Organic & Biomolecular Chemistry (v.16, #7)

Front cover (1041-1041).

Inside front cover (1042-1042).

Contents list (1043-1049).

gem-Diborylalkanes: recent advances in their preparation, transformation and application by Rajender Nallagonda; Kishor Padala; Ahmad Masarwa (1050-1064).
Recently, gem-diborylalkanes have attracted much attention as versatile building blocks and fundamental intermediates in organic synthesis, because they enable multiple C–C bond construction and further transformation at C–B bonds. Importantly, gem-diborylalkanes can be utilised as bisnucleophilic partners in a variety of chemo-selective C–C bond-forming reactions. This review describes recent developments in synthesising gem-diborylalkanes in complex molecules along with their chemical transformation. In the first part of the review the different synthetic approaches used to synthesise gem-diborylalkanes are described. In the second part, an overview of the chemoselective transformation of gem-diborylalkanes into various functionalized materials is discussed along with one-carbon homologation of diborylmethane via a selective uni- and bidirectional method.

A DBU-promoted carbonylative cyclization of propargylic alcohols with sulfur was developed. Various 1,3-oxathiolan-2-ones were produced in 61–98% yields under mild conditions in the absence of metal catalysts. TFBen (benzene-1,3,5-triyl triformate) as an efficient and solid CO surrogate and S8 as an ideal sulfur source were employed and incorporated.

Solvent incorporated sequential [3 + 2] annulation/substitution reaction of azomethine imines and propargyl sulfur ylide by Shoujie Shen; Yanli Yang; Jiangyan Duan; Zhenhu Jia; Jinyan Liang (1068-1072).
A novel solvent incorporated sequential [3 + 2] cycloaddition/substitution reaction of azomethine imines with propargyl sulfur ylide was developed. In the actual three-component reaction, propargyl sulfur ylide acts as a dipole reagent to furnish the annulation with azomethine imines, followed by the protic solvents acting as nucleophiles. The simple, mild, catalyst-free and practical protocol allows for the formation of N,N-bicyclic pyrazolidinones in moderate to excellent yields. Further transformation and gram-scale operations could also be achieved efficiently.

The ability to incorporate non-canonical amino acids (ncAA) using translation offers researchers the ability to extend the functionality of proteins and peptides for many applications including synthetic biology, biophysical and structural studies, and discovery of novel ligands. Here we describe the high promiscuity of an editing-deficient valine-tRNA synthetase (ValRS T222P). Using this enzyme, we demonstrate ribosomal translation of 11 ncAAs including those with novel side chains, α,α-disubstitutions, and cyclic β-amino acids.

A highly diastereoselective synthesis of tertiary α-fluoro carbonyl compounds is reported in only two chemical steps from a simple alkyne through the reaction of stereodefined fully substituted silyl ketene hemiaminal derivatives with Selectfluor.

Anion transport by ortho-phenylene bis-ureas across cell and vesicle membranes by Christopher M. Dias; Hongyu Li; Hennie Valkenier; Louise E. Karagiannidis; Philip A. Gale; David N. Sheppard; Anthony P. Davis (1083-1087).
Ortho-Phenylene bis-ureas serve as anionophores in cells expressing halide-sensitive yellow fluorescent protein, as well as in synthetic vesicles. Activities can reach high levels, and are strongly dependent on the deliverability of the transporters.

A convergent synthesis of vinyloxyimidazopyridine via Cu(i)-catalyzed three-component coupling by Sadhanendu Samanta; Susmita Mondal; Alakananda Hajra (1088-1092).
The synthesis of vinyloxyimidazopyridine with complete regio- and stereoselectivity has been achieved by the Cu(i)-catalyzed three-component coupling of 2-aminopyridine, 2-oxoaldehyde and alkyne. This protocol is operationally very simple and has much potential for the synthesis of heteroarylated vinyl ethers from basic chemicals. Steroidal imidazopyridinyl vinyl ether was obtained successfully from ethynylestradiol.

A C2-symmeric binaphthyl framework bearing phenanthrene as the emitter exhibited circularly polarised luminescence (CPL) in dilute solutions. The CPL and circular dichroism signs of the luminophores were altered by solvents (chloroform, methanol, acetonitrile, and dimethylformamide). DFT and TD-DFT calculations indicated that the dihedral angle between the phenanthrene and naphthyl rings was responsible for the apparent sign inversion. The role of solvent molecules in the ground and photoexcited states was discussed based on Hansen solubility parameters (δ, δd, δp and δh).

