The term organocatalysis describes the acceleration of chemical reactions through the addition of a substoichiometric quantity of an organic compound. The interest in this field has increased spectacularly in the last few years as result of both the novelty of the concept and, more importantly, the fact that the efficiency and selectivity of many organocatalytic reactions meet the standards of established organic reactions. Organocatalytic reactions are becoming powerful tools in the construction of complex molecular skeletons.[1,2]
 Special issue of Adv. Synth. Catal. 2004, 346, Nr. 9-10.
A nonmetal catalytic oxidation of alcohols with preferential oxidation of secondary alcohols by diamine is developed. 1,2-Di(1-naphthyl)-1,2-ethanediamine (NEDA) is used as catalyst to selectively oxidize secondary alcohols in the presence of TBHP as terminal oxidant. The chiral NEDA is also studied and shows promising enantioselectivity in oxidative kinetic resolution of racemic secondary alcohols with good to excellent ee values.
We like Mike: The Michael reaction of nitromethane to β,β-disubstituted α,β-unsaturated aldehydes catalyzed by diphenylprolinol silyl ether was developed to afford Michael adducts with all-carbon quaternary stereogenic centers and excellent enantioselectivity (see scheme). The E/Z isomerization of α,β-unsaturated aldehydes, the retro-Michael reaction, and the different reactivity between nitromethane and nitroethane are discussed.
A highly enantioselective, direct ε-regioselective bisvinylogous 1,6-addition reaction of β-allyl-2-cyclohexenone to β-substituted α,α-dicyanodienes is developed through trienamine catalysis of a bifunctional primary amine–thiourea compound. Excellent enantioselectivity is obtained, and more complex cyclic frameworks can be efficiently constructed in a highly stereoselectivity manner. OFBA = o-fluorobenzoic acid.
Let’s go stereo: A novel activation mode of Morita–Baylis–Hillman alcohols by the formation of a H-bonding-iminium-ion is demonstrated for the first time. Merging such a strategy with well-recognized enamine activation enables the synthesis of bicyclic α-alkylidene-ketones. The developed reaction sequence proceeds in high yields and in a highly diastereo- and enantioselective manner for a wide variety of substrates (see graphic).
Potted products: (−)-Horsfiline and (−)-coerulescine were synthesized through three one-pot operations in 33 and 46 % overall yield, respectively. Key to the success was the efficient use of a diarylprolinol silyl ether to catalyze the asymmetric Michael addition of nitromethane to a 2-oxoindoline-3-ylidene acetaldehyde (see scheme; Bn=benzyl; TMS=trimethylsilyl). This allowed the all-carbon quaternary, spirocyclic carbon stereocenter to be constructed in good yield with excellent enantioselectivity.
An unexplored class of chiral thiohydantoins can be used as efficient catalysts for iodoaminations while additives effect the regiochemistry. Also quaternary stereocenters can be easily generated with this metal-free, organocatalytic protocol.
Aromatics in 3D. Organocatalysis is now reaching beyond the control of stereogenic centers and opens new possibilities for the construction of complex polyaromatic structures with either helical or axial chirality.
An organocatalytic enantioselective Strecker reaction was developed for the synthesis of α-amino nitriles that contain a thiazole moiety by using a cinchona-based squaramide catalyst. The corresponding products were obtained in good to excellent yields (up to 99 %) with excellent enantioselectivities (up to 98 % ee) by starting from aromatic-substituted imines.
Bicyclic silyl ether derivative 1a, which is easily prepared from trans-4-L-hydroxyproline, is much more stable toward protodesilylation than Jørgensen–Hayashi's catalyst 2a. Despite their structural analogy, 1a behaves as a very efficient catalyst in iminium chemistry, but is much less active than 2a in the enamine activation mode. Here, 1a exhibits a higher or equivalent level of stereocontrol.
Formalities: Novel phosphine-catalyzed [4+1] and formal [3+2] annulations of 4,4-dicyano-2-methylenebut-3-enoates with maleimides and maleic anhydride, respectively, have been developed. Maleimides serve as C1 synthons and maleic anhydride behaved as a C3 synthon to afford the corresponding compounds. A phosphinium-containing zwitterion is the key intermediate in both annulations.
