Organic & Biomolecular Chemistry (v.10, #48)

Front cover (9509-9509).

Inside front cover (9510-9510).

Contents list (9511-9518).

Potassium iodide catalyzed simultaneous C3-formylation and N-aminomethylation of indoles with 4-substituted-N,N-dimethylanilines by Lan-Tao Li; Hong-Ying Li; Li-Juan Xing; Li-Juan Wen; Peng Wang; Bin Wang (9519-9522).
A one-pot dual functionalization of indoles has been developed. The simultaneous C3-formylation and N-aminomethylation of indoles can be achieved using readily available potassium iodide as a catalyst and tert-butyl peroxybenzoate as a co-oxidant.

A number of N-aryl ketenimines, substituted at the ortho position either with different non-cyclic acetalic functions (acetals, monothioacetals, dithioacetals) or with only one alkoxymethyl or (alkylthio)methyl group, have been prepared and submitted to thermal treatment in toluene solution. Under smooth heating the ketenimines bearing non-cyclic acetals converted into 3,4-dihydroquinolines following two competitive tandem sequences that involve the alternative 1,5 migration of a hydride or alkoxy group as the first mechanistic step, followed by subsequent 6π electrocyclic ring closure. The heterocumulenes bearing acyclic monothioacetal and dithioacetal functions converted via a unique consecutive process involving the selective migration of the alkanethiolate group. Ketenimines bearing only one ether or thioether group transformed exclusively by the tandem sequence initiated by a 1,5 hydride shift. All these transformations provided as final reaction products a variety of quinoline derivatives with a range of substitution patterns. From these experiments the following order of propensity to migration can be extracted: RS > RO > H. It was also possible to estimate the following order of relative activating activities: RO > RS > H.

Regioselective multicomponent sequential synthesis of hydantoins by Francesca Olimpieri; Maria Cristina Bellucci; Tommaso Marcelli; Alessandro Volonterio (9538-9555).
The development of new practical and green methods for the synthesis of small heterocycles is an attractive area of research due to the well-known potential of heterocyclic small molecule scaffolds in the drug discovery process. Herein we report a one-pot, three-component sequential procedure for the synthesis of diversely 1,3,5- and 1,3,5,5-substituted hydantoins, in high yields and very mild conditions, using readily accessible starting materials such as azides, iso(thio)cyanates and substituted α-halo-acetic carboxylic acids. This methodology is especially convenient for the synthesis of spiro-hydantoins, which are particularly interesting bioactive compounds in medicinal chemistry.

Synthesis of allenamides by Pd-catalyzed coupling of 3-alkoxycarbonyloxy ynamides or 1-alkoxycarbonyloxy allenamides with arylboronic acids by Jian Cao; Yulong Kong; Yuan Deng; Guoqiao Lai; Yuming Cui; Ziqiang Hu; Guanhai Wang (9556-9561).
An efficient palladium-catalyzed method is reported for the synthesis of multi-substituted allenamides by Suzuki–Miyaura cross-coupling reaction between easily prepared 3-alkoxycarbonyloxy ynamides or 1-alkoxycarbonyloxy allenamides and arylboronic acids.

Site-selective sequential coupling reactions controlled by “Electrochemical Reaction Site Switching”: a straightforward approach to 1,4-bis(diaryl)buta-1,3-diynes by Koichi Mitsudo; Natsuyo Kamimoto; Hiroki Murakami; Hiroki Mandai; Atsushi Wakamiya; Yasujiro Murata; Seiji Suga (9562-9569).
Site-selective sequential coupling reactions directed toward bis(diaryl)butadiynes are described. The reaction site could be controlled completely by the on/off application of electricity. The electro-oxidative homo-coupling of terminal alkynes (electricity ON) and the subsequent Suzuki–Miyaura coupling (electricity OFF) afforded bis(diaryl)butadiynes in high yields. The obtained 1,4-bis(diaryl)butadiynes could be converted to a 2,5-bis(diaryl)thiophene derivative, which exhibited blue fluorescence.

