Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5406_Библиотеки_им_академика_М_И_Перельмана.pdf
42 Pharmaceutical Chemistry
EtNH
2
O
O
N
O
O
Pd/C, H
2
(5) Protect Reactive Functionality
Good way
O
N
H
O
O
O
Bad way
Pd/C, H
2
O
N
H
N
EtNH
2
O
HO
TBSO
TBSCI
NEt
3
Br
Br
2
CH3OH
2
TBSO
Br
No reaction
O
Br
OMe
(6) Conditions should be accurate for generating enolate
O O
O O
O
EtO
O O
1. LDA, 0 °C
2. CH
1. LDA, -78 °C
2. CH
O
OEt
1. LDA, 0 °C
2. PhCHO
I
3
I
3
1. Na or NaOEtH
2. CH
Ph
Do not use NaOR/ROH to make thermodynamic enolates
for alkylation. The enolate generation is an equilibrium and
you will end up hydrolyzing the alkyl halide.
O
O
I
3
EtO
Malonates are quite acidic, so you do not need
to worry about equilibria with weak bases and
OEt
there is no need to use costly basic reagent.
O O
1. LDA, -78
2. PhCHO
OH
HO
TBAF
pH 7 (H
°C
Br
OMe
O)
2
OH
Ph
O
1. LDA, 0°C
O
2. PhCHO
O
3. H
3
OO
PhCHO
Ph
NaOMe
MeOH
Ph
O O
1. LDA, -78°C
2. PhCHO
3. H
NaOR bases are usually fine here,
ut LDA is preferable method,
b
especially for crossed aldols.
Ph
O
3
Basic Retrosynthetic Approach 43
(7) Need to find better way to alkylate enolates with 2° and 3° alkyl halides
Bad way
1. LDA
Br
2.
1. Et
2. H
Ph
2
3
O
CuLi
+
O
1. LDA
2. CH
3. H
O
3
Good way
CHO
3
+
O
Ph
O
Ph
(8) Over-alkylation must be avoided
Over-alkylation must be avoided unless we want an extensively alkylated product
(viz., alkylation of amines or benzene must be avoided with alkyl halides).
(9) Play by the rules (read the question properly)
Sometimes we can look directly at the molecule and we observe that if there is
possibility of synthetic equivalents in one look, then we can use direct approach to
synthesize the target molecule.
Examples:
HN
O
N
HOOC
N
NH
2
COOH
VerrucolotoxinL-Phenyl alanine Picolinic acid
Thus, the synthesis may be as follows:
O
HN
N
NH
3
COO
NH
HN
O
N
Cl
O
HN
N
O
2
OH
HN
N
OH
Case Studies
Case 1: We have to synthesize bracketed compound by using the formation of synthons.
There are two pathways for the formation of synthons, using path a and b. Path a is the
right way to perform the reaction in forward direction while path b is not an appropriate
method to do so. In the path b synthetic equivalent 2-bromo propane is unstable as
compared to the other synthetic equivalents.
44 Pharmaceutical Chemistry
Synthons Synthons
NH
NH
2
Br
Proper way to synthesize is path a
Path b Path a
Br
+
Synthetic equivalents
H2N
HNCH
a
CH
3
3
b
CH
3
HNCH
3
HN
Br
H2N
Case 2: Synthesis of circled compound by using reverse synthesis using synthetic
equivalents of synthons.
ab
O
Path a Path b
Synthons Synthons
O
NaH, THF or DMF
O
Br OH
OH
Synthetic equivalents
Br
Path a is the right way to synthesize. In path b, there is a great risk of E2 and SN2 on
secondary halide.
Case 3: How can we synthesize benzocaine using retrosynthesis?
Benzocain can be synthesized by using synthetic equivalents of synthons. Thus, toluene
and ethanol are the main synthetic starting equivalents for the synthesis of benzocaine.
