On the Conformations of Halichlorine and the Pinnaic Acids: Nitrogen Inversion as a Possible Determinant of Biological Profile

Although the marine alkaloids halichlorine ( 1 ) and the pinnaic acids 2 , which contain a quinolizidine ring system, exhibit considerable structural homology, they act upon different biological targets (VCAM‐1 and cPLA₂, respectively). Quinolizidines can exist as cisoid or transoid invertomers. In the recently reported total synthesis of (+)‐halichlorine, it was determined by NMR that advanced intermediates 3 and 4 , containing the spiroquinolizidine core, exhibit the transoid conformation, while the macrolactone‐containing halichlorine has the cisoid conformation. We conclude that constraints imposed upon closure of the macrolactone ring force adoption of the cisoid conformation. The major conformational reorganization upon macrolactonization has implications for the design of pharmacophors and anticipated structure‐activity relationships in their action on biological targets.     

Enantioselective Total Synthesis of Pinnaic Acid and Halichlorine

The enantioselective total synthesis of the bioactive marine natural products pinnaic acid and halichlorine is reported in detail. Our total synthesis features the construction of the five‐membered ring and C9 and C13 stereogenic centers through a palladium‐catalyzed trimethylenemethane [3+2] cyclization; the installation of the nitrogen atom through a regioselective Beckmann rearrangement of a poorly reactive ketone; the stereoselective cyclization of the spiro ring through a four‐step, one‐pot hydrogenation–cyclization; and efficient connection of the sterically hindered lower chain through a reduced‐pressure cross olefin metathesis reaction.     

A Novel Synthesis of 4‐Pyridazineacetic Acids via Ring Expansion of N‐Cyanomethylated 3‐Pyrazoline‐4‐acetic Acids

A novel synthetic route to 4‐pyridazineacetic acids 10 – 12 has been achieved by the ring‐expansion reaction of N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 – 9 . 1H‐Pyrazole‐4‐acetic acids 1 – 3 were reacted with iodoacetonitrile in the presence of triethylamine in refluxing acetonitrile to give the corresponding C‐cyanomethylated 1H‐pyrazole‐4‐acetic acids 4 – 6 as major products together with N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 and 8 as minor products. On the other hand, reactions of 1 and 3 with chloroacetonitrile in the presence of triethylamine in refluxing chloroform afforded the corresponding N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 and 9 as major products. Thermal treatment of 7 – 9 with sodium hydride in N,N‐dimethylformamide caused ring expansion to yield the corresponding 4‐pyridazineacetic acids 10 – 12 .     

Indole‐N‐Carboxylic Acids and Indole‐N‐Carboxamides in Organic Synthesis

Indoles are ubiquitous structures that are found in natural products and biologically active molecules. The synthesis of indoles and indole‐involved synthetic methodologies in organic chemistry have been receiving considerable attention. Indole‐N‐carboxylic acids and derived indole‐N‐carboxamides are intriguing compounds, which have been widely used in organic synthesis, especially in multicomponent reactions and C?H functionalization of indoles. This Minireview summarizes the advances of reactions involving indole‐N‐carboxylic acids and indole‐N‐carboxamides in organic chemistry, and discusses the synthetic potential and perspective of this field.     

基于哌嗪与二羧酸/羟基羧酸的二元体系的超分子自组装

本文选择哌嗪 (pip) 为研究中心,分别和1,4-环己二甲酸 (H2chda)、间苯二甲酸(H2mpda)、6-羟基-2-萘甲酸 (Hohna)、1-羟基-2-萘甲酸 (Hshna) 进行超分子自组装,得到了四种新的氢键超分子体系：H2pip·chda (1), H2pip·2Hmpda (2), H2pip·ohna·2H2O (3),H2pip·shna (4)。单晶结构分析表明：1-3为三维氢键超分子结构,而 4为一维链状氢键结构。     

Potential‐Controlled Chromatography of Short‐Chain Carboxylic Acids

A chromatographic column was constructed which could be operated with an electrically conductive stationary phase of graphite particles. This column allowed chromatographic experiments at variable electric potentials of the column material. The chromatographic behavior of selected carboxylic acids was significantly influenced at positive column potentials. An equimolar mixture of three different carboxylic acids were separated at a potential of +600 mV (versus. Ag/AgCl). Surprisingly, the stereoisomers maleic and fumaric acid, which are identical in molecular mass and charge, could also be separated. Further improvements to the chromatographic performance were achieved by applying potential drops and linear potential gradients.     

