Organic & Biomolecular Chemistry (v.11, #30)

Front cover (4901-4901).

Inside front cover (4902-4902).

Contents list (4903-4908).

Passive fructose transporters in disease: a molecular overview of their structural specificity by D. Tyler McQuade; Matthew B. Plutschack; Peter H. Seeberger (4909-4920).
The SLC2 family of facilitative Glucose transporters (Gluts) contains 14 isoforms divided into three classes based on amino acid sequence. While the majority of these proteins transport glucose, a subset can transport fructose. Recently, fructose and the Gluts responsible for fructose uptake have received increased interest due to the correlation between high fructose consumption and early onset of metabolic syndrome. In addition, the up-regulation of Gluts in certain cancers has made possible the development of a number of fructose probes for imaging cancer. Although structure activity data has defined some aspects of fructose-specific uptake, a far more detailed clarification of the variables governing the onset and progression of fructose-correlated diseases is still needed. Here, we summarize what is known about molecular structure and fructose uptake as it relates to the correlation of fructose and disease.

Enhancing the usefulness of cross dehydrogenative coupling reactions with a removable protecting group by Althea S.-K. Tsang; Katrin Ingram; Jennifer Keiser; D. Brynn Hibbert; Matthew H. Todd (4921-4924).
A removable protecting group has been identified that allows the products of widely-used cross dehydrogenative couplings to be synthetically elaborated. The method can be used with enantiopure amines with no loss of enantiomeric excess. The methodology is exemplified by a new synthesis of enantiopure praziquantel, the drug used in the treatment of millions of people suffering from the neglected tropical disease, schistosomiasis.

Extending the range of supercritical fluid chromatography by use of water-rich modifiers by Jinchu Liu; Erik L. Regalado; Ingrid Mergelsberg; Christopher J. Welch (4925-4929).
In this study we investigate the recently reported use of water-containing modifiers for separation and purification of hydrophilic compounds by supercritical fluid chromatography. Improved peak shape is obtained for a variety of glycosides and otherwise hydrophilic compounds when 5% water is added to the methanol co-solvent used in SFC separations, and examples of the use of this approach in preparative SFC purifications are presented.

Transition metal free hydrolysis/cyclization strategy in a single pot: synthesis of fused furo N-heterocycles of pharmacological interest by Ali Nakhi; Md. Shafiqur Rahman; Guru Pavan Kumar Seerapu; Rakesh Kumar Banote; Kummari Lalith Kumar; Pushkar Kulkarni; Devyani Haldar; Manojit Pal (4930-4934).
A transition metal free tandem two-step strategy has been developed involving hydrolysis of 2-chloro-3-alkynyl quinoxalines/pyrazines followed by in situ cyclization of the corresponding 2-hydroxy-3-alkynyl intermediates in a single pot leading to fused furo N-heterocycles as potential inhibitors of sirtuins. A representative compound showed promising pharmacological properties in vitro and in vivo.

Chemical synthesis of a masked analogue of the fish antifreeze potentiating protein (AFPP) by Sung-Hyun Yang; Joanna M. Wojnar; Paul W. R. Harris; Arthur L. DeVries; Clive W. Evans; Margaret A. Brimble (4935-4942).
A recently identified Antarctic fish protein termed antifreeze potentiating protein (AFPP) is thought to act as an adjunct to the previously characterised antifreeze glycoproteins (AFGPs), the two acting together to inhibit ice crystal growth in vivo. Elucidating the functional properties of the new AFPP requires access to large amounts of pure product, but the paucity of natural material necessitates alternative approaches. We therefore embarked on the total chemical synthesis of the AFPP, through a convergent ligation strategy. After many challenges, mostly due to the solubility issues of the peptide fragments, and several revisions of the original synthetic strategy, we have successfully synthesized a masked analogue of AFPP. The key to the successful synthesis was the use of a solubilising tag attached through a hydrolysable linker.

A cyclization–carbonylation–cyclization coupling reaction (CCC-coupling reaction) of α,β-alkynic hydrazones, catalyzed by (box)PdII complexes, afforded symmetrical ketones bearing two pyrazole groups in good to excellent yields. This method is applicable to a broad range of substrates.

Design and evaluation of improved magnetic stir bars for single-mode microwave reactors by David Obermayer; Markus Damm; C. Oliver Kappe (4949-4956).
Magnetic stirring in sealed cylindrical vessels designed for use in single-mode microwave instruments is typically less than optimal, and is not comparable to the efficient agitation that can be generally obtained in a round-bottomed flask fitted with a suitable magnetic stir bar or using overhead mechanical stirring systems. A new “vertical blade” stir bar design that improves the stirring performance in the very narrow, flow-constricting microwave vessels has been developed and evaluated for several different transformations where stirring and efficient agitation are known to be of importance. The better performance of these novel stirrers compared to the traditional cylindrical stir bar design is not only due to the geometry of the stirrer but also to the utilization of a magnetic material with a stronger magnetic transmission force (Sm2Co17) compared to standard ferrite or AlNiCo alloys. For all three tested cases involving solid/liquid, liquid/liquid and highly viscous reaction systems, the new vertical blade stirrers showed a distinctively improved performance resulting in higher conversions and/or product yields.

