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]
The following is a selection of recent articles in this field from Angewandte Chemie, Chemistry—A European Journal, European Journal of Organic Chemistry and Advanced Synthesis & Catalysis. It is updated on a daily basis, so stay tuned!
 Special issue of Adv. Synth. Catal. 2004, 346, Nr. 9-10.
Ten new organocatalysts derived from the diterpenoid alkaloid lappaconitine are described. Activities for the enantioselective α-hydroxylation of β-dicarbonyl compounds with 30 % hydrogen peroxide as a green and practical source of oxygen is described. This protocol allows convenient access to the corresponding α-hydroxy-β-dicarbonyl compounds with up to 98 % yield and 92 % ee under mild conditions.
Organo-photocatalysts that are based on atropisomeric thioureas and display lower excited-state energies than the reactive substrates have been developed. These photocatalysts were found to be efficient in promoting the [2+2] photocycloaddition of 4-alkenyl-substituted coumarins, which led to the corresponding products with high enantioselectivity (77–96 % ee) at low catalyst loading (1–10 mol %).
In and out of phase: The mechanism of a novel base-free neutral phase-transfer reaction system was investigated (see scheme). The aqueous–organic biphasic reaction system with lipophilic tetraalkylammonium bromide was essential to promote the neutral phase-transfer reactions. The base-free reaction system could be applied to several asymmetric reactions.
Twisting indoles: A novel chiral Brønsted acid, specifically designed for long-range control on a nanoscale, catalyzes the asymmetric synthesis of azahelicenes through a Fischer indolization. The method has the advantage of starting from simple achiral starting materials, which can be modified by changing the protecting group (R2) or the terminal substituents (R1, R3). The products can be further oxidized to polyaromatic systems.
Learning from peptides: A concise route for the catalytic enantioselective synthesis of β-amino nitriles has been achieved by using ureidopeptide-based Brønsted bases as catalysts in the Mannich reaction of N-Boc imines and (arylsulfonyl)acetonitriles (see scheme; Boc=tert-butoxycarbonyl, napht=naphthyl, TMS=trimethylsilyl).
More NHC-organocatalysis: N-Heterocyclic carbene-catalyzed reactions of indolin-3-ones with 2-bromoenals opened an asymmetric access to 3,4-dihydropyrano[3,2-b]indol-2(5 H)-ones in good yields and with good to excellent enantioselectivities. This protocol tolerates a broad substrate scope. In addition, a possible mechanism for the annulation reaction is presented.
The utilization of neighboring ortho-hydroxy group participation in the pretransition state of enamine/iminium-based triple domino Michael/aldol/oxa-Michael reactions catalyzed by (R)-DPPOTMS followed by Wittig and Michael/Wittig–Horner reactions is described. Enantiomerically pure chromanes and tetrahydro-6H-benzo[c]chromenes having three to four contiguous stereocenters are synthesized.
NHC-catalyzed cascade: The addition of an N-heterocyclic carbene (NHC) to the carbonyl group of an α,β,γ,δ-unsaturated enol ester affords a hemiacetal azolium intermediate that enables a cascade olefin isomerization/Diels–Alder reaction. Preliminary studies into the utility of the products using reductive and oxidative cleavage gave substrates for potential use in the synthesis of complex targets.
Embraced enantioselectivity: Mukaiyama–Michael reactions catalyzed by trans-2,5-diphenylpyrrolidine catalyst are highly enantioselective, but why? The answer appears to lie in the attractive, not repulsive, noncovalent interactions in the transition states leading to the major product(s) (see scheme; TIPS=triisopropylsilyl).
Finding the path: The mechanism of bifunctional squaramide-promoted Michael addition of prochiral 1,3-dioxo nucleophiles and nitroolefin has been studied on the basis of DFT calculations. Among the investigated mechanistic scenarios, the pathway corresponding to electrophile activation via the protonated amine unit is found to be the most feasible (see figure). For some of the minor stereoisomeric products, alternative pathways are also accessible.
An organocatalytic regio- and enantioselective cascade conjugate addition reaction is developed for the construction of enantiomerically enriched 1,2,3-trisubstituted indanes. The resulting indane derivatives can be readily converted into optically active (1-indanylmethyl)amine and tetrahydroindeno[2,1-b]pyrrole derivatives. Boc = tert-butoxycarbonyl.
The old one-two: A two-step synthetic strategy was developed for the construction of the bridged benzopyran core present in many natural products. It consisted of an efficient asymmetric catalytic decarboxylative Diels–Alder reaction between enals and coumarin-3-carboxylic acids, and a one-pot protocol for the reduction/acid-catalyzed stereoselective cyclization. TBS=tert-butyldimethylsilyl.
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.
Domino construction: An efficient organocatalytic one-pot domino Michael/intramolecular Povarov reaction has been developed to provide enantiomerically enriched spirooctahydroacridine-3,3'-oxindole derivatives containing five stereogenic centers in good to high yields with excellent diastereo- and enantioselectivities (see scheme). This strategy not only adds to the limited repertory of examples of asymmetric synthesis of chiral spirocyclohexaneoxindoles and octahydroacridines, but also demonstrates a one-pot consecutive synthesis with an ecological and economical protocol.
