An Unexpected Atropisomerically Stable 1,1‐Biphenyl at Ambient Temperature in Solution, Elucidated by Vibrational Circular Dichroism (VCD)

Freedman, Teresa B.; Cao, Xiaolin; Nafie, Laurence A.; Kalbermatter, Monica; Linden, Anthony; Rippert, Andreas Johannes

doi:10.1002/hlca.200390255

Cited by 21 publications

(17 citation statements)

References 18 publications

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“…[66] Die Hinderung der Rotation in Biarylverbindungen mit einem siebengliedrigen Ring ist vergleichbar mit derjenigen ihrer unverbrückten Analoga. [67] Größere Brücken, auch solche, die durch Wasserstoffbrücken gebildet werden, [68] können Atropisomerie durch geometrische Zwänge im Ring hervorrufen. Dies gilt auch für Biaryle mit relativ geringer sterischer Hinderung an der Achse.…”

Section: Verbrückte Biaryleunclassified

Atropselektive Synthese axial‐chiraler Biaryle

et al. 2005

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Eine rotationsgehinderte und dadurch stereogene Biarylachse ist das strukturell und stereochemisch entscheidende Element einer ständig wachsenden Zahl von Naturstoffen, chiralen Auxiliaren und Katalysatoren. Daher ist es nicht überraschend, dass im letzten Jahrzehnt bedeutende Fortschritte in der asymmetrischen Synthese axial‐chiraler Biaryle erzielt worden sind. Neben dem klassischen Zugangsweg, der direkten Aryl‐Aryl‐Kupplung, sind innovative Konzepte entwickelt worden, in denen die asymmetrische Information in ein schon vorhandenes, aber nicht optisch aktives – symmetrisches oder konfigurativ labiles – Biaryl eingeführt oder eine Aryl‐C‐Einfachbindung stereoselektiv in eine Achse umgewandelt wird. In diesem Aufsatz werden die Strategien nach den zugrunde liegenden Konzepten klassifiziert, und ihre Anwendungsbreite und ihre Beschränkungen werden anhand ausgewählter Beispiele kritisch beurteilt. Ferner werden die Voraussetzungen für das Auftreten von Axialchiralität diskutiert.

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Section: Verbrückte Biaryleunclassified

Atropselektive Synthese axial‐chiraler Biaryle

et al. 2005

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“…[37][38][39] More recently, the spectroscopic approach of comparing observed and calculated vibrational circular dichroism (VCD) spectra, electronic circular dichroism (ECD), or optical rotation (OR) values has gained popularity due to the ease of data acquisition and the ability to calculate spectra and values with commercially available software and supercomputers or modern, powerful PCs and Linux clusters. [40][41][42][43][44][45][46][47][48][49] In the case of VCD, besides absolute stereochemistry of molecules containing one or more asymmetric centers, or planes or axes of asymmetry, i.e., atropisomerism, [50][51][52][53] additional information can be obtained, including solution conformation 54,55 and real-time reaction monitoring. 56,57 VCD has been applied specifically to pharmaceuticallyrelevant molecules.…”

Section: Introductionmentioning

confidence: 99%

Application of chiral technology in a pharmaceutical company. Enantiomeric separation and spectroscopic studies of key asymmetric intermediates using a combination of techniques. Phenylglycidols

McConnell¹,

He²,

Nogle³

et al. 2007

Chirality

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Phenylglycidols substituted in the 2-, 3-, and 4- positions with fluorine, chlorine, and trifluoromethyl, and with methoxy in the 3- position, were synthesized from the corresponding E-cinnamic acids and separated into their (R,R)- and (S,S)- enantiomers using subcritical fluid chromatography with mixtures of MeOH in CO(2), on either a Chiralpak AD or AS chiral stationary phase. These compounds and commercially-available (R,R)- and (S,S)-phenylglycidol were analyzed for their vibrational circular dichroism (VCD), electronic circular dichroism (ECD), and optical rotation (OR) properties to exemplify a strategy whereby the absolute stereochemistry of common and key chiral intermediates is established early in the structure-activity and structure-property relationship phase of a drug discovery program in a pharmaceutical company. From this study, substituents in the phenyl group of the synthesized molecules were found not to grossly alter spectroscopic features, and therefore, diagnostic absorption bands in the respective VCD spectra, and the sign and shape of the measured ECD curves could be used to determine and track the absolute stereochemistry of analogs without necessarily requiring time-consuming ab initio calculations of all low energy conformers for all compounds. VCD, OR, and ECD calculations for the determination of absolute configuration carried out at the DFT level with the hybrid B3PW91 functional and the TZVP basis set were found to be especially useful in this study.

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“…With the exception of molecules with intramolecular hydrogen-bonding, 22,27 these are the first examples in the VCD literature, known to the authors, where large populations of conformers with significantly higher calculated energies for the isolated species are required to obtain a close match between experimental and calculated IR and VCD spectra, and this points to an especially strong interaction between the solvent, in this case CDCl 3 , and the fluoro-groups that characterize these molecules compared to other typical organic molecules. These solvent effects are consistent with our calculations on the smaller (R)-2-fluorocyclohexanone.…”

Section: Resultsmentioning

confidence: 99%

VCD configuration of enantiopure/‐enriched tetrasubstituted α‐fluoro cyclohexanones and their use for epoxidation of trans‐olefins

Freedman¹,

Cao²,

Nafie³

et al. 2004

Chirality

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The configurations of three enantiopure tetrasubstituted alpha-fluoro cyclohexanones (-)-5Ia, (-)-5IIa and (-)-6a were determined by VCD and proved to be (-)-(2S,5R)-5Ia, (-)-(2R,5R)-5IIa, and (-)-(2R,5R)-6a. The VCD study also identified the conformers populated in CDCl3 solution, including higher-energy gas-phase conformers with equatorial fluorine for 5Ia and 5IIa that are stabilized in CDCl3 solution. Used as catalysts for epoxidation of trans olefins (beta-methylstyrene, stilbene, methyl p-methoxy cinnamate) by oxone, it was found that (-)-5Ia is the most efficient for all trans olefins (providing, respectively, 62%, 90% and 66% ee) but that all three ketones provide high ee% with stilbene (78-90% ee). Moreover, the configurations predicted from the stereo outcome of the epoxidation reaction are identical to those determined by VCD.

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An Unexpected Atropisomerically Stable 1,1‐Biphenyl at Ambient Temperature in Solution, Elucidated by Vibrational Circular Dichroism (VCD)

Cited by 21 publications

References 18 publications

Atropselektive Synthese axial‐chiraler Biaryle

Atropselektive Synthese axial‐chiraler Biaryle

Application of chiral technology in a pharmaceutical company. Enantiomeric separation and spectroscopic studies of key asymmetric intermediates using a combination of techniques. Phenylglycidols

VCD configuration of enantiopure/‐enriched tetrasubstituted α‐fluoro cyclohexanones and their use for epoxidation of trans‐olefins

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