Organic & Biomolecular Chemistry (v.10, #17)

Front cover (3345-3346).

Contents list (3347-3356).

Making expensive dirhodium(ii) catalysts cheaper: Rh(ii) recycling methods by Nuno R. Candeias; Carlos A. M. Afonso; Pedro M. P. Gois (3357-3378).
Dirhodium(ii) catalysts have been widely used as a remarkable tool in organic synthesis, ultimately resulting in a myriad of transformations and formation of a wide variety of compounds, every so often intermediaries in drug synthesis. Aiming at a more sustainable chemistry, several methods suitable for the reutilisation of expensive dirhodium complexes have been developed. Herein, we provide a combined overview of the available methods for recovering and reusing dirhodium(ii) metal complexes in catalysis, covering homogeneous catalysis as well as heterogenisation methods.

Fluorescence-based active site probes for profiling deubiquitinating enzymes by Joanna F. McGouran; Holger B. Kramer; Mukram M. Mackeen; Katalin di Gleria; Mikael Altun; Benedikt M. Kessler (3379-3383).
Novel ubiquitin-based active site probes including a fluorescent tag have been developed and evaluated. A new, functionalizable electrophilic trap is utilized allowing for late stage diversification of the probe. Attachment of fluorescent dyes allowed direct detection of endogenous deubiquitinating enzyme (DUB) activities in cell extracts by in-gel fluorescence imaging.

Synthesis of (S)-(+)-cericlamine through lipase-catalyzed aminolysis of azo acetates by Agnes Prechter; Harald Gröger; Markus R. Heinrich (3384-3387).
The kinetic enzymatic resolution of azo acetates via aminolysis with Candida antarctica lipase B has been investigated using benzylamine as amine component. The products obtained from this biotransformation in high enantiomeric purity can serve as valuable precursors for various amino alcohols, as exemplified by the synthesis of the serotonin reuptake inhibitor (S)-(+)-cericlamine.

Promiscuous enantioselective (−)-γ-lactamase activity in the Pseudomonas fluorescens esterase I by Leticia L. Torres; Anna Schließmann; Marlen Schmidt; Noella Silva-Martin; Juan A. Hermoso; José Berenguer; Uwe T. Bornscheuer; Aurelio Hidalgo (3388-3392).
A promiscuous but very enantioselective (−)-γ-lactamase activity in the kinetic resolution of the Vince lactam (2-azabicyclo[2.2.1]hept-5-en-3-one) was detected in the Pseudomonas fluorescens esterase I (PFEI). The lactamase activity was increased 200-fold by the introduction of a point mutation and resulted as enantioselective as the Microbacterium sp. enzyme used industrially in this resolution. The structural and mechanistic determinants for the catalytic promiscuity and enantioselectivity were identified by molecular modeling, setting a ground stone to engineer further amidase-related activities from this esterase.

Complexation of neutral 1,4-dihalobutanes with simple pillar[5]arenes that is dominated by dispersion forces by Xiaoyan Shu; Jiazeng Fan; Jian Li; Xiaoyang Wang; Wei Chen; Xueshun Jia; Chunju Li (3393-3397).
The complexation of neutral 1,4-dihalobutanes with simple pillar[5]arenes was investigated. The results indicate the formation of interpenetrated complexes, where the dispersive interactions dominate the complex stability. Typically, 1,4-diiodobutane displays the strongest binding strength with ethylpillar[5]arene [Ka = (1.0 ± 0.1) × 104 M−1], up to 120 fold as compared with 1,4-difluorobutane.

ortho-Phenylene oligomers with terminal push–pull substitution by Jian He; Sanyo M. Mathew; Sarah D. Cornett; Stephan C. Grundy; C. Scott Hartley (3398-3405).
ortho-Phenylenes are an emerging class of helical oligomers and polymers. We have synthesized a series of push–pull-substituted o-phenylene oligomers (dimethylamino/nitro) up to the octamer. Conformational analysis of the hexamer using a combination of low-temperature NMR spectroscopy and ab initio predictions of 1H NMR chemical shifts indicates that, like other o-phenylenes, they exist as compact helices in solution. However, the substituents are found to have a significant effect on their conformational behavior: the nitro-functionalized terminus is 3-fold more likely to twist out of the helix. Protonation of the dimethylamino group favors the helical conformer. UV/vis spectroscopy indicates that the direct charge-transfer interaction between the push–pull substituents attenuates quickly compared to other conjugated systems, with no significant charge-transfer band for oligomers longer than the trimer. On protonation of the dimethylamino group, significant bathochromic shifts with increasing oligomer length are observed: the effective conjugation length is 9 repeat units, more than twice that of the parent oligomer. This behavior may be rationalized through examination of the frontier molecular orbitals of these compounds, which exhibit greater delocalization after protonation, as shown by DFT calculations.

