Organic & Biomolecular Chemistry (v.11, #16)

Front cover (2545-2545).

Inside front cover (2546-2546).

Contents list (2547-2553).

Recent advances in the synthesis of aromatic nitro compounds by Guobing Yan; Minghua Yang (2554-2566).
Aromatic nitro compounds are important intermediates in synthetic organic chemistry as well as in the chemical industry. Numerous useful methods for their preparation have been developed in recent years. In this review, recent advances in the synthesis of aromatic nitro compounds are summarized, including the nitration of aromatic hydrocarbons, aryl boronic acids, aryl halides and pseudohalides, aryl carboxylic acids and the oxidation of aryl primary amines and azides. Their mechanisms are discussed.

A photo-triggerable drug carrier based on cleavage of PEG lipids by photosensitiser-generated reactive singlet oxygen by Chikako Komeda; Atsushi Ikeda; Jun-ichi Kikuchi; Norihiro Ishida-Kitagawa; Hisashi Tatebe; Kazuhiro Shiozaki; Motofusa Akiyama (2567-2570).
To circumvent the limitations of polyethylene glycol (PEG) modified carriers, a photo-triggerable liposome was prepared which was modified by cholesterol derivatives via a cleavable vinyl ether linkage so that the PEGylated coating can be efficiently removed by a photoactivated fullerene. After the photocleavage of the PEG moiety, the intracellular uptake of the photo-triggerable liposome improved.

An efficient synthesis of the enantiomers of fluorenylethylchloroformate (FLEC) has been achieved that allows the routine application of the reagent for the resolution of chiral amines including unusual amino acids. The utility of the fluorenylethoxycarbonyl (Feoc) group as a chiral Fmoc equivalent, for combined resolution and protection of amino acids, in solid phase peptide synthesis is also shown.

A novel Pd/Cu catalyzed domino reaction for the synthesis of functionalized pyrrolo[1,2-b]pyridazines from readily accessible (hetero)aryl propargyl alcohols and 1-amino-2-bromopyrroles was developed. This cascade process involves a Sonogashira cross-coupling reaction, an isomerization and an intramolecular condensation.

Rapid thiolate exchange of dimethylarsonium, Me2As+, is observed between two different thiolate species in solution. NMR is used to characterize the equilibrium constants for interthiol transfer as well the rapid intra molecular conformational dynamics which leads to the coalescence of diastereotopic methyl resonances. These rapid exchange kinetics have important consequences of arsenic's toxicity and pharmacology.

A one-pot two-step synthesis of versatile indenones has been developed. This palladium(ii)-catalyzed transformation involves generation and condensation of ortho-functionalized 1,2-benzils from 2-(2-arylethynylphenyl)acetonitriles using Ph2SO as the oxidant. The resulting 3-cyanoindenones can be converted to various valuable molecules.

Vinyl sulfone-based ferrocenylation reagents: applications in conjugation and bioconjugation by Alicia Megia-Fernandez; Fernando Hernandez-Mateo; Francisco Santoyo-Gonzalez (2586-2596).
The easy vinyl sulfone derivatization of ferrocene allows the preparation of some effective, versatile and valuable ferrocenylation reagents. The applicability of such compounds in conjugation and bioconjugation of amine and/or thiol containing molecules and biomolecules through Michael-type addition under mild conditions that preserve the biological function of the latter is described. The feasibility of the methodology is demonstrated by the preparation of a variety of conjugates and bioconjugates (ferrocenyl terminated dendrimers and ferrocene–sugar, ferrocene–cyclodextrin, ferrocene–peptide and ferrocene–protein conjugates).

Domino synthesis of protochromic “ON–OFF–ON” luminescent 2-styryl quinolines by Rahime Cinar; Jan Nordmann; Elena Dirksen; Thomas J. J. Müller (2597-2604).
The microwave-assisted coupling-isomerization reaction (MACIR) opens a straightforward domino access to 2-styryl quinolines in good to excellent yields. The push–pull character of these lumophores can be enhanced by placing a dimethyl amino group as an auxochrome in the para-position of the styryl moiety whereas anti-auxochromes are located in the 6-position of the quinoline part. The optical absorption and emission properties of the compounds were studied in solvents of different polarity and at various pH. The pronounced proto- and solvochromicity of the absorption and emission properties qualify them as luminescent pH sensors with “ON–OFF–ON” emission profiles triggered by pH variation over a broad pH range. The electronic structure of the chromophores is rationalized by DFT calculations.

