Organic & Biomolecular Chemistry (v.13, #37)

Front cover (9519-9520).

Contents list (9521-9527).

Copper-catalysed azide–alkyne cycloadditions (CuAAC): an update by Estela Haldón; M. Carmen Nicasio; Pedro J. Pérez (9528-9550).
The reactions of organic azides and alkynes catalysed by copper species represent the prototypical examples of click chemistry. The so-called CuAAC reaction (copper-catalysed azide–alkyne cycloaddition), discovered in 2002, has been expanded since then to become an excellent tool in organic synthesis. In this contribution the recent results described in the literature since 2010 are reviewed, classified according to the nature of the catalyst precursor: copper(i) or copper(ii) salts or complexes, metallic or nano-particulated copper and several solid-supported copper systems.

New chiral S,N- and S,P-ligands starting from tert-butanesulfinamide were synthesized in four steps, applying Pd-catalyzed asymmetric allylic substitutions of dimethyl 2-fluoromalonate. The induced effect of the Pd/S,N-ligand catalyst on the enantioselectivity depends on the steric demand of the substituent at the o-position of the pyridine ring. This method produced monofluorinated allylation products in up to high yield with high enantioselectivity.

A dual optical and nuclear imaging reagent for peptide labelling via disulfide bridging by Sally A. Fletcher; Pak Kwan Brian Sin; Muriel Nobles; Erik Årstad; Andrew Tinker; James R. Baker (9559-9563).
We report a concise approach to a multimodal imaging reagent for peptide labelling via disulfide bridging. The reagent is constructed using a one pot, three component, [3 + 2] cycloaddition of a fluorescent azide with a dithiomaleimide-alkyne, with concomitant incorporation of 125I. The dithiomaleimide handle then enables site selective conjugation to a disulfide bond of a peptide whilst retaining the key structural bridging functionality, as exemplified on the therapeutic peptide octreotide.

A series of novel J147 derivatives were synthesized, and their inhibitory activities against β-amyloid (Aβ) aggregation and toxicity were evaluated by using the oligomer-specific antibody assay, the thioflavin-T fluorescence assay, and a cell viability assay in the transformed SH-SY5Y cell culture. Among the synthesized J147 derivatives, 3j with a 2,2-dicyanovinyl substituent showed the most potent inhibitory activity against Aβ42 oligomerization (IC50 = 17.3 μM) and Aβ42 fibrillization (IC50 = 10.5 μM), and disassembled the preformed Aβ42 fibrils with an EC50 of 10.2 μM. Finally, we confirmed that 3j is also effective at preventing neurotoxicity induced by Aβ42-oligomers as well as Aβ42-fibrils.

Metal-free aerobic one-pot synthesis of substituted/annulated quinolines from alcohols via indirect Friedländer annulation by Namrata Anand; Suvajit Koley; B. Janaki Ramulu; Maya Shankar Singh (9570-9574).
Metal-free, operationally simple, and highly efficient one-pot aerobic process for the synthesis of functionalized/annulated quinolines is devised from easily available 2-aminobenzyl alcohol/2-aminobenzophenones and alkyl/aryl alcohols for the first time. The process involves two sequential reactions, namely in situ aerial oxidation of alcohols to the corresponding aldehydes/ketones followed by Friedländer annulation.

A series of regioisomers for dithiafulvenyl-substituted phenylacetylene derivatives was synthesized and characterized to show structure-dependent electronic properties and different reactivities in their oxidized states.

Helical peptaibol mimics are better ionophores when racemic than when enantiopure by Sarah J. Pike; Jennifer E. Jones; James Raftery; Jonathan Clayden; Simon J. Webb (9580-9584).
Helical peptide foldamers rich in α-aminoisobutyric acid (Aib) act as peptaibol-mimicking ionophores in the phospholipid bilayers of artificial vesicles. Racemic samples of these foldamers are more active than their enantiopure counterparts, which was attributed to differing propensities to form aggregates with crystal-like features in the bilayer.