Back to the FTIR: The most efficient organocatalysts have been identified for the reaction of alcohols with isocyanates in supercritical CO2 in a step towards a green process for polyurethane synthesis. The order of activity of the catalysts in supercritical CO2 does not always follow that observed in conventional media.
Thioesters on the rise: β-Amino thioesters with tertiary and even quaternary stereogenic centers can be formed with high diastereo- and enantioselectivities from Mannich reactions with monothiomalonates in the presence of catalytic amounts of cinchona alkaloids. The synthetic value of the β-amino thioesters as preactivated β-amino acids was, for example, shown in coupling-reagent-free peptide synthesis.
Phosphane- and amine-catalyzed ring-opening reactions of cyclopropenones with isatin derivatives are developed. These reactions offer a facile synthetic method to construct carboxylated 1H-indoles and multisubstituted 2H-pyran-2-ones; Boc = tert-butoxycarbonyl, DABCO = 1,4-diazabicyclo[2.2.2]octane.
A novel class of tetrathiahelicene-based diphosphine oxides has been synthesised, and their catalytic behaviour as chiral helical phosphorus Lewis bases has been preliminary investigated in organocatalytic reactions.
The importance of being dispersed: Bifunctional thiourea- or sulfonamide-derived tertiary amines such as Takemoto's catalyst catalyze the enantioselective nitro-Michael addition of N-unprotected 3-substituted 2-oxindoles to nitrostyrene in high yields and enantiomeric and diastereomeric ratios. DFT calculations including van der Waals corrections are performed for the stereoisomers.
Secondary amines come first: A solid-base organocatalyst achieved by grafting amines onto silica surfaces is applied to the gas-phase aldol self-condensation of n-butanal to 2-ethylhexenal. Silica-supported secondary amine catalysts demonstrate a much higher catalytic activity than the primary amine analogues, owing to the respective formation of enamines as shown by in situ FTIR analysis. The reaction pathway is analyzed by DFT calculations.
What a Cinch(ona)! A Cinchona alkaloid derived thiourea is successfully used to catalyze the Friedel–Crafts-type addition of sesamol to isatins to provide chiral 3-aryl-3-hydroxy-2-oxindoles in good yield with good enantioselectivity. Incorporation of a 1,2,3-triazole moiety into one oxindole derivative is performed through click chemistry to obtain a biologically important derivative with good enantiomeric excess (ee). MTBE=methyl tert-butyl ether.
You do the maht: The first asymmetric decarboxylative 1,4-addition of malonic acid half thioesters (MAHTs) to 2-aryl-substituted vinyl sulfones is reported. Excellent enantioselectivities (up to 97 % ee) were obtained by using a quinine-based benzyl- substituted thiourea. The highly enantioselective synthesis of 3-monofluorinated analogues of 3-methyl indanone and (+)-turmerone has been successfully accomplished.
Sturdy as it gets: A highly enantioselective, robust, and scalable method for the synthesis of β-hydroxyamino alcohols were achieved by using the title reaction. MnO2 serves as the oxidant and catechol as Brønsted acid additive. PG=protecting group.
Lighting up S: The thioxanthone 1, which was synthesized in a concise fashion from methyl thiosalicylate, exhibits a significant absorption in the visible-light region. It allows for an efficient enantioselective catalysis of intramolecular [2+2] photocycloaddition reactions, presumably by triplet-energy transfer. Ts=4-toluenesulfonyl.
Two cats are better than one: The combined use of platinum and pyrrolidine catalysts enabled the direct alkylation of allylic alcohols with reactive methylene compounds. Pyrrolidine was essential for obtaining high selectivity of the monoallylation products, which were produced without the use of excess nucleophiles. cod=1,5-cyclooctadiene, EWG=electron-withdrawing group.
Organocatalysis made it possible: The reported methodology gives 14 β-steroids, displaying a broad generality, in one step, and includes various substituents on the A ring, variations of the B ring, hydroxy or alkyl substituents in the 12-position of the C ring, and different substituents in the angular position at C13. Furthermore, the developed reaction concept includes reactions with quinones to form D-homosteroids in excellent yields and stereoselectivities.
Merging O and N: Enantioselective α-amination of β-ketocarbonyl compounds has been achieved by merging enamine catalysis and CuI-catalyzed aerobic oxidation of hydroxycarbamates. Excellent chemoselectivity and enantioselectivity are obtained with the aid of a simple primary/tertiary diamine catalyst. This presents a facile route for the asymmetric synthesis of unnatural amino acids.
Cyclodimerizing MMA! NHCiPr (NHC=N-heterocyclic carbene) unexpectedly reacts with methyl methacrylate (MMA) by forming a stable imidazolium–enolate cyclodimer (NHCiPr/MMA=1:2), in contrast to polymerization, which is induced by NHCtBu (see scheme). DFT calculations on both mechanistic pathways highlight the differences observed between these two very similar NHCs.
Outwitted: The combination of cinchona-alkaloid-derived primary amine and AuI–phosphine catalysts allowed the selective C-H functionalization of two adjacent carbon atoms of pyrroles under mild reaction conditions. This sequential dual activation provides seven-membered-ring-annulated pyrrole derivatives in excellent yields and enantioselectivities (see scheme).
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.
