Organic & Biomolecular Chemistry (v.11, #4)

Front cover (525-525).

Inside front cover (526-526).

Contents list (527-536).

Using singlet oxygen to synthesise the CDE-ring system of the pectenotoxins by Antonia Kouridaki; Tamsyn Montagnon; Dimitris Kalaitzakis; Georgios Vassilikogiannakis (537-541).
A non-classical route to the key CDE-ring fragment of the pectenotoxins has been developed which showcases a remarkable singlet oxygen-mediated cascade reaction sequence to install the complete DE ring system.

A sequential oxidative tandem cyclization reaction mediated by a combination of (diacetoxyiodo)benzene (DIB) with zinc oxide (ZnO) is presented for the synthesis of 5-methyl-2-phenylisoxazol-3(2H)-ones from β-ketobutylanilides. A variety of β-ketobutylanilide compounds were used in this approach, and a wide range of functionalized 5-methylisoxazol-3(2H)-ones were obtained in good to excellent yields.

2-Substituted 3-arylindoles through palladium-catalyzed arylative cyclization of 2-alkynyltrifluoroacetanilides with arylboronic acids under oxidative conditions by Antonio Arcadi; Sandro Cacchi; Giancarlo Fabrizi; Antonella Goggiamani; Antonia Iazzetti; Fabio Marinelli (545-548).
Free NH 2-substituted 3-arylindoles have been prepared usually in good to high yields through the palladium-catalyzed reaction of readily available 2-alkynyltrifluoroacetanilides with arylboronic acids under oxidative conditions. The reaction tolerates a variety of useful functional groups both in the arylboronic acid and in the alkyne, including chloro, formyl, and ester groups.

Reactivity assessment of chalcones by a kinetic thiol assay by Sabine Amslinger; Nafisah Al-Rifai; Katrin Winter; Kilian Wörmann; Rebekka Scholz; Paul Baumeister; Martin Wild (549-554).
The electrophilic nature of chalcones (1,3-diphenylprop-2-en-1-ones) and many other α,β-unsaturated carbonyl compounds is crucial for their biological activity, which is often based on thiol-mediated regulation processes. To better predict their biological activity a simple screening assay for the assessment of the second-order rate constants (k2) in thia-Michael additions was developed. Hence, a clear structure–activity relationship of 16 differentially decorated hydroxy-alkoxychalcones upon addition of cysteamine could be established. Moreover, amongst other naturally occurring α,β-unsaturated carbonyl compounds k2 values for curcumin and cinnamaldehyde were gained while cinnamic acids or esters gave no or very slow reactions.

A BODIPY-based fluorescent dye for mitochondria in living cells, with low cytotoxicity and high photostability by Si Zhang; Tong Wu; Jiangli Fan; Zhiyong Li; Na Jiang; Jingyun Wang; Bairui Dou; Shiguo Sun; Fengling Song; Xiaojun Peng (555-558).
A BODIPY-based dye, OBEP, has been developed to act as a mitochondrial fluorescence probe. This dye is of high stability, low toxicity and insensitive in a pH range as wide as pH 2–10. Its uptake into mitochondria is independent of mitochondrial membrane potential in living cells. OBEP can label swollen mitochondria resulting from different degrees of cell damage in light and resist fading even after 12 h of incubation.

First synthesis of (+)-myrrhanol C, an anti-prostate cancer lead by Victoriano Domingo; Lidia Lorenzo; José F. Quilez del Moral; Alejandro F. Barrero (559-562).
The first synthesis of (+)-myrrhanol C (1), an antitumor polypodane-type bicyclic triterpene with inhibitory activity against androgen insensitive prostate cancers, is reported herein (IC50 10 μmolar). A key step in our convergent synthesis of (+)-myrrhanol C and related analogues is the employment of a microbial stereo- and regioselective late stage C–H oxidation. A low-waste and sustainable process has been developed to prepare (+)-myrrhanol C for further biological studies.

