Organic & Biomolecular Chemistry (v.12, #4)

Front cover (543-543).

Inside front cover (544-544).

Contents list (545-551).

An operationally simple approach for the stereoselective tandem synthesis of novel thiazolo fused naphthyridines 5a–o and thienopyridines 8a–e by the reaction of o-alkynylaldehydes with l-cystine methyl ester hydrochloride via Au(iii)-catalyzed regioselective 6-endo-dig ring closure under mild reaction conditions is described. It is noteworthy that alkynes bearing an alkyl and a strong electron-withdrawing nitro group successfully afforded the desired products in good yields.

Bromo- and thiomaleimides as a new class of thiol-mediated fluorescence ‘turn-on’ reagents by Judith Youziel; Ahmed R. Akhbar; Qadeer Aziz; Mark E. B. Smith; Stephen Caddick; Andrew Tinker; James R. Baker (557-560).
Bromo- and thiomaleimides are shown to serve as highly effective quenchers of a covalently attached fluorophore. Reactions with thiols that lead to removal of the maleimide conjugation, or detachment of the fluorophore from the maleimide, result in ‘turn-on’ of the fluorescence. These reagents thus offer opportunities in thiol sensing and intracellular reporting.

Nucleotide sensing with a perylene-based molecular receptor via amplified fluorescence quenching by Bappaditya Roy; Takao Noguchi; Daisuke Yoshihara; Youichi Tsuchiya; Arnab Dawn; Seiji Shinkai (561-565).
A competitive fluorescence assay of perylene-based molecular receptors has been established, and selective detection of UTP is achieved through improved aggregation arising from the specific interaction of perylene-tethered guanidinium with uridine and phosphate groups in UTP.

Convergent diversity-oriented side-chain macrocyclization scan for unprotected polypeptides by Yekui Zou; Alexander M. Spokoyny; Chi Zhang; Mark D. Simon; Hongtao Yu; Yu-Shan Lin; Bradley L. Pentelute (566-573).
Here we describe a general synthetic platform for side-chain macrocyclization of an unprotected peptide library based on the SNAr reaction between cysteine thiolates and a new generation of highly reactive perfluoroaromatic small molecule linkers. This strategy enabled us to simultaneously “scan” two cysteine residues positioned from i, i + 1 to i, i + 14 sites in a polypeptide, producing 98 macrocyclic products from reactions of 14 peptides with 7 linkers. A complementary reverse strategy was developed; cysteine residues within the polypeptide were first modified with non-bridging perfluoroaryl moieties and then commercially available dithiol linkers were used for macrocyclization. The highly convergent, site-independent, and modular nature of these two strategies coupled with the unique chemoselectivity of a SNAr transformation allows for the rapid diversity-oriented synthesis of hybrid macrocyclic peptide libraries with varied chemical and structural complexities.

Asymmetric synthesis of drug-like spiro[chroman-3,3′-indolin]-2′-ones through aminal-catalysis by Dhevalapally B. Ramachary; M. Shiva Prasad; S. Vijaya Laxmi; R. Madhavachary (574-580).
Asymmetric synthesis of drug-like functionalized spiro[chroman-3,3′-indolin]-2′-ones 5 containing three contiguous stereocenters with high diastereo- and enantioselectivities was achieved using the reflexive-Michael (r-M) reaction of unmodified hydroxyenals 1 with various (E)-3-alkylideneindolin-2-ones 2 in the presence of (R)-DPPOTMS/AcOH (R)-3/4b as a catalyst at room temperature. Chiral spiro[chroman-3,3′-indolin]-2′-ones 5 were transformed into the functionalized spiranes 7, 9, and 10 in good yields with high selectivity through Wittig, TCRA, acetal protection and reduction reactions, respectively. Supporting evidence for the reaction pathway through the formation of the important catalytic species of “aminals” was observed through NMR and ESI-HRMS analysis of an ongoing reaction between 1 and (R)-3 in CDCl3 and also shown by the structural requirement in hydroxyenals 1 to generate the “aminals” with (R)-3 through controlled experiments.

Rhodium-catalyzed allylic C–F bond activation via oxidative addition was found to be a promising approach for the conversion of allylic difluoro-homoallylic alcohols into trisubstituted monofluoroalkenes in good yields with excellent stereoselectivity. The mechanism study shows that C–F bond activation via oxidative addition is involved and PPh3 is responsible for the excellent stereoselectivity.

For functional nitrogen-bridged calix(hetero)aromatic platforms to be further used in the design of more sophisticated receptors, the azacalix[2]arene[2]triazine nitrogen bridges were functionalised with methyl bromoacetate. Three new macrocycles with four N-methyl ester pendant arms were straightforwardly prepared in good yields from the undecorated azacalix[2]arene[2]triazine precursors with chlorine, dimethylamine or dihexylamine substituted triazines. These intermediate macrocycles exhibited different reactivity towards the nucleophilic replacement, which was rationalized from the computed electrostatic potential for these molecules. Subsequently, the N-methyl ester appendages were hydrolyzed with each dialkylamine derivative providing a single macrocycle with four carboxylic groups. In contrast, the hydrolysis of the dichlorinated azacalix[2]arene[2]triazine analogue yielded a mixture of three isomeric macrocycles having two N-methyl esters and two carboxylmethyl pendant arms and the triazine chlorine atoms replaced by hydroxyl groups. The coordination ability of two macrocycles with four carboxylic groups for transition metals was evaluated with copper(ii) by UV-vis titrations.

