Organic & Biomolecular Chemistry (v.12, #16)

Front cover (2491-2491).

Inside front cover (2492-2492).

Contents list (2493-2498).

Chiral cyclohex-2-enones are important building blocks in synthetic chemistry and the life science industries and much attention has been drawn to the development of efficient and practical methodologies for accessing these enantio-enriched cyclohex-2-enone skeletons. This review describes the impressive progress that has been made in terms of employing new methodologies, suitable reactants as well as more efficient catalyst systems for this important enantioselective transformation. Also, the reaction mechanisms are briefly discussed.

A direct access to bioactive fused N-heterocyclic acetic acid derivatives by Raju Adepu; A. Rajitha; Dipali Ahuja; Atul Kumar Sharma; B. Ramudu; Ravikumar Kapavarapu; Kishore V. L. Parsa; Manojit Pal (2514-2518).
A Cu-catalyzed new sequence involving the Ullmann type intermolecular C–C followed by an intramolecular C–N coupling and then intramolecular aza-Michael type addition (and oxidation) in a single pot afforded various fused N-heterocyclic acetic acid derivatives as inhibitors of PDE4.

Biomimetic total synthesis of (±)-yezo'otogirin A by Hiu C. Lam; Kevin K. W. Kuan; Jonathan H. George (2519-2522).
The total synthesis of yezo'otogirin A has been achieved via a biosynthetically-inspired strategy. Diastereoselective synthesis of pre-yezo'otogirin A, the proposed biosynthetic pre-cursor of yezo'otogirin A, was accomplished in eight steps from 3-ethoxy-2-cyclohexenone. A biomimetic oxidative radical cyclization was then used to construct the unique tricyclic ring system of yezo'otogirin A. The synthesis showcases the ability of biomimetic radical cyclizations to generate complex natural products from unprotected intermediates.

A mild gold-catalyzed three-component dehydrogenative coupling of terminal alkynes to amines and indole-2-carboxaldehyde has been developed, which provides a practical synthetic strategy for the synthesis of indole derivatives.

Copper-catalyzed benzylic C(sp3)–H alkoxylation of heterocyclic compounds by Noriaki Takemura; Yoichiro Kuninobu; Motomu Kanai (2528-2532).
We achieved intra- and intermolecular C(sp3)–H alkoxylation of benzylic positions of heteroaromatic compounds using CuBrn (n = 1, 2)/5,6-dimethylphenanthroline (or 4,7-dimethoxyphenanthroline) and (tBuO)2 as a catalyst and an oxidant, respectively. The reaction proceeded at both terminal and internal benzylic positions of the alkyl groups. The intramolecular alkoxylation was performed on a gram scale.

Palladium catalyzed N–H bond insertion and intramolecular cyclization cascade: the divergent synthesis of heterocyclics by Dong Ding; Gang Liu; Guangyang Xu; Jian Li; Guoping Wang; Jiangtao Sun (2533-2537).
The palladium catalyzed carbenoid based N–H insertion and electronic effect controlled 5-exo-trig or 6-endo-trig mode Heck cyclization in one-pot has been realized for ortho-iodoanilines, in which PdCl2 was used as the single palladium resource. The corresponding indoles and quinolines were obtained respectively. However, for ortho-triflateanilines, base promoted cyclization is preferred and the lactones were obtained.

A Pd(ii)-catalyzed oxidative alkoxycarbonylation of phenol derivatives with atmospheric pressure of CO–O2 and alcohols has been achieved. The reaction provides an efficient strategy for the synthesis of carboxylic esters and can be applied to the late-stage modification of complex molecules.

A nanomotor involves a metastable, left-handed DNA duplex by Yingmei Li; Chuan Zhang; Cheng Tian; Chengde Mao (2543-2546).
A newly designed metastable left-handed DNA architecture has been successfully used to power a DNA nanomotor by strand displacement without a toehold.

The ferrocene-pyrylium dyad 1 behaves as a selective redox and colorimetric chemodosimeter for CN and HS anions, exhibiting a clear perturbation in the redox potential of the ferrocene unit and in the absorption band, in the presence of these anions.

