Organic & Biomolecular Chemistry (v.11, #32)

Front cover (5197-5198).

Contents list (5199-5205).

Indole is by far one of the most popular heterocyclic scaffolds in nature. The intriguing and challenging molecular architectures of polycyclic, naturally occurring indolyl compounds constitute a continuous stimulus for development in organic synthesis. The field had a formidable boom across the new millennium when catalysis started revolutionizing the chemistry of indole, providing always more convincing and sustainable solutions to the selective “decoration” of this pharmacophore. A common guideline of these approaches relies on the intrinsic overexpression of electron density of the indole core. Despite less diffusion, the “dark-side” of indole reactivity, electrophilicity, has been also elegantly documented with direct applications towards the realization of specific interatomic connections that would be difficult to obtain by means of conventional indole reactivity. The present Perspective article summarizes the major findings that brought the research area from the pioneering findings of the 60s to the state of the art.

A fluorogenic assay for screening Sirt6 modulators by Jing Hu; Bin He; Shiva Bhargava; Hening Lin (5213-5216).
A fluorogenic high-throughput assay suitable for screening Sirt6 modulators is developed based on the recently discovered efficient activity of Sirt6 to hydrolyze myristoyl lysine. Sirt6 modulators will be useful in investigating the function of Sirt6 and protein lysine fatty acylation.

An organocatalytic conjugate addition of prochiral 3-fluorinated oxindoles to vinyl sulfones was described for the first time. In the presence of bifunctional tertiary amine–thiourea catalysts, 3-fluoro-3-substituted oxindole adducts were obtained in excellent yields and with high enantiomeric excesses.

Herein, we have disclosed a catalytic asymmetric 1,5(6)-selective Michael/cyclization reaction of α-hydroxyimino cyclic ketones with γ,β-unsaturated α-keto esters. Unlike the previous catalytic strategies, this reaction provides a convenient 1,5(6)-selective asymmetric pathway to access synthetically useful ring-fused dihydropyrans. In general, high levels of yield, enantio- and diastereoselectivity (up to 99% yield, >99% ee and >20 : 1 dr) were obtained.

Density functional theory calculations (M06-2X//B3LYP) have been performed to determine the factors responsible for enantioselectivity in Diels–Alder reactions catalysed by two series of camphor-derived amines. Hydrazides 2 and sulfonylhydrazides 3 catalyze the reaction of cyclopentadiene with cinnamaldehyde to give the same enantiomer of cycloadduct. The calculations reveal that the two classes of catalysts control enantioselectivity by opposite mechanisms. Hydrazides 2 favour addition to the bottom face of a trans iminium cation, while sulfonylhydrazides 3 favour addition to the top face of a cis iminium ion. In the transition state for cycloadditions catalysed by 2, a stabilising CH–π interaction between the diene and a benzyl substituent α to the iminium nitrogen accelerates the reaction and enhances the enantioselectivity. The facial selectivity can be reinforced by appending onto the benzyl side-arm an α-methyl group that sterically hinders addition to the top face.

PNA–NLS conjugates as single-molecular activators of target sites in double-stranded DNA for site-selective scission by Yuichiro Aiba; Yuya Hamano; Wataru Kameshima; Yasuyuki Araki; Takehiko Wada; Alessandro Accetta; Stefano Sforza; Roberto Corradini; Rosangela Marchelli; Makoto Komiyama (5233-5238).
Artificial DNA cutters have been developed by us in our previous studies by combining two strands of pseudo-complementary peptide nucleic acid (pcPNA) with Ce(iv)–EDTA-promoted hydrolysis. The pcPNAs have two modified nucleobases (2,6-diaminopurine and 2-thiouracil) instead of conventional A and T, and can invade double-stranded DNA to activate the target site for the scission. This system has been applied to site-selective scissions of plasmid, λ-phage, E. coli genomic DNA, and human genomic DNA. Here, we have reported a still simpler and more convenient DNA cutter obtained by conjugating peptide nucleic acid (PNA) with a nuclear localization signal (NLS) peptide. This new DNA cutter requires only one PNA strand (instead of two) bearing conventional (non-pseudo-complementary) nucleobases. This PNA–NLS conjugate effectively activated the target site in double-stranded DNA and induced site-selective scission by Ce(iv)–EDTA. The complex formation between the conjugate and DNA was concretely evidenced by spectroscopic results based on time-resolved fluorescence. The target scission site of this new system was straightforwardly determined by the Watson–Crick base pairing rule, and mismatched sequences were clearly discriminated. Importantly, even highly GC-rich regions, which are difficult to be targeted by a previous strategy using pcPNA, were successfully targeted. All these features of the present DNA cutter make it promising for various future applications.