Convergent stereoselective synthesis of multiple sulfated GlcNα(1,4)GlcAβ(1,4) dodecasaccharides by Hiroshi Tanaka; Yusuke Tateno; Takashi Takahashi (9570-9582).
In this paper, we describe an effective method for the elongation of a GlcNα(1,4)GlcAβ(1,4) sequence using a GlcNTrocα(1,4)GlcA disaccharide unit and the synthesis of the N- and/or O-sulfated GlcNα(1,4)GlcAβ(1,4) oligosaccharides. N-Troc protection of GlcNα(1,4)GlcA units was effective for the synthesis of the GlcNα(1,4)GlcAβ(1,4) oligosaccharides in comparison with the azido substituent. The GlcNα(1,4)GlcAβ(1,4) dodecasaccharide was successfully prepared by the direct β-selective glycosidation of glucuronate in the GlcNα(1,4)GlcAβ(1,4)GlcNα(1,4)GlcAβ(1,4) tetrasaccharide. In addition, the synthesis of the N- and/or O-sulfated GlcNα(1,4)GlcAβ(1,4) oligosaccharides was accomplished by fluorous-assisted deprotection and sulfation. The fluorous-assisted synthetic technology applied to the highly polar sulfated oligosaccharide permits it to be more easily separated from the highly polar reagents, such as SO3·NEt3.

Synthesis, optical resolution, absolute configuration, and osteogenic activity of cis-pterocarpans by Atul Goel; Amit Kumar; Yasmin Hemberger; Ashutosh Raghuvanshi; Ram Jeet; Govind Tiwari; Michael Knauer; Jyoti Kureel; Anuj K. Singh; Abnish Gautam; Ritu Trivedi; Divya Singh; Gerhard Bringmann (9583-9592).
A convenient synthesis of natural and synthetic pterocarpans was achieved in three steps. Optical resolution of the respective enantiomers was accomplished by analytical and semi-preparative HPLC on a chiral stationary phase. For medicarpin and its synthetic derivative 9-demethoxymedicarpin, the absolute configuration was confirmed by a combination of experimental LC-ECD coupling and quantum-chemical ECD calculations. (−)-Medicarpin and (−)-9-demethoxymedicarpin are both 6aR,11aR-configured, and consequently the corresponding enantiomers, (+)-medicarpin and (+)-9-demethoxymedicarpin, possess the 6aS,11aS-configuration. A comparative mechanism study for osteogenic (bone forming) activity of medicarpin (racemic versus enantiomerically pure material) revealed that (+)-(6aS,11aS)-medicarpin (6a) significantly increased the bone morphogenetic protein-2 (BMP2) expression and the level of the bone-specific transcription factor Runx-2 mRNA, while the effect was opposite for the other enantiomer, (−)-(6aR,11aR)-medicarpin (6a), and for the racemate, (±)-medicarpin, the combined effect of both the enantiomers on transcription levels was observed.

Application of Suzuki arylation, Sonogashira ethynylation and Rosenmund–von Braun cyanation in the exploration of substitution effects on the anticancer activity of 2-aroylquinolines by Hsueh-Yun Lee; Lin-Wen Lee; Chih-Ying Nien; Ching-Chuan Kuo; Pen-Yuan Lin; Chi-Yen Chang; Jang-Yang Chang; Jing-Ping Liou (9593-9600).
A variety of functionalities were introduced at 2-aroylquinoline’s C5 position, which is considered equivalent to C-3′ of the B-ring of CA4, via Suzuki arylation, Sonogashira ethynylation, and Rosenmund–von Braun cyanation. These substitutions are rarely utilized in the modification of 3′-OH of CA4. The resulting products 6 and 7 having cyano and ethynyl groups exhibited comparable antiproliferative and tubulin inhibitory activities to colchicine.

Probing myo-inositol 1-phosphate synthase with multisubstrate adducts by Rania M. Deranieh; Miriam L. Greenberg; Pierre-B. Le Calvez; Maura C. Mooney; Marie E. Migaud (9601-9619).
The synthesis of a series of carbohydrate–nucleotide hybrids, designed to be multisubstrate adducts mimicking myo-inositol 1-phosphate synthase first oxidative transition state, is reported. Their ability to inhibit the synthase has been assessed and results have been rationalised computationally to estimate their likely binding mode.

Highly ordered pyrene π-stacks on an RNA duplex display static excimer fluorescence by Mitsunobu Nakamura; Minoru Fukuda; Tadao Takada; Kazushige Yamana (9620-9626).
The binding and fluorescence properties of complementary RNA sequences attached to different numbers of pyrenes via one carbon linker at the 2′-O-positions have been investigated. Upon hybridization of the pyrene-modified RNA sequences, the modified RNA duplexes with normal thermal stability are formed, and the pyrene arrays are assembled in an inter-strand manner. Because hypochromic effects in the pyrene absorption band and the exciton coupled circular dichroism signals were observed for the pyrene assemblies, the formation of the pyrene array occurs via a π-stacking interaction between the pyrene rings. The pyrene assemblies exhibit strong excimer fluorescence that is characterized by a broad and structureless excitation spectrum. Hence, the excimer is a static excimer due to the direct excitation of the associated pyrenes in the ground state. Based on several spectroscopies, it is revealed that the spatial configuration of the pyrenes in the association is more regulated by the increase in the attached pyrene.

