J. Sep. Sci. 2014, 37, 3451–3460 3451 Sonia Pedotti Angela Patti CNR- Istituto di Chimica Biomolecolare, Catania, Italy Received August 4, 2014 Revised September 10, 2014 Accepted September 10, 2014 Research Article Enantioseparation of aldols by high-performance liquid chromatography on polysaccharide-based chiral stationary phases that bear chlorinated substituents Two families of aldols, obtained from the condensation of aromatic aldehydes with cyclo- hexanone or acetone (ten examples in each group), were analyzed by high-performance liquid chromatography in normal phase elution mode on three polysaccharide-based chi- ral stationary phases of the Lux series, namely, Lux Cellulose-2, Lux Cellulose-4 and Lux Amylose-2, which share the common feature of chlorinated substituents in the chiral selec- tors. Following simple optimization steps, the enantioseparation of all aldols derived from cyclohexanone was achieved and the highest values of separation factor (, 1.32 <  < 2.20) and resolution (R s , 4.5 < R s <17.2) were observed on Lux Cellulose-2, with the only excep- tion of the 4-nitro-substituted derivative that was better resolved on Lux Cellulose-4. On the contrary, Lux Amylose-2 was the best choice for aldols derived from acetone and only specific analytes in this group were resolved on the cellulose-based supports. A variable-temperature study of selected compounds allowed us to determine thermodynamic parameters of the enantioseparation process, which was enthalpy-controlled in all the cases except one. Keywords: Aldols / Enantioseparation / High-performance liquid chromatography / Polysaccharide-based selectors DOI 10.1002/jssc.201400838  Additional supporting information may be found in the online version of this article at the publisher’s web-site 1 Introduction The aldol condensation of two carbonyl compounds is one of the most important methods for the construction of carbon– carbon bonds and the increase of molecular complexity through the introduction of one or two stereogenic centres starting from relatively simple and achiral compounds. The products of such a reaction, the aldols, are important syn- thons in the preparation of polyhydroxylated compounds, and aldol structural units are found in many important molecules, whether naturally occurring or synthetic [1–3]. Many stereoselective methods for the synthesis of chiral aldols have been developed [4–6] and a renewed interest in asymmetric aldol addition has exploded with the advent of organocatalysis following the first report of an L-proline-catalyzed reaction [7, 8]. During the last decade, asymmetric aldol addition has become a benchmark reaction in the search for novel and efficient organocatalysts [9] Correspondence: Dr. Angela Patti, Istituto di Chimica Biomoleco- lare, National Research Council of Italy, Via Paolo Gaifami, 18, I-95126 Catania (Italy) E-mail: angela.patti@cnr.it Fax: 0039 0957338310 Abbreviation: CSP, chiral stationary phase and the evaluation of their performances in different experimental conditions [10–12]. In most cases aromatic aldehydes and acetone or cyclohexanone were used as test carbonyl components and the optical purity of the formed aldols has been exclusively determined by chiral HPLC on a restricted number of chiral stationary phases (CSPs) under normal-phase elution mode. In spite of a variety of commercially available CSPs, most enantioseparations of aldols are reported on polysaccharide-based selectors in which the sugar hydroxyls of the cellulose or amylose chiral backbone are derivatized with 3,5-dimethylphenylcarbamate groups [13–15] and specific compounds are better resolved on tris-(S)--methylbenzylcarbamate amylose [16]. Although optimal conditions for the analysis of a large number of chiral aldols [17–19] have been developed in the context of the extensive research on asymmetric aldol reaction, a systematic study focused on the chromatographic features of this class of compounds on these CSPs is still missing. Polysaccharide-based CPSs that bear chlorinated carba- mate residues [20] have been recently marketed and have shown excellent performances in the enantioseparation of a large variety of structurally unrelated compounds [21–25], but chiral analyses of aldols on these supports are limited to a few examples. Due to the presence of the halogen atoms in their structure, these chiral selectors could offer unique C  2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.jss-journal.com