Organic & Biomolecular Chemistry (v.15, #30)

Front cover (6271-6272).

Contents list (6273-6280).

Recent advances in asymmetric total synthesis of prostaglandins by Haihui Peng; Fen-Er Chen (6281-6301).
Prostaglandins (PGs) are a series of hormone-like chemical messengers and play a critical role in regulating physiological activity. The diversified therapeutic activities and complex molecular architectures of PGs have attracted special attention, and huge progress has been made in asymmetric total synthesis and discovery of pharmaceutically useful drug candidates. In the last 10 years, several powerful syntheses have emerged as new solutions to the problem of building PGs and represent major breakthroughs in this area. This review highlights the advances in methodologies for the asymmetric total synthesis of prostaglandins. The application of these methodologies in the syntheses of medicinally useful prostaglandins is also described. The study has been carefully categorized according to the key procedures involved in the syntheses of various prostaglandins, aiming to give readers an easy understanding of this chemistry and provide insights for further improvements.

Low pH-triggering changes in peptide secondary structures by Kaori Furukawa; Makoto Oba; Kotomi Toyama; George Ouma Opiyo; Yosuke Demizu; Masaaki Kurihara; Mitsunobu Doi; Masakazu Tanaka (6302-6305).
We developed a novel methodology using cyclic α,α-disubstituted α-amino acids (dAAs) with an acetal-side chain to control peptide secondary structures. The introduction of cyclic dAAs into peptides contributed to the stabilization of peptide secondary structures as a helix, while an acidic treatment of peptides resulted in a marked conformational change.

Pd-Catalyzed double N-arylation of primary amines to synthesize phenoxazines and phenothiazines by Lu Zhang; Xin Huang; Shan Zhen; Jing Zhao; Heng Li; Bingxin Yuan; Guanyu Yang (6306-6309).
An efficient and versatile Pd-catalyzed tandem C–N bond formation between aryl halides and primary amines is developed. The transformation allows a one-pot synthesis of phenoxazine and phenothiazine derivatives with a broad range of substitution patterns from readily available precursors.

Structural evidence for the covalent modification of FabH by 4,5-dichloro-1,2-dithiol-3-one (HR45) by Alexander G. Ekström; Van Kelly; Jon Marles-Wright; Scott L. Cockroft; Dominic J. Campopiano (6310-6313).
We use mass spectrometry analysis and molecular modelling to show the established antimicrobial inhibitor 4,5-dichloro-1,2-dithiol-3-one (HR45) acts by forming a covalent adduct with the target β-ketoacyl-ACP synthase III (FabH). The 5-chloro substituent directs attack of the essential active site thiol (C112) via a Michael-type addition elimination reaction mechanism.

An interesting radical coupling reaction of aromatic aldehydes with isocyanides was disclosed for the synthesis of amides catalyzed by copper. According to the experimental results and mechanistic study, the isocyano group acted as an N1 synthon rather than exhibiting the carbene-like reactivity, exploiting a new reactivity profile of isocyanides.

tert-Butyl nitrite (TBN) as the N atom source for the synthesis of substituted cinnolines with 2-vinylanilines and a relevant mechanism was studied by XiaoBo Pang; LianBiao Zhao; DaGang Zhou; Ping Yong He; ZhenYu An; Ji Xiang Ni; RuLong Yan (6318-6322).
A green method to synthesize cinnolines by 6π electrocyclic reaction with alkenyl amines and TBN has been developed. TBN plays a dual role both as a nitrogen atom source and an oxidant in this procedure. Relevant mechanism experiments reveal that the reaction proceeds through electrocyclic reaction and with diazo hydroxide as a key intermediate.

The Cu(i)-catalyzed stereoconvergent borylative cyclization of ω-mesylate-α,β-unsaturated compounds is facilitated by a simple Cu-bisphosphine catalyst. This reaction provides a novel route to cis-β-boron-substituted five- and six-membered carbocycle and heterocycle esters. Mechanistic studies indicate that stereoconvergence and cis-substitution likely stem from the rapid enolation of the borylcopper adduct with the substrate double bond and the formation of a five-membered intermediate, respectively.