H2N
Benzocaine
O
O
H2N
H2N
O
O
Synthons Synthetic
O
OH
O2N
Retrosynthetic equivalents
OH
equivalent
O
OH
O2N
CH
3
CH
3
Basic Retrosynthetic Approach 45
Synthesis using synthetic equivalents
OH
CH
CH
NO
3
KMnO
2
3
HNO
3
H2SO
4
O
4
Pd/C
NO
2
O OH
H
2
NH
EtOH
+
H
2
O
O
NH
2
Case 4: Draw a synthetic plan of synthetic musk from m-cresol using retrosynthetic
approach for the following conversion.
NO
2
NO
2
OMe OH
m-CresolSynthetic Musk
Synthetic musk can be synthesized using synthons and synthetic equivalents in forward
direction. This musk can be synthesized using synthetic equivalents named t-butyl
chloride, 3-hydroxy toluene and HNO
as a starting material.
3
Case 5: Synthesis of bracketed molecule using synthetic equivalent of synthon of particular
molecule. Path b is a favourable condition to synthesize bracketed molecule. The synthetic
equivalents are not stable at path a due to regioselective problem as compared to path b.
46 Pharmaceutical Chemistry
Retrosynthesis:
OH
Ph
O
ab
Ph
OH
O
Path a Path b
Ph
OH
O
Synthon
OH
Ph
OH Br
Synthetic eqivalent
Ph
Synthon
O
HO
Synthetic equivalent
Synthesis of compound using synthetic equivalent
Ph
OH
O
HO
NaH,THF
O
Ph
Case 6: Bracketed compound has been synthesized using synthetic equivalent of synthons
of a particular compound. Thus, synthetic equivalent obtained from bracketed compound
indicates the only possible way which is Path a over Path b.
Retrosynthesis:
ab
Ph
O
Synthon
Path a Path b
R
O
O
Ph
O
O R
O
Ph
O
Synthon
O
R
O
O
Ph
Br
Synthetic equivalent
RHO
O
O
Ph
Synthetic equivalent
OH
Cl
R
O
Synthesis of compound using synthetic equivalent of Path a
Ph
O
Br
NaH CO
HO
O
3
R
Ph
OH
O
R
O
Case 7: Synthesis of anti-fungal agent fluconazole using retrosynthetic approach. For the
synthesis of fluconazole we have designed a retrosynthetic approach where we got
synthetic equivalents named m-diflurobenzene, acetyl chloride and 1H-[1,2,4]-Triazole as
starting materials.
Thus, the final synthetic equivalents are as follows:
Basic Retrosynthetic Approach 47
Synthesis of fluconazole using synthetic equivalent
N
N
N
O
O
F
F
Cl
Cl
Cl
N
F
F
O
NH
N
F
1. Ph3P=CH
2. -CPBAm
F
N
N
N
O
2
F
N
F
N
OH
N
NH
N
N
NN
N
F
F
Case 8: Design the retrosynthesis of captodiamine and synthesize using synthetic
equivalents.
48 Pharmaceutical Chemistry
NMe
S
S
Synthetic equivalent
2
S
S
Captodiamine
SH
NMe
S
Cl
Synthon Synthon
2
Synthetic equivalent
OCl
SH
Synthon
Cl
S
Synthon
S
Synthetic equivalent
Synthetic equivalent
Synthesis of captodiamine using synthetic equivalents
NMe
2
Cl
HS
Synthetic equivalent
S
Synthon
O
S
Synthetic equivalent
O
S
S
Synthon
NaBH
O
SOCl
2
NMe
2
Captodiamine
4
Cl
BuS
HS
Thiourea, base
BuS
n-BuCl
Na
CO
2
PhCOCI
AlCl
3
BuS
3
NMe
2
3
SH
Cl
Na2CO
BuS
S
BuS
Case 9: We have to synthesize 4-phenyl-but-3-en-2-one using retrosynthetic approach.
After disconnections we found that there are two synthetic equivalents participating in the
reaction, one is benzaldehyde and other is ketome. Both are excellent examples of aldol
condensation reaction. Benzaldehyde does not go for ionization due to aldehydic group
while ketone is symmetrical which makes best combination for synthesizing
4-phenyl-but-3-en-2-one.
