1. Chemistry 125: Lecture 32 November 19, 2010 Resolution, Chiral Catalysis, and Conformational Energy Discussion of configuration concludes using esomeprazole as an example of three general methods for producing single enantiomers. A modification of Sharpless chiral catalyst for allylic epoxidation is used to prepare esomeprazole commercially. Conformational isomerism is more subtle than configurational because isomers differ only by rotation about single bonds, which requires careful physico-chemical consideration of energies and their relation to equilibrium and rate constants. Conformations have their own notation and nomenclature. How high is the barrier to rotation about the C-C bond of ethane? If we knew we could estimate the rate of rotation using the 10^(13-3/4 H*) trick. For copyright notice see final page of this file

2. Legal Considerations of Stereochemistry McBride Disclosure I have served as scientific consultant or expert witness to a number of pharmaceutical companies including Eisai. I take Lipitor and served as an expert witness for a generic competitor in a case involving the validity of a Canadian Lipitor patent of Pfizer. My only connection to AstraZeneca or Omeprazole is as an occasional consumer of Prilosec OTC.

3. 1267-page Bible of Stereochemistry (1994) 8 pp. on Biological Properties

4. Court Rejects Suit Over AstraZeneca Nexium Marketing Tuesday November 8, 2005, 4:38 PM EST WILMINGTON, Del. - (Dow Jones Newswire) - A federal court in Delaware Tuesday dismissed a class-action lawsuit that alleged AstraZeneca PLC's (AZN) misleading marketing of Nexium added billions to health-care costs. U.S. District Judge Sue Robinson rejected the suit brought by the Pennsylvania Employee Benefit Trust Fund on behalf of entities that foot the bill in health- care plans.

5. Court Rejects Suit Over AstraZeneca Nexium Marketing According to the health plan paying organizations, the big difference between the two drugs is not effectiveness, but advertising. By selling doctors and patients on the idea that patented Nexium is better than Prilosec, which faced generic competition, AstraZeneca was able to preserve billions in sales. Judge Robinson said that the courts should defer to the U.S. Food and Drug Administration in weighing the differences between drugs and that since the FDA cleared Nexium's label, the lawsuit could not stand. 2003 Nexium mass-media advertising budget $260M 2005 advertising budget $226M; Sales $5.8B

6. Back to Chemistry To test and manufacture Nexium AstraZeneca had to prepare the single enantiomer

7. Resolution a) Pasteur Conglomerate b) Temporary Diastereomers Destroy One Enantiomer React Racemate with Resolved Chiral Reagent or Catalyst Prepare Only One Enantiomer a) Use resolved starting material b) Use resolved reagent/catalyst

8. Resolution of Omeprazole 1) Chromatography on SiO 2 coated with trisphenylcarbamoylcellulose (1990) from Ph-N=C=O and Cellulose Six Chromatograpy Injections 3 mg (+), 4 mg (-) Enough to Measure Racemization t 1/2 : 1 hr at 75°C, ~100 hr at 37°C Ph-N=C=O Not nearly enough for one Human Dose (~20 mg) n R R R R R Ph-N C=O H R = R Ph-N C=O H (like urea from NH 3 + H-N=C=O)

9. H 2 C=O Resolution of Omeprazole 2) Reversible formation of crystalline mandelate ester (1994) Hundreds of mg - enough for biological testing. (R) four times as active as (S) in rats. Reversed in humans! (S)-mandelic acid separate diastereomers by crystallization H H C

10. Resolution a) Pasteur Conglomerate b) Temporary Diastereomers Destroy One Enantiomer React Racemate with Resolved Chiral Reagent or Catalyst Prepare only one Enantiomer a) Use resolved starting material b) Use resolved reagent/catalyst Generally lose half of the material (but see Levenes 1,3-butandiol)

11. OR O OEt O O CO 2 Et RO Ti O 3) Chiral Catalysis by Titanium/Diethyl Tartrate R + RO Ligand Exchange Double Exchange with Diethyltartrate makes catalyst chiral

12. CH 2 C H O H C C H OH CH 2 H OR O OEt O O CO 2 Et Ti RO O 3) Chiral Catalysis by Titanium/Diethyl Tartrate R ROO RO + Ti O O O R OEt O CO 2 Et O RO Ti O O O OEt O CO 2 Et * R CH 2 H C C C H H allyl alcohol (R)-epoxide (S)-epoxide precursor Chiral Oxidizing Agent LUMO? HOMO? is diastereomeric! ( also p O + * C=C )

13. Tsutomu Katsukis discovery -- a memorable day in 1980 at Stanford University! K. B Sharpless, with permission General ! i.e. 95:5

