Retrosynthesis

Retrosynthesis is the process of “deconstructing” a target molecule into readily available

starting materials by means of imaginary breaking of bonds (disconnections) and by the
conversion of one functional group into another (functional group interconversions).

Some common terminology in retrosynthesis:

1) Disconnections: It is the reverse synthetic steps or reaction and we disconnect only

when we have a reliable reaction in mind. e.g.,
O
O
C-O ester OH
OEt EtOH
disconnection H2N
H2N

This disconnection is possible to thik since we know esters are made from acids and alcohols

2) Synthon: Synthons are those idealised fragments which may or may not be involved
in the reaction but which helps us to work out which reagents to use.
O
O
a

MeO
MeO 1 2 3

MeO

When we disconnect a bond to an aromatic ring we normally expect ‘a’ type of

disconnection because aromatic ring behaves as the nucleophile and the acid chloride as an
electrophile. Thus, the fragments 2 and 3 are synthons.

A negatively polarised synthon is known as donor synthon and a positively polarised

synthon is called acceptor synthon. Thus synthon 2 and 3 in the above example are donor
synthon and acceptor synthon respectively.

3) Synthetic equivalent: When the analysis is complete, the synthons must be replaced
by reagents for practical use. These reagents are called synthetic equivalent. For
anionic synthon the synthetic equivalent is often the corresponding hydrocarbon or
organometallic compound. For cationic synthon the synthetic equivalent is often the
corresponding halide or any other leaving group.
O H O
O

MeO Cl
MeO
MeO 1 3
2 Synthetic equivalent

1 S. Debnath
 4) Functional Group Interconversion (FGI): In a retrosynthetic analysis the process of
converting one functional group into another by substitution, elimination, addition,
oxidation or reduction is known as Functional Group Interconversion (FGI). The
reverse operation is used in synthesis. E.g.,

O O
FGI CH3
OH FGI OH

H2N O2N O2N

5) Functional Group addition (FGA): Sometimes a function group is added to a strategic

position to get proper disconnection. This operation of adding functional group is
known as Functional Group addition (FGA). E.g.
O
HN FGA NH
HN O
F3C F3C
F3C

NH2 O
F3C Cl

6) Latent polarity of compounds: The partial positive and negative charges indicate the
latent polarity of the bond in a molecule. They help us to choose the synthons for
key disconnection in a retrosynthetic analysis. E.g.,
OH
OH
i) O

+ +
− − H BrMg

ii) Consider a 1,3 disubstituted molecule

O OH
Latent polarities

O OH
Starting from C=O + + Ph
−


O OH
Ph

Starting from C-OH + + Ph

−

When the latent polarities in a bifunctional molecule overlap, they reinforce each
other. This is termed as consonant polarity. For the molecule with consonant
polarity, the analysis becomes straightforward.
O OH O
O OH
+ PhCHO
+
+ + Ph − Ph
−

2 S. Debnath
 Similar principle applies for other 1,3 and 1,5 bifunctional system as shown below.
OH OH
O O

1,3 System + +
+ + −
− − − − −
 

O O O O
O O +
+

+ + + −
− − − −
1,5 System
Thus the synthesis of 1,5 system will be
O O
O
NaOH

But what about 1,4 disubstituted compound?

O O

+ −
−
 +
+ −
−
 +
O O
Latent polarity from left C=O group Latent polarity from right C=O group

The polarity does not overlap. They termed as dissonant. If we try any disconnection, we will
result in a synthon that has wrong polarity. E.g.,
O O
+

+ −
−

Synthons
O O

+ ?

One way to get this synthetic equivalent is to add a leaving group.

+
−
Br

O O
Therefore, the synthesis will be

3 S. Debnath
Actually, this synthesis is done via enamine pathway or after adding another activating
group on enolate synthon (specific enol equivalent) which will be discussed later.

7. Umpolung: Umpolung means reversal of polarity. E.g., carbonyl carbon is generally

positively polarised but if it is converted to negatively charged end, that
phenomenon is called Umpolung. E.g.,

8. Illogical electrophilic synthon: When a disconnection produces an electrophilic

synthon which does not have the natural polarity. This synthon is called Illogical
electrophilic synthon. E.g.

