Organic & Biomolecular Chemistry (v.13, #35)

Front cover (9143-9143).

Inside front cover (9144-9144).

Contents list (9145-9151).

Recent synthetic additions to the visible light photoredox catalysis toolbox by Ricardo A. Angnes; Zhou Li; Carlos Roque D. Correia; Gerald B. Hammond (9152-9167).
The boom in visible light photoredox catalysis (VLPC) research has demonstrated that this novel synthetic approach is here to stay. VLPC enables reactive radical intermediates to be catalytically generated at ambient temperature, a feat not generally allowed through traditional pyrolysis- or radical initiator-based methodologies. VLPC has vastly extended the range of substrates and reaction schemes that have been traditionally the domain of radical reactions. In this review the photophysics background of VLPC will be briefly discussed, followed by a report on recent inroads of VLPC into decarboxylative couplings and radical C–H functionalization of aromatic compounds. The bulk of the review will be dedicated to advances in synergistic catalysis involving VLPC, namely the combination of photoredox catalysis with organocatalysis, including β-functionalization of carbonyl groups, functionalization of weak aliphatic C–H bonds, and anti-Markovnikov hydrofunctionalization of alkenes; dual catalysis with gold or with nickel, photoredox catalysis as an oxidation promoter in transition metal catalysis, and acid-catalyzed enantioselective radical addition to π systems.

Strategy of total synthesis based on the use of Rh-catalyzed stereoselective 1,4-addition by M. Jean; B. Casanova; S. Gnoatto; P. van de Weghe (9168-9175).
In 1998, Hayashi and Miyaura reported the first asymmetric conjugate addition of aryl- and alkenyl-boronic acids to α,β-unsaturated ketones using chiral rhodium complexes as catalysts. During the last decade, this reaction has been developed quickly and the enantioselectivity was significantly improved with the emergence of new phosphine ligands. In addition to the methodological work, this reaction was applied as a key step in the total synthesis of natural compounds. The purpose of this paper focuses on examples of the use of this reaction to prepare elaborated chiral molecules with high diastereoselectivies and/or enantioselectivities.

Synthesis of a new class of iminosugars based on constrained azaspirocyclic scaffolds by way of catalytic C–H amination by Pierre-Antoine Nocquet; Raphaël Hensienne; Joanna Wencel-Delord; Eric Wimmer; Damien Hazelard; Philippe Compain (9176-9180).
The synthesis of the first examples of a new class of iminosugars based on constrained spirocyclic scaffolds has been achieved via Rh-catalyzed C(sp3)–H amination. In this process, the needed electronic control in securing high regioselectivity from substrates with a high density of activated C–H bonds was achieved by using a combination of activating and electron-withdrawing groups.

A concise and efficient approach to the synthesis of structurally diverse 6,8a-dihydropyrido[2,3-d]pyrimidine derivatives has been accomplished by a three-component reaction involving sulfonyl acetonitrile, an aromatic aldehyde, and 6-aminouracil. The method involves the domino Knoevenagel condensation/Michael addition/cyclization cascade in the presence of triethylamine in refluxing ethanol.

Rh(iii)-catalyzed cyclization reaction of azoles with alkynes: efficient synthesis of azole-fused-pyridines by Xuebing Chen; Youzhi Wu; Jinyi Xu; Hequan Yao; Aijun Lin; Yue Huang (9186-9189).
A Rh(iii)-catalyzed cyclization of azoles with alkynes has been developed. A variety of azole-fused-pyridines were obtained in good to excellent yields and regioselectivity. Both the C5 and the C4 position of azoles were suitable for the reaction.

Synthesis of bicyclic tetrahydrofurans from linear precursors using manganese(iii) acetate by Anne-Caroline Chany; Léo B. Marx; Jonathan W. Burton (9190-9193).
We have recently developed methodology based on oxidative radical reactions for the synthesis of [3.3.0]-bicyclic lactones containing both cyclopentanes and γ-lactams along with application of this methodology to the synthesis of natural products and complex molecular architectures. Herein we report an extension of this methodology to the synthesis of oxygen heterocycles including bicyclic bis-lactones.