pH Induced dual “OFF–ON–OFF” switch: influence of a suitably placed carboxylic acid by Kalyan K. Sadhu; Shin Mizukami; Akimasa Yoshimura; Kazuya Kikuchi (563-568).
The design and synthesis of molecular probes competent for pH signaling within or beyond a certain range is a complicated matter. Herein a new mechanism for ‘‘OFF–ON–OFF’’ absorbance and fluorescence intensities vs. pH behaviour is described. The probe design is based on the connection of carboxylic acid derivatized benzoxazole and 7-hydroxycoumarin/iminocoumarin parts. The protonation/deprotonation of the carboxylic acid (–COOH), N atom of benzoxazole ring and hydroxy part of the coumarin ring have been used for this mechanistic study. We have designed the molecule in such a fashion that deprotonation of the hydroxy part takes place at a lower pKa compared to deprotonation of the –COOH. The dual ‘‘OFF–ON–OFF’’ properties of our probes depend on the C–C bond between the two different heterocyclic parts. Quantum mechanical calculations showed that the particular ‘C–C’ bond has an additional π-character. The twisting around this bond in different forms is responsible for such an ‘‘OFF–ON–OFF’’ property. This mechanism is new in fluorescence alteration processes. The delocalization of charge from one heterocyclic part to the other heterocyclic part in the mono- and dianionic forms controls the ‘‘OFF–ON–OFF’’ properties. The role of the carboxylic acid group was examined using an acetyl substituted derivative. One of our probes was successfully applied in live cell imaging studies in media at different pH.

The CAN-catalyzed reaction between 3,5-disubstituted anilines, vinyl ethers and aromatic aldehydes leads to trans-2-aryl-4-arylaminotetrahydroquinolines, in an AA′BC sequential multicomponent transformation related to the Povarov reaction that was also extended to the use of a second aniline as the C-4 substituent. The unusual trans stereochemistry was explained by stabilization of the corresponding intermediate by intramolecular hydrogen bonding. The presence of the 4-anilino substituent allowed adapting the method to the synthesis of 4-unsubstituted 2-arylquinolines, by treatment of the crude product from the MCR with FeCl3 in methanol.

Thiol-inducible direct fluorescence monitoring of drug release by Jun Wu; Rong Huang; Changcheng Wang; Wenting Liu; Jiaqi Wang; Xiaocheng Weng; Tian Tian; Xiang Zhou (580-585).
A new bifunctional compound NCC, which undergoes thiol-mediated disulfide cleavage after cell entry, produces a red-shifted fluorescent emission in the cytosol and releases free active DNA alkylating agent CLB into the nucleus, and finally leads to DNA damage and cell death.

Treatment of β-fluoroalkylated-α,β-unsaturated ketones with 1.2 equiv. of various arylboronic acids in the presence of 5 mol% of [Rh(COD)2]BF4 and 6 mol% of (S)-BINAP in toluene/H2O (v/v = 4/1) at the reflux temperature for 3 h gave the corresponding Michael adducts in high yields with over 90% enantioselectivity. Though other electron-deficient alkenes, such as vinylsulfone and vinylphosphonate, were found to be much less reactive in the rhodium-catalyzed conjugate addition with arylboronic acids, the reaction of various arylstannanes toward such electron-deficient alkenes took place very smoothly to afford the corresponding adducts in high yields.

Constructing intricate geometric arrangements of components is one of the central challenges of nanotechnology. Here we report a convenient, versatile method to organize discrete length single-walled carbon nanotubes (SWNT) into complex geometries using 2D DNA origami structures. First, a size exclusion HPLC purification protocol was used to isolate uniform length, SWNTs labelled with single stranded DNA (ssDNA). The nanotube-bound ssDNAs are composed of two domains: a SWNT binding domain and a linker binding domain. Although initially bound to the SWNTs, the linker domain is displaced from the surface by the addition of an external ssDNA linker strand. One portion of the linker strand is designed to form a double helix with the linker binding domain, compelling the DNA to project away from the SWNT surface. The remainder of the linker strand contains an ssDNA origami recognition sequence available for hybridization to a DNA origami nanostructure. Two different 2D DNA origami structures, a triangle and a rectangle, were used to organize the nanotubes. Several arrangements of nanotubes were constructed, with defined tube lengths and inter-tube angles. The uniform tube lengths and positional precision that this method affords may have applications in electronic device fabrication.