Selective synthesis of pyrrolo[1,2-a]azepines or 4,6-dicarbonyl indoles via tandem reactions of alkynones with pyrrole derivatives by Yulei Zhao; Yang Yuan; Murong Xu; Zhong Zheng; Runhua Zhang; Yanzhong Li (6328-6332).
Novel methodologies for the selective synthesis of pyrrolo[1,2-a]azepines or 4,6-dicarbonyl indoles starting from pyrrole derivatives and alkynones are described. When reactions were carried out with 1,2,4-trisubstituted N-propargyl pyrroles using a ZnI2 catalyst, pyrrolo[1,2-a]azepines were obtained. Whereas 4,6-dicarbonyl indoles were produced selectively with 1,2-disubstituted pyrroles in the presence of silica gel. The reaction outcomes depend on the substituent pattern of the substrates and the nature of the catalysts chosen. Control reactions suggested that the formation of a conjugated enamine intermediate was crucial for both the processes. With easily accessible starting materials, inexpensive catalysts and an easy-to-handle procedure, this reaction has the potential to become a general protocol for the synthesis of pyrrolo[1,2-a]azepines or indoles.

The synthesis of cycloalka[b]furans via an Au(i)-catalyzed tandem reaction of 3-yne-1,2-diols by Wei-Ting Liu; Zheng-Liang Xu; Xue-Qing Mou; Bang-Hong Zhang; Wen Bao; Shao-Hua Wang; Dongjun Lee; Lin-Sheng Lei; Kun Zhang (6333-6337).
An Au(i)-catalyzed cyclization/1,2-rearrangement/aromatization cascade of 3-yne-1,2-diols has been successfully realized. This reaction not only provides a new and efficient strategy for the synthesis of substituted cycloalka[b]furan compounds as well as their derivatives, but might also facilitate related biological studies.

Lasiodiplactone A, a novel lactone from the mangrove endophytic fungus Lasiodiplodia theobromae ZJ-HQ1 by Senhua Chen; Zhaoming Liu; Hongju Liu; Yuhua Long; Dongni Chen; Yongjun Lu; Zhigang She (6338-6341).
Lasiodiplactone A (1), an unprecedented lactone, was obtained from the mangrove endophytic fungus Lasiodiplodia theobromae ZJ-HQ1. The structure of 1 was established by analysis of NMR spectroscopic data and electronic circular dichroism (ECD) spectra. Lasiodiplactone A (1) was the first example of lactone that possesses a unique tetracyclic system (12/6/6/5) of RAL12 (12-membered β-resorcylic acid lactone) with a pyran ring and a furan ring. A possible biogenetic pathway for 1 was proposed. Compound 1 showed anti-inflammatory activity by inhibiting nitric oxide (NO) production in lipopolysaccharide activated in RAW264.7 cells with IC50 value of 23.5 μM and exhibited potential α-glucosidase inhibitory activity with IC50 values of 29.4 μM.

Stabilizing bubble and droplet interfaces using dipeptide hydrogels by Fernando Aviño; Andrew B. Matheson; Dave J. Adams; Paul S. Clegg (6342-6348).
Hydrophobic dipeptide molecules can be used to create interfacial films covering bubbles and droplets made from a range of oils. At high pH, the dipeptide molecules form micelles which transform into a hydrogel of fibres in response to the addition of salt. We characterize the properties of the hydrogel for two different salt (MgSO4) concentrations and then we use these gels to stabilize interfaces. Under high shear, the hydrogel is disrupted and will reform around bubbles or droplets. Here, we reveal that at low dipeptide concentration, the gel is too weak to prevent ripening of the bubbles; this then reduces the long-term stability of the foam. Under the same conditions, emulsions prepared from some oils are highly stable. We examine the wetting properties of the oil droplets at a hydrogel surface as a guide to the resulting emulsions.

Blue-light-promoted carbon–carbon double bond isomerization and its application in the syntheses of quinolines by Xinzheng Chen; Shuxian Qiu; Sasa Wang; Huifei Wang; Hongbin Zhai (6349-6352).
A blue-light-promoted carbon–carbon double bond isomerization in the absence of any photoredox catalyst is reported. It provides rapid access to a series of quinolines in good to excellent yields under simple aerobic conditions. The protocol is direct, catalyst-free and operationally convenient.

