Professor M. Wills

1
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.
Professor M. Wills
CH3B0 Understanding Organic Synthesis
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.
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
Examples of pericyclic reactions

• 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.

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.
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.
5
Examples of pericyclic reactions, continued
3) Sigmatropic rearrangement reactions A high
level of stereochemical control is often observed.

• Other concerted reactions
• Ene reaction (synthetic chemists), or Norrish
  rearrangement (photochemists) or McLafferty
  rearrangement (for mass spectrometrists).
• Decarboxylation reaction

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. Electr
ocyclisations. 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.
7
Woodward-Hoffmann theory applied to cyclobutene
formation.
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.
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.
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.
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.
Now (see the next page), the manner in which the
molecule changes shape upon cyclisation is very
different.
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.
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.
Although it should be noted that sometimes
stereocontrol is lost due to competing radical
reactions.
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
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
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.
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
The double-bond stereochemistry is critical.
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.
16
Step 1
Note the product is racemic.
Step 2
17
K. C. Nicolaous 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.
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 4n2) 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
19
Nazarov cyclisation, cont....
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
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)
More details of the Diels-Alder reaction.
21
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.
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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
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).
25
Diels-Alder reaction energetics
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
Woodward-Hoffmann theory for prediction of the
stereochemistry of cycloaddition reactions
If you examine 22 and 44 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.
27
Woodward-Hoffmann theory for prediction of the
stereochemistry of cycloaddition reactions
summary of the rules
Ring size 4,8,12 6,10,14
No. electrons 4n 4n2
Thermal Antarafacial Suprafacial
Photochemical Suprafacial Antarafacial
Notethe rules also work in reverse
Although you might also get competing radical
reactions
28
22 cycloadditions involving ketenes an
exception to the Woodward-Hoffmann rules.
This is an important exception to the
Woodward-Hoffmann rules which normally insist
that 22 additions proceed in a (not very
favourable) antarafacial manner. The trick here
is that the ketene uses both the CC and CO
p-orbitals in the reaction, through a twisted
transition state.
How would you make a ketene? n.b useful for
beta-lactam synthesis
Some examples of Diels-Alder reactions will be
given at this stage
29
Endo selectivity in the Diels-Alder reaction.
(see next slide)
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Make sure you can draw the transition state for
the following process
Intramolecular Diels-Alder reactions are very
powerful methods for constructing target
molecules (try the one below)
These reactions are often catalysed by Lewis
acids (see section on the orbitals involved in
Diels- Alder reactions.
32
Application of the Diels-Alder reaction to Taxol
synthesis.
Taxol is a potent anti- cancer compound
How might you be able to construct the substrate?
33
Further applications of Diels-Alder reactions
Alkaloid synthesis
34
Hetero Diels-Alder reactions can be useful too
Three component Cycloadditions
3-body collision Is unlikely.
35
1,3-Dipolar cycloaddition reactions
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.
A similar cycloaddition of nitrile oxides
provides a method for the synthesis of 3-hydroxy
ketones, all these reactions involve 4n2
electrons and are suprafacial
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
Orbital picture
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.
This process allows menthol to be made more
efficiently than through extraction from natural
sources. How would you make the starting material?
38
Woodward-Hoffmann theory for prediction of the
stereochemistry of pericyclic reactions
Sigmatropic reactions.
No. electrons 4n 4n2
Thermal Antarafacial Suprafacial
Photochemical Suprafacial Antarafacial
Ring size 4,8,12 6,10,14
This time the rules will be given first, then
the examples
39
Sigmatropic 1,5-reactions proceed suprafacially
under thermal conditions
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The isomerisation of cyclopentadienes involves a
very rapid sigmatropic 1,5-reactions (try
taking an NMR spectrum of one)
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?
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. 4n2 electrons suprafacial.
42
Sigmatropic 3,3-reactions proceed suprafacially
and are of great synthetic utility
43
Sigmatropic 3,3-reactions proceed suprafacially
and are of great synthetic utility
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
45
Sigmatropic 3,3-reactions CLAISEN
rearrangement applications
Claisen reactions are generally irreversible and
synthetically useful
n.b. Dont get confused with the Claisen
reactions of esters.
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?
Some more complex examples
Application to the synthesis of ascidialactone, a
marine natural product.
47
A summary of the Woodward-Hoffmann rules.
48
Baldwins 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.
49
Baldwins rules for ring formation (sizes 3-7)
classification

• Baldwin first classified all reactions using
  three criteria
• 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.

• 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

50
Baldwins rules for ring formation (sizes 3-7)
examples
So, for example
51
Baldwins 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
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
53
Tetrahedral (TET) systems
A clever deuterium-labelling experiment served
to prove that 6-endo-tet processes are not
intramolecular
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)
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
56
Iodonium cations promote cyclisations in a very
similar manner to epoxides.
Iodine reacts with a double bond to form an
iodonium cation, which can then promote a
cyclisation
Note that the selectivity can change according to
the substitution level
57
Intramolecular epoxide opening reactions
complex natural products
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
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.
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
Trigonal (TRIG) systems
The following reaction works in acid but not in
base why is this?
In base the reaction fails because it requires a
disfavoured 5-endo-trig cyclisation. Why is it
disfavoured consider the orbital alignments?
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
61
This accounts for the earlier question about
amine addition in inter- and intramolecular
reactions
62
Alignment of nucleophile with CC vs CO bond
63
Rules on 5-endo-trig reactions often dictate
mechanism
6-endo-trig reactions are permitted
64
You may have seen the Pictet-Spengler synthesis
of isoquinolines
65
Digonal (DIG) systems
Endo-cyclisations work well, and these
cyclisation are useful for making small
heterocycles
66
Digonal (DIG) systems
Certain exo- cyclisations also work
67
Some genuine exceptions to Baldwins rules
In some cases, if there is no choice, Baldwins
rules can be overridden.
68
Stereoelectronic effects in anomeric bond
formation in carbohydrates
Six-membered carbohydrates, such as glucose,
exist as a mixture of anomers Nb a- is axial,
b- is equatorial
When an ether is formed at the anomeric centre,
two new anomers can be formed. The a-anomer is
more thermodynamically stable, and usually the
major product.
Oxonium cation
69
Stereoelectronic effects in anomeric bond
formation in carbohydrates
The a- 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 b-anomer.
Effectively a partial double-bond. Even
stronger with electron-withdrawing group on R,
e.g. RMe 6733 RCOMe 8614

• 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
• Use normal anomeric effect, or override this with
  a large group.
• Perform an SN2 substitution.
• Use neighbouring-group effects.

70
a) i) Exploit normal anomeric effect
An axial adjacent group strengthens this effect
(galactose)
ii) This can be overridden by a large adjacent
group
71
b) Use SN2 displacement strategy- an excellent
leaving group is required
Likewise, the a- product can be made from the b-
starting material
c) Neighbouring-group effect an adjacent acetyl
group is required (for a)-b) above, a group such
as Bn is used)
(NaOMe can be Used to remove OAc group)
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.
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
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
75
Total synthesis of the erythromycin aglycone
cont.
76
Total synthesis of the erythromycin aglycone
completion.
(from previous slide)