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Chiral Recognition detected by Mass Spectrometry

Chiral Recognition detected by Mass Spectrometry. CHEN Ping. 2013.12.06. Outline. Introduction II. Hyphenated Mass Spectrometric Techniques for Chiral Analysis III. Mass Spectrometric Chiral Recognition Mechanisms Host-Guest (H-G) Associations Guest Exchange Ion-Molecule Reactions

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Chiral Recognition detected by Mass Spectrometry

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  1. Chiral Recognition detected by Mass Spectrometry CHEN Ping 2013.12.06

  2. Outline • Introduction • II. Hyphenated Mass Spectrometric Techniques for Chiral Analysis • III. Mass Spectrometric Chiral Recognition Mechanisms • Host-Guest (H-G) Associations • Guest Exchange Ion-Molecule Reactions • Chiral Recognition Based on Complex Dissociation • IV. Application of Chiral Recognition • Organocatalytic Asymmetric Conjungate Addition of Aldehydes to Nitroolefins • V. Summary

  3. Introduction More than half of the currently approved drugs are chiral molecules. Develop single enantiomer drugs • Reducing the required dose • Increasing the potency • Improving the safety profile 7 of the 10 best-selling US pharmaceutical products are single enantiomer. Asymmetric synthesis (Catalysts screening) Mass Spectrometry Chiral Recognition Chiral analysis (Quality control) Ranking of the top 10 best-selling US pharmaceutical products in 2011 was obtained from webpage: http://www.imshealth.com/.

  4. Introduction Traditionally, MS has been considered a “chiral-blind” technique Enantiomers: Same mass and show identical mass spectra Two strategies to differentiate a pair of enantiomers with MS • 1. Coupling of chiral sensitive analytical tools with MS • Liquid Chromatography-Mass Spectrometry (LC-MS) • Gas Chromatography-Mass Spectrometry (GC-MS) • … • 2. MS is used solely in chiral analysis based on different methods of chiral recognition • Host-Guest (H-G) Associations • Guest Exchange Ion-Molecule Reactions • Chiral Recognition Based on Complex Dissociation H. Awad, A. EI-Aneed, Mass Spectrom Rev, 2013, 32, 466–483

  5. Hyphenated MS techniques Coupling of chiral sensitive analytical tools with MS • Liquid Chromatography-Mass Spectrometry (LC-MS) • Gas Chromatography-Mass Spectrometry (GC-MS) • Capillary Electrophoresis-Mass Spectrometry (CE-MS) • Capillary Electrochromatography-Mass Spectrometry (CEC-MS) • Supercritical Fluid Chromatography-Mass Spectrometry (SFC-MS) New detector: Mass Spectrometer (MS) Advantages: Limitations: • Nonpolar solvents were incompatible with ESI or APCI • Salts and other nonvolatile compounds in the mobile phase were incompatible with ESI • Choosing chiral stationary phase is a daunting task • Sensitive • Accurate • Speed • High throughput H. Awad, A. EI-Aneed, Mass Spectrom Rev, 2013, 32, 466–483

  6. Hyphenated MS techniques Two options for chiral analysis using hyphenated MS techniques: • Indirect approach: • Analysis of covalent diastereomeric complexes • Separated by conventional methods • Direct approach: • Analysis of noncovalentdiastereomeric complexes Direct approach is preferred Indirect approach: Need more time for the reaction step Derivatized by the CS to form covalent complexes Form transient bond with CS CS: chiral derivatization reagent CS: chiral mobile phase additives (CMPAs) chiral stationary phases (CSPs) H. Awad, A. EI-Aneed, Mass Spectrom Rev, 2013, 32, 466–483

  7. Hyphenated MS techniques The HPLC-MS chromatograms of (S ,R) ifosfamide (IF) R. V. Oliveira, et al, J. Pharm. Biomed. Anal. 2007,45, 295–303.

