1

The Diels-Alder reaction

Me
Me Me
CO2Me
CO2Me
+ +

CO2Me
major minor
Me CHO Me Me CHO

+ +
CHO
toluene, 120C, no catalyst 59 : 41 Lewis acid
benzene, 25C, SnCl4 96 : 4 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
NMe2
CO2Me CO2Me
CO2Me
+

regioselectivity often follows simple electronic

argument (consider which C is +ve or ve) HOMO LUMO Advanced organic
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Endo vs. exo selectivity

secondary
A orbital overlap
H A
H A
C
endo
C H
favoured
B B D
A C H
D D B
C
endo
A A
D H
H A
C
B exo
C

B C B D
H D
H B
D
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 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

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Diels-Alder reaction
A A A A A A H
H H H
H H C
D
C C H C C H
B B B B B H
D D H D D H B H
draw a add the add dienophile remember other do reaction should be able to see
cube diene (endo product has substituents (make new relative stereochemistry
substituents directly present bonds)
under diene)

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

H H
MeO MeO
OMe
+
H H
NO2
O2N NO2

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Chiral auxiliaries on the dienophile

O O
BnOH
+ +
Cl OBn
O OBn
O OBn
achiral achiral
+ 1 : 1 mixture of enantiomers
dienophile 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 Cl O O
O
R
O R N O Et2AlCl BnOH
+ O N O R
HN O Me
O OBn
Me
Me
Me Me
Me chiral dienophile achiral single(ish) single
diene diastereoisomer enantiomer
(S)-valine R = H 86% de
derivative R = Me 90% de
>98% endo
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Explanation of diastereoselectivity
s-cis
favoured

Et2
O Al O
H
N O Et2AlCl2
Et Et
O O Me Et2
Al
Me O O
O Al O
N O H
N O N O

Me Et2 Me
Me
Me O Al O Me
H Me
N O

Me
s-trans lower face
disfavoured Me 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
Dienes approach maximises secondary orbital overlap and favours endo product

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Camphor-derived auxiliary

Me Me R
O TiCl4 H
78C
N R +
S O O N
O O2S
Me Me
R = H 99% de
R = Me >97% de
>98% endo

Me Me
R
Me Me
R
N
S O N
O O Ti SO2 O
Ln

A range of auxiliaries can be utilised

Most give good diastereoselectivities

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Chiral auxiliaries II
phenyl group
blocks lower face Me
O Me
H
H O
Me Me BnO
O Me
AlCl3
+
O
OBn H

BnO
Me
Me O Me CO2R

diene approaches O
from the top

BnO Me

It is possible to attach the chiral auxiliary to the diene as well

O
O O OH MeO
OMe O O OH
O B(OAc)3 H
H Ph
H Ph +

O H
O
>95% de
endo
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Chiral catalysis and the Diels-Alder reaction

O Me H O Me
MeO MeO
cat.
+ N Br N Br

O H O
>97% ee

Me Me

Me Me

N N
F3CO2S Al 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

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Chiral catalysis and the Diels-Alder reaction II

O O lig. (10%) H
Cu(OTf)2 (9%) O
+
N O Cl N N Cl
O N
O
Cl Cl
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 Ph
H
BH3 / HOAc
+ OH
OH
OMe H
OH O OH O OMe
>98% ee Ph

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Organocatalysis and the Diels-Alder reaction

OMe cat. (20%)
O COEt
HClO4
+
Et OMe
96% ee
endo / exo >200 : 1
Me
O N

Ph N O
O Me H Me
N O Ar
N Me
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

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Organocatalysis and the Diels-Alder reaction II

OMe O 1. cat. (10%) O
Ph 2. TFA
+ Ph
H O
TBSO O Ph Ph O
87% ee
Tf N N Tf
H H TFA

Ph H Me
Ph O
Tf
N
N Tf O
MeO H
O O H TBS Ph
O
Ph H O
TBSO

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

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Organocatalysis III
TBSO
1. cat. (10%) O Ph
H Ph 2. AcCl
+ O
O
N >98% ee
Me Me Ph Ph
O
Me OH
Me OH
O AcCl
Ph Ph

