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]
The following is a selection of recent articles in this field from Angewandte Chemie, Chemistry—A European Journal, European Journal of Organic Chemistry and Advanced Synthesis & Catalysis. It is updated on a daily basis, so stay tuned!
 Special issue of Adv. Synth. Catal. 2004, 346, Nr. 9-10.
Hi, neighbor! The first organocatalyzed asymmetric transfer hydrogenation of aromatic nitro compounds was successfully developed with up to 99 % ee. The new methodology provides a direct and facile access to enantiopure cyclic nitro compounds with two contiguous stereocenters.
Wring it out: The title reaction proceeds in the presence of chiral Brønsted acid catalysts. This efficient ring-opening process features low catalyst loading, mild reaction conditions, broad functional group compatibility, high enantioselectivity, and the capability to generate chiral quaternary centers. The highly functionalized desymmetrization products are versatile chiral building blocks in organic synthesis.
A one-pot wonder: 1,2,3,4-Tetrahydroisoquinolines with a C4 stereocenter can be formed by using a one-pot multicomponent chiral-phosphoric-acid-catalyzed transformation of a mixture of oxetane-tethered benzaldehydes, amines, and the dimethyl ester derivative of the Hantzsch ester (see scheme). This transformation can be used to prepare the spermidine alkaloid, (+)-(8S,13R)-cyclocelabenzine.
Two solvents, two enantiomers: Enantiodivergent hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2PHAL)-catalyzed chlorocyclization of unsaturated carbamates, controlled solely by the choice of solvent, yields oxazolidinones in high enantioselectivity (see scheme; DCDMH=1,3-dichloro-5,5-dimethyl hydantoin). The origin of the observed enantiodivergence is traced back to a solvent-selected entropy–enthalpy balance between pro-R and pro-S pathways that dictates the course of the reaction.
Organocatalysis: A concise synthesis of L-pyrrolysine has been accomplished in six steps from simple starting materials. The facile synthetic strategy relies on an organocatalytic Michael addition, an efficient amide coupling, and a challenging method for the imine-bond construction (see scheme).
Location of the carboxylate ion: A series of biaryl DMAP catalysts with an internal carboxylate was prepared, and the catalytic activities of the derivatives were evaluated to determine the carboxylate position that most accelerated the DMAP-catalyzed acylation. The carboxylate ion proximal to the pyridine ring in a face-to-face geometry was found to act as an effective general base for the acylation reaction.
Ironing out the details: Proline and pyrrolidine derivatives (Hayashi–Jørgensen catalysts) are considered “work horses” in organocatalysis. This report describes a new effective ferrocenyl pyrrolidine catalyst able to perform well in benchmark organocatalytic reactions (see figure). The ferrocene moiety controls the conformational space and a simple alkyl group effectively covers a face of the derived enamine. This new framework can find applications in organocatalysis, and in general, in new ligand design.
Adding value: The direct vinylogous Michael addition of γ-substituted butenolides with a series of 3-aroyl acrylates and 1,2-diaroylethylenes has been demonstrated. This organocatalytic method delivers highly enantio- and diastereomerically pure γ,γ-disubstituted butenolides with adjacent quaternary and tertiary stereocenters (see scheme).
I(n)organocatalysis: Neutral multidentate halogen-bond donors (halogen-based Lewis acids) catalyze the reaction of 1-chloroisochroman with ketene silyl acetals. The organocatalytic activity is linked to the presence (and number as well as orientation) of iodine substituents. As hidden acid catalysis can be ruled out with high probability, this case constitutes strong evidence for halogen-bond based organocatalysis. TBS=tert-butyldimethylsilyl.
Synthetic methods: An asymmetric catalytic, desulfonylative Mannich reaction of α-keto imines with aldehydes, which is catalyzed by diarylprolinol silyl ether 1, was developed. It gave the Mannich product in good yield with excellent anti and enantioselectivity (see scheme).