9. Illogical nucleophilic synthon: When a disconnection produces a nucleophilic

synthon which does not have the natural polarity. This synthon is called Illogical
nucleophilic synthon. E.g.,

4 S. Debnath
 C-C disconnection (one group):

Alcohols: This type of disconnection involves for the compound having one -OH
functional group and we disconnect an appropriate C-C bond to get the available
starting materials. Since organic molecules contain many C-C bonds, we must learn
which C-C bond to disconnect. Some examples of one group C-C disconnection are given
below.

Examples:

1. If a disconnection gives positive charge at α- position to the –OH group and a negatively
charged alkyl group (route a), we can think carbonyl compound and organometallic
compound as starting materials as shown below.
MgBr

+
+
OH OH O

Br + Mg

Synthesis
MgBr
1.
Br Mg
O
Dry ether
2. NH4Cl
OH

5 S. Debnath
If we try to disconnect any one of the two methyl groups, then we will get the ketone as
starting material which is not easily available one. Thus, we have to prefer the above
disconnection and synthesis.

2. If a disconnection gives positive charge at β- position to the –OH group and a negatively
charged alkyl group (example b), we can think epoxide and organometallic compound as
starting materials as shown below.

3. Alcohols having two identical R group can be disconnected by disconnecting both the
alkyl groups at once to get an ester as starting material as shown below.
O
R
R1 1,1 C-C + 2RMgX

R R1 OEt
OH

O R R
R1 R1
Synthesis RMgX (2 equiv) NH4Cl
normal addition R R
R1 OEt
OMgX OH

The following compound can be disconnected in two ways. Synthesis both routes are found
to be successful.
MgBr
a O
OH route a OH
Ph Ph
+
b Ph

route b

OEt
Ph
+ 2MeMgI

6 S. Debnath
 Ph Ph +
1. OH OH

PhMgBr +
O

Synthesis
m-CPBA 1. PhMgBr
Ph
O 2. H3O+ OH

2. O
OH +
OH MgBr

OH OH Br
A

MgBr Br
CHO +

Synthesis
1. Mg in dry ether 1. PBr3
Br OH MgBr
2. CH3CH2CHO 2. Mg in dry ether
3. H3O+ 1. O
2. H3O+

OH

In example 2 disconnection of A can also be done via another epoxide pathway.

Carbonyl compounds can be derived from alcohols by oxidation, so the same disconnection
can be used for aldehydes, ketones and acids. E.g.

7 S. Debnath
 FGI
1. Ph Ph Ph
O OH OH

PhMgBr +
O
Synthesis
K2Cr2O7
1. PhMgBr Ph
Ph
O H2SO4 O
2. H3O+ OH

2. FGI +
COOH
OH OH

Br +
MgBr O
Synthesis

1. Mg in dry ether
K2Cr2O7
Br 2. OH H2SO4 COOH
O
3. H3O+

3.
Analysis

O OH
C5H11 OH
C5H11
FGI C5H11 CHO
C5H11
+ +
MgBr

FGI
+ CH2OH
MgBr CH2OH
+ HCHO

Synthesis
O
Br 1. Mg in dry ether CH2OH CHO 1. C6H13MgBr C5H11

2. HCHO PCC Oxidation 2. H3O+

3. H3O+ 3. PCC

Alkene: Alkenes can be synthesised via dehydration of alcohol. Therefore, during

disconnection alkene can be converted to an appropriate alcohol via FGI. Then the alcohol
can be disconnected as discussed before. E.g.,

8 S. Debnath
 Ph PhMgBr
Ph
Ph FGI
1. OH OH
a

b FGI
O
Ph

OH

During forward synthesis, dehydration via route b can give two alkenes whereas route a
gives only the target molecule. Thus route a is preferable.

