Organic & Biomolecular Chemistry (v.8, #11)

Front cover (2481-2481).

Inside front cover (2482-2482).

Contents (2483-2496).

In addition to the brilliant chiral phosphorus metalcatalysts, chiral phosphine-free metal complexes find increasing application as catalysts for asymmetric hydrogenation. In this account, two types of chiral phosphine-free ligands, N-heterocyclic carbene-based C,N-ligands and diamine-based N,N-ligands, in the homogeneous asymmetric hydrogenation of prochiral ketones, imines and quinolines are reviewed.

The highly enantioselective Michael addition reaction of ketones to nitrodienes was promoted efficiently by the accessible and fine-tunable organocatalytic system of pyrrolidinyl-thioimidazole and chiral thioureido acid. The corresponding adducts were afforded in good yields with high diastereoselectivities (up to 99 : 1) and excellent enantioselectivities (up to 99% ee).

Synthesis of aminomethylated 4-fluoropiperidines and 3-fluoropyrrolidines by Guido Verniest; Karel Piron; Eva Van Hende; Jan Willem Thuring; Gregor Macdonald; Frederik Deroose; Norbert De Kimpe (2509-2512).
A short and efficient synthesis of 4-aminomethyl-4-fluoropiperidines and 3-aminomethyl-3-fluoropyrrolidines is described. These fluorinated azaheterocycles are of specific interest as bifunctional building blocks for fluorinated pharmaceutical compounds. The key step of the synthetic pathway involves the regioselective bromofluorination of N-Boc-4-methylenepiperidine and 3-methylenepyrrolidine using Et3N.3HF and NBS.

Syntheses of ylidenbutenolide-modified derivatives of peridinin and their stereochemical and spectral characteristics by Takayuki Kajikawa; Kazuyoshi Aoki; Takashi Iwashita; Dariusz M. Niedzwiedzki; Harry A. Frank; Shigeo Katsumura (2513-2516).
Peridinin is a light-harvesting carotenoid found in oceanic photosynthetic organisms. It possesses a unique γ-ylidenbutenolide function and engages in energy transfer to chlorophyll a with very high (>90%) efficiency. In order to examine the relationship between the unique structure of peridinin and its facility in carrying out energy transfer, we have synthesized two different ylidenbutenolide-modified derivatives of peridinin. In this communication, the details of the syntheses are described as are the stereochemical and spectral characteristics of the derivatives; the novel ylidenbutenolide functional group stabilizes the molecule and maintains the conjugated π-electron system in an all-trans configuration.

Long wavelength red fluorescent dyes from 3,5-diiodo-BODIPYs by Lijuan Jiao; Changjiang Yu; Timsy Uppal; Mingming Liu; Yan Li; Yunyou Zhou; Erhong Hao; Xiaoke Hu; M. Graça H. Vicente (2517-2519).
Amphiphilic and long wavelength red fluorescent dyes (4 and 7) were prepared from the Sonogashira coupling reactions of 3,5-diiodo-BODIPYs (1 and 6). One of these compounds, BODIPY7, readily accumulated within human carcinoma HEp2cells and was found to localize mainly within the endoplasmic reticulum (ER).

Synthesis of 3-amino-thiochromanes from 4-benzyl 2-thiazolines, via an unprecedented intramolecular electrophilic aromatic substitution by Guillaume Mercey; Remi Legay; Jean-François Lohier; Jana Sopkova-de Oliveira Santos; Jocelyne Levillain; Annie-Claude Gaumont; Mihaela Gulea (2520-2521).
A one-pot synthesis of various N-substituted 3-amino-thiochromanes from 4-benzyl-2-methyl thiazolinevia a thiazolinium salt is described. The obtained 3-amino-thiochromanes are enantiopure, as their precursors derive from chiral 2-aminoalcohols. The reaction involves the formation of a disulfide, which subsequently takes part in an unprecedented intramolecular electrophilic aromatic substitution.

Biomimetically relevant self-condensations of C5 units derived from lysine by Rim Salame; Edmond Gravel; Pascal Retailleau; Erwan Poupon (2522-2528).
In various conditions, dimerization of pentanedial-derived units gives rise to interesting skeletons, which are reminiscent of alkaloids known to be biosynthesized in Nature vialysine metabolism.

