Allylic substitution reactions provide a valuable tool for the functionalization of CH acidic pronucleophiles. Often, control over the stereocenter generated at the nucleophilic reactant is still a challenge. The majority of studies that address this issue employ metal complexes with a low metal oxidation state (e.g. Pd⁰) to form allyl complexes through oxidative addition. In this article we describe the use of heterobimetallic Pt^II/Pd^II complexes, which probably activate the olefinic substrates through an S_N2′ pathway. The reaction of α-cyanoacetates delivers linear allylation products with exclusive regioselectivity and high E/Z-selectivity for the new C=C double bond. Although the enantioselectivities attained are moderate, they are significantly higher than with related mono-Pd^II or -Pt^II catalysts or the corresponding bis-Pd^II complex, which indicates cooperation of the different metals. Control experiments suggest simultaneous activation of both reaction partners.

The streamlined catalytic access to enantiopure allylic amines as valuable precursors towards chiral β- and γ-aminoalcohols as well as α- and β-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.

Enantiomerenreine Benzylamine sind für die Wirkstoffentwicklung von großer Bedeutung. Ein leicht zugänglicher, planar-chiraler, Ferrocen-basierter Palladacyclus erwies sich als sehr effizienter enantioselektiver Katalysator zur Bildung N-substituierter benzylischer Stereozentren durch Beschleunigung der 1,2-Addition von Arylboroxinen an aromatische und aliphatische Imine. Für Aldimine war kein Einsatz einer exogenen Base zur Aktivierung des Boroxins erforderlich, wenn Acetat als anionischer Ligand verwendet wurde. Verbreitete Probleme, wie Aryl-Aryl-Homokupplungen und die Imin-Hydrolyse, konnten vollständig vermieden werden, letztere sogar ohne Einsatz von Molekularsieb.

Diastereodivergenz ist eine Herausforderung für die katalytische asymmetrische Synthese. Für viele Reaktionstypen ist die Bildung eines Diastereomers inhärent bevorzugt, während das andere Diastereomer nicht direkt und effizient zugänglich ist, sondern umständliche Syntheseumwege erfordert. Das Umgehen dieser natürlichen Präferenz mithilfe eines Katalysators erfordert die räumliche Kontrolle über beide Reaktionspartner. Wir stellen einen neuartigen, polyfunktionellen Katalysator vor, in dem eine Ni^II-Bis(phenoxyimin)-Einheit, freie Hydroxygruppen und ein axial-chiraler Bisimidazolium-Baustein an der Stereokontrolle der direkten 1,4-Addition von Oxindolen an Nitroolefine beteiligt sind. Beide Epimere des 1,4-Adduktes sind nach Belieben durch Variation der Konstitution und Konfiguration des Liganden zugänglich. Wie bereits berichtet wurde, sind die Produkte wertvolle Vorstufen für Indolalkaloide, und die vorliegende Methode sollte somit den Zugang zu den epimeren Derivaten eröffnen.

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.

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.

Isoxazolinone bilden eine Klasse von Heterocyclen, die häufig bei der Entwicklung von potentiellen neuen Wirkstoffen Verwendung findet. Die cyclische Oximester-Einheit ist außerdem synthetisch wertvoll, da sie funktionelle “Stellschrauben” beinhaltet, die den Zugang zu einer Vielzahl von wertvollen Verbindungsklassen ermöglichen, welche durch andere Methoden nur schwer zugänglich sind. Dennoch sind asymmetrische Methoden zu chiralen Isoxazolinonen offenkundig selten. Hiermit stellen wir die erste katalytische, asymmetrische Alkylierung von Isoxazolinonen zur Bildung von all-C-substituierten quartären Stereozentren vor. Die gegenwärtigen Studien wurden durch die Frage nach der Kontrolle der Regioselektivität aufgrund der Konkurrenz von verschiedenen nukleophilen Positionen angetrieben. Die Untersuchung einer direkten 1,4-Addition ließ erkennen, dass ein sterisch anspruchsvoller palladacyclischer Katalysator die Reaktivität in Abwesenheit einer Base nahezu ausschließlich zum nukleophilen C-Atom steuert, während gleichzeitig hohe Enantioselektivitäten und TONs von bis zu 1900 erreicht werden.

Isoxazolinones constitute a class of heterocycles utilized for the development of novel drug candidates. The cyclic oxime ester motif is also synthetically useful as it contains functional handles which have previously been used to provide access to an assortment of valuable compound classes not easily accessible by alternative approaches. However, asymmetric methods towards isoxazolinones are notoriously scarce. Herein we report the first catalytic asymmetric alkylations of isoxazolinones forming all-C-substituted quaternary stereocenters. The present studies were driven by the question of how to control the regioselectivity in the competition of different nucleophilic positions. The investigation of a direct 1,4-addition uncovered that a sterically demanding palladacycle catalyst directs the reactivity in the absence of a base nearly exclusively to the nucleophilic C atom, while at the same time it allows for high enantioselectivity and TONs up to 1900.

