Organic & Biomolecular Chemistry (v.13, #42)

Front cover (10411-10411).

Inside front cover (10412-10412).

Contents list (10413-10419).

The hydroarylation of alkynes with substituted aromatics in the presence of a metal catalyst via chelation-assisted C–H bond activation is a powerful method to synthesize trisubstituted alkenes. Chelation-assisted C–H bond activation can be done by two ways: (a) an oxidative addition pathway and (b) a deprotonation pathway. Generally, a mixture of cis and trans stereoisomeric as well as regioisomeric trisubstituted alkenes was observed in an oxidative addition pathway. In the deprotonation pathway, the hydroarylation reaction can be done in a highly regio- and stereoselective manner, and enables preparation of the expected trisubstituted alkenes in a highly selective manner. Generally, ruthenium, rhodium and cobalt complexes are used as catalysts in the reaction. In this review, a ruthenium-catalyzed hydroarylation of alkynes with substituted aromatics is covered completely. The hydroarylation reaction of alkynes with amide, azole, carbamate, phosphine oxide, amine, acetyl, sulfoxide and sulphur directed aromatics is discussed.

A Bodipy as a luminescent probe for detection of the G protein estrogen receptor (GPER) by T. Papalia; R. Lappano; A. Barattucci; A. Pisano; G. Bruno; M. F. Santolla; S. Campagna; P. De Marco; F. Puntoriero; E. M. De Francesco; C. Rosano; M. Maggiolini; P. Bonaccorsi (10437-10441).
We report the rational design, based on docking simulations, and synthesis of the first fluorescent and selective probe of GPER for bioimaging purposes and functional dissecting studies. It has been conceived as a Bodipy derivative and obtained by accessible and direct synthesis. Its optical properties have been measured in different solvents, showing insensitivity to their polarity. Its binding to GPER was achieved by competition assays with [3H]E2 and [5,6-3H] nicotinic acid in ER-negative and GPER-positive SkBr3 breast cancer cells. SkBr3 cells, transfected with a GPER expression vector containing a FLAG tag, were used to confirm that the fluorophore binds to GPER in a specific manner.

Built upon the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead l-2-amino-7-carboxamidoheptanoic acid (l-ACAH, a close structural analog of Nε-acetyl-lysine) that our laboratory discovered recently, in the current study, its carboxamide NH2-ethylated analog was found to be a ∼2.4–6.6-fold stronger SIRT1/2/3 inhibitory warhead than l-ACAH. Carboxamide NH2-dodecylated and carboxymethylated analogs of l-ACAH were also identified as potent SIRT6 and SIRT5 inhibitory warheads, respectively.

Introducing a static receptor to compete with a dynamic combinatorial library in template binding by Filip Ulatowski; Dawid Lichosyt; Janusz Jurczak (10451-10455).
We show herein that establishing a competition between a static receptor and components of dynamic combinatorial libraries to bind an appropriately selected template can be used to determine association constants by HPLC analysis after freezing of the equilibrium.

N-Protected amino acids can be easily converted into chiral α-amino aldehydes in a one-pot reaction by activation with CDI followed by reduction with DIBAL-H. This method delivers Boc-, Cbz- and Fmoc-protected amino aldehydes from proteinogenic amino acids in very good isolated yields and complete stereointegrity.

A new and efficient potassium carbonate mediated intramolecular tandem O-arylation followed by C–O bond cleavage of furano-hydroxychalcones is described. The treatment of furano-hydroxychalcones pongamol (1a) and ovalitenone (2a) with potassium carbonate in DMF led to the direct formation of the furanoflavones lanceolatin B (3ab) and pongaglabrone (4ab) in excellent yields. This is the first report on the cyclization of furano-hydroxychalcones via C–O bond cleavage (demethoxylation) to produce furanoflavonoids.

