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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5648_Библиотеки_им_академика_М_И_Перельмана.pdf
32 Pharmaceutical Chemistry
Target
molecule
Carry out
synthetic steps in
laboratory
Trial & error
Synthesis
Retrosynthetic
analysis
Recognize the
functional groups
in target and
their relationship
to one another
Repeat as
necessary
Disconnect by methods
corresponding to known
and reliable reactions
Arrive at starting
materials
Synthetic
planning
Write out plan according to
analysis, adding reagents
and conditions
Repeat as
necessary
Modify plan according to
unexpected failures or
successes in the laboratory
Fig. 2.3: Retrosynthetic analysis and synthetic planning
(2) Strategies based on topology or shape: We can identify points based on the shape
of the target structure. Major molecular simplification can be disconnected by
specific bonds or so-called “strategic bonds” and can be of several types:
Basic Retrosynthetic Approach 33
%RQGVLQF\FOLFULQJV\VWHPV
%RQGVLQIXVHGULQJV\VWHPV
3DLUVRIERQGVGRXEOHLQULQJV\VWHPV
3DLUVRIERQGVGRXEOHDQGWULSOHLQWKHULQJV\VWHPV
%RQGVFRQQHFWLQJFKDLQVWRULQJV
%RQGVFRQQHFWHGWRKHWHURDWRPVLQWKHULQJV
%RQGVFRQQHFWLQJFKDLQVWRRWKHUFKDLQV
%RQGVFRQQHFWLQJFKDLQVWRIXQFWLRQDOJURXSV
(3) Strategies based on transform: Retrosynthetic analysis transforms can be provided
by the application of the simplifying transformations, viz., Diels-Alder, Birch
reduction, Hetero Diels-Alder, internal Ene reaction, Robinson annulations, Haloactonization, etc.
(4) Strategies based on structure goal: The retrosynthetic analysis can also be directed
towards a specific structure or substructure, such as:
6WDUWLQJPDWHULDO
&KLUDOEXLOGLQJEORFN
5HWURQFRQWDLQLQJVWUXFWXUH
(5) Strategies based on stereochemistry: Stereochemistry is another important aspect
of strategy. Thus, the main focus is on the removal of stereocentres under
stereocontrol by using either mechanistic control or substrate control.
Example 1: Functional group addition: Target is the synthesis of cyclic amine. If a keto
group is introduced into the ring (as in cyclic amide), the ring system can be generated by
Beckmann rearrangement using oxime. Oxime can be produced from the ketone. Therefore,
the production of cyclic amide is a sub-goal, which can be generated from the cyclic amine
through the functional group addition. From cyclic amide, cyclic amine can be obtained
by reduction as follows:
OH
H
N
FGA
H
N
Beckmann
O
rearrangment
N
OximeAmine Amide Ketone
O
Example 2: Functional group removal: We want to synthesize molecule hydroxyl
benzaldehyde (HB) analogue (ultimate goal). Friedel-Craft’s reaction can be applied for
the synthesis of substituted phenol by reacting 2-chloro-2-methyl propane with phenol in
the presence of anhyd. AlCl
. Now, we have full carbon skeleton except the aldehyde
3
group present in HB. We can even have similar C-skeleton, if we chop the -CHO group
from the HB. Finally, using Reimer-Tiemann reaction the functional group -CHO may be
introduced later.
34 Pharmaceutical Chemistry
,
CHO
OH
HB
FGR
Reimer-
Tiemann
Friedel-Crafts
+
OH OH
Cl
Example 3: Functional group interchange transform: Target is to synthesize molecule
hydroxy-phenyl-acetic acid (HPAA, which is goal). If we can place cyano group instead
of acid group in hydroxy-phenyl-acetic acid (HPAA) then it will be cynohydrin called
hydroxy-phenyl-acetonitrile (HPA). HPA can be easily obtained using reaction between
HCN and benzaldehyde. Thus, benzaldehyde is a commercially and economically available
compound. Therefore, hydrolysis of cyano group will lead to the required acid functionality.
Thus, the following retrosynthetic method can be applied for the synthesis of HPAA.