A novel protecting group directed diversity leading to the synthesis of bridged bicyclic and six-membered iminocyclitols from a common carbohydrate derived diamino triol under Mitsunobu conditions is reported. When the intramolecular cyclization of benzoyl derivative 16 was carried out under Mitsunobu conditions, an unprecedented one-pot domino intramolecular “cyclization–N→O benzoyl migration–cyclization” reaction sequence occurred resulting in the formation of a chiral 2,6-diazabicyclo[3.2.1]octane-4,8-diol 21 in high yield. The structure of this novel bridged bicyclic compound was established through detailed NMR studies and single crystal X-ray analysis. On the other hand, the tert-butyldimethylsilyl derivative of the same substrate afforded protected 6-amino-1,6-dideoxy-l-gulonojirimycin 32 as the sole product under identical conditions. An attempt has been made to explain this difference in their reactivity through conformational analysis. The glycosidase inhibition studies of new compounds reported in this manuscript revealed that these molecules display moderate but selective inhibition against β-N-acetylhexosaminidase.

Escherichia coli LysU is a potential surrogate for human lysyl tRNA synthetase in interactions with the C-terminal domain of HIV-1 capsid protein by Nonlawat Boonyalai; James R. Pullen; Mohd Firdaus Abdul Wahab; Michael Wright; Andrew D. Miller (612-620).
Human lysyl-tRNA synthetase (hLysRS) is known to interact directly with human immunodeficiency virus type-1 (HIV-1) GagPol polyproteins, and both hLysRS with tRNALys3 are selectively packaged into emerging HIV-1 viral particles. This packaging process appears to be mediated by contact between the motif 1 helix h7 of hLysRS and the C-terminal dimerization domain of the HIV-1 capsid protein (CA) segment of Gag or GagPol. Given similarities between hLysRS and Escherichia coli (E. coli) heat shock protein LysU, we investigate if LysU might be an hLysRS surrogate for interactions with Gag or GagPol proteins. We report on a series of studies involving three CA C-domains: CA146 (intact domain), CA151 (truncated domain), and CA146-M185A (M185A, CA dimer interface mutant). After confirming that LysU and CA146 are dimeric whilst CA151 and M185A remain monomeric, we use glutathione S-transferase (GST) pull-down assays to demonstrate the existence of specific interactions between LysU and all three CA-C domains. By means of 1H-NMR titration experiments, we estimate Kd values of 50 μM for the interaction between LysU and CA146 or >500 μM for interactions between LysU and CA151 or LysU and M185A. The reason for these binding affinity differences may be that interactions between LysU and CA146 take place through dimer–dimer interactions resulting in a α2β2 heterotetramer. LysU/CA-C protein interactions are weaker than those reported between hLysRS and the Gag, CA or CA146 proteins, and hLysRS/Gag binding interactions have also been suggested to involve only αβ heterodimer formation. Nevertheless, we propose that LysU could act as a surrogate for hLysRS with respect to Gag and GagPol polyprotein interactions although arguably not sufficiently for LysU to act as an inhibitor of the HIV-1 life cycle without further adaptation or mutation. Potentially, LysU and/or LysU mutants could represent a new class of anti-HIV-1 therapeutic agent.

The conversion of [(4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino]azines into azine fused thiazole-2-carbonitriles by Panayiotis A. Koutentis; Maria Koyioni; Sophia S. Michaelidou (621-629).
The thermolysis of several N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-n-amines (where n = 2, 3 and 4) gives a mixture of thiazolopyridine-2-carbonitriles in low to moderate yields. Introduction, by design, of a chlorine substituent at the C2 or C4 position of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3-amine and other selected azines enables a BnEt3NI mediated ANRORC style ring transformation that provides fourteen heteroazine fused thiazole-2-carbonitriles in moderate to near quantitative yields. The synthesis described herein therefore provides a facile high yielding two-step route to heteroazine fused thiazole-2-carbonitriles starting from 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt) and ortho- or para-chloro substituted meta-aminoazines.

Investigation of the ring-closing metathesis of peptides in water by Stephen A. Cochrane; Zedu Huang; John C. Vederas (630-639).
A systematic study of the ring-closing metathesis (RCM) of unprotected oxytocin and crotalphine peptide analogues in water is reported. The replacement of cysteine with S-allyl cysteine enables RCM to proceed readily in water containing excess MgCl2 with 30% t-BuOH as a co-solvent. The presence of the sulfur atom is vital for efficient aqueous RCM to occur, with non-sulfur containing analogues undergoing RCM in low yields.