One thing led to another... Organometallic catalysis and organocatalysis are integrated in the same reaction pot, starting with an abnormal N-heterocyclic carbene based copper catalyst. This catalyst acts as an efficient catalyst for a click reaction to provide a triazole, which acts as an efficient organocatalyst for different organic transformations in a consecutive fashion in the same reaction pot (see figure).
A catalyst for kinetic resolution: Chiral 4-dimethylaminopyridine catalysts with a fluxional group to relay stereochemical information from a fixed stereogenic center to the catalytic center promoted the acylative kinetic resolution of secondary alcohols and axially chiral biaryl compounds with high enantioselectivity (see scheme). The highly modular design of the chiral DMAP catalysts enables significant variation of their structure.
The highly enantioselective construction of polycyclic spirooxindoles through 1,3-dipolar cycloaddition of cyclohexenone with azomethine ylides is achieved by employing prolinosulfonamides as the catalyst. This catalytic system essentially benefits from iminium activation and hydrogen-bonding formation induced by the prolinosulfonamides.
Concentrate on this one: The Saito photochemical reduction of m-(trifluoromethyl)benzoates has been revisited. In contrast to the conventional conditions, the developed method eliminates the formation of alkene byproducts at high concentrations. Combining direct esterification and the Saito photochemical reduction, a one-pot deoxygenation process of alcohols has also been developed. LED=light-emitting diode; TsOH=4-toluenesulfonic acid.
Sulfenates take center stage: Sulfenate anions are known as highly reactive species in the organic arena. Now they premiere as organocatalysts: A sulfoxide/sulfenate (1–10 mol %) promotes the transformation of benzyl halides into trans-stilbenes under basic conditions (up to 99 % yield). CPME=cyclopentyl methyl ether.
Ring, ring: A highly enantioselective formal [3+2] annulation of α,β-unsaturated aldehydes with azaaurones or aurone is catalyzed by an N-heterocyclic carbene (NHC) and generates spiroheterocycles. The protocol represents a unique NHC activation-based approach to access spiro-heterocyclic derivatives bearing a quaternary stereogenic center with high optical purity.
Center on C: An efficient catalytic asymmetric intermolecular C-C bond-formation process to generate acyclic all-carbon quaternary stereocenters is described. The new asymmetric nucleophilic substitution of a range of racemic tertiary alcohols proceeds with excellent bond-formation efficiency and stereocontrol. The enantioenriched indole-containing products and their derivatives are prevalent in natural products and biologically active molecules.
Benzofuroindolines: The title reaction has been realized. A wide variety of benzofuroindolines have been prepared with moderate to good yields in moderate to excellent enantioselectivities. Ts=4-toluenesulfonyl.
The first application of infrared multiphoton dissociation (IRMPD) spectroscopy to study noncovalent interactions in organocatalysis is reported. Valuable insight into the interactions associated with MacMillan-catalyst-derived α,β-unsaturated iminium ions can be derived in the absence of solvent or counterions. A preliminary structure–catalysis correlation is also disclosed.
Metal-free click: A variety of commercially available aldehydes was used in the metal-free organo-click reaction with aryl azides to obtain 1,4-disubstituted 1,2,3-triazoles. The method constitutes an alternative to previously known metal-catalyzed azide–alkyne cycloaddition reactions (AAC), such as CuAAC, RuAAC, and IrAAC. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; DMSO=dimethyl sulfoxide.
Breaking symmetry: Achiral bislactones (1) undergo desymmetrization by reaction with alcohol in the presence of chiral imidodiphosphoric acids. The monoacids 2, having an all-carbon stereogenic center, were obtained in good to excellent yields and enantioselectivities. Concise total syntheses of (−)-rhazinilam and (−)-leucomidine B were subsequently developed using 2 as a common starting material.