Synthesis of chiral polyazamacrocycles of variable ring size by Seiji Kamioka; Sakae Sugiyama; Takashi Takahashi; Takayuki Doi (2529-2536).
Synthesis and structure elucidation of optically active tri-, tetra-, and penta-azamacrocycles having 4-methoxyphenyl pendants are described. Regioselective ring opening of a nosylaziridine with secondary benzyl amines was repeatedly performed to afford the cyclization precursors. Intramolecular N-alkylation of N-(ω-haloalkyl) nosylamide provided tri-, tetra-, and penta-azamacrocycles. On the basis of our study of the tetra-azamacrocycle previously elucidated by X-ray single-crystal analysis and in solution by NMR analysis, we conclude that the tri-azamacrocycle does not mainly have a vase-type conformation because of the steric hindrance of the 4-methoxyphenyl groups but the penta-azamacrocycle has a vase-type conformation in CDCl3 and in CD2Cl2. The vase-type conformation of the penta-azamacrocycle is, however, not as much stable as that observed in the tetra-azamacrocycle because conformational flexibility of the penta-azamacrocycle was observed in deuterated benzene.

An efficient entry to 1,2-benzisoxazoles via1,3-dipolar cycloaddition of in situ generated nitrile oxides and benzyne by Christian Spiteri; Christopher Mason; Fengzhi Zhang; Dougal J. Ritson; Pallavi Sharma; Steve Keeling; John E. Moses (2537-2542).
An efficient protocol for the synthesis of a range of 1,2-benzisoxazoles using an improved 1,3-dipolar cycloaddition of nitrile oxides and benzyne is described. Key to the procedure is the in situ generation of the reactive nitrile oxide and benzyne reactants simultaneously.

Photosensitized cleavage of plasmidic DNA by norharmane, a naturally occurring β-carboline by M. Micaela Gonzalez; Magali Pellon-Maison; Matias A. Ales-Gandolfo; Maria R. Gonzalez-Baró; Rosa Erra-Balsells; Franco M. Cabrerizo (2543-2552).
UV-A radiation (320–400 nm) induces damages to the DNA molecule and its components through photosensitized reactions. β-Carbolines (βCs), heterocyclic compounds widespread in biological systems, participate in several biological processes and are able to act as photosensitizers. The photosensitization of plasmidic DNA by norharmane in aqueous solution under UV-A radiation was studied. The effect of pH was evaluated and the participation of reactive oxygen species (ROS), such as hydroxyl radical (HO˙), superoxide anion (O2˙) and singlet oxygen (1O2) was investigated. A strong dependence of the photosensitized DNA relaxation on the pH was observed. The extent of the reaction was shown to be higher in the experiments performed at pH 4.7 than those performed at pH 10.2. As was expected, an intermediate extent of the reaction was observed at physiological pH (pH 7.4). Kinetic studies using ROS scavengers revealed that the chemical reactions between ROS and DNA are not the main pathways responsible for the damage of DNA. Consequently, the predominant mechanism yielding the DNA strand break takes place most probably via a type I mechanism (electron transfer) from the single excited state (S1) of the protonated form of norharmane (1[nHoH+]*). Additional information about the nature of the norharmane electronic excited states involved in the photocleavage reaction was obtained by using the N-methyl derivative of norharmane (N-methyl-norharmane).

Reduction of electron deficient guanine radical species in plasmidDNA by tyrosine derivatives by Mandi Tsoi; Trinh T. Do; Vicky J. Tang; Joseph A. Aguilera; Jamie R. Milligan (2553-2559).
Guanine bases are the most easily oxidized sites in DNA and therefore electron deficient guanine radical species are major intermediates in the direct effect of ionizing radiation (ionization of the DNA itself) on DNA as a consequence of hole migration to guanine. As a model for this process we have used gamma-irradiation in the presence of thiocyanate ions to generate single electron oxidized guanine radicals in a plasmid target in aqueous solution. The stable species formed from these radicals can be detected and quantified by the formation of strand breaks in the plasmid after a post-irradiation incubation using a suitable enzyme. If a tyrosine derivative is also present during irradiation, the production of guanineoxidation products is decreased by electron transfer from tyrosine to the intermediate guanyl radical species. By using cationic tyrosine containing ligands we are able to observe this process when the tyrosine is electrostatically bound to the plasmid. The driving force dependence of this reaction was determined by comparing the reactivity of tyrosine with its 3-nitro analog. The results imply that the electron transfer reaction is coupled to a proton transfer. The experimental conditions used in this model system provide a reasonable approximation to those involved in the radioprotection of DNA by tightly bound proteins in chromatin.

