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

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