Synthetic strategies to alpha-trifluoromethyl and alpha-difluoromethyl substituted alpha-amino acids

The combination of the unique physical and chemical properties of fluorine with proteinogenic amino acids represents a new approach to the design of biologically active compounds including peptides with improved pharmacological parameters. Therefore, the development of routine synthetic methods which enable the effective and selective introduction of fluorine into the desired amino acids from readily available starting materials is of significant synthetic importance. The scope of this critical review is to summarize the most frequently employed strategies for the synthesis of alpha-difluoromethyl and alpha-trifluoromethyl substituted alpha-amino acids (114 references).     

Chirality Transfer and Memory of Chirality in Gold‐Catalyzed Reactions

Over the last few years, gold‐catalyzed reactions that involved chirality transfer and memory of chirality (MOC) have emerged as a powerful tool in enantioselective synthesis. This technique has allowed for the single‐step synthesis of enantioenriched compounds from readily available starting materials. This Focus Review discusses this emerging field with an emphasis on mechanistic aspects and their applications in synthetic organic chemistry.     

Moderne Magnesiumorganische Chemie. Neues von der Grignard‐Reaktion

Organomagnesium reagents can be employed for a variety of useful transformations, which are also of relevance for industrial processes. Recent protocols for syntheses of highly functionalized Grignard reagents highlight fascinating new perspectives for organic synthesis. Particularly, the addition of superstoichiometric amounts of LiCl allowed for the preparation of organomagnesium compounds, employing haloarenes or arenes at very mild reaction conditions. These highly functionalized Grignard reagents can be used as starting materials for transition metal‐catalyzed cross‐coupling reactions. New developments in the ligand design resulted in highly active palladium and nickel catalysts for efficient transformations of inexpensive chlorides or tosylates, as well as challenging fluorides. Economically attractive iron‐catalyzed coupling reactions of organomagnesium reagents bear great potential for further developments.     

Asymmetric transfer hydrogenation: chiral ligands and applications

Hydrogen transfer reduction processes are attracting increasing interest from synthetic chemists in view of their operational simplicity and high selectivity. In this tutorial review the most significant advances recently achieved in the stereoselective reduction of unsaturated organic compounds catalyzed by homogeneous transition metal complexes are critically reviewed. A sharp growth of the synthetic applications of this technique in the synthesis of fine chemicals is predictable as the use of transition metal catalyzed reactions will become more familiar to synthetic chemists.     

A highly enantioselective amino acid-catalyzed route to functionalized alpha-amino acids

The development of syntheses providing enantiomerically pure alpha-amino acids has intrigued generations of chemists and been the subject of intense research. This report describes a general approach to functionalized alpha-amino acids based on catalytic asymmetric synthesis. Proline catalyzed Mannich-type reactions of N-PMP-protected alpha-imino ethyl glyoxylate with a variety of unmodified ketones to provide functionalized alpha-amino acids in high yields with excellent regio-, diastereo-, and enantioselectivities. Study of seven examples yielded six with product ee values of > or = 99%. In reactions involving ketone donors where diastereoisomeric products could be formed, two adjacent stereogenic centers were created simultaneously upon carbon-carbon bond formation with complete syn-stereocontrol. Significantly, this methodology utilizes readily available and rather inexpensive starting materials, does not require any preactivation of substrates or metal ion assistance, and can be carried out on a gram scale under operationally simple reaction conditions. The keto-functionality present in the products provides a particularly attractive site for versatile modifications. This study compliments and extends our bioorganic approach to asymmetric synthesis to a versatile synthon class. Given that we have shown that a variety of optically active amino acids can be synthesized with proline catalysis, where an L-amino acid begets other L-amino acids, our results may stimulate thoughts concerning prebiotic syntheses of optically active amino acids based on this route.     

钯催化的酰胺羰基化反应

酰胺羰基化的发现为氨基酸及其衍生物的合成提供了一个新方法。该合成方法 步骤简洁，只需一步即可从醛、酰胺-氧化碳合成N-酰基氨基酸，而且该反应是原 子经济型反应。与钴催化的酰胺羰基化相比，钯催化的反应条件更为温和，催化效 率也大为提高，对基团有更广普的适应性。简述近所来这一领域的新进展。     

Olefin Metathesis in Organic Chemistry

Transition metal catalyzed C? C bond formations belong to the most important reactions in organic synthesis. One particularly interesting reaction is olefin metathesis, a metal-catalyzed exchange of alkylidene moieties between alkenes. Olefin metathesis can induce both cleavage and formation of C? C double bonds. Special functional groups are not necessary. Although this reaction—which can be catalyzed by numerous transition metals—is used in industry, its potential in organic synthesis was not recognized for many years. The recent abrupt end to this Sleeping-Beauty slumber has several reasons. Novel catalysts can effect the conversion of highly fictionalized and sterically demanding olefins under mild reaction conditions and in high yields. Improved understanding of substrate–catalyst interaction has greatly contributed to the recent establishment of olefin metathesis as a synthetic method. In addition to the preparation of polymers with fine-tuned characteristics, the metathesis today also provides new routes to compounds of low molecular weight. The highly developed ring-closing metathesis has been proven to be key step in the synthesis of a growing number of natural products. At the same time interesting applications can be envisioned for newly developed variants of bimolecular metathesis. Improvements in the selective cross-metathesis of acyclic olefins as well as promising attempts to include alkynes as viable substrates provide for a vivid development of the metathesis chemistry.     

Transition metal catalyzed synthesis of 5-azaindoles

In an effort to develop synthetic procedures for the preparation of 2-substituted 5-azaindoles, the synthesis and cyclization reactions of acetylenic aminopyridines was explored. A novel method for the synthesis of 2-substituted 5-azaindoles via a transition metal catalyzed reaction is described.     

N-methyl-N-nosyl-beta(3)-amino acids

N-Methyl-beta(3)-amino acids are important building blocks in the synthesis of biologically active molecules. A very simple and efficient approach to transform natural alpha-amino acids into their corresponding N-methyl-beta(3)-amino acids is here presented. In the method, the key intermediates N-methyl-N-nosyl-alpha-aminoacyldiazomethanes are prepared in only one step, by a simple treatment of the corresponding N-nosyl-alpha-aminoacyl chlorides with diazomethane. The synthetic route takes advantage from the use of the nosyl group. This N-masking moiety activates the NH function, and the N-methylation can directly occur during the acylation step of diazomethane, rendering useless a second step that instead is shown to be necessary in all the classical procedures already reported for the preparation of N-methyl-beta(3)-amino acids. The Wolff rearrangement of N-methyl-N-nosyl-alpha-aminoacyldiazomethanes provides the corresponding N-methyl-N-nosyl-beta(3)-amino acids with total retention of the chiral configuration of the starting alpha-amino acids. No epimerization of the chiral carbon atom is observed also when N-methyl-N-nosyl-beta(3)-amino acids are transformed into chlorides and coupled with alpha-amino acid methyl esters to achieve model scaffolds for biologically important modified peptides.     

Synthesis of Phenolic Compounds via Palladium Catalyzed C−H Functionalization of Arenes

Phenol and its derivatives are extremely useful compounds in organic synthesis, medicinal chemistry and material sciences. The synthesis of phenols involving selective construction of the C?O bond at a C?H bond of arenes using transition‐metal catalysis represents the most appealing strategy. Indeed, active research is currently going on for the synthesis of valuable phenolic compounds using a transition‐metal‐catalyzed C?H functionalization strategy. This short review summarizes recent advances on palladium‐catalyzed C?O bond forming reactions that enable direct access to phenolic compounds. These catalytic reactions proceed either via C?H esterification with trifluoroacetic acid/trifluoroacetic anhydride followed by in situ hydrolysis of the ester or via direct C?H hydroxylation. A brief analysis of substrate scope and limitation, reaction mechanism as well as synthetic utility of these reactions has been included.     

