Chemistry 125: Lecture 28November 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

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 Fragment

became Drug CandidateE7389, now “Eribulin”

219 > 500,000 configurational isomers!

19 “stereogenic centers”Structure-ActivityRelationship Study

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)

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

(CH2)2

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 !

Eisai Research Institute

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

Eribulin

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.

Configurational Nomenclature

Phenomenologicald / l + / -

RelativeD / L

AbsoluteR / S

Tartaric Acid Isomers

Configurational Nomenclature

Defined as “D”-glyceraldehyde (Fischer’s Guess)

m.p.[]D

140°C0°

170°C+13°

170°C-13°(meso) (dextro +) (laevo -)

Phenomenological

Multi-StepSynthesis

D-Tartaric AcidGenealogical (Fischer, 1891)

d-(+)-glyceraldehyde

HOCH2CH(OH)CHO

Relative (by synthesis) to

(1978)

First of 210 Tables

D

D

Glyceraldehyde

Lactic Acid

>2000 Compoundsin 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. Bartlettage 24

24 years old

Absolute Configuration

J. M. Bijvoetvan't Hoff Laboratory, Univ. Utrecht

(1949-51)

Na Rb d-(L)-TartrateX-ray anomalous

dispersion

60 year old

Fischer Guessfor

(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)

Naming Double Bond ConfigurationMalic Acid

(HO2C)CH(OH).CH2. (CO2H)Maleic & Fumaric Acids

(HO2C)HC=CH(CO2H)

H

HOOC COOH

H H

HOOC

COOH

H

cis(on this side of)

trans(across)

H3C

H

CH3

COOH

cis or trans?

Absolute nomenclatureis hard to generalize

O OO

+ H2O

cistrans

(though relative is fine)

Double Bond Configuration

H3C

H

CH3

COOH

H3C

H CH3

COOH

Assign groups at either end "priority"by atomic number (or weight for isotopes)

at first difference

H3C

H

C

C

HOO

O

HH

H

H3C

H

C

C

HH

H

HOO

OO

O

(E)ntgegen (Opposed) (Z)usammen (Together)The names trans and cis are "polluted" by previous usage.

In Assigning PriorityProceed One "Shell" at a Time

(respecting previous decisions)

C

C

OO

O

HH

H

H

C

C

OO

O

CH

H

H

Cl

H3CCl

Tie

Win

Tie

Win

Cl is highin priority,

but irrelevant;the decision

is already made.

Cl

Cl

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. Robinson R. B.Woodward

by p

erm

issi

on J

. D. R

ober

ts

Exercise for Monday:

Eadfrith’s Error

(Click here & create your very own chiral conventions)

http

://w

ww

.bl.u

k/on

line

gall

ery/

them

es/e

urom

anus

crip

ts/l

indi

sfar

ne.h

tml

CIP (R/S) Nomenclaturefor Stereogenic Centers

(S)inister (left)

COOH

COOH

OH

H

H

HO4

3

2

1

1

3

4

2

(2R,3R)-2,3-dihydroxybutanedioic

acid

rightturn

H

(R)ectus (right)

H

HO D

CH3

H

leftturn

HO CH3

D

H

14

2

3

CH3 CH3

HO HODHHD

Bloomer Gate

Organic

End of Lecture 28Nov. 8, 2010

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