Ortho‐carboxylate Effects in Copper‐mediated Nucleophilic Substitution of Halothiophenecarboxylic Acids and Halobenzoic Acids with Sodium Bisulphite

Ortho‐carboxylate effects in Ullmann type nucleophilic substitution reactions were found to be much more pronounced as compared to those of other substituent and steric factors. In this study, we propose an ortho halogen assisted intramolecular oxidative addition‐reductive elimination mechanism that fits our experimental observations. Experimental data has been generated with halothiophenecarboxylic acids and halobenzoic acids by performing copper‐mediated nucleophilic substitution with scant referred sodium bisulphite as nucleophile under aqueous conditions. The novel mechanism was used to establish a new and improved process for preparation of monopotassium salts of 3‐sulphothiophene‐2‐carboxylic acid, 2‐sulphobenzoic acid, and 5‐sulphothiophene‐2‐carboxylic acid. These monopotassium salts are critical intermediates and building blocks in the preparation of several therapeutically valuable drugs. The differences in reactivity between the halogens, chlorine and bromine was utilized to prepare aryl ethers including 2‐acetyl‐3‐phenoxythiophene and 2‐acetyl‐3‐(m‐tolyloxy)thiophene that have not been reported in literature so far.     

Predicting Mole‐Fraction‐Dependent Dissociation for Weak Acids

We demonstrate for formic and acetic acid dissolved in water as examples that the binary quantum cluster equilibrium (bQCE) approach can predict acid strengths over the whole range of acid concentrations. The acid strength increases in a complex rather than a simple way with increasing mole fraction of the acid from 0 to 0.7, reflecting the complex interplay between the dissociated ions or conjugate bases available as compared to the acid and water molecules. Furthermore, our calculated ion concentrations meet the experimental maximum of the conductivity with excellent agreement for acetic acid and satisfactorily for the formic acid/water mixture. As only a limited number of simple quantum‐chemical calculations are required for the prediction, bQCE is clearly a valuable approach to access these quantities also in non‐aqueous solutions. It is a highly valuable asset for predicting ionization processes in highly concentrated solutions, which are relevant for biological and chemical systems, as well as technological processes.     

Cobalt‐Catalyzed Diastereo‐ and Enantioselective Hydroalkenylation of Cyclopropenes with Alkenylboronic Acids

Catalytic diastereo‐ and enantioselective hydroalkenylation of 3,3‐disubstituted cyclopropenes with readily accessible alkenylboronic acids, promoted by a chiral phosphine/Co complex, is presented. Such a process constitutes the unprecedented and direct introduction of a wide range of alkenyl groups onto the cyclopropane motif to afford multisubstituted cyclopropanes in up to 95 % yield with greater than 95:5 d.r. and 99:1 e.r. Functionalization of the products delivered enantioenriched cyclopropanes that are otherwise difficult to access.     

Visible‐Light‐Induced Decarboxylative Functionalization of Carboxylic Acids and Their Derivatives

Visible‐light‐induced radical decarboxylative functionalization of carboxylic acids and their derivatives has recently received considerable attention as a novel and efficient method to create C? C and C? X bonds. Generally, this visible‐light‐promoted decarboxylation process can smoothly occur under mild reaction conditions with a broad range of substrates and an excellent functional‐group tolerance. The radical species formed from the decarboxylation step can participate in not only single photocatalytic transformations, but also dual‐catalytic cross‐coupling reactions by combining photoredox catalysis with other catalytic processes. Recent advances in this research area are discussed herein.     

Palladium‐Catalyzed Aminocarbonylation of N‐Chloroamines with Boronic Acids

Aryl (pseudo)halide‐based (C?X) carbonylation reactions have been extensively studied during the past few decades. From both academic and synthetic points of view, the carbonylative transformation of N?X bonds represents an interesting and attractive area of investigation. In light of this, the first carbonylative cross‐coupling between N‐chloroamines and organoboronic acids has been developed. This new type of aminocarbonylation proceeds at mild temperatures (45–55 °C) with 2 mol % Pd/C (10 wt %) as the ligand‐free catalyst. Not only arylboronic acids, but also alkenyl‐ and alkylboronic acids can be applied as the substrates and bromide and iodide substituents in the substrates are well tolerated. Initial mechanistic investigations have also been performed.     

Metal‐ and Base‐Free Room‐Temperature Amination of Organoboronic Acids with N‐Alkyl Hydroxylamines

We have found that readily available N‐alkyl hydroxylamines are effective reagents for the amination of organoboronic acids in the presence of trichloroacetonitrile. This amination reaction proceeds rapidly at room temperature and in the absence of added metal or base, it tolerates a remarkable range of functional groups, and it can be used in the late‐stage assembly of two complex units.