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200910ch3b0handout.ppt
1. 1
Professor M. Wills CH3B0 Understanding Organic Synthesis
Year 3 Understanding Organic Synthesis Course 2009-2010;
Professor Martin Wills
Contents of the course:
Introductory lecture describing the contents of the course.
Pericyclic reactions and Woodward-Hoffmann rules for concerted cycloadditions,
electrocyclisations and sigmatropic rearrangements. FMO theory.
Baldwin's rules and related cyclisation reactions.
Stereoelectronic effects: How such effects can be moderated to the
advantage of the synthetic chemist.
Additional reading:
Clayden et al.; “Organic Chemistry” by Clayden, Greeves, Warren and Wothers, OUP, 2001.
R. B. Woodward and R. Hoffmann in Angew. Chem., Int Edn. Engl., 1969, 8, 781.
“Molecular Orbitals and Organic Chemical Reactions”, Ian Fleming, Wiley, 2009 (new edition).
Note: Since not all the material is in the handout, it is essential to attend ALL the lectures.
2. 2
Introduction: Unexpected results of cyclisation reactions.
Pericyclic reactions are; “Any concerted reaction in which bonds are formed or broken in a
cyclic transitions state”. (electrons move around in a circle).
i.e. there is a single transition state from start to finish, in contrast to a stepwise reaction.
Transition state
reaction co-ordinate
Energy
starting
material
product
Concerted reaction
Transition states
reaction co-ordinate
Energy
starting
material product
Multistep reaction
inter-
mediate inter-
mediate
Properties of pericyclic reactions:
(a) Little, if any, solvent effect (b) No nucleophiles or electrophiles involved.
(c ) Not generally catalysed by Lewis acids.
(d) Highly stereospecific. (e) Often photochemically promoted.
3. 3
Examples of pericyclic reactions:
1) Electrocyclisation reactions – Linear conjugated polyene converted into a cyclic product
in one step. The mechanism is not particularly surprising, but the stereochemistry changes depending
on whether heat or irradiation (typically UV-light) is used to promote the reaction. e.g.
Me
Me
heat Me
Me
Me
Me
irradiation (h) Me
Me
2) Cycloaddition reactions – Two linear conjugated polyenes converted onto a cyclic product
in one step. Again, the stereochemistry of the reaction is remarkably reproducible. e.g.
(two cis or Z alkenes)
+ but no
irradiation
(h)
4. 4
Examples of pericyclic reactions, continued:
Example of a cycloaddition to give a 6-membered ring:
3) Sigmatropic rearrangement reactions: These involve a concerted migration of atoms or of groups of
atoms. E.g. migration of a s-bond. The numbering refers to the number of atoms in the transition state on either
side of where bonds are made or broken.
H H
This would be classified as a [1,2]-sigmatropic
rearrangement (or shift).
[1,2]
This would be classified as a [1,5]-sigmatropic
rearrangement (or shift).
H
Me
H
Me
[1,5]
(one cis or Z alkene,
and a E,E-diene)
heat
Me
Me
Me
Me
O
O
O
O
O
O
One diastereo-
isomer is favoured.
(Diels-Alder reaction!)
5. 5
Examples of pericyclic reactions, continued:
3) Sigmatropic rearrangement reactions: A high level of stereochemical control is often observed.
This would be classified as a [3,3]-sigmatropic
rearrangement (or shift).
Me
Me
Me
Me
only, no:
Me
Me
observed
heat
[3,3]
Other concerted reactions:
a) Ene reaction (synthetic chemists), or Norrish rearrangement (photochemists) or
McLafferty rearrangement (for mass spectrometrists).
b) Decarboxylation reaction:
O
H
O
H
enol
alkene
n.b. enolate = O
O
H
O C O
H
O
+
6. 6
Woodward-Hoffmann theory for prediction of the stereochemistry
of pericyclic reactions: Electrocyclisations.
The ‘Woodward-Hoffmann’ theory explains the stereochemical outcome of pericyclic reactions by
considering the symmetry of the ‘frontier orbitals’ which are involved in the reaction. These are the
orbitals which actually contribute to the bond making and breaking process. They are also the
‘outermost’ orbitals (of highest energy) in a structure, hence the term ‘frontier’.
Electrocyclisations.
Consider the conversion of butadiene into cyclobutene: The mechanism is quite simple, but the
stereochemistry of the product is directly related to (i) the stereochemistry of the starting material
and (ii) whether heat or irradiation is employed to promote the reaction.
irradiation
(h) or heat ()
irradiation (h)
Heat (
E,E
E,E
cis
trans
E,Z
E,Z
Heat (
irradiation (h)
7. 7
What is happening in the cyclisation is that p-orbitals (which form the p-bonds) are combining
in order for a new s bond to be formed between the ‘ends’ of the conjugated system. However,
in order for this process to happen efficiently, it is necessary for the orbitals with the same
wave-function sign (phase) to ‘join up’. In order to work out where these are, a quick analysis
of the four molecular orbitals (formed from the 4 atomic – p – orbitals) is required.
Woodward-Hoffmann theory applied to cyclobutene formation.
Note: ‘n’ atomic orbitals, when combined, result in the formation of ‘n’ molecular orbitals.
Low-energy orbitals are generally bonding and high energy ones are antibonding. Because the
lower orbitals are filled in the butadiene system, the molecule is stable.
Note: the view of the
butadiene is 'edge-on'
with the single bond
'further back'.
H H
H H
H H
Energy
There are 4
electrons in this
bonding system.
Filling orbitals from
the lowest first soon
reveals the nature
of the outermost or
'frontier' orbital.
0 nodes
1 nodes
2 nodes
3 nodes
8. 8
Woodward-Hoffmann theory applied to cyclobutene formation.