An iterative catalytic enantioselective asymmetric epoxidation coupled with Alder–Rickert reaction led to an efficient synthesis of (S)-8-hydroxy-3-[(S)-2'-hydroxypentyl]-6-methoxyisochroman-1-one and their stereoisomers. This method gives the option of generating diastereomers of the natural products, and it can be efficiently implemented for the synthesis of related molecules.
A pinch of salt: A highly enantioselective Michael addition of β-ketoesters to enones was achieved by using the salt of a readily available primary β-amino acid as the catalyst. The Michael adducts were converted into enantioenriched 1,5-diketones in high yields through a common decarboxylation reaction under acidic conditions. A plausible reaction mechanism for the Michael addition reaction is also described. TBDPS=tert-butyldiphenylsilyl.
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.
Fast aldol reaction: 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was used for aldol reactions of a pyruvic aldehyde derivative with isatins. The reactions were fast and gave the aldol products in 15–30 min at 25 °C. By using this aldol reaction method, a set of furanose spirooxindoles, which would likely be useful in the search for biofunctional molecules, were concisely synthesized.
Worth its salt: Iminium salts derived from substituted cinnamaldehydes and imidazolidinones have been synthesized and characterized by X-ray crystallography. Kinetic investigations of their reactions with cyclic ketene acetals were performed to quantify their electrophilic reactivity.
Set phasers to transfer: Highly enantioselective α-arylation of α-amino acid derivatives was achieved under phase-transfer conditions. This reaction demonstrates a valuable method for the catalytic asymmetric synthesis of α,α-disubstituted α-amino acids containing an aromatic substituent. PTC=phase-transfer catalyst; Tf=trifluoromethanesulfonyl.
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.
Go with the flow: An organocatalytic vinylogous cascade reaction, which yields valuable spirooxindolic cyclopropane derivatives, is presented. This operationally simple chemistry is performed at room temperature and leads to the one-step formation of highly enantioenriched complex frameworks. The cascade follows a 1,6-addition/intramolecular SN2-alkylation sequence driven by vinylogous iminium ion/dienamine activation.
The enantioselective allylation of an aromatic aldehyde to give the corresponding homoallylic alcohol was the key step in the syntheses of a flobufen metabolite and dapoxetine. In the first case, the homoallylic moiety was converted into a chiral five-membered lactone ring. In the second case, it was transformed into a chiral 1,3-amino alcohol moiety.
Double the umpolung, double the fun: Chiral phosphoric acid derivatives catalyse N-H insertion/arylation reactions of nitrodiazoesters, anilines, and indoles. This process enables access to doubly α-electrophilic esters, that is, two nucleophiles undergo addition to the alpha-carbon atom of an ester. The aryl glycine products are prepared in good yield with modest levels of stereocontrol.
A trifyl easy: 1,1-Bis(triflyl)alkadienes are easily available building blocks for the preparation of superacidic carbon acids that contain a bis(triflyl)methyl group. The alkadiene reactions with NaBH4 or an organocerium reagent gave the desired carbon acids through a β-selective nucleophilic addition. When submitted to a Mukaiyama aldol reaction, these β-branched carbon acids had a higher catalyst activity than that of nonbranched derivatives.
Great balls of thia: An organocatalytic formal [3+2] annulation is described. With readily available achiral starting materials, a range of thiazolidines can be assembled in excellent yield and with moderate to good enantioselectivity and diastereoselectivity.
Between phases: An enantioselective method for the construction of all-carbon quaternary stereocenters from 3-aryl-substituted oxindoles via asymmetric phase-transfer alkylation has been developed. The products are obtained in high yields and optical purity of up to 93 % ee by the use of (S,S)-3,4,5-trifluorophenyl-NAS bromide (I) as chiral phase-transfer catalyst. Boc=tert-butyloxycarbonyl.
A carbapenem intermediate undergoes organocatalytic Mannich reaction with anilines to give the corresponding Mannich bases. It reacts with aliphatic or benzylic amines to give highly functionalized diazabicyclo[4.2.1]nonanes.
A catalytic twist: A resin-supported peptide was developed for primary amine catalyzed reactions. Two tryptophan residues attached to a helix-forming sequence formed a peptide that efficiently catalyzes the asymmetric Michael addition of nitromethane to α,β-unsaturated ketones under aqueous conditions. This peptide catalyst is also applicable to other organocatalytic reactions that proceed through iminium-ion and enamine mechanisms. Aib=2-aminoisobutyric acid
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.
A 1,2,3-triazolium salt has been used both as an organocatalyst and as a 1,2,3-triazolylidene precursor for the preparation of a rhodium-based catalyst. The metal complex actively promotes 1,4-additions to α,β-unsaturated carbonyl compounds, and the triazolium salt was tested in the hetero-Michael addition of α,β-unsaturated ketones.
No metal in mine: Anti-HIV drug efavirenz is now available by organocatalysis in 99 % ee. A combination of longer ether-type cinchona alkaloid catalysts and tetramethylammonium fluoride (TMAF) enables enantioselective trifluoromethylation of 1-(5-chloro-2-nitrophenyl)-3-cyclopropylprop-2-yn-1-one with Me3SiCF3 to provide a desired (S)-trifluoromethyl carbinol in up to 80 % ee. (S)-Trifluoromethyl carbinol is a two-step precursor for efavirenz.