Fully functionalized 1,2,3-triazoles were obtained by a metal-free three-component reaction. Simple and readily available building blocks were employed in this organocatalytic transformation, which gave the desired products in good yield and with high regioselectivity. Most of the synthesized triazoles were previously inaccessible.
This review provides an overview of recent advances in catalytic enantioselective protonation of preformed enol derivatives and catalytically generated enolates or equivalents through various cascade reaction sequences giving access to a large range of enantioenriched compounds containing tertiary stereocentres.
Out with the old: The design and synthesis of new chiral phosphines, as well as their application in catalytic asymmetric reactions, have recently drawn a lot of attention. This review summarizes the advances in the field of enantioselective phosphine organocatalysis within the last couple of years.
Chirality on the go: Step-growth polymerization between prochiral bis-anhydrides and diols is triggered by a cinchona alkaloid based organocatalyst, affording new chiral polyesters in good yields with high enantioselectivities (see scheme). The enantioselectivity of the asymmetric polymerization was measured by chiral HPLC analysis of chiral bis-lactones obtained by a controlled depolymerization of the polyesters.
Rational optimization: Kinetic resolution of oxazinones has been studied as a model reaction to develop a sound strategy to achieve the best results with a rational approach rather than by trial-and-error (see scheme). With this strategy, chiral oxazinones can be resolved with ee values up to 99.6 % and ester products with ee values up to 90 % (selectivity factor up to S=98).
Relay tactics: The stereocontrolled assembly of the potent antibiotic (−)-platensimycin in 21 steps and 3.8 % yield from eugenol is described (see scheme; TBAF: tetrabutylammonium fluoride; Ts: toluene-4-sulfonyl). Highlights are 1) a rapid oxidative esterification of an acyl aromatic, 2) a reliable dialkylation protocol to form platensic acid, 3) a π-facial conjugate reduction of a dienone, 4) a TBAF-promoted alkylative dearomatization of a free phenol, and 5) a Friedel–Crafts closure of a free lactol.
First class construction: The first catalytic asymmetric construction of a new class of bispirooxindole scaffold containing a tetrahydro-β-carboline moiety has been established through chiral phosphoric acid catalyzed three-component cascade Michael/Pictet–Spengler reactions of isatin-derived 3-indolylmethanols, isatins, and an amino ester, which afforded structurally complex and diverse bispirooxindoles with two stereogenic centers in excellent stereoselectivities (see scheme; BH*=chiral Brønsted acid, 1,1,2,2-TCE=1,1,2,2-tetrachloroethane; all >95:5 d.r., up to 98:2 e.r.).
Now it's bismuth time! The asymmetric intermolecular α-alkylation of aldehydes with α-bromocarbonyl compounds can be achieved under visible-light irradiation by combining the second-generation MacMillan catalyst and an inexpensive, nontoxic, and commercially available Bi2O3 powder. This reaction also proceeded with high efficiency when the reaction vial was exposed to the morning sunlight in Tarragona, Spain.
Two birds with one stone: The pyrrolidine–camphorsulfonamide-based catalyst 1 a catalyzes the enantioselective conjugate addition of nitroalkanes to α,β-unsaturated aldehydes in the presence of 5 equivalents of water in iPrOH to give the corresponding chiral Michael adducts in good yields and high enantioselectivities (up to 99 % ee) with catalyst loading as low as 1 mol %.
Deracemization does the trick: The catalytic chiral resolution of tropos biarylphosphineoxides is combined with their high stereoinduction in asymmetric double-aldol-additions. The transient diastereomeric interaction of the modified biarylphosphineoxide was maximized by molecular design, which leads to an unusually high deracemization during HPLC.
Off the beaten path: Studies of an unusual inversion of the sense of enantioselectivity for the selenylation of aldehydes catalyzed by a diphenylprolinol ether catalyst provides support for a mechanistic concept beyond the simple steric model developed for enamine catalysis in these systems. A general role for downstream intermediates in selectivity outcomes in organocatalysis is discussed. TMS=trimethylsilyl.