Under the combined catalysis of Cu(OTf)2/HOTf, the domino annulation reaction of o-arylalkynyl acetophenones with 3-phenacylideneoxindoles in refluxing acetonitrile selectively afforded functionalized spiro[indoline-3,7′-tetrapheno[7,6-bc]furans] and spiro[indeno[1,2-b]naphtho[2,1-d]furan-7,3′-indolines] depending on the electronic effect of the substituents on both substrates.

Synthesis and properties of a series of β-cyclodextrin/nitrone spin traps for improved superoxide detection by Florent Poulhès; Egon Rizzato; Patrick Bernasconi; Roselyne Rosas; Stéphane Viel; Laszlo Jicsinszky; Antal Rockenbauer; David Bardelang; Didier Siri; Anouk Gaudel-Siri; Hakim Karoui; Micaël Hardy; Olivier Ouari (6358-6366).
Three new DEPMPO-based spin traps have been designed and synthesized for improved superoxide detection, each carrying a cyclodextrin (CD) moiety but with a different alkyl chain on the phosphorus atom or with a long spacer arm. EPR spectroscopy allowed us to estimate the half-life of the superoxide spin adducts which is close to the value previously reported for CD-DEPMPO (t1/2≈ 50–55 min under the conditions investigated). The spectra are typical of superoxide adducts (almost no features of the HO˙ adduct that usually forms with time for other nitrone spin traps such as DMPO) and we show that at 250 μM, the new spin trap enables the reliable detection of superoxide by 1 scan at the position opposite to the corresponding spin trap without the CD moiety. The resistance of the spin adducts to a reduction process has been evaluated, and the superoxide spin adducts are sensitive to ascorbate and glutathione (GSH), but not to glutathione peroxidase/GSH, reflecting the exposed nature of the nitroxide moiety to the bulk solvent. To understand these results, 2D-ROESY NMR studies and molecular dynamics pointed to a shallow or surface self-inclusion of the nitrone spin traps and of nitroxide spin adducts presumably due to the high flexibility of the permethyl-β-CD rim.

This paper reports a computational study elucidating the reaction mechanism for ynamide-mediated amide bond formation from carboxylic acids and amines. The mechanisms have been studied in detail for ynamide hydrocarboxylation and the subsequent aminolysis of the resulting adduct by an amine. Ynamide hydrocarboxylation is kinetically favorable and thermodynamically irreversible, resulting in the formation of a key low-lying intermediate CP1 featuring geminal vinylic acyloxy and sulfonamide groups. The aminolysis of CP1 by the amine is proposed to be catalyzed by the carboxylic acid itself that imparts favourable bifunctional effects. In the proposed key transition state TSaminolysis-acid-iso2, the amine undergoes direct nucleophilic substitution at the acyl of CP1 to replace the enolate group in a concerted way, which is promoted by secondary hydrogen bonding of carboxylic acid with both the amine and CP1. These secondary interactions are suggested to increase the nucleophilicity of the amine and to activate the Cacyl–O bond to be cleaved, thereby stabilizing the aminolysis transition state. The concerted aminolysis mechanism is competitive with the classic stepwise nucleophilic acyl substitution mechanism that features sequential amine addition to acyl/intramolecular proton transfer/C–O bond cleavage and a key tetrahedral intermediate. Based on the mechanistic model, the carboxylic acid substrate effect and studies of more acidic CF3SO3H as the catalyst are in good agreement with the experimental observations, lending further support for the mechanistic model. The bifunctional catalytic effect of the carboxylic acid substrate may widely play a role in related amide bond-forming reactions and peptide formation chemistry.

A convenient and expeditious strategy to synthesize difluoroboron complexes of β-keto amides has been developed from β-keto nitriles and BF3·OEt2. BF3·OEt2 serves as both a BF2 source and a Lewis acid catalyst in the synthetic strategy. The formation mechanism of the difluoroboron complexes from β-keto nitriles and BF3·OEt2 was proposed. The difluoroboron complexes can be further converted into β-keto amides by treatment with sodium acetate. The strategy features advantages such as a wide substrate scope, non-metal catalysis, and easy operation. Some of the difluoroboron complexes display good fluorescence properties in the solid state and potential application in solid-state luminescent materials.