The cascade radical cyclisation approach to prenylated alkaloids: synthesis of stephacidin A and notoamide B by Nigel S. Simpkins; Ilias Pavlakos; Michael D. Weller; Louise Male (4957-4970).
A strategy for the synthesis of members of the prenylated indole alkaloid family is described, which involves a radical cascade process of an appropriately substituted diketopiperazine (DKP) core structure. Several approaches to the generation of the initial radical were explored, with the most successful involving treatment of a sulfenyl substituted DKP under classical reductive conditions by heating with Bu3SnH and a radical initiator. The required, fully substituted, radical precursor DKP structures were prepared using regio- and stereocontrolled enolate chemistry of simpler proline-tryptophan derived DKPs. The new approach allowed rapid access to a key polycyclic indoline structure, which was converted into either of the natural products stephacidin A or notoamide B.

Simplexides constitute a unique group of immunosuppressive glycolipids that demonstrate antiproliferative activities against activated T-cell lymphocytes via a unique non-cytotoxic inhibition. To investigate the structure–activity relationship of the varied long-chain secondary alcohols on simplexides, we developed an efficient and divergent route to the synthesis of simplexides and congeners, taking advantage of a late-stage olefin cross-metathesis reaction.

The metal ion induced absorption and emission signaling pattern of rhodamine coupled bis-(aminopropyl)-piperazine (1–3) and (aminoethyl)-piperazine (4) based probes evaluated in MeCN as well as in an MeCN–H2O binary mixture medium revealed that these probes exhibit optical signaling perturbations to a varying extent in MeCN, however, their complexation induced signaling could be tuned selectively towards Hg(ii) in the presence of an aqueous component in the solvent medium where competitive interactions such as metal–probe interactions and hydration of metal ions play the determining factor to induce aqueous promoted Hg(ii) selectivity. Attachment of another fluorophore (anthracene and nitrobenzofurazan moieties in 2 and 3 respectively) at the other end of the rhodamine coupled bis-(aminopropyl)-piperazine receptor enabled these probes to facilitate a complexation induced fluorescence resonance energy transfer (FRET) from the excited fluorophore to the ring-opened rhodamine along with contributions through operative PET inhibition and rhodamine delactonization processes. The enhancement in absorption transition of these probes at ∼557 nm upon selective Hg(ii)-complexation and consequent colourless to pink colour change in the solution imply a chromogenic signaling pattern whereas simultaneous fluorescence amplification and/or FRET initiation lead to fluorogenic signaling to facilitate detection at lower concentration. The Hg(ii)-selective photo-physical spectral modulation in the presence of other competitive metal ions, and their reversible dual channel signaling pattern under the action of counter anions or chelating agents such as EDTA or ethylenediamine establish the potential of these probes for highly selective, sensitive and reversible ‘OFF–ON–OFF’ detection of Hg(ii). The complexation induced optical signaling pattern of probes with a propyl-linker in their receptor (1–3) in comparison with that of 4 consisting of an ethyl-spacer indicate that signaling probe design with a substituted ‘aminoalkyl-lactonized-rhodamine’ subunit preferentially exhibit Hg(ii) selective and sensitive dual mode signaling in an organic–aqueous mixture medium irrespective of carbon-length of the flexible alkyl spacer.

A new water-soluble inclusion complex of ilexgenin A (IGA) with β-cyclodextrin polymer (CDP) was prepared by a facile strategy and characterized by 1H NMR , FT-IR, and UV-vis spectroscopy. Compared with IGA and the inclusion complex of IGA with β-cyclodextrin (IGA–CD), the solubility of IGA–β-cyclodextrin polymer (IGA–CDP) was greatly enhanced due to the water-soluble CDP host. The ratio of β-cyclodextrin (β-CD) units in CDP to IGA was determined as 2 : 1. KD of the inclusion complex was evaluated as 2.6 × 10−3 mol L−1. The effects of IGA–CDP on a hyperlipidemia mouse model were studied by intragastric administration. After 4 weeks, the IGA–CDP treatment resulted in decreased serum levels of total cholesterol and low-density lipoprotein-cholesterol. The effects of IGA–CDP on serum apolipoprotein levels were similar to its effects on lipid levels. By comparing liver area, the effects of IGA–CDP on pre-existing lesions were assessed. Furthermore, the efficacy and potency of water-soluble inclusion complex of IGA–CDP was 2–3 times higher than that of IGA. Taken together, it was possible to develop it to a novel drug candidate to regulate lipid abnormality.

A bola-phospholipid probe, carrying a tetrafluorophenylazido chromophore in the middle of the transmembrane diacyl chain, was synthesized and characterized with a view to studying biomembranes by a photolabeling approach. This probe shows the advantageous stability of bola-lipids in giant vesicle formation alongside excellent photochemical properties conferred by the tetrafluorophenylazido chromophore, and thus constitutes a promising probe for biomembrane photolabeling studies.

