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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Here be pyrazoles: A thiourea-based cinchona-derived bifunctional catalyst promotes the addition of 1,3-diketones to differently substituted nitroacrylates in modest to fair yields and up to 93 % enantioselectivity. Enantiomerically enriched 3,4,5-trialkyl substituted pyrazoles can also be synthesized by using this method. Bn=benzyl.
Easy access: Enantioselective organocatalyzed formal [4+2] cycloaddition of cyclic ketimines and α-methyl allenoate has been developed. The highly γ-selective addition of the allenoate to the ketimine mediated by (R)-SITCP, a chiral spiro-type monoaryl phosphine catalyst, leads to the formation of tetrahydropyridines that have chiral tetrasubstituted stereogenic carbon centers in up to 93 % ee with excellent regioselectivity.
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.
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.
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.
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.
Two is better than one! An enantioselective α-hydroxylation of a lactone with a vinylogous pyridone structure has been achieved using a guanidine–urea bifunctional organocatalyst. The hydroxylation product, which is a key synthetic intermediate of (20S)-camptothecin and its analogues, was obtained in 95 % yield with 84 % ee (see scheme; CHP=cumene hydroperoxide).
Fluorine power: The cheap, fast, environmentally friendly oxidation of tertiary amines and azines to the corresponding N-oxides is reported by using polyfluoroalkyl ketones as efficient organocatalysts. Aliphatic tertiary amines and azines are oxidized chemoselectively in high to quantitative yields utilizing 10 mol % catalyst loading and H2O2 as the oxidant (see scheme).
In one go: The first one-pot enantioselective oxidative coupling of cyclic benzylic ethers with aldehydes has been developed. A variety of benzylic ethers could be functionalized with this method, and the corresponding oxygen heterocycles were obtained with high enantioselectivity.
Go organic! α,β-Unsaturated acyl cyanides are key bis-electrophile substrates for successful domino enantioselective organocatalyzed Michael-intramolecular acylation domino sequences (see scheme). This new reactivity has been applied to the synthesis of enantioenriched the azaspiro[4,5]decanone ring systems by a formal [3+3]spiroannulation.
Two birds, one stone! The first kinetic resolution of allyl fluorides was achieved by the development of an organocatalyzed enantioselective allylic trifluoromethylation. Two kinds of chiral fluorinated compounds, which incorporate C*-F and C*-CF3 units, respectively, can thus be accessed by a single transformation.
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).
Dynamic and efficient: Dynamic kinetic asymmetric transformations of racemic β-bromo-α-ketoesters through the direct aldolization of nitromethane and acetone provided access to fully substituted α-glycolic acid derivatives bearing a β-stereocenter (see scheme; PNBA=p-nitrobenzoic acid). The aldol adducts were obtained in excellent yield with high relative and absolute stereocontrol under mild reaction conditions.
A sterically demanding proline derivative promotes the first aminocatalyzed α-alkylation of α-branched aldehydes with benzyl bromides as alkylating agents. Racemic α-branched aldehydes react with alkylating agents in a DYKAT process to give the corresponding α-alkylated aldehydes with quaternary stereogenic centers in good yields and high enantioselectivities.
The three-component Biginelli reaction was catalyzed by BINOL-derived double axially chiral bis-phosphorylimides. The catalyst with 3,3'-2-naphthyl substituents most effectively catalyzed the reaction and a series of chiral dihydropyrimidinethiones (DHPMs) were obtained in high yields up to 97 % with 90–96 % ee in only 12 hours.
The organocatalytic asymmetric synthesis of unique and highly functionalized chiral pyrrolizine-based triheterocycles has been achieved by the cascade aza-Michael–aldol reaction of α-branched α,β-unsaturated aldehydes with 2-(trifluoroacetyl)pyrroles as the N-centered heteroaromatic nucleophiles.
A practical protocol for the DABCO-catalysed synthesis of β-alkoxyacrylates is described. The protocol is efficient and economical, and it allows the transformation of a range of alcohols (including tertiary alcohols) into the corresponding β-alkoxyacrylate derivatives and the selective monoprotection of different diols (primary vs. secondary and tertiary).
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.
The “Big” reaction: An efficient and environmentally benign catalytic system was developed for the highly selective one-pot, three-component Biginelli reaction under solvent-free conditions; with the use of a recoverable ethyl-bridged periodic mesoporous organosilica-supported sulfonic acid.
α-Cyclopropylphosphonates with three stereogenic centres were obtained in good yields and high enantio- and diastereocontrol through a “one-pot” domino process catalysed by a chiral pyrrolidine. The highly functionalised cyclopropanes should be versatile starting materials for biologically important compounds.
We have developed highly effective diastereo- and enantioselective Michael additions of 3-substituted oxindoles to trifluoromethylated nitro olefins catalyzed by a quinine-derived squaramide catalyst. The corresponding adducts are obtained in good to excellent yields (up to 99 %) along with high diastereoselectivities (up to >20:1 dr) and excellent enantioselectivities (up to 99 % ee).
Ring of Fire: Biologically interesting heterocycles, namely, benzo[g][1,2,3]oxathiazocine-4,5-dicarboxylate 2,2-dioxide derivatives, were prepared in high yields by PPh3-catalyzed ring-expansion reactions of sulfamate-derived cyclic imines with acetylenedicarboxylates under very mild conditions (see scheme).
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.
Unmasking the agent: A highly enantioselective catalytic α-hydroxylation of 1-tetralone-derived β-keto esters was achieved by using a guanidine–urea bifunctional organocatalyst and cumene hydroperoxide (CHP; see scheme). The method was successfully applied to synthesize a key intermediate of the anti-cancer agent daunorubicin.
Matching catalyst and substrate: Organocatalytic cycloaddition between dienamines and 1,4-benzo- or 1,4-naphthoquinones affords biologically interesting dihydronaphtho- and dihydroanthraquinone core structures. The enantioselectivity of this new reaction is ensured by a steric shielding catalyst and carefully selecting substrates that greatly favor the endo approach (see scheme) due to electrostatic interactions in the zwitterionic intermediate.
New 3,3'-diiodo-BINOL-fused maleimides were designed as hypervalent iodine(III) organocatalysts and were easily synthesized in a few steps and in high yields. Their use as catalysts in the benchmark α-tosylation of ketones resulted in yields and enantiomeric ratios that were among the best reported.
Chiral 1,3-imidazolin-2-ylidene NHCs functionalized with urea-type hydrogen-bond donors have been evaluated as organocatalysts in enantioselective reactions of homoenolates. Some unprecedented levels of enantioselectivity have been obtained.
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?
Fluoro-catalyst a hero: In the asymmetric Michael addition reaction of nitrostyrene with propanal, the diastereoselectivity (syn/anti=92:8) with our fluorous prolinol methyl ether catalyst is much higher than that (syn/anti=87–80:13–20) with nonfluorinated prolinol methyl ethers, which have two n-octyl groups or two phenyl groups in place of perfluorohexylethyl groups.
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.
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.
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.
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.
Dipoles apart: In situ formed enamines react with diazoacetates under mild conditions to afford the corresponding polysubstituted pyrazoles in good-to-excellent yields through an inverse-electron-demand 1,3-dipolar cycloaddition process (see scheme).
Flustering oxindoles: An enantioselective synthesis of 3,3'-disubstituted oxindoles by conjugate addition of malonates to isatylidene-3-acetaldehydes in high yield and enantioselectivity is developed (see scheme). The synthetic utility of this reaction is demonstrated by the synthesis of three oxindole core structures and the asymmetric total synthesis of debromoflustramine E.
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.