Reductive amination catalyzed by iridium complexes using carbon monoxide as a reducing agent by Alexey P. Moskovets; Dmitry L. Usanov; Oleg I. Afanasyev; Vasilii A. Fastovskiy; Alexander P. Molotkov; Karim M. Muratov; Gleb L. Denisov; Semen S. Zlotskii; Alexander F. Smol'yakov; Dmitry A. Loginov; Denis Chusov (6384-6387).
Development of novel, sustainable catalytic methodologies to provide access to amines represents a goal of fundamental importance. Herein we describe a systematic study for the construction of a variety of amines catalyzed by a well-defined homogeneous iridium complex using carbon monoxide as a reducing agent. The methodology was shown to be compatible with functional groups prone to reduction by hydrogen or complex hydrides.

A β-galactosidase probe for the detection of cellular senescence by mass cytometry by M. A. Lumba; L. M. Willis; S. Santra; R. Rana; L. Schito; S. Rey; B. G. Wouters; M. Nitz (6388-6392).
Mass cytometry (MC) is a powerful method that combines the cellular resolution of flow cytometry with the isotopic resolution of inductively coupled plasma mass spectrometry (ICP-MS). This combination theoretically allows for the simultaneous quantification of >80 different parameters at the single cell level, in turn allowing for the deep profiling of heterogeneous cell populations. The majority of available reagents for MC are antibodies labeled with heavy metal isotopes, allowing for the quantification of static biomarkers. To complement these reagents, we aim to develop small molecule reporters of cellular metabolism that are compatible with MC. Here we report a probe of β-galactosidase activity capable of detecting cellular senescence. The galactoside probe contains a tellurophene reporter group and, when hydrolyzed, generates a quinone alkide. This reactive alkylating agent forms covalent tellurophene bearing conjugates with local nucleophiles, allowing for the quantification of β-galactosidase activity in individual cells. Difluoromethyl and monofluoroethyl quinone alkide generating warheads were examined for their activities and compared in vitro and in vivo. We showed that the difluoromethyl derivative gave higher tellurium labelling in vitro and that the quinone methide was more reactive towards thiols than amines. In vivo the difluoromethyl derivative successfully labeled senescent cells with comparable selectivity to the commonly used fluorescent senescence probe C12FDG.

First stereoselective total synthesis of brevipolide M by Kasa Shiva Raju; Gowravaram Sabitha (6393-6400).
The first stereoselective total synthesis of a cytotoxic brevipolide M, which shares a pyrone framework bearing a tetrahydrofuran moiety and a cinnamate group with the readily available (−)-DET, is described. The key steps involved in the synthesis are the epoxide-opening, Brown's allylation, and the RCM reaction to install an α,β-unsaturated lactone ring and the inversion of the C-6′ stereogenic hydroxyl group using the Mitsunobu reaction.

Unified total synthesis of (+)-chinensiolide B and (+)-8-epigrosheimin by Saumen Hajra; Susit Acharyya; Abhisek Mandal; Ramkrishna Maity (6401-6410).
An expedient synthetic approach has been developed for the unified total synthesis of (+)-chinensiolide B and (+)-8-epigrosheimin. The point of divergence was provided by the lactone aldehyde 6, in which four contiguous stereocenters were achieved by a stereocontrolled Evans syn-aldol reaction of a R-carvone derived enantiopure aldehyde and chiral N-succinyl-oxazolidinone. The lactone aldehyde 6 was synthesized in multigram quantity in three steps. Highly optimized chemo- and stereoselective reactions and functional group interconversion enabled us to assemble (+)-chinensiolide B and (+)-8-epigrosheimin from 6.

Rapid and selective synthesis of spiropyrazolines and pyrazolylphthalides employing Seyferth–Gilbert reagent by Ashis Kumar Gupta; Narendra Kumar Vaishanv; Ruchir Kant; Kishor Mohanan (6411-6415).
An unexpected product-selectivity in the reaction of 2-arylideneindane-1,3-dione with dimethyl diazomethylphosphonate leading to the formation of two different types of products is reported. The reaction carried out in acetone in the presence of catalytic amount of cesium fluoride afforded spiropyrazoline phosphonates via 1,3-dipolar cycloaddition reaction, whereas the reaction in methanol yielded an interesting class of pyrazolylphthalides. This strategy provides an efficient alternative method for the construction of pyrazolylphthalides, and moreover, the process is general, works under mild conditions, and exhibits high functional group compatibility.