OH
FGI
COOH
Hydrolysis
HPAA HPA
OH
CN
CHO
HCN
2.3 BASIC SYNTHETIC STRATEGIES: GENERAL APPROACHES USED FOR SYNTHESIS PROBLEMS
(1) Trained response or reflex: Sometimes, it is not easy to look at a target molecule so
we can immediately see the key functional transformations.
Example 4: Target:
Transforms:
1, 2
Conversion:
O
+
H
Ph
S
Ph
3
S
4
O
NaOH
Ph
Ph
Ph
5
O
1. Terminal olen transform (Wittig olenation)
2. Former carbonyl
3.
b-functionalized carbonyl transform (conjugate addition)
Ph
4. Former
5.
PhCH
pyridine
a, b-unsaturated ketone
a, b -
unsaturated ketone transform (aldol condensation)
2
SH
OPhS
Ph
Ph
PCH
3
4
S Ph
Ph
(2) Atom mapping: The “Forward” approach
Target:
Basic Retrosynthetic Approach 35
O
EtO OEt
O
OO
and anything else with
four or fewer carbons
Approach: If someone has to start the synthesis of target molecule with an appropriate
starting material, the first step is to find out the molecule involved in the product by
matching atoms or functional groups. Example: synthesis of malonic ester is difficult by
decarboxylation which makes mapping harder since some atoms “disappear.”
The –COOR group at D-carbonyl position of the product is essentially a retrosynthetic
decarboxylation product. Afterwards, transformations can be applied for the synthetic details.
3
O
O
1
5
O
O
+
EtO OEt
O
COOEt
4
OO
EtO OEt
1. Add COOEt group to a
2. You can map in the malonic ester
3. 1,3-dicarbonyl transform: Claisen condensation
4.
b-alkylated ketone transform: Michael addition to a, b
unsaturated carbonyl
5. Selective 1,2-addition transform: Alkyllithium addition
OO
2
carbonyl position
Conversion:
O
EtOOC
H
COOEt
1. n-BuLi
O
2. H
3
O
OH
nBu
excess
NaOEt
EtOH
DMP
O
O
O
COOEt
(3) Retrosynthetic analysis: The “backward” approach
Target:
O
O
necessary reagents
O
HO
CONMe
CONMe
2
2
EtO
nBu
NaOH, H3O
Δ
and any other
O O
NaH
O
OEt
O
36 Pharmaceutical Chemistry
Approach:
The product indicates that this might be a Diels-Alder product, however, we must work
backwards to prove this point.
Conversion:
O
TBSO
+
Δ
O
TBSO
O
O
O
O
Me
DCC
2
NH
TBSO
CONMe
CONMe
2
2
KF
O
H
2
O
CONMe
CONMe
2
NaBH
4
2
H2O
HO
CONMe
CONMe
2
2
Synthon
Disconnection of a bond in the target molecule will lead to the imaginary pair of charged
fragments. These charge fragments could stick together and can be used to make the target
molecule. These imaginary charged species are known as synthons. When synthons are
synthesized then we can choose respective chemicals or reagents, known as synthetic
equivalent (or reagents) of the synthon.
Synthons and reagents
OH
R
O
R
O
R
O
R
OH
R
O
R
O
R
O
R
Synthons
Equivalents
Example: First possible approach:
Basic Retrosynthetic Approach 37
OH
Synthons
Synthetic
equivalents
Second possible synthesis:
Similarly,
Ph
Third possible synthesis:
OH
A
OH
CHO
BrMg Br
i) Mg/Et2O
Br
ii) PhCHO
OH
Ph
O
BrMg
Ph
B
OH
?