Isoindolinone Synthesis via One-Pot Type Transition Metal Catalyzed C−C Bond Forming Reactions

Isoindolinone structure is an important privileged scaffold found in a large variety of naturally occurring as well as synthetic, biologically and pharmaceutically active compounds. Owing to its crucial role in a number of applications, the synthetic methodologies for accessing this heterocyclic skeleton have received significant attention during the past decade. In general, the synthetic strategies can be divided into two categories: First, direct utilization of phthalimides or phthalimidines as starting materials for the synthesis of isoindolinones; and second, construction of the lactam and/or aromatic rings by different catalytic methods, including C−H activation, cross-coupling, carbonylation, condensation, addition and formal cycloaddition reactions. Especially in the last mentioned, utilization of transition metal catalysts provides access to a broad range of substituted isoindolinones. Herein, the recent advances (2010–2020) in transition metal catalyzed synthetic methodologies via formation of new C−C bonds for isoindolinones are reviewed.     

Carbonylation of Difluoroalkyl Bromides Catalyzed by Palladium

Although important progress has been made in the fluoroalkylation reactions, the transition‐metal‐catalyzed carbonylative fluoroalkylation reaction remains challenging so far. Herein, we report the first example of a Pd‐catalyzed carbonylation of difluoroalkyl bromides with (hetero)arylboronic acids under one atmosphere pressure of CO. The reaction can also be extended to the aryl potassium trifluoroborate salts. The advantages of this protocol are synthetic simplicity, broad substrate scope, and excellent functional group compatibility. The resulting difluoroalkyl ketones can serve as versatile building blocks for the synthesis of various useful fluorinated compounds.     

过渡金属催化C-H键活化的硅氢化反应

过渡金属催化C-H键活化的硅氢化反应在材料科学和合成化学领域里具有重要意义。有机硅化合物在纺织、橡胶、机械、日化等材料领域有广泛应用,此外,它还是重要的有机合成中间体,作为亲核试剂应用到Hiyama偶联反应,反应具有经济、高效、环境友好等特点。近些年来,很多课题组在该领域进行研究,并取得了一定的成果_^[1]。我们将从过渡金属催化芳基/烷基C-H键活化的硅氢化反应出发,介绍近些年在此领域的研究进展。     

Stereoselective cyclopropanation of serine- and threonine-derived oxazines to access new morpholine-based scaffolds

A general strategy for the synthesis of novel, orthogonally protected scaffolds based on the unique 2-oxa-5-azabicyclo[4.1.0]heptane structure is presented. The described reaction sequence takes advantage of easily available starting materials such as serine and threonine and leads to stereochemically dense structures in few, high-yielding synthetic steps. We show how the stereochemistry can be easily tuned by starting from different beta-hydroxy-alpha-amino acids and also by means of a transition metal-catalyzed cyclopropanation step. The compounds find application as constrained templates for the construction of geometrically diversified libraries of compounds.     

Modular Synthesis of Triarylmethanes through Palladium‐Catalyzed Sequential Arylation of Methyl Phenyl Sulfone

Triarylmethanes, which are valuable structures in materials, sensing and pharmaceuticals, have been synthesized starting from methyl phenyl sulfone as an inexpensive and readily available template. The three aryl groups were installed through two sequential palladium‐catalyzed C? H arylation reactions, followed by an arylative desulfonation. This method provides a new synthetic approach to multisubstituted triarylmethanes using readily available haloarenes and aryl boronic acids, and is also valuable for the preparation of unexplored triarylmethane‐based materials and pharmaceuticals.     

A model for double asymmetric induction in the stereocontrolled reduction of glycosyl alpha-ketoesters with oxazaborolidines

Experimental diastereoselectivities for the stereocontrolled reduction of glycosyl alpha-ketoesters into the corresponding alpha-hydroxyesters have recently been reported with unexpected results. The process is catalyzed by a chiral oxazaborolidine derivative (the so-called CBS catalyst) and represents the key step in the synthesis of glycosyl alpha-amino acids synthons, a class of compounds that allow preparation of natural glycopeptides analogues exhibiting potential therapeutic relevance. Good to very good diastereomeric excesses have been obtained for a series of reactions with different glucidic derivatives, but surprisingly, the major product obtained does not correspond to that predicted by using Corey's model. In the present work, we carry out a theoretical investigation of these reactions at the density functional level. Separated effects from the catalyst and from the glucidic derivative have been computed to rationalize the observed diastereoselectivities and the double asymmetric induction.     

