Organic & Biomolecular Chemistry (v.11, #34)

Front cover (5549-5549).

Inside front cover (5550-5550).

Contents list (5551-5557).

Chemical transformations via catalytic C–H bond activation have been established as one of the most powerful tools in organic synthetic chemistry. Transition-metal-catalyzed addition reactions of C–H bonds to polar C–X (X = N, O) multiple bonds, such as aldehydes, ketones, imines, isocyanates, nitriles, isocyanides, carbon monoxide and carbon dioxide, have undergone a rapid development in recent years. In this review, recent advances in this active area have been highlighted and their mechanisms have been discussed.

Potential use of synthetic α-galactosyl-containing glycotopes of the parasite Trypanosoma cruzi as diagnostic antigens for Chagas disease by Roger A. Ashmus; Nathaniel S. Schocker; Yanira Cordero-Mendoza; Alexandre F. Marques; Erika Y. Monroy; Andrew Pardo; Luis Izquierdo; Montserrat Gállego; Joaquim Gascon; Igor C. Almeida; Katja Michael (5579-5583).
A synthetic glycoarray containing non-reducing α-galactopyranosyl moieties related to mucin O-glycans of the parasite Trypanosoma cruzi was evaluated by a chemiluminescent enzyme-linked immunosorbent assay with sera from patients with chronic Chagas disease. Our data revealed the disaccharide Galα(1,3)Galβ as the immunodominant glycotope, which may eventually be employed as a diagnostic antigen for Chagas disease.

The synthesis of human growth hormone-releasing hormone (hGH-RH), by the chemoselective serine/threonine ligations (STLs) of three unprotected peptide fragments, is reported. To allow for the multiple-fragment ligation, we chose the Msz (p-(methylsulfinyl)benzyloxycarbonyl) group, which is compatible with the preparation of peptide salicylaldehyde esters via Fmoc-SPPS and readily removed by reductive acidolysis, to protect the serine and threonine residue at the N-terminus.

Synergistic effect of additives on cyclopropanation of olefins by Donghao Cheng; Deshun Huang; Yian Shi (5588-5591).
An efficient cyclopropanation of olefins with Zn(CH2I)2, a catalytic amount of CCl3CO2H, and 1,2-dimethoxyethane at room temperature is described. A wide variety of olefins, including acid-sensitive substrates, can be cyclopropanated in 71–99% yield.

In a dynamic six-component library, the formation of the rather weak HETPYP-I complexation can be enforced by exploiting the orthogonality and high stability of its counterpart in the sorting process, a HETTAP complex. The concept was used in a follow-up integrative self-sorting, enabling the formation of two five-component supramolecular structures: a trapezoid and a scalene triangle.

Ligand and substrate effects during Pd-catalyzed cyclizations of alkyne-tethered cyclohexadienones by Rodolfo Tello-Aburto; Kyle A. Kalstabakken; Andrew M. Harned (5596-5604).
The effects of ligand and substrate choice on the Pd-catalyzed cyclization of alkyne-tethered cyclohexadienones were examined. In the presence of a chiral ligand, the enantioselectivity of the desymmetrization is remarkably sensitive to structural changes in both the ligand and the substrate. Additionally, the regioselectivity of the reaction (5- vs. 6-membered ring formation) is dependent on the proximity of heteroatoms to the alkyne.

DNSC: a fluorescent, environmentally sensitive cytidine derivative for the direct detection of GGG triad sequences by Ki Tae Kim; Hyun Woo Kim; Dohyun Moon; Young Min Rhee; Byeang Hyean Kim (5605-5614).
With the goal of developing a fluorescent nucleoside sensitive to its environment, in this study we synthesized DNSC, a novel modified 2′-deoxycytidine bearing a 5-(dimethylamino)naphthalene-1-sulfonyl (dansyl) moiety at the N4 position, and tested its properties in monomeric and oligomeric states. DNSC undergoes intramolecular photoinduced electron transfer between its dansyl and cytosine units, resulting in remarkable changes in fluorescence that depend on the choice of solvent. In addition, the fluorescence behavior and thermal stability of oligonucleotides containing DNSC are dependent on the nature of the flanking and neighboring bases. Notably, DNSC exhibits fluorescence enhancement only in fully matched duplex DNA containing a GGG triad sequence. The environmental sensitivity of DNSC can be exploited as a fluorescence tool for monitoring the interactions of DNA with other biomolecules, including DNA, RNA, and proteins.

A new, convenient and efficient transition metal-free synthesis of S-alkyl dithiocarbamates through one-pot reaction of N-tosylhydrazones, carbon disulfide and amines is reported. Tosylhydrazones derived from various aromatic and aliphatic ketones or aldehydes were tested and gave dithiocarbamates in good to excellent yields. The tosylhydrazones can be generated in situ without isolation, which provides a simpler one-pot method to synthesize dithiocarbamates via the reaction of carbonyl compounds, carbon disulfide and amines in the presence of 4-methylbenzenesulfonohydrazide.

