Retrosynthetic Analysis.

E.J Coreys definition of retrosynthetic analysis:

it is a problem solving technique for transforming the structure of synthetic
target molecule (TM) to a sequence of progressively simpler structures along
the pathway which ultimately leads to simple or commercially available starting
materials for a chemical synthesis.

The transformation of a molecule to a synthetic precursor is accomplished by

Disconnection: the reverse operation to a synthetic reaction, the imagined
cleavage of a bond,
Functional Group Interconversion (FGI): the process of converting
one functional group into another by substitution, addition, elimination,
reduction, or oxidation.

Each structure thus derived from TM then itself becomes a TM for further
analysis. Repetition of the process eventually produces a tree of intermediates
having chemical structures in the nodes and possible chemical transformations as
pathways from bottom to TM. One should avoid excessive branching and
proliferation of useless pathways. Strategies for control and guidance are of the
utmost importance.

Synthetic Strategies: Choosing the way along the retrosynthetic tree, synthetic
planning.
Synthetic Tactics: How a specific bond or set of bonds at a given site can be
efficiently created.

Tactics of synthesis.
Retron The minimal substructural element in a target structure which keys the direct
application of a disconnection to generate a synthetic precursor. For instance, in Diels-Alder
reaction the retron, a minimal keying element, is 6-membered ring with a -bond:
+

Synthon An idealised fragment, usually cation or anion, resulting from a disconnection. May
or may not be an intermediate in the corresponding reaction.
Reagent compound used in practice for a synthon.
Synthon

Reagent

O
+

O
Cl

Li

Disconnections
Basic Guidelines:
1. Use disconnections corresponding to known reliable reactions, choose disconnection
corresponding to the highest yielding reaction.
a

Ph

- CH

+ CH

Ph

+
PhCH2

b
PhCH2

2. Disconnect C-C bond according to the present FGs in the molecule, few examples:
a. C-C bond with no neighbouring functional groups
R

R C

R'

R'

b. C-C bond with one oxygen substituent

R

R C

OH

c. Allylic C-C bond

R

d. C-C bond with two oxygen substituents in positions 1,3

O

OH

R'

O
+
C

R'

e. C-C bond with two heteroatom substituents in positions 1,2 or 1,4. Umpolung methods.
O
R

+ NO2

O a

b
R

R
NO2

NO2

3. Aim for simplification:

a) Disconnect C-X bond (RCO-X)

OH

Quadrone

b) disconnect in the middle of the molecule

CHO

Ph3P+

C9

Faranal, Pharaoh's ant trail pheromone

CHO
protection
needed

C7

EtMgBr.CuBr

C9:

MgBr*CuBr

O
1. LiAiH4

C7:

KMnO4

2. MsCl
3. LiAlH4

O
1.EtOH/H+

HO
HO

2.BH3/THF

EtO
HO

O
1. TsCl

Tetrahedron Lett. 1981, 22, 5001

EtO
I

2. NaI

c) disconnect at a branch point

d) use symmetry
MeCOOEt

MgBr

MgBr

OH
OH

OH

HO

OH

OH

OH

OH

OMe O

OH

(+-)-Hybocarpone

SET

MeO

K.C.Nicolaou
Angew. Chem. Int. Ed. 2001, 40, 761

OH
OMe O

e) disconnect rings from chain

OMe

HO

OMe

+
N

BrMg

f) use rearrangements
O
Claisen

HO

HO

OH O

O
O

OEt

O
O
O

H
Oxy-Cope
H

OH

Cl

CN

4. Carbocyclic Rings:
If one or more 6-membered carbocyclic unit present in the molecule consider a set of
disconnection available for construction of 6-membered rings: Diels-Alder, Robinson annulation,
aldol, Dieckmann, internal SN2, Birch reduction, etc.
Some types of Diels-Alder disconnections:
O

+
O

X
Y

+
O

+
OR

O
O

+
O

X
Y

OR

5. Examples of cleavage of C-C bond as a retrosynthetic reconnection

O

HO

CO2H

h
O

CO2H

AcOH/H2O

CO2Me

h
O

MeOH

CO2Me

Base
TsNHN

ZnBr2

OH

Br

Me

OTs

H
t-BuOK
H

OH

O
OMe

OMe
1. O3

O
OH

2. NaBH4

NOCl
O

H2O

NOH

Examples of effective disconnections:

Tago K and Kogen H Tetrahedron, 2000, 56, 8825

OH

OH
Plaunotol
OH

Br

OH

OH
Key step
(RO)2

O
P

Geraniol

OH

CO2Me
Br

OH

OH

HO

Br

oC,

THF, -78
t-BuOK
18-crown-6, 30 min.

