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.
Tales of the unexpected: An efficient triply hydrogen-bond-directed enantioselective assembly of pyrrolobenzo-1,4-diazine skeletons with quaternary stereocenters by chiral Brønsted acid-catalyzed Pictet–Spengler reaction has been developed. Theoretical calculations reveal that the chiral phosphoric acid catalyst employs unexpected arene C-H···N hydrogen bonding for activation and stereoinduction. SPA=spirocyclic phosphoric acid.
Getting in the pro-zone with pronucleophiles: The asymmetric cross-aldol reaction of chloral hydrate with aldehyde pronucleophiles catalyzed by a CF3-substituted diarylprolinol is accomplished to afford γ-trichloro-β-hydroxy aldehydes in good yields with excellent enantioselectivities. The resulting aldehyde products can be converted into chiral α-azido, α-(4-methyl)phenoxy, and α-fluoro esters without a loss in the diastereo- or enantioselectivities. Bn=benzyl.
One shot complexity: The combination of an organocatalytic conjugate addition with a stereoselective multicomponent reaction (MCR) enables the one-pot synthesis of enantiomerically pure natural product hybrids. Such interplay between organocatalysis and MCRs allows the tunable diversification of up to four structural elements, thus facilitating the rapid exploration of a large chemical space.
Planar chirality was induced on an achiral ferrocenyl compound by peptide-catalyzed desymmetrization. Although such an asymmetric reaction could not be realized with a low-molecular-weight catalyst, a resin-supported peptide with a turn structure afforded products in a highly enantioselective manner.
Without a trace: The covalent activation of α,β-unsaturated aldehydes with malononitrile produced remotely enolizable π-extended allylidene malononitriles. Their amine-catalyzed eliminative [4+2] cycloaddition to aromatic and aliphatic enals enabled the construction of cyclohexadiene-containing polycycles with outstanding diastereo- and enantioselectivities. The essential role of the malononitrile handle as a traceless activating moiety was demonstrated.
Four C's: The chiral secondary amine phosphoramide A was developed and serves as a powerful catalyst for the Michael addition of fluorinated enol silyl ethers to tetrasubstituted olefins. The resulting products are obtained with high enantioselectivities and contain a quaternary carbon stereocenter bearing either a difluoroalkyl or monofluoroalkyl group. TMS=trimethylsilyl.
Super-nucleophilic pyridine catalysts were used to probe elementary steps of a particular reaction. As a consequence Morita–Baylis–Hillman reactions that employ nitroalkenes can now be performed with great efficiency through catalysis with remarkably low amounts of super-DMAP.
Primary research: The origin of higher reactivity in the water-accelerated asymmetric aldol reactions with our designed primary amine organocatalyst was elucidated by both computational and experimental methods.
That important first step: The ability of chiral phosphoric acids to interact simultaneously with a 2,3-dienylboronic ester and an aldehyde through hydrogen bonding enabled enantiospecific C(sp)-C(sp2) bond formation to give versatile synthetic intermediates. A chiral alkyl butadienyl adduct formed in this way on a gram scale was transformed into an optically pure benzo-fused spirocyclic cyclopentenone derivative (see scheme).
Good dynamic: Described is the synthesis of BMS-986001 by employing two novel organocatalytic transformations: a highly selective pyranose to furanose ring tautomerization, and an unprecedented small-molecule-mediated dynamic kinetic asymmetric transformation (DYKAT) to access enantiopure pyranones. BMS-986001 was synthesized in five steps in an overall yield of 44 %. Bz=benzoyl.
Caught in a trap: The first trapping of CO2 through organocatalyzed C-C and C-O bond formation is reported. By using alkynyl indoles, this method generates novel indole lactone derivatives by using as little as 5 mol % of the simple organic base 1,5,7-triazabicyclo-[4.4.0]dec-5-ene as an organocatalyst. The transformation shows excellent atom economy and a broad substrate scope, including aromatic, heteroaromatic, and aliphatic 2-alkynyl indoles.
Xiao-Phos: A new class of chiral sulfinamide phosphine catalyst was developed. These Xiao-Phos catalysts can be prepared from inexpensive commercially available starting materials and show good performance in the enantioselective intramolecular Rauhut–Currier reaction under mild conditions. Moreover, kinetic resolution was also observed with the use of two different substituted racemic precursors.
It takes 2-: Measurement of rate and equilibrium constants for the reaction between N-aryl triazolium NHC precatalysts and substituted benzaldehydes under catalytic and stoichiometric conditions demonstrate the remarkable kinetic and thermodynamic effect of the benzaldehyde 2-substituent in these reactions, potentially providing insight into the chemoselectivity of cross-benzoin reactions.
A BB method: 1H-imidazol-4(5H)-ones serve as effective and easily available α-amino acid surrogates for the catalytic and highly diastereo- and enantioselective direct construction of N-substituted quaternary α-amino acid derivatives. The reaction is catalyzed by a Brønsted base (BB) and proceeds with different Michael acceptors. EWG=electron-withdrawing group.
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.
In one pot: A visible-light-induced photocatalytic cross-dehydrogenative coupling (CDC)/dehydrogenation/6π-cyclization/oxidation cascade converts common 2-aryl-1,2,3,4-tetrahydroisoquinolines into 12-nitro-substituted tetracyclic indolo[2,1-a]isoquinoline derivatives. Key to this new one-pot transformation is the presence of K3PO4 as a base and amino anthraquinone derivatives appear as superior organic photocatalysts.
Ynones give the best: The enantioselective cross-benzoin reaction between aldehydes and ynones by employing a chiral N-heterocyclic carbene (NHC) as catalyst proceeds cleanly, not observing any by-product arising from competitive Stetter-type reactivity. This procedure allows the preparation of tertiary alkynyl carbinols as highly enantioenriched materials, which have the remarkable potential to be used as chiral building blocks in organic synthesis.
A highly enantioselective organocatalytic substitution of 3-(1-tosylalkyl)indoles with oxindoles has been developed, providing an efficient approach to access highly enantioenriched 3,3'-disubstituted oxindoles, which are used as the key step in the total synthesis of (+)-trigolutes B.
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.
Highly functionalized succinimides: The N-heterocyclic carbene (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.
All in one: An asymmetric synthesis of diheteroarylalkanals through a one-pot dienamine and Friedel–Crafts reaction is presented (see scheme). The reaction tolerates a large variety of substituents at different positions of the starting aldehyde, and the use of nucleophiles and different diheterocyclic alkanals can also be achieved. The antiproliferative activity of these new compounds in different cancer tumor cell lines has also been investigated and it was found that, with the appropriate substitution, the compounds are as cytotoxic as Cisplatin.
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).
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.
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.
Organic power for asymmetric catalysis: Properly modified 9-amino-epi-quinine derivatives are anchored onto different supports and used as efficient organocatalysts in a variety of reactions, in some cases outperforming their nonsupported counterparts. The immobilization also extends the catalyst lifetime.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.