Organic & Biomolecular Chemistry (v.12, #41)

Front cover (8102-8102).

Inside front cover (8103-8103).

Contents list (8104-8111).

Non-conventional heating techniques, high-throughput microwave-assisted synthesis and continuous flow penetrate almost every scientific field. Mitsunobu coupling is a ubiquitous choice for the dehydrative redox condensation of primary or secondary alcohols with (pro)nucleophiles. The aim of this review is to showcase the ease of subtle Mitsunobu coupling under super-heating. Surprisingly, this strategy is rather non-trivial; considering the sensitivity of reagents, Mitsunobu chemistry is typically performed at lower temperatures or under ambient conditions. In view of the absence of any previous work focusing on this topic, the current review considers the utility of super-heating in fragile Mitsunobu reactions. Therefore, we anticipate that this review will also bridge some of the apparent gaps in the extant literature by specifically describing the advances made by non-conventional heating assisted by microwave or continuous flow in one of the most powerful stereochemical transformations.

A one-pot multicomponent coupling/cyclization for natural product herbicide (±)-thaxtomin A by Jean Paul Bourgault; Amarendar Reddy Maddirala; Peter R. Andreana (8125-8127).
Herbicide (±)-thaxtomin A has been synthesized in a one-pot process with a 32% isolated yield. A multicomponent coupling reaction was utilized to prepare in situ a dipeptide precursor which then sequentially underwent an alkaline mediated keto-amide cyclization to provide the target molecule. Adjustment of diastereoselectivity was achieved using microwave-induced irradiation. The approach incorporates atom economy and reaction efficiency and allows for facile library development.

A novel and efficient cascade annulation of tertiary α-hydroxy ketones and dimethyl but-2-ynedioate is reported. The reaction, which only requires a base as the promoter, provides a straightforward access to polysubstituted pyrano[4,3-a]quinolizine-1,4,6(2H)-triones and 2H-pyran-2,5(6H)-diones under very mild reaction conditions.

Peptidomimetic inhibitors of N-myristoyltransferase from human malaria and leishmaniasis parasites by Tayo O. Olaleye; James A. Brannigan; Shirley M. Roberts; Robin J. Leatherbarrow; Anthony J. Wilkinson; Edward W. Tate (8132-8137).
N-Myristoyltransferase (NMT) has been shown to be essential in Leishmania and subsequently validated as a drug target in Plasmodium. Herein, we discuss the use of antifungal NMT inhibitors as a basis for inhibitor development resulting in the first sub-micromolar peptidomimetic inhibitors of Plasmodium and Leishmania NMTs. High-resolution structures of these inhibitors with Plasmodium and Leishmania NMTs permit a comparative analysis of binding modes, and provide the first crystal structure evidence for a ternary NMT-Coenzyme A/myristoylated peptide product complex.

Synthesis of substituted azafluorenones from dihalogeno diaryl ketones by palladium-catalyzed auto-tandem processes by Nada Marquise; Vincent Dorcet; Floris Chevallier; Florence Mongin (8138-8141).
Substituted azafluorenones were synthesized from different dihalogeno diaryl ketones under palladium catalysis by combining either Suzuki or Heck coupling with direct cyclizing arylation. Conditions were identified to allow both auto-tandem processes to proceed successfully from 3-(bromobenzoyl)- or 3-benzoyl-4-bromo-2-chloropyridines, as well as 4-benzoyl-2,3- and 4-benzoyl-2,5-dichloropyridines.

