Multimilligram-scale production implementation of atropisomers of 2,2'-bis(2,2'-bithiophene-5-yl)-3,3'-bithianaphthene

Alessia Rosetti; Giorgia Bonetti; Claudio Villani; Tiziana Benincori; Roberto Cirilli

doi:10.1002/chir.23294

Multimilligram-scale production implementation of atropisomers of 2,2'-bis(2,2'-bithiophene-5-yl)-3,3'-bithianaphthene

Chirality. 2021 Apr;33(4):146-152. doi: 10.1002/chir.23294. Epub 2021 Feb 14.

Authors

Alessia Rosetti^{1

2}, Giorgia Bonetti³, Claudio Villani², Tiziana Benincori³, Roberto Cirilli¹

Affiliations

¹ National Center for the Control and Evaluation of Drugs, Istituto Superiore di Sanità, Rome, Italy.
² Department of Bedbug and Drug Technology, Sapienza University of Rome, Rome, Italy.
³ Department of Science and High Technology, University of Insubria, Como, Italy.

PMID: 33586243
DOI: 10.1002/chir.23294

Abstract

2,2'-Bis[2-(5,2'-bithienyl)]-3,3'-bithianaphthene (1) is the progenitor of a class of C₂ symmetric thiophene-based electroactive monomers that, when electrooxidized in the enantiomerically pure form, produce inherently chiral films endowed with outstanding electrochemical enantiorecognition properties. The enantioselective high-performance liquid chromatography (HPLC) is the only approach used so far to resolve the racemic form of 1 into enantiomers. In this work, an improved HPLC method for multimilligram enantiomer production is presented. Key factors controlling the enantioseparation, such as mobile phase composition and column temperature, were identified using a 100 × 4.6 mm i.d. Chiralpak IB-3 column and subsequently scaled up to a 250 × 10.0 mm i.d. Chiralpak IB column. In the optimized semipreparative conditions, about 34 mg of pure (P) and (M) enantiomers per hour could be produced.

Keywords: 3,3′-dibenzothiophene derivative; Chiralpak IB; inherent chirality; semipreparative enantioseparation.