Isovanillin derived N-(un)substituted hydroxylamines possessing an ortho-allylic group: valuable precursors to bioactive N-heterocycles by Balakrishna Dulla; Neelima D. Tangellamudi; Sridhar Balasubramanian; Swapna Yellanki; Raghavender Medishetti; Rakesh Kumar Banote; Girish Hari Chaudhari; Pushkar Kulkarni; Javed Iqbal; Oliver Reiser; Manojit Pal (2552-2558).
The intramolecular 1,3-dipolar cycloaddition of isovanillin derived N-aryl hydroxylamines possessing ortho-allylic dipolarophiles affords novel benzo analogues of tricyclic isoxazolidines that can be readily transformed into functionalized lactams, γ-aminoalcohols and oxazepines. The corresponding N-unsubstituted hydroxylamines give rise to tetrahydroisoquinolines. Anxiogenic properties of these compounds are tested in zebra fish.

Molecular binding behavior of a bispyridinium-containing bis(β-cyclodextrin) and its corresponding [2]rotaxane towards bile salts by Ying-Ming Zhang; Ze Wang; Yong Chen; Hong-Zhong Chen; Fei Ding; Yu Liu (2559-2567).
Bispyridinium-bridged bis(β-cyclodextrin) (1) and its corresponding [2]rotaxane (2) were synthesized by a ‘click’ reaction, in which two different types of macrocycles, cucurbit[7]uril and β-cyclodextrin, are employed as the wheel component and bulky stopper, respectively. Moreover, the molecular binding behaviors of hosts 1 and 2 with four bile salts, namely, the sodium salts of cholic acid (CA), deoxycholic acid (DCA), glycocholic acid (GCA), and taurocholic acid (TCA), were comparatively investigated by 1H NMR spectroscopy and isothermal titration calorimetry experiments. The spectroscopic and microcalorimetric results can jointly demonstrate a cucurbituril-mediated binding process; that is, the introduction of cucurbit[7]uril has a pronounced impact on the electrostatic attraction and hydrogen-bonding interaction between the bispyridinium spacer in the host molecules and the hydrophilic terminal group in the guest molecules, ultimately giving a significant change in the thermodynamic origins of these supramolecular complexes.

Anti-cooperative ligand binding and dimerisation in the glycopeptide antibiotic dalbavancin by Mu Cheng; Zyta M. Ziora; Karl A. Hansford; Mark A. Blaskovich; Mark S. Butler; Matthew A. Cooper (2568-2575).
Dalbavancin, a semi-synthetic glycopeptide with enhanced antibiotic activity compared to vancomycin and teicoplanin, binds to the C-terminal lysyl-d-alanyl-d-alanine subunit of Lipid II, inhibiting peptidoglycan biosynthesis. In this study, micro-calorimetry and electrospray ionization (ESI)-MS have been used to investigate the relationship between oligomerisation of dalbavancin and binding of a Lipid II peptide mimic, diacetyl-Lys-d-Ala-d-Ala (Ac2-Kaa). Dalbavancin dimerised strongly in an anti-cooperative manner with ligand-binding, as was the case for ristocetin A, but not for vancomycin and teicoplanin. Dalbavancin and ristocetin A both adopt an ‘closed’ conformation upon ligand binding, suggesting anti-cooperative dimerisation with ligand-binding may be a general feature of dalbavancin/ristocetin A-like glycopeptides. Understanding these effects may provide insight into design of novel dalbavancin derivatives with cooperative ligand-binding and dimerisation characteristics that could enhance antibiotic activity.

Fructose controlled ionophoric activity of a cholate–boronic acid by James R. D. Brown; Inmaculada C. Pintre; Simon J. Webb (2576-2583).
Wulff-type boronic acids have been shown to act as ionophores at pH 8.2 by transporting Na+ through phospholipid bilayers. A cholate–boronic acid conjugate was synthesised and shown to be an ionophore, although the hydroxyl-lined face of the cholate moiety did not enhance ion transport. Mechanistic studies suggested a carrier mechanism for Na+ transport. The addition of fructose (>5 mM) strongly inhibited ionophoric activity of the cholate–boronic acid conjugate, mirrored by a strong decrease in the ability of this compound to partition into an organic phase. Modelling of the partitioning and ion transport data, using a fructose/boronic acid binding constant measured at pH 8.2, showed a good correlation with the extent of fructose/boronic acid complexation and suggested high polarity fructose/boronic acid complexes are poor ionophores. The sensitivity of ion transport to fructose implies that boronic acid-based antibiotic ionophores with activity modulated by polysaccharides in the surrounding environment may be accessible.