The preference for dual-gold(i) catalysis in the hydro(alkoxylation vs. phenoxylation) of alkynes by Èric Casals-Cruañas; Oscar F. González-Belman; Pau Besalú-Sala; David J. Nelson; Albert Poater (6416-6425).
Dinuclear gold complexes and their use in catalysis have received significant recent attention, but there are few critical comparisons of mono- versus dual gold-catalysed pathways. Herein we study the hydroalkoxylation and hydrophenoxylation of alkynes using density functional theory calculations, and compare two possible mechanisms that have been proposed previously on the basis of theoretical and experimental studies, which unravel different preferences because of both the nature of the alkyne and alcohol and the non-innocent role of the counter-anion of a dual gold based catalyst. Entropy is found to have a significant effect, rendering the nucleophilic attack of the monoaurated intermediate [Au(L)(η2-alkyne)]+ difficult both kinetically and thermodynamically; this mechanism cannot easily form only the trans-alkene product that is observed experimentally. Instead, a reaction via a dual gold catalysed mechanism presents much lower barriers. In addition, for the sake of direct comparison with recent results by Belanzoni and Zuccaccia, oversimplification of the N-heterocyclic carbene (NHC) ligand in the calculations might decrease the enthalpy barrier and lead to results that are not directly applicable to experiments. Moreover, the alkylic or arylic nature of the alkyne and/or alcohol is also tested.

Poly(methylhydrosiloxane) as a green reducing agent in organophosphorus-catalysed amide bond formation by Daan F. J. Hamstra; Danny C. Lenstra; Tjeu J. Koenders; Floris P. J. T. Rutjes; Jasmin Mecinović (6426-6432).
Development of catalytic amide bond formation reactions has been the subject of the intensive investigations in the past decade. Herein we report an efficient organophosphorus-catalysed amidation reaction between unactivated carboxylic acids and amines. Poly(methylhydrosiloxane), a waste product of the silicon industry, is used as an inexpensive and green reducing agent for in situ reduction of phosphine oxide to phosphine. The reported method enables the synthesis of a wide range of secondary and tertiary amides in very good to excellent yields.

Rationalising the effects of ionic liquids on a nucleophilic aromatic substitution reaction by Rebecca R. Hawker; Michaela J. Wong; Ronald S. Haines; Jason B. Harper (6433-6440).
The nucleophilic aromatic substitution reaction between 1-fluoro-2,4-dinitrobenzene and ethanol was examined in a series of ionic liquids across a range of mole fractions. Temperature-dependent kinetic analyses were undertaken to determine the activation parameters for this reaction at the highest mole fraction. As the mole fraction of ionic liquid was increased, the rate constant of the reaction also increased, however the microscopic origin of the rate enhancement was shown to be different between different ionic liquids and also between different solvent compositions. These results indicate a balance between microscopic interactions that result in the observed solvent effects and a qualitative method for analysing such interactions is introduced.

19F CEST imaging probes for metal ion detection by Qiaoli Peng; Yaping Yuan; Huaibin Zhang; Shaowei Bo; Yu Li; Shizhen Chen; Zhigang Yang; Xin Zhou; Zhong-Xing Jiang (6441-6446).
For detecting metal ions with 19F chemical exchange saturation transfer magnetic resonance imaging (19F CEST MRI), a class of novel fluorinated chelators with diverse fluorine contents and chelation properties were conveniently synthesized on gram scales. Among them, a DTPA-derived chelator with high sensitivity and selectivity was identified as a novel 19F CEST imaging probe for simultaneously detecting multiple metal ions.

It has been proved that the reaction between furfuryl amines and N-R-maleimides leads to the formation of aza-Michael addition products – 3-(furylmethylamino)-N-R-pyrrolidine-2,5-diones, instead of 7-oxa-2-azabicyclo[2.2.1]hept-5-enes, as this journal reported previously.

Back cover (6451-6452).