Browsing by Author "Peters, René"

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Open Access
Asymmetric hydrocyanation of N‐phosphinoyl aldimines with acetone cyanohydrin by cooperative Lewis acid/onium salt/Brønsted base catalysis
(2021) Junge, Thorsten; Titze, Marvin; Frey, Wolfgang; Peters, René
α‐Amino acids are of fundamental importance for life. Both natural and artificial α‐amino acids also play a crucial role for pharmaceutical purposes. The catalytic asymmetric Strecker reaction still provides one of the most attractive strategies to prepare scalemic α‐amino acids. Here we disclose a new concept for Strecker reactions, in which an achiral Brønsted base cooperates with a Lewis acid and an aprotic ammonium salt, which are both arranged in the same chiral catalyst entity. The described method could successfully address various long‐standing practical issues of this reaction type. The major practical advantages are that (1) the N‐protecting group is readily removable, (2) acetone cyanohydrin is attractive as cyanation reagent in terms of atom economy and cost efficiency, (3) an excess of the cyanation reagent is not necessary, (4) the new method does not require additives and (5) is performed at ambient temperature.
Open Access
Catalytic asymmetric chlorination of isoxazolinones
(2022) Wannenmacher, Nick; Keim, Noah; Frey, Wolfgang; Peters, René
Organic compounds featuring a chlorine substituted stereocenter are frequently found in nature and are interesting for pharmaceutical applications and as synthetic building blocks. Catalytic methods to generate such stereocenters by C,H bond functionalization are still relatively rare. Here we report the first catalytic asymmetric chlorination of isoxazolinones, a synthetically and biologically interesting class of heterocycles, which can be considered as precursors for β‐aminoacids. The title reaction was catalyzed with high enantioselectivity by a planar chiral ferrocene based palladacycle in high to excellent yields. It is showcased that the products are valuable for post‐synthetic transformations. An SN2 reaction proceeded with smooth inversion of the absolute configuration. The substitution product could then be transformed into an α‐azido β‐aminoacid derivative via a reductive, diastereoselective ring opening.
Open Access
Cooperative Lewis acid‐1,2,3‐triazolium‐aryloxide catalysis : pyrazolone addition to nitroolefins as entry to diaminoamides
(2023) Wanner, Daniel M.; Becker, Patrick M.; Suhr, Simon; Wannenmacher, Nick; Ziegler, Slava; Herrmann, Justin; Willig, Felix; Gabler, Julia; Jangid, Khushbu; Schmid, Juliane; Hans, Andreas C.; Frey, Wolfgang; Sarkar, Biprajit; Kästner, Johannes; Peters, René
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 β,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.
Open Access
Diastereospecific enantiodivergent allylation of pyrazolones as an entry to β‐aminoamides
(2022) Wannenmacher, Nick; Heberle, Martin; Yu, Xin; Demircan, Aysegül; Wanner, Daniel M.; Pfeffer, Camilla; Peters, René
A diastereospecific enantiodivergent allylation of pyrazolones is reported which is catalyzed by a planar chiral pentaphenylferrocene based palladacycle. With the same catalyst batch both product enantiomers were selectively available. The method is applicable to structurally diverse substrates and gave products with enantiomeric excesses between 85 and 94%. In addition, we could show that pyrazolones are transformable into β‐aminoamides.
Open Access
Direkte enantioselektive Addition von Alkinen an Imine unter Verwendung eines hocheffizienten Palladacyclus als Katalysator
(2022) Pfeffer, Camilla; Probst, Patrick; Wannenmacher, Nick; Frey, Wolfgang; Peters, René
Enantiomerenreine Propargylamine sind sehr wertvolle Synthesebausteine. Große Anstrengungen wurden bereits unternommen, um Verfahren zu ihrer Herstellung zu entwickeln. Als vermutlich wichtigste Synthesestrategie ist die 1,2-Addition von Alkinen an Imine zu nennen. Trotz aussichtsreicher Fortschritte sind für die bekannten Verfahren unter Verwendung von Zn- und Cu-Katalysatoren hohe Katalysatorladungen, die typischerweise im Bereich von 2-60 mol % für neutrale Aldiminsubstrate liegen, notwendig. Wir entwickelten einen planar-chiralen Pd-Komplex, welcher als hocheffizienter Katalysator für die direkte asymmetrische Alkin-Addition an Imine dient und sehr geringe Katalysatorladungen ermöglicht. Umsatzzahlen von bis zu 8700 wurden erreicht. Unsere Untersuchungen legen nahe, dass mit Hilfe eines acac-Liganden, der als interne katalytische Base fungiert, ein Pd-Acetylid-Komplex als katalytisch relevantes Intermediat erzeugt wird. Weiterhin konnten wir zeigen, dass der Katalysator unter den Reaktionsbedingungen weitgehend stabil ist und keine Produktinhibierung auftritt. Insgesamt sind 39 Beispiele aufgeführt, die alle nahezu enantiomerenreine Produkte ergaben.
