Research in Organic Chemistry & Total Synthesis in Japan
Transcript of Research in Organic Chemistry & Total Synthesis in Japan
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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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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• 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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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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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: 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? 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.