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.
Organo-click: Organocatalytic azide–ketone [3+2] cycloaddition (OrgAKC) of a variety of 1-aryl-2-(arylthio)ethanones and 1-alkyl-2-(alkylthio)ethanones with aryl/alkyl azides is reported as an efficient and general catalytic intermolecular procedure for the regiospecific synthesis of medicinally important 1,5-disubstituted 4-arylthio- and 4-alkylthio-1,2,3-triazoles and 1,5-disubstituted 1,2,3-triazoles.
Looking back—don't look back: After ten years of asymmetric organocatalysis with diarylprolinol silyl ethers, we look back over the history of this class of aminocatalysts and its impact. We outline the development of this area from reactions via enamine and iminium ion intermediates to remote functionalizations, combinatorial methods, and industrial applications, describing in which directions these catalysts have moved organocatalysis and where the field might be going.
Flexible organocatalysts: Chiral ammonium aryloxides or betaines are efficient organocatalysts able to activate nucleophiles (Nu) or electrophiles (E) owing to their Lewis or Brønsted base behavior. The capabilities of these catalysts to promote a wide range of chemical transformations with a high level of enantioselectivity is highlighted in this Minireview.
Remote control: A new catalytic asymmetric 1,6-conjugate addition reaction of para-quinone methides is disclosed. It is a new addition to the small family of asymmetric reaction of p-QMs. With chiral Brønsted acid catalysis, remarkable remote stereocontrol can be achieved for a range of in situ formed p-QMs to form all-carbon quaternary stereocenters with high efficiency and enantioselectivity.
Detailed mechanistic studies of a complex organocatalytic reaction using a multicatalyst consisting of an oligopeptide backbone equipped with two selective catalytic moieties were carried out by using electrospray ionization mass spectrometry (see figure).
Dual effect: Chiral polyoxometalates, which can be considered as models of chiral metal oxide surfaces, transfer their chirality to organic molecules. Linked to an achiral imidazolidinone, the inorganic framework is the unique source of chirality, whereas the organic part is responsible for the catalysis. High yields and high ee values were obtained when the hybrids catalyzed Diels–Alder reactions.
Three molecular shuttles based upon ammonium/triazolinium salt motifs with one, two, and three catalytic centers are prepared. Their organocatalysis of two Michale-type reactions shows that the catalysis process occurs if the amine is exposed, but this catalysis stops if the ammonium salt is covered by the crown ether.
Positive outcome: The trityl cation (TrBF4) is a highly efficient Lewis acid organocatalyst for the oxa-Diels–Alder reaction of various unactivated aromatic and aliphatic aldehydes and simple unactivated dienes, such as isoprene and 2,3-dimethylbutadiene, to give 3,6-dihydropyrane adducts in excellent to moderate yields with catalyst loadings down to 1.0 mol-%.
Two-photon process: The combination of a visible-to-UV photon upconversion with a chemical electron-transfer reaction mechanism has been applied to the reductive aryl–Br σ-bond activation. Spectroscopic, preparative, and theoretical studies support the operation of a triplet–triplet annihilation process and sequential electron transfer and H-atom-transfer steps (see figure).
PET molecules: A metal-free asymmetric 18F-labeling reaction for an aliphatic C-H bond, employing a chiral imidazolidinone as the organomediator and N-[18F]fluorobenzenesulfonimide ([18F]NFSI) as the 18F source, is reported. The method is used to prepare the 18F-labeled positron emission tomography (PET) radiotracer (2S,4S)-4-[18F]fluoroglutamic acid.
An efficient combination: Enantiomerically pure hetero-organic ligands, which bear a hydroxy moiety, a stereogenic sulfinyl group, and an enantiomeric amine moiety, are highly efficient in the asymmetric aziridination of unsaturated aldehydes to lead to the desired products in high yields (up to 93 %) and with enantiomeric excess values up to 92 %. Cbz=Carboxybenzyl.
Herbertene rides again: A novel and efficient strategy to build α-quaternary cyclopentanones with high yields and excellent enantioselectivities (up to 96 % ee) has been developed. Its application is demonstrated by the first catalytic asymmetric total synthesis of (−)-1,14-herbertenediol and the formal synthesis of (−)-aphanorphine.
Five-membered spirocyclic oxindoles are generated in excellent yields (up to 94 %) and stereoselectivities (up to >20:1 d.r., >99 % ee) in a Michael–Mannich reaction of a ketimine intermediate that is catalyzed by a bifunctional quinine-derived squaramide. A scaled-up variant of this transformation also proceeded smoothly, highlighting the potential of this cascade process.
