More Subjective Answers

1) creativity and elegance

2) the approach involves practical and convenient steps - clearly dependent on the skill of
the operator and the conditions in which they work (e.g. access to equipment).
3) flexibility - difficult to quantify but very desirable for i) the times when we encounter
problems with a planned route and need to modify the synthesis, and ii) when access to
synthetic analogues is required, for example when probing structure-activity relationships.
4) environmentally friendly - so-called 'green' chemistry is becoming increasingly important.
Synthetic routes which avoid the use (or production as unwanted side-products) of large
amounts of toxic compounds and laborious purification procedures requiring large volumes
of solvents and silica are desirable. This becomes increasingly important on scale-up; it is
not usually a priority in the research lab.

IV.B Analysing a Molecule with a View to Synthesis

Some points to consider before you even begin to disconnect the molecule:

1. Look at the molecule - make a model and assess the overall size and shape, conformation of
rings etc; look for symmetry elements (or regions containing pseudosymmetry).
2. Assess bond connectivity (topology) - it is particularly important to understand how the atoms
are connected in polycyclic molecules (e.g. alkaloids (see lycopodine)).
3. Identify functional groups and their relative disposition. Recognise key structural motifs
(pattern recognition) - Claisen, aldol, Mannich, Diels-Alder retrons. These often become the
strategic bond disconnections.
4. Look for stereogenic centres. If there is more than one, assess how they are related. This
will determine the approaches available for installing these centres - can you rely on the
shape of the substrate to dictate the stereochemical outcome of the reaction (substrate
control) or will you need to rely on external sources (reagent control)?
5. Assess the overall stability of the molecule. Identify labile groups and think about
incorporating these at late stages of the synthesis. Is the molecule prone to rearrangement
or decomposition under acidic or basic conditions? The final stages of a synthesis often
involve removal of protecting groups. The stability of the product to the deprotection
conditions is obviously important.
More Subjective Answers

1) creativity and elegance

2) the approach involves practical and convenient steps - clearly dependent on the skill of
the operator and the conditions in which they work (e.g. access to equipment).
3) flexibility - difficult to quantify but very desirable for i) the times when we encounter
problems with a planned route and need to modify the synthesis, and ii) when access to
synthetic analogues is required, for example when probing structure-activity relationships.
4) environmentally friendly - so-called 'green' chemistry is becoming increasingly important.
Synthetic routes which avoid the use (or production as unwanted side-products) of large
amounts of toxic compounds and laborious purification procedures requiring large volumes
of solvents and silica are desirable. This becomes increasingly important on scale-up; it is
not usually a priority in the research lab.

IV.B Analysing a Molecule with a View to Synthesis

Some points to consider before you even begin to disconnect the molecule:

1. Look at the molecule - make a model and assess the overall size and shape, conformation of
rings etc; look for symmetry elements (or regions containing pseudosymmetry).
2. Assess bond connectivity (topology) - it is particularly important to understand how the atoms
are connected in polycyclic molecules (e.g. alkaloids (see lycopodine)).
3. Identify functional groups and their relative disposition. Recognise key structural motifs
(pattern recognition) - Claisen, aldol, Mannich, Diels-Alder retrons. These often become the
strategic bond disconnections.
4. Look for stereogenic centres. If there is more than one, assess how they are related. This
will determine the approaches available for installing these centres - can you rely on the
shape of the substrate to dictate the stereochemical outcome of the reaction (substrate
control) or will you need to rely on external sources (reagent control)?
5. Assess the overall stability of the molecule. Identify labile groups and think about
incorporating these at late stages of the synthesis. Is the molecule prone to rearrangement
or decomposition under acidic or basic conditions? The final stages of a synthesis often
involve removal of protecting groups. The stability of the product to the deprotection
conditions is obviously important.
Now you can begin to disconnect the molecule. The constant goal should be to reduce the
molecule to (often easier said than
done). This simplification should be continued until you reach molecules which are
commercially available.

Some useful points:

1. Look at the most complicating feature and analyse this first.

2. Analyse the oxidation states of functional groups - can you use these to your advantage
or will it be better to introduce these groups in a different oxidation state and oxidise or
reduce at a later stage. Alternatively these groups may be best introduced in masked
form.

O O
H

unmask

OH O O
oxidise reduce
H H OR

unmask

3) Exploit the symmetry or pseudosymmetry elements you have identified. A good

disconnection is one which produces two identical structures. Two-bond disconnections
are also good as they generally simplify the molecule into smaller constituents than would
a one-bond disconnection.
4) Bonds to heteroatoms are relatively easy to form (C−O/N/S/P) and often provide strategic
disconnections. Carbonyl groups are VERY useful.

O O
HO R2
R1 OR2 R1 OH

O O
O HO OH

R O
N
H 2N R

5) Double bonds can be strategic sites for disconnection.

R1 O H R1

R R H PPh3

R1 M
X R1
R R

R1 HO R1
FGI
R R H
6) In polycyclic systems a branch-point disconnection can be strategic in greatly simplifying
the problem.

These ideas and concepts are best illustrated with examples:

Example 1.
Example 2. Further Use of Masked Functionality

Disguising the final reactive functionality in an unreactive form is widespread practice in organic
synthesis. The olefin to carbonyl conversion is one of the most frequently used. Consider a
retrosynthesis of the following molecule.

1,6-relation between
two carboxylic acids masked
dicarboxylic
6
acid
CO2H CO2H

O 1 O reconnection
O O
O O HO OH CO2H
O O
two-bond
disconnection
ketone
oxidation
state you should
Pattern recognise this
Recognition as the retron
for a Diels-Alder
reaction
CO2H

Make sure you can draw an accurate transition state for the Diels-Alder reaction.
 NO2 OH
NO2 NaOH RCHO
R
Na R
NO2
nitro compounds NO2
usually not
isolated
pKa(nitromethane) = 10.2 Henry reaction
( c.f. Knoevenagel condensation)

The low pKa of protons α to the nitro group allows the use of very mild bases such as tertiary
amines for forming the anionic species. These acyl anion equivalents react with α,β-unsaturated
carbonyl groups in a Michael fashion (complementary reactivity to dithianes) therefore providing a
good approach to 1,4-dicarbonyl compounds.

NO2 CO2Me NO2 TiCl3 O

O O
Et3 N H 2O
OMe pH 6 OMe
Example 2. Further Use of Masked Functionality

Disguising the final reactive functionality in an unreactive form is widespread practice in organic
synthesis. The olefin to carbonyl conversion is one of the most frequently used. Consider a
retrosynthesis of the following molecule.

1,6-relation between
two carboxylic acids masked
dicarboxylic
6
acid
CO2H CO2H

O 1 O reconnection
O O
O O HO OH CO2H
O O
two-bond
disconnection
ketone
oxidation
state you should
Pattern recognise this
Recognition as the retron
for a Diels-Alder
reaction
CO2H

Make sure you can draw an accurate transition state for the Diels-Alder reaction.
Example 3 Where is the strategic bond disconnection for the following tricycle?

a O X S O
Li
c a
b
S or H

b
c O disconnections a and b do
not simplify the problem
O

X H
O
Develop a synthesis of the cis decalin
from:
O
X
c is the strategic disconnection. By breaking
a bridgehead bond the problem is reduced O
to a much more simple cis decalin.
Example 4: