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Transcript of Chemistry 125: Lecture 27 November 5, 2010 Prof. Leiserowitz on Determining Absolute Configuration...
Chemistry 125: Lecture 27November 5, 2010
Prof. Leiserowitz on DeterminingAbsolute 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 page of this file
Chemistry 125: Lecture 27November 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.For copyright
notice see final page of this file
Preliminary
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 Acid
Whynot?
Genealogical (Fischer, 1891)
d-(+)-glyceraldehyde
HOCH2CH(OH)CHO
Relative (by synthesis) to
?
D/L designation isambiguous withouthaving a detailed synthesis recipe or a convention.
?Impossible to know which is which!
Impossible to know which is which?
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)
Lew
is B
ookk
eepi
ng e
lect
rons
4
2
6
Inte
grat
ed D
iffer
ence
Den
sity
(e)
How many electrons are there in a bond?
Bond Distance (Å)1.2 1.4 1.6
0.2
0.1
0.3
Berkovitch-Yellin &Leiserowitz (1977)
more
^
Professor Leiserowitz has subsequently applied his skills at solving challenging problems in x-ray diffraction, crystal packing, and crystal growth to address thequestion 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 Tailor-Made 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
300106 infections per year, 1-2106 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
Parasite injection
Liver stage
Red blood cell (RBC) cycle
Uptake of parasite in blood meal
Free Heme
INFECTED RED BLOOD CELL (RBC)
INFECTED RED BLOOD CELL (RBC)
Free Heme
The Structure of β-Hematin (Synthetic HZ)
Heme
Propionic acids
C D
Formation of the different Cyclic Heme Dimer Isomers (cd). Schematic Representation.
C D
axis of pseudo symmetry
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?
vinyl vinyl
methyl
methyl
Centrosymmetric 21cd
Chiral-enantiomeric )/(2 −+cd
The major phase of β-hematin,
reported by Pagola et al., consists of
one isomer
11cdCentrosymmetric
)(
)(
The Isomers of the Heme Cyclic Dimer (cd)
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
12.39 15.10 7.61 99.50 96.8, 93.5
12.08 14.48 7.99 90.83 96.9 97.6a b c
Major phase
Minor phase
According to XRPD analysis minor phase 13% of total amount
β-hematin: minor phase. Five peaks
Structure of hemoglobin shows O2 bound to heme on one side only.
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).
In which case primarily only the enan-tiomeric chiral heme dimer cd2(+) would be formed
cd2(+)
End of Lecture 27Nov. 5, 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).
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