Application of iridium catalyzed allylic substitution reactions in the synthesis of branched tryptamines and homologues via tandem hydroformylation-Fischer indole synthesis

Combination of enantioselective allylation reactions with a tandem hydroformylation-Fischer indole synthesis sequence as a highly diversity-oriented strategy for the synthesis of tryptamines and homologues was explored. This modular approach allows the substituents at C3 of the indole core, the type of the amine moiety, and the distance of the amine moiety to the indole core in the final synthetic step to be defined. The starting materials required for the hydroformylation step were synthesized via iridium catalyzed enantioselective allylic substitution reactions in high yields and excellent enantioselectivities. The Rh catalyzed hydroformylation step in the presence of phenyl hydrazine, allows the in situ formed aldehyde to be trapped as the hydrazone. Subsequent acid catalyzed indolization furnishes the desired indole structures in moderate to good yields.     

New Syntheses with Oils and Fats as Renewable Raw Materials for the Chemical Industry

Oils and fats are the most important renewable raw materials for the chemical industry. Hitherto, industrial oleochemistry has concentrated predominantly on the carboxy functionality of fatty acids but, more recently, modern synthetic methods have been applied extensively to fatty compounds for the selective functionalization of the alkyl chain. Radical, electrophilic, nucleophilic, and pericyclic as well as transition metal catalyzed additions to the C-C double bond of, for example, oleic acid as the prototype of a readily accessible, unsaturated fatty acid have led to a large number of novel fatty compounds from which interesting properties are expected. Functionalization of C-H bonds in the alkyl chain is also feasible with remarkable selectivity. Effective and highly versatile catalysts for the metathesis of esters of unsaturated fatty acids have been developed, which lead to new and interesting omega-unsaturated fatty acids. The epoxidation of unsaturated fatty acids has been developed extensively. Enzymatic reactions allow syntheses with high selectivity and yield of mono- and diglycerides and esters of carbohydrates with a variety of surfactant properties. Regio- and enantioselective microbial hydrations and hydroxylations widen the spectrum of selective reactions. Of considerable significance is that, with the use of gene technology, natural oils and fats have been improved significantly and will be improved still further, insofar as they show a more uniform and often unusual fatty acid spectrum. Numerous fatty acids are now available in a purity which makes them attractive for synthesis and as raw materials for the chemical industry.     

Recent progress in coupling of two heteroarenes

The biheteroaryl structural motif is prevalent in polymers, advanced materials, liquid crystals, ligands, molecules of medicinal interest, and natural products. Many types of synthetic transformations have been known for the construction of heteroaryl–heteroaryl linkages. Coupling reactions provide one of the most efficient ways to achieve these biheterocyclic structures. In this review, four types of coupling reactions are discussed: 1) transition‐metal‐catalyzed coupling reactions of heteroaryl halides or surrogates with heteroarylmetals; 2) direct inter‐ and intramolecular heteroarylations of C? H bonds of heteroarenes with heteroaryl halides or pseudohalides; 3) oxidative C? H/C? H homo‐ and cross‐couplings of two unpreactivated heteroarenes; and 4) transition‐metal‐catalyzed decarboxylative cross‐coupling reactions between haloheteroarenes or heteroarenes and heteroarenecarboxylic acids. The general purpose of this review is to give an exhaustive and clear picture in heteroaryl–heteroaryl bond formation as well as its application in the synthesis of natural products, pharmaceuticals, catalyst ligands, and materials.     

Carbohydrate based chiral iodoarene catalysts for enantioselective dearomative spirocyclization

Organocatalysis using chiral iodoarenes enables many different enantioselective chemical reactions with cheap, easily accessible and robust catalysts. Carbohydrates have often been used as starting materials for the synthesis of chiral ligands for transition metal catalysts. Here, we now present the synthesis of the first carbohydrate based iodoarene catalysts which can be synthesized in one step starting from known compounds. These catalysts were used for oxidative spriolactonization of 3-(1-hydroxynaphthalen-2-yl)propanoic acid to afford the corresponding spirolactone in yields up to 77% and enantiomeric ratios er up to 80:20.