Triazole linker-based trivalent sialic acid inhibitors of adenovirus type 37 infection of human corneal epithelial cells by Rémi Caraballo; Michael Saleeb; Johannes Bauer; A. Manuel Liaci; Naresh Chandra; Rickard J. Storm; Lars Frängsmyr; Weixing Qian; Thilo Stehle; Niklas Arnberg; Mikael Elofsson (9194-9205).
Adenovirus type 37 (Ad37) is one of the principal agents responsible for epidemic keratoconjunctivitis (EKC), a severe ocular infection that remains without any available treatment. Recently, a trivalent sialic acid derivative (ME0322, Angew. Chem. Int. Ed., 2011, 50, 6519) was shown to function as a highly potent inhibitor of Ad37, efficiently preventing the attachment of the virion to the host cells and subsequent infection. Here, new trivalent sialic acid derivatives were designed, synthesized and their inhibitory properties against Ad37 infection of the human corneal epithelial cells were investigated. In comparison to ME0322, the best compound (17a) was found to be over three orders of magnitude more potent in a cell-attachment assay (IC50 = 1.4 nM) and about 140 times more potent in a cell-infection assay (IC50 = 2.9 nM). X-ray crystallographic analysis demonstrated a trivalent binding mode of all compounds to the Ad37 fiber knob. For the most potent compound ophthalmic toxicity in rabbits was investigated and it was concluded that repeated eye administration did not cause any adverse effects.

Understanding the conformational behaviour of Ac-Ala-NHMe in different media. A joint NMR and DFT study by Rodrigo A. Cormanich; Michael Bühl; Roberto Rittner (9206-9213).
The conformational behaviour of Ac-Ala-NHMe was studied in the gas-phase and in solution by theoretical calculations (B3LYP-D3/aug-cc-pVDZ level) and experimental 1H NMR. The conformational preferences of this compound were shown to result from a complex interplay between the strengths of possible intramolecular hydrogen bonds, steric interactions, hyperconjugation, entropy effects and the overall dipole moments. The Ac-Ala-N(Me)2 derivative was studied in addition, to design a system akin to Ac-Ala-NHMe, but with disrupted intramolecular hydrogen bonds involving the -NHMe group, mimicking the effect of polar protic solvents.

Micellization properties of cardanol as a renewable co-surfactant by Antonella Fontana; Susanna Guernelli; Nelsi Zaccheroni; Romina Zappacosta; Damiano Genovese; Lucia De Crescentini; Serena Riela (9214-9222).
With the aim to improve the features of surfactant solutions in terms of sustainability and renewability we propose the use of hydrogenated natural and sustainable plant-derived cardanol as an additive to commercial surfactants. In the present study we demonstrated that its addition, in amounts as high as 10%, to commercial surfactants of different charge does not significantly affect surfactant properties. Conversely, the presence of hydrogenated cardanol can strongly affect spectrophotometric determination of CMC if preferential interactions with the dyes used take place. This latter evidence may be profitably exploited in surfactant manufacturing by considering that the concurrent presence of a rigid organic molecule such as Orange OT and 10% hydrogenated cardanol decreases the CMC of CTAB up to 65 times.

Strand displacement and duplex invasion into double-stranded DNA by pyrrolidinyl peptide nucleic acids by Peggy R. Bohländer; Tirayut Vilaivan; Hans-Achim Wagenknecht (9223-9230).
The so-called acpcPNA system bears a peptide backbone consisting of 4′-substituted proline units with (2′R,4′R) configuration in an alternating combination with (2S)-amino-cyclopentane-(1S)-carboxylic acids. acpcPNA forms exceptionally stable hybrids with complementary DNA. We demonstrate herein (i) strand displacements by single-stranded DNA from acpcPNA–DNA hybrids, and by acpcPNA strands from DNA duplexes, and (ii) strand invasions by acpcPNA into double-stranded DNA. These processes were studied in vitro using synthetic oligonucleotides and by means of our concept of wavelength-shifting fluorescent nucleic acid probes, including fluorescence lifetime measurements that allow quantifying energy transfer efficiencies. The strand displacements of preannealed 14mer acpcPNA–7mer DNA hybrids consecutively by 10mer and 14mer DNA strands occur with rather slow kinetics but yield high fluorescence color ratios (blue : yellow or blue : red), fluorescence intensity enhancements, and energy transfer efficiencies. Furthermore, 14mer acpcPNA strands are able to invade into 30mer double-stranded DNA, remarkably with quantitative efficiency in all studied cases. These processes can also be quantified by means of fluorescence. This remarkable behavior corroborates the extraordinary versatile properties of acpcPNA. In contrast to conventional PNA systems which require 3 or more equivalents PNA, only 1.5 equivalents acpcPNA are sufficient to get efficient double duplex invasion. Invasions also take place even in the presence of 250 mM NaCl which represents an ionic strength nearly twice as high as the physiological ion concentration. These remarkable results corroborate the extraordinary properties of acpcPNA, and thus acpcPNA represents an eligible tool for biological analytics and antigene applications.