A paramagnetic chemical exchange-based MRI probe metabolized by cathepsin D: design, synthesis and cellular uptake studies by Mojmír Suchý; Robert Ta; Alex X. Li; Filip Wojciechowski; Stephen H. Pasternak; Robert Bartha; Robert H. E. Hudson (2560-2566).
Overexpression of the aspartyl protease cathepsin D is associated with certain cancers and Alzheimer’s disease; thus, it is a potentially useful imaging biomarker for disease. A dual fluorescence/MRI probe for the potential detection of localized cathepsin D activity has been synthesized. The probe design includes both MRI and optical reporter groups connected to a cell penetrating peptide by a cathepsin D cleavable sequence. This design results in the selective intracellular deposition (determined fluorimetrically) of the MRI and optical reporter groups in the presence of overexpressed cathepsin D. The probe also provided clearly detectable in vitro MRI contrast by the mechanism of paramagnetic chemical exchange effects (OPARACHEE).

Acid–base properties of functionalised tripodal polyamines and their interaction with nucleotides and nucleic acids by Alejandra Sornosa-Ten; M. Teresa Albelda; Juan C. Frías; Enrique García-España; José M. Llinares; Ana Budimir; Ivo Piantanida (2567-2574).
Novel, highly positively charged tripodal polyamines with appended heterocyclic moieties revealed an intriguing panel of protonation species within the biologically relevant range. Studied compounds bind nucleotide monophosphates by mostly electrostatic interactions but only the imidazole analogue showed selectivity toward UMP in respect to other nucleotides. Strong binding of all the studied compounds to both ds-DNA and ds-RNA is to some extent selective toward the latter, showing rather rare RNA over DNA preference.

Towards understanding secondary structure transitions: phosphorylation and metal coordination in model peptides by Malgorzata Broncel; Sara C. Wagner; Kerstin Paul; Christian P. R. Hackenberger; Beate Koksch (2575-2579).
Secondary structure transitions are important modulators of signal transduction and protein aggregation. Phosphorylation is a well known post-translational modification capable of dramatic alteration of protein secondary structure. Additionally, phosphorylated residues can induce structural changes through metal binding. Data derived from the Protein Data Bank demonstrate that magnesium and manganese are metal ions most favored by phosphate. Due to the complexity of molecular interactions as well as the challenging physicochemical properties of natural systems, simplified peptide models have emerged as a useful tool for investigating the molecular switching phenomenon. In this study using a coiled coil model peptide, we show structural consequences of phosphorylation and subsequent magnesium and manganese ions coordination. In the course of our experiment we obtained a switch cascade starting from a stable helical conformation of the control peptide, continuing through the phosphorylation-induced unfolded structure, and ending with a metal-stabilized α-helix (Mg2+) or helical fibers (Mn2+), each of which could be transferred back to the unfolded form upon EDTA chelation. This study demonstrates how small peptide models can aid in the evaluation and a better understanding of protein secondary structure transitions.

Intrinsic acidity and electrophilicity of gaseous propargyl/allenyl carbocations by Priscila M. Lalli; Yuri E. Corilo; Patrícia V. Abdelnur; Marcos N. Eberlin; Kenneth K. Laali (2580-2585).
The ion/molecule chemistry of four representative propagyl/allenyl cations 1–4 of the general formula R1CH+-CC-R (a) ↔ R1CHCC+-R (b), that is, the reactive C3H3+ ions of m/z 39 from EI of propargyl chloride (H2C+-CC–H, 1a), isomeric C4H5+ ions of m/z 53 from EI of 3-butyne-2-ol (2a, H2C+-CC-CH3) and 2-butyne-1-ol (CH3-CH+-CC–H, 3a), and Ph-C3H2+ ions of m/z 115 from 3-phenyl-2-propyn-1-ol (H2C+-CC-Ph, 4a) was studied via pentaquadrupole mass spectrometry. With pyridine, proton transfer was observed as the predominant process for 1 and the sole reaction channel for the isomeric 2 and 3, whereas 4 reacted preferentially by adduct formation. These outcomes were rationalized using DFT calculations from isodesmic proton transfer reactions. Similar reaction tendencies were observed with acetonitrile and acrylonitrile, with adduct formation appearing again as a minor pathway for 1, 2 and 3, and as a major reaction channel for 4. With 1,3-dioxolane, hydride abstraction was a dominant reaction, with proton transfer and adduct formation competing as side reactions. With 2,2-dimethyl-1,3-dioxolane, an interplay of reactions including methyl anion abstraction, proton transfer, hydride abstraction and adduct formation were observed depending on the ion structure, with 4 reacting again mainly by adduct formation. Proton transfer was also observed as a dominant process in reactions with ethanol for 1, 2 and 3, with 4 being nearly unreactive whereas no adduct formation was observed for any of the carbocations studied. Limited reactivity was exhibited by these ions in cycloaddition reaction with isoprene.