A new mechanism for internal nucleophilic substitution reactions by María J. Aurell; Miguel A. González-Cardenete; Ramón J. Zaragozá (1101-1112).
A new mechanism for the classic internal nucleophilic substitution reactions SNi by means of computational studies in the gas-phase, DCM and acetonitrile is reported. Despite the importance of the SNi mechanism, since the mid-1990s this mechanism has remained unexplored. This study focused mainly on the comparison between the mechanisms postulated to date for the SNi reactions and a new mechanism suggested by us that fits better the experimental observations. This comparative study has been applied to the conversion of ethyl, neopentyl, isopropyl and tert-butyl chlorosulfites into the corresponding alkyl chlorides. This new mechanism occurs through two transition structures. For primary and secondary substrates, the first transition structure is a 6-center syn-rearrangement of the alkanesulfonyl chloride that produces the corresponding olefin by simultaneous expulsion of HCl and SO2. The olefin, HCl and SO2 form a molecular complex. The final syn-addition of HCl to the olefin leads to alkyl chloride with the retention of configuration. For tertiary substrates, a variation of the previous mechanism is postulated with the intervention of contact ion pairs. It is of great importance to emphasize that this new mechanism is able to explain some experimental observations such as the presence of olefins in these types of reactions and the low reactivity of some systems such as neopentyl chlorosulfite. Our results pave the way to a new mechanistic perspective in similar reactions which will need further studies and validation.

A method for the preparation of aryl α,α-difluoroethyl thioethers (ArSCF2CH3) is reported and the synthesis approach is extended to aryl α,α-difluoroethyl oxygen ethers. Selected building blocks are further elaborated in cross-coupling reactions and are incorporated into analogues of established trifluoromethyl ether drugs. Conformations are explored and log P studies of these motifs indicate that they are significantly more polar than their trifluoromethyl ether analogues rendering them attractive for bioactives discovery.

Total synthesis of pipecolic acid and 1-C-alkyl 1,5-iminopentitol derivatives by way of stereoselective aldol reactions from (S)-isoserinal by Sebastian Baś; Rafał Kusy; Monika Pasternak-Suder; Cyril Nicolas; Jacek Mlynarski; Olivier R. Martin (1118-1125).
A short synthesis of iminosugars and pipecolic acid derivatives has been realized through aldol addition of a pyruvate, a range of ketones and (S)-isoserinal, followed by catalytic reductive intramolecular amination. The stereoselective aldol reaction was achieved successfully by using tertiary amines or di-zinc aldol catalysts, thus constituting two parallel routes to optically pure products with good yields and high diastereoselectivities. These carbohydrate analogues may be the inhibitors of potent glycosidases and glycosyltransferases.

PLP-independent racemization: mechanistic and mutational studies of O-ureidoserine racemase (DcsC) by Yeong-Chan Ahn; Conrad Fischer; Marco J. van Belkum; John C. Vederas (1126-1133).
O-Ureidoserine racemase (DcsC) is a PLP-independent enzyme in the biosynthetic route to the antibiotic d-cycloserine. Here we present the recombinant expression and characterization of a significantly more active DcsC variant featuring an N-terminal SUMO-tag. Synthesis of enantiomeric pure inhibitors in combination with site-specific mutation of active site cysteines to serines of this enzyme offers closer insights into the mechanism of this transformation. Homology modelling with a close relative (diaminopimelate epimerase, DapF) inspired C- and N-terminal truncation of DcsC to produce a more compact yet still active enzyme variant.

Suzuki cross-coupling of haloalkenes is generally assumed to occur with retention of the alkene stereochemistry. While studying Suzuki cross-couplings on E-1,2-dichlorovinyl phenyl ketone, we were surprised to observe extensive isomerization. More surprisingly, the ligand employed strongly influenced the degree of isomerization: DPEphos and Xantphos led to 96% isomerized cross-coupled product whereas reactions in the absence of a phosphine ligand, or reactions employing t-BuXantphos, gave 94% retention of stereochemistry. While E–Z isomerization in Pd-catalyzed vinylic couplings has previously been attributed to events within the cross-coupling catalytic cycle, we present experimental and computational evidence for a separate Pd-catalyzed isomerization process in these reactions.