Make it catalytic: A catalytic Mitsunobu reaction using innocuous reagents to recycle the stoichiometric phosphine oxide and hydrazine byproducts was developed. The reported protocol is catalytic in 1-phenylphospholane and uses phenylsilane to recycle the catalyst. Integration of this phosphine catalytic cycle with Taniguchi’s azocarboxylate catalytic system provided the first fully catalytic Mitsunobu reaction.
Cyclopropanes with a quaternary center were efficiently synthesized starting from bromonitroalkenes and alkyl aldehydes under aminocatalysis (see scheme). The products were obtained in good yield and excellent enantioselectivities, meanwhile theoretical calculations were applied to investigate the reaction mechanism. EWG=electron-withdrawing group, LG=leaving group.
Less is more! Electron-deficient pyridinium cations efficiently catalyze the glycosylation of benzyl- and silyl-protected glycals. Both primary and secondary alcohols can act as glycosyl acceptors. The glycosylation shown proceeds at RT and affords exclusively the α-galactoside. The 1,2-addition product of the alcohol component to the pyridinium cation most likely acts as crucial catalysis intermediate.
A visible improvement: A visible-light-mediated, organic photocatalytic radical cascade cyclization of polyprenoids has been developed. By combination of eosin Y as photocatalyst and hexafluoro-2-propanol as solvent, the desired cascade cyclization products are obtained in good yields and high stereoselectivities (see scheme; HFIP=hexafluoro-2-propanol).
An efficient protocol for the preparation of C4-alkyl substituted chiral piperidines using a secondary amine catalyzed formal aza [3+3] cycloaddition reaction with aliphatic α,β-unsaturated aldehydes and thiomalonamate derivatives is described. In addition, the enantioselective total synthesis of (+)-α-skytanthine using this developed reaction as key step was achieved in total 15 % yield.
A splash of EtOH: A highly facile, efficient, and enantioselective bromolactamization of olefinic amides was effected by a carbamate catalyst and ethanol additive. The amide substrates undergo N-cyclization predominantly to give a diverse range of enantioenriched bromolactam products which contain up to two chiral centers. Ts=4-toluenesulfonyl.
On “site”: A new retrosynthetic route to 4-O-acylated natural and unnatural glycosides is demonstrated. The title reaction of unprotected glycoside precursors, possessing multiple hydroxy groups, was performed successfully. The total syntheses of multifidosides A, B, and C were completed using this acylation strategy.
Active duty: 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) catalyzes the C-N bond-forming reactions of active methylenes, as C nucleophiles, with α-diazocarbonyls, as N-terminal electrophiles, under ambient reaction conditions. DBU activates both the active methylene and α-diazocarbonyl.
A chiral disulfonimide (DSI)-catalyzed asymmetric reduction of N-alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc2O was developed. The reaction delivers Boc-protected N-alkyl amines with excellent yields and enantioselectivity. The method was successfully applied to the synthesis of the pharmaceuticals (S)-Rivastigmine, NPS R-568 Hydrochloride, and (R)-Fendiline.
A new intermediate: The coupling of α,β-unsaturated sulfonyl fluorides with silyl enol ethers in the presence of N-heterocyclic carbenes provides δ-sultones in good yields. Various mechanistic studies indicate the formation of an α,β-unsaturated sulfonyl azolium intermediate.
By relay: The previously unknown site-selective attack of arylamines on cyclic carbonates to deliver N-aryl carbamates as the principal product is reported. The organocatalyst TBD guides an effective proton-relay process, thus mediating a chemoselective formation of the carbamate target under extremely mild reaction conditions. The new methodology represents a sustainable, cheap, and attractive process towards these important N-aryl carbamate synthons.
S cat, 2 B, perfect: Simple organosulfides efficiently catalyze the diboration of terminal alkynes under light in the absence of any metals to produce the corresponding bisborylalkenes in good yields. A boryl-centered radical species detected by electron spin resonance (ESR) spectroscopy is thought to be the reactive intermediate in this reaction.
All you need is fluor! The combination of a practical and highly enantioselective organocatalytic reaction with a fluorination step provides a new and effective strategy for the stereoselective synthesis of enantioenriched difluorinated building blocks (see scheme).
Easy as A, B, C: The entire callipeltoside family of natural products have been synthesised in a highly convergent manner. This account details our full research effort and presents further evidence to aid in the stereochemical assignment of the glycosidic linkages present in callipeltosides B and C (see scheme).
Going for Brook: The synthesis of functionalized phenanthrene derivatives was achieved by intramolecular cyclization utilizing the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis. This reaction involves the generation of an ester enolate through the [1,2]-phospha-Brook rearrangement, the intramolecular addition of the enolate to an alkyne, and the [3,3] rearrangement of the allylic phosphate moiety in a consecutive fashion.