Convergent chemoenzymatic synthesis of a library of glycosylated analogues of pramlintide: structure–activity relationships for amylin receptor agonism by Renata Kowalczyk; Margaret A. Brimble; Yusuke Tomabechi; Antony J. Fairbanks; Madeleine Fletcher; Debbie L. Hay (8142-8151).
Pramlintide (Symlin®), a synthetic analogue of the naturally occurring pancreatic hormone amylin, is currently used with insulin in adjunctive therapy for type 1 and type 2 diabetes mellitus. Herein we report a systematic study into the effect that N-glycosylation of pramlintide has on activation of amylin receptors. A highly efficient convergent synthetic route, involving a combination of solid phase peptide synthesis and enzymatic glycosylation, delivered a library of N-glycosylated variants of pramlintide bearing either GlcNAc, the core N-glycan pentasaccharide [Man3(GlcNAc)2] or a complex biantennary glycan [(NeuAcGalGlcNAcMan)2Man(GlcNAc)2] at each of its six asparagine residues. The majority of glycosylated versions of pramlintide were potent receptor agonists, suggesting that N-glycosylation may be used as a tool to optimise the pharmacokinetic properties of pramlintide and so deliver improved therapeutic agents for the treatment of diabetes and obesity.

Friedel–Crafts alkylations of electron-rich aromatics with 3-hydroxy-2-oxindoles: scope and limitations by Lakshmana K. Kinthada; Santanu Ghosh; K. Naresh Babu; Mohd. Sharique; Soumava Biswas; Alakesh Bisai (8152-8173).
A Lewis acid-catalyzed nucleophilic addition of electron rich aromatics with 3-hydroxy-2-oxindoles 5 was developed. The reaction is believed to proceed through the 2H-indol-2-one ring system 9, which eventually reacts with various electron-rich aromatics to afford a variety of 2-oxindoles with an all-carbon quaternary center at the pseudobenzylic position (4, 8, 13, and 16) in high yields. The methodology provides an expeditious route to the tetracyclic core (3) of diazonamide (1), and azonazine (2) as well as the tricyclic core of asperazine (6a), idiospermuline (6b), and calycosidine (6c) viz. C(3a)-arylpyrroloindolines 7 having an all-carbon quaternary center on further synthetic elaboration.

A small synthetic molecule forms selective potassium channels to regulate cell membrane potential and blood vessel tone by Hui-Yan Zha; Bing Shen; Kwok-Hei Yau; Shing-To Li; Xiao-Qiang Yao; Dan Yang (8174-8179).
In living cell membranes, K+ permeability is higher than that of other ions such as Na+ and Cl owing to abundantly expressed K+ channels. Polarized membrane potential is mainly established by K+ outward flow because the K+ concentration in the intracellular side is much higher than that in the extracellular side. We have found that the small synthetic molecule 1 is capable of self-assembling into selective K+ channels, enhancing K+ permeability and hyperpolarizing liposome membrane potential. Interestingly, molecule 1 also functions as K+ channel hyperpolarizing living cell membrane potential and relaxing agonist-induced blood vessel contraction. Therefore, it may have the potential to become a lead compound for the treatment of human diseases associated with K+ channel dysfunction.

Adaptable synthesis of C-lactosyl glycoclusters and their binding properties with galectin-3 by Wang Yao; Meng-jie Xia; Xiang-bao Meng; Qing Li; Zhong-jun Li (8180-8195).
We report here the syntheses of mono- to tetravalent glycoclusters containing 1-methylene-C-β-lactose. The 1-methylene-C-β-lactose moiety has been synthesized from octa-acetyl-β-lactose using the key carbonyl insertion reaction and linked to a series of alkynlated scaffolds via CuAAC reaction to afford mono- to tetravalent glycoclusters. The binding affinities of the final products to galectin-3 were found in the range of 10–100 μM.

Regiodivergent and short total synthesis of calothrixins by Dipakranjan Mal; Joyeeta Roy; Kumar Biradha (8196-8203).
The anionic annulation of MOM-protected furoindolone with 4-bromoquinoline followed by deprotection of the N-MOM group provides calothrixin B, whereas that with 3-bromoquinoline yields isocalothrixin B. The outcomes are explained by the divergence of the reaction mechanism from commonly perceived quinolyne intermediate. A sequence of addition–cyclization–elimination is proposed to account for the formation of calothrixin from 4-bromoquinoline.

