The dynamic kinetic resolution of azlactones with thiol nucleophiles catalyzed by arylated, deoxygenated cinchona alkaloids

A significant improvement of the available organocatalytic methods (in terms of product substrate scope and product enantiomeric excess) for the generation of enantioenriched α-amino acid thioesters via the dynamic kinetic resolution of azlactones is reported. C-9 arylated cinchona alkaloid catalysts have been found to be considerably superior to other bifunctional alkaloid catalysts as the promoters of this asymmetric process.     

Searching for New Reactivity (Nobel Lecture)

The processes for the selective oxidation of olefins have long been among the most useful tools for day‐to‐day organic synthesis. Herein, the focus is on the asymmetric‐epoxidation (AE) and asymmetric‐dihydroxylation (AD) reactions developed by Sharpless and co‐workers. The reactions have a wide scope, are simple to run, and involve readily available starting materials. Ligand‐accelerated catalysis is crucial to these reactions and might be the agent for uncovering more catalytic processes. In addition to the selectivity benefits of catalysis, the phenomenon of turnover (amplification) raises its potential impact. The author and his co‐workers developed small, highly enantioselective catalysts that were unfettered by the “lock‐and‐key” selectivity of Natures enzymes, and tolerant of substrates throughout the entire range of olefin substitution patterns.     

Chiral DMAP‐N‐oxides as Acyl Transfer Catalysts: Design,Synthesis, and Application in Asymmetric Steglich Rearrangement

A DMAP‐N‐oxide, featuring an α‐amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O‐acylated azlactones afforded C‐acylated azlactones possessing a quaternary stereocenter in high yields (up to 97 % yield) and excellent enantioselectivities (up to 97 % ee). Compared to the widespread use of pyridine nitrogen, which serves as the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that chiral DMAP‐N‐oxides, in which the oxygen now acts as the nucleophilic site, are efficient acyl transfer catalysts. Our finding might open a new door for the development of chiral DMAP‐N‐oxides for asymmetric acyl transfer reactions.     

A Practical Aryl Unit for Azlactone Dynamic Kinetic Resolution: Orthogonally Protected Products and A Ligation‐Inspired Coupling Process

The first strategy for bringing about enantioselective azlactone dynamic kinetic resolution to generate orthogonally protected amino acids has been developed. In the presence of a C₂‐symmetric squaramide‐based catalyst, benzyl alcohol reacts with novel yet readily prepared tetrachloroisopropoxycarbonyl‐substituted azlactones to generate trapped phthalimide products of significant synthetic interest with excellent enantiocontrol. These materials are masked amino acids which are demonstrably orthogonally protected: cleavage of the phthalimide can be achieved in the presence of the ester and vice versa. This process could be utilized to bring about a highly stereoselective ligation‐type coupling of protected serines (at stoichiometric loadings) with racemic azlactones derived from both natural and abiotic amino acids. After deprotection, a subsequent base‐mediated O→N acyl transfer occurs to form a dipeptide.     

Chiral DMAP‐N‐oxides as Acyl Transfer Catalysts: Design,Synthesis, and Application in Asymmetric Steglich Rearrangement

A DMAP‐N‐oxide, featuring an α‐amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O‐acylated azlactones afforded C‐acylated azlactones possessing a quaternary stereocenter in high yields (up to 97 % yield) and excellent enantioselectivities (up to 97 % ee). Compared to the widespread use of pyridine nitrogen, which serves as the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that chiral DMAP‐N‐oxides, in which the oxygen now acts as the nucleophilic site, are efficient acyl transfer catalysts. Our finding might open a new door for the development of chiral DMAP‐N‐oxides for asymmetric acyl transfer reactions.     

