Organic & Biomolecular Chemistry (v.17, #1)

Front cover (1-1).

Contents list (3-10).

Non-toxic cyanide sources and cyanating agents by Alexander M. Nauth; Till Opatz (11-23).
The present review gives an overview over non-toxic cyanation agents and cyanide sources used in the synthesis of structurally diverse products containing the nitrile function. Nucleophilic as well as electrophilic agents/systems that transfer the entire CN-group were taken in consideration. Reactions in which a preexisting carbon functionality is transformed into a nitrile function by addition of nitrogen are however not covered here.

Four-component acyloxy-trifluoromethylation of arylalkenes mediated by a photoredox catalyst by Xiaocong Zhou; Guijie Li; Zongzhou Shao; Kun Fang; Hongjun Gao; Yuanqiang Li; Yuanbin She (24-29).
A four-component intermolecular trifluoromethylation–acyloxylation of arylalkenes induced by visible light has been developed in the presence of the photoredox catalyst Ru(bpy)3(PF6)2 under mild reaction conditions. A new Umemoto's reagent was used as a trifluoromethyl radical source, and this redox neutral reaction demonstrated good functional group tolerance for aryl alkenes with high yields up to 91%. The detailed reaction process was investigated based on control, deuterium and O18-labeling experiments to support that N,N-dimethylformamide (DMF)/H2O acted as an acyloxyl source.

Efficient synthesis and characterisation of the amyloid beta peptide, Aβ1–42, using a double linker system by Johanes K. Kasim; Iman Kavianinia; Jin Ng; Paul W. R. Harris; Nigel P. Birch; Margaret A. Brimble (30-34).
The amyloidogenic Aβ42 peptide was efficiently prepared using a double linker system, markedly improving solubility and chromatographic peak resolution, thus enabling full characterisation using standard techniques. The tag was readily cleaved with sodium hydroxide and removed by aqueous extraction, affording Aβ42 in high purity and yield for biophysical characterisation studies.

A Viedma ripening route to an enantiopure building block for Levetiracetam and Brivaracetam by Iaroslav Baglai; Michel Leeman; Richard M. Kellogg; Willem L. Noorduin (35-38).
A simple route to enantiomerically pure (S)-2-aminobutyramide – the chiral component of the anti-epileptic drugs Levetiracetam and Brivaracetam has been developed. This approach is based on the rational design and application of a Viedma ripening process. The practical potential of the process is demonstrated on a large scale.

Heterologous production of asperipin-2a: proposal for sequential oxidative macrocyclization by a fungi-specific DUF3328 oxidase by Ying Ye; Taro Ozaki; Myco Umemura; Chengwei Liu; Atsushi Minami; Hideaki Oikawa (39-43).
Asperipin-2a is a ribosomally synthesized and post-translationally modified peptide isolated from Asperigillus flavus. Herein, we report the heterologous production of asperipin-2a and determination of its absolute structure. Notably, the characteristic bicyclic structure was likely constructed by a single oxidase containing the DUF3328 domain.

An enantioselective synthetic route to hydroxywilfordic acid, a key subunit of sesquiterpene pyridine alkaloids such as wilfortrine, was developed. Asymmetric cyanation using Jacobsen's (R,R)-amino-thiourea and hydrolysis were performed to afford chiral α-hydroxy-α-methyl acid as the (S)-isomer. Naturally derived hydroxywilfordate prepared by methanolysis of wilfortrine was found to be the (R)-isomer upon comparison with the synthetic compound.

Highly selective AlCl3 initiated intramolecular α-alkylation of α,β-unsaturated lactams and lactones by Dawen Xu; Felix Kaiser; Han Li; Robert M. Reich; Hao Guo; Fritz E. Kühn (49-52).
An unprecedented example of AlCl3 initiated intramolecular α-alkylation of α,β-unsaturated lactams and lactones is reported. A variety of substrates containing an intramolecular diene yield exclusively regioselective six-membered ring products. This reaction protocol generates a new stereo centre which may be of high interest for the functionalization of bioactive coumarin and quinolinone derivatives.

