Organic & Biomolecular Chemistry (v.11, #18)

Front cover (2919-2919).

Inside front cover (2920-2920).

Contents list (2921-2927).

Asymmetric autocatalysis triggered by oxygen isotopically chiral glycerin by Arimasa Matsumoto; Shotaro Oji; Shizuka Takano; Kyohei Tada; Tsuneomi Kawasaki; Kenso Soai (2928-2931).
Chiral (S)- and (R)-18O-glycerin induces enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, and the subsequent asymmetric autocatalysis affords (R)- and (S)-pyrimidyl alkanol with high enantiomeric excess, respectively.

A three-component reaction has been developed that allows the regioselective synthesis of thieno[2,3-c]pyrroles. The reaction is based on the ability of 2-acetyl-3-thiophenecarboxaldehyde to react with amine and thiol nucleophiles to produce the corresponding tri-substituted thieno[2,3-c]pyrroles, with water as the only by-product. The developed reaction expands the range of synthetically accessible, tri-substituted thieno[2,3-c]pyrroles.

A concise approach to the spiroiminal fragment of marineosins by Guang Li; Xun Zhang; Qi Li; Pengju Feng; Yian Shi (2936-2938).
A concise approach to the spiroiminal fragment of marineosins A and B is described. The key steps involve an acid-catalyzed N-acyliminium ion cyclization and a Vilsmeier–Haack type reaction with Tf2O.

An expedient stereoselective and chemoselective synthesis of bicyclic oxazolidinones from quinols and isocyanates by Jinzhu Zhang; Jing Wu; Zhiwei Yin; Haisu Zeng; Kunal Khanna; Chunhua Hu; Shengping Zheng (2939-2942).
A mild and efficient synthesis of bicyclic oxazolidinones from quinols and isocyanates, under DBU-mediated conditions at room temperature, is described. The aza-Michael addition to substituted cyclohexadienones is stereoselective and chemoselective.

Synthesis of disulfides and diselenides by copper-catalyzed coupling reactions in water by Zhengkai Li; Fang Ke; Hang Deng; Hualong Xu; Haifeng Xiang; Xiangge Zhou (2943-2946).
A simple and efficient protocol for copper-catalyzed coupling reactions between aryl halides and elemental sulfur or selenium has been developed. A variety of disulfides and diselenides can be obtained in moderate to excellent yields up to 96%.

A green and efficient catalytic redox system for the aerobic oxidative Wacker oxidation of styrene derivatives at room temperature using molecular oxygen as the terminal oxidant without copper chloride has been developed. The newly developed system exhibited excellent catalytic activity for the smooth transformation of terminal styrene derivatives to the desired methyl ketones with up to 96% yield and >99% selectivity.

Synergistic effects within a C2-symmetric organocatalyst: the potential formation of a chiral catalytic pocket by Joshua P. Delaney; Hannah L. Brozinski; Luke C. Henderson (2951-2960).
This study describes the synthesis of five novel C2-symmetric organocatalysts that facilitate the on-water asymmetric aldol reaction at low catalyst loading (1 mol%) without the use of additives. Each catalyst is composed of two diprolinamide units joined by a symmetric alkyl bridging group allowing for systematic modulation of catalytic site proximity. Typically, catalysts in this manuscript which bear the catalytic units in close proximity gave the best reaction outcomes in terms of conversion (up to >99%), diastereomeric ratio (4/96, syn/anti) and enantiomeric excess (up to 97%). This effect has been attributed to the assembly of a chiral pocket, facilitated by hydrogen bonding at the oil-in-water interface.

Dual signaling of hydrazine by selective deprotection of dichlorofluorescein and resorufin acetates by Myung Gil Choi; Jung Ok Moon; Jihee Bae; Jung Woo Lee; Suk-Kyu Chang (2961-2965).
The highly selective chemosignaling behaviors for hydrazine by a reaction-based probe of dichlorofluorescein and resorufin acetates were investigated. Hydrazinolysis of latent dichlorofluorescein and resorufin acetate fluorochromes caused prominent chromogenic and fluorescent turn-on type signals. The probes selectively detected hydrazine in the presence of commonly encountered metal ions and anions as background. Dichlorofluorescein and resorufin acetates selectively detected hydrazine with detection limits of 9.0 × 10−8 M and 8.2 × 10−7 M, respectively. Furthermore, hydrazine was selectively detected over other closely related compounds, such as hydroxylamine, ethylenediamine, and ammonia. As a possible application of the acetate probes, hydrazine signaling in tap water was tested.