A regio- and enantioselective tandem reaction is reported capable of directly transforming readily accessible achiral allylic alcohols into chiral sulfonyl-protected allylic amines. The reaction is catalyzed by the cooperative action of a chiral ferrocene palladacycle and a tertiary amine base and combines high step-economy with operational simplicity (e.g. no need for inert-gas atmosphere or catalyst activation). Mechanistic studies support a Pd^II-catalyzed [3,3] rearrangement of allylic carbamates—generated in situ from the allylic alcohol and an isocyanate—as the key step, which is followed by a decarboxylation.

Eine regio- und enantioselektive Tandemreaktion, die leicht zugängliche achirale Allylalkohole direkt in chirale sulfonylgeschützte Allylamine überführt, wird beschrieben. Die Reaktion wird durch Kooperation eines chiralen Ferrocen-Palladacyclus und einer tertiären Amin-Base katalysiert und kombiniert hohe Stufenökonomie mit leichter Handhabung (ohne Inertgasatmosphäre oder Katalysatoraktivierung). Mechanistische Studien stützen eine Pd^II-katalysierte [3,3]-Umlagerung eines Allylcarbamats – in situ erzeugt aus einem Allylalkohol und einem Isocyanat – als Schlüsselschritt, dem eine Decarboxylierung folgt.

Spirocyclic azlactones are shown to be useful precursors of cyclic quaternary amino acids, such as the constrained cyclohexane analogues of phenylalanine. These compounds are of interest as building blocks for the synthesis of artificial peptide analogues with controlled folds in the peptide backbone. They were prepared in the present study by a step- and atom-economic catalytic asymmetric tandem approach, requiring two steps starting from N-benzoyl glycine and divinylketones. The key of this protocol is the enantioselective formation of the azlactone spirocycles, which involves a Pd^II-catalyzed double 1,4-addition of an in situ generated azlactone intermediate to the dienone (a formal [5+1] cycloaddition). As the catalyst, a planar chiral ferrocene bispalladacycle was used. Mechanistic studies suggest a monometallic reaction pathway. Although the diastereoselectivity was found to be moderate, the enantioselectivity is usually high for the formation of the azlactone spirocycles, which contain up to three contiguous stereocenters. Spectroscopic studies have shown that the spirocycles often prefer a twist over a chair conformation of the cyclohexanone moiety.

Masked and activated highly enantioenriched α,α-disubstituted α-amino acids with an additional adjacent stereocenter were formed by a tandem reaction involving five steps using racemic unprotected amino acid substrates. Key step is the 1,4-addition of in-situ generated azlactones to a broad number of enones. The products of this step-economic route can, e.g., be useful for a divergent and rapid access to biologically interesting unnatural glutamic acid derivatives.

The development and further evolution of the first catalytic asymmetric conjugate additions of azlactones as activated amino acid derivatives to enones is described. Whereas the first-generation approach started from isolated azlactones, in the second-generation approach the azlactones could be generated in situ starting from racemic N-benzoylated amino acids. The third evolution stage could make use of racemic unprotected α-amino acids to directly form highly enantioenriched and diastereomerically pure masked quaternary amino acid products bearing an additional tertiary stereocenter. The step-economic transformations were accomplished by cooperative activation by using a robust planar chiral bis-Pd catalyst, a Brønsted acid (HOAc or BzOH; Ac=acetyl, Bz=benzoyl), and a Brønsted base (NaOAc). In particular the second- and third-generation approaches provide a rapid and divergent access to biologically interesting unnatural quaternary amino acid derivatives from inexpensive bulk chemicals. In that way highly enantioenriched acyclic α-amino acids, α-alkyl proline, and α-alkyl pyroglutamic acid derivatives could be prepared in diastereomerically pure form. In addition, a unique way is presented to prepare diastereomerically pure bicyclic dipeptides in just two steps from unprotected tertiary α-amino acids.

The first catalytic asymmetric synthesis of β-sultones is reported. This development has enabled a rapid access to a number of highly enantioenriched biologically interesting sulfonyl and sulfinyl compound classes, which makes use of the inherent ring strain of the four-membered heterocycles. The products possess either two vicinal stereocenters, such as in β-hydroxy-sulfonamides, -sulfonates, -sulfones, -sulfonic acids, -sulfinic acids, γ-sultines, and γ-sultones or a single stereocenter, such as in α-branched alkyl or allyl sulfonic acids. This work also represents the first application of sulfene intermediates in asymmetric catalysis. The reactivity of a sulfene normally acting as an electrophile could be reverted by the formation of a nucleophilic zwitterionic sulfene–amine adduct. To achieve a combination of high enantioselectivity and reactivity, cooperative catalytic action of a chiral nucleophilic tertiary amine (the cinchona alkaloid derivative diydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)₂PYR)) and Bi(OTf)₃ or In(OTf)₃ was of primary importance.