Diverse reactivity in microwave-promoted catalyst-free coupling of substituted anilines with ethyl trifluoropyruvate and biological evaluation by Chen Zhang; Dao-Min Zhuang; Jia Li; Si-Yuan Chen; Xiao-Long Du; Jian-Yong Wang; Jing-Yun Li; Biao Jiang; Jian-Hua Yao (5621-5633).
Diverse reactivity by coupling of substituted anilines with ethyl trifluoropyruvate was developed under microwave irradiation without catalysts to generate 3-trifluoromethyl-3-hydroxy oxindoles, aromatic hydroxy trifluoromethyl esters, and 1,2-dicarbonyl compounds in a fast and efficient manner. The plausible mechanism for obtaining different products was proposed. Furthermore, the anti-HIV activity of aromatic hydroxy trifluoromethyl esters was first reported. The best inhibitory activity against wild-type HIV-1 IIIB was exemplified by trifluoromethyloxindole 3q with an IC50 = 5.8 μM, which also displayed potential activity against Y181C mutant virus with an IC50 = 7.5 μM. More significantly, the activities of oxindoles 3q and 3r to inhibit K103N/Y181C double mutant HIV-1 reverse transcriptase (RT) are probably similar to that of the second-generation nonnucleoside inhibitor HBY 097 by docking calculation.

The N-heterocyclic carbene catalyzed annulation of benzofuran-2,3-diones and enals via homoenolate intermediates is described. The reaction provided a direct and efficient method for the synthesis of spiro-bis-lactones. The ketone-carbonyl group annulated products and the ester-carbonyl group annulated products can be obtained as major products with good yields by convenient catalyst regulation. Furthermore, commercially available thiazolium salt can also catalyze this reaction with modest yield.

The effect of the 4-amino functionality on the photophysical and DNA binding properties of alkyl-pyridinium derived 1,8-naphthalimides by Swagata Banerjee; Jonathan A. Kitchen; Thorfinnur Gunnlaugsson; John M. Kelly (5642-5655).
The synthesis and characterisation of two cationic pyridinium based 4-amino-1,8-naphthalimide derivatives (2 and 3) are described and compared to those of compound 1. The photophysical properties of 2 and 3 are shown to vary greatly with the solvent polarity and H-bonding ability. The dimethylamino substitution in 3 results in a weak quantum yield of fluorescence emission due to faster non-radiative deactivation of the excited singlet state than that seen for 2. As with 1, the fluorescence of 2 was found to be enhanced in its 1 : 1 complex with 5′-adenosine-monophosphate (5′-AMP) while it was partially quenched in its complex with 5′-guanosine-monophosphate (5′-GMP). In contrast, the fluorescence of 3 was enhanced (‘switched on’) in the presence of both adenine and guanine rich sequences. Linear and circular dichroism studies showed that each of 1, 2 and 3 binds to double-stranded DNA by intercalation. However, 2 and 3 do not show the preference for AT-rich DNA observed for 1. Comparative fluorescence studies with double stranded DNA show that the emission of 3 was 16 times enhanced in its DNA bound form, suggesting potential use of this structure as a spectroscopic probe for studying nucleic acid structure.

We have synthesized and characterized a series of dendritic oligothiophenes comprising peripheral mannose functionalities by copper-mediated 1,3-dipolar cycloaddition reaction. The hybrids were accessible either by attachment of acetyl-protected mannosides at the dendritic oligothiophene or by the direct synthesis of the deprotected mannose–oligothiophene conjugates by applying heterogeneous reaction conditions. The specific interaction of the functional dendritic hybrids with lectin protein Concanavalin A was investigated by absorption and fluorescence spectroscopic measurements. An enhancement of turbidity was observed due to the specific interaction of the mannosidic dendrimer with Con A. The specific interaction was further confirmed by fluorescence quenching upon addition of the mannosidic hybrid to Con A.

Pyridinium-based tripodal chemosensor in visual sensing of AMP in water by indicator displacement assay (IDA) by Kumaresh Ghosh; Sk Sarfaraj Ali; Avik Ranjan Sarkar; Asmita Samadder; Anisur Rahman Khuda-Bukhsh; Ioannis D. Petsalakis; Giannoula Theodorakopoulos (5666-5672).
A simple pyridinium-based tripodal chemosensor, 1, effectively recognizes AMP over ATP and ADP through indicator displacement assay (IDA) technique in water at pH 6.4. The good recognition of 1 is due to the better accommodation of AMP at the core of 1 as well as functional interaction involving hydrogen bonding and charge–charge interaction. The sensor 1 also recognizes intracellular AMP.

