Organic & Biomolecular Chemistry (v.8, #6)

Front cover (1221-1221).

Inside front cover (1222-1222).

Contents (1223-1236).

Triple-helical peptides (THPs) have been utilized as collagen models since the 1960s. The original focus for THP-based research was to unravel the structural determinants of collagen. In the last two decades, virtually all aspects of collagen structural biochemistry have been explored with THP models. More specifically, secondary amino acid analogs have been incorporated into THPs to more fully understand the forces that stabilize triple-helical structure. Heterotrimeric THPs have been utilized to better appreciate the contributions of chain sequence diversity on collagen function. The role of collagen as a cell signaling protein has been dissected using THPs that represent ligands for specific receptors. The mechanisms of collagenolysis have been investigated using THP substrates and inhibitors. Finally, THPs have been developed for biomaterial applications. These aspects of THP-based research are overviewed herein.

Synthesis of 3-substituted indoles via reactive alkylideneindolenine intermediates by Alessandro Palmieri; Marino Petrini; Rafik R. Shaikh (1259-1270).
Elimination of suitable leaving groups from 3-substituted indoles under basic or acidic conditions readily provides alkylideneindolenine intermediates that may react with a large variety of nucleophilic reagents. This article highlights some recent developments of this synthetic approach for the preparation of functionalized indole derivatives.

Synthesis of nucleoside 5′-O-α,β-methylene-β-triphosphates and evaluation of their potency towards inhibition of HIV-1 reverse transcriptase by Y. Ahmadibeni; C. Dash; M. J. Hanley; S. F. J. Le Grice; H. K. Agarwal; K. Parang (1271-1274).
A polymer-bound α,β-methylene-β-triphosphitylating reagent was synthesized and subjected to reactions with unprotected nucleosides, followed by oxidation, deprotection of cyanoethoxy groups, and acidic cleavage to afford nucleoside 5′-O-α,β-methylene-β-triphosphates. Among all the compounds, cytidine 5′-O-α,β-methylene-β-triphosphate inhibited RNase H activity of HIV-1 reverse transcriptase with a Ki value of 225 μM.

A series of thiourea-amine bifunctional catalysts have been developed by a rational combination of prolines with cinchona alkaloids, which are connected by a thiourea motif. The catalyst 3a, prepared from l-proline and cinchonidine, was found to be a highly efficient catalyst for the conjugate addition of ketones/aldehydes to a wide range of nitroalkenes (up to 98/2 dr and 96% ee). The privileged cinchonidine backbone and the thiourea motif are essential to the reaction activity and enantioselectivity.

Micro-scale process development of transaminase catalysed reactions by Matthew D. Truppo; Nicholas J. Turner (1280-1283).
A micro-scale technique has been developed for the process development of transaminase catalysed reactions. This pH indicator based, colorimetric assay can be used to investigate and optimise reaction conditions at 100 μL scale. Enzyme activity and stability as a function of various reaction parameters, including temperature, pH and co-solvent concentration, have been determined. Additionally, reactions have been scaled up from 100 μL to 25 mL under the optimal reaction conditions identified by the micro-scale process development activities. Excellent conversion (>99%) and enantioselectivity (>99% ee) were obtained.

The one-pot Horner–Wadsworth–Emmons/oxa-Michael cascade followed by spiroketalisation affords the tetracyclic benzannulated spiroketal core of berkelic acid, an extremophile natural product with selective activity against ovarian cancer.

A concise synthesis of enantiopure circumdatins E, H and J by Paul E. Zhichkin; Xiaomin Jin; Honglu Zhang; Lisa H. Peterson; Catherine Ramirez; Tara M. Snyder; Hilde S. Burton (1287-1289).
A concise total synthesis of enantiopure circumdatins E, H and J has been developed using a reductive cyclization of chiral N-prolinoyl-2-nitrobenzamides to construct the core quinazolinone ring.