So it is now possible to see what happens when butadiene is converted to cyclobutene. In order for
the new sigma bond to be formed between the newly-connected carbon atoms, the ends of the
molecule have to ‘rotate’ in a very specific way for this to happen. We only need to consider the
highest-energy molecular orbital (highest occupied molecular orbital, or HOMO):
The result is that the ‘X’ groups end up trans to each other, as do the ‘Y’ groups.
Because this involves a concerted rotation of each end of the diene in the same direction (clockwise is
illustrated, although anticlockwise would give same result) this is referred to as a ‘conrotatory’
process. It is also referred to as ‘antarafacial’ because the orbitals which link up have identical signs
on opposite faces of the diene.
H H
X X
Y Y
X X
Y Y
X
X
Y
Y X
X
Y
Y
H
H
X Y
X
Y
overall: X
Y Y
X
heat
X Y
Y X
Orbitals of same
sign form a bond
(HOMO)
9. 9
Woodward-Hoffmann theory applied to cyclobutene formation under
photochemical conditions.
Under photochemical conditions, the orbitals are not changed in structure, but an electron is
excited by one level. As a result, a new ‘highest occupied molecular orbital’ or HOMO, is
defined. The photochemically-excited molecules, whilst not as numerous, are of much higher
energy than the unexcited molecules, and dominate the resulting chemistry.
Note: the view of the
butadiene is 'edge-on'
with the single bond
'further back'.
H H
H H
H H
Energy
thermal
(unexcited)
h
photochemically
excited
Now (see the next page), the manner in which the molecule changes shape upon cyclisation is
very different.
10. 10
Cyclisation under photochemical conditions: In the new HOMO, the ‘ends’ of the orbitals with
the same sign are on the same face of the diene, or ‘suprafacial’. In order for these to ‘join up’
to form a bond, the ends of the alkene have to rotate in opposite directions. This process is
described as ‘disrotation’.
i.e., A suprafacial, disrotation process.
n.b. Note that the hybridisation of the carbon atoms at the ends of the diene changes from sp2 to
sp3 in the process.
H H
X X
Y Y
X X
Y Y
X X
Y
Y
Y
X
X
Y
H
H
Y Y
X
X
overall: X
Y Y
X
h
Y Y
X X
Orbitals of same
sign form a sbond
(photochemical
irradiation)
11. 11
Woodward-Hoffmann theory applied to cyclobutene formation – conclusion:
It is now possible to understand all the stereochemical observations for the butadiene
cyclisations which were described at the start of the section:
Note how antara/conrotation go together, as do supra/disrotation. Logical really.
Note, also, that the rules also work in the reverse direction, e.g.
irradiation (h)
E,E cis
E,Z
Heat (
suprafacial
disrotation
antarafacial
conrotation
irradiation (h)
Heat (
E,E
E,E
cis
trans
E,Z
E,Z
Heat (
irradiation (h)
suprafacial
disrotation
suprafacial
disrotation
antarafacial
conrotation
antarafacial
conrotation
Although it should be noted that sometimes stereocontrol is lost due to competing radical reactions.
12. 12
Woodward-Hoffmann theory applied to cyclohexene formation:
Now that you can see how the theory applies to butadiene, try working out the stereochemical
outcome of a triene electrocyclisation, the mechanism of which is given below:
Heat (
X
X
(E,Z,E)
irradiation (h)
X
X
X
X
Stereochemistry? Stereochemistry?
The mechanism, of course, will be the same whether heat or photochemically-induced. The
difference will be in the observed stereochemistry of the products.
Hopefully you will appreciate that the central alkene needs to be ‘Z’ configuration in order for the
process to work. Why not revise E and Z notation to be on the safe side?
In order to solve the problem, you need to be able to write down the possible molecular orbitals
available to the p-system of the molecule, put them in order and fill them with electrons.
Hint; as the energy of the orbital increases, so does the number of nodes.
We shall work through the solution to this in a lecture. Then you should try the same for a
tetraene and pentene. Can you see a pattern?
13. 13
Synthetic applications of electrocyclisation reactions:
The conversion of ergosterol to vitamin D2 proceeds through a ring-opening (reverse)
electrocyclisation to give provitamin D2, which then undergoes a second rearrangement (a [1,7]-
sigmatropic shift). Stereochemical control in the sigmatropic shift process will be described in a
later section of this course.
H
H
HO
ergosterol
sunlight
photochemically-
promoted electrocyclisation
(antarafacial, conrotation)
H
HO
provitamin D2
H
HO
H
[1,7]-sigma-
tropic shift.
vitamin D2
14. 14
Synthetic applications of electrocyclisation reactions:
A spectacular example of the power of electrocyclisation reactions is in the biosynthesis of
endiandric acids, which are marine natural products.
All of these are derived from the linear polyene shown below:
HO2C
Ph
E
Z
Z
E
E E
The double-bond stereochemistry is critical.
H H
HO2C
Ph
Endiandric acid D
H H
HO2C
Ph
Endiandric acid E
H H
HO2C
H
H
H
Ph
Endiandric acid A
15. 15
Synthetic applications of electrocyclisation reactions:
The endiandric acids are biosynthesised through the following process:
The first two steps are electrocyclisations, whilst the final step, to make acid A, is a cyclo-
addition (Diels-Alder reaction). There will be more discussion of cycloadditions later in this
course. The stereochemical control in the first two steps is addressed in the next slide.
H H
HO2C
Ph
Endiandric acid E
H H
HO2C
H
H
H
Ph
Endiandric acid A
HO2C
Ph
HO2C
Ph
conrotation
(antarafacial)
disrotation
(suprafacial)
Diels-Alder
(cycloaddition
reaction
4n
heat (
4n+2 heat ()
17. 17
K. C. Nicolaou’s research group achieved a direct synthesis of endiandric acid A in the
laboratory. This was achieved by the reduction of the two alkyne groups in the molecule
below by Lindlar catalyst (cis- alkenes are formed selectively) which then formed the product
upon heating in toluene. A pretty impressive ‘one-pot’ cyclisation.