A short circuit: An asymmetric Torgov cyclization, catalyzed by a novel, highly Brønsted acidic dinitro-substituted disulfonimide, is described. The reaction delivers the Torgov diene and various analogues with excellent yields and enantioselectivity. The method was applied in a very short synthesis of (+)-estrone.
A doubly positive development: N,N'-Disubstituted cinchona alkaloids were found to be highly efficient phase-transfer catalysts for the assembly of stereogenic quaternary centers. In comparison to traditional cinchona-alkaloid phase-transfer catalysts they afforded substantial improvements in enantioselectivity and reactivity in intramolecular spirocyclization reactions at catalyst loadings as low as 0.3 mol % under mild conditions (see example).
The enantioselective direct Mannich-type reaction of ketimines with α-isocyanoacetates has been developed. Excellent yields and enantioselectivities were observed for the reaction of various ketimines and α-isocyanoacetates using cinchona alkaloid/Cu(OTf)2 and a base. Both enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts. This process offers an efficient route for the synthesis of α,β-diamino acids.
Taking steps: A stepwise organocatalytic Michael addition/aldol sequence is described involving secondary-amine-catalyzed regioselective addition of azidoacetone to cinnamaldehyde derivatives followed by intramolecular aldolization. Application of this route to aminocyclitols is demonstrated by a short, asymmetric synthesis of the anticancer natural product (+)-trans-dihydrolycoricidine.
The novel chiral iodoarene can be used as an efficient catalyst for the synthesis of diamines. Quaternary stereocenters can be easily generated with this metal-free, organocatalytic protocol (Cbz=benzyloxycarbonyl).
Be there or be square: An efficient approach for the enantioselective synthesis of kojic acid derivatives is developed. Under the catalysis of a chiral bifunctional squaramide incorporated into the (1R,2R)-1,2-diphenylethane-1,2-diamine scaffold, the Michael addition of allomaltol to a great number of β,γ-unsaturated α-ketoesters proceeds smoothly.
Biologically important and synthetically challenging spirocyclopentaneoxindole derivatives containing four consecutive stereocenters, including one spiro quaternary center, are constructed with excellent enantio- and diastereomeric purities by an organocatalytic iminium–enamine cascade sequence between 3-substituted bifunctional oxindoles and α,β-unsaturated aldehydes under mild conditions.
An organocascade reaction enabling the transformation of enals into α-fluoro- and α,α-difluoro-β-amino aldehydes in a single flask is described. This organocascade reaction combines carbon–nitrogen and carbon–fluorine bond-forming reactions. It is thus a new approach to fluorinated β-amino acid precursors, and generates products not accessible by existing one-pot methods.
A great couple: Fullerene and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) moieties combined in molecular assemblies give rise to excellent catalysts for the oxidation of a wide range of alcohols. These hybrids are easily recycled and maintain their activity after seven cycles.
Key structural parameters involved in the anion-binding process and the catalytic activity of the new family of C-H-bond-based, anion-binding bis-triazole catalysts BisTri were evaluated. These studies enabled the in silico design and identification of a new efficient BisTri catalyst (see scheme; R1=3,5-(CF3)2C6H3, R2=CN) for the alkylation reaction with an N-trityl pyridium salt as ionic electrophile.
Organocatalysis with MOFs: A practical synthesis route to chiral metal–organic frameworks is proposed that relies on an acid–base interaction between an acid linker and a chiral primary amino acid derived diamine organocatalyst. High ee values for the aldol condensation of linear ketones and aromatic aldehydes are reported.
Chiral ionic liquids derived from natural amino acids are shown to be efficient solvents or additives for direct asymmetric aldol reactions. A match/mismatch effect between the configuration of the chiral ionic liquid and that of proline has been observed, with a higher enantioselectivity obtained for the (S)-proline/CIL 2 complex.
Breaking the mirror: In an asymmetric synthesis of tricyclic compounds containing a heterocyclic ring by the desymmetrization of cyclohexadienones, a large variety of substituents at different positions of the cyclohexadienone were tolerated, and the size of the heterocyclic ring could be varied. DFT calculations showed that the reaction proceeds through an asynchronous [4+2] cycloaddition (see scheme).