H TBSO Ph
O O H
O
O H O H O
Ph
H
N
Me 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
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[3,3]-Sigmatropic rearrangements
R2 R2 R2
heat
X X X

R1 R3 R1 R3 R1 R3

A class of pericyclic reactions whose stereochemical outcome is governed by the

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 c R
a a
X d d X
c X R X R
a
a b R2 b b R2
b
d R2 H R2 H c d

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Cope rearrangement
H Ph
Me
Me
Ph

Ph Me H Me
91%
Me

Me H Me
Ph
Me
Me

Ph Me H
9%
1,3-diaxial interactions
disfavoured

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

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Claisen rearrangements
Claisen rearrangement

OEt Hg+ O heat O

OH +
H

Johnson-Claisen rearrangement

MeO OMe O O
OH + H+ heat
Me OMe OMe OMe

Eschenmoser-Claisen rearrangement

MeO OMe O O
OH + H+ heat
Me NMe2 NMe2 NMe2

Ireland-Claisen rearrangement

R3SiCl
O O Et3N O O heat O
OH + base

Me O Me Me O OSiR3 OSiR3

One of the most useful sigmatropic rearrangements is the Claisen rearrangement

and all its variants Advanced organic
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Enantioconvergent synthesis
SET reduction gives
most stable alkene
NMe2 NMe2
MeO OMe
OH Na OH
Me NH3 Me Me NMe2 O O
Me H
Me Me
Me Me Me Me Me
Me Me

H NMe2 H NMe2 Me O
O O
H H
i-Pr H i-Pr H
i-Pr O i-Pr O Me
Me2N Me2N NMe2
H Me H Me
Me Me Me

same configuration
H2 NMe2 NMe2
MeO OMe
OH Lindlar OH Me
Me cat. Me Me NMe2 O O
Me Me
Me Me
Me Me Me H
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
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Ireland-Claisen reaction

H H
1. LDA, THF O OSiR3 OSiR3 O
2. R3SiCl
Me Me
Me Me H H Me OSiR3
O O
OSiR3 Me
O Me Me

Me O
1. LDA, H H
Me
THF/HMPA O OSiR3 OSiR3 O
2. R3SiCl Me Me
Me OSiR3 Me O Me Me OSiR3
O
Me Me
H H

Enolate geometry controls relative stereochemistry

Therefore, the enolisation step controls the stereochemistry of the final product

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Substrate control in Ireland-Claisen rearrangement

methyl group is
pseudo-equatorial

Me Me Me H Me H
1. LHMDS OTMS
O O
2. TMSCl Me
O Me Me HO2C
OH
H OTMS H OTMS
O Me
OTMS OTMS
91% ee 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

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Auxiliary control in the Ireland-Claisen rearrangement

Ar*
N
Me
O
Ar* Me Me
N Me
Me LDA O O
O Me Me anti / syn 98:2
94% de for anti
N N
Me Li Ar* Li Ar*
Me
NHAr*

Me O

OMe
Ar*NH2 =
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...
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Chiral reagent control in the Ireland-Claisen rearrangement

i-Pr2NEt R*2B OH
CH2Cl2 O
78C warm Me
Me O
O

O Ph Ph Me
Me
Me >97% ee
O + N N
ArO2S B SO2Ar
R*2B
Me O OH
Br
warm Me
O O
Et3N Me
Tol / hexane
78C 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

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Chiral catalyst control in the Ireland-Claisen rearrangement

Ph
Ph Ph
MeAl(OR*)2
O
Me H
O Si
Me SiMe3 O SiMe3
Me

SiMe2t-Bu

O
MeAl(OR*)2 = Al Me
O

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

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The Heck reaction

cat. PdX2
R1 + R1
X R2 R2
R3N
R1 = Ar, ArCH2, [R33P]
X = Br, I, OTf

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
R3NH Br Br
L Pd L
R3N oxidative
addition