Basic Retrosynthetic Approach 49
Retrosynthesis of 4-Phenyl-but-3-en-one using synthetic equivalents
Synthesis of propranolol using synthetic equivalents
OH
N
H
OH
Cl
K2CO
O
3
O
O
H2N
O
Case 10: Formation of synthetic equivalents of arildone and the synthesis of arildone
(effective against polio and herpes simplex virus) using retrosynthetic equivalents.
Retrosynthetic equivalents of rildonea
Cl
OH
OMe
Synthetic
equivalents
Cl
O
OMe
Br
Synthetic equivalents
O
O
equivalents
Br
O
O
Synthetic
50 Pharmaceutical Chemistry
Synthesis of arildone by using synthetic equivalents
Cl
OMe
OH
Base
Br
Cl
O
Br
OMe
Br
O
Base
O
Cl
OMe
O
O
O
Case 11: Design retrosynthetic equivalent of 1-cyclohexylidene-pentan-2-one. On
dehydration double bond (conjugated) can be prepared, thus we can synthesize aldol
product by using FGI. Therefore, it is very difficult to perform forward reaction where we
can get two carbonyl synthetic equivalents so it is must to try for best enolate selectively.
We can synthesize enolate by low temperature Li-enolate formation before the addition of
cyclohexanone. Thus, the preferable disconnection approach, Path b can be used for such
type of aldol condensation.
Retrosynthetic equivalents of 1-Cyclohexylidene-pentan-2-one
O
Path b
Path a
FGI
Rehydration
OH
OH
O
Retro-Aldol
Synthons
O
O
O
Synthons
O
Synthetic equivalents
Case 12: Plan the retrosynthetic strategy for the 4,4,6-trimethyl-tetrahydro-pyran-2-one.
The disconnection of C–O bond in 4,4,6-Trimethyl-tetrahydro-pyran-2-one is relatively
simple which led to acid and alcohol. We need to look for the functional group disconnection
approach. This might be formed via conjugate addition of an enolate. For creating enolates
we need two carbonyl groups followed by FGI. Now the possibilities of two disconnections
are possible. It depends which enolate we are going to add to which of the activated alkene.
Thus, we can conclude that simpler and commercially available diethyl malonate is the
best. Simple carbonyls can have problem in forming conjugate addition of malonates
which prefers 1,4 to 1,2 addition. NaBH
does not reduce esters so chemoselectivity is not
4
a problem in the reduction step.
Basic Retrosynthetic Approach 51
Retrosynthetic equivalents and synthons of 4,4,6-Trimethyl-tetrahydro-pyran-2-one
O
O
O
O
HO
O
OH
FGI
Reduction
HO
O
O
O
HO
Synthons
OOO
EtO
Synthetic equivalents
OEt
O
Synthesis of 4,4,6-Trimethyl-tetrahydro-pyran-2-one by using synthetic equivalents
EtO
O O
OEt
EtO2C
O
+
Base
CO2Et
O
NaBH
EtO
4
O
C
2
O
H
H2O
+
O
Case 13: Plan the retrosynthetic analysis for the given compounds A, B and C.
COOH
A
COOH
BC
COOH
O
Compound A: This is the easiest way to synthesize compound A D, E-unsaturated ketone.
Thus, we can perform either aldol condensation or Wittig reaction.
PPh
3
COOH
FGI
Hydrolysis
COOEt
COOEt
CHO COOEt
Synthetic equivalentsSynthons
Compound B: This is probably the hardest method to synthesize compound B. In this
method, no simple enolate disconnection was observed so we have to look differently.
Thus, we can follow the preferable way which probably involves FGI to a CN and followed
CN
–
ion.
NaCN
Br
Synthetic equivalentsSynthons
by the C–C bond formation by using substitution with a CN
FGI
COOH
Hydrolysis
N