You can have it both ways! A stereodivergent asymmetric Lewis base catalyzed Michael addition/lactonization of enone acids into substituted dihydrobenzofuran and tetrahydrofuran derivatives is reported, giving products with high d.r. and ee (see scheme).
The natural strategy: Carboxylic acids were activated with chiral phosphoric acid catalysts and the mechanism of epoxide hydrolase served as a model for the asymmetric hydrolysis of meso-epoxides. This method was coupled with the Prilezhaev oxidation and the subsequent hydrolysis of the ester moiety to provide the first highly enantioselective anti-dihydroxylation of simple olefins.
Stereoisomer made to order: Diastereodivergence is realized through controlling the stereoselectivity of the individual steps of a tandem Michael/Michael reaction. Up to 8 of the 16 possible stereoisomers have been successfully obtained in high enantio- and diastereoselectivities using modularly designed organocatalysts for the tandem reaction and an ensuing epimerization. QDT=quinidine thiourea, QNT=quinine thiourea.
Pick your type: In the past several decades, highly useful epoxidation protocols have been developed with a variety of activation modes using a wide range of asymmetric organocatalysts. This review documents the rapid and expansive development in this area, thus providing a clear overview of the various catalyst types available for asymmetric organocatalytic epoxidations, as well as their mechanisms and applications.
Re-evaluating PDA: Polydopamine (PDA) is easily available by oxidation of dopamine and is widely used for persistent coatings of various materials. It is hitherto considered to be inert in many interesting biomedical and other applications. However, results revealed here show that PDA is not an innocent polymer and can act as an organocatalyst in direct aldol reactions under mild conditions (see scheme).
Asymmetric 1,2-addition reactions of α-ketoesters to isatins and imines by using acid–base bifunctional 6'-OH cinchona alkaloid catalysts, followed by cyclization and enolization of the resulting adduct, gives spiroisotetronic acids and 5-1H-pyrrol-2-ones, respectively, in excellent optical purities (see scheme; Tr=trityl, Ts=p-toluenesulfonyl). FT-IR analysis suggests that a hydrogen-bonding interaction between the 6'-OH of the cinchona catalyst and an isatin carbonyl group might be crucial for activity and stereocontrol.
The power of two: A highly enantio- and regioselective aminocatalytic and Lewis acid catalyzed α-hydroxyamination of β-keto esters and 1,3-diketones with N-hydroxycarbamates is realized in “one-pot” under aerobic conditions. The powerful dual catalysis strategy opens opportunities for developing new efficient organic transformations. Cbz=Benzyloxycarbonyl, Boc=tert-butoxycarbonyl.
Since initial reports of organocatalysis through hydrogen bonding interactions, a number of strategies have emerged to allow access to enhanced hydrogen-bond donor (HBD) organocatalysts. These strategies range from augmentation of existing HBDs to the design and synthesis of new HBD catalysts. The effects of recent dual HBD designs on catalyst performance are described.
Get straight to the point! The elusive and direct organocatalytic β-functionalization of saturated carbonyl compounds has been tackled by oxidative enamine catalysis, oxidative NHC catalysis and merging of photoredox catalysis with organocatalysis. This new activation mode expanded the horizons of chemical synthesis and offers new insight for organic transformations and complex molecule synthesis.
This review describes an approach to enantiopure products based on the enantioselective generation, through biocatalysis or organocatalysis, of chiral substrates for a multicomponent reaction (MCR). If the chiral substrates are able to control the newly formed stereogenic centers, this strategy allows fast and diversity-oriented entry to complex chiral substrates.
The Perfect Storm! Water facilitates catalyst turnover in enamine organocatalysis, and it is generated during enamine formation. A synergy between Lewis acids and organocatalysts allows for the development of new, selective, and innovative processes, but water-compatible Lewis acids must be employed that are capable of surviving and maintaining activity in the presence of water.