H H
MeO2C
H
H
H
Ph
Endiandric acid A
(methyl ester derivative)
MeO2C Ph
MeO2C
Ph
(not isolated)
H2 Lindlar catalyst
(Pd/CaCO3, + Pb or quinine poison)
100o
C
Toluene
18. 18
Electrocyclisation reactions of cations and anions also follow the
Woodward-Hoffmann rules.
All you need to know is the number of electrons involved (i.e. 4n or 4n+2) and whether
the reaction is photochemical or thermal:
The reaction above is the Nazarov cyclisation (usually carried out under acidic/thermal
conditions). Note that the position adjacent to the ketone is a mixture of isomers in each case.
Only the relative stereochemistry between the lower hydrogens is controlled.
Mechanism:
irradiation (h)
O
Heat (
and acid
for catalysis
(AcOH or H3PO4)
O O
H H H H
H H
trans
cis
O
H
O
H
O
H
next
slide
19. 19
Nazarov cyclisation, cont....
O
H H
H
O
H
H
H
H
O
H
H
H
-H
enol ->
ketone
Stereochemistry in the key cyclisation step:
O H 4n, thermal
hence
conrotation,
antarafacial
O H
H
H
O
H
H
H
H
H H
Note: although drawn as a localised cation, the positive
charge is spread over five atoms through a delocalised
p system of p-orbitals. There are a total of 4 electrons
in the p system (i.e. two in each alkene), hence it is a
4n electron system, and obeys the rules as usual.
20. 20
Woodward-Hoffmann theory for prediction of the stereochemistry
of pericyclic reactions: Cycloaddition reactions.
In cycloaddition reactions, the situation is slightly different because a) two molecules are used
and b) electron flow takes place from the highest occupied molecular orbital (HOMO) of one
molecule to the lowest unoccupied molecular orbital (LUMO) of the other. The stereochemistry
therefore follows from the wavefunction signs of the orbitals on each molecule.
Consider the reaction of a butadiene with an alkene (the Diels-Alder reaction):
The reaction is usually heat-promoted,
but sometimes it is carried out photochemically.
1) Diene must be in the s-cis conformation:
s-cis s-trans
This will react: But not this:
(ends are too
far apart)
More details of the Diels-Alder reaction.
21. 21
2) Dienophiles with electron-withdrawing groups (EWG) react faster:
Me Me
CO2Me
O
OMe
CO2Me
O
OMe
O
OMe
CO2Me
slow
fast
This is because the electron-
withdrawing group reduces
the LUMO energy and
improves the overlap with the
orbitals in the diene – more
information later in course.
3) The reaction is stereospecfic:
MeO2C
CO2Me
CO2Me
CO2Me
MeO2C
CO2Me
CO2Me
CO2Me
22. 22
3) The reaction is stereospecific cont...
MeO2C
CO2Me
CO2Me
CO2Me
Ph
Ph
Ph
Ph
heat
4) With unsymmetrical dienes, the reactions are regioselective:
CO2Me
OMe
(electron
donating
group)
(electron
withdrawing
group) CO2Me
OMe OMe
CO2Me
not:
CO2Me
not:
MeO
CO2Me
MeO CO2Me
MeO
CO2Me
OMe
Due to size of MOs, and distribution of partial charges:
MOs closely matched in size react with each other more efficiently (stepwise analogy).
CO2Me
MeO
CO2Me
OMe
CO2Me
MeO
+
+
+
+
+
-
-
-
-
Please note this correction to the handout:
23. 23
All these observations can be explained by considering the orbitals involved in the reactions:
In this Diels-Alder reaction the reagents approach each other in a ‘face to face’ manner, i.e. so
that the p- orbitals of the p-system can combine with each other. The relevant orbitals are
shown below:
H H
H
H
H H
H
H
LUMO
HOMO
Alkene Butadiene
H H
H
H
H H
H H
H
H
H H
LUMO
HOMO
5) Endo-product often favoured:
O
O
O O
O
O
+
Two isomers can be formed:
O
O
O
ENDO
MAJOR
H
H
EXO
MINOR H
H
O
O
O
In a kinetically controlled (product is fastest to form, irreversible) the ENDO is favoured but for reversible
reactions (thermodynamic control) the EXO may dominate e.g. with furan.
24. 24
Woodward-Hoffmann theory for prediction of the stereochemistry
of pericyclic reactions: Cycloaddition reactions.
So the following combinations can be employed in the suprafacial cycloaddition reaction:
In both cases, phases of the wavefunctions on the orbitals are matched so that the reagents can
approach each other in a face to face manner and also form bonds easily.
In practice, it is usually the combination of diene HOMO with alkene LUMO which leads to the
product, rather than the diene LUMO and alkene HOMO. Electron-withdrawing groups on the
alkene lower its LUMO energy and improve the matching to the diene HOMO. In turn this
increases the reaction rate. Hence, electron-withdrawing groups on an alkene generally increase
the reaction rate, often very significantly. As might be predicted, electron-donating groups on
the diene also improve the rate – by pushing its HOMO energy closer to that of the alkene
LUMO (see next slide).
H H
H
H
H H
H
H
LUMO
HOMO
Alkene
Butadiene
H H
H
H
H H
H H
H
H
H H
LUMO
HOMO
25. 25
Diels-Alder reaction: energetics:
H
H
Alkene with
e-withdrawing groups
Butadiene
H H
H
H
H H
Energy
H H
H
H
Alkene
O
O
O
HOMO
HOMO
HOMO
LUMO
LUMO
More closely-matched orbitals give a greater energetic benefit when combined. Hence the
closely related butadiene HOMO and alkene LUMO represent the favoured combination.
When electron-withdrawing groups are present on the alkene, the benefit is even greater
because the HOMO/LUMO levels are even closer. Lewis acids speed it even further.