Nickel-catalyzed C–P cross-coupling of diphenylphosphine oxide with aryl chlorides by Hong-Yu Zhang; Meng Sun; Yan-Na Ma; Qiu-Ping Tian; Shang-Dong Yang (9627-9633).
A novel protocol for the preparation of various diarylphosphine oxide compounds via a Ni-catalyzed cross-coupling of aryl chlorides with R2P(O)H has been developed. Notably, this process exhibits the following very attractive features: (i) the process is simpler and operates under mild reaction conditions; (ii) the process is generally cheaper in part because the more accessible aryl chloride is used to form the C–P bond; (iii) the process avoids the need for simultaneous preparation and use of Ar2P(O)M.

Selective off–on fluorescent chemosensor for detection of Fe3+ ions in aqueous media by Liang Huang; Fengping Hou; Ju Cheng; Pinxian Xi; Fengjuan Chen; Decheng Bai; Zhengzhi Zeng (9634-9638).
A Fe3+ chemosensor L1 was successfully synthesized with a quinoline moiety bound to rhodamine 6G hydrazide. The sensor L1 shows high selectivity and sensitivity to Fe3+ in aqueous solution in the presence of other trace metal ions in organisms, abundant cellular cations and prevalent toxic metal ions in the environment. In addition, biological imaging and micro computed tomography (MCT) technology studies have demonstrated that L1 could act as a turn-on fluorescent chemosensor for Fe3+ in living cells.

Oligonucleotides containing 4′-carboxy-, 4′-methoxycarbonyl-, 4′-carbamoyl-, and 4′-methylcarbamoyl-thymidines, and their 2′-methoxy, 2′-amino or 2′-acetamido analogs were prepared. Their duplex-forming ability with DNA and RNA complements was evaluated by UV melting experiments. Interestingly, 4′-carboxythymidine existing in the S-type sugar conformation was found to lead to an increase in the stability of the duplex formed with RNA complements compared to natural thymidine.

Chiral sulfoxides in the enantioselective allylation of aldehydes with allyltrichlorosilane: a kinetic study by Guglielmo Monaco; Chiara Vignes; Francesco De Piano; Assunta Bosco; Antonio Massa (9650-9659).
The mechanism of the allylation of aldehydes in the presence of allyltrichlorosilane employing the commercially available (R)-methyl p-tolyl sulfoxide as a Lewis base has been investigated. The combination of kinetic measurements, conductivity analysis and quantum chemical calculations indicates that the reaction proceeds through a dissociative pathway in which an octahedral cationic complex with two sulfoxides is involved. The lack of turnover is ascribed to the formation of neutral sulfurane derivatives.

Original β,γ-diamino acid as an inducer of a γ-turn mimic in short peptides by Sophie Thétiot-Laurent; Francelin Bouillère; Jean-Pierre Baltaze; François Brisset; Debby Feytens; Cyrille Kouklovsky; Emeric Miclet; Valérie Alezra (9660-9663).
Original αγα tripeptides containing one β,γ-diamino acid have been synthesized and their conformation determined by extensive NMR and molecular dynamic studies. These studies revealed the presence of a C9 hydrogen bonded turn around the β,γ-diamino acid which was stabilized by bulky side chains of the preceding residue. This turn can be considered as a mimic of the well-known γ-turn.

Base-pairing selectivity of a ureido-linked phenyl-2′-deoxycytidine derivative by Shu-ichi Nakano; Hirohito Oka; Daisuke Yamaguchi; Masayuki Fujii; Naoki Sugimoto (9664-9670).
Incorporation of modified nucleotides into nucleic acid strands often produces conformational constraints and steric hindrances that may change the property of base pairing. In this study, we investigated a 2′-deoxycytidine derivative that tethers a phenyl moiety to the exocyclic amino group of cytosine linked through a ureido group. This derivative compound is structurally similar to the carbamoylated DNA base lesions produced in cells. The thermodynamic and structural studies showed that the modified dC formed the base pair with dG in the complementary strand, but the base-pairing selectivity toward dG was decreased under poly(ethylene glycol)-mediated osmotic stress. The phenyl group and the ureido linker attached to dC provided selectivity for the formation of base pairing exclusively with dG in a wide range of pH conditions, whereas unmodified dC stabilized the pairings with dA or dC in acidic solutions. Moreover, this modified base could not form self-pairing through intermolecular hydrogen bonds. We suggest that formation of weak pairing and protonation of the cytosine base are hindered due to the base modification. These data provide insights into the pairing selectivity of carbamoylated cytosine lesions produced in cells, and suggest applications of the 2′-deoxycytidine derivatives in medical technologies, molecular biology experiments, and synthesis of a supramolecular network of DNA strands.