A palladium-catalyzed direct addition of arylboronic acids to unprotected 2-aminobenzonitriles has been developed, leading to a wide range of 2-aminobenzophenones with moderate to excellent yields. The transformation has broad scope and high functional group tolerance. Moreover, 2-oxoindoline-7-carbonitrile and indole-7-carbonitrile were applicable to this process for the construction of 7-benzoyl-2-oxoindolines and 7-benzoylindoles, respectively. Among the compounds examined, compound 4e possessed the most potent anticancer activity against H446 and HGC-27 in vitro, with IC50 values of 0.02 μmol L−1 and 0.09 μmol L−1, respectively, while compound 4a showed the best potent anticancer activity against SGC-7901 with an IC50 value of 0.01 μmol L−1. Furthermore, we also performed in silico molecular docking calculations to investigate the interaction mode and binding affinity between the examined compounds and their tubulin target.

Short synthetic sequences commencing with the photosensitized [2 + 2]-cycloaddition reactions of maleic anhydride with either allyl alcohol or propargyl alcohol have been elaborated to provide access to 1,2,3-trisubstituted cyclobutanes with three differentiated one-carbon substituents and complementary stereochemical patterns. These intermediates were used to prepare three discrete stereo- and regioisomers of hydroxymethylated cyclobutane β-amino acids in orthogonally protected form.

Synthesis and spectroscopic properties of novel meso-cyano boron-pyridyl-isoindoline dyes by Hui Liu; Hua Lu; Fan Wu; Zhifang Li; Nagao Kobayashi; Zhen Shen (8223-8229).
meso-Cyano boron-pyridyl-isoindoline dyes with asymmetrical structures were synthesized through a facile two-step reaction. Broad envelopes of intense vibrational bands were observed for the main spectral bands in the absorption and emission spectra. Moderate fluorescence quantum yields were obtained in solution, with significant intensity also observed in film, powder and crystal forms. An analysis of the structure–property relationships was carried out based on X-ray crystallography, optical spectroscopy, and theoretical calculations.

Development of chemosensor for Sr2+ using organic nanoparticles: application of sensor in product analysis for oral care by Simanpreet Kaur; Amanpreet Kaur; Navneet Kaur; Narinder Singh (8230-8238).
A new series of compounds has been developed for the recognition of metal ions and it was found that the position of substituent in the organic compound proved to be the deciding factor for the development of a chemosensor. Reprecipitation method was used to develop organic nanoparticles (ONPs) in aqueous medium and the suspension of ONP in aqueous medium remained stable for one month. These ONPs were studied for their recognition abilities using fluorescence spectroscopy and only ONPs of compound 1 resulted in a sensor for Sr2+ and the sensor activities were found to be unaffected by the presence of any other cation. The sensor was successfully used to investigate the level of Sr2+ in an oral gel, as well as toothpastes used to cure sensitive teeth.

Enantioselective total syntheses of the proposed structures of prevezol B and evaluation of anti-cancer activity by Anna E. Leung; Riccardo Rubbiani; Gilles Gasser; Kellie L. Tuck (8239-8246).
The first enantioselective total syntheses of the proposed structures of the natural product prevezol B are reported. The reported syntheses complement the previously-reported syntheses of the proposed structures of prevezol C, a stereoisomer of prevezol B. It was previously shown that the structure of the naturally occurring prevezol C had been incorrectly assigned. This work has led us to conclude that the proposed structures of prevezol B are also incorrect and major revision of both of the structures of the prevezols B and C is required. Cytotoxicity studies on the human cervical cancer cell line HeLa revealed that the synthesized prevezol B and C compounds were not active even at the highest concentration used (100 μM). However, one of the synthetic precursors was shown to have modest potency against HeLa cells (IC50 = 23.5 ± 1.8 μM).

Molecular iodine-mediated reaction of 2-(2-phenylethynyl)-Morita–Baylis–Hillman adducts: an easy route to naphthyl ketones and iodo-substituted isochromenes by Donala Janreddy; Veerababurao Kavala; Trimurtulu Kotipalli; R. R. Rajawinslin; Chun-Wei Kuo; Wen-Chang Huang; Ching-Fa Yao (8247-8256).
The molecular iodine-promoted reaction of 2-(2-phenylethynyl)-Morita–Baylis–Hillman adducts is reported. In the presence of I2, naphthyl ketone derivatives are produced, whereas in the presence of I2/K3PO4, iodo-substituted isochromene derivatives are produced.

