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Synthesis
Making molecules you want from
the ones you have.
Synthesis Requires Two Things
a. a library of reactions
b. a strategy or plan for combining
known reactions to reach
the desired target molecule
c. and a little luck always helps
A library of reactions
Functional group manipulations
Oxidations, reductions,
substitutions etc.
Carbon-carbon bond formations
Used to build the carbon skeleton
of the target molecule
How does a
carbocation react?
CH3
CH3
C
Br
Since the carbocation
is a Lewis acid
It can react with a
Lewis base.
CH3
The electron pair on
the base attacks the
electron deficient center
CH3
CH3 C
Br
CH3
How else can a carbocation
gain stability?
CH3
CH3
C
CH3
Instead of reacting as a Lewis acid it can
react as a Bronstead acid and donate a proton!
CH3
CH3
C
C
H
OH
CH3
H H
This is called an
elimination reaction
Because H+ is
eliminated from the
molecule
CH3
C
H
C
H
+ H2O
Addition
Br
CH3
CH3
C
C
CH3
CH3 C
Br
CH3
H
H H
CH3
OH
CH3
Elimination
C
+ H2O
H
C
H
Elimination often competes with
substitution.
Just like substitution where there
are two forms SN1 and SN2 there
are two forms of elimination, E1 and
E2.
Sorting it all out is pretty complicated,
something we are not going to do.
But we would like to use elimination
as a synthetic reaction.
So how can you favor elimination?
Use a very strong base that is a poor
nucleophile.
For example potassium t-butoxide.
HO
+
K
potassium t-butoxide
very strong base
but steric bulk
prevents
t-butoxide from readily
forming ethers
in a substitution
reaction
K O
+
1/2 H2
Br
+
K O
+
H
O
+
KBr
K O
+
Br
major
minor
The alkene with the most substituents is
the most stable and the most favored product.
Br
K O
+
major
minor
K O
Br
major
minor
Similar eliminations can take place with alcohols.
Catalyzed by concentrated strong acids
Concentrated acids are hydrophilic and
will remove water from other molecules
in order to dilute themselves.
O
H2SO4
H
hot
H2SO4
hot
OH
56%
32%
12%
But you can get complicated mixtures.
Alkyne synthesis
K O
Br
Br
Elimination of two moles of HBr
from neighboring carbon atoms
will give an alkyne.
H
Br
K O
Br
You can reduce alkynes back to alkenes
H2
Pd
H
H
or
H2
Pd
H
H
CH3
C C
H
H
Pd
H
Pd
Pd
Pd
Pd
Pd
H
H
CH3 H
CH3 C
H
H
C H
H
Pd
H
Pd
H3C
H
C H
H
Pd
H
H
H
C H
H
H
Pd
Hydrogens come in from the same side.
You can reduce alkynes back to alkenes
H2
Pd
H
H
or
H2
Pd
H
H
For the trans isomer use a different
reducing agent. Sodium metal in ammonia.
Complicated mechanism.
Na
NH3
H
H
or
Na
H
NH3
H
H2O
HO
H
H
NH3
pKa
values
H
H
15.7
25
38
NH2
H
H
44
H
CH3
H
CH3
H
CH3
H
CH2
51
Sodium amide is a very strong base
Na +
Na+ NH2-
NH3
+ 1/2 H2
It can be used to form an acetylide
H
+
Na
NH2-
Na
Acetylides will give us our first
carbon-carbon bond making reaction.
Acetylides are strong bases and good
nucleophiles.
They can undergo substitution reactions
with primary alkyl halides.
H
+
Na
Na
Na
NH2-
+
Br
H
1. Na/NH3
2.
Br
Two ways to make many acetylenes
H
1. Na/NH3
H
2. Br
2.
1. Na/NH3
Br
Now that we have a carbon-carbon
bond forming reaction we are ready
for some real synthesis.
Suppose you wanted to synthesize
3-hexanol
O
H
But your only carbon containing starting
materials are compounds with four carbons
or less.
four carbons
O
H
three carbons
O
two carbons
H
three carbons
Analyze carbon framework first.
Which carbon-carbon bonds must be
put together in our synthesis?
We could make the bond between
carbons 3 and 4.
But we will chose to make the new C-C
bond between carbons 2 and 3.
Work backwards
O
H
H2O
H2O H2SO4
H2SO4
No regiochemistry
control
H
H2
Pd
H
Work backwards
O
H
H2O H2SO4
H
1. Na/NH3
2. Br
H
H2
Pd
H
H2
H
Pd
H
1. Na/NH3
2. CH3CH2Br
H
CH3
1. Na/NH3
2. CH3Br
H
One simple reaction you did in the lab.
Ester Synthesis
O
R
O
R'
H + H
O
O
R
O
+ H2O
R'