Spiralisones A–D: acylphloroglucinol hemiketals from an Australian marine brown alga, Zonaria spiralis by Hua Zhang; Xue Xiao; Melissa M. Conte; Zeinab Khalil; Robert J. Capon (9671-9676).
An intertidal sample of the Australian marine brown alga, Zonaria spiralis, exhibited promising kinase inhibitory and antibacterial activity. Chemical analysis returned six phloroglucinol-derived lipids, the new hemiketal spiralisones A–D (1–4) and the known chromones 5–6, and the known norsesquiterpenoid apo-9′-fucoxanthinone (7). Structures 1–7 were assigned on the basis of detailed spectroscopic analysis, biosynthetic considerations and total synthesis. Spiralisones undergo facile acid-mediated dehydration to yield the corresponding chromones, revealing for the first time that brown algal chromones may be handling artifacts rather than natural products. Hemiketals 1 and 2, and chromone 6, displayed inhibitory activity against the neurodegenerative disease kinase targets CDK5/p25, CK1δ and GSK3β, while hemiketals 1, 3 and 4, and chromone 6, displayed growth inhibitory activity against the Gram-positive bacteria Bacillus subtilis (ATCC 6051 and 6633). The promising kinase inhibitory and antibacterial properties of the Z. spiralis extract were attributed to the cumulative effect of many moderately potent phloroglucinol-derived lipid co-metabolites.

Essential role of phosphines in organocatalytic β-boration reaction by Cristina Pubill-Ulldemolins; Amadeu Bonet; Henrik Gulyás; Carles Bo; Elena Fernández (9677-9682).
The use of phosphines to assist the organocatalytic β-boration reaction of α,β-unsaturated carbonyl compounds has been demonstrated with a selected number of substrates. The new method eludes the use of Brönsted bases to promote the catalytic active species and PR3 becomes essential to interact with the substrate resulting in the formation of a zwitterionic phosphonium enolate. This species can further deprotonate MeOH when B2pin2 is present forming eventually the ion pair [α-(H),β-(PR3)-ketone]+[B2pin2·MeO] that is responsible for the catalysis.

We have constructed a new fluorescence turn-on chemosensor for hydrogen sulfide based on a phenanthroimidazole scaffold, and the novel sensor is suitable for imaging hydrogen sulfide in living cells.

Discovery of novel SERMs with a ferrocenyl entity based on the oxabicyclo[2.2.1]heptene scaffold and evaluation of their antiproliferative effects in breast cancer cells by Yangfan Zheng; Caihua Wang; Changhao Li; Jinxia Qiao; Feng Zhang; Minjian Huang; Wenming Ren; Chune Dong; Jian Huang; Hai-Bing Zhou (9689-9699).
We have synthesized a series of novel SERMs bearing a ferrocenyl unit based on a three-dimensional oxabicyclo[2.2.1]heptene core scaffold. These compounds displayed high receptor binding affinities as well as ERα or ERβ selectivity. In cell proliferation assays, we found that these ligands were cytotoxic at micromolar concentrations in both ER-positive and ER-negative breast cancer cells. On further examination, we found that the antiproliferative effects of compounds 9b, 10h and 11b on MCF-7 cells line does not arise from antiestrogenicity, but rather proceeds through a cytotoxic pathway. Possible mechanisms for the unique activities of these ligands were also investigated by molecular modeling. These new ligands could act as scaffolds for the development of novel anti-breast cancer agents.

Gold versus silver catalyzed intramolecular hydroarylation reactions of [(3-arylprop-2-ynyl)oxy]benzene derivatives by Antonio Arcadi; Federico Blesi; Sandro Cacchi; Giancarlo Fabrizi; Antonella Goggiamani; Fabio Marinelli (9700-9708).
The scope and the generality of gold versus silver catalyzed intramolecular hydroarylation reactions of 3-[(3-arylprop-2-ynyl)oxy]benzene derivatives in terms of rings substitution were investigated. Only products deriving from 6-endo cyclization were exclusively formed. The features of substituents had a considerable effect on the reaction outcome in the presence of silver catalysis, whereas gold catalysis revealed a unique blend of reactivity and selectivity and represented the only choice for the intramolecular hydroarylation reaction of the starting substrates bearing electron deficient arenes.

