Asymmetric aminocatalysis--gold rush in organic chemistry

Catalysis with chiral secondary amines (asymmetric aminocatalysis) has become a well-established and powerful synthetic tool for the chemo- and enantioselective functionalization of carbonyl compounds. In the last eight years alone, this field has grown at such an extraordinary pace that it is now recognized as an independent area of synthetic chemistry, where the goal is the preparation of any chiral molecule in an efficient, rapid, and stereoselective manner. This has been made possible by the impressive level of scientific competition and high quality research generated in this area. This Review describes this "Asymmetric Aminocatalysis Gold Rush" and charts the milestones in its development. As in all areas of science, progress depends on human effort.     

Asymmetric catalysis of Diels-Alder reactions with in situ generated heterocyclic ortho-quinodimethanes

The Diels-Alder reaction is probably the most powerful technology in the synthetic repertoire for single-step constructions of complex chiral molecules. The synthetic power of this fundamental pericyclic transformation has greatly increased with the emergence of asymmetric catalytic variants, and research aimed at further expanding its potential is still exciting and fascinating the chemical community. Here, we document the first asymmetric catalytic Diels-Alder reaction of in situ generated heterocyclic ortho-quinodimethanes (oQDMs), reactive diene species that have never before succumbed to a catalytic approach. Asymmetric aminocatalysis, that uses chiral amines as catalysts, is the enabling strategy to induce the transient generation of indole-, pyrrole- or furan-based oQDMs from simple starting materials, while directing the pericyclic reactions with nitroolefins and methyleneindolinones toward a highly stereoselective pathway. The approach provides straightforward access to polycyclic heteroaromatic compounds, which would be difficult to synthesize by other catalytic methods, and should open new synthetic pathways to complex chiral molecules using nontraditional disconnections.     

Synergistic Strategies in Aminocatalysis

Synergistic catalysis offers the unique possibility of simultaneous activation of both the nucleophile and the electrophile in a reaction. A requirement for this strategy is the stability of the active species towards the reaction conditions and the two concerted catalytic cycles. Since the beginning of the century, aminocatalysis has been established as a platform for the stereoselective activation of carbonyl compounds through HOMO-raising or LUMO-lowering. The burgeoning era of aminocatalysis has been driven by a deep understanding of these activation and stereoinduction modes, thanks to the introduction of versatile and privileged chiral amines. The aim of this review is to cover recent developments in synergistic strategies involving aminocatalysis in combination with organo-, metal-, photo-, and electro-catalysis, focusing on the evolution of privileged aminocatalysts architectures.     

Acid-base bifunctional and dielectric outer-sphere effects in heterogeneous catalysis: a comparative investigation of model primary amine catalysts

Dielectric and acid-base bifunctional effects are elucidated in heterogeneous aminocatalysis using a synthetic strategy based on bulk silica imprinting. Acid-base cooperativity between silanols and amines yields a bifunctional catalyst for the Henry reaction that forms alpha,beta-unsaturated product via quasi-equilibrated iminium intermediate. Solid-state UV/vis spectroscopy of catalyst materials treated with salicylaldehyde demonstrates zwitterionic iminium ion to be the thermodynamically preferred product in the bifunctional catalyst. This product is observed to a much lesser extent relative to its neutral imine tautomer in primary amine catalysts having outer-sphere silanols partially replaced by aprotic functional groups. One of these primary amine catalysts, consisting of a polar outer-sphere environment derived from cyano-terminated capping groups, has activity comparable to that of the bifunctional catalyst in the Henry reaction, but instead forms the beta-nitro alcohol product in high selectivity (approximately 99%). This appears to be the first observation of selective alcohol formation in primary amine catalysis of the Henry reaction. A primary amine catalyst with a methyl-terminated outer-sphere also produces alcohol, albeit at a rate that is 50-fold slower than the cyano-terminated catalyst, demonstrating that outer-sphere dielectric constant affects catalyst activity. We further investigate the importance of organizational effects in enabling acid-base cooperativity within the context of bifunctional catalysis, and the unique role of the solid surface as a macroscopic ligand to impose this cooperativity. Our results unequivocally demonstrate that reaction mechanism and product selectivity in heterogeneous aminocatalysis are critically dependent on the outer-sphere environment.     

