Post on 25-Dec-2015
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.
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
H
DD
D
D
D
D
DD
DD
D
D
DD
DD
D
D
D
D
H
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–, 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 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
Organic Synthesis: 1. Carbon-Carbon Bond Formation2. Functional Group Interconversion
Enantioselectivity
Some Physical Properties of the Stereoisomers of Tartaric Acid
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.
Resolutiondiastereomeric 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
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"for their development of the use of boron- and phosphorus-containing compounds, respectively, into important reagents in organic synthesis"
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
Synthesis of an Enantiomer using a Chiral Catalyst
Asymmetric Synthesis
OHOH
Allyl alcohol
Oxidant
Glycidol
O
Ti
oooo
OH
OHOxidant
'Flat' precursor Product formed with superb selectivity
oooo
Os
TBHP (t-BuOOH), Ti(OPri)4
L-(+)-DET
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 Chemistry
CY MCY H
C M
C M
relatively stable complex
CC C C C
unstable species
stable(neutral)
Carbon Species
carbanion radical carbene carbocation
Organometallic CompoundsOrganometallic Compounds
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
3. organometallic complexes: useful templates (as reagents)
C
C
H
H
(OC)3Co
(OC)3Co
CH2
CH2
C
O
HC
HC CH2
CH2
C
O
Pauson-Khand Reaction: 1970s
- useful method for the synthesis of cyclopentenone
OO
H2C CH2
CO
Co2(CO)8
O
O
O
O
Taylorione
Application to the synthesis of complex molecules
taylorione: synthesis by Williams Kerr in 1990s
4. Catalyze Reactions: efficiency
R
R
R
R
CH2
CH2+
olefin metathesis
catalyst
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
Ru C
PCy3
PCy3
Cl
Cl H
H
P
[Ru] CH
H
active catalyst
PCy3
H3C
H3C
CH3Mes =
catalysts for olefin metathesis: many catalysts based on organometallic reagents "Ru", "Mo", "W"
Grubbs's catalyst Ru
Ph
PCy3
PCy3
Cl
ClRu
PhPCy3
Cl
Cl
NNMes Mes
Olefin Metathesis
[Ru] CH
H C CH
H
R
H
C C HH
R
H
[Ru] CH
H
C CH
H
H
H
CR H
[Ru]
C CH
H
R'
H
C C HR'
R
H
[Ru] CH
H
C CH
R'
R
H
R
R
R
R
CH2
CH2+
[Ru] CH
H
mechanism
Olefin Metathesis
O
O O
HO
OTBS
N
S
O
O O
HO
OTBS
N
S
CH2Cl2
15 mol%
rt, 8h
50% + 35% (E -isomer)
O
O O
HO
OH
N
S
Epothilone A
Osimple starting material
Ring-Closing Olefin Metathesis