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.
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.
Self-assembled organocatalysts: A temperature-triggered conformational change in supramolecular polymers with pendant L-proline units results in highly active and selective organocatalysts for aldol reactions in water (see scheme).
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.
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.
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 with hydrogenation.
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).
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.
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.
Commercially available, inexpensive 2-furanylboronic acid has been identified as an effective catalyst for the direct dehydrative amide formation of carboxylic acids and amines. This transformation can be efficiently carried out at room temperature and is applicable to a wide range of carboxylic acids with primary and secondary amines to afford amides in good to excellent yields.
New iminium-ion reactivity mode: The reactivity of iminium ions containing an α C=O group, generated in situ by reaction of 2-oxoaldehydes with secondary amines, was developed and utilized to generate different cross-coupling products through formation of C-C and N-C bonds (see scheme). These processes proceed due to the unique ability of a three-component intermediate to undergo self-deamination and oxidation by air and, moreover, furnished the mildest possible approach to α-ketoamides.
Super photooxidant: Photoinduced hydroxylation of neat deaerated benzene derivatives to the corresponding phenols occurred under visible-light irradiation of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ; see figure), which acts as a super photooxidant in the presence of water. The reactions are initiated by electron-transfer oxidation of benzene derivatives with the singlet and triplet excited states of DDQ to form the corresponding radical cations and DDQ.−.
Cascade reactions of 7-vinylindoles: The first catalytic asymmetric cascade reaction of 7-vinylindoles has been established by the rational design of such substrates. Cascade reactions with isatin-derived 3-indolylmethanols catalyzed by chiral phosphoric acid (CPA; see scheme) allow the diastereo- and enantioselective synthesis of C7-functionalized indoles as well as the construction of cyclopenta[b]indole and spirooxindole frameworks (all >95:5 d.r., 94–>99 % ee).
Paired off: A new strategy, which combines a chiral phosphine with methyl acrylate to form a homogeneous ion pair, is introduced. This activation mode has been successfully applied to Mannich-type reactions, thus generating a variety of fluorinated amino acid derivatives in high yields and with high ee values.
Cationic RAFTing: A cationic reversible addition–fragmentation chain-transfer (RAFT) polymerization with thiocarbonylthio compounds proceeds in the presence of a small amount of CF3SO3H. Various monomers including vinyl ethers as well as alkoxy- and hydroxystyrene can be used. A transformation from cationic to radical RAFT polymerization enables the synthesis of block copolymers between cationically and radically polymerizable monomers.
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.
Couple up: Recyclable bifunctional ammonium salts are identified as one-component catalysts for the 100 % atom-economic coupling reaction of CO2 and epoxides even at 45 °C. The alcohol moiety that donates a hydrogen bond accelerates the catalytic reaction remarkably. This metal and solvent-free process can be performed on a multigram scale and is applied to the synthesis of a naturally occurring cyclic carbonate.
A metal-free and base-free carbonylation has been developed which affords primary, secondary, and tertiary alkyl benzoates under irradiation with visible light in the presence of eosin Y as a photocatalyst. The mechanism has been studied by spectroscopic, theoretical, and preparative methods, and appears to involve intermediate aryl and aroyl radical species as well as a light-driven one-electron redox cycle without any sacrificial redox partner.
With excellent enantio- and diastereoselectivity, acetamido-substituted tetrahydrobenzoxanthenes and related heterocycles are obtained in one synthetic operation. A specifically optimized chiral phosphoric acid converts ortho-hydroxy benzhydryl alcohols and enamides into highly functionalized target compounds carrying three contiguous chiral centers with typically good overall yields.
Dihydropyran and multifunctional cyclopentene derivatives are constructed from the same starting materials by using different phosphine catalysts. By controlling the nucleophilicity of the phosphine catalysts, the γ-substituted allenoates can selectively act as C3 or C2 synthons. The results suggest that the ethyl group of the γ-substituted allenoates plays a key role in the domino reaction.
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.
Stairway to seven: Bifunctional N-heterocyclic carbenes (NHCs) with a free hydroxy group are demonstrated as efficient catalysts for the [3+4] annulation of enals with aurones to give the corresponding benzofuran-fused ε-lactones in good yields with good diastereoselectivities and excellent enantioselectivities. Control experiments reveal that the [3+4] cycloadducts are kinetically favored and could be transformed to the thermodynamically favored [3+2] cycloadducts with a non-bifunctional NHC catalyst.
A cat. with handles: A multifunctional chiral Lewis base catalyst mediates the highly enantioselective intermolecular cross Rauhut–Currier (RC) reaction of different active olefins. The RC products were obtained in excellent yields and high chemo- and enantioselectivity. The reaction could be performed on a gram scale with a catalyst loading of 1 mol %.