You say goodbye, I say halo: Derivatives of cinchona alkaloids are an important class of organocatalysts. Their applications in asymmetric halofunctionalization of alkenes and alkynes are summarized in this Focus Review. A wide range of nucleophiles, halogenation reagents, and substituted alkenes, alkynes, or enynes can participate in these reactions to afford diverse chiral building blocks.
BINSA, done that: The Brønsted acidity of catalysts is considered to be associated with their catalytic activity. Therefore, chiral 1,1'-binaphthyl-2,2-disulfonic acid (BINSA) has recently received much attention as a strong chiral Brønsted acid catalyst. This Focus Review summarizes the latest achievements in chiral BINSA chemistry from the perspective of their synthesis and their catalytic use in asymmetric organocatalysis.
Less is more: Metal-free systems, including frustrated Lewis pairs (FLPs), have been shown to bind CO2. By reducing the Lewis acidity and basicity of the ambiphilic system, it is possible to generate active catalysts for the deoxygenative hydroboration of carbon dioxide to methanol derivatives with conversion rates comparable to those of transition-metal-based catalysts (see scheme).
Esters—what else! A new strategy in NHC organocatalysis allows the α-, β- and γ-activation of saturated and unsaturated esters. The resulting acyl azolium intermediates efficiently participate in domino reactions with suitable substrates to generate synthetically valuable carbo- and heterocycles with very good diastereo- and excellent enantioselectivities.
All about iodine: Chiral hypervalent iodine chemistry has been steadily increasing in importance in recent years. This Minieview catalogues enantioselective transformations triggered by chiral hypervalent iodine(III/V) reagents, in stoichiometric or catalytic quantities, highlighting the different reactivities in terms of yield and enantioselectivity. Moreover, the synthesis of the most remarkable and successful catalysts has been illustrated in detail.
Control freaks: Chiral amine catalysts prove to be highly proficient mediators in the asymmetric, polyconjugate addition of C-, N-, and S-based nucleophiles to acyclic dienals and cyclic dienones. For high 1,6-selectivities, the stereo spatial matching of the molecular orbitals and ionic charges of the reacting species are key. But can we widen the scope and how far can we go with remote, iminium-stereocontrol?
Smells like team spirit: N-acylimium ions are important reactive intermediates for the enantioselective synthesis of nitrogen-containing compounds. This review summarizes the enantioselective reactions of N-acyliminium ions with two different chiral organocatalysts, thioureas (A) and BINOL-derived phosphoric acid derivatives (B).
Second to none: Secondary amines are well-known enamine and iminium catalysts that can also be used as Lewis bases for the activation of electron-deficient olefins. In this Focus Review, a series of systematic studies on activation of nitroolefins with secondary amines as Lewis bases that give different multicomponent condensation products are described. Asymmetric syntheses of heterocycles based on this strategy are also presented.
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 of the last three years. It is intended to outline the most important current findings focused on especially new synthetic methodologies.
From pine resin to catalyst: The easily available rosin diterpene abietic acid has been transformed into a unique class of bifunctional thiourea catalysts that can also incorporate further substituents, thereby enabling either Lewis base or enamine activation modes. Their application in a wide range of stereoselective transformations has revealed the positive effect of this chiral and rigid skeleton on the catalytic performance of these hybrid thioureas.
Being the alpha: Despite the synthetic utility of chiral alkyl chlorides, catalytic methods for achieving enantioselective chlorination were only developed a decade ago. This Focus Review discusses the catalytic enantioselective α-chlorination of carbonyl compounds, as well as some stereospecific substitution reactions of the resulting optically active chlorides.
Phosphines and hydrogen bonding are good collaborators! Air-stable α-amino acids or dipeptide derived chiral phosphines bearing hydrogen-bond-donating and silicon-based bulky groups are powerful and versatile catalysts for a range of enantioselective processes, including [3+2] and [4+2] cycloadditions, allylic alkylations, Morita–Baylis–Hillman reactions, and Michael addition reactions. They represent a class of novel, economical, and practical chiral phosphine-based organocatalysts.
