A Practical and Robust Zwitterionic Cooperative Lewis Acid/Acetate/Benzimidazolium Catalyst for Direct 1,4-Additions.

A catalyst type is disclosed allowing for exceptional efficiency in direct 1,4-additions. The catalyst is a zwitterionic entity, in which acetate binds to CuII , which is formally negatively charged and serving as counterion for benzimidazolium. All 3 functionalities are involved in the catalytic activation. For maleimides productivity was increased by a factor >300 compared to literature (TONs up to 6700). High stereoselectivity and productivity was attained for a broad range of other Michael acceptors as well. The polyfunctional catalyst is accessible in only 4 steps from N-Ph-benzimidazole with an overall yield of 96 % and robust during catalysis. This allowed to reuse the same catalyst multiple times with nearly constant efficiency. Mechanistic studies, in particular by DFT, give a detailed picture how the catalyst operates. The benzimidazolium unit stabilizes the coordinated enolate nucleophile and prevents that acetate/acetic acid dissociate from the catalyst.

Cooperative Lewis Acid-1,2,3-Triazolium-Aryloxide Catalysis: Pyrazolone Addition to Nitroolefins as Entry to Diaminoamides.

Pyrazolones represent an important structural motif in active pharmaceutical ingredients. Their asymmetric synthesis is thus widely studied. Still, a generally highly enantio- and diastereoselective 1,4-addition to nitroolefins providing products with adjacent stereocenters is elusive. In this article, a new polyfunctional CuII -1,2,3-triazolium-aryloxide catalyst is presented which enables this reaction type with high stereocontrol. DFT studies revealed that the triazolium stabilizes the transition state by hydrogen bonding between C(5)-H and the nitroolefin and verify a cooperative mode of activation. Moreover, they show that the catalyst adopts a rigid chiral cage/pore structure by intramolecular hydrogen bonding, by which stereocontrol is achieved. Control catalyst systems confirm the crucial role of the triazolium, aryloxide and CuII , requiring a sophisticated structural orchestration for high efficiency. The addition products were used to form pyrazolidinones by chemoselective C=N reduction. These heterocycles are shown to be valuable precursors toward ß,γ'-diaminoamides by chemoselective nitro and N-N bond reductions. Morphological profiling using the Cell painting assay identified biological activities for the pyrazolidinones and suggest modulation of DNA synthesis as a potential mode of action. One product showed biological similarity to Camptothecin, a lead structure for cancer therapy.

Enantioenriched γ-Aminoalcohols, ß-Amino Acids, ß-Lactams, and Azetidines Featuring Tetrasubstituted Fluorinated Stereocenters via Palladacycle-Catalyzed Asymmetric Fluorination of Isoxazolinones.

Enantiopure fluorine containing ß-amino acids are of large biological and pharmaceutical interest. Strategies to prepare ß-amino acid derivatives possessing a F-containing tetrasubstituted stereocenter at the α-C atom in a catalytic asymmetric sense are rare, in particular using an enantioselective electrophilic C-F bond formation. In the present study, a highly enantioselective palladacycle-catalyzed fluorination of isoxazolinones was developed. It is demonstrated that isoxazolinones are useful precursors toward enantiopure ß-amino acid derivatives by diastereo- and chemoselective reduction. The formed γ-aminoalcohols served as valuable precursors toward ß-amino acids, ß-amino acid esters, and ß-lactams, all featuring tetrasubstituted fluorinated stereocenters. In addition, by this work, enantioenriched fluorinated azetidines were accessible for the first time.

Direct Enantioselective Addition of Alkynes to Imines by a Highly Efficient Palladacycle Catalyst.

Enantiopure propargylic amines are highly valuable synthetic building blocks. Much effort has been devoted to develop methods for their preparation. The arguably most important strategy is the 1,2-addition of alkynes to imines. Despite remarkable progress, the known methods using Zn and Cu catalysts suffer from the need for high catalyst loadings, typically ranging from 2-60 mol % for neutral aldimine substrates. Here we report a planar chiral Pd complex acting as very efficient catalyst for direct asymmetric alkyne additions to imines, requiring very low catalyst loadings. Turnover numbers of up to 8700 were accomplished. Our investigation suggests that a Pd-acetylide complex is generated as a catalytically relevant intermediate by the aid of an acac ligand acting as internal catalytic base. It is shown that the catalyst is quite stable under the reaction conditions and that product inhibition is not an issue. A total of 39 examples is shown which all yielded almost enantiopure products.

