123.

312 Advanced Organic Chemistry: Retrosynthesis

Tutorial
Question 1.
Propose a retrosynthetic analysis of the following two compounds. Your answer should include both
the synthons, showing your thinking, and the reagents that would be employed in the actual synthesis.
Compound A

Answer:
FGI
O

OH

CC
O

dehydration

OH
O

aldol

!
O

Remember that a conjugated double bond can easily be prepared by dehydration, thus we can perform
an FGI to give the aldol product. The 1,3-diO relationship should make spotting the disconnection very
easy. Of course, in the forward direction the reaction is not quite that simple; we have two carbonyl
groups so we must selectively form the correct enolate but this should be possible by low temperature
lithium enolate formation prior to the addition of cyclohexanone.
The aldol condensation is such a common reaction that it is perfectly acceptable to do the following
disconnection:

!
O

Compound B

O
O

Answer
O
O

O
O

HO 1

FGI
2

OH

HO

3
5

reduction
CC
O

HO

!
O
EtO

O
OEt

The first disconnection should be relatively simple, break the CO bond to give the acid and alcohol.
The next stage might be slightly tougheryour best bet is to look at the relationship between the two
functional groups; it is 1,5. This can be formed via a conjugate addition of an enolate. To do this we
need two carbonyl groups so next move is a FGI to form the dicarbonyl. Two possible disconnections
are now possible depending on which enolate we add to which activated alkene. The one I have drawn
is simpler, diethyl malonate is commercially available as is the enone (or it can be prepared by the selfcondensation of acetone). Additionally, conjugate addition of malonates prefers 1,4 to 1,2 addition,
which can be an issue with simple carbonyls. Chemoselectivity in the reduction step is not an issue;
NaBH4 does not reduce esters.
O
EtO

base

OEt

O
EtO2C

O
NaBH4

EtO2C

H+ ,
H2O

O
O

CO2Et

Question 2.
Give the retrosynthetic analysis for the following three compounds. Pay special attention to the
relationship between the functional groups.
CO2H

CO2H

CO2H

Answers:
The first is the easiest; it is an !,"-unsaturated compound so we are looking at either aldol
condensation or a simple Wittig reaction. Sometimes you will see double bond disconnections drawn
with a double charge synthonIm not convinced it helps but if it allows you to rationalise what is
going on more readily then use it!

FGI

C=C

CO2H

CO2Et

CO2Et

hydrolysis

PPh3
CHO

CO2Et

The second is probably the hardest; there is no simple enolate disconnections so we have to look
slightly further a field. Whilst we can go via an alkyne, the best route probably involves FGI to a
nitrile and then simple CC bond formation by a substitution with a cyanide anion.
FGI

CC

CO2H
hydrolysis

!
Br

NaCN

Alkylation of an enolate offers the most rapid approach to the third structure. Not much needs to be
said about this one.
FGI

CC

CO2H

CO2Et

CO2Et

hydrolysis

!
Br

CO2Et
CO2Et

Question 3.
How would you make these compounds?
H
N

OH

CO2H

NH2

Answers
The first is simply a case of reduction amination. We cannot form an amide so it has to proceed by the
imine.

H
N

FGI

C=N

H 2N

reduction

The next isnt much harderwe have an alcohol, this should yell Grignard addition to a carbonyl and
hence the disconnections are:
OH

CC

BrMg

Br

This one is potentially a little harderbut not much. The best route to the acid is via alkylation of
diethyl malonate. The latter is easily enolised, will only undergo two additions, is fairly robust yet will
readily undergo decarboxylation.
CO2H

FGI

EtO2C CO2Et

CC

Br

Br
EtO2C

CO2Et

decarboxylation

The final compound is a primary amine. This could either be prepared by reductive amination of the
appropriate ketone (made from oxidation of the secondary alcohol made earlier) or by substitution of
an appropriately derivatised secondary alcohol (tosylation of the secondary amine) with azide followed
by reduction.
NH2

FGI

NH

O
C=N

reduction
NH2

FGI

N3

CN

OTs

OH
CS

reduction

Question 4.
Perform the retrosynthetic analysis of the following compound. Remember, your planned synthesis
must be synthetically possible and shouldnt suffer from regio- or chemoselectivity issues.
O

NEt2

O
NH2

Answer

NEt2

OH

O
FGI

CO
O
NH2

OH
FGI

N2+BF4

NH2

NO2
the amine can be problematic
so we convert it to the less
reactive nitro group. This also
prepares the way for its
eventual disconnection

CO

OH

we can now remove the ether.

