1. Chemistry 125: Lecture 27 November 6, 2009 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. Clear notation also aids clarity of thought. The conventional 1891 Fischer projection, which has been indispensable in understanding sugar configurations for over a century, was invented in order to count stereoisomers. 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. Also in 1891 Fischer devised the D,L “genealogical” scheme to describe relative configurations, but it can be cumbersome or ambiguous. For copyright notice see final page of this file

2. 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.)

3. 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

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

5. 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” Structure-Activity Relationship Study

6. E7389 Phase III Nov 2008 ClinicalTrials.gov currently has 80,975 trials with locations in 170 countries. (Nov. 3, 2009) (Nov. 3, 2009)(Nov. 7, 2008)

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

8. 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)

9. … 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

10. 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 !

11. 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

12. 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

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

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

15. Tartaric Acid Isomers Configurational Nomenclature Defined as “D”-glyceraldehyde (Fischer’s Guess) m.p. [  ] D 140°C 0° 170°C +13° 170°C -13° (meso) (d extro +) (l aevo - ) Phenomenological Multi-Step Synthesis D-Tartaric Acid Why not? Genealogical (Fischer, 1891) d-(+)-glyceraldehyde HOCH 2 CH(OH)CHO Relative (by synthesis) to ? D/L designation is ambiguous without having a detailed synthesis recipe or a convention. ?

16. (1978) First of 210 Tables D D Glyceraldehyde Lactic Acid

17. >2000 Compounds in the 210 Tables Problem for Monday: Consider HOMO/LUMO alternatives during the reaction of HI with 1,3-butanediol to give 4-iodo-2-butanol Paul D. Bartlett age 24

18. 24 years old

19. End of Lecture 27 Nov. 6, 2009 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