Synthesis:
Ph Ph
O 1. PhMgBr in dry ether H3O+
OH
2. H3O+ dehydration

OH O
2. FGI OH
Ph Ph
Ph

FGI
Ph-CH2CH2OH Ph-CH2CH2Br PhCH2CH2MgBr

O
Ph + CH2CH2OH

PhMgBr

O 1. PhMgBr PBr3
Synthesis PhCH2CH2OH Ph-CH2CH2Br
2. H3O+
Mg in dry
ether
O
H3O+ OH 1.
Ph Ph PhCH2CH2MgBr
2. H3O+

Alkenes can also be synthesised by Wittig reaction.

Carbonyl compounds: (1,1 disconnection)

9 S. Debnath
 O O O
+ R2MgBr
R1 R2 R1 R2 R1 OEt

O 1. R2MgBr O
Synthesis
reverse addition
R1 OEt R1 R2
2. H3O+

This compound can also be disconnected in the following way

NH NH
O FGI
R1 C N + R2MgBr
R1 R2 R1 R2
R1 R2

1. R2MgBr
O
reverse addition
Synthesis R1 C N R1 R2
2. H3O+

(1,2 disconnection):

R2 R2 R2
R1 R1 R1-Br +
O O O

R2 1. Base
Synthesis
2. R1-Br X TM
O

Execution of this reaction is very difficult though the disconnection is logical. Under the
basic condition the product can also be alkylated further or the reactant ketone can give
aldol condensation. This problem can be overcome by adding an activating group as shown
below.

(1,3 disconnection):

R1 R2 R1 R2 R2
R12CuLi +
O O O

Thus, forward reaction of this synthesis is Michael reaction of α, β-unsaturated carbonyl

compounds with a carbanion of organometallic reagents. E.g.,

10 S. Debnath
 O O O

+ Me2CuLi

Me Me

Synthesis O O
1. Me2CuLi

2. H3O+
Me

Acids: (1,1 disconnection):

Disconnection
O O
R + RMgX + CO2
R
OH OH

O
R + R-X + KCN
OH

Synthesis:

Both the synthesis was found to be successful.

(1,2 disconnection):

11 S. Debnath
(1,3 disconnection): Acids can also be disconnected at 3 position like ketones. In that case
we have to start with α, β unsaturated ester as shown below

C-C disconnection (two groups):

1,1 dioxygenated compounds:

O
O

This type of 1.1 dioxygenated compound has four ether linkages to disconnect. But if we can
recognise that one carbon atom has two C-O bonds, we can use the help of one oxygen
atom to disconnect other. And discover that we have an acetal. Both the C-O bonds should
therefore be disconnected in a single step as shown below.
1,1, diX
O + 2MeOH
Ph Ph CHO
O

Synthesis
MeOH O
Ph CHO Ph
dry H+ O

1,2 dioxygenated compounds: Since 1,2 difunctionalised skeletons are awkward to

construct, one sensible strategy is to disconnect to a readily available compound instead of
disconnecting the 1,2 relationships.

12 S. Debnath
Examples (1): α-hydroxy ketones
HO O
HO
+ H
+
O O
natural polarity
should be +ve
illogical nucleophile H H

Synthesis O
1. HgSO4 HO
NaNH2 HO
H H H
2.H3O+ H2SO4
O

Examples (2): α-hydroxy ketones with same aromatic groups on both sides
O
Benzoin
Ar 2ArCHO
Ar
OH

O
Synthesis KCN Ar
2ArCHO Ar
OH

Examples (3): 1,2 diol- The best method for their synthesis is dihydroxylation of alkenes
O
OH R
hydroxylation +
R R R
R R
PPh3
OH

R-Br + PPh3

Synthesis O
OH
1. PPh3 R 1.m-CPBA
R-Br R R R
2. PhLi R R
PPh3 2. NaOH
OH

Examples (4): 1,2 diketo: This type of compound can be synthesised by oxidation of α-
hydroxy ketones or by oxidation of ketone having –CO-CH2- group by SeO2.

