Organic & Biomolecular Chemistry (v.17, #23)

Front cover (5641-5641).

Inside front cover (5642-5642).

Contents list (5643-5650).

Fluorination of organoboron compounds by Graham Pattison (5651-5660).
Methods for the fluorination of organoboron compounds are described. This review will cover the fluorination of aromatic and aliphatic systems using both electrophilic and nucleophilc sources of fluorine. Emerging methods for radiofluorination using 18F for the synthesis of PET-imaging agents are also described.

Lacto-N-tetraose synthesis by wild-type and glycosynthase variants of the β-N-hexosaminidase from Bifidobacterium bifidum by Katharina Schmölzer; Melanie Weingarten; Kai Baldenius; Bernd Nidetzky (5661-5665).
Lacto-N-biose 1,2-oxazoline was prepared chemo-enzymatically and shown to be a donor substrate for β-1,3-glycosylation of lactose by the wild-type and glycosynthase variants (D320E, D320A, Y419F) of Bifidobacterium bifidumβ-N-hexosaminidase. Lacto-N-tetraose, a core structure of human milk oligosaccharides, was formed in 20–60% yield of donor substrate (up to 8 mM product titre), depending on the degree of selectivity control by the enzyme used.

Experimental and numerical evaluation of a genetically engineered M13 bacteriophage with high sensitivity and selectivity for 2,4,6-trinitrotoluene by Won-Geun Kim; Chris Zueger; Chuntae Kim; Winnie Wong; Vasanthan Devaraj; Hae-Wook Yoo; Sungu Hwang; Jin-Woo Oh; Seung-Wuk Lee (5666-5670).
Selective and sensitive detection of desired targets is very critical in sensor design. Here, we report a genetically engineered M13 bacteriophage-based sensor system evaluated by quantum mechanics (QM) calculations. Phage display is a facile way to develop the desired peptide sequences, but the resulting sequences can be imperfect peptides for binding of target molecules. A TNT binding peptide (WHW) carrying phage was self-assembled to fabricate thin films and tested for the sensitive and selective surface plasmon resonance-based detection of TNT molecules at the 500 femtomole level. SPR studies performed with the WHW peptide and control peptides (WAW, WHA, AHW) were well-matched with those of the QM calculations. Our combined method between phage engineering and QM calculation will significantly enhance our ability to design selective and sensitive sensors.

Copper-mediated anomeric O-arylation with organoboron reagents by Victoria Dimakos; Jacklyn J. W. Liu; Zhenlu Ge; Mark S. Taylor (5671-5674).
Copper-mediated couplings of arylboroxines with glycosyl hemiacetals furnish O-aryl glycosides via Csp2–O bond formation. The method enables the anomeric O-arylation of protected pyranose and furanose derivatives, and is tolerant of functionalized arylboroxine partners. Whereas mixtures of anomers are formed from glucopyranose, galactopyranose and arabinofuranose hemiacetals, the α-anomer is generated selectively from mannopyranose and mannofuranose-derived substrates.

The one-pot nonhydrolysis Staudinger reaction and Staudinger or SPAAC ligation by Longhuai Cheng; Xueying Kang; Dan Wang; Yasi Gao; Long Yi; Zhen Xi (5675-5679).
The combined usage of two bioorthogonal reactions can provide hetero-bifunctional molecules under physiological conditions for various applications. Based on the Nonhydrolysis Staudinger Reaction (NSR), we design and develop a bisazido linker 1 for chemoselective dual-functionalization without the need of protection using catalyst-free and one-pot procedures. The NSR is much faster with tetrafluorinated aromatic azide than that the Staudinger–Bertozzi or SPAAC ligation with alkyl azide, as revealed by HPLC analysis and fluorescence kinetics. Based on the tandem NSR and Staudinger–Bertozzi ligation, we prepare a molecular beacon 7 from 1 in one-pot synthesis with a recovery yield of 32%. When a faster SPAAC ligation is used instead of the Staudinger–Bertozzi ligation, compound 8 is prepared in the tandem NSR and SPAAC reactions with a recovery yield of 59%. As a proof-of-concept study, the tandem NSR and SPAAC ligation is further used to produce a FRET-based dyad in living cells, as revealed by dual-color bioimaging. This work shows that NSR can be combined with other bioorthogonal reactions without the need of protection in one-pot.

