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.
The expedient enantioselective synthesis of several natural products from a common precursor, (+)-3,4-dihydro-γ-ionone, is described. The production of this natural compound in multigram scale from the extract Bellardia trixago is the basis of this approach.
Highly functionalized succinimides: The NHC-catalyzed [3+2] cycloaddition of α-ketoamides with enals via an azolium enolate pathway stereoselectively leads to functionalized succinimides, which are characteristic structural features of various natural products and drugs (see scheme). By simply changing the NHC catalyst, the isomeric γ-lactones are obtained via an azolium homoenolate route.
In control: A readily available chiral Brønsted acid was identified as an efficient catalyst for intramolecular Povarov reactions. Polycyclic amines containing three contiguous stereogenic centers were obtained with excellent stereocontrol in a single step from secondary anilines and aldehydes possessing a pendent dienophile. These transformations constitute the first examples of catalytic enantioselective intramolecular aza-Diels–Alder reactions.
BRD7 and BRD9 are bromodomain proteins and part of some chromatin-remodeling complexes. A fragment lead was rapidly optimized through structure-based design and exploitation of a stereoselective nitro-Mannich/lactamization cascade process to give the first potent and selective BRD7/9 inhibitor, LP99. Treatment with LP99 led to displacement of BRD7 and BRD9 from chromatin and down-regulation of the pro-inflammatory cytokine IL-6.
Short and sweet: Very short total syntheses of ellagitannins were achieved through sequential and regioselective functionalization of the hydroxy groups of unprotected glucose.
In the presence of cinchona-thiourea catalyst C1, the developed organocascade three-component reaction of isatins, malononitrile, and 2-hydroxynaphthalene-1,4-diones readily proceeded to furnish desired chiral pyranonaphthoquinone-fused spirooxindoles in excellent chemical yields and high enantioselectivities (up to 99 % yield and 97 % ee).
Bench-top CuI has been used as a catalyst to obtain a series of functionalised indene, dihydronaphthalene and cyclohexenone derivatives. Notably, the substrates were combined at a 1:1 ratio and no trace of fumarate or maleate side products were observed in spite of using diazo substrate and copper catalyst.
Gentle persuasion: A quinine-derived thiourea organocatalyst was found to promote the asymmetric addition of naphthols and activated phenols to ketimines derived from isatins (see scheme; Boc=tert-butoxycarbonyl). The reaction under mild conditions afforded chiral 3-amino-2-oxindoles containing a quaternary stereocenter in high yields (up to 99 %) with excellent enantioselectivity (up to 99 % ee).
A new series of squaramide-based organocatalysts were developed and successfully applied for the asymmetric allylation reaction of isatins with allyltributltin. The present catalytic system was highly efficient for the allylation of N-protected isatins giving very good yields (75–95 %) and excellent enantioselectivities (62–98 %) of the allylation products.
100 % Organic: A highly enantioselective N-heterocyclic carbene (NHC)-catalyzed intramolecular hydroacylation of aromatic and, more interestingly, aliphatic aldehydes with unactivated olefins offers access to a range of cyclic α-chiral ketones bearing quaternary centers. The reaction was found to be highly robust and proceeds with excellent yield in the presence of a diverse range of functional groups.
Helical P: Specially designed phosphahelicenes demonstrate high efficiency and enantioselectivity in organocatalytic cyclizations. These new helically chiral phosphines complement and outperform previous nucleophilic catalysts used in this field. Ipc*=(1R,2R,3R,5S)-2,6,6-trimethyl-bicyclo[3.1.1]-heptan-3-yl.
A little of bis, a little of that: A number of new chiral bisphosphoric acids were developed starting from (R)-BINOL. Rigid cyclic phosphamide and phosphonate components were converted into bisphosphoric acids, in contrast to the traditional BINOL-based phosphoric acids with only phosphonate motifs.
Three in a row: The title reaction of ortho-quinone methides, generated in situ from ortho-hydroxybenzyl alcohols, has been established. By selecting 3-methyl-2-vinylindoles as a class of competent dienophiles, this approach provides an efficient strategy to construct enantioenriched chroman frameworks with three adjacent stereogenic centers in high yields and excellent stereoselectivities. CPA=chiral phosphoric acid.
Spiraling out of control: A highly efficient organocatalytic enantioselective [3+2] cyclization, which uses trifluoromethylated 2-butenedioic acid diesters for the formation of enantioenriched spiroxindoles that possess a CF3-containing quaternary carbon stereocenter, is explored. This procedure provides an enantiodivergent approach to the synthesis of spirooxindoles at different temperatures. Ts=p-Toluenesulfonyl, Bn=benzyl.
