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Research in Organic Chemistry & Total Synthesis in Japan

François D’HoogeJSPS Post-doctoral FellowGraduate School of Pharmaceutical SciencesThe University of Tokyo

JSPS Science DialogueAt Japan Women’s UniversityJanuary 12th 2006

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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 ChemistryMathematics

PhysicsBiology

Chemistry

TheoreticalChemistry

Organic Chemistry

BiochemistryPhysicalChemistry

Analytical Chemistry

Inorganic Chem.

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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

NMR spectrum

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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 MoleculesCarbohydrates/Sugar:Energy Storage, Structure Element, Marker

Proteins:Variery of fonctions: Cells Tools. Enzyms

Lipids:Main Component of Cells Membrane,Energy storage, Hormones

Nucleic Acids:Genetic Information, DNA, RNA

OO

HO

OH

OH

OO

AcHN

OH

O

OOH

OHHO

O Protéine

O

COOH

HOAcHN

HOOH

HO

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Biochemistry: Cell membrane

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Organic Chemistry

• Studies the structure, properties andreactions 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 andreactions 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 chemicalsystems 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

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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 ProductsChemistry at the Graduate School ofPharmaceutical 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-489Strychnine

VinblastineEcteinascidin 743

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Some new methodologies fromFukuyama’s laboratory

Fukuyama Reduction:

Fukuyama Coupling reaction:

Nosyl-amine strategy:

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My previous research

• Synthesis of fluorinated glycopeptides.

– 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

OF2C

NH2

COOH

NHAc

OH

HO

HO

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Why making such complexmolecules?

• Biological activities:– Some complex natural products have interesting

biological activities• Limited availability

– Natural extracts: several milligrams form kilograms ofmaterial

• 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 complexmolecules?

• 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 EuropeanYew Tree ( doesn’t cut the tree)50% yield in 3 stepsAllowed commercial produtionof 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 theproduct.

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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/SMain City: Paris ( 2M/12M ; Tokyo 12/30M)Economy: Tourism ( 72 M visitors)

Airbus, MachinesFood, 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