Make me a molecule

Aspirin Tamiflu®

Rearrangement of atoms: cleaving and making bonds

Tagamet®

Many of the materials we use today are made by chemical synthesis. Most of the new compounds made today are organic.

Most of the new compounds made today are organic, that is, they are composed largely of carbon.

Organic Chemistry

Organic Compounds

stable and versatile unstable

CC

CC O CCC H

CC

C

Cl

CC

N

H

C C

O O N N

Producte.g. paint and pigment vitamin synthetic fiber pesticide plastic explosive pharmaceutical

MAKING COMPLEX MOLECULES

Hermann Emil Fischer Germany (1852-1919)

Fischer achieved the first synthesis of the first truly complicated organic molecules, the sugar molecule D-glucose in 1890.

The Nobel Prize in Chemistry 1902

H

C

C OH

C HHO

C OHH

C OHH

CH2OH

O H

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.

Sir Robert Robinson United Kingdom (1886-1975)

The Nobel Prize in Chemistry 1947

O I Br

Br

Br

Br

NMe2

NMe2

Br Br Br

NMe2 NMe NMe Br

NMeOH

HNMe ONMe

H

OH

( II )

CHO

CHO

+ H2NMe +

COOH

COOH

O NMe O

COOH

COOH

NMe O

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.

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 James1928–, American organic chemist and educator, 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

Retrosynthetic Analysis by Corey

Retrosynthetic analysis (or retrosynthesis) : the process of mentally breaking down a molecule into starting materialsRetrosynthetic arrow: an open-ended arrow, , used to indicate the reverse of a synthetic reactionSynthon: 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

Efficiency and selectivity are important characteristics that have to be taken into account.

[Efficiency: yields, number of steps][Selectivity: chemoselectivity, regioselectivity, stereoselectivity]

Organic Synthesis:

1. Carbon-Carbon Bond Formation2. Functional Group Interconversion

Organic Synthesis: 1. Carbon-Carbon Bond Formation2. Functional Group Interconversion

Stereoselectivity

Organic Synthesis: 1. Carbon-Carbon Bond Formation2. Functional Group Interconversion

Enantioselectivity

분자식 입체이성질체 (Stereoisomers)

C2H2Cl2

C7H14MeMe

H H Me

Me

H

H

C4H9I C

CH3CH2

CH3

HI C

CH2CH3

CH3

HI

CC

Cl

H

Cl

H

CC

Cl

H

H

Cl

cis-1,2-dichloroethylene (bp: 60 oC)

trans-1,2-dichloroethylene (bp: 48 oC)

cis trans

(+)-2-iodobutane (bp: 119 oC)

(-)-2-iodobutane (bp: 119 oC)

“Enantiomer”

Chiral compounds

Chiral Molecules and Achiral Molecules

Mirror Images

identical(superimposable)

identical(superimposable)

enantiomers(nonsuperimposable)

achiral

achiral

chiral

Enantiomers and the Tetrahedral Carbon

Louis Pasteur Chemist

1822-1895

“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 enantiomersin 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.

Optical ActivityLight restricted to pass through a plane is plane-polarized.

Solutions of chiral compounds rotate plane-polarized light and the molecules are said to be optically active.

Some Physical Properties of the Stereoisomers of Tartaric Acid

To obtain one pure enantiomer, resolution is required.

Only one enantiomer is obtained by asymmetric synthesis.

HO2CCO2H

H2OHO2C

CO2H

OH

fumarase(enzyme)

HO2CCO2H

H2O

H

HO2CCO2H

OH

HO2CCO2H

OH

1 : 1

Synthesis of One Enantiomer using a Chiral Auxiliary

OH

Ochemical steps

Put auxiliary on

Ochemical steps

OH

O

OH

O

NH2 NH2

Both handed forms of product(racemic mixture; 1:1 mixture of enantiomers)

OH

O

OH

O

NH2

take auxiliary offO

NH2

HN O

O

Chiral Auxiliary :[ ]

Asymmetric Synthesis

The Nobel Prize in Chemistry 1979

Hebert C. Brown (1912- )

Me

Me

OMe

Me

OHIpc2BCl

B-Cl

Me

Me

OH

is not formed

Ipc2BCl

2

Synthesis of an Enantiomer using a Chiral Reagent

Asymmetric Synthesis

MeO

CO2H

'Flat' precursor

MeO

CO2H

HMe

Hydrogen

Naproxen anti-inflammatory drug

Ru

oooo

Synthesis of an Enantiomer using a Chiral Catalyst

Asymmetric Synthesis

[Ru-(S)-BINAP], 135 atm H2

PPh2

PPh2

92% yield, 97%ee

OHOH

Allyl alcohol

Oxidant

Glycidol

O

Ti

oooo

OH

OHOxidant

'Flat' precursor Product formed with superb selectivity

oooo

Os

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

C

CCA H

CB X

C

C

Organometallic Chemistr

y

CY MCY H

C M

C M

relatively stable complex

CC C C C

unstable species

stable(neutral)

Carbon Species

carbanion radical carbene carbocation

1. Stabilize unstable organic compounds

C

C C

C

H

H

H

H

cyclobutadiene

C

C C

CH

H

H

H

iron complex

Fe

CO

COOC

- 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

Benzene

C

CC

C

CCH

H

H

H

H

H

chromium complex

Cr

CO

COOC

CCC

C CC

H H

HH

H H

- 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

44 = 256 개 tetramer

Combinatorial Library

4 개의 monomer

••••

Nn Combinations

Combinatorial ChemistryCombinatorial Chemistry

resin +monomer

shakeresin

cleavage

wash

Solid Phase Synthesis 의 기본원리

wash

Split-Mix Process

Mix-SplitCouple

Mix-SplitCouple

33= 27tag each bead!

Solid Phase Library

203 = 8000 tripeptides

20 amino acids

202 = 400 dipeptides

204 = 160,000 tetrapeptides

In 1991s, Houghten & Lam: synthesis of a huge peptide library

peptide

DNA: fully automatic (solution)

Solid-phase synthesis

ln 1992, Jon Ellman: synthesis of non-peptide drug-like molecules by solid phase synthesis

carbohydrate

small molecule (drug-like)

초분자 화학

2. Supramolecular chemistry- Chemistry beyond moleculesAssembly of molecules – Molecular recognition

1987 노벨화학상 : 초분자화학Charles Pedersen, Jean-Marie Lehn, and Donald J. Cram

Non-covalent bonds: - electrostatic forces- hydrogen bonds- van der Waals interactions- dipole interactions- hydrophobic interactions, etc

Supramolecular ChemistrySupramolecular Chemistry

1. Molecular chemistry- Covalent bond

The Binding between Drug and Bilogical Receptorsthrough Non-Covalent Bonds

BiologicalReceptor

DrugMolecule

Biological Effects

‘recognition’

Supramolecular‘complex’

physiologicalresponse

DNA Double Helix

O

O

O

O

N

O

N

O

O OOOO O

K+K+

Cryptand

- 11 kcal/ mol - 18 kcal/ mol

Crown ether

NO

O

N

ON

CH3

CH3

H3C

N+

H

H H

RO

OMeO

OOOMe

MeMe MeMe

Carcerand

O

O

+ CO2

Chemosensors

Signals:- fluorescence- color- electric signal...