13 S. Debnath
 O O
R R
R R
O

Synthesis
O
O SeO2 R
R R
R
O

Examples (5): α-hydroxy acid:

FGI Me OH 1,1 C-C Me OH

Me OH
+ -CN
Ph CN Ph
Ph COOH

Me
O
Ph

Synthesis
Me 1. KCN Me OH
O
Ph 2. H2SO4 Ph COOH

1,3 dioxygenated compounds:

1,3 dicarbonyl compound:

General disconnections:

O O
O O O
_ + X
X= halide, OEt etc
leaving group

Example 1:

14 S. Debnath
 O O
O
O O
_ + EtO
Ph
Ph

Ph

Synthesis O
O O H3O+ O O
O
EtO
Ph Ph
Ph NaOEt in EtOH
This is Claisen condensation reaction. The forward synthesis of this reaction can give some
undesired product. To avoid the undesired product formation, this type of compound
having -CO-CH3 can be synthesized starting with EAA as shown below.

Example 2:

O O
O O O O
a a
+ + EtO
b O
O
O

b
O O O O O O O
CO2Et

CO2Et
OEt OEt
O O O

Both the syntheses were found successful. Since path b gives available starting materials,
path b is more preferred.
Synthesis
O O
O
CO2Et NaOEt

CO2Et
O

15 S. Debnath
Example 3:
O O O
b a
CO2Et EtO
O
a + CO2Et EtO
+

O O
CO2Et OEt
EtO
O

Synthesis via route b is intramolecular and hence fast and clean. Therefore, route b is more
preferable. In fact, five membered cyclic compounds including cyclopentanone are
synthesised via route b.

β-hydroxy carbonyl compounds: one possible route for synthesis of this type of compounds
is Aldol condensation.

Example 1:

O OH O OH O O
_ +
+ +

This is a clean reaction since it is Aldol condensation reaction by self-condensation of a

ketone.
Synthesis
O O OH
NaOH
Aldol condensation

16 S. Debnath
 1,3 dihydroxy compounds: This compound can be converted to β-hydroxy carbonyl
compounds by FGI before disconnection.

Example:
O
OH OH OH O OH O
FGI O +
+
Aldol between
same compound

Synthesis
OH O OH OH
Ba(OH)2 H2, Ni
O

α, β unsaturated carbonyl compounds: This type of compound is easily formed from

dehydration of β-hydroxy carbonyl compound. Thus, in retrosynthesis α, β unsaturated
carbonyl compounds can be converted to β-hydroxy carbonyl compounds by FGI followed
by 1,3 diO disconnection. In short, the disconnection of α, β unsaturated carbonyl
compounds is written in a single step to two carbonyl compounds as shown below.

OH O O
O FGI OH O 1,3-diO O +
+

In short
O , O
O +

Example 1:

O O
O O ,  O
O
O +

Synthesis
O
O O
NaOH O
O

Example 2:

, CHO
Ph
Ph +
CHO CHO

This synthesis is carried out in base with large excess of PhCHO to minimise the self-
condensation of the aliphatic aldehyde.

17 S. Debnath
 Synthesis
NaOH
CHO Ph
3 Ph + H2O, EtOH CHO
CHO

1,4 dioxygenated compounds:

1,4 diketone and ester: As discussed earlier, 1,4 diketones and esters can be disconnected
at its central bond into a natural enolate and also an unnatural synthon as shown below.
O O Br

O O O
unnatural
O synthon

α-halo carbonyl compounds are useful synthetic equivalent for this synthon. But direct
condensation between a carbonyl compound with α-halo carbonyl compounds can give side
reaction since the acidity of α-halo carbonyl compound is also increased. To avoid the side
reaction enamine is used as enolate equivalent. In other way, the ketone is taken as doubly
activated.

Example 1:

Example 2:

18 S. Debnath
Example 3: 1,4 dicarbonyl compounds can also be disconnected via an illogical nucleophilic
synthon pathway.

4- hydroxy ketones or 4- hydroxy acids can be synthesised via epoxide pathway as shown
below.

