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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...
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