Structural characterization of a peptoid with lysine-like side chains and biological activity using NMR and computational methods by Ulrich Sternberg; Esther Birtalan; Igor Jakovkin; Burkhard Luy; Ute Schepers; Stefan Bräse; Claudia Muhle-Goll (640-647).
N-Substituted glycine oligomers or peptoids with charged side chains are a novel class of cell penetrating peptide mimetics and have been shown to serve as drug delivery agents. Here, we investigated by NMR spectroscopy and quantum chemical calculations whether a Rhodamine B labelled peptoid [RhoBSpiro-Ahx]-[But]6ANH2 with lysine-like side chains adopts structural motifs similar to regular peptides. Due to a low chemical shift dispersion, high resolution structure determination with conventional NMR-derived distance restraints and J-couplings was not possible. Instead, a combined assignment and structure refinement strategy using the QM/MM force field COSMOS-NMR was developed to interpret the highly ambiguous chemical shift and distance constraints and obtain a medium resolution three-dimensional structural model. This allowed us to select for the all cis-amide conformation of the peptide with a pseudo-helical arrangement of extended side chains as a faithful representative structure of [RhoBSpiro-Ahx]-[But]6ANH2. We tested the biological activity of the peptoid by live-cell imaging, which showed that the cellular uptake of the peptoid was comparable to conventional cell-penetrating peptides.

Control of the ambident reactivity of the nitrite ion by Hai Dong; Martin Rahm; Niranjan Thota; Lingquan Deng; Tore Brinck; Olof Ramström (648-653).
In previous studies, it was reported that a neighbouring equatorial ester group is essential for a good yield of nitrite-mediated triflate inversion, whereas with neighbouring benzyl ether groups or axial ester groups, mixtures are generally produced. In the present study, the origin of this difference was addressed. The ambident reactivity of the nitrite ion has been found to be the cause of the complex product formation observed, which can be controlled by a neighbouring equatorial ester group. Both N-attack and O-attack occur in the absence of the ester group, whereas O-attack is favoured in its presence. A neighbouring group assistance mechanism is proposed, in addition to steric effects, based on secondary interactions between the neighbouring ester group and the incoming nucleophile. High-level quantum mechanical calculations were carried out in order to delineate this effect. The theoretical results are in excellent agreement with experiments, and suggest a catalytic role for the neighbouring equatorial ester group.

Two mesitylene based probes, having catechol/phenol units in conjunction to the Schiff base have been synthesized. The probe with a catechol unit can be used to sense and discriminate between F and CN through different colorimetric and fluorimetric responses using DMSO as solvent. However in DMSO : water (2 : 1) solution it responds selectively to CN ion. The probe with a phenol unit is highly selective and sensitive for CN and can be used for naked eye, semiquantitative sensing of CN ion in DMSO : water (2 : 1) solution. The chemodosimetry has been attributed to the acid catalyzed Strecker's reaction of an imine bond and is being reported for the first time in a Schiff's base.

The thermal multicomponent 1,3-dipolar cycloaddition (1,3-DC) of diethyl aminomalonate or α-amino esters (derived from glycine, alanine, phenylalanine, and phenylglycine) with ethyl glyoxylate and the corresponding dipolarophile such as maleimides, methyl acrylate, methyl fumarate, (E)-1,2-bis(phenylsulfonyl)ethylene, and electron deficient alkynes allows the diastereoselective synthesis of new polysubstituted pyrrolidine derivatives. Microwave-assisted heating processes give better results than conventional heating ones, affording endo-cycloadducts as major stereoisomers. In general, 2,5-cis-cycloadducts are preferentially formed according to the previous formation of the W-shaped dipole. Only in the 1,3-DC of the disulfone with phenylglycine and ethyl glyoxylate the corresponding exo-trans-cycloadduct was isolated. The compound endo-cis-4b, derived from phenylalanine, ethyl glyoxylate and N-benzylmaleimide, has been further transformed into a very complex diazabicyclo[2.2.1]octane skeleton with potential biological activity.

Synthesis of cyclically constrained sugar derived α/β- and α/γ-peptides by Antonio Franconetti; Sorel Jatunov; Pastora Borrachero; Manuel Gómez-Guillén; Francisca Cabrera-Escribano (676-686).
A general approach to enantiopure conformationally constrained sugar derived α/β- and α/γ-peptides has been established. Five-membered ring α/β-peptides were synthesized via formyl C-glycofuranosides, easy available from hexose-derived azido-2-equatorial-OH-glycopyranosides by DAST-promoted ring contraction. By means of a regioselective oxidation with TEMPO at C-6 of hexose-derived 3-azido glycopyranosides as the key step, two- and three-residue α/γ-peptides having a six-membered ring were obtained in good yields and under very simple experimental conditions.

Back cover (687-688).