“Fisching” for complexity: The chiral Brønsted acid (R)-STRIP catalyzes the asymmetric Fischer indolization of a range of monosubstituted cyclopentanones and cyclohexanones to give chiral fused indolines bearing a quaternary stereogenic center at the 3-position. The method has been extended to include substrates bearing a tethered nucleophile, thus allowing for enantioselective indolization/ring-closing cascades to complex propellanes featuring two vicinal quaternary stereocenters.
Amazing diazo: The title reaction leads to highly functionalized diazo compounds in good yields with excellent enantioselectivities (see scheme; Boc=tert-butoxycarbonyl). The utility of the products was demonstrated by the rapid synthesis of a number of optically pure nitrogen heterocycles. The key to this process was the use of 2,2,2-trifluoroethyl diazoacetate as a superior nucleophilic reagent.
Flustering oxindoles: An enantioselective synthesis of 3,3'-disubstituted oxindoles by conjugate addition of malonates to isatylidene-3-acetaldehydes in high yield and enantioselectivity is developed (see scheme). The synthetic utility of this reaction is demonstrated by the synthesis of three oxindole core structures and the asymmetric total synthesis of debromoflustramine E.
A good synergy: Reaction-progress kinetic analysis and nonlinear chromatography are useful tools for investigating a model aldol reaction performed in continuous-flow microreactors packed with proline-functionalized silica gel (see figure). The study was facilitated by a suitable instrumental arrangement for online monitoring; it also assessed optimal operating and feed variables.
Dipoles apart: In situ formed enamines react with diazoacetates under mild conditions to afford the corresponding polysubstituted pyrazoles in good-to-excellent yields through an inverse-electron-demand 1,3-dipolar cycloaddition process (see scheme).
Good, phosphine! An achiral phosphine is an ideal partner in the chiral-primary-amine-catalyzed enantioselective Michael reaction of aliphatic aldehydes with maleimides, thus enabling enantioselective induction in a dual organocatalytic system.
Lean on me: A soluble, “self-supported” chiral organosilica polymer (ChiOSP) with embedded imidazolidinone catalytic moieties was synthesized by a bottom-up strategy and applied as a highly efficient and recyclable organocatalyst for the asymmetric Diels–Alder reaction.
Rad transition: The combination of transition-metal-catalyzed C-H activation and a NHPI-initiated radical process is essential for the title transformation. The neutral conditions and the ideal oxidant, molecular oxygen, make this hydroxylation environmentally friendly and practical. NHPI=N-hydroxyphthalimide.
Metal-free cooperation: The cooperative combination of Eosin Y as a photoredox catalyst with organocatalytic thiourea allows for the highly diastereoselective construction of trans-1,2-cycloalkanes and heterocycles. This new efficient, cooperative organophotoredox/organocatalysis protocol presents a valuable alternative to metal-based photoredox approaches and is the first example of combining photoredox with hydrogen-bond catalysis (see scheme).
α-Amino ketones, which are versatile building blocks for organic synthesis, were obtained with the title reaction. A free hydroxy group on the NHC catalyst was found to be crucial for the reaction, and the possible competing reaction through a homoenolate or enolate was not observed with this catalyst (see scheme).
An organocatalytic asymmetric direct aldol addition reaction that involves cleavage of a carbon–carbon bond through the release of trifluoroacetate was developed. The protocol is wide in scope, generating the desired oxindoles of biological interest in nearly quantitative yields (up to 99 %) with excellent enantioselectivities (up to 98 % ee) and diastereoselectivities (up to 99:1 d.r.).
The cupreidinium salt 1 catalyzes the highly enantioselective conjugate addition of nitromethane to β-aryl-β-trifluoromethyl aryl enones (2). The biologically important chiral pyrrolines 4 and N-oxide 5, having a trifluoromethylated all-carbon quaternary chiral center, were easily synthesized from the key intermediate (R)-3 in high to excellent yields. M.S.=molecular sieves.
Crafty aminals: The in situ generation of hitherto unattainable alkynyl-substituted N-Boc-protected imines was realized by the acid-catalyzed elimination of tert-butyl carbamate from N-Boc aminals. A wide variety of N-Boc imines can be generated, which can then be utilized for subsequent carbon–carbon bond-forming reactions, such as Mannich-type reactions.