A virtually complete enantioselective synthesis of 3-amino-1,2-diols with three consecutive stereocenters was accomplished by a sequential cascade of two kinetic resolutions, which features a Sharpless or Hafnium-catalyzed asymmetric epoxidation and a subsequent W-catalyzed aminolysis. Enantiopure products with up to >99.9% ee and >99.9 : 0.1 dr were obtained and could serve as potential building blocks for pharmaceutical or biological significant molecules.

Application of design of experiments (DoE) optimization to the one-pot synthesis of 4,6-dihydropteridinones by Steven Stone; Tiansheng Wang; Jianglin Liang; John Cochran; Jeremy Green; Wenxin Gu (10471-10476).
A design of experiments (DoE) analysis of a tandem SnAr-amidation cyclization reaction between 4-chloropyrimidin-5-amine and (S)-N-methylalanine to form (S)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one is reported. Five reaction variables were optimized using DoE and conversion was improved from 26% to 74%, with a significant reduction in reaction time while retaining high optical purity. The optimized conditions were applied to the synthesis of a wide variety of analogs and the expanded reaction substrate scope included a variety of amino acids and pyrimidines. Products were obtained in isolated yields up to 95% and enantiomeric excess as high as 98%.

Enamine/butadienylborane cycloaddition in the frustrated Lewis pair regime by Guo-Qiang Chen; Fatma Türkyilmaz; Constantin G. Daniliuc; Christoph Bannwarth; Stefan Grimme; Gerald Kehr; Gerhard Erker (10477-10486).
The dienylborane 2a was prepared by regioselective alkyne hydroboration of the conjugated enyne 1a with Piers’ borane [HB(C6F5)2]. Its reaction with a series of acetophenone derived enamines 3 resulted in the formation of the strong enamine β-carbon adduct with the borane Lewis acid (4). In contrast B–C adduct formation between the dienylborane 2a and a series of much more bulky cyclohexanone derived enamines (6) is rapidly reversible above ca.−30 °C and then leads to the formation of the [4 + 2]cycloaddition products 8. A DFT study revealed that this reaction is probably taking a stepwise route, proceeding by means of enamine addition to the dienylborane terminus to generate a zwitterionic borata–alkene/iminium ion intermediate that undergoes rapid subsequent ring closure. Heating of the products 8 led to amidoborane elimination from the vicinal amino/borane pair at the product framework to give the respective hexahydronaphthalene product 10. Subsequent treatment with TEMPO (2 equiv.) resulted in selective oxidation of the unsaturated ring to give the respective tetrahydronaphthalene derivative 12.

The first stereoselective total synthesis of (+)-goniothalesacetate and total synthesis of several bioactive styryl lactones, (+)-altholactone, (+)-gonioheptolide A, and (−)-goniofupyrone have been achieved from an advanced intermediate, which can be derived from l-(+)-DET.

Three new Zn(ii)-, oligo- and poly(2,5-thienylene)-linked porphyrins, bearing multiple triethylene glycol (TEG) groups, on all meso aryl positions were synthesized via Stille and Suzuki coupling reactions and their photophysical properties as well as singlet oxygen generation efficiencies have been investigated to elucidate the possibility of their use as a photosensitizer for photodynamic therapy (PDT) and photodynamic inactivation of bacteria.

Regioselective synthesis of fullerene multiadducts via tether-directed 1,3-dipolar cycloaddition by Bolong Zhang; Jonathan M. White; David J. Jones; Wallace W. H. Wong (10505-10510).
The regioselective synthesis of fullerene multiadducts was achieved from commercially available reagents in one pot over two steps. The configuration of the isolated regioisomers was determined using various NMR methods, UV-vis spectroscopy and electrochemical analysis with the structure of one isomer confirmed by single crystal X-ray analysis. Interesting variation in regioselectivity was observed when different amino acid reagents were used in the reactions. Theoretical calculations and additional experiments, such as deuterium exchange, led to a proposed mechanism for the regioselective product formation.