We report a novel Lewis acid catalysed tandem reaction of isocyanides, chromone 3-carboxylic acid and nucleophiles. An experimentally very simple procedure, involving the use of microwave irradiation in the presence of a Lewis acid catalyst, affords a representative collection of chromone-2-carboxamides and chromone-2-carboxamido-3-esters in high yields, in just a few minutes. Such an unprecedented strategy is formally equivalent to a conjugate addition of isocyanides to Michael acceptors.

New pyrimido[4,5-b]carbazolone derivatives have been synthesized through cascade Ullmann N-arylation and aerobic oxidative C–H amidation reactions catalyzed by CuBr under air and ligand-free conditions.

Characterization of hydroxycinnamic acid derivatives binding to bovine serum albumin by Xiao-Ling Jin; Xia Wei; Feng-Ming Qi; Sha-Sha Yu; Bo Zhou; Shi Bai (3424-3431).
Hydroxycinnamic acid derivatives (HCAs) are a group of naturally occurring polyphenolic compounds which possess various pharmacological activities. In this work, the interactions of bovine serum albumin (BSA) with six HCA derivatives, including chlorogenic acid (CHA), caffeic acid (CFA), m-coumaric acid (m-CA), p-coumaric acid (p-CA), ferulic acid (FA) and sinapic acid (SA) have been investigated by NMR spectroscopic techniques in combination with fluorescence and molecular modeling methods. Competitive STD NMR experiments using warfarin sodium and l-tryptophan as site-selective probes indicated that HCAs bind to site I in the subdomain IIA of BSA. From the analysis of the STD NMR-derived binding epitopes and molecular docking models, it was deduced that CHA, CFA, m-CA and p-CA show similar binding modes and orientation, in which the phenyl ring is in close contact with protein surface, whereas carboxyl group points out of the protein. However, FA and SA showed slightly different binding modes, due to the steric hindrance of methoxy-substituents on the phenyl ring. Relaxation experiments provided detailed information about the relationship between the affinity and structure of HCAs. The binding affinity was the strongest for CHA and ranked in the order CHA > CFA > m-CA ≥p-CA > FA > SA, which agreed well with the results from fluorescence experiments. Based on our experimental results, we also conclude that HCAs bind to BSA mainly by hydrophobic interaction and hydrogen bonding. This study therefore provides valuable information for elucidating the mechanisms of BSA–HCAs interaction.

Chemiluminescence from alkoxy-substituted acridinium dimethylphenyl ester labels by Anand Natrajan; David Sharpe; David Wen (3432-3447).
Chemiluminescent acridinium dimethylphenyl ester labels are used in automated immunoassays for clinical diagnostics. Light emission from these labels is triggered by alkaline peroxide in the presence of the cationic surfactant cetyltrimethylammonium chloride (CTAC). The surfactant plays a critical role in the chemiluminescence process of these labels by both accelerating their emission kinetics and increasing total light output enabling high throughout and improved assay sensitivity in automated immunoassays. Despite the surfactant's crucial role in the chemiluminescent reaction, no study has investigated how structural perturbations in the acridinium ring could impact the influence of the surfactant. We describe herein the synthesis and properties of three new alkoxy-substituted, acridinium dimethylphenyl esters where the nature of the alkoxy group in the acridinium ring was varied (hydrophobic or hydrophilic). Chemiluminescence measurements of these alkoxy-substituted labels indicate that hydrophilic functional groups in the acridinium ring, in particular sulfobetaine zwitterions, disrupt surfactant-mediated compression of emission times but not enhancement of light yield. These results support the hypothesis that surfactant-mediated effects require the binding of two different reaction intermediates to surfactant aggregates and, that surfactants influence light emission from acridinium esters by two separate mechanisms. Our studies also indicate that preservation of both surfactant effects on acridinium ester chemiluminescence and low non-specific binding of the label can be achieved with a relatively hydrophobic acridinium ring coupled to a hydrophilic phenolic ester leaving group.