α to Z: Racemic α-chiral allyl boronates, which are readily synthesized from the respective primary allyl halides, undergo a highly efficient kinetic resolution in a face- and Z-selective allylation of aldehydes catalyzed by the chiral Brønsted acid (R)-TRIP (see scheme; Epin=tetraethylethylene glycol).
Remote control: The title reaction facilitates the synthesis of complex chiral molecules while selectively forging multiple stereocenters at distant positions, namely five and six bond lengths away from the catalyst chiral fragment (see scheme; Boc=tert-butoxycarbonyl). The potential of the strategy is demonstrated through the one-step preparation of spirocyclopentane oxindoles having four contiguous stereocenters.
Organocatalytic formal hetero-Diels–Alder reactions of enones with isatins, which gave highly enantiomerically enriched functionalized spirooxindole tetrahydropyranones via an enamine-based mechanism, were developed. The catalyst systems were identified by a screen of combinations of amines, acids, and additives. With the identified catalyst systems, various spirooxindole tetrahydropyranones were synthesized in high yields with high diastereo- and enantioselectivities (see scheme).
A special relationship: Highly nucleophilic and Lewis basic derivatives of 9-azajulolidine have been synthesized and a good correlation between Lewis basicity and nucleophilicity has been obtained. The catalytic performance of these compounds in acylation reactions of sterically hindered alcohols is found to be more complex and quantitative prediction of reaction rates requires a three-component quantitative structure–activity relationship (QSAR) model including Lewis basicity, structural, and charge distribution parameters (see figure).
Organocatalysis and fullerenes merge: The first asymmetric organocatalytic synthesis by phosphine-catalyzed [3+2] cycloaddition of allenoates onto fullerene that occurs under mild conditions giving rise to enantiomerically pure carbocyclic fullerene derivatives is reported. X-ray analysis of a cyclopentenofullerene has allowed the assignment of the absolute configuration of the new stereocenter. Furthermore, the sector rule previously used to assign the chirality in fullerenes has been corrected in the light of these new experimental findings.
A benzoylthiourea–pyrrolidine catalyst was synthesized and used in the asymmetric Michael addition of ketones to nitroalkenes. The corresponding synthetically valuable γ-nitroketones were obtained in moderate to good yields with high levels of diastereo- and enantioselectivities (up to >99:1 dr and up to >99 % ee).
The direct organocatalytic desymmetrization was demonstrated for 4-substituted cyclohexanones by treatment with a vinyl sulfone in CHCl3. The desired Michael adducts were obtained in high chemical yields and stereoselectivities (up to 97 % yield, 93 % ee). Enantiomeric products were obtained by using either a camphor-derived pyrrolidine or a cinchonidine-derived primary amine as a catalyst.
A double take: A highly enantioselective catalytic double-Michael addition reaction of substituted benzofuran-2-ones with divinyl ketones promoted by readily accessible tertiary amine–thiourea Cinchona alkaloids has been developed. A number of optically enriched spirocyclic benzofuran-2-ones were prepared in very good yields (up to 99 %), diastereoselectivities (up to 19:1 d.r.), and very good enantioselectivities (up to 92 % ee).
Cascading catalysis: 3-Isothiocyanato oxindoles act as powerful and versatile precursors for a range of structurally diverse dispirocyclic thiopyrrolidineoxindoles containing two spiro-quaternary and three contiguous stereogenic centers in quantitative yields with excellent disatereo- and enantioselectivities by only using 1 mol % amino-thiocarbamate catalyst.
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.
Come together! A selective Fe-catalysed enantioselective reduction of quinoxalines and benzoxazines with hydrogen is demonstrated. Key to success is the combination of a chiral Brønsted acid and a well-defined non-chiral Fe hydrogenation catalyst. This methodology constitutes an attractive and environmentally favourable alternative to well-established asymmetric hydrogenations by using precious-metal-based catalysts.
In straitened circumstances: In an asymmetric version of the acid-catalyzed acetalization of aldehydes, a novel member of the chiral confined Brønsted acid family significantly outperformed previously established catalysts, providing cyclic acetals with excellent enantioselectivity (see scheme; Ar=2-iPr-5-MeC6H3).
