Chemistry 125: Lecture 30 November 16, 2009 Preparing Single Enantiomers Methods of resolution are described. The aldol reaction. 3D visualization. Omeprazole. For copyright notice see final page of this file

Epimerization (R,R)-Tartaric Acidmeso-Tartaric Acid (R,R) (R,S) Change at One Center of Two (or many) 

Racemization (R) (RS)Resolution (S)+ 1) Pasteur “Conglomerate” Chiral-Resolved Seeding Chiral-Resolved Poison

Crystal in Equilibrium with Saturated Solution Crystal at Equilibrium Interior Molecules more stable than in solution Surface Molecules less stable than in solution Average Molecule same as solution Lengthening Rate Depends on Width Metastable (in  solution) Average molecule less stable than in solution “Critical” Nucleus Average molecule more stable than in solution

Resolution(R) (RS) (S) + 1) Pasteur Conglomerate Chiral-Resolved Seeding Chiral-Resolved Poison 2) Temporary Diastereomers Chromatography with Chiral-Resolved Support Compound with Chiral-Resolved Mate cont. Influence nucleation

van’t Hoff Prediction 1874

Brucine Kohler Walker Tishler 1935 “Alkaloids” organic bases isolated from plants used to make diastereomeric salts with racemic acids

Kohler Walker Tishler 1935 Levo °C [  ] D -28.4° mixed mp 195°C Mole ratio brucine/acid % yield

Pasteur's "Bargain-Basement" Moldy Racemic Acid from Thann Pharmacy (probably apocryphal anecdote via L. F. Fieser ~1960) Penicillium glaucum had "eaten" (R,R) Purified  l-(S,S)-Tartaric Acid ??? (Remember the smell of carvones!)

React with One Enantiomer Diastereomeric Reactions Have Different Rates React Racemate with Resolved Chiral Reagent or Catalyst (e.g. Enzyme)

Nature's Way Prepare only one Enantiomer Use resolved starting material Or resolved reagent/catalyst

Nature can be Subtle and Surprising “A reaction that Prof. McBride will talk about later on called the ‘aldol’ reaction…” “What Levene did was to reduce it with yeast & sugar.” [add H 2 to get optically active product!] “It’ll reduce this.” “The compound we want to get.” “I confuse myself sometimes.”“What did I do wrong?” CH 2 CH 3 O C H O C H H O O C H H H H catalyst as in Levene’s preparation of (R)-Butane-1,3-diol The yeast may have oxidized the alcohol before reducing the aldehyde, and then reduced the ketone back to the alcohol. CH 2 ^ “enolate”

CH 2 O C H O C H CH 3 H CH 2 O C H O C H CH 3 H The yeast may have oxidized the alcohol before reducing the aldehyde, and then reduced the ketone back to the alcohol. CH 2 ^ or CH 3 CH 2 O C H H OH C H H C H H CH 2 O C H CH 3 H O C H O C H H CH 2 CH O C H C H CH 3 Enantiospecific reduction of (R) by yeast/sugar (R) (S) What happens to the (S)?

Eisai Purchase 5 stereocenters. Make the rest. 1 by chiral Simulated Bed Chromatography. 2 by allyl silane additions. 2 by asymmetric dihydroxylations. 2 by oxy-michael reactions. 3 by asymmetric Ni/Cr reactions. 1 by Jacobsen epoxidation. 1 by conjugate reduction. 1 by enolate alkylation 1 by ketal formation Best regards, Frank Only One Chiral Separation Specific or general selective reactions that preferentially form one isomer. In starting materials 19 Stereocenters

Who Cares? Living Things Food & Drug Administration Drug Companies their Lawyers & USPTO (Patent Office) "Chiral Switch"

Pain Reliever Isobutyl Propionic Acid Phenyl Ibuprofen (Advil, Motrin) (S) Active Pain Reliever (R) Inactive Sold as racemate

Sedative Thalidomide (S) Sedative (R) Teratogen Sold as racemate ( ) (S)  (R) 0.12 / hr(R)  (S) 0.17 / hr (S) eliminated 0.24 / hr (R) eliminated 0.08 / hr in vivo racemization (human) 10,000 birth defects ?

O 5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfinyl}1H-benzimidazole Gastric Proton Pump Inhibitor (Acid Reflux) World's largest selling drug in 2000 ($6.2B) "Omeprazole" "Prilosec" omeprazole Benzimidazole Pyridine

OTC ?

O 5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfinyl}1H-benzimidazole "Nexium" O Gastric Proton Pump Inhibitor (Acid Reflux) World's largest selling drug in 2000 ($6.2B) "Omeprazole" "Prilosec" "esomeprazole" (racemate) (S)

N N O O O S T E R E O B I N O C U L A R S T E R E O N N O O O

Stereoviewing

from X-rayof Ohishi et al (S)-Omeprazole - Stereopair View left eye right eye

(S)-Omeprazole - Stereopair View from X-ray of Ohishi et al right-eye view left-eye view Central frame perceived in stereo How it should look when you stare dreamily into the distance “through” the stereo-pair above until the blue lines “swim” together and superimpose.

Sulfide  Sulfoxide Gives Racemate of Course

End of Lecture 30 Nov. 16, 2009 Copyright © J. M. McBride 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