Substrate selectivity and its mechanistic insight of the photo-responsive non-nucleoside triphosphate for myosin and kinesin by Md. Jahirul Islam; Kazuya Matsuo; Halley M. Menezes; Masayuki Takahashi; Hidehiko Nakagawa; Akira Kakugo; Kazuki Sada; Nobuyuki Tamaoki (53-65).
Linear motor proteins including kinesin and myosin are promising biomaterials for developing nano-devices. Photoswitchable substrates of these biomotors can be used to optically regulate the motility of their associated cytoskeletal filaments in in vitro systems. Here, we describe the discovery of the myosin selective azobenzene-tethered triphosphate. It enables the specific photocontrol over myosin in a reversible mode with the composite motility assay composed of both kinesin and myosin. The mechanistic insight into this myosin selectivity is also explained with the docking simulation study.

A cascade or domino sequence of condensation of hydroxylamine and an aldehyde to give an oxime, cyclization to a nitrone, and intramolecular 1,3-dipolar cycloaddition has been successfully employed where there is branching at C-4 as a route to the iboga alkaloids. Cyclization occurs with displacement of chloride as a leaving group and intramolecular cycloaddition occurs with an alkene as a dipolarophile. The reaction gives an azabicyclo[2.2.2]octane product containing a fused isoxazolidine as a single stereoisomer and this was converted to an isoquinuclidine that completed a formal synthesis of the alkaloid (±)-19-hydroxyibogamine.

Base mediated green synthesis of enantiopure 2-C-spiro-glycosyl-3-nitrochromenes by Sabita Nayak; Pravati Panda; Bishnu Prasad Raiguru; Seetaram Mohapatra; Chandra Shekhar Purohit (74-82).
A novel green synthetic methodology has been developed to obtain enantiopure (2S)-2-C-spiro-glycosyl-3-nitrochromenes following the oxa-Michael–aldol condensation reaction of sugar derived 3-C-vinyl nitro olefins with substituted salicylaldehydes using Et3N as a base under neat conditions at rt–40 °C. The stereochemistry of the product is confirmed by a single crystal X-ray study. Several advantages are associated with this protocol such as cost effectiveness, easy accessibility, short reaction time, high yields, wide substrate scope and high enantiopurity.

A new class of anthracene complexes with a metal coordinated at the central ring was applied in catalysis for the first time. As a result, a simple and efficient protocol for reductive amination that involves CO as a reducing agent has been developed. The rhodium complex [(cyclooctadiene)Rh(C10H4Me2(OMe)4)]+ (1 mol%) catalyses such reactions under mild conditions (40–130 °C) and produces a variety of amines in good yields (74–95%) without affecting the functional groups. The protocol is acceptable for all combinations of aldehydes (aromatic and aliphatic), ketones (aromatic and aliphatic) and amines (aromatic and aliphatic; primary and secondary).

The marine natural products cyclomarins have remarkable anti-mycobacterial and antiplasmodial activities. The heptapeptic structure of this compound class comprisis four highly interesting non-canonical amino acids, including a rather unusual synβ-methoxyphenylalanine. To get a deeper insight into the structure–activity realtionship of cyclomarines, a straightforward protocol for the stereoselective synthesis of this building block was developed, based on diazonium chemistry.

Palladium-catalysed ring-opening [3 + 2]-annulation of spirovinylcyclopropyl oxindole to diastereoselectively access spirooxindoles by Jun-An Xiao; Xiu-Liang Cheng; Yu-Chun Li; Yi-Miao He; Jin-Lian Li; Zhi-Ping Liu; Peng-Ju Xia; Wei Su; Hua Yang (103-107).
A novel palladium-catalysed ring-opening [3 + 2]-annulation of spirovinylcyclopropyl oxindole with α,β-unsaturated nitroalkenes is reported. A series of spirooxindole derivatives were synthesized in high yields and good to excellent diastereoselectivities. This developed protocol offers a new and efficient pathway for the assembly of spirooxindoles.

