Marc Radigois; Jonathan D. Wilden (9895-9902).
Alkynyl sulfonamides undergo sequential 1,4- then 1,2-addition/rearrangement with lithium acetylides to yield enediynes in the absence of any promoters or catalysts. Mechanistic investigations suggest that the reaction proceeds via 1,4-conjugate addition of the nucleophile to the unsaturated system to give a key alkenyl lithium species which is stabilised by an intramolecular coordination effect by a sulfonamide oxygen atom. This species can be considered a vinylidene carbenoid given the carbon atom bears both an anion (as a vinyllithium) and a leaving group (the sulfonamide). The intramolecular coordination effect serves to stabilise the vinyllithium but activates the sulfonamide motif towards nucleophilic attack by a second mole of acetylide. The resulting species can then undergo rearrangement to yield the enediyne framework in a single operation with concomitant loss of aminosulfinate.

Efficient cross-coupling of aryl/alkenyl triflates with acyclic secondary alkylboronic acids by Tengda Si; Bowen Li; Wenrui Xiong; Bin Xu; Wenjun Tang (9903-9909).
Aryl–secondary alkyl cross-coupling with aryl sulfonate esters as coupling partners remains a significant challenge. Efficient cross-coupling between aryl/alkenyl triflates and acyclic secondary alkylboronic acids is realized for the first time to provide a series of sterically congested acyclic secondary alkyl arenes/olefins in good to excellent yields. The employment of sterically bulky P,PO ligand L1/L2 is crucial for the high yields and selectivities. The method has enabled a concise and 4-step synthesis of a key intermediate of male contraceptive agent and PAF antagonist gossypol.

Peramivir analogues bearing hydrophilic side chains exhibit higher activities against H275Y mutant than wild-type influenza virus by Din-Chi Chiu; Tzu-Chen Lin; Wen-I Huang; Ting-Jen Cheng; Keng-Chang Tsai; Jim-Min Fang (9910-9922).
Peramivir is an effective anti-influenza drug in the clinical treatment of influenza, but its efficacy toward the H275Y mutant is reduced. The previously reported cocrystal structures of inhibitors in the mutant neuraminidase (NA) suggest that the hydrophobic side chain should be at the origin of reduced binding affinity. In contrast, zanamivir having a hydrophilic glycerol side chain still possesses high affinity toward the H275Y NA. We thus designed five peramivir analogues (5–9) carrying hydrophilic glycol or glycerol side chains, and evaluated their roles in anti-influenza activity, especially for the H275Y mutant. The synthetic sequence involves a key step of (3 + 2) cycloaddition reactions between alkenes and nitrile oxides to construct the scaffold of peramivir carrying the desired hydrophilic side chains and other appropriate functional groups. The molecular docking experiments reveal that the hydrophilic side chain can provide extra hydrogen bonding with the translocated Glu-276 residue in the H275Y NA active site. Thus, the H275Y mutant may be even more sensitive than wild-type virus toward the peramivir analogues bearing hydrophilic side chains. Notably, the peramivir analogue bearing a glycerol side chain inhibits the H275Y mutant with an IC50 value of 35 nM, which is better than the WSN virus by 9 fold.

Improved synthesis of symmetrically & asymmetrically N-substituted pyridinophane derivatives by Andrew J. Wessel; Jason W. Schultz; Fengzhi Tang; Hui Duan; Liviu M. Mirica (9923-9931).
The N,N′-di(toluenesulfonyl)-2,11-diaza[3,3](2,6)pyridinophane (TsN4) precursor was sought after as a starting point for the preparation of various symmetric and asymmetric pyridinophane-derived ligands. Various procedures to synthesize TsN4 had been published, but the crucial problem had been the purification of TsN4 from the larger 18- and 24-membered azamacrocycles. Most commonly, column chromatography or other laborious methods have been utilized for this separation, yet we have found an alternate selective dissolution method upon protonation which allows for multi-gram scale output of TsN4·HCl. This optimized synthesis of TsN4 also led to the development of symmetric RN4 derivatives as well as the asymmetric derivative N-(tosyl)-2,11-diaza[3,3](2,6)pyridinophane (TsHN4). Using this TsHN4 precursor, different N-substituents can be added to create a library of asymmetric RR′N4 macrocyclic ligands. These asymmetric RR′N4 derivatives expand the utility of the RN4 framework in coordination chemistry and the ability to study the electronic, steric, and denticity effects of these pyridinophane ligands on the metal center.

Conformational isomerism in cyclic peptoids and its specification by A. D'Amato; R. Schettini; G. Della Sala; C. Costabile; C. Tedesco; I. Izzo; F. De Riccardis (9932-9942).
Most of the structural studies made on the secondary structure of peptoids describe their geometric attributes in terms of the classic Ramachandran plot (based on the local analysis of ω, ψ, χ, φ dihedral angles). However, little intuitive understanding is available from internal coordinates when stereochemistry is involved. In this contribution we list all the conformationally stable cyclic peptoids reported up to the year 2017 and propose a simple method to define their geometric arrangement in terms of planar chirality. Evidence of conformational isomerism (due to the long average time of single bond rotation) and conformational chirality (induced by the absence of roto-reflection axes) in this promising class of synthetic macrocycles is provided by NMR spectroscopy (using Pirkle's alcohol as chiral solvating agent) and careful evaluation of X-ray crystallographic studies. The full understanding of the oligomeric macrocycles’ structural properties and the clear framing of their conformational isomerism in a proper conceptual scheme is fundamental for future application of peptoids in asymmetric synthesis, chiral recognition and supramolecular chemistry.

Back cover (9943-9944).