Synthesis of a new family of acyclic nucleoside phosphonates, analogues of TPases transition states by Bénédicte Dayde; Samira Benzaria; Claire Pierra; Gilles Gosselin; Dominique Surleraux; Jean-Noël Volle; Jean-Luc Pirat; David Virieux (3448-3454).
A 6-step procedure was developed for the synthesis of a new family of acyclic nucleoside phosphonates (ANPs), “PHEEPA” [(2-pyrimidinyl-2-(2-hydroxyethoxy)ethyl)phosphonic acids] in overall yields ranging from 4.5% to 32%. These compounds, which possess on one side a hydroxy function and on the other side a phosphonate group, can be considered either as potential antiviral agents or as transition state analogues of nucleoside phosphorylases such as thymidine phosphorylase.

Synthesis and properties of thienopyrrole based heteroacenes – indolodibenzothienopyrrole and dicarbazolodithienopyrrole by Ganapathy Balaji; Andrea M. Della Pelle; Bhooshan C. Popere; A. Chandrasekaran; S. Thayumanavan (3455-3462).
We report the syntheses and properties of thienopyrrole based unsymmetrical and extended heteroacenes, which are isoelectronic with heptacene (30π) and nonacene (38π), respectively. Optical and electrochemical properties of these seven and nine rings fused systems are studied. The optoelectronic properties of the syn and anti-isomers of the unsymmetrical heteroacenes are also compared. The influence of the position of the heteroatoms in the fused corona, upon the optical and electrochemical properties, is rationalized based on the contributions from the benzenoid vs. quinonoid-type structures of these molecules.

Core-modified hexaphyrin: synthesis and characterization of 31,34-disilahexaphyrinoid by Janusz Skonieczny; Lechosław Latos-Grażyński; Ludmiła Szterenberg (3463-3471).
Condensation of 16-silatripyrrane with pentafluorobenzaldehyde under catalytic conditions followed by DDQ oxidation leads to 31,34-disilahexaphyrinoid – a four times reduced derivative of 31,34-disilahexaphyrin which contains two built-in silole units flanked by four tetrahedrally hybridized meso carbons. In the preferred folded macrocyclic conformation the silole rings remain perpendicular to each other. The steric hindrance of bulky substituents at silicon atoms and β-positions of siloles prevented aromatization. Only one meso diastereomer (5S, 15S, 20R, 30R) has been isolated and subsequently identified by 1D and 2D NMR techniques. The density functional theory (DFT) has been applied to model the molecular structure of 31,34-disilahexaphyrinoid consistent with constraints imposed by NOE experiments. The total energies calculated at the B3LYP/6-31G**//B3LYP/6-31G** level for four feasible meso diastereomers clearly demonstrated the energetic preference for the meso diastereomer (5S, 15S, 20R, 30R).

Biomimetic synthesis, antibacterial activity and structure–activity properties of the pyroglutamate core of oxazolomycin by Plamen Angelov; Yui Kwan Sonia Chau; Paul J. Fryer; Mark G. Moloney; Amber L. Thompson; Paul C. Trippier (3472-3485).
Biomimetic intramolecular aldol reactions on oxazolidine templates derived from serine may be used to generate densely functionalised pyroglutamates, which are simpler mimics of the right hand side of oxazolomycin. Some of the compounds from this sequence exhibit in vivo activity against S. aureus and E. coli, suggesting that pyroglutamate scaffolds may be useful templates for the development of novel antibacterials, and cheminformatic analysis has been used to provide some structure–activity data.

Reduction of ketosulfonyl indoles with sodium borohydride provides a ready entry to tryptophols in a regiocomplementary fashion with respect to the traditional oxirane ring-opening by indoles under Friedel–Crafts conditions. Compared to traditional β-ketosulfones, ketosulfonyl indoles show a peculiar behavior since they undergo a Lewis acid promoted elimination of the arylsulfonyl group allowing the preparation of indolyl-substituted 1,4-dicarbonyl derivatives.

New fluoride-promoted hypoiodite-catalytic oxidative cycloetherification to aromatic spiroketals by Wei Wei; Liqi Li; Xiaohong Lin; Haifeng Li; Jijun Xue; Ying Li (3494-3499).
A new catalytic application of hypoiodite reagents generated in situ from iodide ions is found, which succeeded in the synthesis of bisbenzannelated spiroketal cores for the first time. Fluoride was proven to be obligatory for this spiroketalization, which is the first fluoride-promoted oxidative cycloetherification to aromatic spiroketals.

