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

Maier, Frank; Trapp, Oliver

doi:10.1002/ange.201402293

Cited by 14 publications

(1 citation statement)

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“…In recent years, enantioselective dynamic chromatographic and electrophoretic techniques in combination with fast and efficient evaluation tools have proven to be highly precise in the determination of enantiomerization barriers of chiral drugs with enantiomerization barriers greater than 75 kJ/mol . The advantage of these techniques is that only minute amounts of the racemic sample are required and can be applied in combination with any separation technique that yields a separation of the desired enantiomeric species as dynamic HPLC (DHPLC) , dynamic GC (DGC) , and dynamic CE (DCE) .…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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Temperaturgesteuerte bidirektionale Enantioselektivität eines dynamischen Katalysators für asymmetrische Hydrierungen

Storch

Trapp

2015

Angewandte Chemie

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Asymmetrische Katalyse mit enantiomerenreinen Katalysatoren ist eine der weitverbreitetsten Methoden zur Herstellung enantiomerenreiner Verbindungen. Die selektive Synthese beider enantiomerenreiner Produkte erfordert dabei die aufwändige Synthese beider enantiomerenreiner Katalysatoren oder alternativ die Enantiomerentrennung racemischer Produkte. Wir stellen einen stereodynamisch flexiblen diastereomeren Rhodium(I)‐Katalysator für die asymmetrische Hydrierung prochiraler (Z)‐α‐Acetamidozimtsäure‐ und α‐substituierter Acrylsäurederivate vor, der seine Enantioselektivität in Abhängigkeit der Temperatur ändert und somit selektiv beide Enantiomere in hoher Ausbeute liefert. Derselbe axial‐chirale Rhodium(I)‐Katalysator bildet (R)‐Phenylalaninderivate mit Enantiomerenverhältnissen bis zu 87:13 (R/S) bei niedriger Temperatur und bis zu 3:97 (R/S) des entsprechenden S‐Enantiomers nach Reäquilibrierung des Katalysators bei erhöhter Temperatur.

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Inducing Axial Chirality in a Supramolecular Catalyst

2018

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An ew type of ligand, which is able to form axially chiral, supramolecular complexes was designed using DFT calculations.T wo chiral monomers,each featuring acovalently bound chiral auxiliary,form abidentate phosphine ligand with at wisted, hydrogen-bonded backbone upon coordination to at ransition metal center whichr esults in two diastereomeric, tropos complexes.The ratio of the diastereomers in solution is very temperature-and solvent-dependent. Rhodium and platinum complexes were analyzed through ac ombination of NMR studies,E SI-MS measurements,a sw ell as UV-VIS and circular dichroism spectroscopy. The chiral self-organized ligands were evaluated in the rhodium-catalyzed asymmetric hydrogenation of a-dehydrogenated amino acids and resulted in good conversion and high enantioselectivity.T his research opens the wayfor new ligand designs based on stereocontrol of supramolecular assemblies through stereodirecting chiral centers.Ligands with an axially chiral backbone are among the most valuable systems used in asymmetric catalysis. [1][2][3][4] However, the asymmetric synthesis of such an inflexible (atropos) backbone is often long and difficult. Am ore intriguing approach is to use ligands with af lexible (tropos)b ackbone. [5,6] In such adynamic system, the resolution into one of the diastereomers is dependent on transfer of chiral information from as tereoregulating unit. This transfer has been achieved by coordination of achiral co-ligand or anion, [7][8][9][10][11] or control of the backbone by acovalently bound chiral auxiliary (Scheme 1). [12][13][14][15][16] Recently,control of axial chirality in a tropos ligand was demonstrated by association of small chiral molecules through hydrogen bonding. [17,18] In this manner, ab y-design nonlinear amplification of stereoselectivity was achieved.Self-assembly ligand systems have also been used successfully in asymmetric catalysis, [19] and the necessary asymmetric induction has so far been achieved using building blocks with either chiral P-donors [20][21][22][23] or an axially chiral biphenyl moiety as as tereoregulating unit. [24] Theg roups of Raynal and Vidal-Ferran achieved stereocontrol through the coassembly of chiral benzene-1,3,5-tricarboxamides (BTA) with achiral BTAs functionalized with P-donor moieties in ahelical scaffold. [25,26] Theg roup of Reek demonstrated that stereocontrol in asupramolecular catalyst system could be achieved by either entrapment of the rhodium center in asupramolecular metallocage [27] or by molecular recognition of ac hiral cofactor in ab identate ligand. [9,28] Also chiral phosphoric acids have been used for supramolecular stereoregulation through ion pairing in asymmetric catalysis. [29,30] Our group has previously developed self-organizing ligand systems based on self-assembly of monodentate building blocks through hydrogen bonding (6-DPPon = 6-diphenylphosphino pyridone,see Scheme 2f or R = Ph and S* = H), [31] and these bidentate ligands were successfully employed in hydroformylation and hydrocyanation of alkenes. [31]...

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

Cited by 14 publications

References 63 publications

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

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

Temperaturgesteuerte bidirektionale Enantioselektivität eines dynamischen Katalysators für asymmetrische Hydrierungen

Inducing Axial Chirality in a Supramolecular Catalyst

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