Regioselective and stereoselective benzylidene installation and one-pot protection of d-mannose by Pratap S. Patil; Chia-Chen Lee; Yu-Wen Huang; Medel Manuel L. Zulueta; Shang-Cheng Hung (2605-2612).
Oligosaccharide syntheses are an important source of well-defined sugar constructs particularly needed for the evaluation of structure–activity relationships. The chemical assembly of oligosaccharides requires several building blocks, that is, glycosyl donors and acceptors, which are prepared in multistep processes and in a generally tedious and time-consuming manner. Having developed one-pot procedures meant to minimise the effort in sugar building block preparation, we tackled herein the one-pot preparation of fully protected and 2-, 3-, 4-, and 6-alcohol derivatives of d-mannose, a widely distributed monosaccharide. As a consequence of the hydroxyl group pattern of d-mannose, regioselective and stereoselective benzylidenations were developed and later seamlessly utilised as the first transformation in the one-pot procedure.

Phosphomolybdic and phosphotungstic acids as efficient catalysts for the synthesis of bridged 1,2,4,5-tetraoxanes from β-diketones and hydrogen peroxide by Alexander O. Terent'ev; Ivan A. Yaremenko; Vera A. Vil’; Igor K. Moiseev; Sergey A. Kon'kov; Valery M. Dembitsky; Dmitri O. Levitsky; Gennady I. Nikishin (2613-2623).
Phosphomolybdic acid (PMA) and phosphotungstic acid (PTA) efficiently catalyze the addition of H2O2 to β-diketones to form bridged 1,2,4,5-tetraoxanes. These reactions are not accompanied by the formation of monocyclic peroxides containing hydroxy and hydroperoxide groups or polymeric peroxides. The use of these catalysts made it possible to obtain bridged tetraoxanes from easily oxidizable benzoylacetone derivatives and α-unsubstituted β-diketones. The syntheses are scaled up to ten grams. The resulting peroxides can be easily isolated from the reaction mixture by column chromatography. The yield of tetraoxanes depends on the structure of β-diketone and varies from 12 to 83%. NMR monitoring of two bridged 1,2,4,5-tetraoxanes synthesis was carried out.

Three alkyne-containing pyrrolysine derivatives were synthesized and genetically encoded into proteins by a mutant PylRS–tRNA pair with high efficiencies. With these alkyne handles, site-specific dual labeling of proteins can be achieved via a bioorthogonal thiol–yne ligation reaction.

4-Pentenols (dihomoallylic alcohols) are oxidized by cobalt(ii)-activated dioxygen in solutions of dimethyl disulfide and cyclohexa-1,4-diene to afford methylsulfanyl (CH3S)-functionalized tetrahydrofurans in up to 74% yield. The reaction is a cascade, composed of oxidative alkenol cyclization providing tetrahydrofuryl-2-methyl radicals, which are trapped in dimethyl disulfide. Homolytic methylsulfanyl substitution by carbon radicals is a slow reaction, as exemplified by the rate constant of kSCH3 = 3 × 104 M−1 s−1 (70 °C) derived from competition kinetics for the reaction between dimethyl disulfide and the trans-2-phenyltetrahydrofuryl-5-methyl radical. Methylsulfanyl-cyclizations therefore are experimentally performed in neat dimethyl disulfide, containing the minimum amount of cyclohexa-1,4-diene necessary for attaining almost quantitative alkenol conversion. The oxidative tetrahydrofuran synthesis occurs with noteworthy (>99%) 2,5-trans-stereoselectivity, as shown by the synthesis of diastereomerically pure 2,3- and 2,3,3-substituted 5-(methylsulfanyl)methyltetrahydrofurans from stereodefined 1,2-di- and 1,2,2-trisubstituted 4-pentenols. Changing the chemical nature of the disulfide reagent or the alkenol extends the scope of alkylsulfanyl-cyclization to ethylsulfanyl-cyclization, allylsulfanyl-transfer, or tetrahydropyran synthesis.