The tin(iv) chloride mediated cyclisation of (Z)-homoallylic alcohols using phenylselenenyl chloride or phthalimide in the presence of a Lewis acid followed by reductive removal of the phenylselenenyl group was found to give 2,5-cis-disubstituted tetrahydrofurans with excellent stereocontrol. Using this procedure, (2S,4S,8R,6Z)-9-benzyloxy-2-tert-butyldiphenylsilyloxy-8-methylnon-6-en-4-ol (11), prepared stereoselectively via the tin(iv) chloride promoted reaction between the (R)-5-benzyloxy-4-methylpent-2-enyl(tributyl)stannane (3) and (S)-3-tert-butyldiphenylsilyloxybutanal (10), gave (2S,3R,6S,8S)-1-benzyloxy-8-tert-butyldiphenylsilyloxy-3,6-epoxy-2-methylnonane (13) after deselenation. This tetrahydrofuran was selectively deprotected, oxidized and esterified to give methyl nonactate (2). Having established this synthesis of 2,5-cis-disubstituted tetrahydrofurans, it was applied to complete a synthesis of pamamycin 607 (1). (2S,3R,6S,8R)-1-Benzyloxy-8-[N-methyl-N-(toluene-4-sulfonyl)amino]-3,6-epoxy-2-methylundecane (35) was prepared stereoselectively from (R)-3-[N-(toluene-4-sulfonyl)-N-methylamino]hexanal (32) by reaction with the stannane 3 followed by cyclisation of the resulting alkenol 33 and deselenation. Following debenzylation and oxidation, an aldol reaction of the aldehyde 37 using the lithium enolate of 2,6-dimethylphenyl propanoate (61) gave mainly the 2,3-anti-3,4-syn-adduct 48. After protection of the secondary alcohol as its tert-butyldimethylsilyl ether 49, reduction using DIBAL-H and oxidation, the resulting aldehyde, (2S,3S,4R,5R,8S,10R)-3-tert-butyldimethylsilyloxy-2,4-dimethyl-5,8-epoxy-10-[N-methyl-N-(toluene-4-sulfonyl)amino]tridecanal (62), was taken through to the bis-tetrahydrofuran 65 by repeating the sequence of the reactions with the stannane 3, cyclisation and deselenation. The N-(toluene-4-sulfonyl) group was then replaced by an N-(tert-butoxycarbonyl) group and O-debenzylation and oxidation gave the carboxylic acid 70 that corresponds to the C(1)–C(18) fragment of pamamycin 607 (1). Similar chemistry was used to prepare the C(1′)–C(11′) fragment 89 of the pamamycin, except that in this case the configuration of the secondary alcohol introduced by the allylstannane reaction had to be inverted using a Mitsunobu reaction before the cyclisation. Esterification of the carboxylic acid of the C(1)–C(18)-fragment 70 using the alcohol 89 of the C(1′)–C(11′) fragment followed by selective deprotection, macrocyclisation, N-deprotection and N-methylation gave pamamycin 607 (1) that was identical to a sample of the natural product.

Efficient synthesis of RITA and its analogues: derivation of analogues with improved antiproliferative activity via modulation of p53/miR-34a pathway by Jinshun Lin; Xiuli Jin; Yiwen Bu; Deliang Cao; Nannan Zhang; Shangfu Li; Qinsheng Sun; Chunyan Tan; Chunmei Gao; Yuyang Jiang (9734-9746).
A novel approach to synthesize RITA by practical palladium-catalyzed C–C bond-forming Suzuki reactions at room temperature was developed, which was used for deriving a series of substituted tricyclic α-heteroaryl (furan/thiophene) analogues of RITA under mild conditions. These novel analogues showed notable antiproliferative activity against cancer cell lines with wild-type p53 (i.e., HCT116, A549, MCF-7 and K562), but much less activity in HCT116/p53−/− cells. In particular, compound 1f demonstrated promising antiproliferative activity compared to RITA, with IC50 = 28 nM in MCF-7 vs. 54 nM for RITA, and cancer cell selectivity. Compound 1f markedly activated p53 in HCT116 cells at 100 nM, triggering apoptosis. Importantly, we found that both RITA and compound 1f induced G0/G1 cell cycle arrest by up-regulating miR-34a, which in turn down-regulated the expression of cell cycle-related proteins CDK4 and E2F1. In summary, this study reports an effective synthetic approach for RITA and its analogues, and elucidates a novel antiproliferative mechanism of these compounds.

Back matter (9747-9750).

Back cover (9751-9752).