Open Access
Enantiodivergent [4+2] cycloaddition of dienolates by polyfunctional Lewis acid/zwitterion catalysis
(2020) Miskov‐Pajic, Vukoslava; Willig, Felix; Wanner, Daniel M.; Frey, Wolfgang; Peters, René
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.
Open Access
Highly active cooperative Lewis acid : ammonium salt catalyst for the enantioselective hydroboration of ketones
(2021) Titze, Marvin; Heitkämper, Juliane; Junge, Thorsten; Kästner, Johannes; Peters, René
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 SN2 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.
Open Access
A practical and robust zwitterionic cooperative Lewis acid/acetate/benzimidazolium catalyst for direct 1,4‐additions
(2023) Hans, Andreas C.; Becker, Patrick M.; Haußmann, Johanna; Suhr, Simon; Wanner, Daniel M.; Lederer, Vera; Willig, Felix; Frey, Wolfgang; Sarkar, Biprajit; Kästner, Johannes; Peters, René
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.
Open Access
Stereoretentive regio‐ and enantioselective allylation of isoxazolinones by a planar chiral palladacycle catalyst
(2022) Yu, Xin; Hu, Lingfei; Frey, Wolfgang; Lu, Gang; Peters, René
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 SN2 mechanism and not via π‐allyl Pd complexes. Crucial for the high control is the stabilization of the allylic fragment in the SN2 transition state by π‐interactions with the phenyl substituents of the pentaphenylferrocenyl catalyst core.
Open Access
Stereoretentive regio‐ und enantioselektive Allylierung von Isoxazolinonen per planar chiralem Palladacyclus‐Katalysator
(2022) Yu, Xin; Hu, Lingfei; Frey, Wolfgang; Lu, Gang; Peters, René
Die katalytische allylische Substitution ist eines der wichtigsten Werkzeuge in der asymmetrischen Synthese zur enantioselektiven Bildung von C-C-Bindungen. Während in vorigen Arbeiten eine hohe Effizienz in Bezug auf Enantio- und Regiokontrolle unter Verwendung verschiedener Katalysatortypen erreicht wurde, besteht eine starke allgemeine Einschränkung in einer sehr ausgeprägten Präferenz für die Bildung von allylischen Substitutionsprodukten mit (E)-konfigurierten C=C-Doppelbindungen. Hier berichten wir, dass mit einem planar-chiralen Palladacyclus-Katalysator unter Verwendung von Isoxazolinonen und Allylimidaten als Substrate ein diastereospezifisches Reaktionsergebnis erzielt wird, wodurch die C=C-Doppelbindungsgeometrie der Allylsubstrate in den hoch enantiomerenangereicherten Produkten beibehalten wird. DFT-Rechnungen zeigen, dass die Reaktionen über einen SN2-Mechanismus und nicht über π-Allyl-Pd-Komplexe ablaufen. Entscheidend für die hohe Kontrolle ist die Stabilisierung des allylischen Fragments im SN2-Übergangszustand durch π-Wechselwirkungen mit den Phenylsubstituenten des Pentaphenylferrocen-Katalysatorkerns.
Open Access
Stereospezifische asymmetrische Synthese tertiärer Allylalkohol‐ Derivate über katalytische [2,3]‐Meisenheimer‐Umlagerungen
(2020) Yu, Xin; Wannenmacher, Nick; Peters, René
Chirale azyklische tertiäre Allylalkohole sind bedeutende Synthesebausteine, deren enantioselektive Synthese eine anspruchsvolle Aufgabe ist. Eine wesentliche Einschränkung bei katalytisch asymmetrischen 1,2-Additionen an Ketone ist die Enantioseitendifferenzierung durch sterische Unterscheidung beider Ketonreste. Um dieses Problem zu überwinden, entwickelten wir eine katalytisch asymmetrische Meisenheimer-Umlagerung, die auf stereospezifische Weise abläuft. Dabei können selbst Produkte, bei denen die Reste am generierten quartären Stereozentrum einen ähnlichen sterischen Anspruch aufweisen, mit hoher Enantioselektivität hergestellt werden. Niedrige Katalysatorbeladungen genügen, und die Bedingungen sind mild genug, um reaktive funktionelle Gruppen wie enolisierbare Aldehyde, primäre Tosylate oder Epoxide zu tolerieren. Unsere Untersuchungen lassen auf eine intramolekulare Umlagerung schließen.