The development of the first trans-selective catalytic asymmetric [2+2] cyclocondensation of acyl halides with aliphatic aldehydes furnishing 3,4-disubstituted β-lactones is described. This work made use of a new strategy within the context of asymmetric dual activation catalysis: it combines the concepts of Lewis acid and organic aprotic ion pair catalysis in a single catalyst system. The methodology could also be applied to aromatic aldehydes and offers broad applicability (29 examples). The utility was further demonstrated by nucleophilic ring-opening reactions that provide highly enantiomerically enriched anti-aldol products.

Previously unexplored enantiopure zwitterionic ammonium dienolates have been utilized in this work as reactive intermediates that act as diene components in hetero-Diels–Alder reactions (HDAs) with aldehydes to produce optically active δ-lactones, subunits of numerous bioactive products. The dienolates were generated in situ from E/Z mixtures of α,β-unsaturated acid chlorides by use of a nucleophilic quinidine derivative and Sn(OTf)₂ as co-catalyst. The latter component was not directly involved in the cycloaddition step with aldehydes and simply facilitated the formation of the reactive dienolate species. The scope of the cycloaddition was considerably improved by use of a complex formed from Er(OTf)₃ and a simple commercially available norephedrine-derived ligand that tolerated a broad range of aromatic and heteroaromatic aldehydes for a cooperative bifunctional Lewis-acid-/Lewis-base-catalyzed reaction, providing α,β-unsaturated δ-lactones with excellent enantioselectivities. Mechanistic studies confirmed the formation of the dienolate intermediates for both catalytic systems. The active Er^III complex is most likely a monomeric species. Interestingly, all lanthanides can catalyze the title reaction, but the efficiency in terms of yield and enantioselectivity depends directly on the radius of the Ln^III ion. Similarly, use of the pseudolanthanides Sc^III and Y^III also resulted in product formation, whereas the larger La^III and other transition metal salts, as well as main group metal salts, proved to be inefficient. In addition, various synthetic transformations of 6-CCl₃- or 4-silyl-substituted α,β-unsaturated δ-lactones, giving access to a number of valuable δ-lactone building blocks, were investigated.

Systematic studies have been performed to develop highly efficient catalysts for the asymmetric aza-Claisen rearrangement of trihaloacetimidates. Herein, we describe the stepwise development of these catalyst systems involving four different catalyst generations finally resulting in the development of a planar chiral pentaphenylferrocenyl oxazoline palladacycle. This complex is more reactive and has a broader substrate tolerance than all previously known catalyst systems for asymmetric aza-Claisen rearrangements. Our investigations also reveal that subtle changes can have a big impact on the activity. With the enhanced catalyst activity, the asymmetric aza-Claisen rearrangement has a very broad scope: the methodology not only allows the formation of highly enantioenriched primary allylic amines, but also secondary and tertiary amines; allylic amines with N-substituted quaternary stereocenters are conveniently accessible as well. The reaction conditions tolerate many important functional groups, thus providing stereoselective access to valuable functionalized building blocks, for example, for the synthesis of unnatural amino acids. Our results suggest that face-selective olefin coordination is the enantioselectivity-determining step, which is almost exclusively controlled by the element of planar chirality.

β-Sultams, biologically interesting sulfonyl analogues of β-lactams, have been prepared by an organocatalytic asymmetric formal [2+2]-cycloaddition approach of non-nucleophilic imines with alkyl sulfonyl chlorides. In the case of very electron poor N-tosyl imines derived from chloral or ethylglyoxylate, this reaction type was catalyzed by cinchona alkaloids providing the heterocycles in high yield, with good diastereoselectivity and up to 94 % ee. Mechanistic investigations suggested that the product formation proceeded via a zwitterionic imine–catalyst adduct. The scope was significantly extended by 2-pyridylsulfonyl imines derived from non-activated aromatic aldehydes employing Yb(OTf)₃ as Lewis acid cocatalyst. The synthetic value of the strained enantioenriched β-sultams was demonstrated by smooth nucleophilic ring opening reactions with O-, N- and C-nucleophiles yielding a variety of acyclic β-aminosulfonyl (taurine) derivatives (sulfonates, sulfonamides, sulfones) without racemization or epimerization.