Diversity-oriented general protocol for the synthesis of privileged oxygen scaffolds: pyrones, coumarins, benzocoumarins and naphthocoumarins by Atul Goel; Gaurav Taneja; Ashutosh Raghuvanshi; Ruchir Kant; Prakas R. Maulik (5239-5253).
A new general methodology for the synthesis of various functionalized privileged oxygen heterocyclic scaffolds, viz. pyrones, coumarins, and benzannulated coumarins, is developed. The synthesis proceeds through carbanion-induced ring transformation of lactones with various methylene carbonyl compounds followed by DDQ-mediated unprecedented oxidative cleavage of oxaylidenes intermediates. Studies of the mechanism of the conversions of oxaylidene intermediates into corresponding carbonyl compounds in the presence of DDQ revealed that the reactions took place via the formation of a Michael adduct instead of an intermolecular charge transfer complex. The methodology offers the fabrication of diverse privileged scaffolds with tolerance for many functional groups onto the oxygen heterocyclic molecular framework.

We describe an efficient one-step synthesis of pyrrolo[3,4-c]quinolinedione derivatives using ethylenediamine diacetate (EDDA)-catalyzed cascade reactions of isatins and β-ketoamides. It is the first direct conversion of isatins to pyrrolo[3,4-c]quinolinedione derivatives via C–N bond cleavage and isatin ring expansion. Furthermore, this reaction provides a one-step synthetic route for the production of biologically interesting complex molecules that are generally prepared using multi-step reactions.

The mechanism for the hydrogenation of ketones catalyzed by Knölker's iron-catalyst by Xi Lu; Yawei Zhang; Peng Yun; Mingtao Zhang; Tonglei Li (5264-5277).
Knölker's iron-based catalysts have some value in “green” transformations given the relatively low toxicity of iron compared to more commonly used precious-metal catalysts. Density functional methods have been used to extensively explore the use of an iron catalyst for hydrogen-transfer processes. Several inner- (with substrate coordination) and outer-sphere mechanisms (with no substrate coordination) were analyzed using a semi-simplified system. An outer-sphere route involving a concerted hydrogen-transfer to the substrate was found to be the most kinetically feasible mechanism, with a free energy barrier of only 10.2 kcal mol−1. This mechanism was then used to explore the complete system at the same theoretical level. The real system had a higher free energy barrier (20.7 kcal mol−1) which is due to the steric effect of the substituent group. All the calculated results were in good agreement with the experimental results.

A selection of imines derived from phenyl t-butyl ketones and substituted 2-phenylethylamines or phenylalanine exhibit slow rotation around the aryl–imino bond at ambient temperature, resulting in a large non-equivalence of the ortho hydrogens in the 1H NMR spectra. This facilitates assessment of aryl substituent effects on the face tilted-T CH–π interaction between a phenyl ring (A) on the imino carbon proximate to the terminal phenyl ring (B). Analysis of the marked temperature dependence of the chemical shift of the interacting ortho hydrogen affords estimates of the opposing enthalpic and entropic factors involved in the rapid equilibrium between the closed edge-to-face conformation and alternative open conformations devoid of a CH–π interaction while in solution. Above ca. 80 °C the entropy term (TΔS) cancels out the enthalpy (ΔH) favouring the closed conformation and open conformations are preferred. Accordingly, commonly reported binding free energies may not be a good measure of the energetic strength of intramolecular aromatic interactions. Investigation of an ortho fluoro substituted compound indicates that a CF–π interaction is at least 1.0 kcal mol−1 weaker in enthalpy than the CH–π interaction. Several X-ray crystal structures depicting an intramolecular edge-to-face interaction are presented.

The formation of tetrahydrofurans from 2-hydroxyalkyl-oxirane or aziridine is reported. The 5-endo-tet cyclization/ring opening of aziridine proceeded smoothly to give tetrahydrofurans (THFs) under mild conditions. In contrast, the corresponding process of oxirane was unsuccessful and a sequence of SN2 substitution/cyclization was required to form THFs. The application of the process to prepare ent-(−)-pachastrissamine is described.

