Download The Diels-Alder reaction

1
The Diels-Alder reaction
Me
CO2Me
+
Me
Me
Δ
CO2Me
+
CO2Me
major
Me
CHO
+
minor
Me
Δ
Me
CHO
+
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
• It is not within the remit of this course to go into detail about this reaction
• We are interested in the stereochemical outcome but need a bit of revision...
• 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
NMe2
CO2Me
CO2Me
+
regioselectivity often follows simple electronic
argument (consider which C is δ+ve or δ–ve)
HOMO
LUMO
NMe2
CO2Me
Advanced organic
2
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
Advanced organic
3
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
Advanced organic
4
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
Advanced organic
5
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
Advanced organic
6
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
Advanced organic
7
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
Advanced organic
8
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
Advanced organic
9
Chiral catalysis and the Diels-Alder reaction II
O
O
+
N
lig. (10%)
Cu(OTf)2 (9%)
H
O
O
O
N
Cl
N
N
Cl
Cl
Cl
O
92% ee
• The oxazolidinone substituent on the dienophile is important
• Good selectivities are only achieved when there are two binding points on the
dienophile
• The two carbonyl groups allow a rigid chelate to be formed & maximise the
commincation of chirality
O
O
BH3 / HOAc
+
OH
O
Ph
H
OMe
OH
OH
O
H
>98% ee
OH
OMe
Ph
Advanced organic
10
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
Advanced organic
11
Organocatalysis and the Diels-Alder reaction II
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
H
O
• 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
Advanced organic
12
Organocatalysis III
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
Advanced organic
13
[3,3]-Sigmatropic rearrangements
R2
R2
R2
heat
X
R1
X
R3
R1
X
R3
R1
R3
• A class of pericyclic reactions whose stereochemical outcome is governed by
•
•
•
geometric requirements of the cyclic transition state
Reactions generally proceed via a chair-like transition state in which 1,3-diaxial
interactions are minimised
General relationship is outlined below...
Indicates that geometry of double bonds important to controlling relative
stereochemistry
R
c
X
a
c
b
d
R2
d
c
a
R
X
b
R2
R
a
X
d
R
X
b
H
the
R2
H
a
b
R2
c
d
Advanced organic
14
Cope rearrangement
Ph
H
Me
Me
Ph
Ph
Me
H Me
91%
Me
Me
H
Me
Ph
Me
Me
Ph
1,3-diaxial interactions
disfavoured
Me H
9%
• A very simple example of a substrate controlled [3,3]-sigmatropic rearrangement is
•
•
•
the Cope rearrangement
To minimise 1,3-diaxial interactions phenyl group is pseudo-equatorial
Note: the original stereocentre is destroyed as the new centre is formed
This process is often called ‘chirality transfer’
Advanced organic
15
Claisen rearrangements
Claisen rearrangement
OEt
OH +
Hg+
O
O
heat
H
Johnson-Claisen rearrangement
OH +
MeO OMe
Me
O
H+
OMe
O
heat
OMe
OMe
Eschenmoser-Claisen rearrangement
OH +
MeO OMe
Me
O
H+
NMe2
O
heat
NMe2
NMe2
Ireland-Claisen rearrangement
O
OH +
Me
O
O
Et3N
Me
R3SiCl
base
O
Me
O
O
heat
OSiR3
• One of the most useful sigmatropic rearrangements is the Claisen
and all it’s variants
O
OSiR3
rearrangement
Advanced organic
16
‘Enantioconvergent’ synthesis
SET reduction gives
most stable alkene
OH
Na
NH3
Me
Me
OH
Me
Me
NMe2
MeO OMe
O
NMe2
Me
O
Me
H
Me
Me
Me
Me
NMe2
Me
Me
Me
≡
H
NMe2
H
NMe2
H
H
i-Pr
i-Pr
O
Me
i-Pr
H
H
Me
O
i-Pr
O
Me
O
Me2N
H
Me
H
Me2N
Me
Me
NMe2
Me
≡
same configuration
H2
Lindlar
cat.
