MAKING COMPLEX MOLECULES Hermann Emil Fischer Germany ( ) Fischer achieved the first synthesis of the first truly complicated organic molecules, the sugar molecule D-glucose in The Nobel Prize in Chemistry 1902 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 20 th century.

Sir Robert Robinson United Kingdom ( ) The Nobel Prize in Chemistry 1947 Willstatter’s synthesis of tropine 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.

Sir Christopher Kelk Ingold ( ) Mechanism?

Sir Derek H. R. Barton ( ) The Nobel Prize in Chemistry 1969 "for their contributions to the development of the concept of conformation and its application in chemistry" Conformational Analysis

1 H NMR spectrum of cyclohexane-d 11 at different temperature

Robert Burns Woodward

Quinine (1944) anti-malarial drug Vitamin B12 (1973) Strychnine (1954) pesticide Some of the Complex Molecules Made by Woodward “There is excitement, adventure, and challenge, and there can be great art in organic synthesis.” - Woodward

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. 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. Prostaglandins “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

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: 1.Carbon-Carbon Bond Formation 2.Functional Group Interconversion Enantioselectivity

Some Physical Properties of the Stereoisomers of Tartaric Acid

Louis Pasteur Chemist “ Chance favors only prepared mind. ” - Louis Pasteur Louis Pasteur was born on December 27, 1822 in Dole, in the region of Jura, France. Resolution of enantiomers in 1848 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.

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.

Synthesis of One Enantiomer using a Chiral Auxiliary Chiral Auxiliary : [ ] Asymmetric Synthesis

The Nobel Prize in Chemistry 1979 "for their development of the use of boron- and phosphorus- containing compounds, respectively, into important reagents in organic synthesis" Hebert C. Brown (1912- ) Synthesis of an Enantiomer using a Chiral Reagent Asymmetric Synthesis

Synthesis of an Enantiomer using a Chiral Catalyst Asymmetric Synthesis 92% yield, 97%ee

Synthesis of an Enantiomer using a Chiral Catalyst Asymmetric Synthesis

The anticancer drug, Taxol Synthesis: K. C. Nicolaou at The Scripps Research Institute Robert Holton at Florida State University

Acid-Base Chemistry Organometallic Chemistry relatively stable complex unstable species stable (neutral) Carbon Species carbanionradical carbene carbocation Organometallic Compounds

1. Stabilize unstable organic compounds - strained, unstable - does not exist at normal temperatures and pressures - reacts with itself to form larger ring - stable - well-behaved and easily-manipulated - readily seperated - a convenient source of cyclobutadiene

2. Change characters of organic compounds - surrounded by a cloud of negative electrons - prefer to interact with positively-charged molecules - reacts with itself to form larger ring - 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 - useful method for the synthesis of cyclopentenone

Application to the synthesis of complex molecules taylorione: synthesis by Williams Kerr in 1990s

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 - alkenes are one of the most important building block - abundant in nature's chemicals: vitamin A, quinine, chlorophyll - manmade organic chemicals: pharmaceuticals, perfumes, flavoring

catalysts for olefin metathesis: many catalysts based on organometallic reagents "Ru", "Mo", "W" Grubbs's catalyst Olefin Metathesis

mechanism Olefin Metathesis

Ring-Closing Olefin Metathesis