Beyond the Pummerer Reaction: Recent Developments in Thionium Ion Chemistry

Since the early 1960s the Pummerer reaction has evolved to become an indispensable tool for synthesis, and continues to serve as a source of inspiration for organic chemists. In recent years, many exciting advances have demonstrated the broad scope and synthetic utility of Pummerer methodology and the versatility of thionium ion intermediates.     

The Rhodium(II) Carbenoid Cyclization-Cycloaddition Cascade of alpha-Diazo Dihydroindolinones for the Synthesis of Novel Azapolycyclic Ring Systems

Tandem carbonyl ylide formation-1,3-dipolar cycloaddition of α-diazo N-acetyl-tetrahydro-β-carbolin-1-one derivatives occur efficiently in the presence of a dirhodium catalyst to afford bimolecular cycloadducts in high yield. The Rh(II)-catalyzed reaction also takes place intramolecularly to give products derived from trapping of the carbonyl ylide dipole with a tethered alkene. The power of the intramolecular cascade sequence is that it rapidly assembles a pentacyclic ring system containing three new stereocenters and two adjacent quaternary centers stereospecifically in a single step and in high yield.     

N-Acyliminium Cyclization as an Approach for an Asymmetric Synthesis of the Pyrrolo[2,1-a]benzazepine Ring System

Abstract

In this article, we report a facile asymmetric synthesis of the pyrrolo[2,1-a]benzazepine ring system based around a stereoselective N-acyliminium cyclization of a novel chiral lactam template.     

Thionium ion promoted Michael acceptor: a sequence of Pummerer/Michael reactions for the stereoselective synthesis of 5-(1-(arylthio)vinyl)-oxazolines

The synthesis of polysubstituted oxazolines is of great interest due to the synthetic and pharmaceutical importance. We developed a sequence of Pummerer/Michael reactions for the stereoselective synthesis of 5-(1-(arylthio)vinyl)-oxazolines.     

分子内Friedel-Crafts环化反应在苯并环状物合成中的应用

Friedel-Crafts反应是有机合成中最有用的反应之一,它的应用范围十分广泛.Friedel-Crafts反应也是合成环状化合物的重要途径,尤其分子内的环化反应一直以来受到广泛的关注.对近年来应用分子内Friedel-Crafts环化反应合成苯并环状化合物进行了详细的综述,并对分子内Friedel-Crafts环化反应在有机合成上发展前景作了展望.     

Synthesis of Phaitanthrin E and Tryptanthrin through Amination/Cyclization Cascade

Phaitanthrin E was biomimetically synthesized from methyl indole‐3‐carboxylate and methyl anthranilate or anthranilic acid using the ester group as an activating group. The reaction proceeds through NCS‐mediated dearomatization/TFA‐catalyzed protonation of indolenine/C(2) amination/Et₃N‐promoted aromatization and cyclization in one‐pot procedure. This method is capable of converting simple biomass materials to phaitanthrin E. The synthesis not only allows assessment of antiproliferative activity, but also affords experimental support for the hypothetical biosynthetic pathway of phaitanthrin E. The resulting phaitanthrin E derivatives were evaluated for in vitro antiproliferative activity against human colorectal cancer cells (DLD‐1). The biogenetic intermediate of phaitanthrin E showed higher antiproliferative activity than the natural product, phaitanthrin E. Furthermore, a concise synthesis of tryptanthrin is also accomplished from indole‐3‐carbaldehyde and methyl anthranilate using the aldehyde group as an activating group.     

Synthesis of Benzodiazepines Through Ring Opening/Ring Closure of Benzimidazole Salts

Pyrido-benzodiazepine derivatives are undoubtedly one of the most important structural motifs in the marketed drugs and the drug candidates. Commonly synthetic methods for construction of the benzodiazepine ring derivatives are based on the condensation reactions of two highly functionalized synthons. The development of synthesis for these compounds, however, is hampered by the regioselectivity and atom economy. In this work, a one-step synthesis of pyrido-benzodiazepine backbones and its analogues is achieved through continuous ring-opening hydrolysis of benzimidazole salts and intramolecular C−H bond activation. The reaction mechanism is explored by control experiments and density functional theory (DFT) calculations.     

