CROATICA CHEMICA ACTA CCACAA, ISSN-0011-1643, ISSN-1334-417X Croat. Chem. Acta 82 (2) (2009) 503–530 CCA-3341 Author's Review Separation of Enantiomers by Chromatography as a Vehicle for Chiral Catalysis. Abridged Review* Vitomir Šunjić Chirallica Ltd., Bijenička 54, 10002 Zagreb, Croatia (E-mail: [email protected]) RECEIVED MAY 14, 2008; REVISED NOVEMBER 19, 2008; ACCEPTED NOVEMBER 22, 2008 Abstract. Chiral, or asymmetric catalysis is the most efficient approach to chiral molecules in the enantio- merically enriched form. Organocatalysis and organometallic catalysis are nowadays the methods of choice in this field. In the first case enantiomerically pure chiral organic molecules of different symmetry classes exhibit catalytic effect, in the second one chiral organic molecule acts as the ligand in the organo- metallic complex that exerts catalytic activity. In both cases small amount, milligrams or grams, of enan- tiopure organic or organometallic catalyst suffice to produce substantial amounts, grams or tons, of chiral products of academic or commercial interest. Due to the need for limited quantities of chiral organic mole- cules in the optically pure form to act as the catalysts or be the part of the catalytic systems, preparative chromatographic separation, and in particular simulated moving bed (SMB) chromatographic resolution of racemic material, represent valuable approach. Examples of separation of racemates by chiral chroma- tography and SMB technology to catalytically useful enantiomers are presented, and application of enan- tiomers from different symmetry classes in efficient catalytic processes is highlighted. Keywords: separation of enantiomers by cromatography, simulated moving bed (SMB) technology, chiral catalysis INTRODUCTION ceuticals, their intermediates, and last not the least, for separation of chiral compounds that will serve as organo- Effective transfer of scientific results from academic catalysts or as the parts of organometallic catalytic com- research into technical, problem-solving sphere of in- plexes. Ready accessibility of optically pure organo- dustrial R&D is ever more demanding process. This catalysts and ligands is one of the most critical factors stays in particular for the results of research in chemi- when a practical methodology for asymmetric catalysis stry, where any larger-scale experimentation requires is emerging. Their availability in homochiral, optically expensive equipment, and consumption of row materials pure form from racemic, easily available, compounds by under huge pressure of prices and ambiental-protection “chiral chromatography” makes novel catalytic proces- requirements. Even when these tasks are solved from ses possible. the financial, ecological and organizational aspects, Such complex research was traditionally per- newly developed technology will meet harsh require- formed in academic laboratories, nowadays however it ments for competitive position on the global market. is shifted to “start-up companies” or “innovation com- Western and Eastern World are responding to panies”, or “biotech companies”.2 Some own results these challenges by founding new, science-based (bio- presented in this abridged review are obtained in early tech) companies in the chemical industry.1 Among them period at CATBIO Laboratory (www.spider.irb.hr/ are companies dealing with the development of new CatBio.htm), more recently at Chirallica Ltd., (www. catalysts, production of new HPLC columns with chiral chiralica.hr.com), spin-off company, both at “Ruđer stationary phases (CSPs) for the separation of pharma- Bošković” Institute, Zagreb. * Dedicated to Professor Emeritus Drago Grdenić, Fellow of the Croatian Academy of Sciences and Arts, on the occasion of his 90th birthday. 504 V. Šunjić, Cromatographic Enantioseparation Triggers Chiral Catalysis APPLICATION OF OPTICALLY PURE their availability from the “chiral pool” of Nature. Na- COMPOUNDS AS THE CATALYSTS AND ture regularly creates chiral molecules with C1 sym- CHROMATOGRAPHIC ENANTIOSEPARATION metry, and almost exclusively in one enantiomeric 5 OF THEIR RACEMATES form. Such C1 symmetric molecules are often submis- sive to further chemical modifications to give catalytic Chirality of the Catalytic Molecules and Ligands and non-catalytic auxiliary agents in synthetic organic chemistry, with already mentioned limitation that only Effective catalytic production of chiral molecules in the one enantiomer is usually available. The first two mole- enantiomerically enriched form generally does not de- cules (1,2) in the Figure 1 are natural compounds, the pend on the symmetry group to which catalytically third chiral molecule with C symmetry (3) is an un- active chiral molecule belongs. Chiral molecule do not 1 natural