APPLICATION OF THE “INVERTED CHIRALITY COLUMNS APPROACH” FOR THE MONITORING OF ASYMMETRIC SYNTHESIS PROTOCOLS

Authors  Ianni F, Tiecco M, Carotti A, Pucciarini L, Saluti G, Galarini R, Sardella R, Natalini, B

Abstract   In the present study, the "Inverted Chirality Columns Approach (ICCA)" was applied to follow an asymmetric synthetic reaction, namely, the addition of butan-2-one to trans-β-nitrostyrene, catalysed by (S)-proline, leading to the formation of 3-methyl-4-phenyl-5-nitro-2-pentan-2-one. The ICCA method was applied to overcome the lack of pure enantiomeric standards. The two widely employed (R,R)- and (S,S)-Whelk-O1 chiral stationary phases (CSPs), incorporating fully synthesized enantiomeric chiral selectors, were profitably used for this purpose. The enantioselective analysis with the two CSPs was performed under optimized reversed-phase conditions with a water/acetonitrile (60/40, v/v) eluent. In the probe reaction under investigation, a diastereomeric excess >90% was found according to a well-established reaction mechanism, thus affording the enantiomer couple (3S,4R)-3-methyl-4-phenyl-5-nitropentan-2-one and (3R,4S)-3-methyl-4-phenyl-5-nitropentan-2-one as the main product. Therefore, the attention was exclusively focused on this enantiomers pair. Rather similar retention and separation factor [1.12 with (R,R)-Whelk-O1 and 1.13 with (S,S)-Whelk-O1] values as well as resolutions [2.06 with (R,R)-Whelk-O1 and 2.30 with (S,S)-Whelk-O1] were produced by the two enantiomeric CSPs. Applying the ICCA concept allowed to identify the two enantiomers-related peaks in the chromatograms, ultimately indicating a 65-to-35 enantiomeric per cent ratio. Electronic circular dichroism (ECD) and high-resolution mass spectrometry analyses of the two peaks collected during the enantioselective analyses further confirmed the enantiomeric nature of the identified compounds. The (3S,4R) < (3R,4S) enantiomer elution order with the (R,R)-Whelk-O1 was fully disclosed thanks to ECD studies coupled with in silico quantum mechanical simulations. As expected, reversed elution order turned out with (S,S)-Whelk-O1.

Publish Date  2019

Volume   203

ISSN  1873-3573

DOI   doi.org/10.1016/j.talanta.2019.05.045

URL  https://www.sciencedirect.com/science/article/pii/S0039914019305296?via%3Dihub

Journal   Talanta

Pages   147-152

PMID  31202319