JSPS Science Dialogue

At Japan Women’s University

January 12th 2006

Research in Organic Chemistry &

Total Synthesis in Japan

François D’Hooge
JSPS Post-doctoral Fellow
Graduate School of Pharmaceutical Sciences
The University of Tokyo
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 Chemistry?
• Chemistry is the science of matter
– deals with the composition, structure and
properties of substances
– Transformations of these substances
– Interaction with energy ( Physics)
– Interaction with life ( Biology)

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 A short History of Chemistry
• Roots: Alchemy, metal work, and medicines
• 4/5 Elements theory in Antiquity
• 17th Century: Scientific Method - Bacon
• 1787: Lavoisier’s Conservation of Mass
• 1805: Dalton’s Atomic Theory
• 1828: Wöhler synthesis of Urea
• 1869: Mandeleyev Periodic Table of Elements
• 1897: Hoffmann Synthesis of Aspirin
• 1926: Schrödinger equation of H atom
• 1953: Crick & Watson DNA structure
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 Differents Chemistry
Mathematics

Theoretical
Chemistry

Chemistry
Inorganic Chem.
Organic Chemistry
Physical
Biochemistry Chemistry
Analytical Chemistry

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Biology Physics
 Analytical Chemistry
• Analysis of material: chemical composition
and structure
• Separative methods: mixture to pure
compounds
• Identification methods:
– Chemical methods: degradation, comparison
– Physical methods: X-Ray, NMR, Mass
Spectrometry
– Biological methods: Bioassay
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Analytical Chemistry: Examples
• Separative method: Chromatography

• Identification method: Nuclear Magnetic Resonance

Analysis

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NMR spectrum
 Biochemistry
• Studies how Chemistry applies to Biology
– Studies the 4 main group of biological
molecules:
– Carbohydrates/Sugars
– Proteins
– Nucleic Acids (DNA, RNA)
– Lipids

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 Biochemistry: Natural Molecules
Carbohydrates/Sugar: Proteins:
Energy Storage, Structure Element, Marker Variery of fonctions: Cells Tools. Enzyms

OH HO OH
COOH OH
HO O
O O
HO O O
AcHN OH O
HO AcHN O Protéine
O
OH
HO
OH

Lipids: Nucleic Acids:

Main Component of Cells Membrane, Genetic Information, DNA, RNA
Energy storage, Hormones

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Biochemistry: Cell membrane

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 Organic Chemistry
• Studies the structure, properties and
reactions of organic compounds
– Organic compound= molecule containing C, H,
and N, O, halogens, P,S, F, etc…
– Polymers
– 2 mains fields:
– Methodology ( new reactions or tools)
– Synthesis ( new molecules)
– Applications: medicines, drugs, etc…
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 Organic Chemistry

• Medicines:

Aspirin, 1897

Taxol, 1993

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 Organic Chemistry
• Methodologies, new reactions
Asymmetric Hydrogenation ( Pr. Noyori, NP 2001):

Metathesis ( Pr. Chauvin, Grubbs& Schrock, NP 2005)

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 Inorganic Chemistry
• Studies the structure, properties and
reactions of inorganic compounds
– Inorganic compound= all but those with C
( salts, metals, minerals…)
– Includes mineralogy, crystallography
– Applications: Silicon chips, optical fibers,
catalysts…

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 Inorganic Chemistry

Minerals:

Metals:

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 Physical Chemistry
• Studies the physical basis of chemical
systems and processes
– Temperature, pressure, equilibrium constants
– Thermodynamics, Kinetics
– Electrochemistry
– Spectroscopy ( used for Analytical Chemistry)
– Applications: Engineering, Analysis.

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 Physical Chemistry
• From Volta battery to Fuel Cells:

Volta Battery, ca 1800 Toyota co. Fuel Cell, ca 2000 16

 Theoretical Chemistry
• Studies Chemistry with Mathematics or
Physics
– Quantum mechanics applied to chemistry
– Predicting chemical reactivities
– Molecular Modelling
– Chemistry with computers.