19 S. Debnath
 O
Home work: How can you synthesise OH ?

1,4 dihydroxy compounds: During retrosynthesis it can be converted to 1,4 diketones or 4-

hydroxy ketones by FGI followed by same way of disconnection as already discussed.

1,5 dioxygenated compounds: Disconnection of 1,5 dicarbonyl compounds at C2-C3 bond

give two logical synthons as shown below.

O O
O O 1,5 diCO
R1 + R2
1 2
R R Synthetic equivalent
of this synthon can be
O either enamine or presence
of another activating group
R1

Example 1:

Example 2:

Example 3: via enamine

20 S. Debnath
Example 3: preparation of Michael acceptor by Mannich reaction

1,6 dicarbonyl compounds: Reconnection is the usual strategy for synthesising 1,6
difunctionalised compounds since it requires cyclohexenes which are easily available. E.g.

Example 1.

CO2H Reconnect
CO2H

Synthesis 1. O3 CO2H
2. H2O, Ozonolysis CO2H

21 S. Debnath
Example 2.
O
OH OH
Reconnect FGI
O CH3
+
COOH
MeMgI
O OH
Synthesis H3O+ 1. O3 O
1. MeMgI,
dry ether 2. H2O, Ozonolysis COOH
2.H3O+

Example 3. Using Baeyer-Villiger oxidation

O O
O OH
FGI Reconnect O via
H CO2Me H CO2Me
Baeyer
Synthesis Villiger

O O
OH O
mCPBA O MeOH PCC
H CO2Me H CO2Me
Heat

Protection and deprotection of functional groups: Protection of groups allow us to

overcome simple problem of chemoseletivity. E.g.,
OH
NaBH4
CO2Et
2
O

CO2Et
O
1
?
CH2OH
3

It is easy to make alcohol 2 from 1 by reducing more reactive carbonyl group. But making
alcohol 3 by reducing less reactive ester carbonyl group keeping more reactive keto
carbonyl intact is not an easy task. This can be done by protection of more reactive group
and after reaction deprotection it.
O
O O O H3O+
HO OH O O LiAlH4 OH
OH
CO2Et CO2Et
dry HCl

A protecting group must be:

22 S. Debnath
 1) Easy to put in and remove.
2) Resistant to reagents which would attack the unprotected functional group.
3) Resistant to as wide as a variety of other reagents as possible.

Protection of –OH group: Acetal and ketals formation are used to protect diol. Generally,
readily available carbonyl compound is used to protect the diol. E.g.

Br C-Br HOOC
HO HO FGI

HO bromination HO HO

Salicylic acid

But in the forward synthesis bromine might oxidise the reactive benzylic alcohol. To avoid
that an acetal protecting group is added.

Acetal protection can be used to protect simple alcohols as well as diol. Two best protecting
group for simple alcohols are ‘THP’ (tetrahyropyran) and ‘MEM’(methoxyethoxymethyl)
derivatives.

Dry H+ RO-THP
R-OH + R O O
O
Dihydropyran
(DHP)
Et3N R O RO-MEM
O O O
R-OH + Cl O

MEM chloride

THP and MEM protection is removed by dilute acid (H3O+).

Protection of ArOH is done by transforming it as –OCH3 which is deprotected with HI.

A OH A O CH3 A O CH3 A OH
Me2SO4 reaction is HI
NaOH done
B B C C

23 S. Debnath
Protection of Carbonyl: Aldehydes and ketones are protected as acetal or ketal with
ethylene glycol under dry acidic condition. E.g.,
O
O O O H3O+
HO OH O O LiAlH4 OH
OH
CO2Et CO2Et
dry HCl

Protection of acids: Acid groups are generally protected as methyl or ethyl ester.
Deprotection is done in acidic or basic hydrolysis condition which one is suitable for the
other part of the molecule.

Protection of amine: Amine group of amino acid is protected by Boc protection. Thus,
during peptide synthesis acid group of one amino acid is protected by formation of ester
and amine group of another amino acid is protected Boc. E.g., Synthesis of ala-phe dipeptide is
done in the following pathway.