Stereoretentive Regio- and Enantioselective Allylation of Isoxazolinones by a Planar Chiral Palladacycle Catalyst.

The catalytic allylic substitution is one of the most important tools in asymmetric synthesis to form C-C bonds in an enantioselective way. While high efficiency was previously accomplished in terms of enantio- and regiocontrol using different catalyst types, a strong general limitation is a very pronounced preference for the formation of allylic substitution products with (E)-configured C=C double bonds. Herein, we report that with a planar chiral palladacycle catalyst a diastereospecific reaction outcome is achieved using isoxazolinones and allylic imidates as substrates, thus maintaining the C=C double bond geometry of the allylic substrates in the highly enantioenriched products. DFT calculations show that the reactions proceed via an SN 2 mechanism and not via π-allyl Pd complexes. Crucial for the high control is the stabilization of the allylic fragment in the SN 2 transition state by π-interactions with the phenyl substituents of the pentaphenylferrocenyl catalyst core.

Highly Active Cooperative Lewis Acid-Ammonium Salt Catalyst for the Enantioselective Hydroboration of Ketones.

Enantiopure secondary alcohols are fundamental high-value synthetic building blocks. One of the most attractive ways to get access to this compound class is the catalytic hydroboration. We describe a new concept for this reaction type that allowed for exceptional catalytic turnover numbers (up to 15 400), which were increased by around 1.5-3 orders of magnitude compared to the most active catalysts previously reported. In our concept an aprotic ammonium halide moiety cooperates with an oxophilic Lewis acid within the same catalyst molecule. Control experiments reveal that both catalytic centers are essential for the observed activity. Kinetic, spectroscopic and computational studies show that the hydride transfer is rate limiting and proceeds via a concerted mechanism, in which hydride at Boron is continuously displaced by iodide, reminiscent to an SN 2 reaction. The catalyst, which is accessible in high yields in few steps, was found to be stable during catalysis, readily recyclable and could be reused 10 times still efficiently working.

Stereospecific Asymmetric Synthesis of Tertiary Allylic Alcohol Derivatives by Catalytic [2,3]-Meisenheimer Rearrangements.

Chiral acyclic tertiary allylic alcohols are very important synthetic building blocks, but their enantioselective synthesis is often challenging. A major limitation in catalytic asymmetric 1,2-addition approaches to ketones is the enantioface differentiation by steric distinction of both ketone residues. Herein we report the development of a catalytic asymmetric Meisenheimer rearrangement to overcome this problem, as it proceeds in a stereospecific manner. This allows for high enantioselectivity also for the formation of products in which the residues at the generated tetrasubstituted stereocenter display a similar steric demand. Low catalyst loadings were found to be sufficient and the reaction conditions were mild enough to tolerate even highly reactive functional groups, such as an enolizable aldehyde, a primary tosylate, or an epoxide. Our investigations suggest an intramolecular rearrangement pathway.

Enantiodivergent [4+2] Cycloaddition of Dienolates by Polyfunctional Lewis Acid/Zwitterion Catalysis.

Diels-Alder reactions have become established as one of the most effective ways to prepare stereochemically complex six-membered rings. Different catalysis concepts have been reported, including dienophile activation by Lewis acids or H-bond donors and diene activation by bases. Herein we report a new concept, in which an acidic prodiene is acidified by a Lewis acid to facilitate deprotonation by an imidazolium-aryloxide entity within a polyfunctional catalyst. A metal dienolate is thus formed, while an imidazolium-ArOH moiety probably forms hydrogen bonds with the dienophile. The catalyst type, readily prepared in few steps in high overall yield, was applied to 3-hydroxy-2-pyrone and 3-hydroxy-2-pyridone as well as cyclopentenone prodienes. Maleimide, maleic anhydride, and nitroolefin dienophiles were employed. Kinetic, spectroscopic, and control experiments support a cooperative mode of action. High enantioselectivity was observed even with unprecedented TONs of up to 3680.