A quin quin situation: An organocatalytic asymmetric conjugate addition of 2-oxindole-3-carboxylate esters to 2-phthalimidoacrylates catalyzed by a quinine-derived thiourea is described, which provides efficient access to a variety of quaternary oxindole-based Cγ-tetrasubstituted α-amino acid derivatives in up to 96 % yield and up to 90 % ee. The opposite enantiomers of the products can also be obtained by using a similar quinidine-based catalyst.
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).
Further and further: A vinylogous Diels–Alder reaction that is catalyzed by a commercially available chiral phosphoric acid has been developed. A range of structurally diverse complex tetrahydrocarbazoles were obtained in high chemical yields and with excellent stereoselectivity. It was thus demonstrated that the synthetic utility of the Diels–Alder reaction can be extended to include a vinylogous reactivity space.
Squared away: The first strategy for bringing about enantioselective Tamura reactions is reported. In the presence of a squaramide-based catalyst, enolizable anhydrides react with alkylidene oxindoles to generate spirooxindole products with excellent enantio- and diastereocontrol. The methodology is of wide scope and leads to structurally diverse products.
Two are better than one or three: α-Dihalogenoacetanilides have an attractive ability to form twofold H-bonds towards C=O groups, involving a N-H···O···H-C interaction (see figure). These nonconventional O···H-CX2 H-bonds are shown to be strong by molecular modeling and solid-state packing. As organocatalysts, α-dihalogenoacetanilides allow the activation of C=O bonds in lactide, enabling full conversion into its polymer, even in the presence of a tertiary amine as cocatalyst.
The reaction of easily accessible nitro olefins with the tBuOOH/1,8-diazabicycloundec-7-ene (TBHP/DBU) organocatalytic system gives rise to the corresponding α-nitro epoxides, which are suitable for subsequent reaction with 1,2-phenylenediamines under mild conditions to give quinoxaline heterocycles in up to 82 % yield.
Stable L-proline-functionalized zirconium phosphonates have been prepared and tested for the direct asymmetric aldol addition of various ketones with p-substituted benzaldehydes. High yields, diastereoselectivities and enantiomeric excesses have been obtained. Moreover, these materials can be easily recovered and used at least six times without loss of activity.
The enantioselective synthesis of β-azido α-oxyaminated aldehydes is performed by iminium/enamine–iron catalysis. In this study, an azide nucleophile is first introduced to the α,β-unsaturated aldehydes in an asymmetric fashion; TEMPO = 2,2,6,6-tetramethylpiperidinyloxy.
Hydroxysulfides acted as catalysts to promote the Morita–Baylis–Hillman alkylation reaction of cyclohexenones and dihydropyridinones. The procedure worked efficiently with a variety of halides as electrophiles. Side reactions were in competition with the MBH alkylation, but fine-tuning the reaction conditions minimized their occurrence.
An efficient method was developed for the synthesis of spirooxindole α-exo-methylene-γ-butyrolactone in good yield and excellent diastereoselectivity and enantioselectivity with a broad range of substrates.
Go bio! A biologically inspired organocatalytic one-pot synthesis of highly functionalized pyridazines has been developed by starting from readily available diazo compounds and Morita–Baylis–Hillman (MBH) carbonates (see scheme; DABCO=1,4-diazobicyclo[2.2.2]octane, Boc=tert-butoxycarbonyl). Under mild reaction conditions, this synthetic route tolerated significant substrate variation to deliver a broad range of substituted products, including CF3-substituted pyridazines derivatives.
An unusual addition: The first catalytic asymmetric formal [3+3] cycloaddition of isatin-derived 3-indolylmethanol with an in situ-generated azomethine ylide has been established to construct a chiral six-membered piperidine framework with two stereogenic centers. This approach represents the first enantioselective cycloaddition of isatin-derived 3-indolylmethanol, and it has realized an unusual enantioselective formal [3+3] cycloaddition of the azomethine ylide (DCE = 1,2-dichloroethane).
Break it up! Unconjugated 2,5-dienals appear to be more reactive substrates than the corresponding fully conjugated α,β,γ,δ-unsaturated aldehydes towards organocatalytic activation through trienamine intermediates. This reactivity has been demonstrated in the Diels–Alder reaction with nitroalkenes, a reaction that proceeds with clean β,ε-selectivity to afford the final products in high yields and stereoselectivities (see scheme; TMS=trimethylsilyl), the related polyconjugated dienals being completely unreactive.
The highly efficient synthesis of enantiomerically enriched substituted piperidines in good to excellent yields and enantioselectivity has been realized by using the title reaction, which is catalyzed by the chiral phosphoric acid (CPA) (R)-1.
Correct chirality critical: Organocatalytic asymmetric Adol-type and Mannich-type reactions of α-isothiocyanato phosphonate have been realized. Michael addition was also applicable under the same catalytic conditions. This versatile approach provides a new route for the synthesis of diverse highly optically active functionalized α-amino phosphonic acid derivatives.