Legonaridin, a new member of linaridin RiPP from a Ghanaian Streptomyces isolate by Mostafa E. Rateb; Yin Zhai; Emmanuelle Ehrner; Christopher M. Rath; Xiaoling Wang; Jioji Tabudravu; Rainer Ebel; Mervin Bibb; Kwaku Kyeremeh; Pieter C. Dorrestein; Kui Hong; Marcel Jaspars; Hai Deng (9585-9592).
Linaridins are rare linear ribosomally-synthesized and post-translationally modified peptides (RiPPs) and only two, cypemycin and SGR-1832, in this family have been identified so far. Legonaridin 1 has been discovered as a new member of linaridins through chemical isolation, peptidogenomics, comprehensive 1- and 2-D NMR and advanced Marfey's analyses from the soil bacterium Streptomyces sp. CT34, an isolate collected from Legon, Ghana. Bioinformatics analysis of the gene cluster suggested that the biosynthesis of legonaridin 1 is different from those of cypemycin and SGR-1832. Consistent with bioinformatics and peptidogenomics analyses, 1 has a total of nine post-modifications, 8 dehydrobutyrine residues and a N,N-dimethylated N-terminus with a carboxylic acid at the C-terminus. Legonaridin 1 is structurally different from the two known linaridins comprising a new subfamily. This is the first time that NMR spectroscopy is used to establish the 2-D structure of a linaridin RiPP.

A new kind of recyclable and reusable PEG-supported Jørgensen–Hayashi catalyst is synthesized for the first time and proven to be efficient for the enamine-catalyzed asymmetric Michael reaction with generally moderate to good diastereoselectivity and high to excellent enantioselectivity (up to 6 : 1 dr, 99% ee). The prepared PEG-supported catalyst can be recovered eight times and was found to provide similar diastereoselectivity and enantioselectivity to unsupported functional catalysts.

An efficient protocol for the asymmetric construction of enantiomerically enriched tetrahydro-6H-benzo[c]chromenes and their derivatives has been developed. The corresponding products were obtained by the cascade double Michael addition of 3-nitro-2H-chromenes and their derivatives with α,β-unsaturated ketones catalyzed by a combination of a quinine-derived primary amine and benzoic acid. Through this methodology, the desired products could be obtained in moderate to good yields (up to 90%), with excellent diastereoselectivities (up to >25 : 1 dr) and moderate to excellent enantioselectivities (up to 95% ee).

Application of RDC enhanced NMR spectroscopy in structural analysis of thiacalix[4]arene derivatives by L. Vrzal; M. Kratochvílová-Šimánová; T. Landovský; K. Polívková; J. Budka; H. Dvořáková; P. Lhoták (9610-9618).
Thiacalix[4]arene spirodienone was rearranged into the corresponding phenoxathiin-based macrocycle. Alkylation of this inherently chiral system to achieve its immobilization led to a mixture of only two (out of four theoretically possible) stereoisomers. As standard NOE and dynamic NMR experiments did not lead to unambiguous determination of the structures we applied the Residual Dipolar Coupling constant (RDC) method. Poly-γ-ethyl-l-glutamate (PELG) and poly-γ-benzyl-l-glutamate (PBLG) were found to be easily applicable lyotropic liquid crystalline alignment media for the conformational analysis of thiacalixarene derivatives. Using these media the 1,2-alternate and the partial cone conformations were determined unequivocally.

Origins of observed reactivity and specificity in the addition of B2Cl4 and analogues to unsaturated compounds by Cristina Pubill-Ulldemolins; Elena Fernánez; Carles Bo; John M. Brown (9619-9628).
In 1954 Schlesinger and co-workers observed the direct reaction of diboron tetrachloride with simple organic compounds under mild conditions, the 1,2 addition product being formed with either ethylene or acetylene. In the following 25 years a series of addition reactions to simple alkenes, alkynes and dienes was demonstrated. B2F4 was shown to react in similar manner, albeit under more forcing conditions. Crucially, it was demonstrated that the addition to (E)- or (Z)-but-2-ene occurred with cis-stereospecificity. Only sporadic interest was shown in this field thereafter until catalysed addition reactions of diboron reagents were realized. Encouraged by this revival of interest through the discovery of transition-metal and nucleophilic catalysis of diboryl additions, DFT analysis of uncatalysed additions of B2X4 has been carried out and interpreted. This includes the relative reactivity of several B–B reagents with ethene, and that of B2Cl4vs. B2F4 additions, including benzene, naphthalene and C60 as reactants. This allows the analysis of relative reactivity vis-à-vis substitution on boron, and also direct comparison with hydroboration by HBCl2. [4 + 2] Addition of diboron reagents to dienes with B–B cleavage competes with direct [2 + 2] addition, favourably so for B2F4. The computational results demonstrate that the stereospecific addition to isomeric but-2-enes is a rare concerted [2σs + 2πs] process.