OH
Me
OH
Me
NMe2
MeO OMe
Me
Me
O
NMe2
Me
Me
Me
O
Me
NMe2
O
Me
H
Me
Me
Me
Me
heterogeneous hydrogenation
leads to syn addition of H2
• Both enantiomers of initial alcohol can be converted into the same enantiomer of
•
product
This process (Eschenmoser-Claisen) shows the importance of alkene geometry
Advanced organic
17
Ireland-Claisen reaction
H
1. LDA, THF
2. R3SiCl
O
OSiR3
Me
Me Me
O
O
OSiR3
Me
H
OSiR3
O
Me
H
H
O
Me
Me
OSiR3
Me
Me
O
Me
H
1. LDA,
THF/HMPA
2. R3SiCl
H
O
Me
OSiR3
OSiR3
Me
Me
Me
O
H
O
OSiR3
Me
Me
O
H
Me
OSiR3
Me
• Enolate geometry controls relative stereochemistry
• Therefore, the enolisation step controls the stereochemistry of the final product
Advanced organic
18
Substrate control in Ireland-Claisen rearrangement
methyl group is
pseudo-equatorial
Me
Me
O
O
91% ee
OH
1. LHMDS
2. TMSCl
Me
O
Me
O
H
H
Me
H OTMS
OTMS
OTMS
Me
H OTMS
OTMS
Me
HO2C
Me
98% syn
91% ee
• In a similar fashion to the Cope rearrangement we saw earlier, the Ireland-Claisen
•
•
rearrangement occurs with ‘chirality transfer’
Initial stereogenic centre governs the conformation of the chair-like transition state
Largest substituent will adopt the pseudo-equatorial position
• Once again, the relative stereochemistry is governed by the geometry of the
enolate
Advanced organic
19
Auxiliary control in the Ireland-Claisen rearrangement
N
Ar*
Me
O
N
O
Ar*
Me
Me
LDA
Me
O
O
Me
Me
Li
Me
N
Ar*
Me
Li
N
anti / syn 98:2
94% de for anti
Ar*
Me
NHAr*
Me
Ar*NH2 =
O
OMe
NH2
• Use of chiral auxiliaries allows the control of absolute stereochemistry
• Good news is that it is hard to predict and so will not be examined...
Advanced organic
20
Chiral reagent control in the Ireland-Claisen rearrangement
i-Pr2NEt
CH2Cl2
–78°C
R*2B
OH
O
Me
O
Ph
O
O
Me
Me
+
ArO2S
N
Ph
B
N
warm
Me
>97% ee
Me
SO2Ar
R*2B
Br
OH
O
warm
Et3N
Tol / hexane
–78°C
Me
O
O
O
Me
Me
Me
Me
96% ee
• Funnily enough, it is possible to carry the reaction out under “reagent” control
• Although, it could be argued that this is just a form of temporary auxiliary control!
• Enolate formation (enolate geometry) governs relative stereochemistry
Advanced organic
21
Chiral catalyst control in the Ireland-Claisen rearrangement
Ph
MeAl(OR*)2
O
Si
Me
Me
Ph
Ph
SiMe3
O
O
H
Me
SiMe3
SiMe2t-Bu
MeAl(OR*)2 =
O
O
Al Me
SiMe2t-Bu
• It is also possible to perform the reactions under chiral catalyst control
• Presumably, the Lewis acid coordinates to the oxygen & influences the reactive
conformation thus controlling enantioselectivity
Advanced organic
22
The Heck reaction
R1
X
+
cat. PdX2
R2
R3N
[R33P]
R1 = Ar, ArCH2,
X = Br, I, OTf
R1
R2
• The Heck reaction is a versatile method for the coupling sp2 hybridised centres
• Again it is not the purpose of this course to teach organometallics etc
Br
R3NH Br
L Pd L
oxidative
addition
R3N
H
L
L Pd Br
L
+L
H
L
Pd
Br
Pd Br
Pd(0)
(14e)
Pd(II)
(16e)
L
Pd(II)
(16e)
–L
L
Pd(II)
(16e)
Pd Br
H
syn
addition
β-hydride
elimination
Br
Pd
L
Advanced organic
23
Alkene isomerisation
0.01% Pd(OAc)2
R3N
+
O
I
L
Pd I
δ+
O
δ–
O
100°C
syn
addition
Pd(I)Ln
H
H
O
β-hydride
elimination
Ph
O
L
hydroI palladation
Pd
H
Ph
O
Pd(I)Ln
H
H
Ph
O
O
H Pd L
I
Ph
Ph
O
O
H
Pd(I)Ln
L
Pd
I
H
• β-Hydride elimination is reversible
• This alkenes can ‘walk’ or migrate to give the most stable alkene
• Only restriction is every step must be syn
Advanced organic
24
Enantioselective Heck reaction
Pd[(R)-BINAP]2
proton sponge
OTf
+
O
CO2Et
NMe2 NMe2
O
EtO2C
62%
>96% ee
PPh2
PPh2
proton sponge
(R)-BINAP
Pd(dba)2 (3%), lig (6%)
i-Pr2NEt
+
O
TfO
O
O
PPh2 N
92%
>99% ee
t-Bu
lig
amino acid derivative
• With the use of chiral ligands the Heck reaction can be enantioselective
• Remember that we often see alkene migration
Advanced organic
25
Enantioselective Heck reaction II
TBSO
TBSO
Pd[(R)-BINAP]Cl2
AgPO4, CaCO3
I
N
Me
O
H
78%
82% ee
PPh2
PPh2
O
N
O
Pd2(dba)3
(R)-BINAP
Me
I
O
O
Ag3PO4
N,N-dimethylaniline
Me
N
(R)-BINAP
O
O
71% ee
• Intramolecular variant allows the construction of ring systems
• The silver salt accelerates the reaction and prevents alkene isomerisation
Advanced organic
26
Suzuki-Miyuara reaction
L Pd0 L
–L
R2
reductive
elimination
L Pd0
oxidative
addition
X
R2
R1
L
Pd
X
R1
L
Pd
R2
R2
transmetallation
R1
B(OH)2
• The Suzuki-Miyuara reaction is (normally) the palladium catalysed coupling of an
•
•
alkenyl or aryl halide with an alkenyl or aryl boronic acid
Normally the components should be sp2 hybridised to avoid β-eliminations
Mechanism etc is (surprise surprise) outside the scope of this course but the
wonderful enantioselective examples are not...