The Diels-Alder reaction proceeds in a suprafacial manner, i.e. the reagents add together
in a perfectly-matched face-to-face fashion.
Please note: the terms ‘dis- and conrotation do not apply to cycloadditions.
26. 26
Woodward-Hoffmann theory for prediction of the stereochemistry
of cycloaddition reactions:
If you examine [2+2] and [4+4] cycloadditions, you will find that the combination of a HOMO
and a LUMO results in an antarafacial component. Often, as a result, the reactions simply fail
under thermal conditions, although they might well succeed using photochemical methods.
H H
H
H
H H
H
H
LUMO
HOMO
H H
H
H
H H
H H
H
H
H H
LUMO
HOMO
[2+2]
[4+4]
thermal
H H
H
H
H H
H
H
LUMO
HOMO
H H
H
H
H H
H H
H
H
H H
LUMO
HOMO
[2+2]
[4+4]
photo-
chemical
(excited state)
(excited state)
antara-
facial
supra-
facial
antibonding antibonding
no reaction no reaction
rapid reaction rapid reaction
27. 27
Woodward-Hoffmann theory for prediction of the stereochemistry
of cycloaddition reactions: summary of the rules:
No. electrons
4n
4n+2
Thermal
Antarafacial
Suprafacial
Photochemical
Suprafacial
Antarafacial
Ring size
4,8,12…
6,10,14…
Note…the rules also work in reverse:
Although you might also get competing radical reactions:
H
H
Me
Me
heat
+
Me
Me
H Me
Me
. .
H
H
Me
Me
heat
+
Me
Me
antarafacial
28. 28
[2+2] cycloadditions involving ketenes; an exception to the Woodward-
Hoffmann rules.
This is an important exception to the Woodward-Hoffmann rules which normally insist that [2+2]
additions proceed in a (not very favourable) antarafacial manner. The trick here is that the ketene
uses both the C=C and C=O p-orbitals in the reaction, through a ‘twisted’ transition state.
C
O
Cl
Cl
O
Cl
Cl
H
H
ketene
C O
Cl
Cl
O
Cl
Cl
O
H H
How would you make a ketene?
n.b useful for beta-lactam synthesis:
R
N
Ar
C
O
H
OPh
R
N O
OPh
ketene
Ar
Some examples of Diels-Alder reactions will be given at this stage
29. 29
Endo selectivity in the Diels-Alder reaction.
e.g.
O
OMe
+
O
MeO
MeO2C
H
H
endo -CO2Me is on
same side of molecule
as the double bond.
H
Primary orbital
interaction creates
bonds
Secondary orbital
interaction
controls
stereochemistry
The reaction of an alkene bearing a carbonyl group with a 1,3-diene is known to proceed with
a high degree of endo selectivity. What this means is that the product is formed through a
transition state in which the carbonyl group overlaps with the diene, a conformation which is
favoured by a secondary orbital interaction:
When attempting to answer a question in this area, first redraw the molecules with the
carbonyl underneath the diene as shown below, then draw the cyclised product without
altering the positions of the groups. Finally redraw a tidy' version with the same relative
stereochemistry. Note: Ys and Bs are on the same side.
(see next slide)
30. 30
Y Y
X
X
B
B
A CO2Me
Y Y
X
X
B
B
A CO2Me
X
X
A CO2Me
Y Y
B B
line up form ring redraw
Example: Intramolecular version
MeO2C
Y
Y
X X'
B B'
A
MeO2C
(Y=H, X=Me, X'-B' is
three carbon bond, A, B=H)
Y
Y
X X
B B
A
MeO2C
X X
A
MeO2C
Y
Y
B
B
Me
H
H
MeO2C
H
H
redraw
replace
groups
Don't redraw again
Remember:
try to redraw the molecule
as few times as possible as
each will result in a higher
chance of errors slipping in.
31. 31
Make sure you can draw the transition state for the following process:
+ O
O
O
O
O
O
H
H
Endo is major
product
O
O
O
H
H
exo product is minor
side-product
Intramolecular Diels-Alder reactions are very powerful methods for constructing target molecules
(try the one below):
Me
MeO2C
H
H
Me
MeO2C
heat
One step: 2 C-C bonds,
4 chiral centres.
These reactions are often catalysed by Lewis acids (see section on the orbitals involved in Diels-
Alder reactions.
32. 32
Application of the Diels-Alder reaction to Taxol synthesis.
O
O
OH
HO
O
O
Ph
O
Ph
NHBz
OH
O
AcO
AcO
H
Taxol
A possible approach (model system):
O
H
O
H H
Taxol is a potent anti-
cancer compound
How might you be able to construct the substrate?
33. 33
Further applications of Diels-Alder reactions: Alkaloid synthesis:
N
H
O
OBn Bn=CH2Ph
CHO
+
N
H
CHO
O
OBn
P
O
nPr
O
MeO
MeO
base
(Wadsworth-Emmons)
N
H
O
OBn
Diels-
Alder
O
nPr
H2, Pd/C
(removes CO2Bn
and reduces alkene)
NH2
O
nPr H+
(catalytic)
N
H
H
nPr
not isolated
NaBH4
(reduces C=N
N
H
H
H H
Pumiliotoxin C
('poison arrow' toxin)
regio and stereo-controlled
34. 34
Hetero Diels-Alder reactions can be useful too:
Three component
Cycloadditions:
N
+
N N
[2+2+2]
4n+2 electron
process.
3-body collision
Is unlikely.
O
OMe
Me3SiO
O
OMe
Me3SiO
O
OMe
Me3SiO
+
Danishefsky
diene.
A novel approach to
the synthesis of
carbohydrates.