Combinatorial approach toward synthesis of small molecule libraries as bacterial transglycosylase inhibitors by Hao-Wei Shih; Kuo-Ting Chen; Shao-Kang Chen; Chia-Ying Huang; Ting-Jen R Cheng; Che Ma; Chi-Huey Wong; Wei-Chieh Cheng (2586-2593).
The development of iminocyclitol-based small molecule libraries against a bacterial TGase is described. An iminocyclitol was conjugated with a pyrophosphate mimic using either a 1,3-dipolar cycloaddition or reductive amination reaction, which was then condensed with a variety of lipophilic carboxylic acids in an amide bond coupling to generate a desired molecular library. With assistance of microtiter plate-based combinatorial chemistry and in situ screening, a potential inhibitor, the first potent iminocyclitol-based inhibitor against bacterial TGases was efficiently developed.

A “threading-stoppering-followed-by-clipping” approach was used for the synthesis of a hetero[4]rotaxane, in which one cucurbit[6]uril (CB[6]) and two hetero crown ethermacrocycles are threaded onto one dumbbell-shaped molecule. The process involves three steps: (1) threading of a CB[6]macrocycle onto a thread containing two dialkylammonium sites to form a CB[6]-based pseudo[2]rotaxane; (2) stoppering of the as-formed pseudo[2]rotaxane by iminecondensation reaction followed by reduction/protonation to afford a CB[6]-based [2]rotaxane with two new dialkylammonium sites; and (3) selective clipping of two hetero crown ethermacrocycles onto the newly-formed ammonium sites and subsequent reduction of the imine bonds in each crown ether to afford the final hetero[4]rotaxane in good yield. The whole process was followed by NMR spectroscopy and the structure of the hetero[4]rotaxane was confirmed by NMR spectroscopy, elemental analysis and mass spectrometry.

Linear and nonlinear photophysics and bioimaging of an integrin-targeting water-soluble fluorenylprobe by Alma R. Morales; Gheorghe Luchita; Ciceron O. Yanez; Mykhailo V. Bondar; Olga V. Przhonska; Kevin D. Belfield (2600-2608).
Linear photophysical characterization and two-photon absorption (2PA) properties of a new water-soluble fluorene derivative, 3-(9-(2-(2-methoxyethoxy)ethyl)-2,7-bis{3-[2-(polyethyleneglycol-550-monomethylether-1-yl)]-4-(benzo[d]thiazol-2-yl)styryl}-9H-fluoren-9-yl)propanoic acid (1), were investigated in several organic solvents and water at room temperature. A comprehensive analysis of the steady-state absorption, emission and excitation anisotropy spectra revealed electronic structures of 1, including mutual orientation of the transition dipoles, relatively weak solvatochromic effects, high fluorescence quantum yield (∼0.5–1.0), and strong aggregation in water. The 2PA spectra of 1 were obtained in the 600–900 nm spectral range by two-photon induced fluorescence (2PF) and open aperture Z-scan methods using femtosecond laser sources. No discrete 2PA bands were apparent and values of the corresponding 2PA cross sections monotonically increased in the short wavelength range up to 3000 GM in organic solvents and ∼6000 GM in aqueous solution, reflecting relatively high two-photon absorptivity. The 2PA efficiency of 1 in water increased 2–3 times relative to aprotic solvents and can be explained by cooperative electronic effects of molecular aggregates of 1 produced in aqueous media. The carboxylic acid fluorenyl probe1 was conjugated with the cyclic peptideRGDfK. Two-photon fluorescence microscopy (2PFM) imaging of U87MG cells (and MCF-7 as control), incubated with fluorene-RGDpeptide conjugate 2, demonstrated high αvβ3 integrin selectivity, making this probe particularly attractive for integrin imaging.