An efficient synthesis of (±)-frondosin B using a Stille–Heck reaction sequence by Kye-Simeon Masters; Bernard L. Flynn (1290-1292).
A concise, convergent synthesis of (±)-frondosin B has been developed based on the application of a Stille–Heck reaction sequence of 2-chloro-5-methoxybenzo[b]furan-3-yl triflate and 2-(3-butenyl)-3-(trimethylstannyl)cyclohex-2-enone giving the racemic natural product in a 34% overall yield.

Thiol-dependent DNA cleavage by aminomethylated Beaucage's reagent by Jiahui Zheng; Xiaoqian Liu; Qing Yuan; Yoon-Joo Shin; Daekyu Sun; Yixin Lu (1293-1295).
Aminomethylated Beaucage's reagent 1 was found to be more potent than 3H-1,2-benzodithiol-3-one 1,1-dioxide (Beaucage's reagent) in causing DNA cleavage. The current study demonstrated the importance of the amino functionality in enhancing DNA-cleaving activities, and such findings may facilitate development of novel sulfur-containing DNA-cleaving molecules in cancer therapy.

Convenient and efficient synthesis of a new environmentally sensitive chlorine-substituted 2,3-naphthalimide-based fluorophore is reported. Benzotriazole carboxyl group activation of the 6-chloro-fluorophore enabled quick labeling of free and Fmoc-protected amino acids. The photophysical properties of the compounds obtained include high quantum yields in solvents of different polarity: water, methanol, acetonitrile and hexane.

Non-α-hydroxylated aldehydes with evolved transketolase enzymes by Armando Cázares; James L. Galman; Lydia G. Crago; Mark E. B. Smith; John Strafford; Leonardo Ríos-Solís; Gary J. Lye; Paul A. Dalby; Helen C. Hailes (1301-1309).
Transketolase mutants previously identified for use with the non-phosphorylated aldehyde propanal have been explored with a series of linear and cyclic aliphatic aldehydes, and excellent stereoselectivities observed.

A coumarin–thiourea conjugate (1) behaves as a highly selective fluorescent probe for Hg2+ in aqueous media. The probe 1 shows selective and quantitative fluorescence decrease upon Hg2+ addition in aqueous media with a broad pH range, 2–12. Ab initio molecular orbital calculations reveal that the fluorescence decrease of 1 upon Hg2+ addition is promoted by a Hg2+-induced desulfurization of the thiourea moiety, leading to a decrease in an intramolecular charge transfer (ICT) character of the excited-state coumarin moiety.

Replacement of Ala by Aib improves structuration and biological stability in thymine-based α-nucleopeptides by Piero Geotti-Bianchini; Alessandro Moretto; Cristina Peggion; Julien Beyrath; Alberto Bianco; Fernando Formaggio (1315-1321).
Three thymine-based nucleo-heptapeptides, each containing two nucleo-amino acids and zero, one or four Aib residues, respectively, have been synthesized. A single Aib residue is enough to promote the adoption of a helical structure in our nucleopeptides and to increase significantly their resistance towards enzymatic degradation. The insertion of four Aib residues, out of seven residues in the sequence, affords a rigid, 310-helical nucleopeptide that is substantially unaffected by serum enzymes and is not cytotoxic.

Stereochemistry of 10-sulfoxidation catalyzed by a soluble Δ9 desaturase by Amy E. Tremblay; Nigel Tan; Ed Whittle; Derek J. Hodgson; Brian Dawson; Peter H. Buist; John Shanklin (1322-1328).
The stereochemistry of castor stearoyl-ACP Δ9 desaturase-mediated 10-sulfoxidation has been determined. This was accomplished by 19F NMR analysis of a fluorine-tagged product, 18-fluoro-10-thiastearoyl ACP S-oxide, in combination with a chiral solvating agent, (R)-AMA. Sulfoxidation proceeds with the same stereoselectivity as hydrogen removal from the parent stearoyl substrate. These data validate the use of thia probes to determine the stereochemistry and cryptoregiochemistry of desaturase-mediated oxidations.