Nickel-catalyzed C–P coupling of aryl mesylates and tosylates with H(O)PR1R2 by Chaoren Shen; Guoqiang Yang; Wanbin Zhang (3500-3505).
A method was developed for the nickel-catalyzed phosphonylation of aryl mesylates and tosylates with H(O)PR1R2. To the best of our knowledge, this is the first example of nickel-catalyzed C–P coupling of aryl mesylates and tosylates. Most of the substrates gave moderate to good yields under our catalytic system.

Conformational preferences of oxy-substituents in butenolide–tetrahydropyran spiroacetals and butenolide–piperidine spiro-N,O-acetals by Sébastien Naud; Sarah J. Macnaughton; Bryony S. Dyson; Daniel J. Woollaston; Jonathan W. P. Dallimore; Jeremy Robertson (3506-3518).
We describe the synthesis of a series of oxy-substituted butenolide spiroacetals and spiro-N,O-acetals by oxidative spirocyclisation of 2-[(4-hydroxy or 4-sulfonamido)butyl]furans. The axial–equatorial preference of each oxy-substituent is investigated (NMR) by an acid-catalysed thermodynamic relay of configuration between the spiro- and oxy-centres. The axial site is preferred for most oxy-substituents at synthetically useful levels. The potential origins of this preference are discussed in terms of a stabilising gauche effect combined with the influence of solvation. These results have relevance to the synthesis of bis(acetylenic)enol ether spiroacetals including AL-1 and related compounds.

An efficient approach for achieving radical cyclizations by using hydroxamate ester as a coordination tether with Lewis acid was studied. The chiral Lewis acid-mediated cascade radical addition–cyclization–trapping reaction proceeded smoothly with good enantio- and diastereoselectivities, providing various chiral γ-lactams.

A convenient and mild chromatography-free method for the purification of the products of Wittig and Appel reactions by Peter A. Byrne; Kamalraj V. Rajendran; Jimmy Muldoon; Declan G. Gilheany (3531-3537).
A mild method for the facile removal of phosphine oxide from the crude products of Wittig and Appel reactions is described. Work-up with oxalyl chloride to generate insoluble chlorophosphonium salt (CPS) yields phosphorus-free products for a wide variety of these reactions. The CPS product can be further converted into phosphine.

An efficient and direct approach to β-heteroarylated (C–N bond) ketones is demonstrated. Base promoted redox isomerization of propargyl alcohol to α,β-unsaturated ketone followed by conjugate addition to NH-heteroarenes affords a wide range of β-heteroarylated ketones in good to excellent yields. Aryl, heteroaryl, alkyl C(sp), and terminal alkynes containing unactivated propargyl alcohols effectively undergo redox-isomerization conjugate addition (RICA) with NH-heteroarenes. Reaction of 3-substituted pyrazoles or indazole with propargyl alcohols enables highly regioselective products. A diverse range of NH-bearing nucleophiles such as: pyrazoles, imidazole, triazoles, pyrrole, indoles and aniline participate in this reaction and deliver the corresponding β-heteroarylated ketones.

Visible light mediated homo- and heterocoupling of benzyl alcohols and benzyl amines on polycrystalline cadmium sulfide by Tatiana Mitkina; Christoph Stanglmair; Wolfgang Setzer; Michael Gruber; Horst Kisch; Burkhard König (3556-3561).
The oxidative coupling of sp3 hybridized carbon atoms by photocatalysis is a valuable synthetic method as stoichiometric oxidation reagents can be avoided and dihydrogen is the only byproduct of the reaction. Cadmium sulfide, a readily available semiconductor, was used as a visible light heterogeneous photocatalyst for the oxidative coupling of benzyl alcohols and benzyl amines by irradiation with blue light. Depending on the structure of the starting material, good to excellent yields of homocoupling products were obtained as mixtures of diastereomers. Cross-coupling between benzyl alcohols and benzyl amines gave product mixtures, but was selective for the coupling of tetrahydroisoquinolines to nitromethane. The results demonstrate that CdS is a suitable visible light photocatalyst for oxidative bond formation under anaerobic conditions.

Back matter (3562-3562).

Back cover (3563-3564).