Protection of other amine groups are done by converting –NH2 to –NHAc. E.g.,

24 S. Debnath
 O O O

NH2 HN HN HN
Ac2O/NaOAc Conc HNO3 NO2
+ Separated by
Conc H2SO4 Chromatography

O NO2
NH2
HN 1. H3O+, reflux
2. NaOH
NO2
NO2

Some Common Synthons and Synthetic equivalents:

25 S. Debnath
 Synthons Synthetic equivalent

R RLi, R2CuLi, RMgX

R C C R C C Na , R C C MgBr

CH(COOEt)2 CH2(CO2Et)2

O O O
N
CO2Et
R1 R1 R1
R2 R1
R2 R2
R2
(Specific Enol Equivalent)
O
H C C Na ,
H3C C
O S
R C
R C
H S
COOH KCN

R+ R-X

R C O R C O R C O
Cl OEt
O O
Br

R2C-CH2-C-R1 R2C=CH-C-R1
O O
R1 R1
OH O
R2 R2

OH O

COOH CO2

Ring synthesis: Thermodynamic and kinetic factors

26 S. Debnath
Intramolecular reactions are usually favoured kinetically over intermolecular reaction for
the reason of entropy because the two reactive sites are part of the same molecule and
there is no need for bimolecular collision. This factor is greatest in three membered ring
formation where the two ends of the reagent are always close (1), and for five membered
ring formation where natural thermal motion brings the reactive groups into bonding
distance (2). Four membered rings formation are uniquely slow. The chain normally adopts
the conformation (3) with the reactive groups far apart and even in the best conformation
(4) for cyclisation, they are still far away. Six membered ring formation is kinetically
reasonable but the problem here is the larger size of ring. Rotation brings the reactive ends
to close (5).

Nu E
Nu E
(1)

Nu E Nu E
Nu E

(2)
Nu E
Nu Nu E
E
(3) (4)
Nu E Nu
E E
Nu

(5)

(6)

The six membered ring is uniquely favoured thermodynamically in its chair

conformation (6) where the bond angle of SP3 hybridised carbon can be maintained. Five
membered rings are also stable but three and four membered rings are strained with bond
angle is 60o and 90o instead of 109o.

Thus, taking both factors into account, five, six and seven membered rings are easy
to make since they are both kinetically and thermodynamically favourable. Three
membered rings are easy to make (kinetically favoured) but often breaks down again under
the condition of their formation. Four membered rings are uniquely awkward since they are
unfavourable from both thermodynamic and kinetic point of view. They often need special
method for synthesis.

Synthesis of rings: Three to seven membered rings can be synthesised by using

Diethylmalonate (DEM).

27 S. Debnath
 (CH2)n CH-C-OH n=2, 3, 4, 5, 6
O

These compounds are synthesised by the reaction of dihalide and DEM as shown below.

O O Br
O O NaOEt/EtOH H
Br CO2Et
C NaOEt/EtOH
EtO OEt EtO OEt CO2Et

Br
O
CO2Et
C CO2Et 1. dil KOH
CO2Et C OH
2. H3O+
CO2Et
Br 3. Heat, 150oC

Three to seven membered ring (Except four membered) can also be synthesised by
using ethyl acetoacetate (EAA).
n=2,4,5,6
(CH2)n CH-C-CH3
O but n= 3

This compound is synthesised by the reaction of dihalide and EAA as shown below.

Br O
O O NaOEt/EtOH O O H
Br CH3 NaOEt/EtOH
C
OEt OEt CO2Et
O Br
O O
C CH3
CH3 1. dil KOH
CO2Et C CH CH3
2. H3O+
CO2Et
Br 3. Heat

If we try to synthesis four membered ring with EAA we will end up with the following
compound.
CO2Et CO2Et
C
Br
O CH3 O CH3

This is because the keto group is more reactive than that of ester group and four
membered ring is very difficult to form due to lack of proper conformational orientation.
Again, six membered ring is more stable than that of four membered ring.
O

CH3
Now synthesis of can be done in the following way.