The asymmetric total syntheses of naturally occurring resorcylic acid lactone paecilomycin E and two of its structural congeners have been reported in this article. The major highlight of the synthetic venture is the application of the late stage Mitsunobu macrolactonization method (as it is difficult to achieve the desired products through the standard carboxyl activation method) of a properly functionalized seco-acid. The macrolactonization precursor was synthesized by applying an “E”-selective Julia–Kocienski olefination of a highly functionalized aromatic aldehyde and a sulphone, which constitutes all the stereocenters (C4′, C5′, C6′ and C10′; 3S,7R,8R,9S) in the target molecule.

Investigation of desilylation in the recognition mechanism to fluoride by a 1,8-naphthalimide derivative by Jeeun Woo; Gunwoo Kim; Kevanie Quintero; Michael P. Hanrahan; Hector Palencia; Haishi Cao (8275-8279).
A reaction-based chemosensor (AF-1) was designed, synthesized and applied as an optical approach for quantitative measurement of F in MeCN. In the presence of F, selective fluoride-assisted desilylation instantly gave colorimetric and fluorogenic signals, providing a dual-optical channel for the detection of F. 1H NMR titration was carried out to investigate the desilylation process, revealing F triggered rapid cleavage of Si–O bond in trimethylsilyl ether. AF-1 exhibited high sensitivity and selectivity to F over other anions. The detection limit to F was calculated to be 0.05 ppm.

Irreversible oxidative damage at both aromatic side chains and dipeptide linkage occurs in the aromatic N- and C-protected dipeptides 7–11 upon exposure to the environmental pollutants NO2˙ and O3. The reaction proceeds through initial oxidation of the aromatic ring by in situ generated NO3˙, or by NO2˙, respectively, which leads to formation of nitroaromatic products. The indole ring in Phe-Trp undergoes oxidative cyclization to a pyrroloindoline. An important reaction pathway for dipeptides with less oxidisable aromatic side chains proceeds through fragmentation of the peptide bond with concomitant acyl migration. This process is likely initiated by an ionic reaction of the amide nitrogen with the NO2˙ dimer, N2O4.

Annulated and bridged tetrahydrofurans from alkenoxyl radical cyclization by Christine Schur; Harald Kelm; Thomas Gottwald; Arne Ludwig; Rainer Kneuer; Jens Hartung (8288-8307).
4-Pentenoxyl radicals sharing two or more carbon atoms with a cycloalkane cyclize in a predictable manner stereoselectively and regioselectively to afford in solutions of bromotrichloromethane cycloalkyl-fused or -bridged 2-bromomethyltetrahydrofurans in up to 95% yield. Stereoselectivity in alkenoxyl radical ring closures arises from cumulative steric effects. The substituent positioned the closest to the alkene carbon, which is being attacked by the oxygen radical, exerts the strongest stereodirecting effect. This principal inductor guides 5-exo-cyclization 2,3-trans- or 2,4-cis-selectively. The substituent located further from the attacked π-bond is the secondary inductor. A secondary inductor in the relative trans-configuration enhances stereodifferentiation by the primary inductor; a cis-configured secondary inductor decreases this effect. A secondary inductor is not able to overrule the guiding effect of a similar sized primary inductor. Intramolecular 4-pentenoxyl radical additions to a cyclohexene-bound exo-methylene group or to endocyclic double bonds proceed cis-specifically, as exemplified by synthesis of a diastereomerically pure bromobicyclo[2.2.1]heptyl-annulated tetrahydrofuran from the verbenylethyloxyl radical. According to theory, the experimental 2,3-cis-specificity in alkoxyl radical cyclization to an endocyclic π-bond arises from strain associated with the 2,3-trans-ring closure.