BnO BnO BnO
35. 35
1,3-Dipolar cycloaddition reactions
A similar cycloaddition of nitrile oxides provides a method for the synthesis of 3-hydroxy
ketones, all these reactions involve 4n+2 electrons and are suprafacial:
O
N
Ph
Ph Ph
HO
NH
Ph
Ph Ph
Zn(s)
(reducing
agent)
O
N
Ph
Ph Ph
O
N
Ph
Ph
Ph
[3+2]
cycloaddition
The cycloaddition of nitrones to alkenes (below) is a 6-electron process which proceeds in a
suprafacial manner. The cycloaddition product can be reductively opened, thus providing a
stereoselective method for the synthesis of 1,3-aminoalcohols.
O
N
Ph
Ph Ph
Zn(s)
(reducing
agent)
O
N
Ph Ph
O
N
Ph
Ph
[3+2]
cycloaddition
HO
N
Ph
Ph Ph
Zn(s) (reducing
agent) H+
/H2O
HO
O
Ph Ph
36. 36
The Ene reaction; a type of cycloaddition
The ene reaction involves a cycloaddition between two alkenes, but with the formation of only a
single C-C bond. A C-H bond is also formed in the process:
O
H
O
O
O
H
O
O
+ O
O
O
H
4n+2 electrons
suprafacial
O
O
O
H
(sp3
)
O
O
O
H
LUMO
HOMO
LUMO
More complex as it
involves 3 molecular
orbital systems.
Orbital picture:
37. 37
Menthol is prepared through an ene reaction:
The reaction below uses a mild Lewis acid. The chirality of the product comes entirely from the
single chiral centre of the starting material. Note that the lone pair on the carbonyl oxygen is
available for participation in this cyclisation.
OH OH
H2, Pd/C
O O
H
via
ZnBr2
ZnBr2
(catalyst)
H
O
H
O
ZnBr2
H
O
ZnBr2
L-menthol
LUMO
HOMO
LUMO
This process allows menthol to be made more efficiently than through extraction from natural sources.
How would you make the starting material?
38. 38
This time the rules will be given
first, then the examples:
Woodward-Hoffmann theory for prediction of the stereochemistry
of pericyclic reactions: Sigmatropic reactions.
H
H
Me Me
H
Me a [1,3] sigmatropic shift
(or rearrangement)
Thermal conditions:antarafacial
(disfavoured)
Photochemical conditions:suprafacial
(favoured)
Me
H
Me
H
H
H
'H' needs to migrate to other face
(difficult)
'H' is on correct side for easy migration
H
H
H H
H H
Alkene LUMO
s-bond HOMO
Alkene HOMO
(excited state)
s-bond LUMO
(ground state)
Me
H
H H
H
This is not often observed.
No. electrons
4n
4n+2
Thermal
Antarafacial
Suprafacial
Photochemical
Suprafacial
Antarafacial
Ring size
4,8,12…
6,10,14…
39. 39
Sigmatropic [1,5]-reactions proceed suprafacially under thermal conditions
H H H
6 electron (4n+2) process
hence suprafacial
H
H
H
H
H
H H
H
H H
LUMO of diene
HOMO
s-bond
H
H
H
H
H
H
H
H
H
H
H
same phase
H
H
H
H
40. 40
Classic experiment:
D
Me
Me
H
D
Me
D
Me Me
H
E
R
H
H
D
Me
Me
H
D Me
Me
D
Me Me
H
Me
D
H
Me
Z
S
From the (S,E) starting material, both the (E, R) and the (Z,S) products are formed.
However the (Z,R) and (E,S) products are not formed.
This proves that the reaction proceeds in high stereoselectivity.
S
E
H
D
Me
Me
S
E
D
Me
Me
H
Me
D
H
Me
heat
+
Explanation
41. 41
The isomerisation of cyclopentadienes involves a very rapid sigmatropic [1,5]-reactions
(try taking an NMR spectrum of one)
H
R
R
R1
H
R1
R2
R3
R4
R2
R3
R4
etc.
[1,7] sigmatropic rearrangements involves an antarafacial component if carried out thermally.
Because the ring is quite large, this sometimes works smoothly.
Remember the vitamin D2 synthesis?
H
HO provitamin D2
H
HO
H
[1,7]-sigma-
tropic shift.
vitamin D2
The rules make this a (4n) antarafacial reaction
But the molecule is flexible enough to allow it.
In general, sigmatropic rearrangements:
Under thermal conditions:
4n electrons; antarafacial.
4n+2 electrons: suprafacial.
H
H
OH
H
42. 42
Sigmatropic [3,3]-reactions proceed suprafacially and are of great synthetic utility:
COPE rearrangement CLAISEN rearrangement
O O
often reversible usually irreversible
Me
Me
Me
Me
H
H
O Me
Me
O Me
Me
H
H
Both reactions proceed via a chair-like transition state.
43. 43
Sigmatropic [3,3]-reactions proceed suprafacially and are of great synthetic utility:
cation
anion
HOMO
HOMO LUMO
LUMO
Think of reaction as cation +
anion:
forming
bond
breaking
bond
cation LUMO
anion HOMO
44. 44
Sigmatropic [3,3]-reactions – COPE rearrangement applications
Cope rearrangements are often limited due to the reversibility of the reaction. However
the reaction can be made irreversible by release of strain:
MeO O
Li MeO
O O
MeO
O
MeO
O
H
H
MeO
H+
O
H
H
MeO
45. 45
Sigmatropic [3,3]-reactions – CLAISEN rearrangement applications
Claisen reactions are generally irreversible and synthetically useful:
O O O
re-
aromatises OH
NH
H
N
NH
H
N
NH
NH steps
A [3,3]-sigmatropic reaction is
pivotal to the Fischer indole synthesis:
H
-NH3
H
N
H
n.b. Don’t get confused with the Claisen reactions of esters.
46. 46
Sigmatropic [3,3]-reactions – CLAISEN rearrangement applications
The Ireland-Claisen reaction is a useful method for constructing esters,
particularly of difficult medium-ring products, with high stereoselectivity. How
would you make the starting material?