Harmonious cooperation: An N-heterocyclic carbene (NHC) and (in situ generated) Brønsted acid cooperatively catalyze the aminomethylation of α,β-unsaturated aldehydes. This cooperative catalytic reaction provides a redox neutral strategy for quick access to β2-amino esters in an enantioselective manner.
A revelation: Enamine activation of α-branched β-ketocarbonyl compounds is actually possible, very efficient, and highly enantioselective with a bifunctional primary amine/tertiary ammonium triflate salt catalyst. This covalent HOMO activation mode competes with existing strategies for the enantioselective activation of β-ketocarbonyls and their analogues. E=Electrophile; X=CH2, O, NR; OTf=Triflate.
Stay tuned: A redox tuning strategy has been developed for asymmetric aminocatalysis using a chiral ferrocenophane. Under redox control, the catalyst catalyzes the asymmetric aldol reaction at room temperature with excellent yield and good stereoselectivity. Moreover, the catalyst is recyclable.
Challenging substrates: The generation in situ of ortho-quinone methides (o-QMs) through sulfinic acid elimination was combined for the first time with an organocatalytic process (see scheme). This combination allowed the engagement of sensitive and unstable o-QMs in asymmetric reactions with active methylene compounds, under the promotion of bifunctional catalysts, giving access to 2,3-dihydrocoumarins, 4H-chromenes, and xanthen-1-ones.
Enantioenriched derivatives of 2-azabicyclo[3.3.1]nonane, a key motif common to many alkaloids, are obtained by a catalytic asymmetric desymmetrization reaction with a cyclohexanediamine-derived primary-amine organocatalyst. A range of prochiral cyclohexanone derivatives with an α,β-unsaturated ester moiety linked to the 4-position afford the bicyclic products as single diastereoisomers in high enantioselectivity and good yields.
Phased out: A squaramide organocatalyst mediates the asymmetric synthesis of α-aryl- and α-alkyl-substituted benzyl mercaptans through the thiolation of in situ generated ortho-quinone methides at a water–oil interface. The reactions exhibit wide substrate scope and excellent enantioselectivity because of the spatial separation of the inorganic base in the aqueous phase from the chiral components in the organic phase.
Shifting economy: The catalytic enantioselective arylation of 3-indolylmethanols has been established in an atom-economic fashion, which assembles isatin-derived 3-indolylmethanols and 3-methylindoles into biologically important 3,3'-bis(indolyl)oxindoles bearing a quaternary stereogenic center in high yields and good enantioselectivities [≈99 % yield and 91:9 enantiomeric ratio (er)]. CPA=Chiral phosphoric acid.
Steady as she goes: Stable indolyl carbenium salts have been employed in the direct alkylation of aldehydes. Excellent enantiomeric excesses and good diastereomeric ratios were obtained using a number of aryl or heteroaryl(3-indolyl)carbenium ions as the highly stable o-benzenedisulfonimide salts and with the reaction promoted by the Hayashi–Jørgensen catalyst.
This microreview outlines recent advances in achiral to asymmetric organocatalytic reactions based on chitosan, a biodegradable chiral polysaccharide obtained from marine wastes, in a sustainable chemistry context. The use of chitosan and its derivatives either as insoluble organocatalysts or as supports for organocatalysts is reviewed, together with shaping and reusability issues.
Densely substituted enantiopure proline esters obtained through [3+2] cycloadditions catalyze aldol reactions. These synthetic organocatalysts produce different enantiomeric aldol adducts depending on the stereochemical dispositions of the substituents at distal positions with respect to the catalytic site. Design criteria are proposed for this kind of organocatalysts.
A straightforward method for the asymmetric fluorination of 4-substituted isoxazolinones catalyzed by a bis-cinchona alkaloid catalyst was developed. A series of 4-fluoroisoxazolinone derivatives with a fluorine-containing quaternary stereocenter were obtained in good to high yields with good enantioselectivities (up to 91 % yield, 85 % ee).
The intermolecular ketone–aldehyde and aldehyde–aldehyde aldol reactions and the Hajos–Parrish–Eder–Sauer–Wiechert versions with the employment of chiral L-prolinamides containing the (R,R)- and (S,S)-trans-cyclohexane-1,2-diamine scaffold and a 2-pyrimidinyl unit are successfully performed under solvent-free conditions; WMK = Wieland–Miescher ketone.
