1. Chem 125 Lecture 31 11/19/08 This material is for the exclusive use of Chem 125 students at Yale and may not be copied or distributed further. It is not readily understood without reference to notes or the wiki from the lecture.

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 enough for 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. OR O OEt O O CO 2 Et RO Ti O 3) Chiral Catalysis by Titanium/Diethyltartrate Ti (etc) + RO Ligand Exchange Double Exchange with Diethyltartrate makes catalyst chiral

11. RO ~ racemic OR O OEt O O CO 2 Et Ti RO O 3) Chiral Catalysis by Titanium/Diethyltartrate 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 ** 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

12. 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 All "isomers" represent local energy minima (not just different phases of vibration) Conformation

13. 19 th Century Organic Stereochemistry was Qualitative.

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

15. GenealogyBottom Physical-Organic Chemistry

16. Genealogy Top Physical-Organic Chemistry

17. 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)

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

19. 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.”

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

21. “ 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.”

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

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

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

25. 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

26. Conformation involves rotational isomerism about single bonds.

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

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

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

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

31. Absorption of Heat by Ethane (1936) cal / mole / degree Depends on how much Heat is absorbed, For T = 298.1 K Barrier (kcal/mole) S Calculated 0.0 56.4 0.3 56.3 3.1 54.6 S Experimental 54.8  0.2 0 T CPCP T d T S "entropy" and on the Temperature at which it is absorbed. With larger quantized spacings, less Heat is absorbed, and at higher T,  smaller S.

32. 1Kcal Harmonic Oscillator at RT 81.9% 2.7% 14.8% 0.5%0.1% average  Equilibrium ratio of 0:1 quantum (or 1:2, etc.)?  10 3/4 = 5.6

33. 1Kcal Harmonic Oscillator at RT 364 cal/mol  1.2 cal/mol K @ 300 K (of 1.8) average  at 1 kcal 0.8% 4.2% lowest level 33% 59% 6% 2.7% 14.8% 81.9%

34. End of Lecture 31 Nov. 19, 2008