Polyfunctional Imidazolium Aryloxide Betaine/Lewis Acid Catalysts as Tools for the Asymmetric Synthesis of Disfavored Diastereomers.

Enzymes are Nature's polyfunctional catalysts tailor-made for specific biochemical synthetic transformations, which often proceed with almost perfect stereocontrol. From a synthetic point of view, artificial catalysts usually offer the advantage of much broader substrate scopes, but stereocontrol is often inferior to that possible with natural enzymes. A particularly difficult synthetic task in asymmetric catalysis is to overwrite a pronounced preference for the formation of an inherently favored diastereomer; this requires a high level of stereocontrol. In this Article, the development of a novel artificial polyfunctional catalyst type is described, in which an imidazolium-aryloxide betaine moiety cooperates with a Lewis acidic metal center (here Cu(II)) within a chiral catalyst framework. This strategy permits for the first time a general, highly enantioselective access to the otherwise rare diastereomer in the direct 1,4-addition of various 1,3-dicarbonyl substrates to ß-substituted nitroolefins. The unique stereocontrol by the polyfunctional catalyst system is also demonstrated with the highly stereoselective formation of a third contiguous stereocenter making use of a diastereoselective nitronate protonation employing α,ß-disubstituted nitroolefin substrates. Asymmetric 1,4-additions of ß-ketoesters to α,ß-disubstituted nitroolefins have never been reported before in literature. Combined mechanistic investigations including detailed spectroscopic and density functional theory (DFT) studies suggest that the aryloxide acts as a base to form a Cu(II)-bound enolate, whereas the nitroolefin is activated by H-bonds to the imidazolium unit and the phenolic OH generated during the proton transfer. Detailed kinetic analyses (RPKA, VTNA) suggest that (a) the catalyst is stable during the catalytic reaction, (b) not inhibited by product and (c) the rate-limiting step is most likely the C-C bond formation in agreement with the DFT calculations of the catalytic cycle. The robust catalyst is readily synthesized and recyclable and could also be applied to a cascade cyclization.

Asymmetric Carboxycyanation of Aldehydes by Cooperative AlF/Onium Salt Catalysts: from Cyanoformate to KCN as Cyanide Source.

Asymmetric 1,2-additions of cyanide yield enantioenriched cyanohydrins as versatile chiral building blocks. Next to HCN, volatile organic cyanide sources are usually used. Among them, cyanoformates are more attractive on technical scale than TMSCN for cost reasons, but catalytic productivity is usually lower. Here, the development of a new strategy for cyanations is described, in which this activity disadvantage is overcome. A Lewis acidic Al center cooperates with an aprotic onium moiety within a remarkably robust bifunctional Al-F-salen complex. This allowed for unprecedented turnover numbers of up to 104 . DFT studies suggest an unexpected unique trimolecular pathway in which the ammonium bound cyanide attacks the aldehyde, which itself is activated by the carbonyl group of the cyanoformate binding to the Al center. In addition, a novel practical carboxycyanation method was developed that makes use of KCN as the sole cyanide source. The use of a pyrocarbonate as carboxylating reagent provided the best results.

Polyfunctional Bis-Lewis-Acid-/Bis-Triazolium Catalysts for Stereoselective 1,4-Additions of 2-Oxindoles to Maleimides.

Achieving enzyme-like catalytic activity and stereoselectivity without the typically high substrate specificity of enzymes is a challenge in the development of artificial catalysts for asymmetric synthesis. Polyfunctional catalysts are considered to be a promising tool for achieving excellent catalytic efficiency. A polyfunctional catalyst system was developed, which incorporates two Lewis acidic/Brønsted basic cobalt centers in combination with triazolium moieties that are crucial for high reactivity and excellent stereoselectivity in the direct 1,4-addition of oxindoles to maleimides. The catalyst is assembled through click chemistry and is readily recyclable through precipitation by making use of its charges. Kinetic studies support a cooperative mode of action. Diastereodivergency is achievable with either Boc-protected or unprotected maleimide.

In Situ Generated Gold Nanoparticles on Active Carbon as Reusable Highly Efficient Catalysts for a C sp 3 -C sp 3 Stille Coupling.