A new method was developed for synthesizing 2-alkyl-2-boryl-tetrahydrofuran derivatives from aliphatic ketones using a copper(i)/N-heterocyclic carbene complex catalyst. This reaction presumably proceeds through the nucleophilic addition of a borylcopper(i) intermediate to ketone, followed by intramolecular substitution of the resulting alkoxide for the halide leaving group. The new borylation products, 2-alkyl-2-boryl-tetrahydrofuran derivatives with a condensed structure around the C–B bond, cannot be synthesized by other methods.

Iron-catalyzed domino Knoevenagel-hetero-Diels–Alder reaction: facile access to oxabicyclo[3.3.1]nonene derivatives by Mingchang Wu; Junhang Yang; Fang Luo; Cungui Cheng; Gangguo Zhu (5684-5687).
A Fe-catalyzed domino Knoevenagel-hetero-Diels–Alder reaction of alkenyl aldehydes and 1,3-diketones has been developed. It provides straightforward access to a series of oxabicyclo[3.3.1]nonene derivatives in promising yields with excellent diastereoselectivity and functional group tolerance. The resultant bridged dihydropyrans can be smoothly converted into chromene derivatives, thus highlighting the synthetic utility of this method.

An operationally simple synthesis of activated ynesulfonamides and enesulfonamides is described. Ynesulfonamides can be obtained through reaction of sulfonylamides with activated bromoalkynes and Triton B in a short time at room temperature. Likewise, terminal alkynes react with sulfonylamides to provide enesulfonamides. Z/E enesulfonamides can be transformed exclusively into E enesulfonamides.

Importance of the main chain of lysine for histone lysine methyltransferase catalysis by Abbas H. K. Al Temimi; Ruben S. Teeuwen; Vu Tran; Arthur J. Altunc; Danny C. Lenstra; Wansheng Ren; Ping Qian; Hong Guo; Jasmin Mecinović (5693-5697).
Histone lysine methyltransferases (KMTs) are biomedicinally important class of epigenetic enzymes that catalyse methylation of lysine residues in histones and other proteins. Enzymatic and computational studies on the simplest lysine analogues that possess a modified main chain demonstrate that the lysine's backbone contributes significantly to functional KMT binding and catalysis.

Robust synthesis of C-terminal cysteine-containing peptide acids through a peptide hydrazide-based strategy by Chao Zuo; Bing-Jia Yan; Han-Ying Zhu; Wei-Wei Shi; Tong-Kuai Xi; Jing Shi; Ge-Min Fang (5698-5702).
A new robust strategy was reported for the epimerization-free synthesis of C-terminal Cys-containing peptide acids through mercaptoethanol-mediated hydrolysis of peptide thioesters prepared in situ from peptide hydrazides. This simple-to-operate and highly efficient method avoids the use of derivatization reagents for resin modification, thus providing a practical avenue for the preparation of C-terminal Cys-containing peptide acids.

Sterically controlled C–H/C–H homocoupling of arenes via C–H borylation by Xiaocong Pei; Guan Zhou; Xuejing Li; Yuchen Xu; Resmi C. Panicker; Rajavel Srinivasan (5703-5707).
A mild one-pot protocol for the synthesis of symmetrical biaryls by sequential Ir-catalyzed C–H borylation and Cu-catalyzed homocoupling of arenes is described. The regiochemistry of the biaryl formed is sterically controlled as dictated by the C–H borylation step. The methodology is also successfully extended to heteroarenes. Some of the products obtained by this approach are impossible to obtain via the Ullmann or the Suzuki coupling protocols. Finally, we have shown a one-pot sequence describing C–H borylation/Cu-catalyzed homocoupling/Pd-catalyzed Suzuki coupling to obtain π-extended arene frameworks.

Leak-free million-fold DNA amplification with locked nucleic acid and targeted hybridization in one pot by K. Komiya; M. Komori; C. Noda; S. Kobayashi; T. Yoshimura; M. Yamamura (5708-5713).
An isothermal cascade reaction that exponentially amplifies pre-designed, single-stranded DNA as a sensor and signal amplifier module for DNA-based computing and molecular robotics was developed. Taking advantage of the finding that locked nucleic acid can suppress problematic ab initio DNA synthesis, up to million-fold amplification rates and concurrent hybridization were achieved at a physiological temperature in a single reactor. Although the effect of locked nucleic acid introduction to the templates was complicated, undesired leak DNA amplification was generally suppressed in the amplification reaction for distinct DNA sequences. The present reaction that senses one DNA as an input and generates a large amount of another DNA as an output, exhibiting a high correlation between the molecular concentration and the amplification time, is applicable for nucleic acid quantification.

A transition-metal-free method for the synthesis of gem-silylboronate esters with arylboronic acids and trimethylsilyldiazomethane (TMSCHN2) has been developed. This transformation is a straightforward homologation of arylboronic acids and features wide substrate scope and good functional-group tolerance. The gem-silylboronate esters undergo efficient Suzuki–Miyaura cross-coupling with aryliodides and the silyl group of the product can be further functionalized. Tertiary carbon centers with different substituents can be constructed successfully by selective and sequential functionalization.

Development of a self-immolative linker for tetrazine-triggered release of alcohols in cells by Sarah Davies; Bruno L. Oliveira; Gonçalo J. L. Bernardes (5725-5730).
Bioorthogonal decaging reactions are a promising strategy for prodrug activation because they involve bond cleavage to release a molecule of interest. The trans-cyclooctene (TCO)-tetrazine inverse electron-demand Diels–Alder reaction has been widely applied in vivo for decaging of amine prodrugs, however, the release of alcohol-containing bioactive compounds has been less well studied. Here, we report a TCO-carbamate benzyl ether self-immolative linker for the release of OH-molecules upon reaction with a tetrazine trigger. The benzyl ether linker proved to be highly stable and can rapidly liberate alcohols under physiological conditions upon reaction with tetrazines. The mechanism and decaging yield were systematically examined by fluorescence and HPLC analysis by using a fluorogenic TCO–benzyl ether-coumarin probe and different 3,6-substituted tetrazine derivatives. This study revealed that decaging occurs rapidly (t1/2 = 27 min) and the cycloaddition step happens within seconds (t1/2 = 7 s) with reaction rates of ≈100 M−1 s−1. Importantly, the reaction is compatible with living organisms as demonstrated by the decaging of a prodrug of the antibacterial compound triclosan in the presence of live E. Coli, that resulted in complete cell killing by action of the released “OH-active drug”. Overall, this work describes a new linker for masking alcohol functionality that can be rapidly reinstated through tetrazine-triggered decaging.

We herein report the first formal (3 + 2)-cyclisation between 3,3,3-trifluoropyruvate-derived imines and indandione-based Michael acceptors. This reaction gives access to a novel class of spirocyclic α-CF3-α-proline derivatives with complete control of the diastereoselectivity under phase transfer-catalysed reaction conditions.

Multifunctional γ-azido/γ-fluoro-β-iodo-vinyl phosphine oxides/phosphonates/esters/sulfone were synthesised by iodination followed by azidation/fluorination of phosphorus-based allenes or allenoates (allenyl esters) or a sulphur based allene. Surprisingly, the reaction of (γ,β)-diiodo-vinyl-phosphonate with TBAF [n-Bu4NF] led to the corresponding allenylphosphonate; in contrast, the use of CsF in a similar reaction led to novel γ-diiodo-allenylphosphonate along with the corresponding non-halogenated allenylphosphonate. The combination AgF2/CuBr could be used to obtain the γ-fluoro-β-iodo-vinyl phosphine oxides and related phosphorus-free γ-fluoro-β-iodo-vinyl esters. In many cases, I⋯O halogen to oxygen non-covalent bonding interactions (‘halogen bonding’) involving the phosphoryl (PO) oxygen, as evidenced by single crystal X-ray crystallography, are also observed.

A facile protocol for the synthesis of highly substituted fused γ-alkylidene butenolides using direct annulation of ketones with α-ketoesters, which proceeds through TiCl4-n-Bu3N mediated aldol addition followed by an intramolecular enol-lactonization/cyclization cascade, is reported. Diverse 6-5, 7-5 and 8-5 fused bicyclic γ-ylidene butenolides and highly substituted monocyclic analogs related to biologically relevant natural products were prepared from readily accessible ketone and α-ketoester building blocks. The highly step-economic cascade nature, good substrate scope, easy access to complex products with good to excellent yields, gram-scalability, demonstration of synthetic utility, and unambiguous structural confirmation through X-ray crystallography analyses and analogy are the salient features of this work.

Treatment of β-arylpropionitriles with aryllithiums, followed by the reaction with water and then with NIS under irradiation with a tungsten lamp gave 2-arylquinolines in good to moderate yields. The present reaction proceeds through the formation of N-iodoimines from imines with NIS, the generation of imino-nitrogen-centered radicals, and their cyclization onto the aromatic rings of the imines to form 2-aryl-3,4-dihydroquinolines. Finally, the oxidation of 2-aryl-3,4-dihydroquinolines with NIS proceeds smoothly to generate 2-arylquinolines.

A computational study on H2S release and amide formation from thionoesters and cysteine by Yuan-Ye Jiang; Ling Zhu; Xia Fan; Qi Zhang; Ya-Jie Fu; He Li; Bing Hu; Siwei Bi (5771-5778).
The recognition of the biological activity of H2S has drawn much attention to the development of biocompatible H2S release reactions. Thiol-, particularly cysteine-triggered systems which mimic the enzymatic conversion of cysteine or homocysteine to H2S have been intensively reported recently. Herein, a density functional theory (DFT) study was performed to address the reaction mechanism of H2S release and potential amide bond formation from thionoesters and cysteine to gain deeper mechanistic insights. Three possible mechanisms were considered and we found that the one starting from the nucleophilic addition of the ionized mercapto of cysteine on thionoester to generate a dithioester intermediate (Path A) is kinetically favored over the others starting from the nucleophilic addition of the amine of cysteine to generate thionoamide intermediates (Paths B and C). Dithioester then undergoes intramolecular nucleophilic addition of an amine group and the rate-limiting water-assisted proton transfer to generate a cyclic thiol intermediate, and finally affords H2S and dihydrothiazole via water-assisted elimination. The hydrolysis of thionoamide or dihydrothiazole to produce amide is highly difficult under neutral conditions but is operative under strong basic conditions, which explains the experimental observation that dihydrothiazole rather than amide is the major product. Meanwhile, the ring opening reaction of the cyclic thiol intermediate to form the more stable thionoamide is detrimental to H2S release and becomes competitive under basic conditions.

pH-Regulated anion transport activities of bis(iminourea) derivatives across the cell and vesicle membrane by Abhishek Saha; Nasim Akhtar; Vishnu Kumar; Suresh Kumar; Hemant Kumar Srivastava; Sachin Kumar; Debasis Manna (5779-5788).
Recently, synthetic anion transporters have gained considerable attention because of their ability to disrupt cellular anion homeostasis and promote cell death. Herein, we report the development of bis(iminourea) derivatives as a new class of selective Cl ion carrier. The bis(iminourea) derivatives were synthesized via a one-pot approach under mild reaction conditions. The presence of iminourea moieties suggests that the bis(iminourea) derivatives can be considered as unique guanidine mimics, indicating that the protonated framework could have much stronger anion recognition properties. The cooperative interactions of H+ and Cl ions with these iminourea moieties results in the efficient transport of HCl across the lipid bilayer in an acidic environment. Under physiological conditions these compounds weakly transport Cl ions via an antiport exchange mechanism. This pH-dependent gating/switching behavior (9-fold) within a narrow window could be due to the apparent pKa values (6.2–6.7) of the compounds within the lipid bilayer. The disruption of ionic homeostasis by the potent compounds was found to induce cell death.

Ene reactions of 2-borylated α-methylstyrenes: a practical route to 4-methylenechromanes and derivatives by Chaima Boureghda; Aurélie Macé; Fabienne Berrée; Thierry Roisnel; Abdelmadjid Debache; Bertrand Carboni (5789-5800).
4-Methylenechromanes were prepared via a three-step process from 2-borylated α-methylstyrenes. This sequence is based on a key glyoxylate-ene reaction catalyzed by scandium(iii) triflate. The resulting γ-hydroxy boronates, which cyclise to seven-membered homologues of benzoxaborole on silica gel, were cleanly oxidized with sodium perborate, and then cyclised under Mitsunobu conditions. Additionally, several further functional transformations of 4-methylenechromanes or their precursors were carried out to illustrate the synthetic potential of these intermediates.