A mitochondria-targeted near-infrared fluorescent probe with a large Stokes shift for real-time detection of hypochlorous acid by Xiaojie Jiao; Kun Huang; Song He; Chang Liu; Liancheng Zhao; Xianshun Zeng (108-114).
Hypochlorous acid (HOCl) has been known to be intertwined with various pathophysiological processes. In this paper, a novel mitochondria-targeted near-infrared (NIR) fluorescent probe L based on a chromenylium-phenothiazine conjugate has been designed and synthesized for the detection of hypochlorous acid. Due to the HOCl-promoted intramolecular charge transfer processes, the probe L shows near-infrared fluorescence emission at 672 nm, large Stokes shifts of 97 nm, fast response, and high selectivity and sensitivity. Furthermore, the probe L is biocompatible, cell-membrane permeable and mitochondria-targetable, and can be used for endogenous HOCl imaging in living cells.

An effective protocol of photoredox catalyzed C2-alkylation of benzothiazoles with aliphatic carboxylic acids was disclosed. In the presence of an acridinium salt as a photocatalyst and air as an oxidant, a wide range of secondary or tertiary aliphatic carboxylic acids were employed as alkylation reagents, providing the desired products in good to excellent yields under mild reaction conditions with a broad substrate scope.

Alkoxyallene-based syntheses of preussin and its analogs and their cytotoxicity by Arndt Hausherr; Gerhard Siemeister; Hans-Ulrich Reissig (122-134).
Short syntheses of oxa-preussin, racemic preussin and (−)-preussin are reported. Starting from a racemic 3-nonyl-substituted methoxyallene derivative, its lithiation and addition to phenylethanal provided the corresponding allenyl alcohol that was converted into two diastereomeric dihydrofuran derivatives by silver nitrate-catalyzed 5-endo-trig cyclization. The acid hydrolysis of the enol ether moiety gave heterocyclic ketones and subsequent highly stereoselective reductions with l-selectride furnished 2-benzyl-5-nonylfuran-3-ol derivatives in good overall yield. The major all-cis-diastereomer has the skeleton and relative configuration of preussin and is hence called oxa-preussin. An analogous sequence with the same allene, but an N-sulfonyl imine as the electrophile, finally led to racemic preussin. The stereoselectivities of the individual steps are discussed in detail. With an enantiopure 2-benzyl-5-nonylpyrrolidin-3-one intermediate the preparation of (−)-preussin with an enantiomeric ratio of >95 : 5 could be accomplished in a few steps. The sign of the optical rotation of this product finally proved the absolute configurations of its precursors and demonstrated that our chiral auxiliary-based route led to the antipode of the natural product. The cytotoxicity of several of the prepared heterocycles against MCF-7 tumor cells was investigated and five compounds, including racemic and enantiopure (−)-preussin, were identified as highly cytotoxic with IC50 values in the range of 3–6 μM.

The present work documents an operationally simple, clean and practical method for accessing the 2,2-disubstituted indolin-3-one (pseudoindoxyl) scaffold. The rhodium carbenoid mediated reaction between N-o-alkylamino benzoylbenzotriazoles and aryl diazoacetates occurs smoothly in water and exploits the leaving group ability of the benzotriazole moiety to install the carbonyl function in the product. Other highlights of the methodology are a wide substrate scope and experimental practicality given the re-use of the benzotriazole byproduct for starting material preparation.

