Diastereochemical differentiation of some cyclic and bicyclic β-amino acids, via the kinetic method

Anna R. M. Hyyrylinen 0 1 3 Jaana M. H. Pakarinen 0 1 3 Ferenc Flp 0 1 2 Pirjo Vainiotalo 0 1 3 0 Address reprint requests to Professor Pirjo Vainiotalo, Department of Chemistry, University of Joensuu , P.O. Box 111, FI-80101 Joensuu, Finland 1 Published online September 25, 2008 Received August 5, 2008 Revised September 12, 2008 Accepted September 13, 2008 2 Institute of Pharmaceutical Chemistry, University of Szeged , Szeged, Hungary 3 Department of Chemistry, University of Joensuu , Joensuu, Finland Stereochemical differentiation of five diastereomeric pairs of -amino acids, di-endo- and di-exo-2,3disubstituted norbornane and norbornene amino acids, cis- and trans-2-aminocyclohexane-, 2-amino-4-cyclohexene-, and 2-aminocyclopentanecarboxylic acids, was investigated via the kinetic method with metal-bound trimeric complexes. This is the first time that diastereomers (di-endo/di-exo and cis/trans) have been differentiated with metal-bound trimeric complexes and the kinetic method. Moreover, determination of diastereochemical excess by the kinetic method was applied to norbornane -amino acids and cyclopentane -amino acids. Experiments showed that a remarkable differentiation of the studied diastereomers was achieved. It was observed that better selectivity values correlated to more rigid structures. The reference compounds for the studied -amino acids varied from -amino acids to some -amino acids. In addition, variation of the metal ion (Cu2 and Ni2 ) had some role in the selectivity values obtained. Ab initio and hybrid density functional theory calculations were performed to clarify the results obtained by mass spectrometry. (J Am Soc Mass Spectrom 2009, 20, 34 - 41) 2009 Published by Elsevier Inc. on behalf of American Society for Mass Spectrometry - where A is an analyte of interest, M2 is a divalent metal ion, and ref* is a chiral reference compound. The abundance ratios of these [M2 (ref*)(A) H] and [M2 (ref*)2 H] fragment ions strongly depend on the stereochemistry of the ligands in the trimeric complex [M2 (ref*)2(A) H] ion. The electronic and steric effects of the chiral reference compound have major roles in achieving the selectivity. Together with the reference molecule, the metal ion plays a large role in achieving the differentiation of isomers. Because different transition-metal ions have different electronic configurations, they also have different stereochemical effects [9]. In this method, a chiral selectivity (Rchiral) is defined as the ratio of RR/RS, where RR or RS is defined as: In this study, the applicability of the kinetic method and trimeric complexes was tested for its ability to differentiate diastereomeric -amino acids (both diendo/di-exo and cis/trans isomers). The diastereoselectivity (Rd) is defined as the ratio of Rdiendo/Rdiexo (respectively Rcis/Rtrans). As in the case of chiral analysis, the larger the difference between Rd and unity (1) the higher the degree of diastereoselectivity. Stereochemical differentiation by the kinetic method was performed for both bicyclic (14) and cyclic TCooks, is a technique used for the determination he kinetic method, introduced by R. Graham of thermochemical values such as proton affinity, ionization energy, and gas-phase basicity [13]. Another application of the kinetic method has been the differentiation of isomers, mainly enantiomers [4 6]. In the field of chiral analysis, Cooks and coworkers showed that dissociation kinetics of transition-metal ion trimeric complexes can be used to differentiate enantiomers of -amino acids [6 8]. Later on, differentiation of enantiomers using the kinetic method received a lot of interest, thus different kinds of enantiomers have been separated [9 20]. In this method, singly charged trimeric metal-bound complexes are formed and the ion of interest, a trimeric metal bound complex [M2 (ref*)2(A) H] , is isolated. These trimeric complex ions are then dissociated to form dimeric complexes via collision-induced dissociation (CID), CID [M2 (ref )(A) Scheme 1. Di-endo- and di-exo-isomers of the bicyclic -amino acids (14), and cis- and trans-isomers of the cyclic -amino acids (510) studied. -amino acids (510) (Scheme 1). Among the cyclic -amino acids, the most widely investigated are the five- and six-member compounds, for example (1R,2S)2-aminocyclopentanecarboxylic acid (cispentacin), an antifungal antibiotic which has been isolated from Bacillus cereus and Streptomyces setonii [21]. In addition, cyclic -amino acids are mentioned as building blocks for the preparation of modified analogues of biologically active peptides, as starting substances for different heterocycles, as potential pharmacons, and as building blocks in drug research [21, 22]. The differentiation of some of these studied diastereomeric -amino acids has been evaluated before with chemical and electron ionization, but differentiation of isomers has proved to be challenging [23]. In our earlier study, we differentiated these -amino acids through ion/molecule reactions [24, 25]. Especially for the studied cyclic -amino acids, moderate selectivities were achieved by using host guest complexes and ion/ molecule reactions. So, in view of achieving better differentiation, the kinetic method was applied. This method proved interesting because it offered wide opportunities to alternate reference compounds, as well as metal ions. Different reference compounds for the different -amino acids studied varied from -amino acids [d-proline (d-Pro), l-proline (l-Pro), and lphenylalanine (l-Phe)] to some -amino acids. The -amino acids used as reference compounds were diexo norbornane -amino acid (2), cis-cyclohexane -amino acid (5), cis- and trans-cyclohexene -amino acid (7 and 8), and (1S,2R)-cycloheptane -amino acid. In addition, we tried to use other reference compounds, but a trimeric metal-bound complex was not observed in some cases, or the abundance of the ion of interest was too low for isolation, and thus for dissociation. In this study, both Cu2 and Ni2 were used as the central metal ions for all diastereoisomeric -amino acids (1 10). Apart from the diastereomeric differentiation of the studied -amino acids, determination of diastereomeric excess was also performed for the norbornane (1 and 2) and cyclopentane (9 and 10) -amino acids. For the kinetic method experiments, the trimeric metalbound complexes were generated by mixing a 1:1 solution of methanol-water that contained a stereoisomer of interest and a reference compound, at a concentration of 50 M each, and 10 M transition-metal salt. In some experiments, a higher concentration of metal salt (50 M) was needed due to a low abundance of the trimeric complex. Variation of the metal concentration, however, did not contribute to the selectivity values obtained. Cupric chloride (CuCl2 2H2O) and nickel nitrate (Ni(NO3)2 6H2O), obtained from Merck (Darmstadt, Germany), were used as sources of metal ions. Reference compounds, l-phenylalanine a (...truncated)