Molecular recognition of N-protected dipeptides by pseudopeptidic macrocycles: a comparative study of the supramolecular complexes by ESI-MS and NMR by Ignacio Alfonso; Michael Bolte; Miriam Bru; M. Isabel Burguete; Santiago V. Luis; Cristian Vicent (1329-1339).
The molecular recognition properties of pseudopeptidic macrocycles have been studied by ESI-MS and NMR spectroscopy, as highly complementary experimental techniques in solution and in the gas phase. We used ESI-MS competition experiments for the high throughput screening of the supramolecular interaction between four macrocyclic receptors and different peptide-like substrates in solution, rendering the best-fitted host–guest pairs. Further insights on the non-covalent recognition process in the gas-phase were obtained through collision induced dissociation (CID) experiments. Solution studies using NMR spectroscopy (1H NMR titrations, NOESY and DOSY) were carried out to prove the validity of ESI-MS as a high-throughput screening method for studying the molecular recognition of the investigated pseudopeptidic macrocycles. A clear selectivity for N-protected dipeptides over N-protected amino acids, and a slight preference for dipeptides bearing aromatic side chains were observed. On the basis of the results obtained from this approach, a mode of binding has been proposed.

One-electron oxidation of DNA: thymine versus guanine reactivity by Sriram Kanvah; Gary B. Schuster (1340-1343).
One-electron oxidation of anthraquinone (AQ)-linked DNA oligonucleotides containing A/T base pairs with repeating TT steps results in the distance-dependent reaction of the resulting radical cation and base damage at the TT steps that is revealed by subsequent reaction as strand cleavage. However, the inclusion of a remote guanine or GG step inhibits the reaction at thymine and results in predominant reaction at the guanine bases. For the oligomers examined in this work, the results reveal that the specific sequence of nucleobases determines the distance dependence, location of reaction and the efficiency of radical cation migration. In particular, a sequence of A/T base pairs can behave either as a trap, shuttle or barrier, depending on the context of the entire oligomer. The A/T sequences act as a shuttle when reaction occurs at a remote G or GG step and the same sequence of A/T bases acts as a barrier when there is more than one GG step in the sequence. In contrast, the A/T steps act as a trap in sequences that lack guanines.

Versatile chiroptics of peptide-induced assemblies of metalloporphyrins by Hirokuni Jintoku; Takashi Sagawa; Tsuyoshi Sawada; Makoto Takafuji; Hirotaka Ihara (1344-1350).
Zinc porphyrin functionalized with double long-chain alkylated l-glutamide (GTPP-Zn) was synthesized for the first time, and its self-assembling behaviour was investigated in nonpolar organic solvents. The uniqueness of this functionalized porphyrin is characterized by its drastic colour change from dark green to purple via the formation of chirally stacked structures through selective axial coordination on zinc with pyridine derivatives. In this paper, we report the versatility of the GTPP-Zn assembly process as a stimuli-responsive chiroptical switching system and describe the remarkable ligand-specific induction of secondary chirality accompanied by aggregation morphological change.

Exploring neoglycoprotein assembly through native chemical ligation using neoglycopeptide thioesters prepared via N→S acyl transfer by Jonathan P. Richardson; Chung-Hei Chan; Javier Blanc; Mona Saadi; Derek Macmillan (1351-1360).
Sugars and simplified oligosaccharide “mimics” can be joined with protein fragments at pre-defined sites using reliable chemical reactions such as thiol alkylation and Cu(i) catalysed azide/acetylene ligation (click chemistry). These fragments have the potential to be assembled into neoglycoprotein therapeutics using native chemical ligation.

A combined spin trapping/EPR/mass spectrometry approach to study the formation of a cyclic peroxide by dienolic precursor autoxidation by Mathilde Triquigneaux; Laurence Charles; Christiane André-Barrès; Béatrice Tuccio (1361-1367).
The spontaneous addition of air oxygen to a dienolic compound, yielding a cyclic peroxide, was followed by spin trapping (ST) combined with EPR spectroscopy and mass spectrometry (MS). Using two different nitrones, the ST/EPR study allowed the detection of the spin adduct of a radical intermediate, and the radical centre in the addend was identified after similar experiments performed with two different 13C-labelled analogues of the substrate. The media were also submitted to electrospray ionisation, in both positive and negative modes, for structural characterisation of the spin adducts by tandem mass spectrometry. This allowed the structure of the hydroxylamine derivatives of the nitroxides formed to be identified. Following these results, a mechanism pathway was proposed for this autoxidation.

