Enantioselective Chromatography and Absolute Configuration of N,N-Dimethyl-3-(naphthalen-2-yl)- butan-1-amines: Potential Sigma1 Ligands SIMONA COLLINA, 1 GUYA LODDO, 1 MARIANGELA URBANO, 1 DANIELA ROSSI, 1 MARIA GRAZIA MAMOLO, 2 DANIELE ZAMPIERI, 2 STEFANO ALCARO, 3 ANDREA GALLELLI, 3 AND ORNELLA AZZOLINA 1 * 1 Dipartimento di Chimica Farmaceutica, Universita ` di Pavia, Pavia, Italy 2 Dipartimento di Scienze Farmaceutiche, Universita ` di Trieste, Trieste, Italy 3 Dipartimento di Scienze Farmacobiologiche ‘‘Complesso Ninı ` Barbieri,’’ Universita ` di Catanzaro ‘‘Magna Graecia,’’ Roccelletta di Borgia, Italy ABSTRACT We describe the preparation of racemic N,N-dimethyl-3-(naphthalen-2-yl)- butan-1-amines, potential sigma1 ligands, and their resolution via chiral HPLC. In order to obtain enantiopure compounds, direct chromatographic methods of separation using chiral stationary phases were investigated. Different methods suitable for both analytical and semipreparative purposes are proposed. The best resolutions were achieved using cellulose tris (3,5-dimethylphenyl carbamate) (Chiralcel OD and OD-H) and amylose tris (3,5-dimethylphenyl carbamate) (Chiralpak AD). On the basis of the preliminary chroma- tographic results, the resolution of compound 1 was transferred onto a Chiralcel OD semipreparative column. The enantiomers were obtained in high enantiomeric excess. The configurational assignment was performed by circular dichroism. Computational analysis was used to explore the enantioselective recognition process of compound 1 with the Chiralcel OD stationary phase. Chirality 18:245–253, 2006. V V C 2006 Wiley-Liss, Inc. KEY WORDS: chiral resolution; configurational assignment; circular dichroism; Chi- ralcel OD model; chiral recognition mechanism; N,N-dimethyl-3-(naph- thalen-2-yl)-butan-1-amines During our recent research on the preparation of subtype selective sigma1 receptor ligands, we investi- gated the synthesis and chiral resolution of several naph- thylamines. Sigma receptors have not yet been fully char- acterized because of the lack of endogenous ligands and because of the wide variety of chemically unrelated com- pounds that show a high affinity for such receptors. 1 Sigma1 and sigma2 subtypes have been defined by differ- ent drug binding profiles and different stereoselectivity. 2 For this reason, and taking into account that the drug dis- covery and development process requires pure stereo- isomers in order to gain knowledge on the role of config- uration in binding affinity, we investigated the preparation of both racemic and enantiomeric 1–3 (Scheme 1). To the best of our knowledge, resolution of enantiomeric 3-(naphthalen-2-yl)-butan-1-amines, structurally related to compounds 1–3, has never been described. On the basis of our previous experience, 3,4 we selected fractional crystalliza- tion and chiral chromatography as the most suitable proce- dures, from among all the possible approaches, for obtain- ing both enantiomers. Racemic 1–3 were synthesized by nucleophilic addition of the appropriate naphthalenic anions to 4-dimethylami- nobutan-2-one 4, dehydration of the alcoholic intermedi- ates, and catalytic reduction of the corresponding olefins. Chiral HPLC, a valid approach for obtaining enantio- merically pure compounds [100% enantiomeric excess (ee)], was used in attempts to separate the enantiomers. In order to determine the best resolution conditions, analytical methods on different chiral stationary phases (CSPs) were investigated. On the basis of the preliminary chromatographic results, the resolution of compound 1 was transferred onto a Chiralcel OD column for semipre- parative production. The absolute configuration of the isomers was assigned by circular dichroism (CD). Since chiral recognition plays an essential role in the field of the separation of enan- tiomers, several approaches to clarifying this process have been taken. Recently, Okamoto and co-workers reported detailed computational studies concerning enan- tioselective recognition processes between CSP based on phenylcarbamate derivatives of cellulose and analytes, *Correspondence to: Ornella Azzolina, University of Pavia, Department of Pharmaceutical Chemistry, Via Taramelli 12 Pavia, Italy. E-mail: ornella.azzolina@unipv.it Received for publication 25 July 2005; Accepted 31 October 2005 DOI: 10.1002/chir.20227 Published online 6 March 2006 in Wiley InterScience (www.interscience.wiley.com). CHIRALITY 18:245–253 (2006) V V C 2006 Wiley-Liss, Inc.