chiral recognition detected by mass spectrometry chen ping 2013.12.06 1
TRANSCRIPT
Outline
I. Introduction
II. Hyphenated Mass Spectrometric Techniques for Chiral Analysis
III. Mass Spectrometric Chiral Recognition Mechanisms1. Host-Guest (H-G) Associations2. Guest Exchange Ion-Molecule Reactions3. Chiral Recognition Based on Complex Dissociation
IV. Application of Chiral Recognition Organocatalytic Asymmetric Conjungate Addition of Aldehydes to Nitroolefins
V. Summary
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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
Asymmetric synthesis(Catalysts screening)
Chiral analysis(Quality control)
Chiral RecognitionMass SpectrometryMass Spectrometry
Introduction
Ranking of the top 10 best-selling US pharmaceutical products in 2011 was obtained from webpage: http://www.imshealth.com/.
7 of the 10 best-selling US pharmaceutical products are single enantiomer.
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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)
•…
Introduction
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
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• 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)
Coupling of chiral sensitive analytical tools with MS
Hyphenated MS techniques
New detector: Mass Spectrometer (MS)
Sensitive Accurate Speed High throughput
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
H. Awad, A. EI-Aneed, Mass Spectrom Rev, 2013, 32, 466–483
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Two options for chiral analysis using hyphenated MS techniques:
Hyphenated MS techniques
Indirect approach:
Analysis of covalent
diastereomeric complexes
Separated by conventional
methods
CS: chiral derivatization reagent
Direct approach:
Analysis of noncovalent
diastereomeric complexes
CS: chiral mobile phase additives (CMPAs) chiral stationary phases (CSPs)
Indirect approach:Need more time for the reaction step
Direct approach is preferred
H. Awad, A. EI-Aneed, Mass Spectrom Rev, 2013, 32, 466–483 6
Derivatized by the CS to form covalent complexes
Form transient bond with CS
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.
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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
Chiral Recognition Mechanisms
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Chiral Recognition Mechanisms
1. Host-Guest (H-G) Associations
One of the two enantiomers (guest) tagged with deuterium atomsCS (host)
Ion abundance ratio:The affinity of each enantiomer towards the CS
J. Kim, et al, Bull. Korean. Chem. Soc. 2008, 29, 1069-1072.9
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 R
Chiral Recognition Mechanisms
J. Ramirez, et al, J. Am. Chem. Soc. 1998, 120, 7387–7388. G. Grigorean, et al, Anal. Chem. 2001, 73, 1684–1691.
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Can’t be separated in a single stage MS
The complex ions are mass selected and allowed to react with a neutral gas-phase reagent R
Different intensity ratio
Relative abundances based on two factors:the enantiomeric ratio of the used chiral analytethe time of the exchange reaction
Solely varying the enantiomeric ratios of the chiral analytes
Chiral Recognition Mechanisms2. Guest Exchange Ion-Molecule Reactions
J. Ramirez, et al, J. Am. Chem. Soc. 1998, 120, 7387–7388. G. Grigorean, et al, Anal. Chem. 2001, 73, 1684–1691.
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Chiral Recognition Mechanisms3. 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. 12
3. Chiral Recognition Based on Complex Dissociation
Chiral Recognition Mechanisms
IR ISIref*(1) 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.
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Chiral selectivity Rchiral is defined as
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Mass Spectrometric Chiral Recognition Mechanisms
3. Chiral Recognition Based on Complex Dissociation
Chiral Recognition Mechanisms
1. Host-Guest (H-G) Associations 2. Guest Exchange Ion-Molecule Reactions
Enamine mechanism•Widely accepted•Not been validated experimentally
Application of Chiral Recognition
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Possible mechanisms of amine catalyzed reaction of aldehyde with electrophiles
Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615 – 1621.
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
Problem: Enamine mechanism not been validated experimentally
Experimental proof of enamine mechanism:Detect an enamine intermediate by ESI-MS
Application of Chiral Recognition
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Enamine mechanism
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
Application of Chiral Recognition
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The stereoselectivity 2/ent-2’(= k1/k2) is determined by ΔΔG≠ of the transition state.
If En/En’ ratio (back reaction) = 2/ent-2’ ratio (forward reaction), it will provides strong evidence to enamine mechanism.
Application of Chiral Recognition
19R=k1/k2= IEn/IEn’ = eΔΔG≠/RT
ent-2’
2
Im
Im’
En
En’
ΔΔG≠
Back reaction
Back-reaction screening and enantioselectivity of the forward reaction in DMSO
Application of Chiral Recognition
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En/En’ (back reaction) = 2/ent-2’ (forward reaction):Enamine mechanism Stereomeric determining step is En to Im.
Additional organocatalysts investigated in this study
Application of Chiral Recognition
Catalyst Screening
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I. Chirality is significant
Summary
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II. Concepts of hyphenated MS techniquesIII. Mass Spectrometric Chiral Recognition Mechanisms
Host-Guest (H-G) Associations
Guest Exchange Ion-Molecule Reactions Chiral Recognition Based on Complex Dissociation
Hyphenated MS techniques
IV. An example that using chiral recognition to solve mechanistic problem
Studying Reaction Mechanism
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Interesting reaction systems
Propose reaction mechanism
Combine MS with DFT calculation
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
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Mass Spectrometry to study reaction mechanism
ESI-MS to capture reaction intermediates
Propose reaction mechnism
Combined with DFT calculation
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H. Guo, et al, J. Am. Chem. Soc. 2005, 127, 13060-13064
Chiral Recognition Mechanisms3. Chiral Recognition Based on Complex Dissociation
W. A. Tao, R. G. Cooks, Anal. Chem. 2003, 25-31. 28
Metal: Cu2+
Ref: two L-TrpAnalytes: (+)-ephedrine (–)-ephedrine
Cu2+ (L-Trp)2 (+)-ephedrine
Cu2+ (L-Trp)2 (-)-ephedrine
Chiral selectivity Rchiral :
I+/I ref*(1) = 3.8I-/I ref*(2) = 0.91R chiral = 4.7
-A
-A
-Ref
-Ref
The interaction between (+)-ephedrine and ref* is stronger
Chiral Drug
Asymmetric Synthesis
Chiral Analysis
Chiral Resolution
Chiral Recognition
Mass Spectrometry
Introduction
PPT from Xinhao
Catalyst screening
Quality control
Chromatography
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Catalysts Screening by Mass Spectrometry
Screening Methodology
Mass Spectrometric Screening of Their Racemic Forms
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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
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Structural Characterization of Oligomer-Aggregates of β-Amyloid Polypeptide
ESI-mass spectra (LC-MS) of Aß(1–40)
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3. Chiral Recognition Based on Complex Dissociation
Chiral Recognition Mechanisms
Quantitative chiral analysis
The relative rates of the two competitive dissociations (kA and kref) can be expressed as the relative abundance ratio:
Calibration curves for chiral analysis
Different ratio of AR and AS
W. A. Tao, R. G. Cooks, J. Am. Chem. Soc., 2000, 122, 10598-10609
△ [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
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