structure, prepared in the laboratory to act as posses 2nd order elements of chirality; alternating axis of monodentate ligand, see section Centro-chiral Ligands. symmetry of the second order (Sn), center of symmetry (i), or plane of symmetry (σ).3,4 Alternating axes, centers What about availability of axial-chiral, as exempli- and planes of symmetry are elements that correspond to fied by C2 and C3 symmetric molecule in the Figure 1, “symmetry operations of the second kind” which cannot and planar-chiral molecules? They can be prepared be performed on chiral molecules. Chiral molecules either in the enantiomerically pure form, often a dif- belong to Cn and Dn point groups; in the former Cn axis ficult task, or as racemate and then submitted to sepa- is the only symmetry element, the later are characterized ration of single enantiomers. It is this last approach that 3 by n C2 axis perpendicular to the main Cn axis. They is so attractive for preparation of chiral catalysts, in are usually named centro-chiral, axial-chiral and planar- particular when completed by chromatographic sepa- chiral molecules; representatives of chiral molecules (1– ration on chiral stationary phases (CSPs). This method 7) and one achiral molecule (8) active as organocata- affords both enantiomers with high optical purity and in lysts or ligands are given in the Figure 1. quantities sufficient for testing in the enantioselective catalytic reaction. If one enantiomer proves effective, As will be exemplified in the next chapters, there but specific target molecule is obtained with “wrong” are many representatives of above classes of chiral configuration, application of the second enantiomer as molecules that are highly effective organocatalysts or catalyst elegantly resolves the problem. ligands in organometallic complexes. It is still an art in synthetic chemistry to design an effective chiral catalyst Some axially chiral enantiomers are characterized for specific organic reaction, as e.g. C–C, C–H, C–N by relatively low configurational stability, based on the and C–O bond-forming reactions, or skeletal rear- hindered rotation around C–C bond which is perpen- rangements under formation of a new stereogenic cen- dicular to C2 axis. Low configurational stability characte- ter. There is an important practical aspect that differen- rizes also some planar-chiral molecules, as will be dis- tiates three classes of chiral molecules in the Figure 1; cussed in the section Planar-chiral Complexes. Figure 1. Examples of catalytically active molecules and ligands that belong to various symmetry groups. Croat. Chem. Acta 82 (2009) 503–530 V. Šunjić, Cromatographic Enantioseparation Triggers Chiral Catalysis 505 recent monographs and reviews.6–10 We published an author-review related to our research on novel CSPs in this Journal,11 and informative overviews in the tech- nology oriented journal.12,13 Mechanism of chiral recog- nition by various CSPs, specific application of the bio- polymer-based CSPs, polysaccharide-type and protein- type being the most important ones, and brush-type CSPs, will not be discussed and interested reader is directed to consult the above references. For the purpose of easier following of discussion in the next chapters, only two aspects of chiral chromatography will be shortly commented here; types of chiral selectors (CS) nowa- days in the common use, and elementary thermodynam- ics of chromatographic enantioseparation. Figure 2. Four most important polysaccharide-based chiral selectors (“golden four”). Two important elements distinguish two main types of CS; molar mass and type of binding to silica. There is one peculiarity related to the molecules According to molar mass CS are either derived from possessing C3-axis. They are chiral if no element of the chiral polymers, usually from polysaccharides or pro- second order (i, Sn, σ) is present, as represented by tri- teins, or they are small chiral molecules, often designed podal phosphane 7 in the Figure 1. In the molecule 8 on purpose for separation of specific racemate, and three σ-planes are present, it is achiral and belongs to named “brush-type” or “Pirkle type”, according to the 14 C3v (D3) symmetry group. On coordination to Pd, how- inventor of such CSPs. Polysaccharide based CS ever, the whole complex adopts planar chirality. represent over 90 % of the market, and in even higher percentage considering the number of reported sepa- Rarity of chiral organic molecules in Nature with ration of racemates. Four of them, called “golden four”, axial and planar symmetry, but their availability in both practically cover this market, two of them are based on enantiomeric forms by chromatographic separation of cellulose (Chiralcel), and the other two on amylose racemic mixtures