Amide bonds have gained much attention from numerous scientists and acyl transfer is a good way to form amide bonds. The acylation mechanism of polyamines and their high selectivity in dichloromethane were investigated by the use of the density functional theory (DFT), M06-2X/6-311+G (d, p)//M06-2X/6-31G (d, p) method combined with the solvation SMD model. The calculated results suggest that the reaction process involved two steps: an acylation step and a proton-transfer step, with the former being the rate-limiting step. Meanwhile, with the substituent group effects of amines and 5-acyl-5-phenyl-1,5-dihydro-4H-pyrazol-4-one (BCPP) on the acylation step, different substituent groups of amines have little influence on the kinetic properties of the acylation step, and the para-substituent groups of the phenyl group in BCPP lead to a linear relationship according to the electronegativity of the substituents. Furthermore, regarding the rate-selectivity of amines, the rate-selectivity of primary amines is higher than that of secondary amines, and polyamines very easily take part in acylation owing to the intramolecular hydrogen bond interaction. Moreover, it is harder for the amine group which has an α-position substituent group in polyamines to take part in an acylation reaction compared to the one without an α-position substituent group. The site-selectivity of the acylation process in polyamines is determined by steric hindrance. What's more, the auxiliary analysis of the distortion/interaction analysis and the frontier molecular orbital (FMO) analysis is used to investigate the origins of the rate- and site-selectivities.

A highly enantio- and diastereoselective method for the synthesis of functionalized chroman-2-ones and chromanes was achieved by using an organocatalytic domino Michael/hemiacetalization reaction of aliphatic aldehydes and (E)-2-(2-nitrovinyl)phenols followed by a PCC oxidation and dehydroxylation, respectively. Using the modularly designed organocatalysts (MDOs) self-assembled from cinchona alkaloid derivatives and amino acids in the reaction media, the title products were obtained in good to high yields (up to 97%) and excellent diastereoselectivities (up to 99 : 1 dr) and enantioselectivities (up to 99% ee).

In this paper, a selective synthesis of pyrrolidin-2-ones and 3-iodopyrroles via the cascade reactions of N-substituted piperidines is presented. Mechanistically, the formation of pyrrolidin-2-ones involves a domino process including the in situ formation of pyrrolidine-2-carbaldehyde followed by carboxylic acid formation, decarboxylation and ipso-oxidation. On the other hand, 3-iodopyrroles are believed to be formed via the initial generation of pyrrolidine-2-carbaldehyde followed by carboxylic acid formation, decarboxylation, dehydrogenation, iodination and aromatization. Interestingly, either pyrrolidin-2-ones or 3-iodopyrroles could be obtained selectively from the same substrates, and the selectivity was easily tuned by using a specific oxidant and additive.

A convenient and reproducible method for the synthesis of astatinated 4-[211At]astato-l-phenylalanine via electrophilic desilylation by Shigeki Watanabe; Mohammad Anwar-Ul Azim; Ichiro Nishinaka; Ichiro Sasaki; Yasuhiro Ohshima; Keiichi Yamada; Noriko S. Ishioka (165-171).
The 211At-labeled compound, 4-[211At]astato-l-phenylalanine, is one of the most promising amino acid derivatives for use in targeted alpha therapy (TAT) for various cancers. Electrophilic demetallation of a stannyl precursor is the most widely used approach for labeling biomolecules with 211At. However, the low acid-resistance of the stannyl precursor necessitates the use of an N- and C-terminus-protected precursor, which results in a low overall radiochemical yield (RCY) due to the multiple synthetic steps involved. In this study, a deprotected organosilyl compound, 4-triethylsilyl-l-phenylalanine, was employed for the direct synthesis of astatinated phenylalanines. 211At was separately recovered from the irradiated 209Bi target using chloroform (CHCl3) and N-chlorosuccinimide-methanol (NCS-MeOH) solution. The RCYs of 4-[211At]astato-l-phenylalanine obtained from the triethylsilyl precursor with the use of 211At, isolated in CHCl3 and NCS-MeOH solution, were 75% and 64% respectively. In both cases, the retention time of the 4-[211At]astato-l-phenylalanine was found to be about 20 min, which showed reasonable correlation with the retention time of non-radioactive 4-halo-l-phenylalanines (4-chloro-, 4-bromo-, and 4-iodo-l-phenylalanine). The one-step reaction examined in this study involved mild reaction conditions (70 °C) and a short time (10 min) compared to the other currently reported procedures for astatination. Electrophilic desilylation was found to be very effective for the labeling of aromatic amino acids with 211At.

