The Stereodynamics of 5,5’‐Disubstituted BIPHEPs

Maier, Frank; Trapp, Oliver

doi:10.1002/chir.22125

Cited by 24 publications

(20 citation statements)

References 44 publications

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“…15,16 Recently, we developed a self-amplifying, asymmetric hydrogenation reaction for prochiral olefins. 17 It features a tropos biphenyl-based ligand [18][19][20][21][22] with a low barrier of inversion. 17,23 The ligand backbone was modified with interaction sites for efficient noncovalent bonding, 24,25 which were derived from a chiral recognition system developed by Pirkle and Murray.…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of a stereodynamic catalyst with reversal of selectivity by enantioselective self‐inhibition

Scholtes

Trapp

2019

Chirality

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Chirality plays a pivotal role in an uncountable number of biological processes, and nature has developed intriguing mechanisms to maintain this state of enantiopurity. The strive for a deeper understanding of the different elements that constitute such self‐sustaining systems on a molecular level has sparked great interest in the studies of autoinductive and amplifying enantioselective reactions. The design of these reactions remains highly challenging; however, the development of generally applicable principles promises to have a considerable impact on research of catalyst design and other adjacent fields in the future. Here, we report the realization of an autoinductive, enantioselective self‐inhibiting hydrogenation reaction. Development of a stereodynamic catalyst with chiral sensing abilities allowed for a chiral reaction product to interact with the catalyst and change its selectivity in order to suppress its formation, which caused a reversal of selectivity over time.

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Section: Introductionmentioning

confidence: 99%

Design and synthesis of a stereodynamic catalyst with reversal of selectivity by enantioselective self‐inhibition

Scholtes

Trapp

2019

Chirality

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“…In recent years, enantioselective dynamic chromatographic and electrophoretic techniques [22][23][24][25][26][27][28] in combination with fast and efficient evaluation tools have proven to be highly precise in the determination of enantiomerization barriers [29][30][31][32][33][34] of chiral drugs with enantiomerization barriers greater than 75 kJ/mol [35][36][37][38][39][40][41][42][43][44][45][46][47]. 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) [41,[48][49][50][51][52][53][54][55][56], dynamic GC (DGC) [42,46,[57][58][59][60][61][62], and dynamic CE (DCE) [43][44...…”

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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“…Recently, we have studied in detail the stereo dynamics of tropos 5,5'-disubstituted BIPHEPO ligands. [16] These compounds show an ideal Scheme 1. Asymmetric reactions using interconverting racemic catalysts.…”

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confidence: 99%

Selector‐Induced Dynamic Deracemization of a Selectand‐Modified Tropos BIPHEPO‐Ligand: Application in the Organocatalyzed Asymmetric Double‐Aldol‐Reaction

Maier¹,

Trapp²

2014

Angew Chem Int Ed

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Stereolabile interconverting catalysts open up the possibility of directing enantioselectivity in asymmetric synthesis by formation of diastereomeric complexes with chiral auxiliaries and deracemization. However, the stoichiometrically used auxilliaries can significantly limit the potential applications of such systems. We synthesized a new BIPHEPO tropos ligand containing achiral selectands in the backbone, which forms transient diastereomeric associates with amylose-tris-3,5-dimethylphenyl carbamate as a selector and thus deracemizes. The enantiomerically enriched BIPHEPO obtained was successfully used in the organocatalytic asymmetric double aldol addition of substituted methyl ketones to form benzaldehyde. This strategy combines an on-column deracemization with the high stereoinduction of chiral biarylphosphineoxides and opens up new possibilities in the field of self-amplified asymmetric syntheses.

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The Stereodynamics of 5,5’‐Disubstituted BIPHEPs

Cited by 24 publications

References 44 publications

Design and synthesis of a stereodynamic catalyst with reversal of selectivity by enantioselective self‐inhibition

Design and synthesis of a stereodynamic catalyst with reversal of selectivity by enantioselective self‐inhibition

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

Selector‐Induced Dynamic Deracemization of a Selectand‐Modified Tropos BIPHEPO‐Ligand: Application in the Organocatalyzed Asymmetric Double‐Aldol‐Reaction

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