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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