Top cat: An in situ N-heterocyclic carbene (NHC)-catalyzed activation strategy to β-functionalize saturated carboxylic acid was developed (see scheme). This asymmetric formal [3+2] annulation delivered spirocyclic oxindolo-γ-butyrolactones from saturated carboxylic acid and isatin in good yields with high to excellent enantioselectivities. The availability of the starting materials, direct installation of functional units at unreactive carbon atom and the convergent assembly make this protocol attractive for organic synthesis.
Planar chiral azolium salts that incorporate a sterically demanding iron sandwich complex are synthesized. These new N-heterocyclic carbenes can be employed both as organocatalysts and as ligands for transition-metal catalysis, which demonstrates their unprecedented versatility and potential broad utility in asymmetric catalysis.
All in one pot: The organocatalytic oxidation of tertiary allylic amines followed by a Meisenheimer rearrangement leads to protected hydroxylamines (see scheme).
In recent years, interest in organocatalytic intermediates has intensified. Through their study, various mechanistic anomalies have been illuminated, new reaction manifolds have been identified, and the intermediates themselves have proven to be valuable platforms for the study of many noncovalent interactions more commonly found in complex biomolecules. Cat=catalyst, P=product, S=substrate.
Light it up! Synthetic and mechanistic aspects of a novel protocol for the defunctionalization of aniline derivatives are presented. Arenediazonium salts undergo facile reductive defunctionalization in the presence of eosin B as cheap organic catalyst under visible light. DMF and deuterated DMF serve as stoichiometric hydride and deuteride donors to give benzenes and deuterobenzenes, respectively (see scheme). Both photoredox catalysis and radical chain propagation mechanisms are operating.
Masked crusaders: This Concept article summarizes strategies regarding the use of masked unsaturated esters/amides in asymmetric organocatalysis (see scheme). Useful substrates are categorized by their inherent templates which enable interactions with organocatalysts and define their transformation back to the parent carboxylates. Examples showing the entire process (from substrates-to-functionalized esters/amides) are given.
Charming fluorine: This Essay examines the recent surge in late-stage fluorination reactions and outlines challenges that need to be overcome to increase the impact of modern fluorination methods on the synthesis of complex organofluorine compounds. It is outlined how an improved understanding of the bonding interactions of fluoride could lead to a new class of mild fluorinating reagents and a range of functional-group-tolerant reactions.
Cyclobutenones are explored as a new type of chiral 1,4-dipole four-carbon synthons, which readily undergo asymmetric intermolecular 1,4-dipolar spiroannulations with isatylidenemalononitrile in the presence of an amino acid derived chiral phosphine catalyst (TP7) to furnish enantioenriched 3-spirocyclohexenone 2-oxindoles in good yields with up to 87 % ee.
Lose to win: The organocatalytic enantioselective decarboxylative Mannich reaction of malonic acid half thioesters (MAHTs) with cyclic ketimines by using N-heteroarenesulfonyl cinchona alkaloid amides afforded products with high enantioselectivity (see scheme). Both enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts. The reaction proceeds through a nucleophilic addition of the MAHTs to the ketimines prior to decarboxylation.
By using all its powers of persuasion, a bifunctional secondary-amine/squaramide catalyst encouraged 1-acetoxyisochroman-4-ones to react as benzopyrylium ylides with α,β-unsaturated aldehydes in efficient [5+2] cycloaddition reactions with high diastereo- and enantioselectivity. The transformation proceeds by dienamine activation and involves β,γ-functionalization of the enal (see scheme).
Abra‘capraza’: Caprazamycin A has significant antibacterial activity against Mycobacterium tuberculosis (TB). The first total synthesis is herein reported and features the scalable preparation of the syn-β-hydroxy amino acid with a thiourea-catalyzed diastereoselective aldol reaction, construction of a diazepanone with an unstable fatty-acid side chain, and global deprotection by hydrogenation.
Traceless stereocontrol: The nucleophilic addition of ethyl nitroacetate to isatin-derived ketimines, followed by the removal of the nitro group, opens an efficient route to oxindole key intermediates of pyrroloindoline alkaloids and related pharmaceuticals of high enantiomeric purity. The Mannich or aza-Henry-type reaction is catalyzed by a dihydroquinine-based Brønsted base (see scheme). The easily scalable protocol is demonstrated by a formal synthesis of the bioactive lead compound AG-041R.
Asymmetric intramolecular aza-Michael reactions with cinchoninium phase-transfer organocatalysts are used for the synthesis of optically active isoindolinones. The resulting compounds are useful intermediates for the synthesis and development of benzodiazepine-receptor agonists.