Conversion of a non-selective adenosine receptor antagonist into A3-selective high affinity fluorescent probes using peptide-based linkers by Andrea J. Vernall; Leigh A. Stoddart; Stephen J. Briddon; Hui Wen Ng; Charles A. Laughton; Stephen W. Doughty; Stephen J. Hill; Barrie Kellam (5673-5682).
Advances in fluorescence-based imaging technologies have helped propel the study of real-time biological readouts and analysis across many different areas. In particular the use of fluorescent ligands as chemical tools to study proteins such as G protein-coupled receptors (GPCRs) has received ongoing interest. Methods to improve the efficient chemical synthesis of fluorescent ligands remain of paramount importance to ensure this area of bioanalysis continues to advance. Here we report conversion of the non-selective GPCR adenosine receptor antagonist Xanthine Amine Congener into higher affinity and more receptor subtype-selective fluorescent antagonists. This was achieved through insertion and optimisation of a dipeptide linker between the adenosine receptor pharmacophore and the fluorophore. Fluorescent probe 27 containing BODIPY 630/650 (pKD = 9.12 ± 0.05 [hA3AR]), and BODIPY FL-containing 28 (pKD = 7.96 ± 0.09 [hA3AR]) demonstrated clear, displaceable membrane binding using fluorescent confocal microscopy. From in silico analysis of the docked ligand-receptor complexes of 27, we suggest regions of molecular interaction that could account for the observed selectivity of these peptide-linker based fluorescent conjugates. This general approach of converting a non-selective ligand to a selective biological tool could be applied to other ligands of interest.

Bisacenaphthopyrazinoquinoxaline derivatives: synthesis, physical properties and applications as semiconductors for n-channel field effect transistors by Chenhua Tong; Jingjing Chang; Jun Min Tan; Gaole Dai; Kuo-Wei Huang; Hardy Sze On Chan; Chunyan Chi (5683-5691).
Several bisacenaphthopyrazinoquinoxaline (BAPQ) based derivatives 1–3 were synthesized by condensation between the acenaphthenequinones and 1,2,4,5-tetraaminobenzene tetrahydrochloride. Their optical, electrochemical and self-assembling properties are tuned by different substituents. Among them, compound 3 possesses a homogeneously distributed low-lying LUMO due to the peripheral substitution with four cyano groups. The corresponding n-channel field effect transistors showed a field effect electron mobility of 5 × 10−3 cm2 V−1 s−1.

The Lewis acid-catalyzed domino 1,2-addition/1,4-addition/elimination between (Z)-3-hexene-2,5-dione and 1,3-dicarbonyls delivers 3-methyl-6,7-dihydrobenzofuran-4(5H)-ones exclusively with yields up to 82%. The combination of this new process with the laccase-catalyzed formation of (Z)-3-hexene-2,5-dione by oxidative cleavage of 2,5-dimethylfuran allows for the synthesis of 6,7-dihydrobenzofuran-4(5H)-ones starting directly from 2,5-dimethylfuran.

Synthesis of alkylcarbonate analogs of O-acetyl-ADP-ribose by Marcela Dvorakova; Radim Nencka; Milan Dejmek; Eva Zbornikova; Anna Brezinova; Marie Pribylova; Radek Pohl; Marie E. Migaud; Tomas Vanek (5702-5713).
The non-hydrolyzable alkylcarbonate analogs of O-acetyl-ADP-ribose have been synthesized from the phosphorylated ribose derivatives after coupling with AMP morpholidate promoted by mechanical grinding. The analogs were assessed for their ability to inhibit the human sirtuin homolog SIRT1.

Activity-based probes (ABPs) are powerful tools for functional proteomics studies. Their selectivity can be influenced by modification of a recognition element that interacts with pockets near the active site. For serine proteases there are a limited number of simple and efficient synthetic procedures for the development of selective probes. Here we describe a new synthetic route combining solid and solution phase chemistries to generate a small library of diphenyl phosphonate probes. Building blocks carrying a P1 recognition element and an electrophilic phosphonate warhead were prepared in solution and ‘clicked’ on-resin onto a tripeptide. We show the ability to modulate the activity and selectivity of diphenyl phosphonate ABPs and demonstrate activity-dependent labeling of endogenous proteases within a tissue proteome. The herein described synthetic approach therefore serves as a valuable method for rapid diversification of serine protease ABPs.

An unprecedented N-heterocyclic carbene (NHC) catalyzed Morita–Baylis–Hillman (MBH) reaction of β-substituted nitroalkenes and azodicarboxylates has been developed. Both β-aryl and β-alkyl nitroalkenes worked well for the reaction using 5 mol% of NHC catalyst, giving the desired α-hydrazino-α,β-unsaturated nitroalkenes in good to excellent yields.

The relative hydrolytic reactivities of pyrophosphites and pyrophosphates by Dharmit Mistry; Nicholas Powles (5727-5733).
The pH-rate profiles for the hydrolysis of pyrophosphate (PP(v)) and pyrophosphite (PP(iii), pyro-di-H-phosphonate) are a complex function of pH, reflecting the different ionic species and their relative reactivities. PP(iii) is more reactive than PP(v) at all pHs and only PP(iii) shows a hydroxide-ion reaction at high pH, so it is 1010-fold more reactive than PP(v) in 0.1 M NaOH. The pKa2 of PP(iii) ∼0.44, so the dominant species at pH's > 1 is the di-anion PP(iii)2−. Although there is no observable (NMR or ITC) binding of Mg2+ to the PP(iii) di-anion there is a modest increase in the rate of hydrolysis of PP(iii) by Mg2+. PP(iii) is neither a substrate nor an inhibitor of pyrophosphatase, the enzyme that efficiently catalyses the hydrolysis of PP(v).

Inside back cover (5735-5736).