A pyrene-bridged macrocage showing no excimer fluorescence by Hirokuni Shionari; Yusuke Inagaki; Kentaro Yamaguchi; Wataru Setaka (10511-10516).
Pyrene is a common organic luminescent material. To improve the fluorescence properties of pyrene, we have designed a pyrene-2,7-diyl bridged macrocage in which the pyrene moiety is sterically protected by the outside alkyl chains. The macrocage shows intense fluorescence from a monomeric excited state without excimer fluorescence even in saturated solutions, although the parent pyrene shows excimer fluorescence in highly concentrated solutions. These results indicate that the steric shielding by the cage prevents the formation of the excimer. Intensities of florescence in the presence of nitrobenzene were investigated to clarify the cage effects on fluorescence quenching. Lower efficiency of the fluorescence quenching caused by intermolecular collision between the caged pyrene (fluorophore) and nitrobenzene (quencher) was revealed by the analysis of the bimolecular quenching constants kq.

Metal complexes of pyridine-fused macrocyclic polyamines targeting the chemokine receptor CXCR4 by Sunil Hamal; Thomas D'huys; William F. Rowley; Kurt Vermeire; Stefano Aquaro; Brian J. Frost; Dominique Schols; Thomas W. Bell (10517-10526).
The chemokine receptor CXCR4 acts as a key cell surface receptor in HIV infections, multiple forms of cancer, and various other pathologies, such as rheumatoid arthritis and asthma. Macrocyclic polyamines and their metal complexes are known to exert anti-HIV activity, many acting as HIV entry inhibitors by specifically binding to CXCR4. Three series of pyridopentaazacylopentadecanes, in which the pyridine ring is fused to zero, one, or two saturated six-membered rings, were synthesized by manganese(ii)-templated Schiff-base cyclization of triethylenetetramine with various dicarbonyl compounds. By evaluating these macrocyclic polyamines and their complexes with Mn2+, Cu2+, Fe3+, and Zn2+, we have discovered novel CXCR4-binding compounds. The MnCl2 complex of a new pentaazacyclopentadecane with one fused carbocyclic ring (11) was found to have the greatest potency as an antagonist of the chemokine receptor CXCR4 (IC50: 0.014 μM), as evidenced by inhibiting binding of CXCL12 to PBMCs (peripheral blood mononuclear cells). Consequently, this compound inhibits replication of the CXCR4-using (X4) HIV-1 strain NL4-3 in the TZM-bl cell line with an IC50 value of 0.52 μM and low cytotoxicity (CC50: >100 μM). In addition, 18 other compounds were evaluated for their interaction with CXCR4 via their ability to interfere with ligand chemokine binding and HIV entry and infection. Of these, the metal complexes of the two more hydrophobic series with one or two fused carbocyclic rings exhibited the greatest potency. The Zn2+ complex 21 was among the most potent, showing that redox activity of the metal center is not associated with CXCR4 antagonist activity.

A late stage Diels–Alder reaction is used to prepare a mixture of JBIR-22, a natural product from the Equisetin family of tetramic acids, and one of its diastereomers. This is achieved in just 8 steps from pyruvate. The success of the late stage DA approach is discussed in the context of the biosynthesis of JBIR-22 (and perhaps related natural products).

The development of a short route to the API ropinirole hydrochloride by Zeshan Yousuf; Andrew K. Richards; Andrew N. Dwyer; Bruno Linclau; David C. Harrowven (10532-10539).
A four-step, three-stage synthesis of the API ropinirole hydrochloride has been developed from a commercially available naphthalene derivative. The new route has half the step-count and twice the overall yield of the current manufacturing process. Key features of the synthesis are a regioselective Birch reduction and an ozonolysis with concomitant ring closure to induce the required ring contraction.

