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 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.
Active duty: 1,8-Diazabicyclo[5.4.0]undec-7-ene 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 plays activates both the active methylene and α-diazocarbonyl.
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.
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.
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.
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.
By relay: The previously unknown site-selective attack of arylamine 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.
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.
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.
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.
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.
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).
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.
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.
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).
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.
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.
Ether/or: The reactions of α,β-unsaturated aldehydes with cyclopentadiene in the presence of diphenylprolinol silyl ethers and trifluoromethyl-substituted diarylprolinol silyl ethers (see figure) as amine organocatalysts occur by two different reactions involving iminium ions to give Michael adducts or Diels–Alder products. The mechanisms of these two processes are discussed.
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.
A broadly applicable, highly E-selective and enantioselective conjugate addition of 2-benzyloxythiazol-5(4H)-ones to β-substituted alkynyl N-acyl pyrazoles was developed. A P-spiro chiral iminophosphorane 1 is used as the catalyst. This method leads to structurally diverse, optically active α-amino acid derivatives bearing a geometrically defined trisubstituted olefinic component at the α-position. PMB=p-methoxybenzyl.
Fluoride has to go: Bis-heteroaryl or bis-aryl stereocenters are formed through an organocatalytic enantioselective conjugate addition using heteroaryl or aryl trifluoroborate salts, respectively, as nucleophiles. Control experiments suggest that fluoride dissociation in the anhydrous conditions is necessary. The reaction was applied toward the synthesis of discoipyrrole D, an inhibitor of DDR2-dependent migration of BR5 fibroblasts.
One carbon makes a difference: The efficient and controlled formation of poly(propylene oxide) (PPO) at a very low catalyst loading of N-heterocyclic olefins showcases the use of this group of highly polarized alkenes as catalysts for organopolymerization. A strong structure–activity relationship is found, which is fundamentally different from the reactivity of N-heterocyclic carbenes (TON=turnover number, PDI=polydispersity index).
A highly regioselective intermolecular haloetherification that proceeds with excellent enantioselectivity, catalyzed by cinchona alkaloid dimers, is reported. The regioselectivity is preserved for unbiased alkyl substituted allyl amides with either E or Z geometry. (DHQD)2PHAL=hydroquinidine 1,4-phthalazinediyl diether.
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.
A combination of photoredox catalysis and enamine catalysis has enabled the development of an enantioselective cyanoalkylation of aldehydes. This synergistic catalysis protocol makes possible the coupling of two highly versatile yet orthogonal functionalities.
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.
Multiple players: The first highly stereoselective multicomponent reaction of diazooxindoles, nitrosoarenes, and nitroalkenes with a newly developed hydrogen-bond catalyst has been successfully developed. The spirooxindole products are isolated in excellent yields and stereoselectivities, and contain three contiguous stereogenic centers. R'''=aryl or alkyl.
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.
A remarkable proline-catalyzed Knoevenagel condensation/[4+2] cycloaddition cascade reaction was uncovered for the construction of biologically interesting tricyclic ketal skeletons. This approach mimics a biosynthetic sequence and establishes a viable synthetic strategy for the efficient formal synthesis of averufin.
The synthesis of a wide range of 5–7 membered ring fused 1,2,3-triazoles has been realized through a tandem organocatalyzed reaction.
The scalable diastereoselective Mannich reaction of functionalized aldehydes with phenethylamine-derived iminium precursors, by activation with prolines and prolinol derivatives is reported. The new robust process allows the simple preparation of enantiomerically pure Fmoc-protected β2-serine and β2-threonine on multi-gram quantities.
A kinetic resolution of a planar-chiral [2.2]paracyclophane was attained through the Michael addition of nitromethane in the presence of a resin-supported peptide catalyst. A helical peptide with an appropriate N-terminal sequence was effective for a selective resolution.
A quinine-catalyzed enantioselective method has been reported to generate polysubstituted cyclohexenes that have an all-carbon quaternary center. The resulting isomeric product mixtures were easily converted into the corresponding pyrazoles through a one-pot procedure.
Steric clash: The trans diastereoselectivity observed in the [2+2] cycloaddition of ketenes and N-protected imines catalyzed by N-heterocyclic carbenes was rationalized based on the molecular structure of the zwitterionic imidazolinium enolate derived from 1,3-dimesitylimidazolin-2-ylidene and ethylphenylketene (see scheme).
The all-C-ing I: Enantioselective dearomatizative spirocyclization of 1-hydroxy-N-aryl-2-naphthamide derivatives is accomplished by chiral organoiodine catalysis to stereoselectively construct an all-carbon stereogenic center, providing a straightforward approach to access spirooxindole derivatives in good yields and with high to excellent levels of enantioselectivity.
Going Mannich: Boc-protected aminals serve as versatile imine precursors in phase-transfer-catalyzed Mannich reactions with glycine and alanine Schiff bases. The reaction also worked well for the less-accessible alkenyl- and alkynyl-substituted imines. Boc=tert-butoxycarbonyl.
Choose your partner: An asymmetric isothiourea-catalysed [3+2] formal cycloaddition of homoanhydrides and oxaziridines for the formation of stereodefined oxazolidin-4-ones in high yields and with high enantioselectivities is described (see scheme). The use of racemic and enantioenriched oxaziridines is studied, leading to the observation of a matched/mismatched effect between the catalyst and the oxaziridine.
A good substitute: The regio-, diastereo-, and enantioselective conjugate addition of aldehydes to β-tosyl enones, which serve as ynone surrogates, was promoted by a simple axially chiral amine catalyst. The conjugate adducts were readily converted into less accessible enones with a γ stereogenic center through β elimination of the tosyl group (see scheme) and could thus be used in a further conjugate addition reaction.
How it works: Oxidative N-heterocyclic carbene (NHC) organocatalysis provides a unique way to functionalize aldehydes. The present study provides mechanistic insights into the oxidative γ-carbon addition of enal to imine. This route also provides highly enantioselective access to bioactive tricyclic sulfur amides.
Get it together: A novel family of privileged dipeptide-derived multifunctional phosphonium salts has been developed as highly efficient phase-transfer catalysts for the construction of the chiral five- or six-membered carbocycles and heterocycles by a tandem asymmetric Michael addition/SN2 sequence (see scheme).
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.
Towards β2,2-amino acid derivatives: The first example of organocatalytic asymmetric aza-Michael reaction of β,β-disubstituted nitroalkenes was developed, producing the corresponding adducts, bearing quaternary stereogenic centers, in good yields and high enantioselectivities.
Diphenylprolinol silyl ether is an effective organocatalyst in the asymmetric cross-aldol reaction of α,α-disubstituted acetaldehydes with commercial ethyl glyoxylate polymer to generate all-carbon quaternary stereogenic centers with good enantioselectivity.
The Michael addition reaction of α-substituted cyclic ketones was efficiently promoted by a primary amine-based organocatalyst under high-pressure conditions (1.0 GPa) in tetrahydrofuran.
The scope and limitations of the microwave-assisted catalytic Wittig reaction have been evaluated with respect to the catalyst, silane, solvent, reaction conditions, and substrates.
cis-Disubstituted nitropentenes are obtained with excellent diastereoselectivities and enantioselectivities by a formal [3+2] cycloaddition reaction. The first reaction is a domino reaction composed of the diphenylprolinol silyl ether mediated Michael reaction of nitroalkene with succinaldehyde followed by a Henry reaction. The next reaction is a dehydration achieved by using Ac2O and pyridine.
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.