24a synthesis

24-24-11
Diels-Alder ReactionDiels-Alder Reaction
Diels-Alder reaction:Diels-Alder reaction: A cycloaddition reaction
of a conjugated diene and certain types of
double and triple bonds.
• dienophile:dienophile: Diene-loving.
• Diels-Alder adduct:Diels-Alder adduct: The product of a Diels-Alder
reaction.
Diels-Alder adduct3-Buten-2-one
(a dienophile)
1,3-Butadiene
(a diene)
+
O
O
3-Buten-2-one
(a dienophile)
1,3-Butadiene
(a diene)
+
O
O

24-24-22
• Alkynes also function as dienophiles.
• Cycloaddition reaction:Cycloaddition reaction: A reaction in which two
reactants add together in a single step to form a
cyclic product.
Diels-Alder adductDiethyl
2-butynedioate
(a dienophile)
+
1,3-butadiene
(a diene)
COOEt
COOEt
COOEt
COOEt

24-24-33
• We write a Diels-Alder reaction in the following
way:
• The special value of D-A reactions are that they:
1. form six-membered rings.
2. form two new C-C bonds at the same time.
3. are stereospecific and regioselective.
Note the reaction of butadiene and ethylene
gives only traces of cyclohexene.
Diene Dieno-
phile
Adduct

24-24-44
• The conformation of the diene must be s-cis.
s-trans
conformation
(lower in energy)
s-cis
conformation
(higher in energy)

24-24-55
Diels-Alder Reaction Steric RestrictionsDiels-Alder Reaction Steric Restrictions
• (2Z,4Z)-2,4-Hexadiene is unreactive in Diels-
Alder reactions because nonbonded interactions
prevent it from assuming the planar s-cis
conformation.
(2Z,4Z)-2,4-Hexadiene
s-trans conformation
(lower energy)
s-cis conformation
(higher energy)
methyl groups
forced closer than
allowed by van
der Waals radii

24-24-66
• Reaction is facilitated by a combination of
electron-withdrawing substituents on one reactant
and electron-releasing substituents on the other.
CyclohexeneEthylene1,3-Butadiene
200°C
pressure
3-Buten-2-one
140°C
+
1,3-Butadiene
O O
+
2,3-Dimethyl-
1,3-butadiene
+ 30°C
3-Buten-2-one
O O

24-24-77
Electron-Withdrawing
Groups
Electron-Releasing
Groups
-C N (cyano)
- OR (ether)
- OOCR (ester)
- CHO (aldehyde, ketone)
- COOH (carboxyl)
- COOR (ester)
- NO2 (nitro)
- CH3, alkyl groups

24-24-88
• The Diels-Alder reaction can be used to form
bicyclic systems.
+
room
temperature
170°C
Diene Dienophile
Dicyclopentadiene
(endo form)
H
H

24-24-99
• Exo and endo are relative to the double bond
derived from the diene.
the double bond
derived from
the diene
endo (inside)
exo (outside) relative to
the double
bond

24-24-1010
• For a Diels-Alder reaction under kinetic control,
endo orientation of the dienophile is favored.
Methyl bicyclo[2.2.1]hept-5-en-
endo-2-carboxylate
(racemic)
Methyl
propenoate
Cyclopentadiene
+ OCH3
O
H
COOCH3
COOCH3
redraw 1 2
3
45
6
7

24-24-1111
• The configuration of the dienophile is retained.
COOCH3
COOCH3 COOCH3
COOCH3
A cis
dienophile)
Dimethyl cis-4-cyclohexene-
1,2-dicarboxylate
+
COOCH3
H3 COOC COOCH3
COOCH3
A trans
dienophile)
Dimethyl trans-4-cyclohexene-
1,2-dicarboxylate
(racemic)
+

24-24-1212
• The configuration of the diene is retained.
CH3
CH3
CH3
O
O
O
O
O
O
O
O
O
H3 C
H3 C
O
O
OH3C
H3 C
CH3
+
+
H
H
H
H
Check
that
this is
endo.

24-24-1313
Mechanism
• No evidence for the participation of either radical
of ionic intermediates.
• Chemists propose that the Diels-Alder reaction is
a concerted pericyclic reaction.
Pericyclic reactionPericyclic reaction: A reaction that takes
place in a single step, without intermediates,
and involves a cyclic redistribution of
bonding electrons.
Concerted reaction: All bond making and
bond breaking occurs simultaneously.