Synergy,Compatibility, and Innovation: Merging Lewis Acids with Stereoselective Enamine Catalysis

In recent years there has been an accelerated rate of development in the field of organocatalysis, with asymmetric organocatalysis now reaching full maturity. The invention of new organocatalytic reactions and the exploration of new concepts now appear in tandem with the application of organocatalytic techniques in the synthesis of natural products and active pharmaceutical ingredients (APIs). After a “golden rush” in organocatalysis, researchers are now starting to combine different methods, thereby taking advantage of the significant benefits of synergy. Metals are used in combination with organocatalytic processes, thus reaching complexity that is found in nature, where enzymes take advantage of the presence of certain metals to increase the arsenal of organic transformations available. In this Focus review, we illustrate the possibility of a “happy marriage” between Lewis acids and organocatalytic stereoselective processes. Questions have been raised about the combination of Lewis acids and organocatalysis owing to the presence of water and/or strong bases in these processes. Some Lewis acids have been shown to be compatible with organocatalysis and concepts relating to their use will be illustrated herein. To summarize the fruitful use of Lewis acids in stereoselective organocatalytic processes, we will draw attention to the advantages and selectivity achieved using this method.     

Umpolung Strategy for α‐Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles

Nucleophile–nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α‐functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone‐promoted oxidation to access O‐bound quinol‐intermediates that undergo nucleophilic substitution reactions. These quinol‐intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α‐thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α‐branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.     

Bispalladacycle‐Catalyzed Michael Addition of In Situ Formed Azlactones to Enones

The development and further evolution of the first catalytic asymmetric conjugate additions of azlactones as activated amino acid derivatives to enones is described. Whereas the first‐generation approach started from isolated azlactones, in the second‐generation approach the azlactones could be generated in situ starting from racemic N‐benzoylated amino acids. The third evolution stage could make use of racemic unprotected α‐amino acids to directly form highly enantioenriched and diastereomerically pure masked quaternary amino acid products bearing an additional tertiary stereocenter. The step‐economic transformations were accomplished by cooperative activation by using a robust planar chiral bis‐Pd catalyst, a Brønsted acid (HOAc or BzOH; Ac=acetyl, Bz=benzoyl), and a Brønsted base (NaOAc). In particular the second‐ and third‐generation approaches provide a rapid and divergent access to biologically interesting unnatural quaternary amino acid derivatives from inexpensive bulk chemicals. In that way highly enantioenriched acyclic α‐amino acids, α‐alkyl proline, and α‐alkyl pyroglutamic acid derivatives could be prepared in diastereomerically pure form. In addition, a unique way is presented to prepare diastereomerically pure bicyclic dipeptides in just two steps from unprotected tertiary α‐amino acids.     

Recent Advances in Organocatalytic Methods for Asymmetric C?C Bond Formation

Beyond a doubt organocatalysis belongs to the most exciting and innovative chapters of organic chemistry today. Organocatalysis has emerged not only as a complement to metal‐catalyzed reactions and to biocatalysis over the last decade, but also provides new asymmetric organocatalyzed reactions that cannot be accomplished by metal‐ or biocatalyzed reactions so far. A large number of organocatalytic processes are already well established in organic synthesis. Nevertheless, the number of publications in this field is still on the increase; new important results are produced constantly. This review gives a detailed overview of the latest developments and main streams in organocatalyzed asymmetric C? C bond formation processes of the last three years. It is intended to outline the most important current findings focused on especially new synthetic methodologies.     

Highly Regioselective Organocatalyzed Synthesis of Pyrazoles from Diazoacetates and Carbonyl Compounds

A general, organocatalytic inverse‐electron‐demand [3+2] cycloaddition reaction between a range of carbonyl compounds and diazoacetates has been developed. This reaction is catalyzed by secondary amines as a “green promoter” to generate substituted pyrazoles with high levels of regioselectivity. It is noteworthy that this [3+2] cycloaddition reaction proceeds efficiently at room temperature with a simple and inexpensive catalyst. Considering the large variety and ready availability of the starting materials (e.g. ketones, β‐ketoesters, β‐diketones, and aldehydes), as well as the operational simplicity of this process, a convenient, practical, and highly modular pyrazole synthesis has been developed. We believe that this work will arouse more research interest in the organocatalytic synthesis of other biologically active heterocycles. Such studies are currently underway in our laboratory.     