Catalyst screening: By using dynamic covalent chemistry, systems of bifunctional catalysts incorporating dynamic imine bonds within the scaffold have been developed and have been shown to equilibrate under catalysis of one of the system members. Furthermore, the optimal catalyst for a Morita–Baylis–Hillman reaction could be identified in situ through strategic dynamic deconvolution (see scheme).
Large and practical: Three new supported organocatalysts containing two, twelve, and ninety six (+)-cinchonine moieties are prepared, and are found to catalyze the α-hydrazination of 1,3-dicarbonyl compounds. The dendritic organocatalysts show unprecedented recyclability with reproducible activity and enantioselectivity.
The organocatalytic asymmetric Michael addition of aldehydes to a nitro olefin catalysed by (S,S)-diphenylethylenediamine proceeds in good yields and with good to high enantioselectivities (45–96 % ee). Remarkably high enantioselectivities were observed for the demanding conjugate addition of α,α-disubstituted aldehydes to nitrostyrene (96–98 % ee) in aqueous organic solvent mixtures.
Organocatalytic domino aldol–oxa-Michael reactions were developed to construct novel chroman derivatives with quaternary (chroman) stereocenters with high stereoselectivities and interesting regioselectivities.
The diphenylprolinol silyl ether mediated asymmetric nitrocyclopropanation of α-substituted α,β-unsaturated aldehydes with bromonitromethane, followed by base-promoted isomerization affords trans-nitrocyclopropanecarbaldehydes with all-carbon quaternary stereogenic centers with excellent diastereo- and enantioselectivities. The reaction is believed to proceed via an s-trans iminium ion intermediate.
A recyclable prolinamide-derived ionic-liquid-supported organocatalyst bearing an auxiliary Brønsted-acidic group has been developed. It catalyzes asymmetric mono- and bis-aldol reactions of aromatic aldehydes with cyclic or linear ketones in aqueous medium and retains excellent catalytic performance (up to 96:4 dr and 81–99 % ee) over ten cycles.
A practical acid/base-regulated recyclable strategy for cinchona alkaloid-derived organocatalysts by means of protonation and deprotonation of primary and tertiary amine groups was developed and applied in asymmetric aldol, vinylogous Michael and double-Michael cascade reactions.
Chiral, enantioenriched, medium-sized-ring lactones are prepared by an innovative approach. Starting with the organocatalytic Michael addition of cycloalkan-1,3-diones to α,β-unsaturated aldehydes combined with subsequent reductively initiated Claisen fragmentation, 10- and 11-membered-ring natural-product-resembling chiral lactones are synthesized with 91 to >99 % ee.
Doubled up: The title reaction of α,β-unsaturated γ-butyrolactams and sterically congested β-substituted cyclic dienones proceeds with high site-, diastereo-, and enantioselectivity. An unprecedented cascade reaction takes place with five-membered dienones, leading to complex tricyclic γ-lactams with four newly formed stereocenters.
The right environment: Enantioselective formal hetero-Diels–Alder reactions of trifluoromethylated enones and 2-amino-1,3-butadienes generated in situ from aliphatic acyclic enones and chiral primary amines are reported (see scheme).
A hydrogen-bond acceptor plays an important role in the catalytic cycle of organo-enamine catalysis. It can effectively accelerate the rate of reaction through hydrogen-bonding interactions with the enammonium (N-protonated enamine) intermediate. These findings are supported by both kinetic experiments and quantum chemical calculations.
Efficiency of pentanidiums: Enantioselective conjugate addition between 3-alkyloxindoles and phenyl vinyl sulfone was achieved with a pentanidium phase-transfer catalyst. Various enantioenriched oxindole derivatives with versatile functional groups were synthesized. Gram-scale experiments also indicate the high efficiency and practicality of the current strategy.
The direct asymmetric self-aldol reactions of various α-oxyaldehydes catalyzed by tertiary amines have been demonstrated. By using 10 mol-% of quinine catalyst, dimerization products have been formed in high yields, with good anti-diastereocontrol, and up to 80 % ee.
Forgotten, yet positive! Ever since a series of reports almost 30 years ago, the carbocation has been almost completely neglected as a Lewis acid catalyst. However, in light of recent work the carbocation is reemerging as a versatile and efficient catalyst for various organic transformations.
A new sheriff in town: para-Quinone methides (p-QMs) have been successfully used in asymmetric organocatalysis. Particularly, the asymmetric 1,6-addition of phenyl malonate and different aldehydes to 2,6-disubstituted p-QMs has provided a rapid access to important chiral diarylmethines, highlighting the importance of these synthetic intermediates. These new structures will open up the development of important asymmetric transformations in the future.
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.
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.
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.
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.
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.
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.