Advanced organic
27
Enantioselective biaryl formation
Me
O
B
(PdClC3H5)2
lig1
CsF
+
Me
Me
O
Me
I
PPh2
NMe2
Fe
H
Me
lig1
60%
85% ee
Br
P(O)(OMe)2
+
Pd2(dba)3 (0.2%)
lig2
Me
Me
NMe2
P(O)(OMe)2
PCy2
B(OH)2
95%
86% ee
lig2
• Virtually every (if not every...) reaction we have covered in this course has formed a
•
•
stereogenic centre (central chirality)
These two examples form axially chiral compounds
Please note: both ligands are thought to be mono-dentate (in the active species at
least, although they may be bidentate in ‘resting state’) via the phosphine
Advanced organic
28
Other catalytic enantioselective reactions
Br
O
Ph
Me
N
+
O
Pd2(dba)3 (1%)
lig1
Ph
NaOt-Bu
Me
Me
O
N
i-Pr2P
Me
80%
93% ee
lig1
• Pd(0) chemitry has been utilised in the enantioselective arylation of enolates
• The reaction is related to much of Pd chemistry you have covered
• Below is an example of a chiral variant of the Schrock metathesis catalyst
• The reaction involves desymmetrisation by selective reaction if one disubstituted
alkene
O
O
L2 (10mol%),
PhH, 22°C, 48h
N
Me
N
i-Pr
i-Pr
Ar
Me
Me
Me
91%
98% ee
N
O Mo THF Me
O
Ar
Ph
Me
L2
Advanced organic
29
Enantioselective Negishi reactions
NiCl2•glyme (10mol%),
L1 (13mol%), DMI:THF
(7:1), 0°C
O
Bn
Et
N
Ph
+
hex
ZnBr
O
Bn
Et
N
Ph
hex
90%
95% ee
Br
NiBr2•diglyme
(10mol%), L1
(13mol%), DMA, 0°C
Br
O
+
BrZn
O
O
O
Cl
Cl
82%
91% ee
O
N
i-Pr
O
N
N
L1
i-Pr
• Last year (2005) saw the first examples of catalytic enantioselective Negishi couplings
• The system still has some limitations but is an exciting development
• On a practical note, many of the reactions above were run in air!!!
Advanced organic
30
Summary of methods for stereoselective synthesis
Method
Advantages
Disadvantages
resolution
both enantiomers available maximum 50% yield
synthesis of (–)-propranolol
chiral pool
100% ee guaranteed
synthesis of (R)-sulcatol
often only 1 enantiomer
available
Examples
chiral auxiliary often excellent ee’s; built in extra steps to introduce
resolving agent
and remove auxiliary
oxazolidinones
chiral reagent
alpine-borane®, Brown
allylation reagents
often excellent ee’s;
stereoselectivity can be
independent of substrate
control
chiral catalyst economical; only small
amounts of recyclable
material used
only a few reagents are
successful and often only
for a few substrates
only a few reactions are
asymmetric hydrogenation;
really successful; frequently Sharpless epoxidation
a lack of substrate
generality
• Hopefully this course has shown that the area of stereoselective synthesis (or more
particularly, methodology for stereoselective synthesis) is a vast & fascinating topic
• There are many reactions we have not covered (there is already far too much
material in the course)
• I hope you found the course as interesting as I did...
Advanced organic