Quantity into quality: A very strong manifestation of a positive multivalency effect on the catalytic activity is observed in dendritic polymer-supported catalysts, based on N-alkylimidazoles, in the Baylis–Hillman reaction (see scheme). Tethering the catalytically active units to a dendritic spacer enhances the activity per unit dramatically, sometimes by an order of magnitude.
Triple Michael to pentagon! An organocatalytic three-component domino cyclization has been developed through a triple Michael sequence catalyzed by a secondary amine. Three bonds and six stereocenters, including a quaternary one, are formed by using equimolar reactants. A series of fully functionalized cyclopentane-oxindoles with potential bioactivity are obtained in good yields, very good diastereo-, and excellent enantioselectivities under mild conditions (see scheme).
Squared away: A strategy for enantioselective azlactone dynamic kinetic resolution to generate orthogonally protected amino acids has been developed. In the presence of a squaramide-based catalyst, benzyl alcohol reacts with tetrachloroisopropoxycarbonyl-substituted azlactones to generate phthalimide products with excellent enantiocontrol. Removal of the phthalimide can be achieved in the presence of the ester and vice versa.
Increased substrate scope in phase-transfer-catalyzed asymmetric SNAr reactions was achieved by the use of arene chromium complexes as electrophiles. An efficient asymmetric synthesis of α,α-disubstituted α-amino acids containing various aromatic substituents is shown. PTC=phase-transfer catalyst.
From theory to practise: The mechanism of asymmetric organocatalysed Michael addition of β-ketoamides to enones was studied theoretically, demonstrating for the first time the unique role of the hydrogen atom of the amide in controlling both the reactivity and the enantioselectivity (see scheme). Additional reactions afforded original spiro hemiaminals, taking advantage of the reactivity of the Michael adducts with acrolein. Post-functionalisation led to valuable enantioenriched glutarimides and pyridones.
Two roles for NFSI: The N-heterocyclic carbene (NHC) catalyzed asymmetric fluorination of readily available simple aliphatic aldehydes, α-chloro aldehydes, and even alcohols proceeds via azolium enolates and yields a wide range of α-fluoro esters, amides, and thioesters with excellent enantioselectivity. N-Fluorobenzenesulfonimide (NFSI) acts as both a fluorinating reagent and an oxidant in this transformation.
Useful skeletons: An electrophilic amination reaction catalyzed by chiral phosphoric acid is the basis for a highly efficient asymmetric dearomatization of naphthols. This protocol provides functionalized β-naphthalenone compounds with a chiral quaternary carbon center in excellent yields and enantioselectivity. These motifs are found in various biologically active natural products and therapeutic reagents.
A chiral disulfonimide catalyst is used to achieve the first catalytic enantioselective Abramov reaction. Several functionalized α-hydroxy phosphonates were synthesized in good yields and with excellent enantiomeric ratios of up to >99:1. The process was shown to be scalable and up to 1 g of starting material could be employed under mild reaction conditions.
Stuck in the middle: Diazoacetate esters are suitable neutral guests for the self-assembled resorcinarene hexameric capsule. The hydrogen-bonded supramolecular host efficiently catalyzes 1,3-dipolar cycloadditions between such substrates and electron-poor alkenes, which leads to 4,5-dihydro-1H-pyrazole derivatives. The presence of competitive cationic guests for the capsule confirms that the reaction occurs within the cavity.
A family of BINOL-derived enantiopure silanediols has been prepared and studied. The effect of the substitution pattern of the BINOL backbone on catalyst performance is detailed. The acidities and chloride binding constants are also reported for this new and exciting class of hydrogen-bond donor (HBD) catalysts.
A carbapenem intermediate serves as a useful nucleophile in organocatalyst-mediated α-heterofunctionalization reactions leading to the formation of diverse products.
A crushing victory: The organocatalytic activity of α,β-dipeptides 1 a–c was evaluated in the asymmetric aldol reaction between ketones 2 and aldehydes 3. The best results in terms of yield and stereoselectivity were obtained under solvent-free conditions with ball-milling activation.
Giving metal catalysis the slip: The asymmetric epoxidation of 2-oxoindoline-3-ylidene acetaldehydes with hydrogen peroxide, catalyzed by diarylprolinol silyl ether, has been developed. Good to excellent diastereo- and enantioselectivities were realized even though the starting material 2-oxoindoline-3-ylidene acetaldehydes pre-existed as a mixture of E/Z-isomers.