Attepts to do this earlier
would have met with failure
due to alkylation of the amine
OH

CN

diazonium

FGI
diazonium
O

reduction

O
remove the ester
(with the reactive
functionality)

OH

NO2

I would stop here as I don't know how much

aromatic chemistry you have done. But if you
have done enough then we can take the
synthesis all the way back to the acid

OH

OH

FGI

NH2

OH

OH

the phenol group is ortho, para

directing but should favour the
leaser hindered position (and
we might be able to argue
about H-bonding)

OH

CN

reduction

NO2
remember, the acid is electron
withdrawing so is meta directing

Question 5.

(a)
How would you synthesise

From

Answer:
i. BH3
ii. H2O2 /
NaOH

PBr3
OH

Br

Remember, we need to get anti-Markovnikof addition of the hydroxyl group so we use hydroboration /
oxidation.

(b)
How would you synthesise
OH

From

Answer:
Br2,
hv

Br

t-BuOK

i. BH3
ii. H2O2 /
NaOH
OH

The key to this one is functionalisation of the hydrocarbon. This is achieved by radical bromination,
then its plain sailing.
(c)
How would you synthesise
OH

From
Br

Answer:
Br

Mg
Et2O

MgBr

CH3CHO

Lets be honest, if you cant do this one then youre in trouble!

(d)
How would you synthesise

HO

From

OH

HO

Answer:
EtMgBr

PCC
O

HO

HO

Likewise, this one is not that taxing but hopefully gets you thinking about functional group
interconversions.
(e)
How would you synthesise
OH

From
Br

Answer:
Br

t-BuOK

mCPBA

EtMgBr

OH

This one is quite hard. But again, it is all about FGI and recognising where the original carbons are. I
recommend number you carbons and then trying to identify relationships between functional groups
and this numbering.
(f)
How would you synthesise

Br

From
OH

Answer:
OH

acid
dehydration

HBr
ROOR
Br

Quick, but not necessarily straightforward; the more reactions you know the easier this becomes. Here
we require anti-Markovnikov addition of the HBr. Therefore, we add peroxide to allow a radical
reaction.
(g)
How would you synthesise
NH2
O

From
O

Answer:
HBr
ROOR

Br
O

PPh3
H 2O

N3

NaN3

NH2
O

Again, need anti-Markovnikov so use radical bromination. The add nitrogen via the azide. Of course,
there are other answers (hydroboration , oxidation and reductive amination??)
(h)
How would you synthesise
N
H

Ph

From
O
OEt

Answer:
O

H3O+
OEt

O
OH

SOCl2

PhNH2
Cl

Hopefully, this one doesnt cause too many problems.

(i)
How would you synthesise

O
N
H

Ph

LiAlH4

N
H

Ph

OH
Et
Et

From
EtO2C

CO2Et

Answer:

EtO2C

CO2Et

i. base
ii. EtI

EtO2C

CO2Et

i. base
ii. EtI

EtO2C

CO2Et

i. H3O+
ii. heat

Et Et

Et

Et

CO2H

LiAlH4

Et

OH
Et
Et

This one is all about recognising which functional groups are required and how they can be
interconverted.
(j)
How would you synthesise
OH

OH

From
O

Answer:
i. base
ii. EtCHO

OH

NaBH4

OH

OH

Dont get fooled by how similar molecules may appear. Count the atoms, look for real relationships.
In this case we have a 1,3-diol derived from a ketone; start thinking about an aldol reaction right away.
(k)
How would you synthesise

Br

From

OH

Answer:
OH

PCC

MeMgBr
OH

acid

HBr
ROOR
Br