Tight-binding inhibition of jack bean α-mannosidase by glycoimidazole clusters by Maëva M. Pichon; Fabien Stauffert; Anne Bodlenner; Philippe Compain (5801-5817).
The best multivalent effects observed in glycosidase inhibition have been achieved so far with jack bean α-mannosidase (JBα-man) using iminosugar clusters based on weakly binding mismatching active-site-directed inhibiting epitopes (inhitopes) in the d-gluco series. Here, we synthesize and evaluate as JBα-man inhibitors a series of mono- to 14-valent glycoimidazoles with inhitopes displaying inhibition values up to the range of hundreds of nMs to study the impact of inhitope affinity on the multivalent effect. The most potent inhibitor of the series, a 14-valent mannoimidazole derivative, inhibits JBα-man with a nanomolar Ki value (2 ± 0.5 nM) and binding enhancements observed are, at best, relatively small (up to 25-fold on a valency-corrected basis). The results of this study support the fact that JBα-man-inhitope affinity and the strength of the inhibitory multivalent effect evolve in the opposite direction. The major impact of the glycoimidazole-based inhitope is found on the binding scenario; most of the synthesized mannoimidazole clusters as well as a 14-valent glucoimidazole derivative prove to be tight binding inhibitors of JBα-man.

A click mediated route to a novel fluorescent pyridino-extended calix[4]pyrrole sensor: synthesis and binding studies by Ahmad Rifai; Nancy AlHaddad; Manale Noun; Ismail Abbas; Malek Tabbal; Rania Shatila; Francine Cazier-Dennin; Pierre-Edouard Danjou (5818-5825).
A novel fluorescent aryl-extended phenoxycalix[4]pyrrole ditopic sensor with enhanced cation recognition properties was efficiently synthesized via click chemistry and characterized through both molecular fluorescence and nuclear magnetic resonance spectroscopy. Results demonstrate the selectivity of this fluorescent sensor for fluoride when taking into account its interaction with anions, while its cation binding properties showed selectivity for iron, and its sensing properties for several cations in dimethylsulfoxide. This work introduces a new ditopic receptor able to complex major environmentally relevant species and depicts the importance of click chemistry in the introduction of new tetra-chromophoric calix[4]pyrrole binding platforms with specific photophysical properties.

From prebiotic chemistry to supramolecular oligomers: urea–glyoxal reactions by Nieves Lavado; Juan García de la Concepción; Mario Gallego; Reyes Babiano; Pedro Cintas (5826-5838).
A fundamental question in origin-of-life studies and astrochemistry concerns the actual processes that initiate the formation of reactive monomers and their oligomerization. Answers lie partly in the accurate description of reaction mechanisms compatible with environments plausible on early Earth as well as cosmological scenarios in planetary factories. Here we show in detail that reactions of urea—as archetypal prebiotic substance—and reactive carbonyls—exemplified by glyoxal—lead to a vast repertoire of oligomers, in which different five- and six-membered non-aromatic heterocycles self-assemble and insert into chains or dendritic-like structures with masses up to 1000 Da. Such regular patterns have been interpreted by experimental and computational methods. A salient conclusion is that such processes most likely occur through SN-type mechanisms on hydrated or protonated species. Remarkably, such supramolecular oligomeric mixtures can be easily isolated from organic solvents, thus opening the door to the generation of novel urea-containing polymers with potential applications in materials chemistry and beyond.

The first chemical synthesis of the dimeric repeating unit of serotype Ia group B Streptococcus capsular polysaccharide was achieved. The on-site elongation and dual glycosylation strategies were utilized to construct two sialotrisaccharide branches based on a hexasaccharide containing adjacent 3,4-di-branched Gal units, which were synthesized via a preactivation-based one-pot glycosylation method.

Correction: Lacto-N-tetraose synthesis by wild-type and glycosynthase variants of the β-N-hexosaminidase from Bifidobacterium bifidum by Katharina Schmölzer; Melanie Weingarten; Kai Baldenius; Bernd Nidetzky (5849-5849).
Correction for ‘Lacto-N-tetraose synthesis by wild-type and glycosynthase variants of the β-N-hexosaminidase from Bifidobacterium bifidum’ by Katharina Schmölzer et al., Org. Biomol. Chem., 2019, DOI: 10.1039/c9ob00424f.

Back cover (5851-5852).