Direct asymmetric aldol reactions between aldehydes and ketones catalyzed by l-tryptophan in the presence of water by Zhaoqin Jiang; Hui Yang; Xiao Han; Jie Luo; Ming Wah Wong; Yixin Lu (1368-1377).
Primary amino acids and their derivatives were investigated as catalysts for the direct asymmetric aldol reactions between ketones and aldehydes in the presence of water, and l-tryptophan was shown to be the best catalyst. Solvent effects, substrate scope and the influence of water on the reactions were investigated. Quantum chemical calculations were performed to understand the origin of the observed stereoselectivity.

A novel base-promoted cascade desalicyloylative dimerization of 3-(1-alkynyl)chromones to produce 2-alkynyl xanthones has been developed. This tandem process involves multiple reactions, such as Michael additions/cyclizations/desalicyloylation without a transition metal catalyst and inert atmosphere.

Towards identifying preferred interaction partners of fluorinated amino acids within the hydrophobic environment of a dimeric coiled coil peptide by Toni Vagt; Elisabeth Nyakatura; Mario Salwiczek; Christian Jäckel; Beate Koksch (1382-1386).
Phage display technology has been applied to screen for preferred interaction partners of fluoroalkyl-substituted amino acids from the pool of the 20 canonical amino acids. A parallel, heterodimeric α-helical coiled coil was designed such that one peptide strand contained one of three different fluorinated amino acids within the hydrophobic core. The direct interaction partners within the second strand of the dimer were randomized and coiled coil pairing selectivity was used as a parameter to screen for the best binding partners within the peptide library. It was found that despite their different structures, polarities and fluorine contents, the three non-natural amino acids used in this study prefer the same interaction partners as the canonical, hydrophobic amino acids. The same technology can be used to study any kind of non-canonical amino acids. The emerging results will provide the basis not only for a profound understanding of the properties of these building blocks, but also for the de novo design of proteins with superior properties and new functions.

Organic co-solvents in aqueous DNA-based asymmetric catalysis by Rik P. Megens; Gerard Roelfes (1387-1393).
Water-miscible organic co-solvents can be used in DNA-based catalytic asymmetric reactions at appreciable concentration without a negative effect on enantioselectivity. While the rate of the copper(ii) Diels–Alder reaction is affected negatively by the presence of organic co-solvents, the copper(ii) catalyzed Michael addition and Friedel–Crafts alkylation reaction are significantly faster. Additionally, the presence of organic co-solvents allows for reaction temperatures <0 °C, which results in higher ee's. This is used to perform enantioselective Michael additions and Friedel–Crafts alkylations at gram scale, using catalyst loadings as low as 0.75 mol%. These results are an important step towards application of the DNA-based catalysis concept in organic synthesis

Fulleroids, obtained from the 1,3-dipolar cycloaddition of fullerene with a diazoalkane, have a [5,6]-open methylene bridge and two highly twisted bridgehead double bonds. The [H,H]- and [H,CN]-substituted fulleroids were found to display significantly enhanced and regioselective Diels–Alder addition as compared with the [6,6] closed methanofullerene and C60 with 2,3-dimethyl-1,3-butadiene, but reduced and nonregioselective addition with cyclopentadiene. NMR analysis of the 1 : 1 adduct and quantum calculations indicated that the high reactivity and the regioselective addition are due to π-orbital misalignment at the bridgehead double bond.

Brønsted acid-catalyzed efficient Strecker reaction of ketones, amines and trimethylsilyl cyanide by Guang-Wu Zhang; Dong-Hua Zheng; Jing Nie; Teng Wang; Jun-An Ma (1399-1405).
A general method for the one-pot, three-component Strecker reaction of ketones was developed using Brønsted acids as organocatalysts. A series of α-aminonitriles were obtained in good to excellent yields (79–99%). A preliminary extension to a catalytic enantioselective three-component Strecker reaction of ketones (up to 40% ee) is also described.