Isolation and structural determination of non-racemic tertiary cathinone derivatives by M.-J. Zhou; S. Bouazzaoui; L. E. Jones; P. Goodrich; S. E. J. Bell; G. N. Sheldrake; P. N. Horton; S. J. Coles; N. C. Fletcher (9629-9636).
The racemic tertiary cathinones N,N-dimethylcathinone (1), N,N-diethylcathinone (2) and 2-(1-pyrrolidinyl)-propiophenone (3) have been prepared in reasonable yield and characterized using NMR and mass spectroscopy. HPLC indicates that these compounds are isolated as the anticipated racemic mixture. These can then be co-crystallized with (+)-O,O′-di-p-toluoyl-d-tartaric, (+)-O,O′-dibenzoyl-d-tartaric and (−)-O,O′-dibenzoyl-l-tartaric acids giving the single enantiomers S and R respectively of 1, 2 and 3, in the presence of sodium hydroxide through a dynamic kinetic resolution. X-ray structural determination confirmed the enantioselectivity. The free amines could be obtained following basification and extraction. In methanol these are reasonably stable for the period of several hours, and their identity was confirmed by HPLC and CD spectroscopy.

Stable analogues of nojirimycin – synthesis and biological evaluation of nojiristegine and manno-nojiristegine by Agnete H. Viuff; Louise M. Besenbacher; Akiko Kamori; Mikkel T. Jensen; Mogens Kilian; Atsushi Kato; Henrik H. Jensen (9637-9658).
Two novel iminosugars called nojiristegines, being structural hybrids between nor-tropane alkaloid calystegine and nojirimycins, have been synthesised and found to be stable molecules despite the presence of a hemiaminal functionality. The synthesised iminosugars were evaluated against a panel of glycosidases and the best inhibition (IC50), found against α-glucosidases, was in the micromolar region. The compounds were also evaluated as potential antibiotics but no useful level of activity was observed.

Unsymmetrical 1,1-diborated multisubstituted sp3-carbons formed via a metal-free concerted-asynchronous mechanism by Ana B. Cuenca; Jessica Cid; Diego García-López; Jorge J. Carbó; Elena Fernández (9659-9664).
We have experimentally proved the unsymmetrical 1,1-diboration of diazo compounds, formed in situ from aldehydes and cyclic and non-cyclic ketones, in the absence of any transition metal complex. The heterolytic cleavage of the mixed diboron reagent, Bpin–Bdan, and the formation of two geminal C–Bpin and C–Bdan bonds has been rationalised based on DFT calculations to occur via a concerted-asynchronous mechanism. Diastereoselection is attained on substituted cyclohexanones and DFT studies provide understanding on the origin of the selectivity. The alkoxide-assisted selective deborylation of Bpin from multisubstituted sp3-carbon and generation of a Bdan stabilized carbanion, easily conducts a selective protodeboronation sequence.

NMR study on the interaction of the conserved CREX ‘stem–loop’ in the Hepatitis E virus genome with a naphthyridine-based ligand by N. Dyubankova; M. Froeyen; M. Abramov; H. P. Mattelaer; P. Herdewijn; E. Lescrinier (9665-9672).
A 2-amino-1,8-naphthyridine derivative that is described to bind single guanine bulges in RNA–DNA and RNA–RNA duplexes was synthesized and its interaction with the single G bulge in the conserved CREX of the Hepatitis E Virus (HEV) genome was explored by NMR and molecular modeling. Results indicate that the ligand intercalates in the internal loop, though none of the expected hydrogen bonds with the single G in the bulge could be demonstrated.

