Make me a molecule
Rearrangement of atoms: cleaving and making bonds
Aspirin
Tagamet®
Tamiflu®
Many of the materials we use today are made by
chemical synthesis. Most of the new compounds made
today are organic.
Organic Chemistry
Organic Compounds
Most of the new compounds made today are organic,
that is, they are composed largely of carbon.
C C H
C C O C
C
C H
N
C
O O
C Cl
C
C
C
stable and versatile
C
N N
C
unstable
Product
e.g. paint and pigment
vitamin
synthetic fiber
pesticide
plastic
explosive pharmaceutical
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
Br
Br
NMe
H
NMe
NMe
Br
( II )
NMe
O
NMe
OH
H
OH
Willstatter’s synthesis of tropine
Sir Robert Robinson
United Kingdom
(1886-1975)
COOH
COOH
CHO
+
The Nobel Prize
in Chemistry 1947
H2NMe +
O
NMe
O
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.
NMe
O
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
Prostaglandins
Corey, Elias James
1928–, 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.
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
Efficiency and selectivity are important
characteristics that have to be taken into account.
[Efficiency: yields, number of steps]
[Selectivity: chemoselectivity, regioselectivity, stereoselectivity]
Organic Synthesis:
Stereoselectivity
1. Carbon-Carbon Bond Formation
2. Functional Group Interconversion
Organic Synthesis:
Enantioselectivity
1. Carbon-Carbon Bond Formation
2. Functional Group Interconversion
분자식
입체이성질체(Stereoisomers)
Cl
C2H2Cl2
Cl
C
C7H14
C
C
H
H
cis-1,2-dichloroethylene
(bp: 60 oC)
Cl
H
H
Cl
trans-1,2-dichloroethylene
(bp: 48 oC)
H H
Me H
Me Me
H Me
cis
trans
CH2CH3
CH3CH2
C HI
C4H9I
CH3
(+)-2-iodobutane
(bp: 119 oC)
Chiral compounds
“Enantiomer”
C
H C
I
CH3
(-)-2-iodobutane
(bp: 119 oC)
Enantiomers and the Tetrahedral
Carbon
Chiral Molecules and Achiral Molecules
Mirror Images
identical
(superimposable)
identical
(superimposable)
achiral
achiral
enantiomers
chiral
(nonsuperimposable)
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
Optical Activity
Light 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.
OH
HO2C
H2O
CO2H
HO2C
OH
HO2C
CO2H
H
1
:
1
Only one enantiomer is obtained by asymmetric synthesis.
HO2C
OH
H2O
CO2H
fumarase
(enzyme)
HO2C
CO2H
CO2H
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
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
Allyl alcohol
Glycidol
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
Carbon Species
C
stable
(neutral)
C
carbanion
C
C
C
carbene
radical
unstable species
carbocation
Organometallic Chemistry
Acid-Base Chemistry
Y C H
A C H
B C X
Y C M
C
C
C M
C
C M
C
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
Combinatorial Chemistry
Combinatorial Library
•
•
•
•
4 개의 monomer
Nn Combinations
44 = 256개
tetramer
Solid Phase Synthesis의 기본원리
resin +
monomer
shake
wash
wash
resin
cleavage
Split-Mix Process
tag each bead!
Mix-Split
Couple
Mix-Split
Couple
33= 27
Solid Phase Library
In 1991s, Houghten & Lam: synthesis of a huge peptide library
20 amino acids
Solid-phase synthesis
202 = 400 dipeptides
DNA: fully automatic (solution)
peptide
203 = 8000 tripeptides
carbohydrate
204 = 160,000 tetrapeptides
small molecule (drug-like)
ln 1992, Jon Ellman: synthesis of non-peptide drug-like molecules by
solid phase synthesis
Supramolecular Chemistry
초분자 화학
1. Molecular chemistry- Covalent bond
2. Supramolecular chemistry- Chemistry beyond molecules
Assembly of molecules – Molecular recognition
Non-covalent bonds:
- electrostatic forces
- hydrogen bonds
- van der Waals interactions
- dipole interactions
- hydrophobic interactions, etc
1987 노벨화학상: 초분자화학
Charles Pedersen, Jean-Marie Lehn, and Donald J. Cram
The Binding between Drug and Bilogical Receptors
through Non-Covalent Bonds
‘recognition’
Drug
Molecule
Biological
Receptor
physiological
response
Supramolecular
‘complex’
Biological
Effects
DNA Double Helix
Cryptand
Crown ether
O
K+
O
O
O
O
O
O
O
O
O
O
- 11 kcal/ mol
N
K+
N
O
- 18 kcal/ mol
CH3
N
O H
H3C
N
+H
O
N
R
N
H
O
CH3
OMe
O
O
Me
Me Me
Me
O
O
OMe
Carcerand
O
O
+ CO2
Chemosensors
Signals:
- fluorescence
- color
- electric signal...