Download The Diels-Alder reaction

1
The Diels-Alder reaction
Me
δ–
δ+
CO2Me
δ–
+
δ+
Me
Me
Δ
CO2Me
+
δ+
δ–
CO2Me
major
Me δ+
δ–
δ–
CHO
+
δ–
Me
Δ
Me
CHO
+
δ+
δ+
minor
CHO
toluene, 120°C, no catalyst
benzene, 25°C, SnCl4
59
96
:
:
41
4
Lewis acid
improves
selectivity
• Diels-Alder (DA) reaction is incredibly valuable method for the synthesis of 6-rings
• Normally DA is highly regioselective (as seen above)
• It is controlled by the ‘relative sizes’ of the p orbitals in the LUMO & HOMO involved
• More accurately referred to as the orbital coefficients
• In the presence of a Lewis acid dienophile is polarised giving higher regioselectivity
and a faster reaction
NMe2
δ–
NMe2
δ+
δ–
CO2Me
CO2Me
+
δ+
δ–
NMe2
CO2Me
δ+
HOMO
LUMO
regioselectivity often follows simple electronic argument (consider which C is δ+ve or δ–ve)
123.702 Organic Chemistry
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Endo vs. exo selectivity
A
secondary
orbital overlap
H
H
A
A
endo
B
A
B
D
C
H
C
D
A
D
B
C
H
C
B
D
favoured
D
B
endo
H
A
A
C
H
H
≡
H
exo
B
C
C
≡
D
D
B
exo
• Endo transition state & adduct is more sterically congested thus thermodynamically
•
•
less stable
But it is normally the predominant product
The reason is endo transition state is stabilised by π orbital overlap of the group on
C or D with the diene HOMO; an effect called ‘secondary orbital overlap’
• The reaction is suprafacial and we observe that the geometry of the diene &
dienophile is preserved
123.702 Organic Chemistry
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Diels-Alder reaction
A
A
A
H
A
H
B
draw a
cube
add the
diene
D
C
B
D
add dienophile
(endo product has
substituents directly
under diene)
C
B
H
H
D
remember other
substituents
present
C
B
D
do reaction
(make new
bonds)
C
B
A
H
H
H
H
A
H
B
H
H
C
D
H
should be able to see
relative stereochemistry
• The ‘cube’ method is a nice way to visualise the relative stereochemistry
• Finally, remember that the dienophile invariably reacts from the less hindered face
• If you are a little rusty on the Diels-Alder reaction either re-read your lecture notes or
any standard organic text book
MeO
OMe
H
+
MeO
H
NO2
O2N
H
H
NO2
123.702 Organic Chemistry
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Chiral auxiliaries on the dienophile
O
O
BnOH
+
+
Cl
OBn
achiral
dienophile
O
+
OBn
O
OBn
1 : 1 mixture of enantiomers
achiral
diene
• One diastereoisomer is formed - the endo product
• But mixture of enantiomers
• If we add a chiral auxiliary then there are two possible endo diastereoisomers
• But one predominates - thus we can prepare a single enantiomer
O
R
O
HN
R
O
O
O
Cl
N
O
Et2AlCl
+
Me
(S)-valine
derivative
O
N
O
O
Me
Me
Me
Me
R
chiral dienophile
achiral
diene
Me
single(ish)
diastereoisomer
R = H 86% de
R = Me 90% de
>98% endo
BnOH
R
O
OBn
single
enantiomer
123.702 Organic Chemistry
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Explanation of diastereoselectivity
s-cis
favoured
Et2
O Al O
H
N
O
Me
O
O
Me
N
Et2AlCl2
Et Et
Al
O
O
O
N
Me
Me
s-trans
disfavoured
Et2
O Al O
H
N
O
Me
Me
O
Et2
O Al O
H
N
O
Me
Me
Me
Me
lower face
blocked
• Coordination to the Lewis acid activates dienophile
• The rigid chelate governs reactive conformation (s-cis) as s-trans disfavoured
• iso-Propyl group blocks bottom face
• Diene’s approach maximises secondary orbital overlap and favours endo product
123.702 Organic Chemistry
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Camphor-derived auxiliary
Me
Me
R
O
N
R
+
TiCl4
–78°C
H
S O
O
Me
O
N
O2S
Me
Me
R = H 99% de
R = Me >97% de
>98% endo
Me
R
Me
Me
R
N
S
O
O O Ti
Ln
N
SO2
O
• A range of auxiliaries can be utilised
• Most give good diastereoselectivities
123.702 Organic Chemistry
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Chiral auxiliaries II
phenyl group
blocks lower face
H
Me
O
O
BnO
Me
Me
AlCl3
OBn
O
BnO
H
Me
Me
≡
≡
+
Me
O
Me
O
diene approaches
from the top
H
CO2R
Me
O
Me
BnO
• It is possible to attach the chiral auxiliary to the diene as well
O
O
O
O
OH
MeO
O
OMe
H Ph
B(OAc)3
+
O
H Ph
H
O
OH
H
O
>95% de
endo
123.702 Organic Chemistry
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Chiral auxiliary controlled DA in total synthesis
S
S
S
Me2AlCl
PMBO
O
Me
PMBO
Ph
O
Me
O
H
H
S
H
H
Me
O
N
O
O
NR2*
H
N
H
(–)-stenine
• Use of a chiral auxiliary in an intramolecular Diels-Alder reaction (IMDA)
• Note how it sets up 4 stereocentres and the central ring of (–)-stenine
• (–)-Stenine is isolated from Stemona family of subshrubs is a constituent of a variety
of Eastern folk medicines
• This synthesis is by Morimoto Y, Iwahashi M, Nishida K, Hayashi Y, Shirahama H,
Angew. Chem. Int. Ed. Engl., 1996, 35, 904
123.702 Organic Chemistry
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Chiral catalysis and the Diels-Alder reaction
O Me
MeO
+
N
MeO
cat.