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 Theoretical Chemistry
• Chemistry with computer:
– Predicting future drugs

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 My Host Laboratory in Japan
• Laboratory of Synthetic Natural Products
Chemistry at the Graduate School of
Pharmaceutical Sciences, Univ. Tokyo
• 天然物合成化学教室、大学院薬学院、東京大学
– Research interests:
• Total Synthesis of complex natural products.
• New Synthetic methodologies.
– Director: Pr. Fukuyama Tohru/福山透

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 Some molecules Synthesized in
Fukuyama’s Laboratory

Agel-489
Strychnine

Vinblastine
Ecteinascidin 743
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 Some new methodologies from
Fukuyama’s laboratory
Fukuyama Reduction:

Fukuyama Coupling reaction:

Nosyl-amine strategy:

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 My previous research
• Synthesis of fluorinated glycopeptides.
COOH
F2
O C
HO NH2

HO NHAc

OH

– Replacement of one oxygen atom by a CF2 group

– Useful for anti-freeze glycoproteins
• Prevent formation of ice at temperatures below 0°C
• Allow conservation of cells and organs at lower temperatures

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 Why making such complex
molecules?
• Biological activities:
– Some complex natural products have interesting
biological activities
• Limited availability
– Natural extracts: several milligrams form kilograms of
material
• Chemical challenges
– Often very interesting and very complex synthetic
challenges
• Training and discovery
– Useful method to train synthetic chemists and test
new reactions or discover new ones.

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 How to make such complex
molecules?
• 4 needed things for good research
– Brain (good advisor, good chemists)
– Money (salaries, chemicals, apparatuses)
– Time (chemistry and research takes time)
– Working place (equipment…)
• Method for total synthesis:
– Retrosynthesis plan (Pr. Corey, NP, 1990)
– Synthesis

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Example: Taxol

●Taxol was isolated in 1967 from the bark of Pacific Yew Tree
●Very efficicent for lung, ovarian and breast cancer
●Problem: for one patient treatment, you need to cut down
6 100 years old trees.
→Need for an other source: chemical synthesis, but complex
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Taxol: Retrosynthesis

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Taxol: Synthesis of 3 and 4

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Taxol: completion of synthesis

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 Taxol: Problems
• Very complex synthesis
– 30 differents chemical reactions (30 steps)
– Total Yield = 1%, very inefficient ( 99% lost)
– Useless for medicine production.
• Solution:
– Baccatin
From the needles of European
Yew Tree ( doesn’t cut the tree)
50% yield in 3 steps
Allowed commercial prodution
of Taxol ( 2000: US$ 1.6 Billion)
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 Total synthesis: and now?
• Still plenty of unknown new molecules to
discover in plants
• Still very far from Nature efficiency in
synthesis ( very good yields)
• New reserch fields:
– New catalysis methods
– Making non-natural molecules
– Is it possible to be as efficient as Nature?

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 How do we work?
• Write an experiment in laboratory book
• Then choose reagents

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 How do we work? 2
• Mix the reagents and check the reaction

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 How do we work? 3
• When the reaction is completed: purify the
product.

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 How do we work? 4
• Analysis of product

NMR apparatus NMR spectrum

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 How do we work? 5
• Think about the result:
– Is it expected product?
– Is it different product? Why
– Did the reaction proceeded well? Yield? Purity?
• Improve the result
» OR

• Find out why it didn’t work. Library

• Proceed to next experiment.
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 A few words about me:
• Born in Reims, France, 1977
• Studied in Rouen, France until PhD in sept. 2004
• Moved to Tokyo in sept 2004.

France: 12 hours away from Tokyo ( by plane)

(about 10.000 km)
Population: 63 Millions people ( half of Japan)
density 111hab/km (1/3 Japan)
Size: 1000km W/E 1000km N/S
Main City: Paris ( 2M/12M ; Tokyo 12/30M)
Economy: Tourism ( 72 M visitors)
Airbus, Machines
Food, Luxuries.

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My favorites spots in France

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 Acknowledments:
• Japan Society for the Promotion of Science
– Post-doctoral Fellowship Program
– Science Dialog Program
• Pr. Fukuyama and all members of Tengo.

• Ms. Tsukada and Takada

• Mr. Okano
• Dr. D. Lemin

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