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

Notation: Using Dashes and Wedgesto Show Tetrahedral Carbons

Planar

AcuteAngle

Right & 180°Angles

OK(Conventional)

OK109° angles

"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

COOH

C OHH

CHOH

COOH

Rotate 90°

"Fischer Projection" (1891)

May rotate in-plane by 180°but NOT by 90°

because horizontal bondsare taken as wedges

enantiomers diastereomers

diastereomers

meso

names of relationships Its own mirror image

namegeneralized

Configurational Isomer Counting

n "Stereogenic Centers" 2n isomers?

No, because of meso compounds

"Next we consider a symmetrical formula:

C(R1 R2 R3)C(R4 R4)C(R1 R2 R3) , and

C(R1 R2 R3)C(R4 R5)C(R1 R2 R3) as well.

As is easily conceived from the forgoingdiscussion, they lead to only three isomers."

van't Hoff (1877)(Baeyer & Fischer gave up on using bread rolls.)

H OH

H OH

HO H

COOH

COOH

Trihydroxyglutaric Acids

1 2 3 (2)

(1)(4)(3)42 meso isomers and a pair of enantiomers /

23 = 8

Meso?

?

HOOC-CH(OH)-CH(OH)-CH(OH)-COOH

easy with Fischer projections

H OH H OH H OH H OH

H OH HO H

H OH HO H H OH HO H

H OH HO H

H OH H OH

H OH H OH HO HHO H

HO HHO H

HO H HO HHO H HO H

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

4

COOH

COOH

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

Discovery of E7389 Starting From the Halichondrin B C.1-C.38 Macrolide

O

O

O

O O

O

O

O

O

HO

HO

MeO

O

H

H H

MeH

H

H

O O

OMe

OO

O

O

O

OO

Me

HH

H

H

H2N

OH

E7389halichondrin B C.1-C.38 macrolide

"In Vitro and In Vivo Anticancer Activities of Synthetic Macrocyclic Ketone Analogues of Halichondrin B"M.J. Towle, K.A. Salvato, J. Budrow, B.F. Wels, G. Kuznetsov, K.K. Aalfs, S. Welsh, W. Zheng, B.M.Seletsky, M.H. Palme, G.J. Habgood, L.A. Singer, L.V. DiPietro, Y.Wang, J.J. Chen, D.A. Quincy, A.DavisK. Yoshimatsu, Y. Kishi, M.J. Yu, and B.A. Littlefield, Cancer Res., February 1, 2001; 61(3): 1013-1021

SARActive Fragment

of Halichondrin B

"Simplified" Versionof Active Fragmentis Drug Candidate

E7389

219 > 500,000 configurational isomers!

19 “stereogenic centers”

E7389 Phase III Nov 2008

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

Lipitor

The world’s best selling drug ($10.86 billion in 2004)

A $10,000,000,000 Problem in Stereochemical Notation

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)

…

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 -OCa+2

F

O

i-PrH-N

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.

I X

Thus Pfizer’s later patent on the single enantiomer is an invalid repeat, and patent protection will run out three years earlier !

Constitutional Nomenclature Conventions

Geneva (1892)

Formal name should be:• Clearly Descriptive

• Unambiguous

• Unique

• Manageable

Unfortunately "Amide" means

both R2N- and RCONH2

(e.g. Quick, Easy, Short, Pronounceable)

Indexing Alternatives: composition, computer graphics

Composition, Constitution,Configuration, Conformation

IUPAC, International Unionof Pure & Applied Chemistryhttp://www.chem.qmw.ac.uk/iupac/http://acdlabs.com/iupac/nomenclature

One name one structure

One structure one name

i.e. Stereochemistry

Cl

Br

Systematic Constitutional Nomenclature

Choose the “Main Chain”for Greek Root Name

Number the Chain Atoms

Name Substituents

Alphabetize (& Count)

• Longest

• Most Substituents

• Lowest number atFirst Difference

Cl

Br octane

Cl

Br

12

132

34

56

7

7-bromo-2-chloro-3-ethyl-6,7-dimethylnonane

Cl

Br ?

3

(to give simpler names)

(1-chloroethyl)

methyl

methylbromo

ethyl

chloro

http://acdlabs.com/iupac/nomenclature/93/r93_338.htm

WOW!

Thank God for pictures and computer graphics.

Some Useful Non-Systematic Names

Isobutane Isopentane Neopentane

NeopentylIsopropyl sec-Butyl tert-Butyl

XX X

X

Nomenclature Drillavailable on course website.

End of Lecture 27Nov. 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).

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