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.
A straightforward and fully stereoselective access to α-hydroxy-γ-acylaminoamides, α-oxo-γ-acylaminoamides, and chromanes is achieved by exploiting a sequence of: 1) an asymmetric organocatalytic Mannich reaction; 2) a Passerini multicomponent reaction; 3) an amine deprotection–acyl migration protocol; and 4) a final oxidation or cyclization. The whole sequence can be performed without purification of the intermediates.
Key to success: The title reaction provides facile access to enantioenriched 3,4-dihydroquinazolin-2(1H)-ones containing a quaternary stereogenic center in high yields with excellent enantioselectivities. Subsequent transformations lead to the convenient preparation of the anti-HIV drug DPC 083 and N-fused polycyclic compounds without loss of enantiomeric excess.
Light up my ring: The title reaction is catalyzed by an acridinium/phenylmalononitrile photoredox system. A variety of readily available olefins and unsaturated alcohols can be employed to furnish tetrahydrofuran adducts with complete regiocontrol and up to four contiguous stereogenic centers.
A highly enantioselective Michael–Henry acetalization reaction of glutaraldehyde and 3-aryl-2-nitroprop-2-enols was achieved by the reaction with organocatalysts. Subsequent oxidation of the adducts provided the efficient synthesis of 3-oxabicyclo[3.3.1]nonan-2-ones with four consecutive stereogenic centers. X-ray analysis of the appropriate products confirmed the structures and absolute configurations of these adducts.
Arthur Michael and Johannes Nicolaus Brønsted as best friends: By combining different α,β-unsaturated enones and azlactones with a catalytic amount of (±)-camphorsulfonic acid (CSA), the corresponding Michael adducts were obtained with high diastereoselectivities.
The synthesis of multifunctional organocatalysts, easily obtained by the condensation of (S)-proline with 2-aminopyridine, 2,6-diaminopyridine, or 2-aminoimidazole is reported. These chiral prolinamides promoted the aldol condensation between cyclohexanone and different aromatic aldehydes (up to 98 % ee), and also catalysed Diels–Alder and Michael reactions.
A one-pot synthesis of β-(4-hydroxy-2-oxo-2H-chromen-3-yl)-substituted carboxylates or amides has been developed by using a bifunctional-squaramide-catalysed asymmetric Michael addition of 4-hydroxycoumarins to β,γ-unsaturated α-oxophosphonates and the subsequent nucleophilic attack with alcohol or amine in the presence of DBU.
A structure–activity relationship with regard to formamides as organocatalysts is explored. This study highlights that the cis conformation of secondary formamides is the reactive conformation in the allylation of aldehydes with allyltrichlorosilane. Therefore, conditions that promote an increase in the cis conformation result in greater amounts of product formed.
Cyclopropenone-catalyzed conversion of aldoximes and primary amides into nitriles in a one-pot procedure is described. The reaction proceeds smoothly under mild conditions with low catalyst loading. The convenient and catalytic procedure widens the scope of the utilization of cyclopropenones in organic synthesis.
Reverse to success! A new formal [3+2] annulation reaction combining alkynyl aldehydes and β,γ-unsaturated α-ketoesters has been disclosed by using a NHC-catalyzed/Lewis acid mediated strategy. This cooperative catalysis strategy first allows the “allenolate” intermediate as a nucleophilic synthon at the β-position to react with activated electrophilic reagents by an addition reaction as the key C-C bond-forming step.
Bridging the gap: Brønsted acids catalyze an intramolecular SN2-type alkylation of alcohols with ethers by bridging a pentacoordinate transition state, thus simultaneously activating both the leaving group and nucleophile (see scheme). Density functional calculations provide detailed insight into the course of the reaction and the transition-state structure.
Pot luck: Prostaglandins regulate a broad range of physiological processes and some of their derivatives are used as effective drugs, but previously their preparation has required many steps. The title compounds were efficiently synthesized in a small number of synthetic steps by using a recently developed organocatalyst and practical, one-pot operations involving several successive reactions.