OH
Ph
OH
Ph
Ph
O
BrMg
Besides disconnected fragments (synthon), we can also consider functional group interconversion (FGI). Our target molecule is a 2° alcohol, which could be prepared by reducing
the ketone. This can be shown as follows:
Ph
OH
FGI
O
Ph
Synthetic
equivalents
Ph
Ph
O
O
Synthons
Br
Synthetic
equivalents
38 Pharmaceutical Chemistry
Fourth possible synthesis:
O
Ph
Ph
O
ii)
i) base
Br
Fifth possible synthesis:
O
Ph
O
Ph
O
Ph
Sixth possible synthesis:
O
Ph
Ph
O
t-Bu2CuLi NaBH
Disconnecting heteroatoms can also be a good idea:
OH
OH
LiAlH
LiCu(
4
4
"H2O"
Target Molecule
)
2
Target Molecule
Ph
Ph
Ph
Seventh possible approach:
OH
Ph
Ph
i) Hg(OAc)
ii) NaBH
2
4
Retron: A retron is a structural subunit in the target molecule (TM) which allows using of
a specific transformation. For example, the retron for the Diels-Alder transformation is a
six-member ring containing a S-bond.
+
Diels-Alder retron
Basic Retrosynthetic Approach 39
Example: Aldol retron: 3-Hydroxyketones (and D,E-unsaturated ketones) are aldol retrons:
OH
O
Aldol retron
R
O
O
+
H R
2.4 RETROSYNTHETIC ANALYSIS: OTHER SIMPLIFICATION RULES
There are some rules which can make synthesis more convenient for complex molecules:
Make the synthesis as short as possible.
The optimal disconnection leads to fragments of roughly equal complexity.
Use only transforms which correspond to the known reliable reactions (e.g.,
transformation of Viridenomycin).
MeO
Enol-ester
HO
HO
formation
Heck-Mizoroki
coupling
O
O
Viridenomycin
O
Amide
coupling
NH
MeO
HO
HO
O
OR
2
HO
Synthetic equivalents
4
OI
OR
3
NH
2
Simplify rings by disconnecting side chains: Simple example: Peptide synthesis:
H2N
OH H
O
Gly Phe
H3N
O
H
N
O
N
2
N
H
O
O
OH
H2N
O
H
N
O
SMe
H2N
OH
O
Ale Met
O
SMe
OH
Compound
Synthetic
equivalent
s
Disconnect strategic bonds.
Are often those to heteroatoms (O, N, S, P), e.g., ester, amide, imine, acetals, and ethers.
40 Pharmaceutical Chemistry
Strategic bonds are easy to form.
H
N
HO HO
Paracetamol
O
NH
Cl O
2
++
O
Synthetic equivalents
O O
For acyclic systems disconnect a branch point.
Give straight chain fragments which are normally easier to obtain.
+
XGM
OH
O
Synthetic equivalents
Disconnect linked rings: Often strategic bonds.
O
OMeOMichael retron
O
OMe
+
O
Synthetic equivalents
Polycyclic systems: Fused rings: disconnect to give “equal” sized fragments.
Double bond or other functionality might indicate “strategic bond”.
O
Aldol retron
O
O
O
O
+
Synthons
OO
O
Bridged ring systems: Disconnect to get a simple fused ring system
ʊ Look for “common atoms”
ʊ Disconnect the ring with maximum bridging
Avoid generation of large rings (>8 atoms)
FGA
O
Electrophilic
site
Nucleophilic
site
OX
CH3NO
Reagent
2
Basic Retrosynthetic Approach 41
Make use of symmetry: If symmetry is present regioselective issues is no concern.
Actual symmetry.
OH
O
2
+
OR
MgX
“Latent” symmetry: Sometimes the symmetry is more “hidden”.
O
O
O
MgX
O
O
+
X
SS
SS
2.5 RETROSYNTHETIC ANALYSIS: SYNTHETIC IMPROPRIETY TO AVOID
(1) When applicable, include all necessary reagents
OO
H3O
Bad Bad
OO OHHO
H2O
OHHO
OO OHHO
H
(2) Attention towards sequential addition of reagents
Good way Bad way
O
1. H3CMgBr
2. H
O
3
OH
O
H3CMgBr
H
O
3
OH
(3) Carbon counting
O
NaOH
O
H
2
O O O O
not
(4) Use the reactive functional groups of the starting material (in order of decreasing
reactivity): Using most reactive functionality first is the measure to minimize the
possibility of deleterious side reactions.