Quantifizierung der Stationärphasen‐ und Lösungsmitteleinflüsse auf die Stereodynamik von biphep‐Liganden durch dynamische Drei‐Säulen‐HPLC

Maier, Frank; Trapp, Oliver

doi:10.1002/ange.201107907

Cited by 21 publications

(9 citation statements)

References 48 publications

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“…We exclude stationary phase effects, because results of a previous publication indicate only a negligible influence for this compound class. Similar to a recently described effect by us about compensation of the activation parameters Δ H ╪ and Δ S ╪ for 3,3’‐disubstituted BIPHEP molecules, we determined the same phenomena for the 5,5’‐disubstituted BIPHEPs analyzed here. Comparison of BIPHEPs 2 and 5 , where Δ G ╪ has almost the same value (90.5 and 90.6 kJ mol –1 , respectively), have strongly different activation parameters (Δ H ╪ : 69.5 ± 0.3 and 38.9 ± 1.0 kJ mol –1 ; Δ S ╪ : ‒70 ± 1 and ‒173 ± 32 J mol –1 K –1 , respectively).…”

Section: Resultssupporting

confidence: 66%

“…). As expected, the unsubstituted BIPHEP has the lowest rotation barrier (Δ G ╪ = 86.8 kJ mol –1 ) of the BIPHEPs shown in Figure . To compare the rotation barriers of the substitution pattern of the 3,3’‐, 5,5’‐, and 6,6’‐disubstituted BIPHEP ligands it is important to observe the same substituents.…”

Section: Resultsmentioning

confidence: 60%

“…Thus, a robust and broadly applicable method to determine the dynamics and kinetics is required. Recently, we introduced a method using dynamic HPLC (DHPLC) and a novel three‐column HPLC setup to determine dynamics and kinetics in dependence of the stationary phase and solvent used . In the past, dynamic chromatographic techniques were successfully employed to study the stereodynamics of substituted biphenyl compounds …”

Section: Introductionmentioning

confidence: 99%

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The Stereodynamics of 5,5’‐Disubstituted BIPHEPs

Maier

Trapp

2012

Chirality

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We investigated the stereodynamics of 5,5'-substituted tropos BIPHEP ligands (2,2'-bis(diphenylphosphino)-biphenyls) by enantioselective dynamic high-performance liquid chromatography (DHPLC) to elucidate the influence of the substitution pattern and electronics of the substituents (methyl, methoxy, and hydroxyl groups). By temperature-dependent dynamic HPLC measurements the activation parameters ΔG(╪), ΔH(╪), and ΔS(╪) could be determined with high precision, revealing that the activation barrier of these 5,5'-substituted BIPHEP ligands ranges in a narrow band between 87.8 and 93.0 kJ mol(-1), making them highly attractive as deracemizable dynamic chiral ligands in asymmetric catalysis. Interestingly, the activation parameters are highly influenced by a hydroxyl or methoxy group in the 5,5'-position of the BIPHEP ligands.

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Section: Resultssupporting

confidence: 66%

Section: Resultsmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

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The Stereodynamics of 5,5’‐Disubstituted BIPHEPs

Maier

Trapp

2012

Chirality

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“…It is possible to determine these different reaction rates and it is important to note that the principle of microscopic reversibility has to be considered in the evaluation of reaction rate constants to take the selectivity of the selector into account . Very recently, we presented in another study that the selector or stationary phase does not typically change the interconversion barrier, when catalytic effects are absent; however the activation enthalpy and entropy are influenced. Enthalpy–entropy compensation is a broadly observed phenomenon .…”

Section: Resultsmentioning

confidence: 99%

Investigation of the enantiomerization barriers of the phthalimidone derivatives EM12 and lenalidomide by dynamic electrokinetic chromatography