Recent Advances in Ynenamine Chemistry

Enamines are formed by reacting a carbonyl compound with an amine under dehydration conditions. A vast array of transformations has been achieved via preformed enamine chemistry. Recently, by introducing conjugating double bonds to the enamine functionality, dienamines, and trienamines have propelled the discovery of several previously unattainable remote-site functionalization reactions of carbonyl compounds. Comparatively, alkyne-conjugating enamine analogues have recently shown high potential in multifunctionalization reactions while remaining underexplored. In this account, we systematically summarized and discussed recent advances in synthetic transformations based on ynenamine-containing compounds.     

Aromatic Aminocatalysis

Aromatic aminocatalysis refers to transformations that employ aromatic amines, such as anilines or aminopyridines, as catalysts. Owing to the conjugation of the amine moiety with the aromatic ring, aromatic amines demonstrate distinctive features in aminocatalysis compared with their aliphatic counterparts. For example, aromatic aminocatalysis typically proceeds with slower turnover, but is more active and conformationally rigid as a result of the stabilized aromatic imine or iminium species. In fact, the advent of aromatic aminocatalysis can be traced back to before the renaissance of organocatalysis in the early 2000s. So far, aromatic aminocatalysis has been widely applied in bioconjugation reactions through transamination; in asymmetric organocatalysis through imine/enamine tautomerization; and in cooperative catalysis with transition metals through C?H/C?C activation and functionalization. This Focus Review summarizes the advent of and major advances in the use of aromatic aminocatalysis in bioconjugation reactions and organic synthesis.     

Breaking Aromaticity with Aminocatalysis: A Convenient Strategy for Asymmetric Synthesis

Since the turn of the millennium, catalytic reactions promoted by primary or secondary amines have emerged as a highly useful method for organic chemistry. Very recently, the potential of such synthetic strategies has been vastly expanded by incorporating the principle of aromaticity breaking. Novel reaction pathways can now be accessed through the intermediacy of polyenamine intermediates derived from (hetero)aromatic systems. The proper design of carbonyl starting materials, combined with the high stereochemical efficiency provided by well‐established aminocatalysts, has enabled the synthesis of products with (hetero)aromatic frameworks in highly enantio‐ and diastereomerically enriched form. In this Minireview, we provide an overview of recent advances in this field of research and familiarize the reader with new synthetic opportunities offered by these interesting methodologies.     

Catalytic Asymmetric Electrochemical α-Arylation of Cyclic β-Ketocarbonyls with Anodic Benzyne Intermediates

Asymmetric catalysis with benzyne remains elusive because of the highly fleeting and nonpolar nature of benzyne intermediates. Reported herein is an electrochemical approach for the oxidative generation of benzynes (cyclohexyne) and its successful merging with chiral primary aminocatalysis, formulating the first catalytic asymmetric enamine–benzyne (cyclohexyne) coupling reaction. Cobalt acetate was identified to stabilize the in situ generated arynes and facilitate its coupling with an enamine. This catalytic enamine-benzyne protocol provides a concise method for the construction of diverse α-aryl (α-cyclohexenyl) quaternary carbon stereogenic centers with good stereoselectivities.     

The Diarylprolinol Silyl Ethers: Ten Years After

Asymmetric organocatalysis has experienced an incredible development since the beginning of this century. The expansion of the field has led to a large number of efficient types of catalysts. One group, the diarylprolinol silyl ethers, was introduced in 2005 and has been established as one of the most frequently used in aminocatalysis. In this Minireview, we will take a look in the rear‐view mirror, ten years after the introduction of the diarylprolinol silyl ethers. We will focus on the perspectives of the different activation modes made available by this catalytic system. Starting with a short introduction to aminocatalysis, we will outline the properties that have made the diarylprolinol silyl ethers a common choice of catalyst. Furthermore, we will describe the major tendencies in the activation and reaction concepts developed with regard to reactivity patterns and combinations with other activation concepts.     