A modular lead-oriented synthesis of diverse piperazine, 1,4-diazepane and 1,5-diazocane scaffolds by Thomas James; Paul MacLellan; George M. Burslem; Iain Simpson; J. Andrew Grant; Stuart Warriner; Visuvanathar Sridharan; Adam Nelson (2584-2591).
Piperazines are found widely in commercially-available compounds and bioactive molecules (including many drugs). However, in the vast majority of these molecules, the piperazine ring is isolated (i.e. not fused to another ring) and is not substituted on any of its carbon atoms. A modular synthetic approach is described in which combinations of cyclic sulfamidate and hydroxy sulfonamide building blocks may be converted into piperazines and related 1,4-diazepine and 1,5-diazocane scaffolds. By variation of the combinations of building blocks used, it was possible to vary the ring size, substitution and configuration of the resulting heterocyclic scaffolds. The approach was exemplified in the synthesis of a range of heterocyclic scaffolds that, on decoration, would target lead-like chemical space. It was demonstrated that lead-like small molecules based on these scaffolds would likely complement those found in large compound collections.

2-Deoxy-2-fluoroglycosides bearing dibenzyl phosphate and phosphonate aglycones were synthesised and tested as covalent inactivators of several retaining α- and β-glycosidases. β-d-Gluco-, -manno- and -galacto-configured benzyl-benzylphosphonate derivatives efficiently inactivated β-gluco-, β-manno- and β-galactosidases, while α-gluco- and α-manno-configured phosphate and phosphonate derivatives served instead as slow substrates.

Efficient synthesis of biscarbazoles by palladium-catalyzed twofold C–N coupling and C–H activation reactions by Tran Quang Hung; Ngo Ngoc Thang; Do Huy Hoang; Tuan Thanh Dang; Alexander Villinger; Peter Langer (2596-2605).
A new and efficient strategy for the synthesis of 3,9′- and 2,9′-biscarbazoles was developed. Our strategy relies on the cyclization of 1,1′-biphenyl-2,2′-diyl bis(trifluoromethanesulfonate) with 4- or 3-anisidine, transformation of the methoxy to a triflate group and subsequent oxidative Pd-catalyzed cyclization with various anilines.

Versatile C3-symmetric scaffolds and their use for covalent stabilization of the foldon trimer by Arne Berthelmann; Johannes Lach; Melissa A. Gräwert; Michael Groll; Jutta Eichler (2606-2614).
C3-Symmetric trimesic acid scaffolds, functionalized with bromoacetyl, aminooxyacetyl and azidoacetyl moieties, respectively, were synthesized and compared regarding their utility for the trivalent presentation of peptides using three different chemoselective ligation reactions, i.e. thioether and oxime formation, as well as the “click” reaction. The latter ligation method was then used to covalently stabilize the trimer of foldon, a 27 amino acid trimerization domain of bacteriophage T4 fibritin, by linking the three foldon monomers to the triazido-functionalized trimesic acid scaffold. This reaction dramatically enhanced the thermal stability of the trimer, while maintaining the correct fold, as demonstrated by CD spectroscopy and X-ray crystal structure analysis, respectively, of the foldon–scaffold conjugates.

Diversity oriented synthesis of novel haloglycolipids potentially useful for crystallization of integral membrane proteins by Laxminarayan Sahoo; Anadi Singhamahapatra; Duraikkannu Loganathan (2615-2625).
A series of novel haloglycolipids were synthesized based on Cu(i) catalyzed Huisgen's [3 + 2] cycloaddition reaction of diversely functionalized azides and alkynes, using a mixture of N-bromosuccinimide and Cu(i) halide as the halogen source. Since halogen atoms, like bromine and iodine, with a very high scattering power facilitate the solving of crystal structures, the title haloglycolipids could prove to be invaluable in structure-based drug design involving membrane proteins as targets.

Back cover (2627-2628).