Synthesis of a novel HER2 targeted aza-BODIPY–antibody conjugate: synthesis, photophysical characterisation and in vitro evaluation by Miffy. H. Y. Cheng; Antoine Maruani; Huguette Savoie; Vijay Chudasama; Ross. W. Boyle (1144-1149).
We herein report the synthesis and analysis of a novel aza-BODIPY–antibody conjugate, formed by controlled and regioselective bioconjugation methodology. Employing the clinically relevant antibody, which targets HER2 positive cancers, represents an excellent example of an antibody targeting strategy for this class of near-IR emitting fluorophore. The NIR fluorescence and binding properties were validated through in vitro studies using live cell confocal imaging.

A red-emitting fluorescent probe for hydrogen sulfide in living cells with a large Stokes shift by Lei Yang; Yuanan Su; Zhankui Sha; Yani Geng; Fengpei Qi; Xiangzhi Song (1150-1156).
A red-emitting fluorescent probe was developed for the sensitive and selective detection of H2S. Upon treatment with H2S, this probe exhibited a remarkable fluorescence enhancement (10 fold) with a large Stokes shift (125 nm). The detection limit of this probe was as low as 5.7 nM based on S/N = 3. The application of this probe in the detection of intracellular H2S in living cells is successfully demonstrated.

Synthesis of branched and linear 1,4-linked galactan oligosaccharides by Mathias C. F. Andersen; Irene Boos; Christine Kinnaert; Shahid I. Awan; Henriette L. Pedersen; Stjepan K. Kračun; Gyrithe Lanz; Maja G. Rydahl; Louise Kjærulff; Maria Håkansson; Raymond Kimbung; Derek T. Logan; Charlotte H. Gotfredsen; William G. T. Willats; Mads H. Clausen (1157-1162).
We report the synthesis of linear and branched (1→4)-d-galactans. Four tetrasaccharides and one pentasaccharide were accessed by adopting a procedure of regioselective ring opening of a 4,6-O-naphthylidene protecting group followed by glycosylation using phenyl thioglycoside donors. The binding of the linear pentasaccharide with galectin-3 is also investigated by the determination of a co-crystal structure. The binding of the (1→4)-linked galactan to Gal-3 highlights the oligosaccharides of pectic galactan, which is abundant in the human diet, as putative Gal-3 ligands.

Efficient construction of bioactive trans-5A5B6C spirolactones via bicyclo[4.3.0] α-hydroxy ketones by Y. J. Zhu; J. Q. Huo; Z. J. Fan; Q. F. Wu; X. Li; S. Zhou; L. X. Xiong; T. Kalinina; T. Glukhareva (1163-1166).
An efficient, convenient short synthetic procedure for the synthesis of the intricate 5A5B6C-ring fusion topologies of tricyclic spiranoid β-hydroxybutyrolactones through lactonization of the key intermediate trans-α-hydroxyindenones with malonates is described. All the compounds synthesized exhibited environmentally benign characteristics, moderate fungicidal, nematocidal, and anti-TMV activities.

Supramolecular chiroptical switching of helical-sense preferences through the two-way intramolecular transmission of a single chiral source by Ryo Katoono; Keiichi Kusaka; Yuki Tanaka; Kenshu Fujiwara; Takanori Suzuki (1167-1171).
We demonstrate a chiroptical switching system with a simple molecule. The molecule contains a pair of chromophores of diphenylacetylene that are linked with a diyne bond and arranged to exert exciton coupling in helically folded forms with (M)- or (P)-helicity. A tertiary amide group is attached to each end of the looped molecule. The amide carbonyls were used to capture a ditopic hydrogen-bonding guest. A chiral auxiliary group on the amide nitrogen acted as a chiral handle to control the helical-sense preference of dynamic helical forms of the loop. The helical-sense preference is brought about by an intramolecular transmission of point chirality associated with the loop. The preferred sense was switched upon complexation with an achiral additive through the formation of hydrogen bonds. In both states, before and after complexation, the helical-sense preferences were controlled through two-way transmission of the single chiral source.