  8. Chiral Recognition Mechanisms Two strategies to differentiate a pair of enantiomers with MS • 1. Coupling of chiral sensitive analytical tools with MS • Liquid Chromatography-Mass Spectrometry (LC-MS) • Gas Chromatography-Mass Spectrometry (GC-MS) • … • 2. MS is used solely in chiral analysis based on different methods of chiral recognition • Host-Guest (H-G) Associations • Guest Exchange Ion-Molecule Reactions • Chiral Recognition Based on Complex Dissociation

  9. Chiral Recognition Mechanisms 1. Host-Guest (H-G) Associations Ion abundance ratio: The affinity of each enantiomer towards the CS One of the two enantiomers (guest) tagged with deuterium atoms CS (host) J. Kim, et al, Bull. Korean. Chem. Soc. 2008, 29, 1069-1072.

  10. Chiral Recognition Mechanisms 2. Guest Exchange Ion-Molecule Reactions Unlabeled analyte enantiomers (guest) react with the CS (host) forming identical diastereomeric complexes Principle: Depends on the different exchange behavior of enantiomers with a foreign reagent Can’t be separated in a single stage MS Different intensity ratio R The complex ions are mass selected and allowed to react with a neutral gas-phase reagent R J. Ramirez, et al, J. Am. Chem. Soc.1998, 120, 7387–7388. G. Grigorean, et al, Anal. Chem. 2001, 73, 1684–1691.

  11. Chiral Recognition Mechanisms 2. Guest Exchange Ion-Molecule Reactions • Relative abundances based on two factors: • the enantiomeric ratio of the used chiral analyte • the time of the exchange reaction Solely varying the enantiomeric ratios of the chiral analytes J. Ramirez, et al, J. Am. Chem. Soc.1998, 120, 7387–7388. G. Grigorean, et al, Anal. Chem. 2001, 73, 1684–1691.

  12. Chiral Recognition Mechanisms 3. Chiral Recognition Based on Complex Dissociation The chiral analyte and chiral reference compound (ref*) are complexed with a transition-metal ion (M) to generate high-order metal ion-bound cluster ions W. A. Tao, R. G. Cooks, Anal. Chem. 2003, 25-31.

  13. Chiral Recognition Mechanisms 3. Chiral Recognition Based on Complex Dissociation Chiral selectivity Rchiral is defined as Iref*(1) IR IS Iref*(2) R chiral =1 : no chiral discrimination R chiral is more different from 1, the chiral recognition ability is higher W. A. Tao, R. G. Cooks, Anal. Chem. 2003, 25-31. R. Berkecz, et al, J. Mass. Spectrom. 2010,45, 1312–1319.

  14. Chiral Recognition Mechanisms Mass Spectrometric Chiral Recognition Mechanisms 1. Host-Guest (H-G) Associations 2. Guest Exchange Ion-Molecule Reactions 3. Chiral Recognition Based on Complex Dissociation

  15. Application of Chiral Recognition B. Florian, et al, Angew. Chem. Int. Ed. 2013 , 52 ,1–6

  16. Application of Chiral Recognition Possible mechanisms of amine catalyzed reaction of aldehyde with electrophiles • Enamine mechanism • Widely accepted • Not been validated experimentally Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615 – 1621.

  17. Application of Chiral Recognition Addition reaction between aldehydes and nitroolefins catalyzed by H-d-Pro-Pro-Glu-NH2 • Excellent yields and stereoselectivities • Catalyst loadings lower than 1 mol % Proposed catalytic cycle Enamine mechanism Problem: Enamine mechanism not been validated experimentally Experimental proof of enamine mechanism: Detect an enamine intermediate by ESI-MS

  18. Application of Chiral Recognition Methodology: ESI-MS back-reaction screening A pair of mass-labeled quasienantiomeric conjugate addition products Concept: Host-Guest (H-G) Associations Host (Chiral Selector) Guests

  19. Application of Chiral Recognition If En/En’ratio (back reaction) = 2/ent-2’ ratio (forward reaction), it will provides strong evidence to enamine mechanism. ΔΔG≠ Im’ En’ ent-2’ En Im Back reaction 2 The stereoselectivity 2/ent-2’(= k1/k2) is determined by ΔΔG≠of the transition state. R=k1/k2= IEn/IEn’ = eΔΔG≠/RT

  20. Application of Chiral Recognition Back-reaction screening and enantioselectivity of the forward reaction in DMSO • En/En’ (back reaction) = 2/ent-2’ (forward reaction): • Enamine mechanism • Stereomeric determining step is En to Im.