Gold nanoparticle catalysts are important in many industrial production processes. Nevertheless, for traditional C sp 2 -C sp 2 cross-coupling reactions they have been rarely used and Pd catalysts usually give a superior performance. Herein we report that in situ formed gold metal nanoparticles are highly active catalysts for the cross coupling of allylstannanes and activated alkylbromides to form C sp 3 -C sp 3 bonds. Turnover numbers up to 29 000 could be achieved in the presence of active carbon as solid support, which allowed for convenient catalyst recovery and reuse. The present study is a rare case where a gold metal catalyst is superior to Pd catalysts in a cross-coupling reaction of an organic halide and an organometallic reagent.

Double Regioselective Asymmetric C-Allylation of Isoxazolinones: Iridium-Catalyzed N-Allylation Followed by an Aza-Cope Rearrangement.

Isoxazolinones are biologically and synthetically interesting densely functionalized heterocycles, which for a long time were not accessible in enantioenriched form by asymmetric catalysis. Next to the deficit of enantioselective methods, the functionalization of isoxazolinones is often plagued by regioselectivity issues due to the competition of various nucleophilic centers within the heterocycles. We report the first regio- and enantioselective C-allylations of isoxazolinones. These occur with high regioselectivity in favor of the linear allylation products, although Ir phosphoramidite catalysts were used, which commonly results in branched isomers. Our studies suggest that this outcome is the result of a reaction cascade via an initial regio- and enantioselective N-allylation to provide a branched allyl intermediate, followed by a spontaneous [3,3]-rearrangement resulting in chirality transfer.

Highly Enantioselective Ferrocenyl Palladacycle-Acetate Catalysed Arylation of Aldimines and Ketimines with Arylboroxines.

Benzylic N-substituted stereocenters constitute a frequent structural motif in drugs. Their highly enantioselective generation is hence of technical importance. An attractive strategy is the arylation of imines with organoboron reagents. Chiral Rh complexes have reached a high level of productivity for this reaction type. In this article we describe that an electron rich PdII catalyst also performs well in the arylation of aldimines, comparable to the best Rh catalysts. The ferrocenyl palladacycle-acetate catalyst allows for a broad substrate scope and very high enantioselectivities. Commonly observed side reactions like aryl-aryl homocouplings and imine hydrolysis could be blocked. Mechanistic studies implicate that a) the acetate ligand is crucial for transmetallation, b) the active catalyst is most likely a palladacycle-OAc monomer, c) the rate limiting step is probably the product release. By added KOAc the arylation could also be applied to ketimines.

An Aluminum Fluoride Complex with an Appended Ammonium Salt as an Exceptionally Active Cooperative Catalyst for the Asymmetric Carboxycyanation of Aldehydes.

Al-F bonds are among the most stable σ bonds known, exhibiting an even higher bond energy than Si-F bonds. Despite a stability advantage and a potentially high Lewis acidity of Al-F complexes, they have not been described as structurally defined catalysts for enantioselective reactions. We show that Al-F salen complexes with appended ammonium moieties give exceptional catalytic activity in asymmetric carboxycyanations. In addition to aromatic aldehydes, enal and aliphatic substrates are well accepted. Turnover numbers up to around 104 were achieved, whereas with previous catalysts 101 -102 turnovers were typically attained. In contrast to Al-Me and Al-Cl salen complexes, the analogous Al-F species are remarkably stable towards air, water, and heat, and can be recovered unchanged after catalysis. They possess a considerably increased Lewis acidity as shown by DFT calculations.

Dual Palladium(II)/Tertiary Amine Catalysis for Asymmetric Regioselective Rearrangements of Allylic Carbamates.

The streamlined catalytic access to enantiopure allylic amines as valuable precursors towards chiral ß- and γ-aminoalcohols as well as α- and ß-aminoacids is desirable for industrial purposes. In this article an enantioselective method is described that transforms achiral allylic alcohols and N-tosylisocyanate in a single step into highly enantioenriched N-tosyl protected allylic amines via an allylic carbamate intermediate. The latter is likely to undergo a cyclisation-induced [3,3]-rearrangement catalysed by a planar chiral pentaphenylferrocene palladacycle in cooperation with a tertiary amine base. The otherwise often indispensable activation of palladacycle catalysts by a silver salt is not required in the present case and there is also no need for an inert gas atmosphere. To further improve the synthetic value, the rearrangement was used to form dimethylaminosulfonyl-protected allylic amines, which can be deprotected under non-reductive conditions.