Cyclopropane-containing amino acids can be synthesised through an organocatalytic asymmetric Michael reaction. The cyclopropane ring, as well as two different nitrogen-containing functional groups (tert-butoxycarbonylamino and nitro) are introduced in one step. The products were isolated in good yields with moderate to excellent enantio- and diastereoselectivities.
A powerful divergent cascade strategy has been developed for the rapid construction of five distinct diverse enantioenriched pyrazole-derived scaffolds using only six simple building blocks. Furthermore, screening of 10 compounds exemplifying the five synthesized scaffolds revealed potent anticancer lead compounds.
New photochemical life of ArCHO: The recent breakthrough discovery by Melchiorre and co-workers in the use of aromatic aldehydes as energy-transfer photoorganocatalysts in atom-transfer radical addition reactions is discussed. ISC=Intersystem crossing; X=I, Br, Cl.
A new partner in the metathesis dance: Trityl tetrafluoroborate (TrBF4) catalyzes the direct oxo-metathesis of aldehydes and unactivated olefins to give β-alkylstyrene derivatives and acetone through an unusual metal-free formal [2+2]/retro [2+2] reaction sequence.
An effective asymmetric organocatalytic synthesis of polysubstituted cyclohexenes from 1-hydroxy-1,4-dien-3-ones and 2-alkylidenemalononitriles by a domino double-Michael reaction sequence using quinine as catalyst has been achieved. The products were obtained in moderate-to-good yields (up to 96 %) and enantioselectivities (up to 92 % ee).
Confirming the conformation: The synthesis, characterization, and evaluation of a new highly efficient imidazolidinone organocatalyst is achieved. The catalyst is investigated in enantioselective Diels–Alder reactions, and a conformation study confirms the approach on the less hindered Si face. [mPy][OTf]=Methylpyridinium triflate.
Self-assembled organocatalysts: A temperature-triggered conformational change in supramolecular polymers with pendant L-proline (Pro) units results in highly active and selective organocatalysts for aldol reactions in water (see scheme; BTA=benzene-1,3,5-tricarboxamide).
Modern continuous flow techniques are reshaping the chemical landscape by providing tools for more efficient chemical processes. Enantioselective catalysis can also benefit from these advantages, and the combination of these two fields is a perfect match in terms of sustainable chemistry. Here we focus on the use of immobilized organocatalysts to promote enantioselective processes in flow.
Selective oxidation with electricity only: Electrodes functionalized with the organocatalyst 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) hold great potential for the development of the entirely waste-free industrial synthesis of valuable carbonyl compounds in the fine chemical and pharmaceutical industries.
This review covers the design and applications of artificial flavinium-based organocatalytic systems for chemoselective and stereoselective oxygenations with hydrogen peroxide and oxygen as stoichiometric oxidising agents.
Organophosphorus reagents play pivotal roles in modern organic synthesis and have found many applications for the preparation both of synthetically important compounds and of biologically relevant ones. They are now widely employed in asymmetric organocatalysis to afford optically active organophosphorus compounds. This review summarizes recent progress in this field of enantioselective synthesis.
Two series of dianhydrohexitol derivatives, the first preserving the original bis-fused THF backbones and the second originating from single THF ring-opening reactions, are used as asymmetric ligands in organometallic catalysis or as asymmetric organocatalysts. Their synthesis and their application in different asymmetric reactions for the formation of C–H, C–C, C–N, and C–S bonds are discussed.
Versatile C-H bonds: We discuss Manna and Antonchick's metal-free isoquinolone synthesis through the dehydrogenative condensation of benzamides with alkynes and what it means for the fields of C-H functionalization and organic synthesis. DG=Directing group, E=electrophile.
Introducing...Sulfenate! The sulfenate anion is introduced for the first time as a catalyst and was found to facilitate the conversion of benzyl halides to trans-stilbenes. CPME=Cyclopentyl methyl ether.
Organocatalytic click! Recent advances in the metal-free enamine/enolate-mediated azide–carbonyl [3+2] cycloaddition reaction are discussed. These approaches require neither a metal catalyst nor alkyne substrates. Owing to the ready availability of carbonyl compounds, these methods thus offer excellent alternatives for the synthesis of 1,4-/1,5-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles.
Hand-in-hand: Recent developments in Brønsted acid-assisted chiral phosphoric acid catalysis are discussed, which exhibit the superiority of the self-assembly and the specificity of substrate recognition.
Carbohydrates, with their rigid backbones, large numbers of functional groups and high contents of chiral centres, are an appealing natural resource for the development of organocatalysts. They are becoming increasingly popular new tools for enantioselective synthesis, and this subject is reviewed for the period from 2009 to mid-2014.
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.
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.
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.
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.
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.
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.
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.
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.