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 Wedges
to Show Tetrahedral Carbons
Planar
OK
109° angles
Right & 180°
Angles
OK
(Conventional)
Acute
Angle
"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:
COOH
C
C
H
OH
OH
H
COOH
Bent to go back from BOTH atoms
Rotate 90°
"Fischer Projection" (1891)
names of relationships
enantiomers
diastereomers
Its own mirror image
diastereomers
May rotate in-plane by 180°
but NOT by 90°
because horizontal bonds
are taken as wedges
meso
name
generalized
Configurational Isomer Counting
? n
n "Stereogenic Centers"  2 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 forgoing
discussion, they lead to only three isomers."
(Baeyer & Fischer gave up on using bread rolls.) van't Hoff (1877)
Trihydroxyglutaric Acids
23 = 8
HOOC-CH(OH)-CH(OH)-CH(OH)-COOH
1
2
3
(2)
COOH
Meso?
COOH
H
COOH
H
H
OH
HO
H
OH
H
OH
HO
H
OH
H
OH
H
COOH
?
COOH
H
HO
H
OH
H
OH
COOH
COOH
COOH
OH
HO
H
HO
H
HO
H
HO
H
HO
H
H
OH
H
H
OH
H
OH
H
COOH
H
COOH
HO
H
HO
HO
COOH
OH
H
OH
COOH
H
HO
COOH
COOH
COOH
COOH
4
(3)
4
(4)
(1)
2 meso isomers and a pair of enantiomers / easy with Fischer projections
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
19 “stereogenic centers”
HO
O
HO
H
H
Active Fragment
of Halichondrin B
OMe
Me
OH
O
O
O
H
O
O
H
O
H2N
O
O
H
SAR
O
O
O
halichondrin B C.1-C.38 macrolide
Me
H
"Simplified" Version
of Active Fragment
is Drug Candidate
E7389
H
O O
O O
Me
H
O
O
H
O
H
O
E7389
"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.Davis
K. Yoshimatsu, Y. Kishi, M.J. Yu, and B.A. Littlefield, Cancer Res., February 1, 2001; 61(3): 1013-1021
219 > 500,000 configurational isomers!
ClinicalTrials.gov currently has 64,268 trials
with locations in 158 countries. (Nov. 7, 2008)
E7389 Phase III Nov 2008
Lipitor
A $10,000,000,000 Problem
in Stereochemical Notation
The world’s best selling drug ($10.86 billion in 2004)
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. (Analogus decision 8/2/2006 in U.S. Court of Appeals)
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.
What is Patented?
single enantiomer (Lipitor, drawn in figure)
… in text)
or racemate (described
F
OH -O
Ca+2
O
H-N
i-Pr
Number of permutations
much greater than the
total number of protons,
neutrons, and electrons
in the Solar system!
Opinion of Sir Nicholas Pumfrey
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.
When one comes to claim 1, which echoes the purpose of the
invention with its conventional reference to pharmaceutically
Pfizer’s
latertopatent
acceptable salts, he will, in myThus
judgment,
continue
see the
formulae in this light.
on the single enantiomer
In my view, the claim
is an invalid repeat, and
covers the racemate and
patent protection will run
the individual enantiomers.
out three years earlier !
I
X
Constitutional Nomenclature Conventions
Geneva (1892)
IUPAC, International Union
of Pure & Applied Chemistry
http://www.chem.qmw.ac.uk/iupac/
http://acdlabs.com/iupac/nomenclature
Formal name should be:
• Clearly Descriptive
• Unambiguous
•
Composition, Constitution,
Configuration, Conformation
i.e. Stereochemistry
Unfortunately "Amide" means
One name  one structure
both R2N and RCONH2
Unique Indexing Alternatives: composition, computer graphics
One structure  one name
• Manageable
(e.g. Quick, Easy, Short, Pronounceable)
Systematic Constitutional Nomenclature
bromo
Choose the “Main Chain”methyl
for Greek Root Name
• Longest
• Most Substituents
(to give simpler names)
Number the Chain Atoms
methyl
Br
6
7
3
2 1
5
4
chloro
Cl
2
1
7-bromo-2-chloro-3-ethyl-6,7-dimethylnonane
?
Br
• Lowest number at
First Difference
Name Substituents
3
ethyl
Cl
(1-chloroethyl)
octane
Br
Alphabetize (& Count)
Cl
http://acdlabs.com/iupac/nomenclature/93/r93_338.htm
WOW!
Thank God for pictures and computer graphics.
Some Useful Non-Systematic Names
Isopentane
Isobutane
X
X
Neopentane
X
X
Isopropyl
sec-Butyl
tert-Butyl
Neopentyl
Nomenclature Drill
available on course website.
End of Lecture 27
Nov. 7, 2008
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J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0