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Chemistry 125: Lecture 27
November 5, 2010
Prof. Leiserowitz on Determining
Absolute Configuration and the
“Stereochemistry of Malaria”
Emil Fischer, seeing that it was impossible to determine “absolute” configuration by the
methods available, decided to define relative configuration by chemical transformations
beginning with D-glyceraldehyde. 60 years later Bijvoet used a special x-ray methods to
show that Fischer had guessed right about glyceraldehyde. Professor Leiserowitz explains
to the class first how simple x-ray work, together with a knowledge about how “tailor made
additives” influence crystal growth, can be used in a simpler way to determine absolute
configuration of amino acids, a task that experts thought impossible. He then shows how
the same concepts apply in the study of hemozoin, the crystals that malaria parasites use to
keep from poisoning themselves with heme. Stopping hemozoin crystallization
might help control malaria. The stereochemistry of hemozoin is instructive.
For copyright
notice see final
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Chemistry 125: Lecture 27
November 5, 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.
Preliminary
For copyright
notice see final
page of this file
Configurational Nomenclature
m.p.
[a]D
140°C
0° (meso)
170°C
+13° (dextro +)
170°C
-13° (laevo -)
Phenomenological
Tartaric
Acid Isomers
D/L designation
is
ambiguous without
having a detailed
?
synthesis recipe
Why
or a convention.
not?
D-Tartaric Acid
Genealogical (Fischer, 1891)
Impossible to know
? which is which!
Relative (by synthesis) to
HOCH2CH(OH)CHO
d-(+)-glyceraldehyde
Defined as “D”-glyceraldehyde (Fischer’s Guess)
Multi-Step
Synthesis
Impossible to know which is which?
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 of our
“The question of nomenclature is beyond the scope
investigation... The problem of nomenclature (L)-Tartrate
now concerns
given configurations, and requires a notation which denotes
these configurations in an unambiguous and if possible selfexplanatory way.” (Bijvoet, 1951)

Lewis Bookkeeping
Density (e)
Differenceelectrons
Integrated
more
How many electrons are there in a bond?
^
6
0.3
4
0.2
2
0.1
1.2
1.4
1.6
Bond Distance (Å)
Berkovitch-Yellin &
Leiserowitz (1977)
Professor Leiserowitz has
subsequently applied his skills at
solving challenging problems in
x-ray diffraction, crystal packing,
and crystal growth to address the
question of determining absolute
chirality and more recently the
possibility that preventing crystal
nucleation could make malaria
parasites poison themselves with
the dissolved heme by-product
they generate by living off their
host’s hemoglobin. He gives the
class a brief synopsis of some
aspects of this recent work.
Effect of Capping Molecules
and TailorMade Additives
on Crystal Growth
Nucleation of Crystalline Hemozoin in the
Malaria-Infected Red Blood Cell
Leslie Leiserowitz, Dept of Materials & Interfaces,
The Weizmann Institute of Science
Geographic Distribution of Malaria in
the World (1989)
Reproduced from the book, Malaria: Obstacles and Opportunities
MALARIA
REEMERGING INFECTIOUS DISEASE
300106 infections per year,
1-2106 deaths, mostly children and
pregnant women
•Poverty: Inadequate housing and water
control. Lack of bed nets (impregnated
with slowly released mosquito repellant)
•The Anopheles mosquito has developed
resistance to insecticides
Malaria parasites have developed
resistance to commonly-used synthetic
quinoline drugs
LIFE CYCLE of MALARIA PARASITE
Uptake of
parasite in
blood meal
Parasite
injection
Liver stage
Red blood cell (RBC) cycle
INFECTED RED BLOOD CELL (RBC)
Free Heme
INFECTED RED BLOOD CELL (RBC)
Free Heme
The Structure of β-Hematin (Synthetic HZ)
Heme
C
D
Propionic acids
Formation of the different Cyclic Heme Dimer
Isomers
(cd). Schematic Representation.
methyl
vinyl
vinyl
C
D
axis of pseudo
symmetry
methyl
Note: The dimers form as a sort of slipped sandwich held together by one of two
propionic acid groups (left or right) of the lower heme (both of which project toward
the viewer) binding to the Fe atom in the center of the upper heme. At the same time
one of the two acids (right or left) of the upper heme (both of which project away from
the viewer) binds to Fe of the lower heme. So in addition to the substituents of each
heme being arranged either clockwise or counterclockwise, the center of the dimer could
have the upper heme offset to the right or to the left of the lower heme. The problem is
to figure out how many isomers are possible. This is a bit more complex that van’t
Hoff’s tartaric acid problem in frame 5 of Lecture 26.
See if you can figure out how many stereoisomers are possible. Do you agree with
Prof. Leiserowitz?
The Isomers of the Heme Cyclic Dimer (cd)
Centrosymmetric
cd 11
The major phase of
β-hematin,
reported by Pagola
et al., consists of
one isomer
( )
Chiral-enantiomeric
Centrosymmetric
cd 2( / )
cd 12
( )
β-hematin crystal structure study
β-hematin crystals precipitated quickly within 1-2 days vs. several days or
weeks by Pagola et al.
Powder X-ray data collected at Spring-8, Japan by T. Straasø, University of
Copenhagen.
Powder sample cooled down to 100 K to reduce thermal motion. Better
characterization of possible molecular disorder
β-hematin: X-ray powder data
peaks not explained by the
Pagola dimer structure
β-hematin: minor phase. Five peaks
Major phase
Minor phase
c
a
b
a


12.08 14.48 7.99 90.83 96.9 97.6
12.39 15.10 7.61 99.50 96.8, 93.5
According to XRPD analysis minor phase 13% of total amount
XRPD of biogenic hemozoin crystals shows only one
crystalline phase. May be related to the state of
heme in hemoglobin (which is 4 hemes plus the protein that the parasite eats).
cd2(+)
Structure of hemoglobin shows O2 bound to heme on
one side only. In which case primarily only the enantiomeric chiral heme dimer cd2(+) would be formed
End of Lecture 27
Nov. 5, 2010
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