Light- and Manganese-Initiated Borylation of Aryl Diazonium Salts: Mechanistic Insight on the Ultrafast Time-Scale Revealed by Time-Resolved Spectroscopic Analysis

Manganese-mediated borylation of aryl/heteroaryl diazonium salts emerges as a general and versatile synthetic methodology for the synthesis of the corresponding boronate esters. The reaction proved an ideal testing ground for delineating the Mn species responsible for the photochemical reaction processes, that is, involving either Mn radical or Mn cationic species, which is dependent on the presence of a suitably strong oxidant. Our findings are important for a plethora of processes employing Mn-containing carbonyl species as initiators and/or catalysts, which have considerable potential in synthetic applications.     

Catalytic Asymmetric Electrochemical α‐Arylation of Cyclic β‐Ketocarbonyls with Anodic Benzyne Intermediates

Asymmetric catalysis with benzyne remains elusive because of the highly fleeting and nonpolar nature of benzyne intermediates. Reported herein is an electrochemical approach for the oxidative generation of benzynes (cyclohexyne) and its successful merging with chiral primary aminocatalysis, formulating the first catalytic asymmetric enamine–benzyne (cyclohexyne) coupling reaction. Cobalt acetate was identified to stabilize the in situ generated arynes and facilitate its coupling with an enamine. This catalytic enamine‐benzyne protocol provides a concise method for the construction of diverse α‐aryl (α‐cyclohexenyl) quaternary carbon stereogenic centers with good stereoselectivities.     

Syntheses and transformations of α-azido ketones and related derivatives

Organic azides are known and utilized in the synthetic organic chemistry as amine precursors, potential sources of nitrenes, dipoles useful in 1,3-dipolar cycloadditions and starting materials of phosphoranes for a long time, and their literature has been overviewed by several authors. On the other hand, there are some special subclasses within the azides which possess peculiar and interesting properties differing from those of the majority and offering extra synthetic possibilities. In this critical review we wish to give an exhaustive overview on the synthesis and synthetic potential of α-azido ketones and related systems, an underestimated group of compounds. The enhanced acidity of the α-hydrogen offers various new synthetic applications including the creation of a new C-C bond, while the joint presence of the carbonyl and vinyl functions of α-azido-α,β-unsaturated ketones results in a special reactivity, too. Chemo- and stereoselectivity issues also represent important points which are discussed in detail. Finally, the usefulness of the titled derivatives in the synthesis of various heterocycles is reviewed (273 references).     

Trifluoromethylation‐Initiated Remote Cross‐Coupling of Carbonyl Compounds to Form Carbon–Heteroatom/Carbon Bonds

By involving the reversal of conventional reactivity expectations without external oxidants, we describe a novel and convenient protocol of remote cross‐coupling of carbonyl compounds with a series of common and simple nucleophiles. This cross‐coupling is triggered by radical trifluoromethylation of alkenes, thereby achieving highly selective remote difunctionalization of alkenes and α‐position of the carbonyl group for facile access to trifluoromethyl α‐halo‐ and α‐cyanocarbonyl compounds. The reaction exhibits a broad substrate scope with excellent functionality tolerance and many different types of nucleophiles; further synthetic applicability of the obtained compounds proved to be suitable, thus showing great potential for synthetic utility.     

Enantioselective metallo-organocatalyzed preparation of cyclopentanes bearing an all-carbon quaternary stereocenter

Enantioselective metallo-organocatalyzed carbocyclizations of formyl-alkynes have been developed. The cooperation between aminocatalysis and a chiral copper(I) complex granted access to enantio-enriched cyclopentanes through the challenging formation of all-carbon quaternary stereocenters.     

TRIMETHYLAMMONIUM CHLOROCHROMATE ADSORBED ON ALUMINA AS A NEW REAGENT FOR THE CLEAVAGE OF OXIMES AND P-NITROPHENYLHYDRAZONES

Derivatives of carbonyl compounds such as oximes and p-nitrophenylhydrazones have played an important role in the protection of carbonyl compounds,as they are highly crystalline and stable compounds. They are also very extensively used for the characterization and purification of carbonyl compounds. Regeneration of carbonyl compounds from their derivatives under mild condition is an important process in synthetic organic chemistry.     