Br
H
O Me
N
Br
H
O
O
>97% ee
Me Me
Me
F3CO2S
Me
N
Al
N
SO2CF3
Me
• The fact the Diels-Alder reaction is mediated or catalysed by Lewis acids means
enantioselective variants are readily carried out
• The aluminium catalyst above has been utilised in enolate chemistry (aldol) reaction
and is very effective in this Diels-Alder reaction
123.702 Organic Chemistry
10
Bis(oxazoline)-based catalysts & the DA reaction
Diels-Alder reaction
Me Me
O
O
O
N
O
N
O
Me
+
N
Cu
TfO OTf
Me
Me
Me
Me
Me
Me
cat 5-10mol%
92%
97%ee
O
Me Me
O
H
O
N
2+
Cu
R2N
N
H
Me
same as
O
O
Me
Me
Me
Me
Me O
Me Me
N
Me
H
H
O
N
O
O
Hetero-Diels-Alder reaction (HDA)
O
+
OEt
H
O
cat 2-5mol%
72%
97%ee
i. KOH
ii. HCl
O
H
OH
O
H
CO2Et
O
H
• Bis(oxazoline) ligands (Box) are amongst the most versatile & well used ligands known
• Simply prepared from amino alcohols (& hence amino acids)
• Here used in both DA and the equally useful HDA
123.702 Organic Chemistry
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Catalytic enantioselective HDA in total synthesis
Me
Me
N
OBn
O
+
O
H
O
Cl
N
neat, 25°C
64%
97%ee
TBDPSO
TBSO
Cr
Cr
O
O
OBn
O
TBDPSO
TBSO
Me
TESO
OBn
Et
Et
O
+
ent-cat
neat, 25°C
H
OTBS
64%
97%ee
Me
H
O
O
TESO
TBSO
OTBS
OTBDPS
• From the synthesis of (+)-ambruticin by Ping Liu and Eric N. Jacobsen, J. Am.
Chem. Soc. 2001, 123, 10772
123.702 Organic Chemistry
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Catalytic enantioselective HDA in total synthesis
OH
OH
Me
O
CO2H
O
Me
Me
(+)-ambruticin
Et
Me
• (+)-Ambruticin is an antifungal agent extracted from the myxobacterium Polyangium
cellulsoum
• It has shown activity against Coccidioides immitis the cause of coccidioimycosis...
123.702 Organic Chemistry
13
Organocatalysis and the Diels-Alder reaction
OMe
cat. (20%)
HClO4
O
+
COEt
Et
OMe
96% ee
endo / exo >200 : 1
Me
O
Ph
O
Me
N
N
H
O
Me
Ar
N Me
O
N
N
N
OMe
O
Et
Et
Me
• Organic secondary amines can catalyse certain Diels-Alder reactions
• The reaction proceeds via the formation of an iminium species
• This charged species lowers the energy of the LUMO thus catalysing the reaction
• In addition one face of dienophile is blocked thus allowing the high selectivity
123.702 Organic Chemistry
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Organocatalysis and total synthesis
O
Me
N
O
Bn
CHO
Me
N
H
t-Bu
Me
Me
CHO
cat 20mol%
71%
>20:1 dr
90%ee
O
O
H
H
H
OMe
H
H
solanapyrone D
• The marine metabolite solanapyrone D is a phytotoxic polyketide isolated from the
fungus Altenaria solani
123.702 Organic Chemistry
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Organocatalysis and the Diels-Alder reaction
OMe
O
+
Ph
H
O
1. cat. (10%)
2. TFA
Ph
O
O
TBSO
Ph
Tf
Ph
N
N
O
87% ee
Tf
H H
Ph
TFA
H
Ph
O
Me
Tf
N
N
MeO H
O
O H
Ph
TBSO
Tf
O
TBS
Ph
O
O
H
• This is an example of a hetero-Diels-Alder reaction
• The aldehyde is the dienophile
• We have to use a very electron rich diene
• The amine catalyst acts as a Lewis acid via two hydrogen bonds
123.702 Organic Chemistry
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Organocatalysis
TBSO
H
1. cat. (10%)
2. AcCl
Ph
+
Me
N
Ph
Me
Me
O
Ph
>98% ee
OH
OH
O
Ph
O
Ph
O
O
Me
H
O
AcCl
Ph
TBSO
O
O H O H O
H
Ph
H
O
Ph
Me
N
Me
• Another hetero-Diels-Alder reaction
• It looks very similar to the previous reaction but...
• It is believed that only one hydrogen bond activates the aldehyde
• The other is used to form a rigid chiral environment for the reaction
123.702 Organic Chemistry