  21. Application of Chiral Recognition Catalyst Screening Additional organocatalysts investigated in this study

  22. Summary I. Chirality is significant II. Concepts of hyphenated MS techniques III. Mass Spectrometric Chiral Recognition Mechanisms IV. An example that using chiral recognition to solve mechanistic problem Host-Guest (H-G) Associations Hyphenated MS techniques Chiral Recognition Based on Complex Dissociation Guest Exchange Ion-Molecule Reactions

  23. Mass Spectrometry What can we do by using MS?

  24. Studying Reaction Mechanism Interesting reaction systems Propose reaction mechanism Combine MS with DFT calculation

  25. Catalysts Screening by Mass Spectrometry Simultaneous screening of a mixture of five catalysts C. Markert, A. Pfaltz, Angew. Chem. Int. Ed. 2004, 116, 2552-2554

  26. Thanks for your attention!

  27. Mass Spectrometry to study reaction mechanism ESI-MS to capture reaction intermediates Propose reaction mechnism Combined with DFT calculation H. Guo, et al, J. Am. Chem. Soc. 2005, 127, 13060-13064

  28. Chiral Recognition Mechanisms 3. Chiral Recognition Based on Complex Dissociation Cu2+ (L-Trp)2 (+)-ephedrine Metal: Cu2+ Ref: two L-Trp Analytes: (+)-ephedrine (–)-ephedrine -Ref Chiral selectivity Rchiral : -A Cu2+ (L-Trp)2 (-)-ephedrine I+/I ref*(1) = 3.8 I-/I ref*(2) = 0.91 R chiral = 4.7 -Ref -A The interaction between (+)-ephedrine and ref* is stronger W. A. Tao, R. G. Cooks, Anal. Chem. 2003, 25-31.

  29. Introduction Asymmetric Synthesis Catalyst screening Chiral Analysis Chiral Drug Chiral Recognition Quality control Chiral Resolution Chromatography Mass Spectrometry PPT from Xinhao

  30. Catalysts Screening by Mass Spectrometry Screening Methodology Mass Spectrometric Screening of Their Racemic Forms

  31. Conformation Analysis by Ion Mobility Spectrometry-Mass Spectrometry Drift time versus m/z plot measured by Mass Spectrometer Conformers produced for cyclic peptide from Molecular Dynamics simulations Plot of Normalized MD energy versus collision cross-section from the simulated annealing T. R. Brandon, J. Am. Soc. Mass. Spectrom. 2004, 15, 870-878

  32. Structural Characterization of Oligomer-Aggregates of β-Amyloid Polypeptide ESI-mass spectra (LC-MS) of Aß(1–40)

  33. Chiral Recognition Mechanisms 3. Chiral Recognition Based on Complex Dissociation Quantitative chiral analysis • △ [CuII(Pro)2(Tyr)-H]+ complex, Pro as the analyte • [CuII(Phe)2(Ile)-H]+ complex, Phe as the analyte • [CuII(Trp)2(Met)-H]+ complex, Trp as the analyte The relative rates of the two competitive dissociations (kA and kref) can be expressed as the relative abundance ratio: Different ratio of AR and AS Calibration curves for chiral analysis W. A. Tao, R. G. Cooks, J. Am. Chem. Soc., 2000, 122, 10598-10609

  34. Chiral Recognition Mechanisms 3. Chiral Recognition Based on Complex Dissociation Quantitative chiral analysis W. A. Tao, R. G. Cooks, J. Am. Chem. Soc., 2000, 122, 10598-10609

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