R = Et mixture E:Z
R = CF3CH2 exclusively E

Tetracyclic Tigliane ring system

Claisen

OH
O

OH

OH

anionic
cyclisation

OH

OH

MeLi cat., Ph2O, heat

Phorbol

Ovaska TV et al, Org. Lett. 2001, 3, 115

MeHN

NMe
Tropinone
Willstatter, 1902, 19 steps, yield 0.75%

COOH
MeNH2

O
Robinson, 1917, yield 17%

O
COOH

Functional Group Interconversion (FGI):

Classification of functional groups by oxidation state of carbon atoms:
Oxidation state of carbon in alkanes (cycloalkanes ) is 0,
the carbon in the fragment C-H is approximated as carbanion

-e

-e

C+

O
-

2+

3+

2-

2-

..

..

C
C

L
L

Oxidation level 1 (alkane 2e):

C-X (X = Hal, OH, OR, OAc, OTs, NR2, NO2, SR, etc);
C=C
Oxidation level 2 (alkane 4e):
C=X (X = O, NR); CXY (X, Y = Hal, OR, SR); C=C-X (X = Hal, OR, OSiR3); CC; X-CC-Y; epoxides.
Oxidation level 3 (alkane 6e):
COOH, COX (X = OR, Hal, OCOR, NR2);CN, C=C-C=O, C=C-CC

Based on this classification FGI can be divided into two groups:

Type 1. Isohypsic transformations with no change to the oxidation level of carbon
Type 2. Non-isohypsic transformations, where carbon atom is either reduced or oxidised.
In general, on the same oxidation level any functional group interconversion can be
performed in more or less easy way. However, transformations between levels can be achieved
only on certain derivatives.
R
O

R'

R'

but

OH

R'O

???
but Hal

Hal

Hal

Type 1 (no change in oxidation state), Level 1. The most common functions resulting
from C-C bond construction are alcohol (Grignard addition to carbonyl compounds, aldol
reaction, etc) and olefin (Wittig and related processes, croton condensation, olefin methathesis,
etc). In addition, FGI of type 2 often lead to alcohols and olefines (reduction of carbonyl
compounds, partial hydrogention)
R OSO2R'
R OH
R Hal
R

R'

sythones

X
H

R'

R'

HX

R Y

X = Hal, OTs, OMs, OTf

Y = OR', OCOR', SR', NR'2, N3, NO2

-HX
R

R X

Markovnikov

anti-Markovnikov

Conclusion: in practice all functions of oxidation level 1 are synthetically equivalent as they
can be easily transformed into each other.

Type 1 (no change in oxidation state), Level 2. The main functional groups are carbonyl
compounds (aldehydes and ketones) and alkynes.
Formation of synthetic equivalents of carbanions:
O

Base

HC

RLi

OTMS

TMSCl

Li

Formation of vinyl derivatives.

X

X = Hal, OR, OCOR

In organic synthesis vinyl halides can play a dual role: as electrophiles in reaction with
organocuprates and as nucleophiles when transformed themselves into organometallic
derivatives.
Compounds having two functional groups of level 1 which react as a whole belong to level 2
(1,2-disubstituted compounds, oxiranes, allylic systems)
X

-H+

-XO

OH

+YO

+H+
OH

Formation of epoxides in a C-C bond forming procedure (apart from epoxidation of olefines):
O

CH2

+
SMe2

Formation of allylic systems:

OH
O

MgX
H-

NBS

OH

Br

1) TMSOTf, 2) Base

Or LDA, heat
H

HO

Type 1 (no change in oxidation state), Level 3. The main functional group that allows
formation of any other derivative on the same level is acid halide. This is a typical electrophile
used to make derivatives of carboxylic acids and in Friedel-Crafts C-C bond forming reactions.
Et3N

Polyfunctional compounds of level 3 are ,-unsaturated aldehydes and ketones good Michael
acceptors:
O

HX

X = OH, Hal, SR. NR2, etc

Type 2 transformations. Availability of methods to go from alcohol to carboxylic acid

derivatives and back makes alkohol, carbonyl and carboxyl functions synthetically equivalent.
[O]

OH

[O]

OH
O

[H-]

OR

[H-]

OH

Other important kind of transformations interconversion of nitrogen containing functions.

RCN

O
OH

NR2

NR2

NO2

Hal

NO2

NR2

NH2

NH2

[H]
N3-

NR2
NO2-

RNH2

NH2

O
R

[O]

N3

RNO2
R

OMe
OMe

Conclusions:
1. Many functional groups, especially on the same level of oxidation, can be considered as
synthetically equivalent so their retrosynthetic interconversions can be planned.
2. As any functional group can be removed, retrosynthetically we can put a functional group
in any position of alkane or cycloalkane chain and that would allow assembly of a given
C-C fragment. Unfortunately, reverse is not achievable as yet.
Example:

HO
H

NH2. HCl

Br

GABAB receptor agonist

(R)-balcofen hydrochloride

N
N

Catalyst

O
Ph

E.J.Corey, F-Y Zhang, Org. Lett, 2000, 2, 4257

Cl

PhO

NO2

mCPBA

MeNO2
Cl
NiCl2/NaBH4

HN
O

cat.

Cl
5N HCl

Cl

TM

Cl

NO2