Grignard Reagent/CuI/LiCl‐Mediated Stereoselective Cascade Addition/Cyclization of Diynes: A Novel Pathway for the Construction of 1‐Methyleneindene Derivatives

Diynes containing a cyclopropane group smoothly undergo a novel intramolecular and stereoselective cascade addition/cyclization reaction to produce the corresponding 1‐methyleneindene derivatives in moderate to good yields. This interesting transformation is mediated by Grignard reagent/CuI with LiCl as an additive under mild conditions. The obtained product can easily be further functionalized through cyclopropyl ring opening. A plausible reaction mechanism has also been presented on the basis of deuterium labeling and control experiments.     

A New Method for the Synthesis of C/D Ring Synthon of Vitamin D

Inrecentyears,vitaminDresearchareahasbeenstimulatedbythediscoveriesthatIQ,25-dihydroxyvitaminD,,theactivemetaboliteofvitaminD,,inadditiontotheclassicalrolesofregulatingcalciumandphosphorusmetabolisms',hasamuchbroaderspectrumofactivitiesthanoriginallythought,suchaspromotingcelldifferelltiationandinhibitingcellproliferation"'.Thebiologicalsignificanceandmedicalneedshaveledeffortstowardthesearchforanaloguesofpotentcelldifferelltiationandantiproliferationactivitywithouttoxichypercalcemiaassociate…     

Asymmetric Ring Opening/Cyclization/Retro‐Mannich Reaction of Cyclopropyl Ketones with Aryl 1,2‐Diamines for the Synthesis of Benzimidazole Derivatives

A highly efficient asymmetric ring‐opening/cyclization/retro‐Mannich reaction of cyclopropyl ketones with aryl 1,2‐diamines has been realized using a chiral N,N′‐dioxide/Sc^III catalyst. Benzimidazoles containing chiral side chains were generated under mild reaction conditions in excellent outcomes (up to 99 % yield and 97 % ee). This method also provides efficient access to chiral benzimidazole‐substituted amide and cycloheptene derivatives.     

Oxidative transformations of 6-trifluoromethyl-2H-thiopyran as a route to fluoro-containing thiopyranosides

The synthesis of cis- and trans-6-(trifluoromethyl)-3,4-dihydro-2H-thiopyran-3,4-diols from 6-(trifluoromethyl)-2H-thiopyran via an OsO₄-catalysed dihydroxylation and bromohydroxylation-alkaline hydrolysis sequence is described. Acetylation of the diols followed by S-oxidation affords the corresponding cis- and trans-3,4-diacetoxy-6-(trifluoromethyl)-3,4-dihydro-2H-thiopyran S-oxides which reacted with acetic anhydride and boron trifluoride diethyl ether complex by an additive Pummerer pathway giving tetraacetyl derivatives of trifluoromethyl-containing thiopyranoses.     

Advances in Artificial Cell Membrane Systems as a Platform for Reconstituting Ion Channels

An artificial cell membrane that is composed of bilayer lipid membranes (BLMs) with transmembrane proteins incorporated within them represents a well‐defined system for the analysis of membrane proteins, especially ion channel proteins that are major targets for drug design. Because the BLM system has a high compatibility with recently developed cell‐free expression systems, it has attracted attention as a next‐generation drug screening system. However, three issues associated with BLM systems, i. e., their instability, the need for non‐volatile organic solvents and a low efficiency of ion channel incorporation, have limited their use as a drug screening platform. In this personal account, we discuss our recent approaches to address these issues based on microfabrication. We also discuss the potential for using the BLM system combined with cell‐free expression systems as a drug screening system for future personalized medicine.     

Highly Enantioselective Construction of Strained Spiro[2,3]hexanes through a Michael Addition/Ring Expansion/Cyclization Cascade

We herein report a general organocatalytic enantioselective strategy for the construction of highly strained spiro[2,3]hexane skeletons from methylenecyclopropanes and a broad selection of α,β‐unsaturated aldehydes. The reaction proceeds through a Michael addition followed by ring expansion of methylenecyclopropanes and nucleophilic attack of an enamine to realize the construction of spiro[2,3]hexanes. Key to the success of this approach are the utilization of an electron‐deficient difluoro‐substituted secondary amine catalyst and the intrinsic reactivity of methylenecyclopropanes.     