Abiesatrines A–J: anti-inflammatory and antitumor triterpenoids from Abies georgei Orr by Xian-Wen Yang; Su-Mei Li; Liang Wu; Yong-Li Li; Lin Feng; Yun-Heng Shen; Jun-Mian Tian; Jian Tang; Ning Wang; Yonghong Liu; Wei-Dong Zhang (2609-2616).
A novel spiro-lanostane (abiesatrine A, 1) was isolated from the aerial parts of Abies georgei together with 9 new (abiesatrines B–J, 2–10) and 10 known triterpenes (11–20). The new structures were established by the extensive analysis of their spectroscopic data. The configuration of 1, featuring a unique spirolactone formed by C-13 and C-23viaoxygen-bridge, was confirmed by X-ray crystallography, and its biopathway was tentatively proposed. Among these isolates, compound 16 showed the strongest inhibitory activity against LPS-induced NO production in RAW264.7 macrophages (IC50 = 8.9 μg mL−1). While compounds 1 and 20 exhibited potent anti-proliferative effects on QGY-7703 cells with IC50 values of 9.3 and 7.6 μg mL−1, respectively. Preliminary structure–activity relationship (SAR) investigations defined structural feature of the 24Z-olefinic bond key to the lanostane and cycloartane pharmacophore.

The interaction of luminescent dinuclear ruthenium(ii) complexes containing the bridging ligand tetrapyrido[3,2-a:2′,3′-c:3′′,2′′-h:2′′,3′′-j]phenazine with several intramolecular and intermolecular quadruplex DNA structures has been explored. It was found that these interactions produced distinctly different luminescence signatures. Binding curves constructed from these optical changes reveal that binding affinities for the quadruplex structures vary by over two orders of magnitude. The differences in quadruplex binding affinity and optical signature are rationalized through a consideration of the structural features of the quadruplexes. In particular we conclude large blue shifted emission enhancements are only observed on binding to quadruplexes containing lateral loops that are at least three base pairs long.

Phosphatediesters cleavage mediated by Ce(iv) complexes self-assembled on gold nanoparticles by Renato Bonomi; Paolo Scrimin; Fabrizio Mancin (2622-2626).
Monolayer protected gold nanoparticles (MPGN) coated with metal chelatinggroups were prepared. In the presence of Ce(iv), the MPGN proved to be highly active in promoting the hydrolytic cleavage of the DNA model bis-p-nitrophenyl phosphate (BNP). A 2.5 million-fold rate acceleration of the BNPhydrolysis was measured at a concentration of Ce(iv) as low as 120 μM (pH 7, 25 °C). This corresponds to a reduction of the substrate half-life time from 2000 years to few hours. The MPGN-Ce(iv) system is 1 to 2 orders of magnitude more reactive than any mono- and binuclear Ce(iv) complex so far reported. The source of such reactivity is the cooperation between the metal ions self-organized on the surface of the nanoparticles.

Kinetic resolution of 6-aryl-2,6-hexanediones was achieved with chiral secondary amine catalyzed intramolecular aldolization. The current kinetic resolution protocol enables the synthesis of both enantiomers of cyclohexenones with moderate to good enantioselectivity.

In this article the first enantioselective epoxidation reaction of acyclic and cyclic 2-arylidene-1,3-diketones is reported. Easily accessible or commercially available α,α-diaryl prolinols as the organocatalysts in the presence of tert-butyl hydroperoxide (TBHP) provide the corresponding epoxides in high to excellent yield (up to 99%) and up to 85% ee (ee >90% after crystallisation). These epoxides are pharmaceutically important building blocks and intermediates for the synthesis of densely functionalised epoxide derivatives.

A facile, versatile and stereoselective synthesis of bicyclic polyhydroxylated alkaloids as castanospermine analogues is described. The synthetic route started from methyl pyranosides. The key steps involved a high-yielding expeditious one-pot tandem reaction from alkenes to N-substituted δ-lactams. The δ-lactams were stereoselectively vinylated to give the dienes, which were followed by the ring-closing metathesis to produce the cyclized products. The functional group transformations of the resulting bicyclic compounds furnished diverse polyhydroxylated alkaloids in good yields.

Back matter (2650-2650).

Back cover (2651-2652).