H-Transfer reactions of internal alkenes with tertiary amines as H-donors on carbon supported noble metals by Guoju Yang; Thomas J. Bauer; Gary L. Haller; Eszter Baráth (1172-1177).
A hydride transfer reaction with tertiary amines was observed in the presence of noble metals on a carbon support. Hydride transfer had been documented previously in terms of activated allyl-type carbon–carbon double bonds containing carbonyl derivatives in the presence of triethyl amine (conjugate reduction). The proposed mechanism is a hydride transfer reaction in which the metal serves as the reaction partner of the hydrido-metal iminium adduct formation. The saturation of a non-activated internal double bond containing compound, such as methyl oleate and trans-5-decene as substrates, was observed for the first time in this work. The pre-reduced catalyst samples showed high activity; in the presence of Pd/C, Pt/C and Rh/C partial to complete conversion was detected at 140 °C in a p-xylene solvent without molecular hydrogen. Higher molecular weight byproducts of the amines were formed, while in the case of the substrates negligible amounts of unreacted but double bond migrated species were present. There is a possibility of usage of alkyl amines other than triethylamine; thus use of tributyl-, tripentyl-, trihexylamine and N,N-diisopropylethylamine, as well as cyclic 1-ethylpyrrolidine and 1-ethylpiperidine, was investigated. Cyclic amines and diisopropyl derivatives as H sources produced the highest conversion, while amines with longer alkyl chains showed minor activity. As a clear indication of H-donation, the formation of unsaturated amine species such as 1-ethyl-pyrrole and pyridine was observed.

Kinetics and thermodynamics of triplex formation between 9-mer homopyrimidine PNA (H2N-Lys-TCTCCTCCC-CONH2) and double-stranded RNA (dsRNA, 5′-AGAGGAGGG-3′/3′-UCUCCUCCC-5′) at acidic pH were studied by means of a stopped-flow technique and isothermal titration calorimetry (ITC). These results revealed the following main findings: (i) the stable PNA–dsRNA triplex formation mostly originated from the large association rate constant (kon), which was dominated by both the charge neutral PNA backbone and the protonation level of the PNA cytosine. (ii) The temperature dependence of the enthalpy change (ΔH) and kon suggested that the association phase of the PNA–dsRNA triplex formation comprised a non-directional nucleation–zipping mechanism that was coupled with the conformational transition of the unbound PNA. (iii) The destabilization by a mismatch in the dsRNA sequence mainly resulted from the decreased magnitude of both kon and ΔH. (iv) There was sequence and position dependence of the mismatch on ΔH and the activation energy (Eon), which illustrated the importance of base pairing in the middle of the sequence. Our results for the first time revealed an association mechanism for the PNA–dsRNA triplex formation. A set of the kinetic and thermodynamic data we reported here will also expand the scope of understanding for nucleic acid recognition by PNA.

Synthesis of oligosaccharides related to galactomannans from Aspergillus fumigatus and their NMR spectral data by V. B. Krylov; D. A. Argunov; A. S. Solovev; M. I. Petruk; A. G. Gerbst; A. S. Dmitrenok; A. S. Shashkov; J.-P. Latgé; N. E. Nifantiev (1188-1199).
The synthesis of model oligosaccharides related to antigenic galactomannans of the dangerous fungal pathogen Aspergillus fumigatus has been performed employing pyranoside-into-furanoside (PIF) rearrangement and controlled O(5) → O(6) benzoyl migration as key synthetic methods. The prepared compounds along with some previously synthesized oligosaccharides were studied by NMR spectroscopy with the full assignment of 1H and 13C signals and the determination of 13C NMR glycosylation effects. The obtained NMR database on 13C NMR chemical shifts for oligosaccharides representing galactomannan fragments forms the basis for further structural analysis of galactomannan related polysaccharides by a non-destructive approach based on the calculation of the 13C NMR spectra of polysaccharides by additive schemes.

Deoxygenation of sulphoxides to sulphides with trichlorophosphane by Xia Zhao; Xiancai Zheng; Bo Yang; Jianqiao Sheng; Kui Lu (1200-1204).
An efficient route to deoxygenation of sulphoxides to sulphides with PCl3 under mild reaction condition was developed. PCl3 was used as a reducing agent for the first time to convert sulphoxides to sulphides. The mild conditions, use of cheap and readily available reagent, and broad substrate scope render it a useful strategy for preparing sulphides.

Back cover (1205-1206).