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Christina LeGay , Darren Derksen St. Francis Xavier University

Determination of Absolute Configuration Using Enantioselective Acylation Reactions. Christina LeGay , Darren Derksen St. Francis Xavier University. Stereochemistry. Stereoisomers can have vastly different biological activities ex. Thalidomide: S- enantiomer is teratogenic

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Christina LeGay , Darren Derksen St. Francis Xavier University

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  1. Determination of Absolute Configuration Using EnantioselectiveAcylation Reactions Christina LeGay, Darren Derksen St. Francis Xavier University

  2. Stereochemistry • Stereoisomers can have vastly different biological activities • ex. Thalidomide: S-enantiomer is teratogenic • Important to know absolute configuration before continuing synthesis and/or testing • Biological activity • Patents Huang, Y.; Hsu, C. W.; Chiu, T. H. Tzu Chi Med. J.2008, 20, 188-195. 1

  3. Our Method • Asymmetric acylation using chiral catalysts • Enantiomeric starting alcohol reacts selectively with one catalyst • Compare reaction rates to deduce absolute configuration (−)-Catalyst (+)-Catalyst 2

  4. Our Method • Asymmetric acylation using chiral catalysts • Enantiomeric starting alcohol reacts selectively with one catalyst • Compare reaction rates to deduce absolute configuration (−)-Catalyst k1 = 1 [Pdct] k2 = 0.5 (+)-Catalyst Time 2

  5. Detection Methods • TLC: qualitative method • Operationally simple to use • More sensitive than NMR spectroscopy • Multiple visualization methods • 1H-NMR: quantitative method • Requires expertise for use and analysis • Fast, automated detection • Determine rate of conversion • TLC and NMR most readily available methods 3

  6. Detection Methods: TLC • Reactions carried out in vials, 16 mM of starting alcohol • Prepare stock solutions of each reagent • 10 eq. NEt3, 10 eq. Ac2O, 10 mol% catalyst • Set in chemical refrigerator • Progress of reaction checked at hourly intervals • Best results = most significant difference by TLC • 30 minutes to 24 hours reacting • t-amyl alcohol or chloroform • Minimal amount of reaction mixture spotted on plate 4

  7. Detection Methods: NMR • Reactions carried out in NMR tubes, 16 mM of starting alcohol • Prepare stock solutions of each reagent • 10 eq. NEt3, 10 eq. Ac2O, 10 mol% catalyst • Set in chemical refrigerator • Progress of reaction checked at 30 or 60 min intervals • Ideal result = greatest difference in conversion of reactant to product • Compile integration data from several NMR experiments • First 4-5 hours of reacting • CDCl3 consistently results in good selectivity 5

  8. Chiral Starting Materials • Develop method for a variety of chiral starting materials 6

  9. Cycloalkanol TLC Results L-Menthol D-Menthol (−) (−) (+) (+) Catalyst Catalyst 7

  10. Arylalkylcarbinol TLC Results (S)-(-)-1-phenylethanol (R)-(+)-1-phenylethanol (−) (−) (+) (+) Catalyst Catalyst 8

  11. (S)-(-)-1-PhenylEthanol, (+)-DMAP-C5Ph5 9

  12. (S)-(-)-1-PhenylEthanol, (-)-DMAP-C5Ph5 10

  13. Arylalkylcarbinol NMR Results (−)-catalyst (+)-catalyst 11

  14. Propargylic Alcohol NMR Results (−)-catalyst (+)-catalyst 12

  15. Predictive Model • Model developed is consistent with precedent • k(+) > k(−),R1 = unsaturated, R2 = alkyl • k(+) < k(−), R1 = alkyl, R2 = unsaturated (+)-catalyst (−)-catalyst 13

  16. Lobeline NMR Results (−)-catalyst (+)-catalyst 14

  17. Chloramphenicol TLC Results 5 hours 3 x 15% E/PE 30 min 25% E/PE (−) (−) (+) (+) Catalyst Catalyst 15

  18. Chloramphenicol NMR Results (−)-catalyst (+)-catalyst 16

  19. Solvent Selectivity: TLC • t-amyl alcohol generally the most selective • Catalyst solutions require heating & sonication • Chloroform less selective • Reactions need to be checked within a few hours 24 h 5 h 24 h (−) (+) (−) (+) (−) (+) Catalyst Catalyst Catalyst 17

  20. Solvent Selectivity: NMR • D-chloroform ranges in selectivity for NMR spectroscopy • Highly selective for arylalkylcarbinols and Chloramphenicol • D8-toluene used for lobeline • similar selectivity as CDCl3 • Starting material not easily dissolved in D8-toluene • Ideal: multiple 1H-NMR experiments within first 5 hours reacting 18

  21. Selectivity of Natural Product • Propargylic alcohols more selective if have alkyl or unsaturated substituent on terminal end of alkyne • Stereochemistry of substituents interferes with selectivity • Lobeline has pyrrolidine substituent with two chiral centers 19 Tao, B.; Ruble, J. C; Hoic, D. A.; Fu, G.C. J. Am. Chem. Soc. 1999, 121, 5091-5092.

  22. Future Work • Develop additional models for comparison • Test more chiral alcohols and natural products • Improved detection methods • Increased sensitivity: Fluorescent acylating agents, Mass spectroscopy • Purify and detect: HPLC/UV/Vis, LC-MS 20

  23. Conclusions • Developed a method for determination of absolute configuration • Simple: only four reagents • Cheap: recoverable catalysts • Easy analysis: TLC and NMR • Quick results: can continue synthesis with knowledge of absolute configuration • If (k(+)-catalyst > k(−)-catalyst) implies R1 = unsaturated, R2 = alkyl • If (k(+)-catalyst < k(−)-catalyst) implies R1 = alkyl, R2 = unsaturated 21

  24. Acknowledgments and Funding • Derksen Research Group • Colton Boudreau • Shawn Brophy • Christine Parsans • Deanna Webb • Laura Brothers • St. FX Chemistry Department • Stephen Smith • St. FX Center for Biofouling Research

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