1. Chemistry 125: Lecture 27 Communicating Molecular Structure in Diagrams and Words It is important that chemists agree on notation and nomenclature in order to communicate molecular constitution and configuration. It is best when a diagram is as faithful as possible to the 3-dimensional shape of a molecule, but the conventional Fischer projection, which has been indispensable in understanding sugar configurations for over a century, involves highly distorted bonds. Ambiguity in diagrams or words has led to multibillion dollar patent disputes involving popular pharmaceuticals. International agreements provide descriptive, unambiguous, unique, systematic “IUPAC” names that are reasonably convenient for most organic molecules of modest molecular weight. Synchronize when the speaker finishes saying “…and the ‘words’ have to be generalized.” Synchrony can be adjusted by using the pause(||) and run(>) controls. For copyright notice see final page of this file

2. Notation: Using Dashes and Wedges to Show Tetrahedral Carbons Planar Acute Angle Right & 180° Angles OK (Conventional) OK 109° angles

3. "Fischer Projection" (1891) With the help of Friedländer's convenient rubber models, one can construct molecules of right-handed tartaric acid, left-handed tartaric acid, and inactive tartaric acid and lay them in the plane of the paper so that the four carbon atoms are in a straight line and the attached hydrogens and hydroxyls lie above the plane of the paper: Bent to go back from BOTH atoms Rotate 90°

4. "Fischer Projection" (1891) May rotate in-plane by 180° but NOT by 90° because horizontal bonds are taken as wedges enantiomersdiastereomers meso names of relationships Its own mirror image name generalized

5. Configurational Isomer Counting n "Stereogenic Centers"  2 n isomers ? No, because of meso compounds "Next we consider a symmetrical formula: C(R 1 R 2 R 3 )C(R 4 R 4 )C(R 1 R 2 R 3 ), and C(R 1 R 2 R 3 )C(R 4 R 5 )C(R 1 R 2 R 3 ) as well. As is easily conceived from the forgoing discussion, they lead to only three isomers." van't Hoff (1877) (Baeyer & Fischer gave up on using bread rolls.)

6. HOH H HO H COOH Trihydroxyglutaric Acids 123(2) (1)(4)(3)4 2 meso isomers and a pair of enantiomers / 2 3 = 8 Meso? ? HOOC-CH(OH)-CH(OH)-CH(OH)-COOH easy with Fischer projections HOH H H H H HO H HOHHO H HOHHO H HOHHO H HOH H H H HO H H H H H H H H COOH 4

7. Halichondrin B: A Marine Natural Product with Potent In Vitro and In Vivo Antitumor Activity

8. Discovery of E7389 Starting From the Halichondrin B C.1-C.38 Macrolide Active Fragment of Halichondrin B "Simplified" Version of Active Fragment is Drug Candidate E7389 2 19 > 500,000 configurational isomers! 19 “stereogenic centers”

9. E7389 Phase III Nov 2008 ClinicalTrials.gov currently has 64,268 trials with locations in 158 countries. (Nov. 7, 2008)

10. Lipitor The world’s best selling drug ($10.86 billion in 2004) A $10,000,000,000 Problem in Stereochemical Notation

11. Oct. 12, 2005 NEW YORK - Pfizer Inc. won a significant victory on Wednesday when a British judge upheld a key patent covering its blockbuster cholesterol drug Lipitor in the United Kingdom but the medication still faces a similar yet more important case in the United States. Judge Nicholas Pumfrey upheld the patent covering atorvastatin, Lipitor’s active ingredient, but ruled that another patent was invalid. Indian pharmaceutical company Ranbaxy Laboratories Ltd. had challenged both patents, and was joined by Britain’s Arrow Generics Ltd. against the second patent that was ruled invalid. Pfizer said the decision upholding the exclusivity of the patent covering atorvastatin until November 2011 was an important victory for scientists. (Analogus decision 8/2/2006 in U.S. Court of Appeals)

12. … What is Patented? single enantiomer (Lipitor, drawn in figure) or racemate (described in text) Number of permutations much greater than the total number of protons, neutrons, and electrons in the Solar system! OH - O Ca +2 F O i-Pr H-N

13. Opinion of Sir Nicholas Pumfrey In my view, the claim covers the racemate and the individual enantiomers. In the '633 patent, it is absolutely clear from context throughout that formula (I) is being used to denote a racemate. In my judgment, every time the skilled person sees formula I or formula X he will see it with eyes that tell him that in that racemate, there is a single enantiomer that is the effective compound, and that he can resolve the racemate using conventional techniques to extract that enantiomer. In the '633 patent, it is absolutely clear from context throughout that formula (I) is being used to denote a racemate. When one comes to claim 1, which echoes the purpose of the invention with its conventional reference to pharmaceutically acceptable salts, he will, in my judgment, continue to see the formulae in this light. IX Thus Pfizer’s later patent on the single enantiomer is an invalid repeat, and patent protection will run out three years earlier !

14. Constitutional Nomenclature Conventions Geneva (1892) Formal name should be: Clearly Descriptive Unambiguous Unique Manageable Unfortunately "Amide" means both R 2 N - and RCONH 2 (e.g. Quick, Easy, Short, Pronounceable) Indexing Alternatives: composition, computer graphics Composition, Constitution, Configuration, Conformation IUPAC, International Union of Pure & Applied Chemistry http://www.chem.qmw.ac.uk/iupac/ http://acdlabs.com/iupac/nomenclature One name  one structure One structure  one name i.e. Stereochemistry

15. Systematic Constitutional Nomenclature Choose the “Main Chain” for Greek Root Name Number the Chain Atoms Name Substituents Alphabetize (& Count) Longest Most Substituents Lowest number at First Difference octane 1 2 1 3 2 3 4 5 6 7 7-bromo-2-chloro-3-ethyl-6,7-dimethyl nonane ? 3 (to give simpler names) (1-chloroethyl) methyl bromo ethyl chloro

16. http://acdlabs.com/iupac/nomenclature/93/r93_338.htm WOW! Thank God for pictures and computer graphics.

17. Some Useful Non-Systematic Names Isobutane IsopentaneNeopentane Neopentyl Isopropyl sec-Butyltert-Butyl Nomenclature Drill available on course website.

18. End of Lecture 27 Nov. 7, 2008 Copyright © J. M. McBride 2009. 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