Organocatalysis: A unified, catalytic, and highly stereocontrolled synthesis of a broad range of indolizidine-based alkaloids has been developed that delivers the target alkaloids with high overall yields and excellent optical purity. As a key step, a very convenient three-component Brønsted acid catalyzed vinylogous Mukaiyama–Mannich reaction (VMMR) was employed (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.
The use of β-oxo-amides in organocatalytic cycloaddition with aryl azidophenyl selenides has been developed, with the corresponding (arylselanyl)phenyl-1H-1,2,3-triazole-4-carboxamides being obtained in good to excellent yields. This organocatalytic protocol proved to be an efficient methodology for the combinatorial synthesis of new selenium-containing triazole compounds.
An enantioselective domino reaction was developed to construct 3-amino-2-oxindoles. With 1 mol-% of a bifunctional squaramide organocatalyst, the desired products were achieved in high yields and with excellent enantioselectivities.
Four rings, three stereocenters: The asymmetric cascade sulfa-Michael–Mannich reaction of 2-mercapto-quinoline-3-carbaldimines with maleimides catalyzed by a bifunctional tertiary amine–thiourea affords tetracyclic quinoline derivatives with three contiguous stereocenters in high yield with excellent diastereo- (>99:1 dr) and enantioselectivities (90–>99 % ee).
The quest for the forgotten Lewis acid: A potential Lewis acid catalyst that has received negligible attention is the carbocation. The ability of the triphenylmethyl (trityl) carbocation as a powerful catalyst for the Diels–Alder reaction is demonstrated for a range of substrates. Low catalyst loadings, excellent yields, and good endo/exo selectivities were achieved (see scheme).
Smashing the mirror: The symmetry breaking of meso primary diols was employed to control all-carbon quaternary stereocenters using catalytic asymmetric acyl transfer. The planar chiral Fu DMAP catalyst was used to reach a high degree of enantioselectivity (up to 97:3 e.r.) through a synergic effect, combining a desymmetrization step and a kinetic resolution.
Self-promotion: Mechanistic studies on the organocatalytic epoxidation of α,β-unsaturated aldehydes reveal the autoinductive behavior and establish that the hydrate/peroxyhydrate of the product is acting as a phase-transfer catalyst. Based on these results, an improved methodology that provides high selectivities and decreased catalyst loading, through the addition of chloral hydrate, has been developed (see scheme).
Hit for six: (±)-Stemoamide was synthesized in six steps starting from readily accessible 2-trimethylsilioxy-3-methylfuran, methyl-4-nitrobutyrate, and acrolein after converting the nitro group into a ketone and a subsequent reductive amination.
Gold and amine team up: Gold and an amine catalyst work synergistically to promote either an α-vinylidenation or an α-vinylidenation/γ-functionalization of aldehydes to generate tri- and tetrasubstituted allenes. The allene products also undergo an additional reaction to generate polysubstituted furans.
Going through a phase: The highly selective kinetic resolution of the title compounds, which are important chiral building blocks, was achieved by phase-transfer-catalyzed N-allylation. This synthetic method was applied to the highly enantioselective desymmetrization of a biaryl compound.
Three-star compounds: The title reaction of β-ketoamides, acrolein, and aminophenols, catalyzed by a bifunctional thiourea-tertiary amine organocatalyst, enables the preparation of an enantioenriched diazabicyclo[2.2.2]octanone (2,6-DABCO) scaffold. The chemoselective reaction sequence installs five new bonds and three stereocenters, two of which are contiguous tetrasubstituted centers, with excellent yields and high levels of stereocontrol. M.S.=molecular sieves.
(−)-Oseltamivir, a neuraminidase inhibitor, was synthesized in a one-pot operation (see scheme). A mechanistic study of the key Michael reaction revealed that both E and Z enamines are generated, acid accelerates E–Z enamine isomerization, and reactivity depends on the geometry of both Michael acceptor and enamine.
Caught in the act: A new concept for asymmetric Brønsted acid catalysis is presented. Compounds containing an acidic functionality in addition to an anion recognition site act as powerful conjugate-base-stabilized Brønsted acid catalysts. This strategy was applied to the first catalytic enantioselective three-component Povarov reaction of indoline and other secondary aromatic amines (see scheme; M.S.=molecular sieves).
Testing the waters: An efficient dodecyl benzene sulfonic acid (DBSA) catalyzed approach to the synthesis of the title compounds in water is reported. Furthermore, upon cleavage of the pyrrolidine group from the trans-3-alkenyl-2-pyrrolidine-2H-indazoles with Zn in CH3COOH, trans-3-alkenyl-1H-indazoles are obtained in good to excellent yields.
Newly framed: The δ,ε C=C bond of an interrupted cyclic 2,5-dienone induces the formation of a linear trienamine in the presence of a chiral primary amine, thus enabling the δ,ε-C=C bond to participate in a highly asymmetric inverse-electron-demand aza-Diels–Alder (DA) reaction with electron-deficient 1-azadienes. The DA reaction can be coupled with a Michael addition to produce a polycyclic framework with complete stereocontrol.
All about iodine: Chiral hypervalent iodine chemistry has been steadily increasing in importance in recent years. This Minieview catalogues enantioselective transformations triggered by chiral hypervalent iodine(III/V) reagents, in stoichiometric or catalytic quantities, highlighting the different reactivities in terms of yield and enantioselectivity. Moreover, the synthesis of the most remarkable and successful catalysts has been illustrated in detail.