Hydrophobic moieties like lipid membrane anchors are highly demanded modifications for nucleic acid oligomers. Membrane-anchor modified oligonucleotides are applicable in biomedicine leading to new delivery strategies as well as in biophysical investigations towards the assembly and fusion of liposomes or the construction of DNA origami structures. We present herein the synthesis and applications of versatile lipid membrane anchor building blocks suitable for solid-supported oligonucleotide synthesis. These are readily synthesized in bulk in five to seven steps from commercially available precursors and can be incorporated at any position within an oligonucleotide without significantly altering the duplex stability and structure as was proven by thermal denaturation experiments and circular dichroism. Furthermore, their applicability could be demonstrated by the assembly and fusion of liposomes mediated by lipid-modified oligonucleotides.

Copper catalyzed oxygen assisted C(CNOH)–C(alkyl) bond cleavage: a facile conversion of aryl/aralkyl/vinyl ketones to aromatic acids by Pochampalli Sathyanarayana; Owk Ravi; Prathap Reddy Muktapuram; Surendar Reddy Bathula (9681-9685).
A novel copper-catalyzed aerobic oxidative C(NOH)–C(alkyl) bond cleavage reaction of aryl/aralkyl/vinyl ketones for the synthesis of aromatic/acrylic acids is described. A series of ketones having aryl/aralkyl/vinyl at the one end and methyl to any higher alkyl at the other end can be selectively cleaved and converted into the corresponding acids via oxime intermediates.

Grob fragmentation of suitably designed bicyclic species often generates novel organic skeletons in a facile manner. Herein, we report a comprehensive account of an effective acid-catalyzed Grob fragmentation of trihalonorbornyl ketones to dihalophenol derivatives in good yields. The transformation entails tri-n-butyltin hydride (TBTH) mediated regioselective reduction of one of the two bridgehead halogens of readily available Diels–Alder adducts resulting from 1,2,3,4-tetrahalo-5,5-dimethoxycyclopentadiene and vinyl acetate derivatives, followed by its conversion to substituted halophenol species via a three-step hydrolysis–oxidation–rearrangement/aromatization strategy. Both alkyl and aryl substituted norbornyl ketones were studied. A detailed mechanistic analysis employing an isotope labeling experiment revealed plausible mechanistic pathways. Among the two bridgehead substituents, when halogen (X = Cl, Br) stays at C-1 and hydrogen (H, or deuterium, D) at C-4, then product formation takes place via exclusive protonation (supplied by an external acid) at β carbon (i.e. C-1) of a dienol moiety formed in situ during the Grob-fragmentation, followed by the removal of acidic 4-H (or 4-D) and halide ion (X) from the resulting cyclohexenone intermediate prior to nucleophilic attack on the oxocarbenium ion by X and final enolisation of cyclohexadienone species. A sharp deviation was observed with the regioisomeric bicyclic ketone, wherein the 4-X triggers a facile removal of X and forms the end products without necessitating the involvement of the C-1 substituent (i.e. 1-H/D), thereby retaining it in the final halophenols. It clearly demonstrates how the bridgehead substituents in the two regioisomeric trihalo-norbornyl ketones steer the bicyclic systems to follow entirely different reaction pathways thus suggesting their crucial yet distinct roles in the overall reaction. The present transformation thus manifests the relevance of bridgehead substituents in the Grob fragmentation of such norbornyl systems. Our current strategy also allows one to access ortho-deuterated halophenol compounds.

The strategic use of a sequential Sonogashira coupling/intramolecular alkyne–carbonyl metathesis process for the synthesis of a pyridine ring from 1-(2-haloaryl)-1H-pyrrole-2-carbaldehydes allowed ready access to diverse novel benzo-fused indolizines, pyrrolo[1,2-a]quinolines, in good to excellent yields. As a hybrid structure of indolizine and quinoline, the resulting scaffold has an acyl substituent at the C5 position, which is difficult to make by any other known approaches.

Back cover (9709-9710).