O O
H
n
O
O
n via
O
O
n
H
O
O
n
H
O O
H
OSi(tBu)Me2
OSi(tBu)Me2
O
O
OSi(tBu)Me2
OSi(tBu)Me2
Application to the
synthesis of
ascidialactone, a
marine natural
product.
O
OMe
O
OMe
O
OMe
Some more complex examples:
48. 48
Baldwin’s rules for ring formation (sizes 3-7)
Prof J. E. Baldwin formulated a number of rules which may be used to predict why some
cyclisations work well, and others did not. These were initially empirical rules derived through a
study of the literature, but have since been rationalised through experimentation and molecular
modelling. e.g.
Why is it that a primary amine normally adds to the
beta-position of an unsaturated ester:
Whereas the equivalent intramolecular cyclisation
proceeds via addition to the carbonyl group?:
O
OMe
R
NH2
O
OMe
R
NH
H
work-
up
O
OMe
R
NH
O
OMe
NH2
O
OMe
N H
H
O
H
N
49. 49
Baldwin’s rules for ring formation (sizes 3-7); classification
Baldwin first classified all reactions using three criteria:
a) The size of the ring being formed, or the ring size of the cyclic transition state.
b) ENDO (if the bond being broken is in the ring) or EXO (if the bond being broken
is outside the ring, I.e.:
X
Endo: X
Exo:
c) The hybridisation of the C atom undergoing attack in the cyclisation:
If this is an sp3 (tetrahedral) atom then this is classified as ‘TET’
If this is an sp2 (trigonal) atom then this is classified as ‘TRIG’
If this is an sp (digonal) atom then this is classified as ‘DIG’
X
X
X
50. 50
Baldwin’s rules for ring formation (sizes 3-7); examples
So, for example:
X
X
O
Y
X
+ Y
is a 5-Exo-Tet reaction
X
O
is a 6-Exo-Trig reaction
N
X N
X is a 5-Endo-Dig reaction
51. 51
Baldwin’s rules for ring formation (sizes 3-7); The rules
Baldwin examined the literature and classified all the reported cyclisation reactions
according to his rules. A remarkable pattern emerged; some types of cyclisation had
never been reported. When he had attempted these he found that some simply failed. In
the end he came up with the following simple table of rules:
Ring size
3
4
5
6
7
TET TRIG DIG
Endo
N
N
N
N
Y
Exo
Y
Y
Y
Y
Y
Endo
N
N
N
Y
Y
Exo
Y
Y
Y
Y
Y
Endo
Y
Y
Y
Y
Y
Exo
N
N
Y
Y
Y
N= no reaction
cyclisation fails
Y= successful
cyclisation
i.e.
Y= allowed
N=diallowed
52. 52
The rules are now known to work because of orbital alignments.
Nucleophiles have to approach single, double or triple bonds in very specific directions in order
to overlap effectively with the antibonding orbitals. The requirements are summarised below:
TET sp3
systems
TRIG sp2
systems
DIG sp systems
Br
Nu
Must approach from behind
leaving group.
Nu + Br
O
Nu
ca. 109o
OH
Nu
Must approach at this angle
N
Nu
N
Nu
Must approach at this angle
ca. 60o
Br
Nu
s* antibonding
orbital
O
p* antibonding
orbital
Nu
53. 53
Tetrahedral (TET) systems
A clever deuterium-labelling experiment served to prove that 6-endo-tet processes are not
intramolecular:
CH3
O
O2
S
O2S
CH3
CH3
O
O2
S
O2S
CH3
CH3
O
O2
S
O2S
CH3
CD3
O
O2
S
O2S
CD3
CD3
O
O2
S
O2S
CD3
CD3
O
O2
S
O2S
CD3
But you also get:
CH3
O
O2
S
O2S
CD3
CD3
O
O2
S
O2S
CH3
nBuLi
(strong
base)
nBuLi
(strong
base)
Hence 'scrambling' is taking place
and the reaction is intermolecular.
These would be
the only products
if the reaction was
intramolecular.
54. 54
Tetrahedral (TET) systems
Epoxide-opening reactions (all-exo-tet) are particularly useful because they exhibit a high level
of regioselectivity (note that the epoxide is equally substituted at each end):
O
O
O O
6-exo-tet 5-exo-tet
favoured
disfavoured
but
O
O
O O
5-exo-tet 4-exo-tet
favoured
disfavoured
but
O
O
O O
4-exo-tet 3-exo-tet
favoured
disfavoured
but
rate: 3>4>5<6 for ring size.
55. 55
Intramolecular epoxide opening reactions
The synthesis of Grandisol, the sex pheromone of the male cotton boll weevil, has been
achieved in a very concise and elegant synthesis using a key epoxide-opening step. The
high level of ring strain provides a means for the synthesis of similarly strained targets:
O
E
mCPBA
mCPBA =
Cl
O
O O
H
O
O
4-exo-tet
CN
CN OTBDMS
OTBDMS= OSitBu(Me)2
(the silyl group protects the alcohol,
and is removed with fluoride).
OTBDMS
CN
OTBDMS
base
NaOMe
CN
OTBDMS
H
HO
OTBDMS
'steps'
OH
CN
CH3
Grandisol
(racemic product is formed,
but this is the correct
diastereoisomer)
56. 56
Iodonium cations promote cyclisations in a very similar manner to epoxides.
Note that the selectivity can change according to the substitution level:
Iodine reacts with a double bond to form an iodonium cation, which can then promote a cyclisation:
OH
O
I2
OH
O
I
I
-I
O
O
I
OH
O
I
O
O
I
H
O
5-exo-tet Favoured by attack
at least hindered end.