Add acetic acid: A highly stereoselective N-heterocyclic carbene (NHC)-catalyzed formal [4+2] annulation between α,β-unsaturated aldehydes and imidazolidinones for the synthesis of imidazoles has been developed. Acetic acid serves as a key additive to achieve high chemoselectivity for the formal [4+2] annulation product.
NHC-enolate plus 3: N-heterocyclic carbenes (NHCs) serve as organocatalysts for the [2+3] annulation of nitrovinylindoles with α-chloroaldehydes via an intermediate azolium enolate. The method provides trans-disubstituted pyrroloindolones with good yields and excellent diastereo- and enantioselectivities. Further transformations lead to tetracyclic pyrrolo[1,2-a]indoles with potential psychotropic and other bioactivities.
All in a sequence: An organocatalyzed Morita–Baylis–Hillman (MBH)/bromination/[3+2] annulation sequence for highly stereoselective syntheses of bis(spirooxindole)s featuring adjacent spiro-stereocenters is described. The key step is an unprecedented catalytic asymmetric [3+2] annulation of isatin-derived MBH adducts, containing a tetrasubstituted alkene moiety, with isatins.
Chiral phosphoric acids (HB*) catalyze the asymmetric desymmetrization of meso 1,3-diols through mono-transacetalization with a tethered acetal unit (see scheme). This new strategy leads to the efficient assembly of tetrahydrofuran and tetrahydropyran skeletons bearing remote all-carbon-substituted quaternary stereocenters that are not straightforward to access by other methods.
Taming the beast, asymmetrically: Modulation of the reactivity of acid chlorides, using cinchona alkaloid catalysts, results in chiral α,β-unsaturated acylammoniums, which react with nucleophiles enantioselectively to give pyrrolidinones, piperid-2-ones, and dihydropyridinones. This nucleophile-catalyzed Michael/proton transfer/lactamization or lactonization organocascade leads to chiral intermediates previously employed for the synthesis of bioactive pharmaceuticals.
Smells like team spirit: N-acylimium ions are important reactive intermediates for the enantioselective synthesis of nitrogen-containing compounds. This review summarizes the enantioselective reactions of N-acyliminium ions with two different chiral organocatalysts, thioureas (A) and BINOL-derived phosphoric acid derivatives (B).
Control freaks: Chiral amine catalysts prove to be highly proficient mediators in the asymmetric, polyconjugate addition of C-, N-, and S-based nucleophiles to acyclic dienals and cyclic dienones. For high 1,6-selectivities, the stereo spatial matching of the molecular orbitals and ionic charges of the reacting species are key. But can we widen the scope and how far can we go with remote, iminium-stereocontrol?
Looking back: The asymmetric organocatalytic 1,4-addition of aldehydes to nitroolefins was studied by ESI-MS. Analysis of the back reaction starting from quasienantiomeric mass-labeled 1,4-adducts (see scheme) provided conclusive evidence for an enamine rather than an enol mechanism, and allowed identification of the enantioselectivity-determining step.
Be like Mike: The title reaction in the presence of the catalyst 1 afforded Michael adducts in excellent yields and enantioselectivities. The adducts were readily converted into α,α'-disubstituted α-amino acids. The enantioselective total synthesis of both (+)- and (−)-trigonoliimine A was accomplished using one of the Michael adducts derived from this methodology. M.S.=molecular sieves.
Back to BACs: In the pursuit of novel carbene organocatalysts, bis(amino)cyclopropenylidenes (BACs) were explored as alternatives to N-heterocyclic carbenes. They were effective in catalyzing the Stetter reaction, and displayed unique advantages over the commonly used thiazolylidenes and triazolylidenes. They also mediated extended umpolung reactions of enals. In addition, chiral analogues can be accessed readily for applications in enantioselective catalysis.
Strong, silent type: A novel alkoxyamine-type organocatalyst has been discovered for alcohol oxidation (see scheme). The alkoxyamine exhibits a high catalytic activity for the oxidation of alcohols to afford the corresponding carbonyl compounds in high yield by oxidative transformation into an oxoammonium ion, which is proposed to serve as an active species.
Pace Stetter: A new N-heterocyclic carbene (NHC)-catalysed transformation is described—the intramolecular vinylogous Stetter reaction. This transformation can be effected with both thiazolium and triazolium-based catalysts, using aromatic and aliphatic aldehydes, employing α,β,γ,δ-unsaturated esters, ketones, phosphonates and N-acylpyrroles, and can be conducted enantioselectively (see scheme).
Many hands make light work: In an organocatalytic asymmetric sulfonation of enones, the activation of a sulfonyl imine by an N-heterocyclic carbene (NHC) catalyst led to the release of a sulfinic anion, which underwent nucleophilic addition to the enone. The enantioselectivity of the process was controlled by a chiral thiourea/amine co-catalyst through anion recognition and hydrogen-bonding interactions. Tol=p-tolyl.
Sugar sugar: In the glycosylation of racemic alcohols with 1 using the chiral phosphoric acid 2 as an activator, one enantiomer of the racemic alcohol selectively reacts with 1 to give the corresponding glycoside with good to excellent α/β-stereo- and diastereoselectivity in high yield. The reaction was successfully applied to the synthesis of a chiral natural flavan glycoside using a racemic aglycon.