Phenyl trifluorovinyl sulfide: a radical acceptor for preparation of gem-difluoromethylene compounds

Phenyl trifluorovinyl sulfide was prepared from the reaction of trifluorovinyllithium and S-phenyl benzenethiosulfonate. The fluorinated olefin showed reactivity with alkyl radicals generated from halogen-abstraction from alkyl halides. Reactions with alkyl halides required tris(trimethylsilyl)silane as a chain transfer reagent to improve selectivity of the products. Initiation of radical reaction was effected by thermal decomposition of AIBN. Oxidation of the thioether products gave the corresponding sulfoxides, which were successively converted into α,α-difluoroalkanecarboxylic acid thiol esters by Pummerer reaction.     

Synthesis of 5-aryl-2-oxopyrrole derivatives as synthons for highly substituted pyrroles

A small library of 2-oxo-5-(hetero)arylpyrroles was prepared starting from 2,3-dioxo-5-(hetero)arylpyrrolidines. The large synthetic possibilities of these 2-oxopyrroles were investigated. The 2-oxopyrroles offer a large number of possible derivatizations including reactions with electrophiles. The chloroformylation of 2-oxo-5-(hetero)arylpyrroles provides pyrrole carbaldehydes. Some pyrrole carbaldehydes were used to synthesize polycyclic compounds like pyrrolo[3,4-d]pyridazinones, a thienopyrrole, a pyrrolobenz[1,4]oxazepine, a pyrrolobenzo[1,4]thiazepine, and a pyrrolobenzo[1,4]diazepine. Hereby we showed through a short exploration that the oxopyrroles and analogues are interesting and versatile synthetic building blocks.     

抗癌大环化合物的环合方法

大环化合物具有广泛的生物活性.一些具有抗癌活性的天然大环化合物已开发成上市药物或应用于临床研究.在抗癌大环化合物的合成中,环合步骤是整个合成过程中的关键,同时也是难点所在.目前已经发展出了一些方便实用的环合方法.文章以具有抗癌作用的大环化合物为例,简要介绍各种常用的大环环合方法及应用.     

Single‐Electron/Pericyclic Cascade for the Synthesis of Dienes

The highly efficient and diastereoselective synthesis of E dienes has been accomplished through radical cyclization of bromoallyl hydrazones. This methodology has been further extended to generate these products through a one‐pot condensation/radical cyclization/cycloreversion cascade from simple aldehyde starting materials in high yields (>75 %) and high diastereoselectivities (>95:5). Mechanistic investigations suggest that the cascade reaction proceeds through a cyclic diazene intermediate prior to the cycloreversion.     

用于环酯单体开环聚合的无金属引发/催化体系

环酯单体在不同引发/催化体系作用下的开环聚合是制备可生物降解脂肪族聚酯的主要方法。综述了近年来用于环酯单体开环聚合的无金属引发/催化体系,主要涉及水、醇、胺、羧酸等引发剂及质子酸、膦类、氮杂环类化合物等催化剂体系。     

用于环酯单体开环聚合的无金属引发/催化体系

环酯单体在不同引发/催化体系作用下的开环聚合是制备可生物降解脂肪族聚酯的主要方法.综述了近年来用于环酯单体开环聚合的无金属引发/催化体系,主要涉及水、醇、胺、羧酸等引发剂及质子酸、膦类、氮杂环类化合物等催化剂体系.     

Three‐Component Triple Organocascade Synthesis of Hexahydropyridazine Derivatives via a Sequential Michael/Amination/Cyclization Reaction

The organocatalytic asymmetric synthesis of hexahydropyridazines were performed through a unique Michael/amination/cyclization reaction. The organocascade reaction proceeded smoothly between 2‐arylidene‐1,3‐indandiones and aldehydes followed by the addition of azodicarboxylates catalyzed by the privileged organocatalyst α,‐α‐L‐diphenylprolinol trimethylsilyl ether (10 mol%) in the presence of a base additive Et₃N (20 mo%) at 0 °C. A series of substituted hexahydropyridazines were obtained in good to high chemical yields (55–78 %) and reasonable to high levels of stereoselectivities (51–93 % ee and 4 : 1 d.r.).