24-24-1414
• Mechanism of the
Diels-Alder reaction

24-24-1515
Aromatic Transition StatesAromatic Transition States
Hückel criteria for aromaticity:Hückel criteria for aromaticity: The presence
of (4n + 2) pi electrons in a ring that is
planar and fully conjugated.
Just as aromaticity imparts a special stability
to certain types of molecules and ions, the
presence of (4n + 2) electrons in a cyclic
transition state imparts a special stability to
certain types of transition states.
• Reactions involving 2, 6, 10, 14.... electrons in a
cyclic transition state have especially low
activation energies and take place particularly
readily.

24-24-1616
Aromatic Transition States,Aromatic Transition States,
ExamplesExamples
• Decarboxylation of β-keto acids and β-
dicarboxylic acids.
• Cope elimination of amine N-oxides.
O O
H
O
O
H
C
O
O
O
CO2+
enol of
a ketone
(A cyclic six-membered
transition state)
O
heat
+
A cyclic six-membered
transition state
N,N-dimethyl-
hydroxylamine
C C
H N
CH3
CH3
N
CH3
CH3
O
HC C
An alkene
+

24-24-1717
Aromatic Transition StatesAromatic Transition States
• the Diels-Alder reaction
• pyrolysis of esters (Problem 22.42)
We now look at examples of two more
reactions that proceed by aromatic transition
states:
• Claisen rearrangement.
• Cope rearrangement.
Diene Dieno-
phile
Adduct

24-24-1818
Claisen RearrangementClaisen Rearrangement
Claisen rearrangement:Claisen rearrangement: A thermal
rearrangement of allyl phenyl ethers to 2-
allylphenols.
Allyl phenyl ether
200-250°C
2-Allylphenol
O OH

24-24-1919
Claisen RearrangementClaisen Rearrangement
O
Allyl phenyl
ether
heat
OH
o-Allylphenol
O
H
A cyclohexadienone
intermediate
keto-enol
tautomerism
O
Transition
state

24-24-2020
Cope RearrangementCope Rearrangement
Cope rearrangement:Cope rearrangement: A thermal
isomerization of 1,5-dienes.
3,3-Dimethyl-
1,5-hexadiene
2-Methyl-2,6-
heptadiene
heat

24-24-2121
Cope RearrangementCope Rearrangement
Example 24.8Example 24.8 Predict the product of these Cope
rearrangements.
(a)
(b)
350°C
OH
H
320°C

24-24-2222
Synthesis of Single EnantiomersSynthesis of Single Enantiomers
• We have stressed throughout the text that the
synthesis of chiral products from achiral starting
materials and under achiral reaction conditions of
necessity gives enantiomers as a racemic
mixture.
• Nature achieves the synthesis of single
enantiomers by using enzymes, which create a
chiral environment in which reaction takes place.
• Enzymes show high enantiomeric and
diastereomeric selectivity with the result that
enzyme-catalyzed reactions invariably give only
one of all possible stereoisomers.

24-24-2323
How do chemists achieve the synthesis of
single enantiomers?
The most common method is to produce a
racemic mixture and then resolve it. How?
• the different physical properties of diastereomeric
salts.
• the use of enzymes as resolving agents.
• chromatographic on a chiral substrate.

24-24-2424
• In a second strategy, asymmetric inductionasymmetric induction, the achiral
starting material is placed in a chiral environment by
reacting it with a chiral auxiliarychiral auxiliary. Later it will be removed.
• E. J. Corey used this chiral auxiliary to direct an
asymmetric Diels-Alder reaction.
• 8-Phenylmenthol was prepared from naturally occurring
enantiomerically pure menthol.
Me
HO
Me Me
Me
HO
Me Me
Ph
8-Phenylmenthol
(an enantiomerically
pure chiral auxillary)
Menthol
(enantiomerically pure)
several
steps

24-24-2525
• The initial step in Corey’s prostaglandin
synthesis was a Diels-Alder reaction.
• By binding the achiral acrylate with
enantiomerically pure 8-phenylmenthol, he thus
placed the dienophile in a chiral environment.
• The result is an enantioselective synthesis.
OBn
Me
O
Me Me
Ph
O
ORO
BnO
RO O
OBn
+
Diels-Alder
+
Enantiomerically
pure
97% 3%
89%
Achiral

24-24-2626
• A third strategy is to begin a synthesis with an
enantiomerically pure starting material.
• Gilbert Stork began his prostaglandin synthesis
with the naturally occurring, enantiomerically
pure D-erythrose.
• This four-carbon building block has the R
configuration at each stereocenter.
• With these two stereocenters thus established,
he then used well understood reactions to
synthesize his target molecule in enantiomerically
pure form.
HO
H
O
OH
OH
D-Erythrose

24a synthesis

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24a synthesis