Photoresponsive vesicle permeability based on intramolecular host–guest inclusion by Ulrike Kauscher; Avik Samanta; Bart Jan Ravoo (600-606).
This article describes light-responsive vesicles that can release their contents in response to a light-sensitive molecular trigger. To this end, liposomes were equipped with amphiphilic β-cyclodextrin that was covalently labeled with azobenzene. Using dye encapsulation and confocal laser scanning microscopy, we show that the permeability of these vesicles strongly increases upon UV irradiation (λ = 350 nm) with concomitant isomerization of apolar trans-azobenzene to polar cis-azobenzene on the liposome surface.

The thermodynamics of the self-assembly of covalently linked oligomeric naphthalenediimides into helical organic nanotubes by Koujiro Tambara; John-Carl Olsen; David E. Hansen; G. Dan Pantoş (607-614).
The mechanism and thermodynamic functions of the self-assembly of a family of covalently linked oligomeric naphthalenediimides (NDIs) were investigated through variable-temperature NMR and CD studies. The NDIs were shown to self-assemble into helical supramolecular nanotubes via an isodesmic polymerisation mechanism, and regardless of the oligomer length a surprising entropy–enthalpy compensation was observed.

Different optically active amido esters, mixed acid esters, amido acids, and diamides derived from trans-cyclopropane-1,2-dicarboxylic acid were prepared from the commercially available diethyl (±)-trans-cyclopropane-1,2-dicarboxylate. The key step was the Rhodococcus rhodochrous IFO 15564 catalyzed hydrolysis of the corresponding racemic amide. The amidase present in this microorganism showed moderate to high enantioselectivity towards these substrates. In addition a simple and efficient Curtius rearrangement of some of the enzymatically prepared cyclopropanecarboxylic acids allowed us to obtain optically active β-aminocyclopropanecarboxylic acid derivatives with high yields and enantiomeric excesses.

2-Arylacetic anhydrides as ammonium enolate precursors by Louis C. Morrill; Lyndsay A. Ledingham; Jean-Philippe Couturier; Jasmine Bickel; Andrew D. Harper; Charlene Fallan; Andrew D. Smith (624-636).
Readily prepared 2-arylacetic anhydrides act as convenient ammonium enolate precursors in isothiourea (HBTM-2.1)-mediated catalytic asymmetric intermolecular Michael addition–lactonisation processes, giving diverse synthetic building blocks in good yield with high diastereo- and enantiocontrol (up to 98 : 2 dr and >99% ee).

Total synthesis of (S)-14-azacamptothecin by Feng Liu; Chaozhong Li (637-642).
A concise synthesis of (S)-14-azacamptothecin has been accomplished in 8 steps from commercially available (R)-2-hydroxybutanoic acid. The key strategy involved in this synthesis is the Michael addition/β-elimination sequence to construct the chiral quaternary carbon center, followed by palladium catalyzed cyanation and formal [4 + 2] cycloaddition/elimination/aromatization in a one pot manner to form the pyrrolopyrimidin-4-one moiety.

Electrophilic ipso-iodocyclization of N-benzyl-N-(1-naphthyl)propiolamides: synthesis of complex polycyclic lactams by Li-Jing Wang; Hai-Tao Zhu; Yi-Feng Qiu; Xue-Yuan Liu; Yong-Min Liang (643-650).
An intramolecular electrophilic ipso-iodocyclization of N-benzyl-N-(1-naphthyl)propiolamides combined with the Friedel–Crafts-type reaction for the synthesis of complex polycyclic lactams is reported. The resulting iodinated cyclization product can provide a very useful handle for further structural manipulation.

A recyclable and base-free method for the synthesis of 3-iodothiophenes by the iodoheterocyclisation of 1-mercapto-3-alkyn-2-ols in ionic liquids by Raffaella Mancuso; Christian S. Pomelli; Cinzia Chiappe; Richard C. Larock; Bartolo Gabriele (651-659).
The first example of an iodocyclisation reaction made recyclable by the use of an ionic liquid as the reaction medium is reported. Readily available 1-mercapto-3-alkyn-2-ols were smoothly converted into the corresponding 3-iodothiophenes (50–81% yields, 10 examples) when allowed to react with iodine (1–2 equiv.) in a proper ionic liquid, such as 1-ethyl-3-methylimidazolium ethyl sulfate (EmimEtSO4), as the solvent under mild reaction conditions (25 °C) and in the absence of an external base. The reaction medium can be recycled several times without significantly affecting the reaction outcome. Theoretical calculations have also been performed to investigate the role of the ionic liquid anion in the reaction.