Take two: By employing two equivalents of an aldehyde in an asymmetric organocatalytic domino reaction, the nucleophilic enamine intermediate is also converted into the corresponding iminium species through oxidation with o-iodoxybenzoic acid. Thus, polyfunctionalized cyclohexene derivatives are formed from two simple starting materials in good yields and stereoselectivities (see scheme; Bn=benzyl, EWG=electron-withdrawing group).
Facilitated by axially-unfixed biaryl-based bifunctional organocatalysts, the direct Michael addition reactions of ketones and aldehydes to nitro olefins gave Michael adducts in high chemical yields (up to 99 %) and with excellent stereoselectivities (up to 99:1 dr and 96 % ee).
Chiral cyclobutane containing 1,3-amino alcohols and 1,3-diamines have been synthesized from a common chiral precursor. Regioselective transformations of these precursors led to bifunctional thioureas which have been tested as organocatalysts in preliminary experiments
Asymmetric 1,4-Michael addition catalyzed by a cinchona alkaloid proceeds by a dual activation mechanism involving a primary amine and quinuclidine moiety interacting simultaneously with electrophiles and nucleophiles through iminium catalysis. Steric interactions force the ketiminium ion intermediate to adopt a conformation more accessible to Re-face attack.
Formal attire: An enantioselective formal total synthesis of the alkaloids isorhynchophylline and rhynchophylline is described. The key steps include an organocatalyzed asymmetric Michael addition reaction and an efficient diastereoselective intramolecular iminium ion spirocyclization/lactamization cascade sequence.
An intramolecular, organocatalyzed Michael addition to obtain biologically important 2,3-disubstituted cis-2,3-dihydrobenzofurans has been developed. By using mandelic acid salts of primary aminocatalysts, derived from cinchona alkaloids, the intramolecular cyclization reaction proceeded in high yield, with moderate to good diastereoselectivity, and up to 99 % ee.
Reduce your waist: A highly efficient synthesis of α-CF3 γ-keto esters and trifluoromethylated 4,5-dihydro pyridazinones is reported based on tandem Wittig–conjugate reduction reactions, which directly utilize the Ph3PO waste from the Wittig reaction as the Lewis base catalyst to activate HSiCl3 for the chemoselective conjugate reduction.
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).
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.
In control: The computational study of the title reaction catalyzed by the planar-chiral 4-(pyrrolidino)pyridine is reported (see scheme). The resting state is a chiral Brønsted acid complex and the rate-determining step involves a chiral base. The catalyst controls the enantioselectivity through a combination of stereoelectronic effects and CH···O interactions.
Shining light on increased activity: Aryl rings that are perpendicularly oriented relative to the flavin chromophore substantially decrease aggregation relative to nonsubstituted derivatives. These 10-arylflavin derivatives are more efficient photocatalysts for the oxidation of 4-methoxybenzyl alcohol (see scheme).
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.
Cooperativity is the key for mild catalytic epoxidation: The immobilization of fluoroalcohols on dendritic polyglycerol (by “click chemistry”) provides organocatalysts that can form multiple hydrogen bonds. The epoxidation of alkenes with aqueous hydrogen peroxide proceeds efficiently in the presence of dendritic fluoroalcohol catalysts. The supported catalysts can be separated by membrane filtration and reused.
Catalyst inhibition: Clean-surface, porous, platinum nanoparticles were obtained by a surfactant-free method. Compared with a Pt/C catalyst, the porous nanostructures exhibit higher mass and specific activities. The inhibition effects of various surfactants was investigated electrochemically, and a surface-group-induced selective inhibition was discovered (see figure; CTAB=cetyltrimethylammonium bromide, SDS=sodium dodecyl sulfate, PVP=poly(vinylpyrrolidone)).
Giving directions: Optically active dihydropyrans bearing three contiguous stereogenic centers can be efficiently prepared by the title reaction. High stereo- and regiocontrol can be achieved by employing a bifunctional H-bond-directing aminocatalyst.