Highly Stereoselective [4+2] and [3+2] Spiroannulations of 2‐(2‐Oxoindolin‐3‐ylidene)acetic Esters Catalyzed by Bifunctional Thioureas

A new Michael–Michael cascade reaction between 2‐(2‐oxoindolin‐3‐ylidene)acetic esters 1 and nitroenoates 2 , catalyzed by bifunctional thioureas, is investigated. The combination of the two Michael reactions results in a novel and facile [4+2] or [3+2] spiroannulation process, which is characterized by the following features: 1) two carbon–carbon bonds and four stereocenters, including a quaternary spiro carbon, are formed under mild conditions; 2) an unprecedented and stereochemically defined substitution pattern on the spirocarbocyclic unit is obtained; 3) the double‐bond configuration of the donor–acceptor nitroenoate 2 determines the absolute configuration of the spiro center, whereas the remaining stereocenters are formed under control of the catalyst. The effect on the final stereochemical outcome of structural variations of each starting material, catalyst, and experimental conditions is analyzed in detail. In particular, the use of specifically designed chiral nitroenoates enables diverse polyfunctional spirocyclohexane derivatives containing six consecutive stereogenic centers to be constructed. To our knowledge, this is the first asymmetric organocatalytic strategy enabling both five‐ and six‐membered β‐nitro spirocarbocyclic oxindoles.     

Progress in Hyperpolarized Ultrafast 2D NMR Spectroscopy

An important development in the field of NMR spectroscopy has been the advent of hyperpolarization approaches, capable of yielding nuclear spin states whose value exceeds by orders‐of‐magnitude what even the highest‐field spectrometers can afford under Boltzmann equilibrium. Included among these methods is an ex situ dynamic nuclear polarization (DNP) approach, which yields liquid‐phase samples possessing spin polarizations of up to 50 %. Although capable of providing an NMR sensitivity equivalent to the averaging of about 1 000 000 scans, this methodology is constrained to extract its “superspectrum” within a single—or at most a few—transients. This makes it a poor starting point for conventional 2D NMR acquisition experiments, which require a large number of scans that are identical to one another except for the increment of a certain t₁ delay. It has been recently suggested that by merging this ex situ DNP approach with spatially encoded “ultrafast” methods, a suitable starting point could arise for the acquisition of 2D spectra on hyperpolarized liquids. Herein, we describe the experimental principles, potential features, and current limitations of such integration between the two methodologies. For a variety of small molecules, these new hyperpolarized ultrafast experiments can, for equivalent overall durations, provide heteronuclear correlation spectra at significantly lower concentrations than those currently achievable by conventional 2D NMR acquisitions. A variety of challenges still remain to be solved before bringing the full potential of this new integrated 2D NMR approach to fruition; these outstanding issues are discussed.     

In memory of Prof. Venkataraman: Recent advances in the synthetic methodologies of flavones

Flavones are present in a variety of medicines and natural products and are important structural motif due to their unique mode of physiological action. Hence the structural importance of flavone moiety has elicited a great deal of interest in the field of organic synthesis and chemical biology to develop some new and improved synthesis of this molecular skeleton. Herein, we have described an up to date overview on the recent advances in the diverse synthetic methodologies of flavones. The review covers the basic conceptual and practical catalytic synthesis like carbonylative annulation, cyclodehydration, Suzuki Miyaura coupling, Heck coupling, green methodologies, metal catalyzed reactions, organocatalytic transformations, microwave irradiation, etc. which are significant for constructing flavone skeleton. This review will satisfy the expectations of readers who are interested in the development of the field and looking for an update. It will stimulate researchers to develop new and creative synthetic access to this heterocyclic system, which will be instrumental in the advancement of flavone chemistry.     

Triphenylphosphine (PPh3) Catalyzed Erlenmeyer Reaction for Azlactones under Solvent‐free Conditions

This study presents triphenylphosphine catalyzed process for the synthesis of azlactones and their derivatives using hippuric and substituted aromatic aldehydes. The methodology also found to be effective for the synthesis of azlactones from 5‐(2,6‐dichlorophenyl)‐3‐methyl‐1,2‐oxazol‐4‐yl carbonyl amino acetic acid and offers several advantages such as solvent‐free conditions, excellent yields, simple procedure, mild conditions, and reduced environmental consequences.     