Array-based sensing of purine derivatives with fluorescent dyes by Ziya Köstereli; Kay Severin (9231-9235).
Natural and synthetic purine derivatives such as caffeine, theophylline, 6-mercaptopurine and 8-chlorotheophylline are important drugs. Due to the structural similarity of these compounds, it is intrinsically difficult to prepare chemosensors for their selective optical detection. Here, we describe a sensor array which can be used to differentiate pharmacologically important purine derivatives with good accuracy. The array is composed of four polysufonated fluorescent dyes, all of which can bind purines viaπ-stacking interactions. The complexation of the analytes results in partial quenching of the fluorescence. The fluorescence response of the four dyes provides a characteristic signal pattern, enabling the identification of thirteen purine derivatives at low millimolar concentration. Furthermore, it is possible to use the array for obtaining information about the quantity and purity of purine samples.

Regio- and stereoselective synthesis of 2′-β-substituted-fluoroneplanocin A analogues as potential anticancer agents by Akshata Nayak; Pramod K. Sahu; Jayoung Song; Sang Kook Lee; Lak Shin Jeong (9236-9248).
A series of 2′-β-substituted-6′-fluoro-cyclopentenyl-pyrimidines and -purines 8 and 9 were successfully synthesized from d-ribose in a regio- and stereoselective manner. The functionalization at the C2-position of 6′-fluoro-cyclopentenyl nucleosides was achieved via regioselective protection of a hydroxyl group at the C3-position and stereoselective formation of C2-triflate followed by direct SN2 reaction with a fluoro or azido nucleophile. All the synthesized compounds were evaluated for their anticancer activities in several tumor cell lines, but were found to be neither active nor toxic.

Achiral, acyclic nucleic acids: synthesis and biophysical studies of a possible prebiotic polymer by P. Srivastava; R. Abou El Asrar; C. Knies; M. Abramov; M. Froeyen; J. Rozenski; H. Rosemeyer; P. Herdewijn (9249-9260).
The search for prebiotic, nucleic acid precursors is, at its best, a speculative undertaking. Given the complex structure of RNA, it is not very likely that RNA was the first information system in the universe and thus finding possible precursor/s i.e. pre-RNA remains an open challenge. We, in this paper, have tried to construct nucleic acid polymers with a simple acyclic, achiral backbone. Such a linear, achiral backbone may have been formed from simple monomers that may have existed in the “prebiotic soup”. We have shown that such polymers are capable of identifying the complementary “other self” and thus forming a potential system for information storage and transmission. This study thus involves investigation of nucleic acid analogues with a modified backbone that are likely to have formed in the prebiotic setting.

Metal-free cycloaddition to synthesize naphtho[2,3-d][1,2,3]triazole-4,9-diones by Ping-Fan Chen; Kung-Kai Kuo; Jaya Kishore Vandavasi; Siva Senthil Kumar Boominathan; Chung-Yu Chen; Jeh-Jeng Wang (9261-9266).
A metal-free domino [3 + 2] cycloaddition is reported to construct naphtho[2,3-d][1,2,3]triazole-4,9-dione derivatives and provide an alternative approach to the azide–alkyne cycloadditions. The key features are easily available starting materials, mild reaction conditions, a good atom economy, eco-friendly characteristics and a broad substrate scope with high yields.

Reverse N-prenylated 3-hydroxytryptophan, the rather exotic amino acid of the cyclomarins, is obtained in enantio- and diastereomerically pure and fully protected form by a combination of a highly stereoselective addition of a zincated indole toward protected serinal and subsequent palladium-catalyzed N-prenylation.

A regioselective synthesis of substituted pyrroloquinolinones via a ruthenium-catalyzed oxidative cyclization of substituted N-carbamoyl indolines with alkynes is described. The cyclization reaction was compatible with various symmetrical and unsymmetrical alkynes including substituted propiolates. Later, we performed the aromatization of pyrroloquinolinones into indole derivatives in the presence of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ).

