1. Chemistry 125: Lecture 28 November 8, 2010 Communicating Molecular Structure in Diagrams and Words Correct configuration is vital in drug molecules, like eribulin. 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 Preliminary

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

3. Discovery of E7389 Starting From the Halichondrin B C.1-C.38 Macrolide Active Fragment of Halichondrin B "Simplified" Version of Active Fragment became Drug Candidate E7389, now “Eribulin” 2 19 > 500,000 configurational isomers! 19 “stereogenic centers” Structure-Activity Relationship Study

4. E7389 Phase III Nov 2008 (Nov. 3, 2009) (Nov. 7, 2008) (Nov. 3, 2010) ClinicalTrials.gov currently has 98,100 trials with locations in 174 countries. (Nov. 3, 2010)

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 (CH 2 ) 2

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. Eisai Research Institute 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 Eribulin

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-dimethylnonane ? 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. Configurational Nomenclature Phenomenological d / l + / - Relative D / L Absolute R / S

16. 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 Genealogical (Fischer, 1891) d-(+)-glyceraldehyde HOCH 2 CH(OH)CHO Relative (by synthesis) to

17. (1978) First of 210 Tables D D Glyceraldehyde Lactic Acid

18. >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

19. 24 years old

20. Absolute Configuration J. M. Bijvoet van't Hoff Laboratory, Univ. Utrecht (1949-51) Na Rb d-(L)-Tartrate X-ray anomalous dispersion 60 year old Fischer Guess for (L)-Tartrate “The question of nomenclature is beyond the scope of our investigation... The problem of nomenclature now concerns given configurations, and requires a notation which denotes these configurations in an unambiguous and if possible self- explanatory way.” (Bijvoet, 1951)

21. Naming Double Bond Configuration Malic Acid (HO 2 C)CH(OH).CH 2. (CO 2 H) Maleic & Fumaric Acids (HO 2 C)HC=CH(CO 2 H)  cis (on this side of) trans (across) cis or trans? Absolute nomenclature is hard to generalize O O O + H 2 O cis trans (though relative is fine) 

22. Double Bond Configuration Assign groups at either end "priority" by atomic number (or weight for isotopes) at first difference O O (E) ntgegen (Opposed) (Z) usammen (Together) The names trans and cis are "polluted" by previous usage.

23. In Assigning Priority Proceed One "Shell" at a Time (respecting previous decisions) Tie Win Tie Win Cl is high in priority, but irrelevant; the decision is already made. Cl

24. Robinson: "Hello Katchalsky. What are you doing here in Zurich?" from V. Prelog, My 132 semesters of chemistry studies (1981) The 1950s "CIP" Priority Scheme is Conventional R. S. Cahn C. K. Ingold V. Prelog Robinson: "Well then, if it is not wrong, it is absolutely unnecessary." Robinson: "You know, Prelog, your and Ingold's configurational notation is all wrong." Prelog: "Excuse me, Sir Robert, I am only Prelog, and I live here." Prelog: "Sir Robert, it can't be wrong. It is just a convention. You either accept it or not." R. RobinsonR. B.Woodward by permission J. D. Roberts

25. Exercise for Monday: Eadfrith’s Error (Click here & create your very own chiral conventions) (Click here & create your very own chiral conventions) http://www.bl.uk/onlinegallery/themes/euromanuscripts/lindisfarne.html

26. CIP (R/S) Nomenclature for Stereogenic Centers (S) inister (left) 4 3 2 1 1 3 4 2 (2R,3R)- 2,3-dihydroxy butanedioic acid right turn H (R) ectus (right) H H left turn H 1 4 2 3 CH 3 HO D H H D

27. Bloomer Gate

28. Organic

29. End of Lecture 28 Nov. 8, 2010 Copyright © J. M. McBride 2009,2010. 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