et al. 2015

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The phthalimidone derivatives EM12 and lenalidomide, which are both structurally related to thalidomide, are highly interesting drugs and very recently lenalidomide attracted great attention as an antitumor and immune-modulating drug in the therapy for multiple myeloma. EM12 and lenalidomide are chiral, and the stereogenic carbon C-3 in the piperidine-2,6-dione moiety of these phthalimidone derivatives is prone to interconversion due to keto-enol tautomerization. The knowledge of the enantiomerization barrier is mandatory for pharmacokinetic studies and to develop a tailored therapy using the enantiopure or racemic drug. Here, we used dynamic EKC in combination with direct-calculation methods to determine the enantiomerization barriers of EM12 and lenalidomide. The separations of the enantiomers of EM12 and lenalidomide were performed in 50 mM aqueous disodium hydrogen phosphate buffer at pH 8 and 50 mM aqueous sodium tetraborate buffer at pH 9.3, respectively, using 20 mg/mL heptakis-(2,3-diacetyl-6-sulfato)-β-CD as a chiral additive. Enantiomerization of the compounds during the electrokinetic chromatographic separation resulted in pronounced plateau formation between the well-separated enantiomers. Peak form analysis of the experimentally obtained interconversion profiles yielded the enantiomerization rate constants k1 of EM12 and lenalidomide as well as the kinetic activation parameters ΔG(‡), ΔH(‡‡), and ΔS(‡) of enantiomerization by the evaluation of temperature-dependent measurements. The enantiomerization barrier ΔG(‡) was determined to be 98.3 ± 1.0 kJ/mol; the activation parameters ΔH(‡) = 46.1 ± 2.4 kJ/mol and ΔS(‡) = -170 ± 61 J/(K·mol) for EM12 and ΔG(‡) = 91.5 ± 1.0 kJ/mol, ΔH(‡) = 62.4 ± 5.4 kJ/mol, and ΔS(‡) = -98 ± 7 J/(K·mol) for lenalidomide. These findings were corroborated by density functional theory calculations at the B3LYP/3-21G level of theory of the ground state and intermediates considering an enantiomerization pathway via a keto-enol tautomerism.

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“…[1] Unter diesen nehmen die fluxionalen axial-chiralen 2,2'-Bis(diphenylphosphanyl)biphenyle (BIPHEP) eine herausragende Stellung als Liganden für asymmetrische Katalysen ein. [4] Mikami und Noyori et al nutzten diese dynamische Eigenschaft und verwendeten unsubstituiertes BIPHEP als Ligand für asymmetrische Katalysen. [4] Mikami und Noyori et al nutzten diese dynamische Eigenschaft und verwendeten unsubstituiertes BIPHEP als Ligand für asymmetrische Katalysen.…”

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Selektorinduzierte dynamische Deracemisierung eines selektandmodifizierten tropos‐BIPHEPO‐Liganden: Anwendung in der organokatalysierten asymmetrischen Doppelaldolreaktion

Maier

Trapp

2014

Angewandte Chemie

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Stereolabile interkonvertierende Katalysatoren erçffnen die Mçglichkeit, die Enantioselektivität in asymmetrischen Synthesen gezielt durch Bildung diastereomerer Komplexe mit chiralen Auxiliaren und Deracemisierung zu steuern. Jedoch kçnnen die stçchiometrisch eingesetzten Auxiliare die Anwendungsmçglichkeiten solcher Systeme erheblich limitieren. Wir haben einen neuartigen tropos-BIPHEPO-Liganden mit achiralen Selektanden im Rückgrat synthetisiert, der transiente diastereomere Assoziate mit Amylose-tris-3,5-dimethylphenylcarbamat als Selektor eingeht und dadurch deracemisiert. Das so erhaltene enantiomerenangereicherte BIPH-EPO-Derivat wurde erfolgreich in der organokatalytischen asymmetrischen Doppelaldoladdition substituierter Methylketone an Benzaldehyd eingesetzt. Diese Strategie kombiniert eine Deracemisierung mit der hohen Stereoinduktion chiraler Biarylphosphinoxide und erçffnet neue Mçglichkeiten im Bereich selbstamplifizierender asymmetrischer Synthesen.

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Quantifizierung der Stationärphasen‐ und Lösungsmitteleinflüsse auf die Stereodynamik von biphep‐Liganden durch dynamische Drei‐Säulen‐HPLC

Cited by 21 publications

References 48 publications

The Stereodynamics of 5,5’‐Disubstituted BIPHEPs

The Stereodynamics of 5,5’‐Disubstituted BIPHEPs

Investigation of the enantiomerization barriers of the phthalimidone derivatives EM12 and lenalidomide by dynamic electrokinetic chromatography

Selektorinduzierte dynamische Deracemisierung eines selektandmodifizierten tropos‐BIPHEPO‐Liganden: Anwendung in der organokatalysierten asymmetrischen Doppelaldolreaktion

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