28 S. Debnath
 O O O

OH SOCl2 Cl 1. Me2CuLi in THF CH3

2. H3O+
(using DEM)

These ring compounds can also be synthesised by Dieckmann and Acyloin

condensation.

Synthesis of large rings: Application of high dilution principle

In organic chemistry, the High Dilution Principle is a strategy for the synthesis of some
large ring compounds i.e., the synthesis of macrocycles. Unlike the synthesis of 5- and 6-
membered rings, the preparation of larger rings competes with unfavourable
polymerization reactions. Polymers arise from intermolecular coupling of long chain
precursors i.e., from intermolecular reaction. This intermolecular reaction can be reduced if
we use very dilute solution of the bifunctional compound. Thus, large rings are generally
synthesised by carrying out the reaction in very dilute solutions (high-dilution technique) to
reduce the possibility of coupling of reactive groups on the ends of different molecules.

For the formation of the larger rings via intramolecular reaction is both
thermodynamically and kinetically favourable than intermolecular reactions. Intramolecular
reaction is thermodynamically favoured since ΔS for the reaction is more positive than that
of intermolecular reactions. Again, intramolecular reaction is kinetically more preferred
since ΔS‡ is less negative than that of intermolecular reactions. E.g.
CH2-C=O
CH2-C N t-BuOK
CH2-C=NH H3O+
(CH2)n (CH2)n
(CH2)n Hydrolysis
t-BuOH CH-COOH
CH2-C N CH-C N
Heat
-CO2
CH2-C=O
(CH2)n
CH2

This is Thorpe-Zeigler reaction. This type of large ring compounds can also be synthesised by
Dieckmann and Acyloin condensation.

29 S. Debnath
Some Important retrosynthesis:

1.
HO
HCHO
1,1 diO HO FGI
O O CH
HO CH
O
HO HCHO

Synthesis HO

H2/Pd/BaSO4 HO O O
1. Na in lig NH3
H H HO O
(excess) dry HCl
2. HCHO (2 mole) HO
3. H3O+

2.

3.

30 S. Debnath
 O OH O
Ph CO2Et + 2 PhMgBr

Ph
Synthesis HO
O OH
O 2 PhMgBr O O
OMgBr H3O+
HO O O Ph
CO2Et CO2Et Dry ether Ph
Dry HCl
Ph
Ph
The carbonyl group is protected first since it is more reactive than ester towards Grignard
reagent.

4.
Ph Ph
Ph Ph PhCHO
Ph Ph + KCN
  O OH
O O
Ph Ph
Ph Ph Ph Ph
O
O O

Ph
PhCH2Br PhCH2MgBr +
N
Synthesis
Ph Ph conc. HNO3 Ph Ph
KCN
2 PhCHO
Benzoin condensation O OH O O
and Ph Ph Ph Ph
1. Mg in dry ether
PhCH2Br Ph Ph O O
Ph Ph
2. Ph-CH2-CN O NaOEt/EtOH
O
3.H3O+

31 S. Debnath
5.
O
O O O
CO2Et
CO2Et   CO2Et CO2Et
O 1,5 diCO O EAA

Ph Ph Ph Ph Ph Ph

O O
OHC  
Ph
Ph CH3 + Ph Ph

Synthesis O
O O
NaOH
+ Ph CH3
Ph H Aldol Ph Ph
Now
O O O
CO2Et CO2Et CO2Et Heat
NaOEt/EtOH O NaOEt/EtOH HO TM
O + -H2O
Micheal addition Ph Ph intramolecular Ph Ph
Ph Ph aldol

6.

1, 3 diCO FGA CO2Et

1, 5 diCO CO2Et
O O O O O O O
O
OEt OEt O O
OEt

  CO2Et
+
O O
O O
Synthesis OEt

CH2(CO2Et)2 CO2Et
Ba(OH)2 OH H3O+
O NaOEt/EtOH
O O O O
Michael addition OEt
NaOEt

1. dil KOH CO2Et

2. H3O+
O O O O
3. Heat, -CO2

Similar question: Show retrosynthesis and synthesis of

32 S. Debnath
33 S. Debnath