Copycat: A highly enantioselective biomimetic aldol reaction of malonic acid half thioesters with a variety of aldehydes affords optically active β-hydroxy thioesters by employing the cinchona-derived sulfonamide organocatalyst 1. The synthetic utility of this protocol was demonstrated by performing formal syntheses of the antidepressants (R)-fluoxetine, (R)-tomoxetine, (−)-paroxetine, and (R)-duloxetine.
Bifunctional catalysts: The performance of (thio)squaramide and (thio)urea-derived aminocatalysts was probed computationally within the context of Diels–Alder cycloadditions of nitrostyrene and anthracene (see figure). A proposed thiosquaramide-based catalyst is predicted to give the lowest reaction barrier, which stems from the ability of thiosquaramides to engage in stronger hydrogen-bonding interactions.
A point of difference: By utilizing an organosilane to chemoselectively reduce a phosphane oxide precatalyst to a phosphane (see scheme), the first catalytic (in phosphane) Wittig reaction has been developed. The methodology has been applied to the synthesis of 22 disubstituted and 24 trisubstituted olefins, including a multigram synthesis of a precursor to the anti-Alzheimer drug donepezil hydrochloride.
Second to none: Secondary amines are well-known enamine and iminium catalysts that can also be used as Lewis bases for the activation of electron-deficient olefins. In this Focus Review, a series of systematic studies on activation of nitroolefins with secondary amines as Lewis bases that give different multicomponent condensation products are described. Asymmetric syntheses of heterocycles based on this strategy are also presented.
A large number of organocatalytic processes are already well established in organic synthesis. Nevertheless, the number of publications in this field is still on the increase; new important results are produced constantly. This review gives a detailed overview of the latest developments and main streams in organocatalyzed asymmetric C-C bond formation of the last three years. It is intended to outline the most important current findings focused on especially new synthetic methodologies.
From pine resin to catalyst: The easily available rosin diterpene abietic acid has been transformed into a unique class of bifunctional thiourea catalysts that can also incorporate further substituents, thereby enabling either Lewis base or enamine activation modes. Their application in a wide range of stereoselective transformations has revealed the positive effect of this chiral and rigid skeleton on the catalytic performance of these hybrid thioureas.
Being the alpha: Despite the synthetic utility of chiral alkyl chlorides, catalytic methods for achieving enantioselective chlorination were only developed a decade ago. This Focus Review discusses the catalytic enantioselective α-chlorination of carbonyl compounds, as well as some stereospecific substitution reactions of the resulting optically active chlorides.
Valiant catalysis: Hoveyda et al. have developed a set of catalysts derived from valine for enantioselective syntheses. Reagents are inexpensive, allyl additions are scalable, harsh conditions are avoided, and reactions can be performed with 0.25 mol % catalyst in under 6 h at room temperature. The efficiency, economy, selectivity, and simplicity of the transformations and the range of boron reagents look to have sustained impact on future progress in amine and alcohol syntheses.
When one catalyst meets another: Since chiral Brønsted acids catalysts were discovered more than a decade ago, they have become prevalent in organocatalysis. Researchers have recently used cooperative catalysis to improve existing transformations and discover new reactions. This Focus Review summarizes the achievements made in the field of asymmetric cascade/multicomponent reactions with the help of cooperative catalysis from chiral Brønsted acids.
Phosphines and hydrogen bonding are good collaborators! Air-stable α-amino acids or dipeptide derived chiral phosphines bearing hydrogen-bond-donating and silicon-based bulky groups are powerful and versatile catalysts for a range of enantioselective processes, including [3+2] and [4+2] cycloadditions, allylic alkylations, Morita–Baylis–Hillman reactions, and Michael addition reactions. They represent a class of novel, economical, and practical chiral phosphine-based organocatalysts.
An unusual specificity for acetone as the nucleophile is observed in asymmetric cross-aldol reactions with aldehydes catalyzed by a fluorous proline derivative. The reactions take place in acetone/perfluorohexane under biphasic conditions, and the valuable catalyst/perfluorohexane phase can be repeatedly recycled.
A highly efficient asymmetric allylic alkylation reaction of Morita–Baylis–Hillman carbonates with phosphorus ylides under the catalysis of modified cinchona alkaloids is described. Chiral 3-substituted 2,4-functionalized 1,4-pentadienes can be obtained with excellent enantioselectivities (up to 98 % ee) under mild reaction conditions. Boc = tert-butoxycarbonyl.
New balls please: A PCy3-catalyzed ring-expansion reaction of aziridine-fused fullerenes (aziridinofullerenes) by the insertion of CO2 and aryl isocyanates is disclosed (see scheme). This allows for CO2 fixation by aziridinofullerenes. The expansion with aryl isocyanates led to a new fullerene family, imidazolidinone-fused fullerenes, in high yields. A mechanistically related unprecedented fullerenyl phosphonium salt was also successfully isolated (Cy=cyclohexyl).
The inexpensive and readily available ex-chiral-pool building block (–)-isosteviol provides unique geometric features such as the rigid and concave arrangement of its functional groups. Consequently, this valuable architecture has found significant applications in various fields of organic chemistry.