O
O

R
O
H
O
H
SOCl2
R
Much faster
R'
Cl
O
O
O
H
SOCl2
Cl
H
O
O
CH3
O
H
CH3
O
O
O
O
O
Butyl butyrate
odor of pineapples
How could you make it from 1-butanol?
O
O
O
Cl
SOCl2
+
H
O
CrO3
O
O
H

O

The last reaction we
are going to study.
The Grignard Reaction
Reaction of an nucleophilic carbon atom
with a carbonyl group.

O

The Grignard Reaction
Br
Mg

Mg

Br

O

Br
Mg
Br
Mg


O
The Grignard Reaction converts aldehydes
or ketones to alcohols.
O
Br
Mg
H
+
H
O
Br
Br
Mg
Mg
Mg
Mg Br
Br
BrMgCH3
BrMg
BrMg
O
H
1. BrMg
2. H+
1. BrMg
2. H+
O
O
1. BrMgCH3
2. H+
O
Reactions with aldehydes give secondary alcohols
O
O
1. BrMg
H
2. H+
H
O
Mg
Br
1.
H
2. H+
H
O
H
O
O
H
?
O
1.
H
H
2. H+
HBr
Br
Mg
Mg
Br
H
OH
Pheromone of the European Bark Beetle
How could you synthesize it from organic
compounds with four carbons or less?
First analyze the carbon skeleton
Then work backwards.
OH
O
H
+ Br
OH
O
Br
+
H
Br
HBr
or
HBr
O
O
H
H
+ BrMgCH3
or
H
MgBr +
O
H
O
1.
O
MgBr
H
2. H+
O
H
HBr
O
1.
H
2. H+
Mg
Br
O
Odor of Rum
PCC
OH
1.
BrMg
O
H
+
2. H
PCC
O
1.
MgBr
H
H
+
2. H
OH
CHE 503 Organic Synthesis
Professor Frank Fowler
Syntheses of Discodermolides Useful for Investigating
Microtubule Binding and Stabilization
Deborah T. Hung, Jennie B. Nerenberg, and Stuart L. Schreiber*
Contribution from the Howard Hughes Medical Institute, Department
of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts 02138
J. Am. Chem. Soc. 1996, 118, 11054-11080
Me
HO
O
O
Me
Isolated from a
marine sponge
Me
Me
Me
Me
OH
Me
Me
OH
OH
OCONH2
OH
For geometric isomers
are possible. Only one
is the correct compound.
OH
OH
or
or
OH
or
OH
or
Me
HO
O
O
Me
Me
Me
Me
Me
Me
OH
Isolated from a
marine sponge
Me
OH
OH
OCONH2
Me
HO
O
O
Me
Me
Me
Me
Me
Me
Me
OH
OCONH2
OH
OH
How Many Stereoisomers?
= isomer choice
216 = 65,536 isomers
Me
HO
O
O
Me
Me
Me
Me
Me
Me
Me
OH
OCONH2
OH
OH
O
Ph
S
H
O
Me
Me
OTBS
Me
Y
Me
X
Me
OTBS
Me
Me
O
Me
OCONH2
Possible Grignard?
O
Ph
S
H
Me
Y
O
Me
Me
Me
X
Me
OTBS
OTBS
No, too reactive, use some
acetylene chemistry instead.
I
O
H
R'
R
Ni
HO
H2
Pd
R
R'
Me
HO
O
O
Me
Me
Me
Me
Me
Me
OH
Isolated from a
marine sponge
Me
OH
OH
OCONH2