A Complete Gear System in N-Benzoyl-Carbazole Derivatives

Tabata, Hidetsugu; Kayama, Susumu; Takahashi, Yuka; Tani, Norihiko; Wakamatsu, Shintaro; Tasaka, Tomohiko; Oshitari, Tetsuta; Natsugari, Hideaki; Takahashi, Hideyo

doi:10.1021/ol500417t

Cited by 11 publications

(11 citation statements)

References 25 publications

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“…In addition, hindered amides ( 9 ), substituted medium‐sized seven‐ ( 10 ) and eight‐membered rings ( 11 ) are scaffolds frequently encountered in pharmaceutical research . Recently, atropisomeric systems have been designed and used also as “tropos ligands” , molecular motors (as 12 ) , and gears by exploiting the inherent rotational mobility of these systems as smart tool.…”

Section: Introductionmentioning

confidence: 99%

Recent trends and applications in liquid‐phase chromatography enantioseparation of atropisomers

et al. 2017

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The term Atropisomerism defines a type of enantiomerism that arises from hindered rotation around an axis that makes two rotational isomers enantiomers. Atropisomeric compounds are present in nature, being important building blocks of many biologically active compounds. Atropisomers have been extensively studied in environmental and toxicological chemistry and, in particular, separating them has become a need in specific fields as organic synthesis and pharmaceutical research. High-performance LC has been fruitfully applied in this context, and despite HPLC separation on chiral stationary phase is considered as mature technology nowadays, in the last years several advancements and applications contributed to study compounds where axial chirality is of utmost importance. Moreover, dynamic chromatography has been exploited as a versatile tool for kinetic studies of systems with slow internal motion gaining essential information on their stereodynamic behavior. On this basis, current topics and trends in liquid-phase chromatography enantioseparation of atropisomers are presented herein with specific focus on new representative applications with HPLC, covering years 2010-2016. Some examples concerning supercritical fluid chromatography applications are also reported. This review aims to provide the reader with a modern overview of the field to highlight the renewed interest toward the chemistry of molecules with atropisomeric properties. A systematic compilation of all published literature has not been attempted.

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Section: Introductionmentioning

confidence: 99%

Recent trends and applications in liquid‐phase chromatography enantioseparation of atropisomers

et al. 2017

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“…Following the established method, 1) 2′-t-butyl-6′-iodosubstituted N-benzoyl-3-bromocarbazole 1 was prepared as a crude solid. HPLC analysis using a nonchiral column showed two peaks corresponding to trans-1 and cis-1 (54 : 46).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we have reported on the atropisomeric properties of the 2′-t-butyl-6′-iodo-substituted N-benzoyl 3-bromocarbazole (1). 1) Because the rotations about the N-C7′ and C7′-C1′ axes are fully restricted, four stereoisomers (cis/trans for the N-C7′ axis, aR/aS for the C7′-C1′ axis) of 1 were resolved on a chiral column (CHIRALPAK IB) (Fig.…”

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confidence: 99%

“…1) Because the rotations about the N-C7′ and C7′-C1′ axes are fully restricted, four stereoisomers (cis/trans for the N-C7′ axis, aR/aS for the C7′-C1′ axis) of 1 were resolved on a chiral column (CHIRALPAK IB) (Fig. 1).…”

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confidence: 99%

“…It is clear that the rotation about the C7′-C1′ axis must be in perfect concert with the rotation about the N-C7′ axis at 37°C. 1) With our interest in this gear molecule, 2,3) we studied its physicochemical properties in detail to discover a crystallization-induced diastereomeric transformation (CIDT). [4][5][6][7][8] Crystallization, where the pure isomer is crystallized from diastereomeric mixtures, could be cost-effective compared with conventional column chromatography.…”

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confidence: 99%

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Crystallization-Induced Diastereomeric Transformation of N-2′-t-Butyl-6′-iodobenzoyl-3-bromocarbazole

Kayama

Tani

Takahashi

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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We previously reported the atropisomeric properties of 2′-t-butyl-6′-iodo-substituted N-benzoyl-3-bromocarbazole, i.e., the steric or electronic effects of the substituents restricted the rotation about the N-C7′ and C7′-C1′ bonds to separate four stereoisomers (cis/trans for the N-C7′ axis, aR/aS for the C7′-C1′ axis). Furthermore, the 2′-t-butyl-6′-iodo-substituted N-benzoyl 3-bromocarbazole was confirmed to be a gear molecule, in which the rotation about the C7′-C1′ bond was in perfect concert with that about the N-C7′ bond. Herein, we report a unique crystallization-induced diastereomeric transformation found in this molecule. In the isolation process, where the product is recrystallized from the diastereoisomeric mixture, in situ isomerization and selective crystallization could lead to a diastereomeric transformation, and a mixture of diastereomers (trans/cis 54 : 46) was converted to trans-isomer-enriched crystals (trans/cis>96 : 4) in 95% yield. Conformational analysis clarified the preference for the trans versus cis isomer.Key words axial chirality; crystallization; diastereomer transformation; carbazole Recently, we have reported on the atropisomeric properties of the 2′-t-butyl-6′-iodo-substituted N-benzoyl 3-bromocarbazole (1).1) Because the rotations about the N-C7′ and C7′-C1′ axes are fully restricted, four stereoisomers (cis/trans for the N-C7′ axis, aR/aS for the C7′-C1′ axis) of 1 were resolved on a chiral column (CHIRALPAK IB) (Fig. 1). Using the enantiomerically pure stereoisomer, the stereochemical stability was examined at 37°C. It was found that (cis, aS)-1 was converted to (trans, aR)-1 with a ΔG ‡ value of 102 kJ/mol, and no interconversion between any other pair [i.e., (cis, aS)-1/ (cis, aR)-1, (cis, aS)-1/(trans, aS)-1] was observed. Similarly, (trans, aS)-1 was converted to (cis, aR)-1 with a ΔG ‡ value of 103 kJ/mol, and no interconversion between any other pair [i.e., (trans, aS)-1/(trans, aR)-1, (trans, aS)-1/(cis, aS)-1] was observed. It is clear that the rotation about the C7′-C1′ axis must be in perfect concert with the rotation about the N-C7′ axis at 37°C. 1)With our interest in this gear molecule, 2,3) we studied its physicochemical properties in detail to discover a crystallization-induced diastereomeric transformation (CIDT). [4][5][6][7][8] Crystallization, where the pure isomer is crystallized from diastereomeric mixtures, could be cost-effective compared with conventional column chromatography. In particular, diastereomeric transformation allowing an isomer to be converted to the desired one through in situ isomerization and selective crystallization might be very practical. Such in situ isomerization and crystallization (CIDT) has been researched recently by many groups. 4-8) Results and DiscussionIn the course of the crystallization experiments on 1, we discovered that the diastereoisomeric mixture 1 was crystallized through isomerization to give trans-isomer-enriched crystals in nearly quantitative yield (Fig. 2).Following the established method, 1)2′-t-butyl-6′-iodo...

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