The biolabile 2′-O-pivaloyloxymethyl modification in an RNA helix: an NMR solution structure by Carine Baraguey; Eveline Lescrinier; Thomas Lavergne; Françoise Debart; Piet Herdewijn; Jean-Jacques Vasseur (2638-2647).
The pivaloyloxymethyl (PivOM) group is a biolabile 2′-O-ribose protection that is under development in a prodrug-based approach for siRNA applications. Besides an expected cellular uptake, nucleic acid sequences carrying PivOM showed also increased nuclease resistance and, in most cases, an affinity for complementary RNA. The r(CGCU*ACGC)dT:r(GCGUAGCG)dT model duplex containing a single modified residue (U*) was synthesized and its solution structure was determined by NMR. The duplex showed a maintained A-RNA helix. In U*, both 2′-O-acetal ester side chain and ring pucker presented a notable rigid conformation. The PivOM moiety was oriented with the carbonyl group turned outside the minor groove and with trans, -ac and -ac torsion angles around the C2′–O2′, O2′–CA and CA–OB1 bonds respectively. Gauche effects and dipolar interactions between the PivOM and the backbone appeared to be the predominant factors influencing the PivOM conformation and the orientation of the two supplementary H acceptors suggested that hydration could also play a role in the duplex stability.

Remarkable effect of CF3CH2OH for the halogen induced oxidative rearrangement reaction of aminals leading to 3,4-dihydroquinazolines by Kenichi Murai; Masato Shimura; Ryu Nagao; Daisuke Endo; Hiromichi Fujioka (2648-2651).
CF3CH2OH was found to be a useful solvent for the oxidative rearrangement reactions of aminals promoted by N-chlorosuccinimide, which proceed via the intermediacy of in situ formed chloro-aminals and that produce 3,4-dihydroquinazolines.

The Staudinger reaction with 2-imino-1,3-thiaselenanes toward the synthesis of C4 spiro-β-lactams by Yosuke Toyoda; Masayuki Ninomiya; Masahiro Ebihara; Mamoru Koketsu (2652-2659).
The Staudinger ketene–imine [2 + 2] cycloaddition reaction for conversion of α-heteroatom-substituted exocyclic imines to C4 heterocyclic spiro-β-lactams has rarely been investigated due to their instability. Herein, we describe the Staudinger reaction between ketenes and α-selenium-substituted exocyclic imines to synthesize C4 spiro-β-lactams.

Aqueous synthesis of N,S-dialkylthiophosphoramidates: design, optimisation and application to library construction and antileishmanial testing by Milena Trmčić; Frances L. Chadbourne; Paul M. Brear; Paul W. Denny; Steven L. Cobb; David R. W. Hodgson (2660-2675).
We recently reported the use of PSCl3 for the thiophosphorylation of alkylamines where the resulting N-thiophosphoramidate ions could be readily S-alkylated (Chem. Commun., 2011, 47, 6156–6158.). Herein we report the development of this methodology using amino acid, amino sugar, aminonucleoside and aniline substrates. The hydrolysis properties of N-thiophosphoramidate ions and their reactivities towards alkylating agents are also explored. In addition, we demonstrate the application of our approach to the preparation of a small library of compounds, including quinoline-based N,S-dialkylthiophosphoramidates which were tested for antileishmanial activity.

Scaffold optimization in discontinuous epitope containing protein mimics of gp120 using smart libraries by Gwenn E. Mulder; H (Linda). C. Quarles van Ufford; Jeroen van Ameijde; Arwin J. Brouwer; John A. W. Kruijtzer; Rob M. J. Liskamp (2676-2684).
A diversity of protein surface discontinuous epitope mimics is now rapidly and efficiently accessible. Despite the important role of protein–protein interactions involving discontinuous epitopes in a wide range of diseases, mimicry of discontinuous epitopes using peptide-based molecules remains a major challenge. Using copper(i) catalyzed azide–alkyne cycloaddition (CuAAC), we have developed a general and efficient method for the synthesis of collections of discontinuous epitope mimics. Up to three different cyclic peptides, representing discontinuous epitopes in HIV-gp120, were conjugated to a selection of scaffold molecules. Variation of the scaffold molecule, optimization of the ring size of the cyclic peptides and screening of the resulting libraries for successful protein mimics led to an HIV gp120 mimic with an IC50 value of 1.7 μM. The approach described here provides rapid and highly reproducible access to clean, smart libraries of very complex bio-molecular constructs representing protein mimics for use as synthetic vaccines and beyond.

Most reported Zn2+ probes suffer from the interference of background fluorescence originated from the conjugated structures of commonly utilized fluorophores. In this work, three novel meso-hydroxyl group substituted dipyrromethanes DPMOH1–DPMOH3 were synthesized and found to be colourless and nonfluorescent due to the interruption of the conjugated π system by an sp3 carbon between the two pyrrolic units. Interestingly, only the addition of Zn2+ to the solutions of DPMOH1–DPMOH3 promoted their oxidation to dipyrrin forms, and bright fluorescence “turn on” was observed due to the formation of corresponding dipyrrin complexes with the dipyrrin : zinc stoichiometry of 2 : 1. Zn2+ detection mechanism was investigated by UV-Vis, fluorescence, 1H NMR and HRMS analyses, which can be ascribed to the CHEF type fluorescence enhancement, resulting from good rigidity of the dipyrrin complexes. Hence, DPMOH1–DPMOH3 can be used as fluorescence turn-on Zn2+ probes with the advantage of no background fluorescence.

