Michael Koscho

Assistant Professor of Organic Chemistry

 
Mike Koscho Michael Koscho received a B.S. in Chemistry from Purdue University in 1993, and a Ph.D. in organic chemistry from the University of Illinois at Urbana-Champaign in 1999. He continued his education as a Postdoctoral Scholar at the California Institute of Technology, until the fall of 2001 when he accepted a faculty appointment at Mississippi State.
email:
telephone: (662) 325-9500
 

Research Interests

Research in this group is directed toward the development of methods that can be used for the rapid analysis of enantiomeric composition, and applying these techniques to various applications in the chirotechnology domain. The development of fast enantiomeric composition determinations should eventually lead to viable high-throughput enantiomer assays. Currently, we are focused on developing a method that utilizes Electrospray Ionization-Mass Spectrometry (ESI-MS) for this purpose.

The ability to produce single-enantiomer products is of paramount importance to a number of industries, particularly the pharmaceutical industry due to its direct impact on human health. It has long been known that the enantiomers of a chiral drug can have very different, and even dangerous side-effects. The development of single-enantiomer products requires not only efficient asymmetric synthetic methods, but also the ability to identify and quantify enantiomeric mixtures. With the advent of combinatorial asymmetric catalysis, whereby libraries of potential asymmetric catalysts are produced in parallel and each catalyst is screened for its ability to produce a product of high enantiomeric purity, it has become necessary to develop high throughput enantiomer assays.

For the mass spectrometric method, we have discovered that when a solution of pseudo-enantiomeric selectors is mixed with an analyte, and the solution is assayed by ESI-MS, chiral recognition may be observed in the mass spectrum. In order to observe chiral recognition, the pseudo-enantiomeric chiral selectors must meet three requirements: (1) they must have a different mass so that they can be differentiated in the mass spectrum, (2) each must have a higher affinity for the opposite enantiomer of the analyte, and (3) selector-analyte complexes must be observed in the mass spectrum.

scheme 1

For example, the chiral selectors 2 and 3 are soluble analogs of the chiral selectors used in the commercially available chiral stationary phases DNB-leucine and DNB-phenylglycine, respectively. From chiral chromatography, it is known that the (R)-enantiomer of analyte 1 has a higher affinity for the (R)-enantiomer of each of these chiral selectors, 2 and 3. Therefore, using (R)-2 and (S)-3 will satisfy requirement (2), additionally the mass of 2 and 3 are different satisfying requirement (1). Using ESI, which is a very mild ionization technique, satisfies requirement (3). The mass spectra (negative ion mode) of mixtures of chiral selectors 2 and 3, with analyte 1 (plus one equivalent sodium hydroxide in 1 : 1 methanol : water) are shown in Figure 1: (a) enriched in (R)-1, (b) racemic, (c) enriched in (S)-1. From these data it is apparent that the enantiomeric composition of analyte 1 is related to the relative heights of the complex ion peaks in the mass spectrum.

figure 1

Figure 1. Partial mass spectra of pseudo-enantiomeric selectors (R)-2 and (S)-3 (5.0 mM each) and analyte 1 (5.0 mM) with added sodium hydroxide (10 mM) in methanol / water (1:1). Spectrum (a) 89.8% (R)-1, 10.2% (S)-1; (b) racemic 1; (c) 9.1% (R)-1, 90.9% (S)-1.

In fact, a plot of the natural log of the relative peak intensities (RPI) versus enantiomeric composition (Figure 2) affords a straight line where the slope can be related to the extent of enantioselectivity. This line can be used as a calibration for subsequent enantiomeric composition determinations. Additionally, the sense of chiral recognition is what would be predicted from chromatographic studies. When the amount of (R)-1 in the sample is increased the intensity of the complex with the (R)-selector is increased (m/z 626), and when the amount of (S)-1 in the sample is increased the intensity of the complex with the (S)-selector is increased (m/z 646). When the data are collected by flow injection, each sample requires less than ten seconds for completion, which is fast compared to contemporary methods of enantiomer analysis (chiral HPLC typically requires minutes per sample).

figure 2

Figure 2. Plot of the natural log of the ratio of peak intensities (RPI) for the selector-analyte complexes in the ESI-MS versus the mole fraction of (R)-1 in the solution, using pseudo-enantiomeric chiral selectors (R)-2 and (S)-3.

Further work in this area includes the development of new chiral selectors, determining the scope / limitations for each, transforming this method into a viable high-throughput method, and using this method to screen combinatorial libraries for the discovery of new chiral selectors and chiral catalysts. In the area of new selector development, promising results have recently been obtained using chiral selectors that have been designed to separate the two main functions of the chiral selectors: (1) efficient chiral recognition, and (2) ionization. For example, the pseudo-enantiomeric chiral selectors 4 and 5 are readily protonated at the tertiary nitrogen which allows ready detection by MS, and this site is removed from the other interaction sites needed for chiral recognition. The synthesis and evaluation of other side-chain ionizable chiral selectors is on-going.

Publications 2002 - 2007

  1. Michael E. Koscho, Patrick L. Spence, William H. Pirkle, "Chiral Recognition in the Solid State: Crystallographically Characterized Diastereomeric Co-crystals Between a Synthetic Chiral Selector (Whelk-O1) and a Representative Analyte" Tetrahedron: Asymmetry, 2005, 16, 3147 – 3153.
  2. Chengli Zu, Bobby N. Brewer, Michael E. Koscho, "Tertiary Amine Appended Derivatives of N-(3,5-Dinitrobenzoyl)leucine as Chiral Selectors for Enantiomer Assays by Electrospray Ionization Mass Spectrometry" Anal. Chem., 2005, 77, 5019 - 5027.
  3. Bobby N. Brewer, Chengli Zu, and Michael E. Koscho, "Determination of Enantiomeric Composition by Negative Ion Electrospray Ionization-Mass Spectrometry Using Deprotonated N-(3,5-Dinitrobenzoyl)amino Acids as Chiral Selectors" Chirality, 2005, 17, 456 - 463.
  4. Michael E. Koscho, Chengli Zu, and Bobby N. Brewer, "Extension of Chromatographically Derived Chiral Recognition Systems to Chiral Recognition and Enantiomer Analysis by Electrospray Ionization Mass Spectrometry" Tetrahedron: Asymmetry, 2005, 16, 801-807.
  5. Michael E. Koscho, Eric Tillman, Nathan S. Lewis, Robert H. Grubbs "Use of Basic Polymers in Carbon Black Composite Vapor Detectors to Obtain Enhanced Sensitivity and Classification Performance For Volatile Fatty Acids" Anal. Chem. 2003, 75, 1748 - 1753
  6. Michael E. Koscho, Nathan S. Lewis, Robert H. Grubbs; "Properties of Vapor Detector Arrays Formed through Plasticization of Carbon Black-Organic Polymer Composites" Anal. Chem. 2002, 74, 1307 - 1315.