Valiant catalysis: Hoveyda et al. have developed a set of catalysts derived from valine for enantioselective syntheses. Reagents are inexpensive, allyl additions are scalable, harsh conditions are avoided, and reactions can be performed with 0.25 mol % catalyst in under 6 h at room temperature. The efficiency, economy, selectivity, and simplicity of the transformations and the range of boron reagents look to have sustained impact on future progress in amine and alcohol syntheses.
When one catalyst meets another: Since chiral Brønsted acids catalysts were discovered more than a decade ago, they have become prevalent in organocatalysis. Researchers have recently used cooperative catalysis to improve existing transformations and discover new reactions. This Focus Review summarizes the achievements made in the field of asymmetric cascade/multicomponent reactions with the help of cooperative catalysis from chiral Brønsted acids.
The inexpensive and readily available ex-chiral-pool building block (–)-isosteviol provides unique geometric features such as the rigid and concave arrangement of its functional groups. Consequently, this valuable architecture has found significant applications in various fields of organic chemistry.
Strategic move: Isatin as a core structure has inspired the development of useful catalytic strategies to give access to interesting molecular architectures with biological activity.
Ready, amine, fire! Amine catalysis is a useful and well-studied method for constructing a wide variety of chiral scaffolds in asymmetric synthesis. However, organocatalysis with amines that is not centered on asymmetric transformations is also developing at a rapid rate. In this Focus Review, reports on amine catalyzed non-asymmetric transformations are examined.
From all natural to bioactive: This review shows that organocatalytic methods based on the use of nucleophilic phosphorus catalysts have been successfully applied as key steps in the formal or total synthesis of complex natural products. These methods also afford suitable tools for the constitution of either focused or diversity-oriented-synthesis inspired libraries of small molecules for biological screening.
The heat is on: A new [3+2] cycloaddition/cycloreversion strategy allows for catalytic and thermally allowed carbonyl–olefin metathesis (see scheme). This strategy opens opportunities for new developments in the field of carbonyl–olefin metathesis, which traditionally relied on stoichiometric amounts of transition-metal reagents or photochemical promotion.
Work in process: The variations in the synthetic applications of phase-transfer reactions between 2006 and the middle of 2012 have been summarized to show the recent progress made in this field. The reactions have been applied to the synthesis of biologically active natural products and the large-scale preparation of drugs. The conceptually new catalyst design, reaction system, and reaction mode are also described.
Cascading down: Reaction of an aldehyde with an NHC provides the corresponding Breslow intermediate A, which can be readily oxidized with various organic and inorganic oxidants to give the acylazolium ion B (see scheme). Intermediate B can react with various nucleophiles either at the 2 or 4-position. With enals as starting aldehydes, elegant cascade processes have been developed using oxidative carbene catalysis.
Strap in with organocatalysis: Organocatalysis can often give rise to unprecedented selectivities by encapsulation of the catalytic active site in an analogous manner as enzymes. Catalyst encapsulation can be considered as a powerful strategy for achieving unique transformations in a very efficient way.
Two views: The mechanism of the conjugate addition of linear aldehydes to nitro olefins has been investigated by two research groups. In spite of extensive experimental data, important questions remain unanswered (see scheme; TMS=trimethylsilyl, En=enamine).
What to do with vitamin B2: Flavins are ubiquitous cofactors for enzymes and have been explored extensively as organocatalysts. Recent developments in the synthesis and use of flavin derivatives are discussed in this Minireview.
Taking the Michael: Recent progress in asymmetric organocatalysis has led to the development of several asymmetric transformations that employ various substrates. Among these substrates, maleimides have emerged as excellent Michael acceptors, dienophiles, and dipolarophiles. In this Focus Review we highlight the advances in the asymmetric synthesis of succinimide derivatives.
Opposites attract: This simple realization is the basis for asymmetric counteranion-directed catalysis (ACDC). All reactions proceeding via cationic intermediates are accompanied by a counteranion. Inducing high enantioselectivities in these reactions merely by ion pairing with an enantiomerically pure counteranion has been achieved for the first time during recent years.