CN CN
H
HO
57. 57
Intramolecular epoxide opening reactions – complex natural products
O
Me
O
Me
Me
O
O
O
Me2N H
H
H
Me
O
Me
O
Me
Me
O
O
O
Me2N H
H
H
Me
O
O
O
O
Me2N
Me
OH
Me
H
H
O
O
O
O
O
Me
OH
Me
H
H
O
Me
O
Me
Me
Me2N H
H
H
Me
Selective
oxidation
BF3
BF3
hydrolysis
Complex target molecule
A large group of natural products contain a series of fused 5-8 membered ether rings, and are
believed to have been formed by epoxide opening processes
So far this has been
used to give relatively
small products in the
laboratory
58. 58
Intramolecular epoxide opening reactions – complex natural products
A prime example of a complex target of this type is Brevitoxin
A marine neurotoxin associated with ‘red tide’
toxic marine organisms.
O
O
O
O
O
O
O
O
O
O O
O
O
H
H H H
H H H
H
H
H
HO
H H
H
H
H
H
For a total synthesis of this molecule see:
K. C. Nicolaou et al; J. Am. Chem. Soc., 1995, 117, 1171, 1173.
(The method was not prepared by polyepoxide cyclisations,
but no doubt one day it will be)
59. 59
Trigonal (TRIG) systems
The following reaction works in acid but not in base; why is this?
O
O
OMe
OH
O
OMe
base (NaOMe) 0%
acid (HCl) 100%
In base the reaction fails because it requires a disfavoured 5-endo-trig cyclisation.
Why is it disfavoured – consider the orbital alignments?
O
O
OMe
O
O
OMe
60. 60
Trigonal (TRIG) systems
In acid the reaction mechanism changes due to carbonyl protonation, and it becomes a 5-
exo-trig process at the key cyclisation step:
O
OH
OMe
O
O
OMe
OH
O
OMe
OH
O
OMe
OH
OH
OMe
H H
H
5-exo-trig
61. 61
This accounts for the earlier question about amine addition in inter- and intramolecular
reactions:
Intramolecular reactions prefer addition
to the -carbon on enthalpic grounds:
Whereas the equivalent intramolecular cyclisation
proceeds via a 5-exo-trig cyclisation. This overcomes the
enthalpic advantage of addition to the -carbon, which
would require a 5-endo-trig step:
O
OMe
R
NH2
O
OMe
R
NH
H
work-
up
O
OMe
R
NH
O
OMe
NH2
O
OMe
N H
H
O
H
N
5-exo-trig
The same cyclisation of a 6-membered ring precursor
works, because the 6-endo-trig process is allowed:
NH2
6-endo-trig
O OMe
N
O OMe
H
H
H
N
O OMe
H
62. 62
O
OMe
NH2
5-endo-trig
NH2
MeO
O
5-exo-trig
(these are the same molecule)
NH2
O
OMe
:
N lone pair orthogonal to p* orbital.
CYCLISATION FAILS.
NH2
:
O
OMe
N lone pair aligned with p* orbital on C=O.
CYCLISATION WORKS.
Alignment of nucleophile with C=C vs C=O bond:
63. 63
Rules on 5-endo-trig reactions often dictate mechanism
O
OMe
+
H2N NH2
O
NH
HN
+ MeOH
Predict the mechanism of this reaction:
6-endo-trig reactions are permitted
OH
O
R
base (e.g.) NaOMe
6-endo-trig
O
O
R
N
O OH
H
N
O O
O H
HCO2H
N
O
O
O H
6-endo-trig
N-acyliminium cation
64. 64
You may have seen the Pictet-Spengler synthesis of isoquinolines:
NH2 HCl (catalyst)
MeO
MeO
CH2O
N
MeO
MeO H
N
MeO
MeO H
H
N
MeO
MeO H
6-endo-trig
65. 65
Digonal (DIG) systems
Endo-cyclisations work well, and these cyclisation are useful for making small heterocycles:
O2
S N
C
Ph
Base
e.g. NaOMe
O2
S N
C
Ph
isonitrile
H
MeO O
R
O2
S N
C
Ph
O
R
5-endo-dig
O2
S N
C
Ph
O
R
H
O2
S N
C
Ph
O
R
H
RCHO
quench
R
N
C
H
base
R
N
C
N
R
H
(after
protonation)
66. 66
Digonal (DIG) systems
Certain exo- cyclisations also work:
R
O
R'
H2N NH2 R
N
R'
NH2
R
N
N
H
5-endo-dig
R'
CN
C
N
NH
RO
CN
N
N
H
RO
H
CN
C
N
NH2
RO
base
CN
N
N
H
RO
H
H
H
CN
NH2
N
H
RO workup
67. 67
Some genuine exceptions to Baldwin’s rules
In some cases, if there is no choice, Baldwin’s rules can be overridden.
O O
O
HO OH
H
HO O OH
H
O OH
5-endo-trig
H O O
NH2
SO2Ph
N
H
SO2Ph
via
NH
SO2Ph
5-endo-trig
base
SH
SO2Ph
S
SO2Ph
via
S
SO2Ph
5-endo-trig
base
68. 68
Stereoelectronic effects in anomeric bond formation in carbohydrates
O
HO
HO
HO
OH
OH
O
HO
HO
HO
OH
OH
-anomer -anomer
Six-membered carbohydrates,
such as glucose, exist as a
mixture of ‘anomers’
Nb : - is axial, - is equatorial
When an ether is formed at the ‘anomeric’ centre, two new anomers can be formed.
The -anomer is more thermodynamically stable, and usually the major product.
O
HO
HO
HO
OH OH
or -anomer H
ROH
acid catalysis
O
HO
HO
HO
OH
ROH
O
HO
HO
HO
OH
OR
O
HO
HO
HO
OH
ROH O
HO
HO
HO
OH
OR
or
Oxonium cation
69. 69
Stereoelectronic effects in anomeric bond formation in carbohydrates
O
HO
HO
HO
OH
OR
O
HO
HO
HO
OH
OR
O line
pair C-O
s*
O line
pair
C-O
s*
overall overall
The - anomer is more stable because of an energetically-favourable overlap between one of
the ring-oxygen lone pairs with an antibonding orbital in the C-O bond. The orbitals align
because they are parallel to one another. This overlap is not possible for the -anomer.
