Presentation on theme: "Chemistry 125: Lecture 32 November 19, 2010 Resolution, Chiral Catalysis, and Conformational Energy Discussion of configuration concludes using esomeprazole."— Presentation transcript:
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
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.
1267-page Bible of Stereochemistry (1994) 8 pp. on Biological Properties
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.
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
Back to Chemistry To test and manufacture Nexium AstraZeneca had to prepare the single enantiomer
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
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)
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
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)
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
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 )
Tsutomu Katsukis discovery -- a memorable day in 1980 at Stanford University! K. B Sharpless, with permission General ! i.e. 95:5
K. B Sharpless, with permission 5% L-Tartaric Acid
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
~ 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
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
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
19 th Century Organic Stereochemistry was Qualitative.
Conformation involving rotational isomerism about single bonds is more subtle, requiring quantitative thought about equilibria, rates, & energies.
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)
Principles of Chemistry An Introduction to all Chemical Textbooks by Wilhelm Ostwald 1907
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.
Dedication of Sterling Chemistry Laboratory April, 1923 G. N. Lewis (Student of Richards) T. W. Richards Wilder Bancroft Students of Ostwald
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.
High St. Gibbs Ostwald became fixated on energy because he was so impressed by the man who lived here.
Physical Chemists were (and are) Quantitative about Equilibrium Constant (K) Rate Constant (k) Energy (E, or H, or G )
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
Conformation involves rotational isomerism about single bonds.
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
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
IUPAC "Basic Terminology of Stereochemistry" Pure Appl. Chem. 68, 2193-2222 (1996) pretty pedantic
Is 3-Fold Barrier to Rotation Significant? 0°120° 240° 360° Torsional Angle Energy Is Energy Quantized in Triple Minimum?