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 OH C–C OH

O
dehydration O aldol O

!
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 O
!

Compound B
 O

Answer

O O O O
FGI
O O
! HO 1 2
OH HO O
3
5 reduction
4

C–C

O O

HO

!
O O O
EtO OEt

The first disconnection should be relatively simple, break the C–O bond to give the acid and alcohol.
The next stage might be slightly tougher…your 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 self-
condensation 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 O H+ , O
O O O base NaBH4 EtO2C H2O
EtO2C O O
EtO OEt
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 synthon…I’m 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 C–C bond formation by a substitution with a cyanide anion.

FGI
C–C
CO2H N
N
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
C–C
CO2H CO2Et CO2Et
hydrolysis
!

!
CO2Et
Br
CO2Et

Question 3.
How would you make these compounds?

H OH CO2H NH2
N

Answers

The first is simply a case of reduction amination. We cannot form an amide so it has to proceed by the
imine.
 H FGI N O H 2N
N C=N

reduction

The next isn’t much harder…we have an alcohol, this should yell Grignard addition to a carbonyl and
hence the disconnections are:

OH O
C–C BrMg Br

This one is potentially a little harder…but 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

C–C 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 OTs OH

C–N C–S

reduction

Question 4.
Perform the retrosynthetic analysis of the following compound. Remember, your planned synthesis
must be synthetically possible and shouldn’t suffer from regio- or chemoselectivity issues.

O O
NEt2

O
NH2

Answer
O O O OH O OH
NEt2
FGI
C–O

O O reduction O
NH2 remove the ester NH2 NO2
(with the reactive
functionality) the amine can be problematic we can now remove the ether.
so we convert it to the less Attepts to do this earlier
reactive nitro group. This also C–O would have met with failure
prepares the way for its due to alkylation of the amine
eventual disconnection
O OH
O OH O OH
FGI
C–N

diazonium OH
N2+BF4– OH
NO2
I would stop here as I don't know how much the phenol group is ortho, para
aromatic chemistry you have done. But if you directing but should favour the
FGI have done enough then we can take the leaser hindered position (and
diazonium synthesis all the way back to the acid we might be able to argue
about H-bonding)
O OH O OH O OH
FGI
C–N

reduction
NH2 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:

i. BH3
Br2, ii. H2O2 /
hv t-BuOK NaOH
Br
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:

Mg OH
Br Et2O MgBr CH3CHO

Lets be honest, if you can’t do this one then you’re in trouble!

(d)
How would you synthesise

HO

From
HO

Answer:

PCC EtMgBr

HO O 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:

t-BuOK mCPBA O EtMgBr OH

Br

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:

HBr
OH acid ROOR
dehydration 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

Answer:

HBr PPh3
Br NaN3 N3 H 2O NH2
O ROOR
O O 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

Ph
N
H

From

OEt

Answer:

O O O O
H3O+ SOCl2 PhNH2 LiAlH4 Ph
Ph N
OEt OH Cl N H
H

Hopefully, this one doesn’t cause too many problems.

(i)
How would you synthesise
 OH
Et

Et

From

EtO2C CO2Et

Answer:

i. base i. base i. H3O+ OH

ii. Et–I EtO2C CO2Et ii. Et–I EtO2C CO2Et ii. heat Et CO2H LiAlH4
EtO2C CO2Et Et
Et Et Et 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

Answer:

i. base O OH OH OH
O ii. EtCHO NaBH4

Don’t 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:

HBr
OH PCC O MeMgBr acid ROOR
OH
Br