Aromatic donor–acceptor interaction promoted catalyst assemblies for hydrolytic kinetic resolution of epichlorohydrin by Daniel R. Blechschmidt; Matthew D. Woodhouse; Sebastien Inagaki; Melita Whitfield; Ayokunnumi Ogunsanya; Aaron Yoder; Daniel Lilly; Eric W. Heim; Luke N. Soucie; Jian Liang; Yu Liu (172-180).
Three generations of Co(iii)–salen complexes containing electron-deficient aromatic moieties (acceptors) have been synthesized. When electron-rich aromatic compounds (donors) were introduced, these complexes were designed to form catalyst assemblies through aromatic donor–acceptor interaction. For all three generations of complexes, the addition of a proper donor led to higher catalytic efficiency in the hydrolytic kinetic resolution (HKR) of epichlorohydrin. The reaction rates are in the following order: Generation 3 > Generation 2 > Generation 1. The aromatic donor–acceptor interaction was verified by NMR spectroscopy and UV-vis absorption spectroscopy studies. These results demonstrated that aromatic donor–acceptor interaction can be a valuable driving force in the assembly of supramolecular catalysts.

A metal-free visible light promoted C(sp3)–C(sp) coupling reaction of alkynyl bromides and Hantzsch esters was developed, giving internal alkynes with primary, secondary, tertiary alkyl or other functional groups in good to high yields.

Discovery of fluorescent 3-heteroarylcoumarin derivatives as novel inhibitors of anaplastic lymphoma kinase by Shinmee Mah; Jaebong Jang; Daesun Song; Yongje Shin; Muhammad Latif; Yongwon Jung; Sungwoo Hong (186-194).
Altered expression or hyperactivation of anaplastic lymphoma kinase (ALK), as a consequence of translocations or point mutations, is one of the main oncogenic drivers in non-small cell lung cancer. Using structure-based design and in vitro enzyme assays, we identified 3-heteroarylcoumarin as a new template for the development of novel fluorescent ALK inhibitors. Molecular simulation provided structural insights for the design of 3-heteroarylcoumarin derivatives, which were easily prepared through efficient synthetic approaches including direct C–H cross coupling. Importantly, these coumarin-based ALK inhibitors can be tracked using microscopy techniques: we illustrated the use of the most potent compound in this series, 5a, (ALK/IC50 = 0.51 μM, λemi = 500 nm, ϕF = 0.29) to monitor its subcellular distribution pattern by confocal fluorescence microscopy.

Crotonols A and B, two rare tigliane diterpenoid derivatives against K562 cells from Croton tiglium by Junfeng Wang; Li Qin; Biqing Zhao; Liang Cai; Zhenping Zhong; Yonghong Liu; Xiaojiang Zhou (195-202).
Crotonols A and B (1 and 2), two tigliane diterpenoids featuring a rare C-7/C-14 cyclized and novel 5/7/7-fused carbon skeleton, along with the known tigliane wallichiioid A, were isolated from the leaves of Croton tiglium. Their structures were determined through spectroscopic methods, X-ray crystallography and ECD analysis. To the best of our knowledge, crotonol B (2) represents the first example of 13,14-seco-tigliane diterpenoids. Crotonols A and B displayed strong cytotoxic activities against the K562 cell line with IC50 values of 0.20 and 0.21 μM, respectively. Furthermore, crotonol A promoted the apoptosis of K562 cells through the cleavage of PARP and the accumulation of bax as well as the degradation of bcl-2.

Back cover (203-204).