The first “ready-to-use” benzene-based heterotrifunctional cross-linker for multiple bioconjugation by Guillaume Viault; Sébastien Dautrey; Nicolas Maindron; Julie Hardouin; Pierre-Yves Renard; Anthony Romieu (2693-2705).
The synthesis and applications of the first water-soluble benzene derivative bearing a set of three different and orthogonal bioconjugatable groups (aminooxy, azido and thiol) are described. The combined use of a 5-amino isophthalic acid scaffold and unusual acid-labile protecting groups for temporarily masking aminooxy and thiol moieties has enabled the development of a highly convergent approach towards the synthesis of such a trivalent bioconjugation platform in good yields. The potential utility of this “ready-to-use” cross-linking reagent for creating complex and fragile tri-component (bio)molecular systems was illustrated through (1) the rapid preparation of a three-colour FRET cascade with valuable spectral properties and (2) the luminescent/fluorescent labelling of peptides and peptide–oligonucleotide conjugates. Thus, such (bio)molecular assemblies were readily obtained via a three-step process or in a “one-pot” manner, both involving oxime ligation, thiol-alkylation (SN2 or Michael addition) and copper-catalysed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reactions.

PEGylation enables the specific tumor accumulation of a peptide identified by phage display by Walter Mier; Susanne Krämer; Sabine Zitzmann; Annette Altmann; Karin Leotta; Ursula Schierbaum; Martina Schnölzer; Michael Eisenhut; Uwe Haberkorn (2706-2711).
Peptides are excellent alternatives to small molecules and proteinaceous drugs. Their high medicinal potential for diagnostic and therapeutic applications has prompted the development of tumor targeting peptides. Despite its excellent tumor binding capacity, FROP–DOTA (H-Glu-Asn-Tyr-Glu-Leu-Met-Asp-Leu-Leu-Ala-Tyr-Leu-Lys(DOTA)-NH2), a peptide that we had identified in phage display libraries, revealed slow binding kinetics. Consequently, biodistribution studies showed that its excretion forestalled a significant tumor accumulation. The aim of this study was to investigate whether the conjugation of PEG to FROP–DOTA resulted in a derivative with a prolonged residence time in the blood. A synthetic method for the PEGylation of the tumor specific peptide FROP–DOTA was developed. Thereafter, binding studies were done in vitro and a biodistribution was performed in tumor bearing animals. These were compared to the data obtained with FROP–DOTA. The binding kinetics of the PEGylated FROP–DOTA was even slower than that of FROP–DOTA. Biodistribution studies of the labeled conjugate in mice bearing human FRO82-2 tumors showed a time dependent increased uptake of the PEGylated peptide with a high retention (at 24 h p.i. 76% of the maximal activity concentration persisted in the tumor). The highest uptake values were determined at 120 min p.i. reaching 2.3%ID/g tumor as compared to 0.06%ID/g observed for the non-PEGylated derivative at 135 min p.i. Apparently, PEGylation provides a substantially improved stabilization in the circulation which allowed a stable tumor accumulation.

Using C-3 di-deuterated morpholin-2-ones bearing N-2-iodobenzyl and N-3-bromobut-3-enyl radical generating groups, only products derived from the more stabilised C-3, rather than the less stabilised C-5 translocated radicals, were formed after intramolecular 1,5-hydrogen atom transfer, suggesting that any kinetic isotope effect present was not sufficient to offset captodative stabilisation.

Total synthesis of (+)-pentamethylsalvianolic acid C by Benjamin L. Alford; Helmut M. Hügel (2724-2727).
The total synthesis of a methylated analogue of (+)-Salvianolic acid C has been achieved. Key aspects of the synthetic route include an economical Cu(i) acetylide coupling, unique carboxyl activation conditions via microwave irradiation and a novel lipase catalysed kinetic resolution of a racemic mixture of secondary alcohol Danshensu. The preparation of this methylated analogue will not only improve the bioavailability, but also enable access to new and wider bioactivity applications for (+)-Salvianolic acid C.

Back cover (2729-2730).