A novel environmentally sensitive fluorescent (ESF) purine nucleoside, cnaA, was synthesized and its photophysical properties were investigated. The base-modified fluorescent nucleoside cnaA exhibited remarkable solvatochromicity and environmentally sensitive dual fluorescence. By using cnaA, we have developed highly thymine (T) selective fluorescent DNA probes that can sense the corresponding T in a target DNA/RNA sequence, as measured by a distinct change in emission wavelength.

The first synthesis of (−)-isoambreinolide, (+)-vitexifolin D and (+)-vitedoin B by Hanane Bouanou; Rubén Tapia; M. José Cano; Jose M. Ramos; Esteban Alvarez; Ettahir Boulifa; Abdelaziz Dahdouh; Ahmed I. Mansour; Ramón Alvarez-Manzaneda; Rachid Chahboun; Enrique Alvarez-Manzaneda (667-672).
A very efficient method for synthesizing spirolactones is reported. Treatment of δ,ε-unsaturated carboxylic acids with iodine and triphenylphosphine under mild conditions leads to the corresponding spiro γ-lactones in high yield and with complete stereoselectivity. Utilizing this, the first synthesis of the terpene spirolactones (−)-isoambreinolide, (+)-vitexifolin D and (+)-vitedoin B has been achieved.

Steric vs. electronic effects in the Lactobacillus brevis ADH-catalyzed bioreduction of ketones by Cristina Rodríguez; Wioleta Borzęcka; Johann H. Sattler; Wolfgang Kroutil; Iván Lavandera; Vicente Gotor (673-681).
Lactobacillus brevis ADH (LBADH) is an alcohol dehydrogenase that is commonly employed to reduce alkyl or aryl ketones usually bearing a methyl, an ethyl or a chloromethyl as a small ketone substituent to the corresponding (R)-alcohols. Herein we have tested a series of 24 acetophenone derivatives differing in their size and electronic properties for their reduction employing LBADH. After plotting the relative activity against the measured substrate volumes we observed that apart from the substrate size other effects must be responsible for the activity obtained. Compared to acetophenone (100% relative activity), other small substrates such as propiophenone, α,α,α-trifluoroacetophenone, α-hydroxyacetophenone, and benzoylacetonitrile had relative activities lower than 30%, while medium-sized ketones such as α-bromo-, α,α-dichloro-, and α,α-dibromoacetophenone presented relative activities between 70% and 550%. Moreover, the comparison between the enzymatic activity and the obtained final conversions using an excess or just 2.5 equiv. of the hydrogen donor 2-propanol, denoted again deviations between them. These data supported that these hydrogen transfer (HT) transformations are mainly thermodynamically controlled. For instance, bulky α-halogenated derivatives could be quantitatively reduced by LBADH even employing 2.5 equiv. of 2-propanol independently of their kinetic values. Finally, we found good correlations between the IR absorption band of the carbonyl groups and the degrees of conversion obtained in these HT processes, making this simple method a convenient tool to predict the success of these transformations.

Effect of configuration of 2-vinyldiazocarbonyl compounds on their reactivity: experimental and computational study by Murat B. Supurgibekov; David Cantillo; C. Oliver Kappe; G. K. Surya Prakash; Valerij A. Nikolaev (682-689).
Non-fluorinated vinyldiazo compounds with trans-configuration irrespective of the nature of 3-R1-substituent (R1 = H, Me, TBSO) even under ambient conditions easily cyclize to produce pyrazoles, while cis-stereoisomers undergo similar ring closure only at elevated temperatures or decompose to produce vinyloxocarbene reaction products. The 3-CF3-substituted analogues with cis- or trans-configuration do not produce pyrazoles at all, but on heating furnish only vinylcarbene derived products. DFT calculations of theoretical energy barriers adequately explain the different experimental reactivity found for stereoisomeric vinyldiazocarbonyl compounds, and a new model for their interconversion through the corresponding pyrazoles has been suggested.

Synthesis of substituted exo-glucals via a modified Julia olefination and identification as selective β-glucosidase inhibitors by Samuel Habib; Florent Larnaud; Emmanuel Pfund; Teresa Mena Barragán; Thierry Lequeux; Carmen Ortiz Mellet; Peter G. Goekjian; David Gueyrard (690-699).
A series of fluorine and non-fluorine-substituted C-glucosylidenes (exo-glucals) has been synthesized via a modified Julia olefination. The deprotected exo-glucals were prepared in five steps from commercially available d-gluconolactone. The evaluation of this original family of compounds against a panel of glycosidases showed a highly specific in vitro activity towards mammalian β-glucosidase depending on the double bond substituents.

Synthesis of thioamides via one-pot A3-coupling of alkynyl bromides, amines, and sodium sulfide by Yadong Sun; Huanfeng Jiang; Wanqing Wu; Wei Zeng; Jianxiao Li (700-707).
We herein describe a novel method for the synthesis of thioamides by a three component condensation of alkynyl bromides, amines, and Na2S·9H2O. The developed method is applicable for a wide range of amines and alkynyl bromides bearing different functional groups furnishing the corresponding products in moderate to excellent yields.

Back cover (709-710).