Synthesis and SARs of indole-based α-amino acids as potent HIV-1 non-nucleoside reverse transcriptase inhibitors by Xin Han; Haoming Wu; Wei Wang; Chune Dong; Po Tien; Shuwen Wu; Hai-Bing Zhou (8308-8317).
A series of non-nucleoside reverse transcriptase inhibitors derived from indole-based α-amino acids were designed and synthesized. Their inhibitory activities were detected by a TZM-bl cell assay on HIV virus type HIV-1IIIB. The comprehensive understanding of the SAR was obtained by utilizing the variation of the substituents of the indole-based α-amino acids. From the screened compounds, the novel inhibitors 19 and 29 were identified to be highly potent candidates with EC50 values of 0.060 μM and 0.045 μM respectively (CC50 values of 109.545 μM and 49.295 μM and SI values of 1825.8 and 1095.4). In most cases, the variation of substituents at different positions had a significant effect on the potency of activities. The results also indicate that the indole-based α-amino acids as efficient NNRTIs displayed comparable anti-HIV-1 activities to the reference drug NVP. We hope the identification of these indole-based amino acids as efficient NNRTIs of RT could stimulate researchers to develop more diversified anti-HIV drugs.

Enantiomerically enriched indolines and tetrahydroisoquinolines were synthesized within 5 min to 2 h in high yields from easily accessible (S)-amino acid derived chiral carbocations. The diastereoselective Friedel–Crafts reaction is promoted by a Lewis acid (AlCl3) offering trans-diastereoselectivity. The rate of the reaction and diastereoselectivity of the product are significantly influenced by steric hindrance of the amino acids substituents and aryl groups. The methodology can be applied for the synthesis of the enantiomerically enriched bioactive scaffold (3S,4R)-demethoxy-3-isopropyl diclofensine.

Synthesis and characterisation of glucosamine–NSAID bioconjugates by Rachel A. Jones; Yann Thillier; Siva S. Panda; Nicole Rivera Rosario; C. Dennis Hall; Alan R. Katritzky (8325-8335).
Strategies to couple non-steroidal anti-inflammatory drugs (NSAIDs) to a glucosamine hydrochloride salt via an amino acid linker are investigated and a series of novel NSAID–glucosamine bioconjugates have been prepared.

9-Amino-(9-deoxy)cinchona alkaloid-derived new chiral phase-transfer catalysts by Wenwen Peng; Jingwei Wan; Bing Xie; Xuebing Ma (8336-8345).
A new class of 9-amino-(9-deoxy)cinchona alkaloid-derived chiral phase-transfer catalysts bearing amino groups was developed by using known cinchona alkaloids as the starting materials. Due to the transformation of the 9-hydroxyl group into a 9-amino functional group, the catalytic performances were significantly improved in comparison with the corresponding first generation phase-transfer catalysts, and excellent yields (92–99%) and high enantioselectivities (87–96% ee) were achieved in the benchmark asymmetric α-alkylation of glycine Schiff base. Based on the special contribution of the amino group to the high yield and enantioselectivity, the possible catalytic mechanism was conjectured.

Enantioselectivities for the allylation and propargylation of benzaldehyde catalyzed by bipyridine N,N′-dioxides were predicted using popular DFT methods. The results reveal deficiencies of several DFT methods while also providing a new explanation for the stereoselectivity of these reactions. In particular, even though many DFT methods provide accurate predictions of experimental ee's for these reactions, these predictions sometimes stem from qualitatively incorrect transition states. Overall, B97-D/TZV(2d,2p) provides the best compromise between accurate predictions of low-lying transition states and stereoselectivities for these reactions. The origin of stereoselectivity in these reactions was also examined, and arises from electrostatic interactions within the chiral electrostatic environment of a hexacoordinate silicon intermediate; the previously published transition state model for these reactions is flawed. Ultimately, these results suggest two strategies for the design of highly stereoselective catalysts for the propargylation of aromatic aldehydes, and pave the way for the computational design of novel catalysts for these reactions.

Back cover (8354-8355).