Palladium-catalyzed arylation of 2H-chromene: a new entry to pyrano[2,3-c]carbazoles by K. Ranjith Reddy; A. Siva Reddy; Devendra K. Dhaked; S. K. Rasheed; Anup Singh Pathania; Ravi Shankar; Fayaz Malik; Parthasarathi Das (9285-9293).
Pyrano[2,3-c]carbazoles which are biologically valuable and synthetically challenging frameworks are synthesized in high yields over five steps from commercially available resorcinol. Palladium-catalyzed arylation remains a key step in this novel strategy. The versatility of this protocol has been demonstrated by the synthesis of naturally occurring alkaloid clauraila C and 7-methoxyglycomaurin. The anti-proliferative activity of these designed compounds (5a, 5f, and 5l) has been evaluated in a cancer cell line (MOLT-4). The molecular docking study revealed that this pyrano[2,3-c]carbazole class of molecules selectively occupies the colchicine binding site of the tubulin-polymer.

A fluorescent calix[4]arene triazole-linked pyrene (CP) was carefully designed and synthesized via click chemistry. The modification of CP with graphene oxide (GO) by a simple non-covalent interaction strategy is presented. Further inspection by electrochemical impedance spectroscopy reveals that the CP-GO could exhibit a very high supramolecular recognition for carbaryl, in particular in serum samples with a nanomolar concentration detection. Additionally, it is easy to directly observe macroscopic recognition by the contact angle, and expand practical applications.

Synthesis and biological evaluation of conformationally restricted adenine bicycloribonucleosides by Hubert Hřebabecký; Eliška Procházková; Michal Šála; Pavla Plačková; Eva Tloušťová; Ona Barauskas; Yu-Jen Lee; Yang Tian; Richard Mackman; Radim Nencka (9300-9313).
We prepared a novel series of conformationally restricted bicyclonucleosides and nucleotides. The synthetic approach employed a ring closing metathesis to provide access to both 6 and 7 membered saturated and unsaturated rings linking the 3′ to 5′ methylene groups of the sugar. The bicyclonucleosides were also transformed to the corresponding phosphoramidate prodrugs by an innovative one-pot protocol of boronate ester protection, coupling of the phosphoryl chloridate and deprotection of the boronate. A similar strategy was also employed for the synthesis of the corresponding monophosphates as crucial intermediates for the synthesis of selected triphosphates. The biological properties of the nucleosides and monophosphate prodrugs were assessed for antiviral and cytostatic activities in cell based assays whilst the triphosphates were evaluated in enzymatic assays. The lack of significant effects suggests that the linkage of the 3′ to 5′via a ring system and the subsequent conformational restriction of the ribose ring to the South conformation are incompatible with the kinases and polymerases that recognize nucleosides and their metabolites.

Polytopic bis(oxazoline)-based ligands for recoverable catalytic systems applied to the enantioselective Henry reaction by Beatriz Angulo; José I. García; Clara I. Herrerías; José A. Mayoral; Ana C. Miñana (9314-9322).
Several kinds of polytopic chiral ligands (including ditopic, tritopic and tetratopic), based on the bis(oxazoline) and azabis(oxazoline) motifs, have been tested in the preparation of recoverable catalytic systems for the Henry reaction. The results obtained with the different ligands are, in general, good, but they point to the existence of a delicate balance between the coordinating ability of the ligand, the catalytic activity and the recovery of the catalyst by formation of the coordination polymer, related to the easiness to form oligomeric species in solution.

Correction: Synergism between genome sequencing, tandem mass spectrometry and bio-inspired synthesis reveals insights into nocardioazine B biogenesis by Norah Alqahtani; Suheel K. Porwal; Elle D. James; Dana M. Bis; Jonathan A. Karty; Amy L. Lane; Rajesh Viswanathan (9323-9323).
Correction for ‘Synergism between genome sequencing, tandem mass spectrometry and bio-inspired synthesis reveals insights into nocardioazine B biogenesis’ by Norah Alqahtani et al., Org. Biomol. Chem., 2015, 13, 7177–7192.

Correction for ‘Comparison of the reactivity of β-thiolactones and β-lactones toward ring-opening by thiols and amines’ by Amandine Noel et al., Org. Biomol. Chem., 2012, 10, 6480–6483.

Back cover (9325-9326).