Regioselective Pd-Catalyzed Synthesis of 2,3,6-Trisubstituted Pyridines from Isoxazolinones.

Substituted pyridines are prevalent heterocycles of fundamental importance. Their efficient regioselective preparation is often still a challenge despite a large number of reported synthetic methodologies. In this letter we report an operationally simple approach that makes use of readily accessible isoxazolinones. The protocol involves a Pd(II)-catalyzed C-regioselective 1,4-addition to vinylketones, followed by a Pd(0)-catalyzed transformation, which is assumed to proceed via vinylnitrene-Pd intermediates. Both hydrogen and air are necessary for the pyridine formation step and could be employed at ratios above the upper explosive limit thus avoiding a safety issue. This new strategy allows an effective, scalable and practical access to various previously unknown 2,3,6-trisubstituted pyridines.

Baseline NT-ProBNP level predicts success of cardioversion of atrial fibrillation with flecainide.

BACKGROUND: Patients with acute-onset symptomatic atrial fibrillation (AF) can be treated with flecainide. However, flecainide may induce arrhythmias and/or exaggerate heart failure. Therefore, validated markers to predict the efficacy of flecainide and prevent adverse effects are required. We hypothesised that lower NT-proBNP plasma levels correlate with higher success rates of cardioversion with flecainide in patients with AF. METHODS: In this prospective single-centre study, we included 112 subsequent patients with acute-onset (< 24 h) symptomatic AF. Patients with symptoms of heart failure and ECG signs of ischaemia were excluded. Baseline laboratory measurements, including NT-proBNP, were done. Echocardiograms were performed ~ 2 weeks after restoration of SR. RESULTS: Cardioversion with flecainide was successful in 91 patients (87 %). NT-proBNP was lower in patients with successful cardioversion (P < 0.001). Logistic regression indicated NT-proBNP as an independent predictor of successful cardioversion. A cut-off NT-proBNP value of 1550 pg/ml provided optimal test accuracy to predict successful cardioversion. CONCLUSION: In patients with < 24 h of symptomatic AF, NT-proBNP levels up to 1550 pg/ml correlate with high success rates (94 %) of cardioversion with flecainide. Conversely, NT-proBNP higher than 1550 pg/ml correlates with poor success rates (36 %). Further research is needed to validate the predictive value of NT-proBNP for successful cardioversion with flecainide.

Diastereodivergent Asymmetric 1,4-Addition of Oxindoles to Nitroolefins by Using Polyfunctional Nickel-Hydrogen-Bond-Azolium Catalysts.

Diastereodivergency is a challenge for catalytic asymmetric synthesis. For many reaction types, the generation of one diastereomer is inherently preferred, while the other diastereomers are not directly accessible with high efficiency and require circuitous synthetic approaches. Overwriting the inherent preference by means of a catalyst requires control over the spatial positions of both reaction partners. We report a novel polyfunctional catalyst type in which a Ni(II) -bis(phenoxyimine) unit, free hydroxy groups, and an axially chiral bisimidazolium entity participate in the stereocontrol of the direct 1,4-addition of oxindoles to nitroolefins. Both epimers of the 1,4-adduct are accessible in excess on demand by changes to the ligand constitution and configuration. As the products have been reported to be valuable precursors to indole alkaloids, this method should allow access to their epimeric derivatives.

Exogenous-Base-Free Palladacycle-Catalyzed Highly Enantioselective Arylation of Imines with Arylboroxines.

Enantiomerically pure benzylic amines are important for the development of new drugs. A readily accessible planar-chiral ferrocene-derived palladacycle is shown to be a highly efficient catalyst for the formation of N-substituted benzylic stereocenters; this catalyst accelerates the 1,2-addition of arylboroxines to aromatic and aliphatic imines with exceptional levels of enantioselectivity. Using aldimines an exogenous base was not necessary for the activation of the boroxines, when acetate was used as an anionic ligand. Common problems such as aryl-aryl homocouplings and imine hydrolysis were fully overcome, the latter even in the absence of molecular sieves.