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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
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Synthesis
Making molecules you want fromthe 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 manipulationsOxidations, reductions, substitutions etc.
Carbon-carbon bond formations
Used to build the carbon skeletonof the target molecule
C
CH3
CH3CH3
How does acarbocation react?
Br
C
CH3
BrCH3
CH3
Since the carbocationis a Lewis acid It can react with aLewis base.
The electron pair onthe base attacks theelectron deficient center
C
CH3
CH3CH3
How else can a carbocationgain stability?
Instead of reacting as a Lewis acid it can react as a Bronstead acid and donate a proton!
C
CH3
CCH3H
H H
OH
CC
CH3
CH3 H
H
+ H2O
This is called anelimination reaction
Because H+ iseliminated from the molecule
C
CH3
CCH3H
H HOH C
C
CH3
CH3 H
H
+ H2O
Br
Addition
Elimination
C
CH3
BrCH3
CH3
Elimination often competes withsubstitution.
Just like substitution where thereare two forms SN1 and SN2 thereare two forms of elimination, E1 andE2.
Sorting it all out is pretty complicated,something we are not going to do.
But we would like to use eliminationas a synthetic reaction.
So how can you favor elimination?
Use a very strong base that is a poornucleophile.
For example potassium t-butoxide.
HO + K OK + 1/2 H2
potassium t-butoxide
very strong basebut steric bulk preventst-butoxide from readily forming ethersin a substitutionreaction
OKBr+
OH
+ KBr
+
OK
Br+
major minor
The alkene with the most substituents isthe most stable and the most favored product.
OKBr
major minor
+
OK
Br major minor
Similar eliminations can take place with alcohols.
Catalyzed by concentrated strong acids
Concentrated acids are hydrophilic andwill remove water from other moleculesin order to dilute themselves.
OH
H2SO4
hot
H2SO4
hotOH
56% 32% 12%
But you can get complicated mixtures.
OK
Br
Br H
Alkyne synthesis
Elimination of two moles of HBrfrom neighboring carbon atomswill give an alkyne.
K OBr
Br
You can reduce alkynes back to alkenes
H H
H
H
H2
Pd
H2Pd
or
C CH H
HCH3
Pd Pd PdPd Pd
PdPd
H H
C C
PdH
CH3H H
H
H
C
Pd
HH
H
H
CH3
H
C HH
H
H
H3C
H
Pd
Hydrogens come in from the same side.
You can reduce alkynes back to alkenes
H H
H
H
H2
Pd
H2Pd
or
H H
H
H
or
NaNH3
NaNH3
For the trans isomer use a differentreducing agent. Sodium metal in ammonia.Complicated mechanism.
H H
H2O 15.7HO
H 25
NH3 NH2 38
H
HH
H
HH
H44
CH3 CH3 CH3 CH2 51
pKa
values
Na + NH3 Na+ NH2- + 1/2 H2
Sodium amide is a very strong base
It can be used to form an acetylide
Na+ NH2-
H Na
Acetylides will give us our first carbon-carbon bond making reaction.
Acetylides are strong bases and goodnucleophiles.
They can undergo substitution reactionswith primary alkyl halides.
Na+ NH2-
H Na
Na + Br
H
Na/NH31.
2. Br
H
1. Na/NH3
2. Br
H
1. Na/NH3Br
2.
Two ways to make many acetylenes
Now that we have a carbon-carbonbond forming reaction we are readyfor some real synthesis.
Suppose you wanted to synthesize3-hexanol
But your only carbon containing startingmaterials are compounds with four carbons or less.
OH
Analyze carbon framework first.
Which carbon-carbon bonds must beput together in our synthesis?
We could make the bond betweencarbons 3 and 4.
But we will chose to make the new C-Cbond between carbons 2 and 3.
OH
OH
three carbons
three carbons
four carbons
two carbons
H2OH2SO4
H2Pd
OH
H H
H2O H2SO4
No regiochemistrycontrol
Work backwards
H2Pd
OH
H H
H2O H2SO4
Work backwards
2.
1. Na/NH3
Br
H
H H
H2
Pd
H
1. Na/NH3
2. CH3Br
1. Na/NH3
2. CH3CH2Br
H CH3
One simple reaction you did in the lab.
Ester Synthesis
O
OR'
R
O
OH
R OH R'+
+ H2O
O
OH
R
HO
R'
O
ClRSOCl2
Much faster
O
O
HCl
OSOCl2
HO
O
O
HO
CH3
O
O
CH3
O
O
Butyl butyrate odor of pineapples
How could you make it from 1-butanol?
O
O
Cl
O
+ HO
CrO3
O
O
H
SOCl2
O
The last reaction weare going to study.
The Grignard Reaction
Reaction of an nucleophilic carbon atomwith a carbonyl group.
O
The Grignard Reaction
MgBr MgBr
Mg
BrO
OMg
Br
OMg
Br
H+OH
The Grignard Reaction converts aldehydesor ketones to alcohols.
Br Mg
Br
Mg
Br Mg BrMg
BrMgCH3 BrMg BrMg
OH
O
BrMg1.2. H+
O
BrMgCH31.2. H+
O
2. H+1. BrMg
Reactions with aldehydes give secondary alcohols
BrMg
H
O
2. H+
1. OH
MgBr
O
HH1.
2. H+ OH
OH O
H?
HBr
Br Mg MgBr
1.O
HH2. H+
OH
Pheromone of the European Bark Beetle
How could you synthesize it from organiccompounds with four carbons or less?
First analyze the carbon skeleton
Then work backwards.
OH
H
O
Br+
OH
BrO
H+
Br HBr
OH
HBrO
H+ BrMgCH3
H O
+MgBr
or
or
H O
1.
2. H+MgBr
OH
HBr
BrO
H
MgH
O1.
2. H+
O
Odor of Rum
OH
PCC
BrMg1.
2. H+H
O
OH
PCC
2. H+MgBr
O
HH1.
Syntheses of Discodermolides Useful for InvestigatingMicrotubule Binding and Stabilization
Deborah T. Hung, Jennie B. Nerenberg, and Stuart L. Schreiber*Contribution from the Howard Hughes Medical Institute, Department of Chemistry and ChemicalBiology, Harvard University, Cambridge, Massachusetts 02138J. Am. Chem. Soc. 1996, 118, 11054-11080
CHE 503 Organic SynthesisProfessor Frank Fowler
OMe
MeOH
Me
OMe
Me
OH
Me
OCONH2
OH
Me
Me
HO
Isolated from a marine sponge
OH
OH OH
or
OH OHor or
or
For geometric isomersare possible. Only oneis the correct compound.
OMe
MeOH
Me
OMe
Me
OH
Me
OCONH2
OH
Me
Me
HO
Isolated from a marine sponge
OMe
MeOH
Me
OMe
Me
OH
Me
OCONH2
OH
Me
Me
HO
How Many Stereoisomers?
= isomer choice
216 = 65,536 isomers
OMe
MeOH
Me
OMe
Me
OH
Me
OCONH2
OH
Me
Me
HO
O
MeOTBS
Me
S
O HPh
Me Me
OTBS
MeYX Me
O
Me
OCONH2
Me
O
MeOTBS
Me
S
O HPh
Me Me
OTBS
MeYX
Possible Grignard?
No, too reactive, use some acetylene chemistry instead.
I
R'R
O H
Ni
H2
Pd R R'
HO
OMe
MeOH
Me
OMe
Me
OH
Me
OCONH2
OH
Me
Me
HO
Isolated from a marine sponge