Reaction-based dual signaling of fluoride ions by resorufin sulfonates by Hyun Gyu Im; Hong Yeong Kim; Myung Gil Choi; Suk-Kyu Chang (2966-2971).
We developed new reaction-based probes for the dual signaling of fluoride ions. Selective fluoride-assisted deprotection of resorufin nosylate to generate resorufin fluorochrome was used for signaling. Resorufin nosylate exhibited selective colorimetric and fluorogenic signaling of fluoride ions in acetonitrile. The response from sulfide ions was effectively masked by using the TPEN–Cu2+ complex as a source of Cu2+ ions for masking sulfide. Selective optical signaling of fluoride was possible in the presence of commonly encountered anions with a detection limit of 1.9 × 10−6 M.

We report here our results on the FeCl3–diorganyl dichalcogenides intramolecular cyclization of 2-organochalcogen-3-alkynylthiophenes. The cyclization reaction proceeded cleanly under mild reaction conditions giving the (S)-Se-, (S)-S- and (S)-Te-heterocycles in good yields. In addition, the obtained chalcogenophenes were readily transformed into more complex products using the palladium cross-coupling reaction with boronic acids. Conversely, using a metal–halogen exchange reaction with n-BuLi, the chalcogenophenes produced the lithium-intermediate which was trapped with aldehyde furnishing the desired secondary alcohol in good yield.

The role of imidazole in peptide cyclization by transesterification: parallels to the catalytic triads of serine proteases by Kendall G. Byler; Yangmei Li; Richard A. Houghten; Karina Martinez-Mayorga (2979-2987).
The improved bioavailability, stability and selectivity of cyclic peptides over their linear counterparts make them attractive structures in the design and discovery of novel therapeutics. In our previous work, we developed an imidazole-promoted preparation of cyclic depsipeptides in which we observed that increasing the concentration of imidazole resulted in the concomitant increase in the yield of cyclic product and reduction in dimerization, but also resulted in the generation of an acyl-substituted side product. In this work, we used transition state analysis to explore the mechanism of the imidazole-catalyzed esterification of one such peptide, Ac-SAFYG-SCH2ϕ, and determined the acyl substitution product to be an intermediate in a competing reaction pathway involving acyl substitution of the thioester by imidazole. Our findings indicate that imidazole plays an essential role in this side-chain to C-terminal coupling, and by extension, in transesterifications in general, through a concerted mechanism wherein imidazole deprotonates the nucleophile as the nucleophile attacks the carbonyl. The system under study is identical to the histidine-serine portion of the catalytic triads in serine proteases and it is likely that these enzymes employ the same concerted mechanism in the first step of peptide cleavage. Additionally, relatively high concentrations of imidazole must be used to effectively catalyze reactions in aprotic solvents since the overall reaction involves imidazole acting both as an acid and as a base, existing in solution as an equilibrium distribution between the neutral form and its conjugate acid.

Substrate scope and synthetic applications of the enantioselective reduction of α-alkyl-β-arylenones mediated by Old Yellow Enzymes by Elisabetta Brenna; Sara Lucia Cosi; Erica Elisa Ferrandi; Francesco G. Gatti; Daniela Monti; Fabio Parmeggiani; Alessandro Sacchetti (2988-2996).
The ene-reductases mediated bioreduction of a selection of open-chain α-alkyl-β-aryl enones afforded the corresponding saturated α-chiral ketones in high yield and optical purity in several cases. The stereo-electronic requirements of the reaction have been investigated, considering the nature and location of substituents on the aromatic ring as well as the steric hindrance at the α-position and adjacent to the carbonyl functionality. The general considerations drawn allow us to guide the design of α,β-unsaturated ketones to be employed as substrates of ene-reductases in future preparative applications. An interesting case of orthogonality between enzyme-based and substrate-based stereocontrol within the highly homologous ene-reductases from Saccharomyces species (OYE1–3) has been reported and rationalized with the help of computational docking studies. Furthermore, to demonstrate the synthetic versatility of the reaction, the key chiral precursors of biologically active compounds such as (2′R)-stenusines and (S)-iopanoic acid were obtained. The very robust protocol allowed us to run the reactions on preparative scale in quantitative yields, with a simple work-up and no chromatographic purification steps.