Mechanisms of DNA damage by photoexcited 9-methyl-β-carbolines by Mariana Vignoni; Federico A. O. Rasse-Suriani; Kathrin Butzbach; Rosa Erra-Balsells; Bernd Epe; Franco M. Cabrerizo (5300-5309).
It has been well documented that β-carboline alkaloids, particularly the 9-methyl derivatives, are efficient photosensitizers. However, structure–activity relationships are missing and the photochemical mechanisms involved in the DNA photodamage still remain unknown. In the present work, we examined the capability of three 9-methyl-β-carbolines (9-methyl-norharmane, 9-methyl-harmane and 9-methyl-harmine) to induce DNA damage upon UVA excitation at physiological pH. The type and extent of the damage was analyzed together with the photophysical and binding properties of the β-carboline derivatives investigated. The results indicate that even at neutral pH most of the DNA damage is generated from the protonated form of the excited β-carbolines in a type-I reaction. Oxidized purine residues are produced in high excess over oxidized pyrimidines, single-strand breaks and sites of base loss. In addition, the excited neutral form of the β-carbolines is responsible for significant generation of cyclobutane pyrimidine dimers (CPDs) by triplet–triplet-energy transfer. In the case of 9-methyl-norharmane, the yield of CPDs is increased in D2O, probably due to less rapid protonation in the deuterated solvent.

Discovery of N-(4-sulfamoylphenyl)thioureas as Trypanosoma brucei leucyl-tRNA synthetase inhibitors by Fenglong Zhang; Jin Du; Qing Wang; Qinghua Hu; Jiong Zhang; Dazhong Ding; Yaxue Zhao; Fei Yang; Enduo Wang; Huchen Zhou (5310-5324).
Human African trypanosomiasis (HAT) is one of the most neglected diseases in the tropic regions, which is fatal if not treated in time. There is an urgent need for new therapeutics, especially those in new chemical classes. Leucyl-tRNA synthetase (LeuRS) has been paid much attention as a recently clinically validated antimicrobial target. Our group has previously reported T. brucei LeuRS (TbLeuRS) inhibitors, including benzoxaboroles targeting the editing site and pyrrolinones targeting the synthetic site. Here we report the discovery of N-(4-sulfamoylphenyl)thioureas as a new class of TbLeuRS inhibitors. The R1 and R2 groups, reminiscent of the leucyl and adenyl regions of aa-AMP and aa-AMS, were optimized to result in a significant 13-fold increase of inhibitory activity (compound 19, IC50 = 13.7 μM). Aided by ligand–protein docking, the 1,3-substitution at the central phenyl ring was predicted and proved to give significantly improved activity (59, IC50 = 1.1 μM). This work provided a new scaffold for the exploration of novel inhibitors against TbLeuRS, which may become potential therapeutics for the treatment of HAT.

Photo-switchable α-helical peptides offer a valuable tool to probe protein-biomacromolecule interactions in a spatiotemporally controlled manner. We synthesized a series of 32 residue peptides (AA32 s) with the core structure Ac-W-(E1A2A3A4R5)6-Q-NH2 and introduced the azobenzene based cross-linker BSBCA via reaction with Cys residues spaced at i, i + 7 intervals in different positions along the helix. UV/Vis measurements show that the composition of the photostationary state as well as thermal relaxation rates do not change considerably with changes in cross-linker position. CD analysis shows that photo-control of helix folding/unfolding is most effective when the cross-linker is targeted to the middle of the peptide so long as this segment has a high intrinsic helical propensity. The largest degree of photo-controlled conformational change occurred when a cross-linked central region of high intrinsic helicity was followed on the C-terminal side by a region of lower intrinsic helicity. This indicates the BSBCA cross-linker can act as a nucleation site for N-to-C propagation of a helix. These data help to guide the choice of cross-linking site in larger peptides and proteins where photo-control of conformation is desired.

Exploring NMR methods as a tool to select suitable fluorescent nucleotide analogues by Patrick Groves; Agnieszka Strzelecka-Kiliszek; Anna Sekrecka-Belniak; Angeles Canales; Jesús Jiménez-Barbero; Joanna Bandorowicz-Pikula; Sławomir Pikula; F. Javier Cañada (5332-5338).
Fluorescent analogues provide important tools for biochemical/biophysical research. However, the analogues contain chemical modifications much larger than those known to affect ligand-binding, such as the inversion of a carbon centre or substitution of an atom. We lack experimental tools and protocols to select the most appropriate fluorescent analogue. Herein, we use several NMR spectroscopy methods, including Saturation Transfer Difference (STD), STD competition and transferred nuclear Overhauser effect spectroscopy (Tr-NOESY), as tools to select appropriate fluorescent probes. Annexin A6 (AnxA6) is a ubiquitous protein that forms in vitro GTP-induced ion channels. We used this protein as a model and screened guanosine triphosphate (GTP) and four fluorescent analogues against AnxA6. STD reported that the GTP moiety of all ligands made similar contacts with the protein, despite additional interactions between the fluorescent tags and AnxA6. Competition STD experiments verified that the analogues and GTP bind to the same site. Tr-NOESY indicated that the bound conformation of the base relative to ribose is altered for some analogues compared to GTP. MANT-GTP or the BODIPY thioester of guanosine 5′-O-(3-thiotriphosphate) are the most suitable fluorescent analogues for AnxA6, according to NMR. These results reveal NMR as a useful technique to select and design proper fluorescent tags for biochemical/biophysical assays.