Ureidopeptide‐Based Brønsted Bases: Design,Synthesis and Application to the Catalytic Enantioselective Synthesis of β‐Amino Nitriles from (Arylsulfonyl)acetonitriles

The addition of cyanoalkyl moieties to imines is a very attractive method for the preparation of β‐amino nitriles. We present a highly efficient organocatalytic methodology for the stereoselective synthesis of β‐amino nitriles, in which the key to success is the use of ureidopeptide‐based Brønsted base catalysts in combination with (arylsulfonyl)acetonitriles as synthetic equivalents of the acetonitrile anion. The method gives access to a variety of β‐amino nitriles with good yields and excellent enantioselectivities, and broadens the stereoselective Mannich‐type methodologies available for their synthesis.     

Phosphoric Acid Catalyzed Asymmetric [2+2] Cyclization/Penicillin–Penillonic Acid Rearrangement

Enantioselective synthesis of imidazolidin‐5‐ones through a phosphoric acid catalyzed reaction between azlactones and N‐substituted β‐carbolines is reported. The reaction takes place via an initial formal [2+2] cycloaddition to generate an α‐amino‐β‐lactam, which subsequently undergoes an acid‐catalyzed asymmetric penicillin–penillonic acid (PPA) rearrangement with high diastereo‐ and enantioselectivity. To the best of our knowledge, this represents the first [2+2] cyclization of azlactones with imines and the first asymmetric PPA rearrangement, which are linked together by the phosphoric acid catalyst.     

Catalytic Asymmetric [2+3] Cyclizations of Azlactones with Azonaphthalenes

The first catalytic asymmetric [2+3] cyclization of azlactones with azonaphthalenes has been established. This strategy allowed the synthesis of a variety of chiral isatin derivatives in generally good yields and excellent enantioselectivities (up to 99 % yield, 98 % ee). The developed reaction has not only established a catalytic enantioselective [2+3] cyclization using azlactones as two‐carbon building blocks, but also enriches the chemistry of catalytic asymmetric cyclizations of azonaphthalenes. In addition, this protocol will provide a useful method for constructing enantioenriched 3,3′‐disubstituted isatin‐type frameworks.     

Synthesis of enantiomerically enriched secondary and tertiary phenylthio- and phenoxy-aldols

α-Phenoxy- and phenylthio-ketones have been explored as donors and acceptors in organocatalytic aldol reactions. Our studies have revealed effective methodologies for accessing structurally varied and enantiomerically enriched secondary and tertiary phenylthio- and phenoxy-aldols, expanding the scope and potential synthetic utility of organocatalytic direct aldol reactions.     

Organocatalytic Access to Tetrasubstituted Chiral Carbons Integrating Functional Groups

Three-dimensional organic structures containing sp³ carbons bearing four non-hydrogen substituents can provide drug-like molecules. Although such complex structures are challenging targets in synthetic organic chemistry, efficient synthetic approaches will open a new chemical space for pharmaceutical candidates. This review provides an account of our recent achievements in developing organocatalytic approaches to attractive molecular platforms based on optically active sp³ carbons integrating four different functional groups. These methodologies include asymmetric cycloetherification and cyanation of multifunctional ketones, both of which take advantage of the mild characteristics of organocatalytic activation. Enzyme-like but non-enzymatic organocatalytic systems can be used to precisely manufacture molecules containing complex chiral structures without substrate specificity problems. In addition, these catalytic systems control not only stereoselectivity but also site-selectivity and do not induce side reactions even from substrates with rich functionality.     

Recent methodologies mediated by sodium borohydride in the reduction of different classes of compounds

Reduction is a fundamental transformation in organic synthesis. Since its discovery by Brown and co‐workers, sodium borohydride is the most frequently hydride used in reduction processes. Owing to the importance of this reagent in modern organic synthesis, the aim of this review is to highlight recent methodologies (2000–2006) mediated by sodium borohydride in the reduction of different classes of compounds. Copyright © 2006 John Wiley & Sons, Ltd.