Strategic move: Isatin as a core structure has inspired the development of useful catalytic strategies to give access to interesting molecular architectures with biological activity.
Catalysts caught in the act: The N-heterocyclic carbenes 1,3-dimesitylimidazolin-2-ylidene (SIMes) and 1,3-dimesitylimidazol-2-ylidene (IMes) react with N-tosyl benzaldimine or diphenylketene to afford the corresponding zwitterions in high yields (see scheme). The molecular structures of three of them were determined by X-ray crystallography and their thermal stability was monitored by thermogravimetric analysis. The NHC·ketene betaines were found to be key intermediates for the Staudinger reaction catalyzed by NHCs.
Some assembly required: The first enantioselective aza-Morita–Baylis–Hillman (MBH) reaction with imines of β,γ-unsaturated α-ketoesters and acrolein was developed. The transformation is catalyzed by a combined system of β-ICD and (R)-BINOL (1) or a bifunctional tertiary amine–thiourea 2. Experimental results and preliminary spectroscopy studies demonstrated that self-assembly between β-ICD and the additive may occur, which then promotes the asymmetric aza-MBH reaction through a synergistic activation mode.
Aromatic enamines: para-Vinylanilines were identified as unique nucleophiles, closely resembling enamines, to undergo C-C coupling with aldehydes catalyzed by a simple primary–tertiary diamine/Brønsted acid. The resulting bis(allylic) adducts, which have potential as functional materials, were obtained in high yields under rather mild conditions (see scheme).
I(n)organocatalysis: Neutral multidentate halogen-bond donors (halogen-based Lewis acids) catalyze the reaction of 1-chloroisochroman with ketene silyl acetals. The organocatalytic activity is linked to the presence (and number as well as orientation) of iodine substituents. As hidden acid catalysis can be ruled out with high probability, this case constitutes strong evidence for halogen-bond based organocatalysis. TBS=tert-butyldimethylsilyl.
Ready, amine, fire! Amine catalysis is a useful and well-studied method for constructing a wide variety of chiral scaffolds in asymmetric synthesis. However, organocatalysis with amines that is not centered on asymmetric transformations is also developing at a rapid rate. In this Focus Review, reports on amine catalyzed non-asymmetric transformations are examined.
Location of the carboxylate ion: A series of biaryl DMAP catalysts with an internal carboxylate was prepared, and the catalytic activities of the derivatives were evaluated to determine the carboxylate position that most accelerated the DMAP-catalyzed acylation. The carboxylate ion proximal to the pyridine ring in a face-to-face geometry was found to act as an effective general base for the acylation reaction.
From all natural to bioactive: This review shows that organocatalytic methods based on the use of nucleophilic phosphorus catalysts have been successfully applied as key steps in the formal or total synthesis of complex natural products. These methods also afford suitable tools for the constitution of either focused or diversity-oriented-synthesis inspired libraries of small molecules for biological screening.
The heat is on: A new [3+2] cycloaddition/cycloreversion strategy allows for catalytic and thermally allowed carbonyl–olefin metathesis (see scheme). This strategy opens opportunities for new developments in the field of carbonyl–olefin metathesis, which traditionally relied on stoichiometric amounts of transition-metal reagents or photochemical promotion.
Work in process: The variations in the synthetic applications of phase-transfer reactions between 2006 and the middle of 2012 have been summarized to show the recent progress made in this field. The reactions have been applied to the synthesis of biologically active natural products and the large-scale preparation of drugs. The conceptually new catalyst design, reaction system, and reaction mode are also described.
Cascading down: Reaction of an aldehyde with an NHC provides the corresponding Breslow intermediate A, which can be readily oxidized with various organic and inorganic oxidants to give the acylazolium ion B (see scheme). Intermediate B can react with various nucleophiles either at the 2 or 4-position. With enals as starting aldehydes, elegant cascade processes have been developed using oxidative carbene catalysis.
Strap in with organocatalysis: Organocatalysis can often give rise to unprecedented selectivities by encapsulation of the catalytic active site in an analogous manner as enzymes. Catalyst encapsulation can be considered as a powerful strategy for achieving unique transformations in a very efficient way.
Two views: The mechanism of the conjugate addition of linear aldehydes to nitro olefins has been investigated by two research groups. In spite of extensive experimental data, important questions remain unanswered (see scheme; TMS=trimethylsilyl, En=enamine).
What to do with vitamin B2: Flavins are ubiquitous cofactors for enzymes and have been explored extensively as organocatalysts. Recent developments in the synthesis and use of flavin derivatives are discussed in this Minireview.
Taking the Michael: Recent progress in asymmetric organocatalysis has led to the development of several asymmetric transformations that employ various substrates. Among these substrates, maleimides have emerged as excellent Michael acceptors, dienophiles, and dipolarophiles. In this Focus Review we highlight the advances in the asymmetric synthesis of succinimide derivatives.
Opposites attract: This simple realization is the basis for asymmetric counteranion-directed catalysis (ACDC). All reactions proceeding via cationic intermediates are accompanied by a counteranion. Inducing high enantioselectivities in these reactions merely by ion pairing with an enantiomerically pure counteranion has been achieved for the first time during recent years.