Effectively a ‘partial
double-bond’.
Even stronger with
electron-withdrawing
group on R, e.g.
R=Me 67:33
R=COMe 86:14
This anomeric bond effect can be used to control the stereochemistry of anomeric bonds in
sugars, which is both challenging and essential for the properties of the compounds.
There are three major methods for control:
a) Use normal anomeric effect, or override this with a large group.
b) Perform an SN2 substitution.
c) Use neighbouring-group effects.
70. 70
a) i) Exploit normal anomeric effect:
An axial adjacent group strengthens this effect (galactose):
O
RO
RO
RO
RO
Br
or -anomer
Ag salt O
RO
RO
RO
RO
ROH
O
RO
RO
RO
RO
OR
Ag
ii) This can be overridden by a large adjacent group:
O
RO
RO
RO
O Br
or -anomer
O
RO
RO
RO
O
ROH O
RO
RO
RO
O
OR
Ag
The large group
blocks the lower
face.
O
RO
RO
RO
OBn Br
or -anomer
Ag salt O
RO
RO
RO
OBn
ROH
O
RO
RO
RO
OBn
OR
Ag Bn=CH2Ph
71. 71
b) Use SN2 displacement strategy- an excellent leaving group is required:
O
RO
RO
RO
OR
OH
-anomer
O
RO
RO
RO
OR
ROH
O
RO
RO
RO
OR
OR
TsCl
Et3N
OTs
Likewise, the - product can be made from the - starting material
c) Neighbouring-group effect: an adjacent acetyl group is required (for a)-b) above, a group such
as Bn is used):
O
RO
RO
RO
O
Br
or -anomer
Ag salt O
RO
RO
RO
O
Ag
O
O
O
RO
RO
RO
O
OR
O
O
RO
RO
RO
O O
H
ROH
SN2
(NaOMe can be
Used to remove
OAc group)
72. 72
The potent anticancer molecule Calicheamicin, which is one of a family of ‘enediyne’
natural products. It works by intercalating into, and then cleaving, DNA at selective
positions. It has a remarkable mode of action.
The oligosaccharide part acts as a ‘targeting’ mechanism and engages in a molecular
recognition with the DNA strand. The enediyne unit acts as the ‘warhead’ which damages
the DNA.
In a total synthesis of the molecule (K. C. Nicolaou, 1992), the anomeric bonds in the sugars are
made by a combination of the methods already outlined.
O
S
OH
O
N
H
O
HO
O
O
H
N
MeO
O
I
OMe
OMe
O
O
HO
MeO HO
O
O
NHCO2Me
HO
H
MeSSS
-, prepared
using method
c) (OAc on
adjacent OH)
-, prepared
using (b); SN2 process
with OTs leaving group.
thio-
ester
bond
-, prepared
using (a,ii); anomeric
control overidden by
large group on
adjacent OH.
-, prepared using
(a, i); anomeric control
73. 73
Spiro acetals can adopt three possible conformations, the stability of which depends on the
number of anomeric effects. The more anomeric effects there are, the more stable the isomer
n.b. The formation of the spiro acetal is reversible. Initially a mixture of isomers is formed. As the
reaction proceeds, the quantity of the major isomer increases.
The stereoselective
formation of a spiro
acetal is pivotal to the
total synthesis of the
aglycone of the
antibiotic erythromycin O
O
O
Me
Me
OH
OH
Me
Me
Me
OH
HO
H
Me
OH
Me
Erythromycin
aglycone
(in the full
molecule, two
carbohydrates
are attached
to OHs *)
*
*
O
O
spiro acetal
O
O
2 anomeric effects
-most stable isomer
O
O
0 anomeric effects
least stable isomer
1 anomeric effect
intermediate stablity
O
O
74. 74
Total synthesis of the erythromycin aglycone:
Spiroacetal formation leads selectively to a single isomer:
(2 anomeric
interactions
The rest of the synthesis involves some chemistry featured earlier in this course:
O
O
CO2Me
Me
Me
Me
O
O
Ph
O
O
O
CO2Me
Me
Me
Me
O
O
Ph
OH
Me
CO2Me
steps:
i) Oxidation to enone
ii) Me2CuLi conjugate
addition
iii) Dibenzoyl peroxide
oxidation
i) MeMgBr -
axial addition
ii) Elimination
of CO2Me
O
O
CO2Me
CO2Me
Me
Me
HO
HO
CO2Me
CO2Me
Me
Me
O
H
OH
O
OH
MeO2C CO2Me
acid catalysis
-H2O
75. 75
Total synthesis of the erythromycin aglycone cont.:
O
O
CO2Me
Me
Me
Me
O
O
Ph
OH
Me
O
O
Me
Me
Me
O
O
Ph
OH
Me
O
OMe
(MeO)3CCH2CH3, H
O
O
Me
Me
Me
O
O
Ph
OH
Me
O
OMe
Me
O
O
Me
Me
Me
O
O
Ph
OH
Me
Me
O
O
I
I
H
Claisen
rearrangement
[3.3] sigmatropic
i) LiAlH4
Hydrolysis
of acid
76. 76
Total synthesis of the erythromycin aglycone completion.:
O
O
Me
Me
Me
O
O
Ph
OH
Me
Me
O O
I
O
O
Me
Me
Me
O
O
Ph
OH
Me
Me
Me
O O
O
O
Me
Me
Me
O
O
Ph
OH
Me
Me
OH
H
O
HO
HO
Me
Me
Me
HO
OH
Me
Me
Me
OH
O
O
OH
Me
OH
I2 (iodine)
5-exo-trig
iodolactonisation
Reduction
Open ester and convert
to aldehyde
Deprotect
Ring-open
spiroacetal
with aqueous acid
form
ester
here
Erythromycin aglycone
(from previous slide)