Functionalized alkoxy arene diazonium salts from paracetamol by Bernd Schmidt; René Berger; Frank Hölter (1406-1414).
Arene diazonium tetrafluoroborates can be synthesized from aromatic acetamides via a sequence of deacetylation, diazotation and precipitation, induced by anion exchange. The reaction is conducted as a convenient one-flask transformation with consecutive addition of the appropriate reagents. Exchange of solvents or removal of byproducts prior to isolation of the product is not required. The arene diazonium salts are isolated from the reaction mixture by simple filtration. Two complementary protocols are presented, and the utility of the reaction is exemplified for a synthesis of the diarylheptanoid natural product de-O-methyl centrolobine.

Chemoenzymatic synthesis of the carbasugars carba-β-l-galactopyranose, carba-β-l-talopyranose and carba-α-l-talopyranose from methyl benzoate by Derek R. Boyd; Narain D. Sharma; Nigel I. Bowers; Gerard B. Coen; John F. Malone; Colin R. O'Dowd; Paul J. Stevenson; Christopher C. R. Allen (1415-1423).
The cis-dihydrodiol metabolite from methyl benzoate has been used as a synthetic precursor of carba-β-l-galactopyranose, carba-β-l-talopyranose and carba-α-l-talopyranose. The structures and absolute configurations of these carbasugars were determined by a combination of NMR spectroscopy, stereochemical correlation and X-ray crystallography.

CO2-induced amidobromination of olefins with bromamine-T by Junpei Hayakawa; Mitsuhiro Kuzuhara; Satoshi Minakata (1424-1430).
The carbon dioxide (CO2)-induced amidobromination of olefins with bromamine-T is described. The method can be used in reactions with a wide range of olefins, both aromatic and aliphatic, as well as electron-rich and deficient olefins, leading to the regioselective formation of amidobrominated compounds.

Biocatalysed concurrent production of enantioenriched compounds through parallel interconnected kinetic asymmetric transformations by Ana Rioz-Martínez; Fabricio R. Bisogno; Cristina Rodríguez; Gonzalo de Gonzalo; Iván Lavandera; Daniel E. Torres Pazmiño; Marco W. Fraaije; Vicente Gotor (1431-1437).
Parallel interconnected kinetic asymmetric transformations were performed in order to obtain enantioenriched derivatives starting from a set of racemic or prochiral compounds. Thus, in a one-pot reaction using two redox biocatalysts (a BVMO and an ADH) and a catalytic amount of cofactor that acts as a mediator, enantioenriched ketones, sulfoxides, and sec-alcohols were concurrently obtained in a strict parallel way, minimising the quantity of reagents employed. By selecting the appropriate biocatalysts, this methodology represents a potential tool for performing stereodivergent transformations.

Drug discovery: phosphinolactone, in vivo bioisostere of the lactol group by Jean-Noël Volle; Damien Filippini; Bartlomiej Krawczy; Nikolay Kaloyanov; Arie Van der Lee; Tangui Maurice; Jean-Luc Pirat; David Virieux (1438-1444).
In drug discovery, structural modifications over the lead molecule are often crucial for the development of a drug. Herein, we reported the first in vivo bioisosteric effect of phosphinolactone function in relation to the lactol group constituting the bioactive molecule: Hydroxybupropion. The preparation of phosphinolactone analogues and their antidepressant evaluation towards forced swimming test in mice showed that biological activity was regained and even strengthen.

Synthesis and O-phosphorylation of 3,3,4,4-tetrafluoroaryl-C-nucleoside analogues by Laurent Bonnac; Sarah E. Lee; Guy T. Giuffredi; Lucy M. Elphick; Alexandra A. Anderson; Emma S. Child; David J. Mann; Véronique Gouverneur (1445-1454).
Enantioenriched tetrafluorinated aryl-C-nucleosides were synthesised in four steps from 1-benzyloxy-4-bromo-3,3,4,4-tetrafluorobutan-2-ol. The presence of the tetrafluorinated ethylene group is compatible with O-phosphorylation of the primary alcohol, as demonstrated by the successful preparation of the tetrafluorinated naphthyl-C-nucleotide.