H L
L Pd Br Pd(0) Pd Br
L (14e) L

+L Pd(II) Pd(II)
(16e) (16e)
L L
H L
Pd
Br Pd(II)
(16e) Pd Br

H
-hydride syn
elimination addition
Pd
Br L Advanced organic
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Alkene isomerisation
0.01% Pd(OAc)2
R3N
+
O
O 100C
I

L Ph
syn -hydride Ph L hydro-
Pd I I palladation
addition Pd(I)Ln elimination Pd
+ O Pd(I)Ln
H O H
O H
O
H H

Ph
Ph Ph

O
O O L
O
Pd
H Pd L I
H Pd(I)Ln H
I

-Hydride elimination is reversible

This alkenes can walk or migrate to give the most stable alkene
Only restriction is every step must be syn
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Enantioselective Heck reaction

OTf Pd[(R)-BINAP]2 NMe2 NMe2

proton sponge
+ O PPh2
CO2Et O PPh2
EtO2C
62%
>96% ee proton sponge
(R)-BINAP

Pd(dba)2 (3%), lig (6%)

i-Pr2NEt O
+
O O
TfO PPh2 N
92% t-Bu
>99% ee lig
amino acid derivative

With the use of chiral ligands the Heck reaction can be enantioselective
Remember that we often see alkene migration

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Enantioselective Heck reaction II

TBSO
TBSO
Pd[(R)-BINAP]Cl2
AgPO4, CaCO3

I N O H
Me
78%
82% ee PPh2
PPh2
O Me
Pd2(dba)3 O
Me N
N (R)-BINAP (R)-BINAP
O
I
Ag3PO4 O
O N,N-dimethylaniline
O
71% ee

Intramolecular variant allows the construction of ring systems

The silver salt accelerates the reaction and prevents alkene isomerisation

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Suzuki-Miyuara reaction
L Pd0 L

L
R2 reductive oxidative X
elimination L Pd0 addition

R2
R1

L X
Pd R1 Pd R2
L

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 -eliminations
Mechanism etc is (surprise surprise) outside the scope of this course but the
wonderful enantioselective examples are not...
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Enantioselective biaryl formation

(PdClC3H5)2
lig1
CsF Me PPh2
Me +
Fe NMe2
Me Me
B H
O O I Me
lig1
60%
85% ee

Br Pd2(dba)3 (0.2%)
P(O)(OMe)2 lig2 Me
+ NMe2
Me 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
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Other catalytic enantioselective reactions

O Br Pd2(dba)3 (1%) O
lig1 Me
Ph Me + Ph
N O
N
NaOt-Bu Me 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%), i-Pr i-Pr
N
N PhH, 22C, 48h Ar N
Me
Me Me O Mo THF Me
O
Me Ar
Ph
Me
91%
98% ee
L2

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Enantioselective Negishi reactions

NiCl2glyme (10mol%),
O L1 (13mol%), DMI:THF O
Bn Et (7:1), 0C Bn Et
+ hex ZnBr
N N
Ph Br Ph hex
90%
95% ee
NiBr2diglyme
Br (10mol%), L1
O O
(13mol%), DMA, 0C
+ O
BrZn O
Cl Cl
82%
91% ee

O O
N
N N

i-Pr 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!!!
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Summary of methods for stereoselective synthesis

Method Advantages Disadvantages Examples

resolution both enantiomers available maximum 50% yield synthesis of ()-propranolol

chiral pool 100% ee guaranteed often only 1 enantiomer synthesis of (R)-sulcatol

available

chiral auxiliary often excellent ees; built in extra steps to introduce oxazolidinones
resolving agent and remove auxiliary

chiral reagent often excellent ees; only a few reagents are alpine-borane, Brown
stereoselectivity can be successful and often only allylation reagents
independent of substrate for a few substrates
control

chiral catalyst economical; only small only a few reactions are asymmetric hydrogenation;
amounts of recyclable really successful; frequently Sharpless epoxidation
material used 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