The sEDA() and pEDA() descriptors of the double bonded substituent effect by Andrzej Mazurek; Jan Cz. Dobrowolski (2997-3013).
New descriptors of the double bonded substituent effect, sEDA() and pEDA(), were constructed based on quantum chemical calculations and NBO methodology. They show to what extent the σ and π electrons are donated to or withdrawn from the substituted system by a double bonded substituent. The new descriptors differ from descriptors of the classical substituent effect for which the pz orbital of the ipso carbon atom is engaged in the π-electron system of the two neighboring atoms in the ring. For double bonded substituents, the pz orbital participates in double bond formation with only one external atom. Moreover, the external double bond forces localization of the double bond system of the ring, significantly changing the core molecule. We demonstrated good agreement between our descriptors and the Weinhold and Landis’“natural σ and π-electronegativities”: so far only descriptors allowing for evaluation of the substitution effect by a double bonded atom. The equivalency between descriptors constructed for 5- and 6-membered model structures as well as linear dependence/independence of the constructed parameters was discussed. Some interrelations between sEDA() and pEDA() and the other descriptors of (hetero)cyclic systems such as aromaticity and electron density in the ring and bond critical points were also examined.

A selective turn-on fluorescent probe for Cd2+ based on a boron difluoride β-dibenzoyl dye and its application in living cells by Li Xin; Yu-Zhe Chen; Li-Ya Niu; Li-Zhu Wu; Chen-Ho Tung; Qing-Xiao Tong; Qing-Zheng Yang (3014-3019).
Herein we report the first example of a difluoroboron dibenzoyl based fluorescent probe for Cd2+ detection. The probe displays high selectivity and sensitivity toward Cd2+ over Zn2+ in aqueous solution under physiological conditions. Fluorescence imaging experiments demonstrate its potential application for detecting Cd2+ in living cells.

Chemoenzymatic synthesis of monocyclic arene oxides and arene hydrates from substituted benzene substrates by Derek R. Boyd; Narain D. Sharma; Vera Ljubez; Peter K. M. McGeehin; Paul J. Stevenson; Marine Blain; Christopher C. R. Allen (3020-3029).
Enantiopure cis-dihydrodiol bacterial metabolites of substituted benzene substrates were used as precursors, in a chemoenzymatic synthesis of the corresponding benzene oxides and of a substituted oxepine, via dihydrobenzene oxide intermediates. A rapid total racemization of the substituted benzene 2,3-oxides was found to have occurred, via their oxepine valence tautomers, in accord with predictions and theoretical calculations. Reduction of a substituted arene oxide to yield a racemic arene hydrate was observed. Arene hydrates have also been synthesised, in enantiopure form, from the corresponding dihydroarene oxide or trans-bromoacetate precursors. Biotransformation of one arene hydrate enantiomer resulted in a toluene-dioxygenase catalysed cis-dihydroxylation to yield a benzene cis-triol metabolite.

FRET-based imaging of transbilayer movement of pepducin in living cells by novel intracellular bioreductively activatable fluorescent probes by Mieko Tsuji; Satoshi Ueda; Tasuku Hirayama; Kensuke Okuda; Yoshiaki Sakaguchi; Aoi Isono; Hideko Nagasawa (3030-3037).
To elucidate the mechanisms of direct transmembrane penetration of pepducins, which are artificial lipopeptide G protein-coupled receptor (GPCR) modulators, we developed two types of FRET-based probes, Pep13-FL-SS-Dab (13) targeting the inner leaflet of the lipid bilayer and Pep13-Dab-SS-FL (14) targeting the cytosol, respectively. They are composed of a pepducin moiety and a fluorescent switch component consisting of 5(6)-carboxyfluorescein (FAM) as a fluorophore and dabcyl as a quencher connected through disulfide bond linkage. When they are internalized into the cytosol, intracellular glutathione can cleave the disulfide bond to release the quencher, which results in a turn-on fluorescence signal. Using these probes, we performed live cell imaging of transbilayer movements of pepducins on MCF-7 cells for the first time. The results suggested that the lipid moiety of the probes facilitated pepducin flipping across and tethering to the membrane. The present study raises the possibility of applying the probe architecture for direct intracellular drug delivery.