Tosylhydrazones: new uses for classic reagents in palladium-catalyzed cross-coupling and metal-free reactions

Tosylhydrazones are useful synthetic intermediates that have been used in organic chemistry for almost 60 years. The recent discovery of a palladium-catalyzed cross-coupling reaction involving a tosylhydrazone coupling partner has triggered renewed interest in these reagents. This reaction shows nearly universal generality with regard to the hydrazone and can be employed for the preparation of polysubstituted alkenes. In the course of this research, novel metal-free C-C and C-O bond-forming reactions have been discovered. Since tosylhydrazones are readily prepared from carbonyl compounds, these transformations offer new synthetic opportunities for the unconventional modification of carbonyl compounds. This Minireview discusses all of these new reactions of a classic reagent.     

Selective α-bromination of aryl carbonyl compounds: prospects and challenges

The α-bromination of carbonyl compounds is one of the most important transformations and also important precursors in synthetic organic chemistry. Particularly, the side chain monobromination of carbonyl compounds has been a challenging task, because during the reaction a small amount of disubstituted or ring brominated products as an impurity is always accompanied with monosubstituted product in the reaction mixture. In recent years substantial advances have been made for the synthesis of brominated aromatic carbonyl compounds with high selectivity. In this review, we have summarized various methods for the synthesis of α-bromo aromatic carbonyl compounds.     

Carbon-carbon bond-forming enantioselective synthesis of chiral organosilicon compounds by rhodium/chiral diene-catalyzed asymmetric 1,4-addition reaction

[reaction: see text] A new synthetic method for chiral organosilicon compounds through a rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to beta-silyl alpha,beta-unsaturated carbonyl compounds has been developed. By employing (R,R)-Bn-bod* as a ligand, a range of arylboronic acids can be coupled with these substrates in very high enantiomeric excess. The resulting beta-silyl 1,4-adducts can be converted to beta-hydroxy carbonyl compounds or allylsilanes while retaining their stereochemical information.     

An iron carbonyl approach to the influenza neuraminidase inhibitor oseltamivir

A novel synthetic route towards oseltamivir, an influenza neuraminidase inhibitor, has been achieved employing a cationic iron carbonyl complex, providing an alternate pathway with the potential to access diverse analogues.     

Catalytic Asymmetric Hetero-Diels-Alder Reactions of Carbonyl Compounds and Imines

Asymmetric catalysis is a challenge for chemists: How can we design catalysts to achieve the goal of forming optically active compounds? This review provides the reader with an overview of the development of catalytic asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines. Since its discovery, the Diels-Alder reaction has undergone intensive development and is of fundamental importance for synthetic, physical, and theoretical chemists. The Diels-Alder reaction has been through different stages of development, and at the beginning of the 21st century catalytic Diels-Alder reactions are one of the main areas of focus. The preparation of numerous compounds of importance for our society is based on cycloaddition reactions to carbonyl compounds and imines. There are several parallels between the reactions of carbonyl compounds and those of imines, which, however, begin to vanish on entering the field of catalytic reactions. Why? From a mechanistic point of view some similarities can be drawn, but the synthetic development of catalytic enantioselective hetero-Diels-Alder reactions of imines are several years behind those of the carbonyl compounds. For hetero-Diels-Alder reactions of carbonyl compounds there a number of different chiral catalysts, and great progress has been achieved in developing enantioselective reactions for unactivated and activated carbonyl compounds. In contrast the development of catalytic enantioselective hetero-Diels-Alder reactions of imines is in its infancy and only few catalytic reactions have been published. This review will focus on the most important developments, and discuss the synthetic and mechanistic aspects of enantioselective hetero-Diels-Alder reactions of carbonyl compounds catalyzed by chiral Lewis acids. For the hetero-Diels-Alder reactions of imines, the diastereoselective reactions of optically substrates catalyzed by Lewis acids will be presented first, followed by the catalytic enantioselective reactions.