Structural, conformational properties, and gas phase reactivity of two representative diastereoisomeric members of a series of α,α-tetrahydropyridazine amino acid derivatives have been investigated by using X-ray crystallography, tandem mass spectrometry and theoretical calculations. Both diastereoisomers show an unusual screw-boat conformation of the tetrahydropyridazine ring. While protonated molecules mainly decompose in the gas phase by loss of acetamide, the main reactivity of the [M + Na]+ species consists of loss of PhNCO followed by acetamide and it is strictly dependent upon the stereochemistry of the parent compound. The most stable energy minimized structures obtained by theoretical calculations are in full agreement with the experimental data and allowed us to rationalize the gas phase reaction pathways.

We developed a fluorescein aldehyde probe with disulfide functionality for the fluorescence detection of biologically important thiols. The probe displayed highly selective responses to cysteine (Cys) and homocysteine (Hcy) over glutathione (GSH) due to the rapid ring formation reaction of Cys and Hcy with the aldehyde group of the probe and the concomitant cleavage of the disulfide group followed by subsequent intramolecular cyclization. The fluorescent probe also exhibited a highly sensitive fluorescence turn-on response to Hcy with a detection limit of 2.4 μM Hcy in HEPES buffer.

Based on a preactivation protocol with (p-Tol)2SO/Tf2O, a practical, straightforward, and high-yielding synthesis of α-sialyl C-glycosides was accomplished by coupling N-acetyl-5-N,4-O-oxazolidione protected thiosialoside with various trimethylsilyl enol ethers and allyltrimethylsilanes. High yields and excellent α-selectivities were obtained for the strong π-nucleophiles with large nucleophilicity values (N = 4.4–9.0), irrespective of whether silyl enol ethers, silyl ketene acetals or allyltrimethylsilanes were used for the electrophilic C-sialylation.

Photoreactions of isoquinoline-1,3,4-triones and oxazoles with different substituents were found to give different chemo-, regio- and diastereoselectivities. The substituent at the C5 on the oxazole ring showed great influence on the chemoselectivity of the photoreaction as well as on the transformation of the photocycloadducts. The 2-methyl-5-methoxyoxazoles reacted with isoquinoline-1,3,4-triones rapidly and gave spirooxetanes with high regio- and diastereo-selectivity. Diastereoselectivity in the reaction of 2-phenyl-5-methoxyoxazoles with isoquinoline-1,3,4-triones was relevant to the substituent on the 4-position on the oxazole ring. Replacement of the 5-methoxy group with 5-methyl or 5-phenyl resulted in significant decrease on the reactivity of the oxazole as well as change on the diastereoselectivity in photocycloaddition with isoquinoline-1,3,4-triones. Acid-mediated transformations of the photocycloadduct spirooxetanes was found to give different type of products including β-hydroxy-α-aminocarbonyl compounds and spiroisoquinolineoxazolines under different reaction conditions. Substituents on the spirooxetanes as well as the type and amount of acid used in the reaction played important roles in determining the type and diastereoselectivity of the products in the transformations.

Synthesis and biological activity of phosphoglycolipids from Thermus thermophilus by Yukari Fujimoto; Kunihiro Mitsunobe; Satoko Fujiwara; Motoko Mori; Masahiro Hashimoto; Yasuo Suda; Shoichi Kusumoto; Koichi Fukase (5034-5041).
An extreme thermophile, Thermus thermophilus, has very unique glycolipids on the cell surface. The acidic immunostimulatory phosphoglycolipid of T. thermophilus was synthesized for the first time, with newly developed glycosylation methods using 3-nitropyridyl (3NPy) and 4,6-dimethoxy-1,3,5-triazin-2-yl (DMT) glycosides as glycosyl donors. The analogues of the phosphoglycolipid, which include a diastereomer possessing the opposite configuration at the diacyl glycerol moiety, were also synthesized. The biological activities of the synthesized compounds were elucidated with cytokine inductions (IL-6 and TNF-α). A synthetic phosphoglycolipid with a natural-type diacyl glycerol configuration showed apparent immunostimulatory activity, whereas its diastereomer did not. The present study revealed that the configuration at the diacyl glycerol moiety of the phosphoglycolipids is important for immunostimulation, suggesting the existence of the particular receptor/recognizing protein that can recognize the stereochemistry of the glycerol part.

E-Factor minimized hydrophosphonylation of aldehydes catalyzed by polystyryl-BEMP under solvent-free conditions by Tommaso Angelini; Simona Bonollo; Daniela Lanari; Ferdinando Pizzo; Luigi Vaccaro (5042-5046).
An efficient protocol for the hydrophosphonylation of aromatic and aliphatic aldehydes catalyzed by PS-BEMP under solvent-free conditions (SolFC) has been reported. Addition reactions were performed by using equimolar amounts of reagents and the resulting α-hydroxyphosphonates were isolated with simple workup procedures. A large scale protocol for the preparation of a representative α-hydroxyphosphonate 3a has been also set up using a flow reactor.

Back cover (5047-5048).