The presence of two vicinal single-nucleotide oxidative lesions constitutes a pitfall case for DNA repair. Quantum mechanics calculations are performed to elucidate the formation of peroxyl-bridged adducts, where a purine and a pyrimidine base become covalently tethered. A dispersion-corrected density functional theory (DFT-D) screening along the 32 possible adducts built by a combination of the four different nucleobases outlines that guanine is a better tandem partner than adenine, in line with experimental data. In contrast, cytosine and thymine have an overall comparable reactivity as revealed by a highly localized spin density. For a given purine and pyrimidine combination, our computational approach also sketches some differences concerning the syn vs. anti configurations and the orientation strand.

A structure-based design of new C2- and C13-substituted taxanes: tubulin binding affinities and extended quantitative structure–activity relationships using comparative binding energy (COMBINE) analysis by Claire Coderch; Yong Tang; Javier Klett; Shu-En Zhang; Yun-Tao Ma; Wang Shaorong; Ruth Matesanz; Benet Pera; Angeles Canales; Jesús Jiménez-Barbero; Antonio Morreale; J. Fernando Díaz; Wei-Shuo Fang; Federico Gago (3046-3056).
Ten novel taxanes bearing modifications at the C2 and C13 positions of the baccatin core have been synthesized and their binding affinities for mammalian tubulin have been experimentally measured. The design strategy was guided by (i) calculation of interaction energy maps with carbon, nitrogen and oxygen probes within the taxane-binding site of β-tubulin, and (ii) the prospective use of a structure-based QSAR (COMBINE) model derived from an earlier series comprising 47 congeneric taxanes. The tubulin-binding affinity displayed by one of the new compounds (CTX63) proved to be higher than that of docetaxel, and an updated COMBINE model provided a good correlation between the experimental binding free energies and a set of weighted residue-based ligand–receptor interaction energies for 54 out of the 57 compounds studied. The remaining three outliers from the original training series have in common a large unfavourable entropic contribution to the binding free energy that we attribute to taxane preorganization in aqueous solution in a conformation different from that compatible with tubulin binding. Support for this proposal was obtained from solution NMR experiments and molecular dynamics simulations in explicit water. Our results shed additional light on the determinants of tubulin-binding affinity for this important class of antitumour agents and pave the way for further rational structural modifications.

Design and synthesis of an on–off “click” fluorophore that executes a logic operation and detects heavy and transition metal ions in water and living cells by Ganesh Chandra Midya; Sushovan Paladhi; Sudipta Bhowmik; Subhadeep Saha; Jyotirmayee Dash (3057-3063).
We have designed and synthesized a novel fluorescent molecular probe using the Cu(i)-catalyzed Huisgen cycloaddition of 1,3-diethynyl-6-fluoroisoquinoline with 1-(2-azidoethyl)pyrrolidine. This water soluble “click” fluorescent chemosensor displays good sensitivity towards heavy and transition metal ions. It shows pronounced fluorescence enhancement and high selectivity for Zn2+ over other biologically relevant metal ions in water at pH 7.0. The fluorescence response of the bis-triazole derivative in the presence of Zn2+ is switchable and reversible as a function of pH. The chemosensor also exhibits fluorescence quenching with Fe2+ and Cu2+ in water at pH 7.0. A modified YES logic gate property has been proposed using the “turn-on” and “turn-off” behavior of the bis-triazole with Zn2+ and Fe2+. The sensor is cell membrane permeable and applicable for intracellular Zn2+ imaging.

Synthesis of 2-amino-imidazo[4,5-b]pyridines by Adam J. Rosenberg; Theresa M. Williams; Abraham J. Jordan; Daniel A. Clark (3064-3072).
The C2 amination of imidazo[4,5-b]pyridines was accomplished through C2 halogenation followed by substitution (SNAr) with functionalized primary and secondary amines. This regioselective sequence is operationally simple and provides an easy access to derivatives of protected imidazo[4,5-b]pyridines.

Back cover (3073-3074).