Pyrene-labeled 3-deaza-2′-deoxyadenosine comprising a non-π-conjugated linker py3zA (1) was synthesized and its photophysical properties were investigated. Oligodeoxynucleotide (ODN) probes containing py3zA (1) exhibited remarkable fluorescence quenching only when the opposite base of the complementary strand was the perfectly matched thymine. Such fluorescence quenching-based ODN probes exhibited excellent on-off switching properties, making them useful tools for single nucleotide polymorphism (SNP) genotyping and for the identification of target genes and structural studies of nucleic acids.

(+)-Dehydroabietylamine (1a), the novel derivatives (2a–6a) and their NTf2 salts (1b–6b) were tested as chiral NMR solvating agents for the resolution of enantiomers of the model compound Mosher's acid (7) and its n-Bu4N salt (8). Best enantiomeric discrimination of 7 was obtained using bisdehydroabietylamino-N1,N2-ethane-1,2-diamine (6a), and of 8 using N-(dehydroabietyl)-2-(dehydroabietylamino)ethanaminium bis((trifluoromethyl)-sulfonyl)-amide (6b). For the maximal resolution of enantiomers of 8, 1.0 eq. of 6b were needed. However, 0.5 eq. of 6a sufficed for the maximal resolution of enantiomers of 7. Enantiomeric excess studies were successfully conducted using 6a and 6b. The capability of 6a and 6b to recognize the enantiomers of various α-substituted carboxylic acids and their n-Bu4N salts were examined. Best resolutions were observed for aliphatic and aromatic carboxylic acids bearing an electronegative α-substituent. Now the ee studies on such non-aromatic carboxylic acids are also feasible.

Systematic synthesis of low-molecular weight fucoidan derivatives and their effect on cancer cells by Akihiro Kasai; Shinsuke Arafuka; Nozomi Koshiba; Daisuke Takahashi; Kazunobu Toshima (10556-10568).
Low-molecular weight type I and II fucoidan derivatives with different sulfation patterns were designed and systematically synthesized from the corresponding common key intermediate and their anti-proliferative activities and apoptosis-inducing activities against human breast cancer (MCF-7) and human cervical epithelioid carcinoma (HeLa) cells were evaluated. Our results demonstrated that one of the type II fucoidan derivatives, 9, effectively reduced the number of viable MCF-7 and HeLa cells in a dose-dependent manner without causing cytotoxicity toward normal WI-38 cells, and that the anti-proliferative activity of 9 was comparable to that of fucoidan 2 isolated from Fucus vesiculosus. Moreover, it was found that both 2 and 9 exhibited similar apoptosis-inducing activities through activation of caspase-8 and -9 on MCF-7 and HeLa cells, respectively.

Evaluating hydrogen bonding control in the diastereoselective Diels–Alder reactions of 9-(2-aminoethyl)-anthracene derivatives by R. A. Bawa; F.-M. Gautier; H. Adams; A. J. H. M. Meijer; S. Jones (10569-10577).
Several 9-(2-aminoethyl)anthracene derivatives were prepared with different nitrogen substitutents including alkyl, acetamide, trifluoroacaeamide and t-butyl carbamate. The selectivity in Diels–Alder cyclodaddition reaction with N-methyl maleimide was evaluated through single crystal X-ray analysis of the products. Models for the change in selectivity with hydrogen bond acceptor are proposed, supported by DFT level calculations.

Correction: Stereoselective synthesis of the head group of archaeal phospholipid PGP-Me to investigate bacteriorhodopsin–lipid interactions by Jin Cui; Satoshi Kawatake; Yuichi Umegawa; Sébastien Lethu; Masaki Yamagami; Shigeru Matsuoka; Fuminori Sato; Nobuaki Matsumori; Michio Murata (10578-10578).
Correction for ‘Stereoselective synthesis of the head group of archaeal phospholipid PGP-Me to investigate bacteriorhodopsin–lipid interactions’ by Jin Cui, et al., Org. Biomol. Chem., 2015, DOI: 10.1039/c5ob01252j.

Back cover (10579-10580).