Enantioseparation of Phenylglycinol in Chiral-Modified Zeolite HY: A Molecular Simulation Study SIRICHARN S. JIRAPONGPHAN, 1 JULIUSZ WARZYWODA, 1 DAVID E. BUDIL, 2 AND ALBERT SACCO JR 1 * 1 Department of Chemical Engineering, Center for Advanced Microgravity Materials Processing, Northeastern University, Boston, Massachusetts 2 Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts ABSTRACT A mechanism has been proposed for the separation of valinol enantio- mers using a chiral-modified zeolite HY (i.e., zeolite HY containing (+)-(1R;2R)-hydro- benzoin) Molecular modeling of chiral-modified zeolite HY employed in enantioselective separation. Jirapongphan SS, Warzywoda J, Budil DE, Sacco A Jr. Chirality 2007; in press, which accurately predicted the experimentally measured enantioseparation. This methodology has been applied to predict the separation of an enantiomeric pair of phe- nylglycinol molecules (a precursor in the synthesis of HIV-1 protease inhibitors) using the modified zeolite HY as a CSP. Phenylglycinol and valinol molecules are similar in terms of the presence of polar (i.e., amine and hydroxyl) groups. These functional groups are important in the proposed chiral discrimination. Supercage-based docking simulations yielded an enantioselectivity of 1.3 with (+)-(S)-phenylglycinol molecule bet- ter retained in the zeolite. Also, the simulations predicted two binding modes that were the same as those in the valinol system. This suggests that specific structural features (i.e., number and type of polar groups), which generate the hypothesized binding modes, are required in an enantioseparation utilizing the chiral-modified zeolite HY. Chirality 19:514–517, 2007. V V C 2007 Wiley-Liss, Inc. KEY WORDS: chiral discrimination; enantioseparation; hydrobenzoin; phenylglycinol; supercage-based docking simulation; valinol; zeolite HY INTRODUCTION In 2004, nine of the top-ten selling drugs ($53.5 billion (US) in global sales) had chiral active ingredients. 1 Isola- tion of the desired enantiomer is needed to obtain the desired therapeutic effect in the chiral drugs. In a resolu- tion of valinol enantiomers in a chiral-modified zeolite HY, the (+)-(S)-valinol was better retained inside the pores of the modified zeolite at experimental conditions (i.e., 294 K). 2,3 In the chiral-modified zeolite, a binding site for this enantioseparation was theoretically determined to be located in zeolite HY supercage that contained a physi- sorbed (+)-(1R;2R)-hydrobenzoin molecule, which acted as a chiral modifier (Fig. 1). 1–5 The supercages are the repeating sphere-like cavities (*12.6 A ˚ in diameter) con- nected to each other in three dimensions in the zeolite HY structure. A separation mechanism has been proposed for this (i.e., valinol) enantioseparation system based on low energy configurations that were obtained from supercage- based docking simulations. 1 To demonstrate the useful- ness of the proposed mechanism, an enantioseparation of phenylglycinol molecules (i.e., (+)-(S)-phenylglycinol and (À)-(R)-phenylglycinol) in the chiral-modified zeolite HY was simulated in the present investigation. The enantio- meric pair of phenylglycinol molecules was selected for the new separation system because of: (1) a potential appli- cation of (À)-(R)-phenylglycinol in the synthesis of a key precursor of HIV-1 protease inhibitors, 6 and (2) the simi- larity between phenylglycinol and valinol molecules in terms of the presence of polar (i.e., amine and hydroxyl, Fig. 2) groups. A chiral discrimination in the phenylglyci- nol system can be expected if the mechanism proposed for the valinol system that involves interactions generated by the amine and hydroxyl groups 1 is valid. COMPUTATIONAL METHODOLOGY The Compass force field, which has been parametrized for zeolites, 7 was employed in the energy calculation. Anal- ogous to the modeling of the valinol system, 1 the van der Waals interactions were calculated using atom-based sum- mation with a nonbonded cutoff of 12.0 A ˚ . The Coulombic interactions were calculated using the Ewald summation. All calculations were performed using Materials Studio software package from Accelrys. Contract grant sponsor: NASA and Massachusetts Space Grant Consor- tium. *Correspondence to: Albert Sacco Jr., 147 Snell Engineering, Northeast- ern University, Boston, MA 02115. E-mail: asacco@coe.neu.edu Received for publication 5 December 2006; Accepted 23 February 2007 DOI: 10.1002/chir.20407 Published online 16 April 2007 in Wiley InterScience (www.interscience.wiley.com). CHIRALITY 19:514–517 (2007) V V C 2007 Wiley-Liss, Inc.