Drop it! A highly enantioselective catalytic cascade reaction of α-ketoacids and aldehydes is achieved using the title catalyst and water as the solvent. Fluorescence imaging shows that the catalyst is mainly distributed on the surface of emulsion droplets. Optically active isotetronic acids can be obtained with this method and the emulsion droplets are responsible for the high reactivity and enantioselectivity.
Breaking up the party: Arenes can be transformed efficiently into enantiomerically enriched, versatile ring systems by catalytic asymmetric dearomatization reactions. Known reaction types include oxidative dearomatization, dearomatization by Diels—Alder reactions, alkylative dearomatization of electron-rich arenes, transition-metal-catalyzed dearomatization reactions (see example), and cascade reaction sequences involving asymmetric dearomatization as the key step.
Top cat! Tetrahydrothiophene is an efficient organocatalyst for the synthesis of highly substituted furfuryl products from readily accessible electron-poor enynes under neutral reaction conditions. This process is applicable to a wide range of nucleophiles and enynes and can be used in a domino organocatalysis sequence.
Teamwork: Through relay catalysis by a RuII complex and a chiral phosphoric acid ((S)-BPA in the scheme) recently developed by Zhou's group, hydrogen gas can act as the terminal reductant in the catalytic asymmetric hydrogenation of heterocycles. This is a completely new concept in the area of asymmetric hydrogenation.
Breaking symmetry: Discrimination between enantiotopic hydroxyl groups in prochiral and meso-diols is a powerful methodology for the preparation of important chiral building blocks (see scheme). Organocatalysis offers a valuable alternative to the classical methods used in this transformation, which is beginning to provide promising results in cheaper and cleaner processes.
Enantioselective multicomponent reaction: In the presence of a catalytic amount of chiral BINOL-derived phosphoric acid (TRIP), the reaction of an α-isocyanoacetate 1, an aldehyde 2, and an aniline 3, followed by addition of a toluene solution of α,β-unsaturated acyl chloride 4 afforded the oxa-bridged tricycle 5 in excellent yield, diastereoselectivity, and enantioselectivity. Six chemical bonds, five stereogenic centers, and three cycles were formed in this one-pot four-component reaction.
Primary choice: In only five years, cinchona-based primary amine catalysis has almost equaled the high level of efficiency and reliability of aminocatalysis by proline-derived catalysts, offering the unique possibility of effecting reactions between sterically demanding carbonyl compounds (see picture).
Trap it: A combination of aminocatalysis with H-bonding activation is used in two new approaches to carry out formal enantioselective organocatalyzed [2+2] cycloaddition reactions. This cooperative catalysis solves the inconveniences associated with this transformation. These two new reactions will open opportunities to find reactivities involving other organocatalytic cycloadditions.
Impressive and elegant approaches to the enantioselective synthesis of spiroketals starting from achiral substrates have been described recently. These strategies based on transition-metal catalysis and organocatalysis hold great potential for further applications.
Simple, but effective: The asymmetric heterodimerization of two different ketenes (see scheme) has been developed 65 years after the first seminal studies on ketene dimerization. The key to sufficiently suppressing the competing homodimerization of the monosubstituted ketene donor (shown in blue) is its slow addition to the disubstituted acceptor (shown in red).
On/off catalysts: Control over catalysis can be gained when the catalysts can be switched between an active and a nonactive state by external stimuli. In recent examples, orthogonal signals—light, pH, or the addition of ions—are used for the switching.
A ‘golden’ handshake: While organocatalysis and gold catalysis have evolved as pivotal areas in modern organic synthesis, a novel niche area, namely, the merger of both catalytic systems in the same reaction flask, has not been put under the spotlight until the last four years. Moreover, the synthetic utility of this young emerging concept has permeated major areas of organocatalysis, and therefore, a systematic Minireview of this rapidly growing area is presented.
Asymmetric organocatalysis: Lewis base-catalyzed cyclization reactions of allenoates with electron-deficient olefins and imines have been applied in the preparation of biologically active natural products and pharmaceutically interesting substances and have emerged as powerful synthetic tools in the rapid construction of cyclic molecular complexity. In contrast to phosphine-containing Lewis bases, nitrogen-containing Lewis base amines display markedly different reaction profiles; however, this area is not well-developed.