Systematic study on free radical hydrothiolation of unsaturated monosaccharide derivatives with exo- and endocyclic double bonds by László Lázár; Magdolna Csávás; Ádám Hadházi; Mihály Herczeg; Marietta Tóth; László Somsák; Terézia Barna; Pál Herczegh; Anikó Borbás (5339-5350).
Exo- and endocyclic double bonds of glycals and terminal double bonds of enoses were reacted with various thiols by irradiation with UV light in the presence of a cleavable photoinitiator. The photoinduced radical-mediated hydrothiolation reactions showed highly varying overall conversions depending not only on the substitution pattern and electron-density of the double bond but also on the nature and substitution pattern of the thiol partner. Out of the applied thiols thiophenol, producing the highly stabilized thiyl radical, exhibited the lowest reactivity toward each type of alkene. In most cases, the hydrothiolations took place with full regio- and stereoselectivities. Successful addition of 1,2 : 3,4-di-O-isopropylidene-6-thio-α-d-galactopyranose to a 2,3-unsaturated N-acetylneuraminic acid derivative, providing a (3 → 6)-S-linked pseudodisaccharide, demonstrated that the endocyclic double bond of Neu5Ac-2-ene, bearing an electron-withdrawing substituent, shows sufficient reactivity in the photoinduced thiol–ene coupling reaction.

Synthesis and reactivity of 5-polyfluoroalkyl-5-deazaalloxazines by Sergii Dudkin; Viktor O. Iaroshenko; Vyacheslav Ya. Sosnovskikh; Andrey A. Tolmachev; Alexander Villinger; Peter Langer (5351-5361).
Reaction of 6-arylamino-1,3-dialkyluracils with anhydrides of polyfluorocarboxylic acids in the presence of pyridine and subsequent cyclization with concentrated H2SO4 gave the corresponding 1,3-dialkyl-5-(polyfluoroalkyl)pyrimido[4,5-b]quinoline-2,4(1H,3H)-diones (5-polyfluoroalkyl-5-deazaalloxazines). The reactivity of these compounds towards nucleophilic reagents, such as sodium cyanoborohydride, acetophenone, nitromethane, potassium cyanide, indole and p-thiocresol, as well as Suzuki and Sonogashira couplings are described. The nucleophilic addition takes place at the 5-position of the 5-deazaalloxazine system and is in many cases irreversible to give 5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-dione derivatives in good to excellent yields.

An approach to hyperolactone C and analogues using late stage conjugate addition on an oxonium ylide-derived spirofuranone by David M. Hodgson; Elena Moreno-Clavijo; Sophie E. Day; Stanislav Man (5362-5369).
A stereocontrolled synthesis of norphenyl hyperolactone C together with its utility as a direct precursor to the anti-HIV agent hyperolactone C and analogues by addition of organolithiums, are described. Preliminary studies to access this key building block in a catalytic enantioselective manner are also reported.

A novel catalyst system has been indentified for addressing the long-standing issue of Z/E stereoselectivity in palladium-catalyzed exo-mode cyclization reactions of allenes bearing a nucleophilic functionality with organic halides or their equivalents. The readily accessible, sterically hindered monophosphine ligand Gorlos-Phos·HBF4 imparts a remarkable stereocontrolling ability with broad generality under Pd catalysis.

Enantioselective cycloaddition of carbonyl ylides with arylallenes using Rh2(S-TCPTTL)4 by Janagiraman Krishnamurthi; Hisanori Nambu; Koji Takeda; Masahiro Anada; Akihito Yamano; Shunichi Hashimoto (5374-5382).
The first catalytic asymmetric carbonyl ylide cycloaddition with arylallenes is described. With dirhodium(ii) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh2(S-TCPTTL)4, the cycloaddition of carbonyl ylides derived from diazoketoesters with arylallenes proceeded in a fully chemo- and regioselective manner to give highly functionalized 8-oxabicyclo[3.2.1]octanes with up to 99% ee and perfect exo diastereoselectivity.

Inside back cover (5383-5384).