14. K. B Sharpless, with permission 5% L-Tartaric Acid

15. K. B Sharpless, with permission

17. 1980

18. RO ~ racemic OR O OEt O O CO 2 Et Ti RO O 3) Chiral Catalysis by Titanium/Diethyl Tartrate Ti (etc) ROO RO + Ti O O O Ti (etc) OEt O CO 2 Et O RO Ti O O O Ti (etc) OEt O CO 2 Et 94% e.e. (3% R) with added iPr 2 NEt (discovered in 2000) n LUMO * R S R' O Ti O O O Ti (etc) OEt O CO 2 Et + (for no obvious reason) catalytic cycle RO ROO S R R' Chiral Oxidizing Agent R S R' + O R S O R S

19. ~ racemic OR O OEt O O CO 2 Et Ti RO O 3) Chiral Catalysis by Titanium/Diethyl Tartrate Ti (etc) ROO RO + Ti O O O Ti (etc) OEt O CO 2 Et O RO: Ti O O O Ti (etc) OEt O CO 2 Et R O 94% e.e. (3% R) add iPr 2 NEt AstraZeneca (2000) H HH H LUMO * R S R' O Ti O O O Ti (etc) OEt O CO 2 Et + (for no obvious reason) catalytic cycle RO ROO S R R' Chiral Oxidizing Agent R S R' n O R S O R S add H 2 O! Kagan, Pitchen (1983) + R O RO Still

20. DFT calculation by Szabó, et al. (2009) N(CH 3 ) 3 CH 3 -O-O Ti R-S-CH 3 CRUNCH! Something New in the Molecular Model! O O bent by 7° S S

21. One "C" to Go Composition Constitution "Stereoisomers" distinction based on bonding model Change by breaking bonds (van't Hoff) Change by rotating about single bonds (Paternó) Isomers Configuration Conformation HARD EASY Conformation

22. 19 th Century Organic Stereochemistry was Qualitative.

23. Conformation involving rotational isomerism about single bonds is more subtle, requiring quantitative thought about equilibria, rates, & energies.

24. GenealogyBottom Physical-Organic Chemistry

25. Genealogy Top Physical-Organic Chemistry

26. In the late 19th Century organic chemists focused their efforts on molecular structure, while physical chemists focused on energy. (sometimes to the exclusion of structure)

27. Principles of Chemistry An Introduction to all Chemical Textbooks by Wilhelm Ostwald 1907

28. In all 554 pages Ostwald used the word atom only this once - in the subordinate clause of a footnote! Footnote, p. 421 Dalton, who developed the law of combining weights on the basis of an hypothesis he had pro- posed about the composition of matter from atoms, at first took hydrogen as unity, since it had the smallest atomic weight, i.e. combining weight.

29. Dedication of Sterling Chemistry Laboratory April, 1923 G. N. Lewis (Student of Richards) T. W. Richards Wilder Bancroft Students of Ostwald

30. Ostwald's gift for leadership showed itself in the way his pupils regarded him all through their lives. Ostwald obituary by Wilder Bancroft (1933) They usually believed what Ostwald said even when they knew that he was not right.

31. High St. Gibbs Ostwald became fixated on energy because he was so impressed by the man who lived here.

32. Josiah Willard Gibbs (1839-1904) ~1855

33. Physical Chemists were (and are) Quantitative about Equilibrium Constant (K) Rate Constant (k) Energy (E, or H, or G )

34. Energy determines what can happen (equilibrium) K = e - E/kT and how fast (kinetics) 10 -(3/4) E kcal/mole @ room Temp k (/sec) = 10 13 e - E /kT 10 13-(3/4) E kcal/mole @ room Temp activation energy

35. Conformation involves rotational isomerism about single bonds.

36. How Free is Single-Bond Rotation? Paternó (1869) Not at all van't Hoff (1874) Entirely (Note that all are shown eclipsed) (Count Isomers)(Dont Count Isomers) as are both versions of the ACS molecule of the week L-(+)-Tartaric Acid

37. Eclipsed The Newman Projection (1952) Melvin Newman 1908-1993 Yale '29, Ph.D. '32 Staggered Anti Syn (or fully eclipsed) Gauche (+) (-) (+) (-) conventional (but rare) by permission J. D. Roberts

38. IUPAC "Basic Terminology of Stereochemistry" Pure Appl. Chem. 68, 2193-2222 (1996) pretty pedantic

39. Is 3-Fold Barrier to Rotation Significant? 0°120° 240° 360° Torsional Angle Energy Is Energy Quantized in Triple Minimum?

40. End of Lecture 32 Nov. 19, 2010 Copyright © J. M. McBride 2009, 2010. Some rights reserved. Except for cited third-party materials, and those used by visiting speakers, all content is licensed under a Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0).Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0) Use of this content constitutes your acceptance of the noted license and the terms and conditions of use. Materials from Wikimedia Commons are denoted by the symbol. Third party materials may be subject to additional intellectual property notices, information, or restrictions. The following attribution may be used when reusing material that is not identified as third-party content: J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0