Hydrogen bonding properties of non-polar solvents by Rafel Cabot; Christopher A. Hunter; Lisa M. Varley (1455-1462).
A combination of high-throughput NMR titration experiments, UV-Vis absorption titrations and data collected from the literature on 1 : 1 H-bonded complexes has been used to characterise the H-bond properties of non-polar organic solvents: alkanes, perfluorocarbons, aromatic and halogenated organic solvents. The results are analysed in the context of the electrostatic solvent competition model, which assumes that solvent effects on intermolecular interactions can be interpreted based on the exchange of specific functional group contacts, with minimal involvement of the bulk solvent. For solvents where the H-bond parameters have been measured as solutes in carbon tetrachloride solution, the H-bond parameters measured here for the same compounds as solvents are practically identical, i.e. solute and solvent H-bond parameters are directly interchangable. For the very non-polar solvents, alkanes and perfluorocarbons, the experimental H-bond parameters are significantly larger than expected based on calculated molecular electrostatic potential surfaces. This suggests an increase in the relative importance of van der Waals interactions when electrostatic effects are weak, but there is no detectable difference between the solvation properties of cyclic and linear alkanes, which have different van der Waals interaction properties.

The synthesis of oligodeoxynucleotides containing 3′-thionucleosides has been explored using a reverse-direction (5′→3′) approach, based on nucleoside monomers which contain a trityl- or dimethoxytrityl-protected 3′-thiol and a 5′-O-phosphoramidite. These monomers are relatively simple to prepare as trityl-based protecting groups were introduced selectively at a 3′-thiol in preference to a 5′-hydroxyl group. As an alternative approach, trityl group migration could be induced from the 5′-oxygen to the 3′-thiol function. 5′→3′ Synthesis of oligonucleotides gave relatively poor yields for the internal incorporation of 3′-thionucleosides [to give a 3′-S-phosphorothiolate (3′-SP) linkage] and multiple 3′-SP modifications could not be introduced by this method. However, the reverse direction approach provided an efficient route to oligonucleotides terminating with a 3′-thionucleoside. The direct synthesis of these thio-terminating oligomers has not previously been reported and the methods described are applicable to 2′-deoxy-3′-thionucleosides derived from thymine, cytosine and adenine.

New family of polyamine macrocycles containing 2,5-diphenyl[1,3,4]oxadiazole as a signaling unit. Synthesis, acid–base and spectrophotometric properties by Gianluca Ambrosi; Mauro Formica; Vieri Fusi; Luca Giorgi; Eleonora Macedi; Mauro Micheloni; Giovanni Piersanti; Roberto Pontellini (1471-1478).
Synthesis and acid–base properties for three fluorescent polyamine macrocycles 9,12,15,24,25-pentaaza-26-oxatetracyclo[21.2.1.02,7.017,22]hexaicosa-2,4,6,17,19,21,23,251-octaene (L1), 9,12,15,18,27,28-hexaaza-29-oxatetracyclo[24.2.1.02,7.020,25]enneicosa-2,4,6,20,22,24,26,281-octaene (L2) and 9,12,15,18,21,30,31-heptaaza-32-oxatetracyclo[27.2.1.02,7.023,28]diatriconta-2,4,6,23,25,27,29,311-octaene (L3) are reported. Each ligand contains the 2,5-diphenyl[1,3,4]oxadiazole (PPD) unit incorporated in the polyamine macrocycle. The protonation constants of L1–L3 were determined by means of potentiometric measurements in 0.15 mol dm−3 NaCl aqueous solution at 298.1 K. All the ligands are highly fluorescent in aqueous solution under acidic conditions (pH < 2) and their emission drastically decreases when the pH is increased. At pH > 8, a total quenching of fluorescence is observable in all the ligands. The fluorescence is given by the PPD unit, while the behavior as a function of pH can be rationalized on the basis of photoinduced intramolecular electron transfer (PET) from the HOMO of the donor macrocycle nitrogen atoms to the excited fluorophore unit. The insertion of PPD in a polyamine skeleton strongly improves the fluorescence quantum yield of this class of ligands with respect to those already known.

Back cover (1479-1480).