3,5,6-Trifluoro-2-pyridone is an efficient catalyst for the α-addition of isocyanides to aldehydes in the presence of water in benzene. Various aldehydes and isocyanides performed well in this reaction to provide the α-hydroxyamides. Even highly constrained substrates were well tolerated. This is the first example of pyridone-catalyzed α-addition of isocyanides.
Just a matter of H bonding: The efficient valorization of carbon dioxide to cyclic carbonates was performed under mild and metal-free conditions by activation of the epoxide through hydrogen bonding of a hydroxyl-functionalized bisimidazolium salt.
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.
The asymmetric synthesis of fluorinated 1,3-diketones is achieved through quinine–sulfonamide mediated asymmetric Michael addition of racemic 2-fluoro-1,3-diketones to nitroalkenes. Subsequent stereoselective reduction of the carbonyl groups led to a functionalized fluoroisostere of the triol and generation of four stereogenic carbon centers, including one quaternary center, in two reaction steps.
A new, organocatalytic approach to the hydrolytic deprotection of dithianes has been developed involving a low-toxicity imidazolium-ion-based catalyst in an aqueous medium.
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.
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.
Small ring, big ring: A novel strategy for the one-pot synthesis of substituted pyridines from N-arylmethyl 3-aziridinylpropiolate esters is described. The method employs a three-step procedure including the formation of allenyl imines, phosphine-catalyzed cyclization, and subsequent oxidation of the dihydropyridines. Depending on the reaction conditions of the final oxidation step, tri- and tetrasubstituted pyridines can be selectively produced.
Typecast: Reactions catalyzed by diphenylprolinol silyl ether can be categorized into three types (see figure): two involve an iminium ion intermediate, such as for a Michael-type reaction (type A) and a cycloaddition reaction (type B), and one proceeds via an enamine intermediate (type C). In type A, good enantioselectivity is realized if a catalyst with a bulky silyl moiety is employed. In types B and C, good enantioselectivity is obtained even when the silyl group is less bulky.
Fully functionalized 1,2,3-triazoles were synthesized by a metal-free clicking through an enolate-mediated organocatalytic azide–ketone [3+2]-cycloaddition (OrgAKC) reaction. Very simple and readily available aryl azides and enolizable arylacetones/deoxybenzoins were employed in this organocatalytic transformation (see scheme; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene).
Two chiral carboxylic acid functionalized micro- and mesoporous metal–organic frameworks (MOFs) are constructed. The mesoporous MOF functions as a host for encapsulation of an enantiopure organic amine by acid–base interactions. The organocatalyst-loaded MOF is an efficient and recyclable heterogeneous catalyst for asymmetric direct aldol reactions, with significantly enhanced stereoselectivity relative to the homogeneous organocatalyst.
Lewis acid catalysis: A chiral disulfonimide (DSI) serves as a highly efficient precatalyst for vinylogous Mukaiyama–Mannich reactions of a readily available silyloxydiene with protected imines, delivering δ-amino-β-ketoesters. The synthetic utility of the reaction is illustrated by the preparation of valuable enantiomerically enriched building blocks and the formal synthesis of (−)-lasubin.
A bifunctional squaramide-catalyzed sulfa-Michael/aldol cascade reaction between benzylidenechroman-4-ones and 1,4-dithiane-2,5-diol has been developed. This reaction enables facile asymmetric access to chiral spirocyclic tetrahydrothiophene chromanone derivatives with three contiguous stereocenters in high to excellent yields (up to 99 %) and with high enantioselectivities (up to 92 % ee).
An efficient process for the enantioselective synthesis of optically active 3,4-dihydrothiacarbazol-2(9H)-one derivatives has been developed The cascade Michael addition/thiolysis reactions of 9-methylindoline-2-thiones and N-alkenoylphthalimides were promoted by a chiral bifunctional squaramide catalyst to give the desired products in acceptable yields with 54–98 % ee.
Cyclopeptoids are a novel class of efficient and tunable chiral macrocyclic phase-transfer catalyts. Screening of catalysts for the enantioselective alkylation of N-(diphenylmethylene)glycine tert-butyl ester shows the crucial role of N-arylmethyl residues.
Three in one to ease organocatalysis: A robust, tunable, and recyclable organocatalytic system has been prepared by anchoring N-heterocyclic carbenes on an all-aliphatic vinylic addition polynorbornene (VA-PNB) scaffold. These three features make this heterogeneous NHC-based organocatalyst most convenient.
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.
The synthesis of ferrocenophane–amines is developed. Compound L1 can be used as a ligand in the the copper-catalyzed oxidative coupling of 3-hydroxy-2-naphthoate to give the product in good yield with up to 92 % ee, and it also efficiently catalyzes the asymmetric Michael addition reaction as an organocatalyst.
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.
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.
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.
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.