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MAKING COMPLEX MOLECULES Fischer achieved the first synthesis of the first truly complicated organic molecules, the sugar molecule D-glucose in 1890. H O C H C OH HO C H Hermann Emil Fischer Germany (1852-1919) The Nobel Prize in Chemistry 1902 H C OH H C OH CH2OH D-Glucsoe Fischer’s work on the total synthesis of D-glucose is regarded as the catalyst for the development of synthetic organic chemistry in the 20th century. O I Br Br NMe 2 Br Br NMe 2 NMe 2 Br Sir Robert Robinson United Kingdom (1886-1975) The Nobel Prize in Chemistry 1947 Br Br H NMe Br NMe NMe ( II ) NMe O OH NMe H OH Willstatter’s synthesis of tropine COOH COOH CHO + H2NMe + O NMe O NMe CHO COOH COOH Robinson’s synthesis of tropinone in 1917 The Robinson’s synthesis of tropinone was hailed as revolutionary. This was to look at the target molecule and try to imagine how the molecule could be constructed from simpler chemical units. O Sir Christopher Kelk Ingold (1893-1970) Mechanism? Sir Derek H. R. Barton (1918-1998) The Nobel Prize in Chemistry 1969 "for their contributions to the development of the concept of conformation and its application in chemistry" Conformational Analysis 1H NMR spectrum of cyclohexane-d11 at different temperature D D D D D D D D D D D H D D D D D D D D H D Robert Burns Woodward Some of the Complex Molecules Made by Woodward “There is excitement, adventure, and challenge, and there can be great art in organic synthesis.” Quinine (1944) anti-malarial drug - Woodward Vitamin B12 (1973) Strychnine (1954) pesticide Some prostaglandins affect human blood pressure at concentrations as low as 0.1 microgram per kilogram of body weight. Substances that inhibit prostaglandin synthesis may be useful in controlling pain, asthma attacks, and anaphylactic shock and in reducing the clotting ability of blood. Corey, Elias James 1928–, b. Methuen, Mass., grad. Massachusetts Institute of Technology (B.S. 1948, Ph.D. 1951). In 1990, he was awarded the Nobel Prize in Chemistry. “The organic chemist is more than a logician and strategist; he is an explorer strongly influenced to speculate, to imagine, and even to create.” - Corey Prostaglandins Retrosynthetic Analysis by Corey Retrosynthetic analysis (or retrosynthesis) : the process of mentally breaking down a molecule into starting materials Retrosynthetic arrow: an open-ended arrow, , used to indicate the reverse of a synthetic reaction Synthon: idealized fragments resulting from a disconnection. Synthons need to be replaced by reagents in a suggested synthesis Retrosynthetic analysis for violet oil component Synthesis of violet oil component Organic Synthesis: Enantioselectivity 1. Carbon-Carbon Bond Formation 2. Functional Group Interconversion Some Physical Properties of the Stereoisomers of Tartaric Acid Louis Pasteur was born on December 27, 1822 in Dole, in the region of Jura, France. Louis Pasteur Chemist Resolution of enantiomers in 1848 1822-1895 Twenty years later, J. H. van’t Hoff and J.-A. Le Bel independently explained the origins of enantiomers based on the tetrahedral nature of carbon bonding. “Chance favors only prepared mind.” -Louis Pasteur Resolution diastereomeric salts seperation by selective crystallization or some other means Once separated, acidification of the two diastereomeric salts with strong acid gives pure enantiomers and recover the chiral amine. Asymmetric Synthesis Synthesis of One Enantiomer using a Chiral Auxiliary O O O chemical steps OH OH OH NH 2 Put auxiliary on NH 2 Both handed forms of product (racemic mixture; 1:1 mixture of enantiomers) O O chemical steps O take auxiliary off OH NH 2 NH 2 O [ HN Chiral Auxiliary : O ] Asymmetric Synthesis Synthesis of an Enantiomer using a Chiral Reagent O Me OH Ipc2BCl Me Me Me OH Me Hebert C. Brown (1912) The Nobel Prize in Chemistry 1979 "for their development of the use of boron- and phosphoruscontaining compounds, respectively, into important reagents in organic synthesis" Me B-Cl Ipc2BCl 2 is not formed Asymmetric Synthesis Synthesis of an Enantiomer using a Chiral Catalyst o o o o Ru Me CO 2H CO 2H Hydrogen MeO H MeO Naproxen anti-inflammatory drug 'Flat' precursor 92% yield, 97%ee [Ru-(S)-BINAP], 135 atm H2 PPh2 PPh2 Asymmetric Synthesis Synthesis of an Enantiomer using a Chiral Catalyst o o o o Ti O OH OH Oxidant Glycidol Allyl alcohol TBHP (t-BuOOH), Ti(OPri)4 L-(+)-DET o o o o Os OH Oxidant 'Flat' precursor OH Product formed with superb selectivity The anticancer drug, Taxol Synthesis: K. C. Nicolaou at The Scripps Research Institute Robert Holton at Florida State University Organometallic Compounds Carbon Species C stable (neutral) C C C carbanion radical carbene C carbocation unstable species Organometallic Chemistry Acid-Base Chemistry A C H Y C H C C B C X Y C M C M C C C M relatively stable complex 1. Stabilize unstable organic compounds H H C C C C H - strained, unstable - does not exist at normal temperatures and pressures - reacts with itself to form larger ring H cyclobutadiene H H C C C H OC C H Fe CO CO iron complex - stable - well-behaved and easily-manipulated - readily seperated - a convenient source of cyclobutadiene 2. Change characters of organic compounds H H C C H C C H C C H H - surrounded by a cloud of negative electrons - prefer to interact with positively-charged molecules - reacts with itself to form larger ring Benzene H H C C H C C H C C H OC H Cr CO CO chromium complex - Cr(CO)3 sucks away electrons from benzene - prefer to interact with negatively-charged molecules 3. organometallic complexes: useful templates (as reagents) Pauson-Khand Reaction: 1970s (OC) 3Co (OC) 3Co H C C H O C CH 2 CH 2 O C HC CH 2 HC CH 2 - useful method for the synthesis of cyclopentenone Application to the synthesis of complex molecules taylorione: synthesis by Williams Kerr in 1990s O O O Co 2(CO) 8 O O CO H2C CH 2 O Taylorione 4. Catalyze Reactions: efficiency in early 1990s, Bob Grubbs at California Institute of Technology Olefin metathesis - for some time had been used for synthesis of polymers but had been overlooked by organic chemists R R olefin metathesis R catalyst + R CH 2 CH 2 - alkenes are one of the most important building block - abundant in nature's chemicals: vitamin A, quinine, chlorophyll - manmade organic chemicals: pharmaceuticals, perfumes, flavoring Olefin Metathesis catalysts for olefin metathesis: many catalysts based on organometallic reagents "Ru", "Mo", "W" Mes N PCy 3 Cl Grubbs's catalyst Cl Ru Cl Ru Cl Ph PCy 3 N Mes PCy 3 PCy3 Cl H Ru C P PCy3 H Cl PCy3 active catalyst H3C CH3 Mes = H [Ru] C H H3C Ph Olefin Metathesis H R [Ru] C R H CH2 CH2 + R R mechanism R H H C C H [Ru] C R' R H H [Ru] C H H C R' R C H C C H H [Ru] H R C H C H H C H [Ru] R' H C C H H C H R H H H C C H H Ring-Closing Olefin Metathesis S S HO HO N O O OTBS O N 15 mol% O CH 2Cl2 rt, 8h O OTBS O 50% + 35% (E -isomer) O S simple starting material HO N O O OH O Epothilone A