No slow down: A microporous recyclable heterogeneous catalyst made from a 1,1'-binaphthalene-2,2'-diol (binol)-derived phosphoric acid chloride is as active as the corresponding homogeneous catalyst when using the same mass of both in different reactions. Reaction rates, yields, and enantioselectivities are comparable.
Teaming up: The title reaction has been developed to deliver the product α-alkylidene-γ-butyrolactones as single diastereomers with up to 98 % ee (see scheme; Ts=4-toluenesulfonyl). The enantioselective process is catalyzed by 1, which contains both Lewis base and Brønsted acid moieties.
Increasingly remote stereocenters are being targeted in asymmetric aminocatalysis. Application of the HOMO-raising activation concept to δ,δ-disubstituted 2,4-dienones confirms the powerful potential of the trienamine strategy. A cinchona-based primary amine catalyst enables the extension of this activation mode to a highly selective asymmetric Diels–Alder reaction of enones with electron-deficient dienophiles (see scheme; TFA: trifluoroacetic acid).
Amide nucleophiles on demand: Rationally designed pyrazoleamides function as Michael donors in urea-catalyzed asymmetric Michael reactions with excellent chemical and optical yields (see scheme). The pyrazoleamide group performs as an ester equivalent, a directing group, an activating group, and functions as a good leaving group in further transformations of the product.
Dream team: Heterogeneous inorganic semiconductors and chiral organocatalysts team up for the stereoselective photocatalytic formation of carbon–carbon bonds. However, the connection between the organic and inorganic catalysts should not be too tight: Covalent immobilization inactivates the system.
By design: New chiral bis(betaine)s, for example 1, containing two catalytically active centers have been designed. They have proven to be promising organocatalysts for the direct Mannich-type reaction of azlactones with a broad spectrum of aliphatic imines, thus affording α-tetrasubstituted α,β-diamino acid surrogates with excellent enantioselectivities.
Two can play this game: The title reaction is catalyzed by a chiral secondary amine in the presence of an achiral thiourea for the enantio- and diastereoselective synthesis of highly functionalized cyclobutanes (see scheme; TMS=trimethylsilyl). Mechanistically, two consecutive Michael reactions proceed through an unprecedented combination of an dienamine/iminium activation mode.
Technical difficulties: Enantioselective, electrophilic halogen additions to alkenes have often been described as difficult reactions. Recently, this problem has been addressed with many novel catalytic methods. In this focus review these methods will be summarized highlighting common themes and mechanistic considerations.
Merging three in one by a three-component organocatalytic asymmetric reaction of imines and α-bromoesters or ketones with α,β-unsaturated aldehydes provides optically active pyrrolo-isoquinolines—an important class of molecules in life science. The reaction proceeds with excellent enantioselectivity and a number of transformations of the products obtained demonstrated the potential of the new reaction.
This microreview describes the reaction engineering of dienamine catalysis for single-step syntheses of highly functionalized molecules such as natural products orbioactive compounds. Here we discuss the entire saga of dienamine chemistry from “preformed dienamines” to “in situ dienamines” and its evolution as unique technology in organic synthesis.
Every Jack will find his Jill: Uniting unique activation modes of N-heterocyclic carbene (NHC) catalysts with the concept of domino reactions (see picture, EWG=electron-withdrawing group), a new fast-growing field came into the spotlight in last three years. The state of the art of this field is presented and the definition of the domino reactions for the NHC catalysis is re-considered.
Organocatalysis likes them too! 1,2-dicarbonyl compounds possess high synthetic potential because of their adjacent multiple reactive centers. Recent contributions indicate that these reactive species, with an appropriate activation mode, may also act as efficient pronucleophiles in asymmetric organocatalyzed sequential or domino transformations including C-C or C-N bond formation (see scheme).
Think electrophilic: While the classical π-excessive indole is well-known for its electrophilic substitutions at position C3, recent advances in asymmetric catalysis resulted in a surge in utilizing the less discussed electrophilic properties of iminium-type intermediates (see picture) in complex annulations of indoles. Advances in AuI catalysis also allow an umpolung of the classical indole C3 reactivity.