Anwar.Asymmetric synthesis

1. Asymmetric synthesis
Dr. Shaikh A. R

2. • Asymmetric catalytic reduction:
Asymmetric catalytic reduction is the use of various chiral catalysts to
reduce a pro-chiral organic compound to obtain a chiral product. This is
one of the several techniques used in chiral synthesis.
e.g. H (g)
O O
2
OH O
RuCl2 [(R)-BINAP]
R OMe
MeOH R OMe
BINAP=2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
The Noyori asymmetric hydrogenation is a chemical reaction described as an
asymmetric reduction of β-keto esters.
Example in drug synthesis: Synthesis of Naproxen

3. Synthesis of Naproxen:

4. • Asymmetric catalytic oxidation:
• Is a technique of oxidising various substrate to give an
enantiopure product using a catalyst.
• Reactions:
• Jacobsen epoxidation of alkenes using manganese-
salen complex and NaOCl
• Sharpless epoxidation of allyl alcohols using
titanium isopropoxide, diethyl tartrate, and
t-butyl hydroxyperoxide
• Sharpless asymmetric dihydroxylation of alkenes using
dihydroquinine or dihydroquinidine ligands on an
osmium metal center
• Shi epoxidation of alkenes using oxone and a fructose-
derived chiral catalyst
• Sulfonyloxaziridine enolate oxidation

5. • Sharpless epoxidation:
Example in drug synthesis: Synthesis of Propranolol

6. • Synthesis of propranolol:
HO SiCH3
SiCH3 H
OH
H

7. • Sharpless epoxidation:
Example in drug synthesis: Synthesis of Propranolol

8. O
HO SiCH3 HO SiCH3
ArONa
ONa
CH3
H3C
NH
NH 2 H O
H3C CH3
OH 4
SCH SiCH3
OH
O Tetra-n-butylammonium fluoride
SCH3 O Na
Bu4NF
iprNH2

9. Synthesis of penicillamin
NaOH or Penicillinase
- H+
:OH
R
NH S CH3
CH3
H + O
R N OH ..- N:
-
+ NH
CH2 CH HS CH3 COOH
+ O OH
OH
O
CH3
NH
..- CH Decarboxylation
H COOH
R NH
C
CH S CH3
H2
O O N CH3
OH H
Hydrolysis

10. Synthesis of penicillamin
H OH
R N
CH2 CH HS CH3
+
OH
O
CH3
NH
..- CH
H COOH

11. Synthesis of Aspartame
MeOOC H O
COOH
N NH2
H H
O
MeOOC
HOOC H
C
NH C 3
CH
COOH
NH2
H

12. Catalytic asymmetric hydrogenation
COOH
(1)-(R,R)-PNNP-Rh (I) (Cat)
NHAC Me
COOH
(1)-H +. MeOH
(z)-2-acetamido-3-phenylacrylic acid H NHAC
S-phenylalanine methyl ester (97 %)
Or (s)- methyl 2-acetamido-3-phenylpropanoate
COOMe
MeOOC H
NH AC .. O
+
H .. NH
COOH
AC
H NH2
O
O HO COOH
- CH3+C CH3
COOH H NH2
:OH
Aspartic acid

13. Synthesis of ethambutol (S,S)
OH
H
Me N
N Me
H
HO
COOH
NH2
MeS
L-Methionine

14. COOH
a. MeOH, ACCl
NH2
MeS b. ClCOCOCl (0.5 Aq.), Pyridine, CHCl2
COOMe
H SMe
N
H
N
MeS
O
O COOMe
Oxalyl diamide

15. COOH COOH
..
NH
..
2 H2N
..
NH
COOH
MeS .
.. MeS
COOH
+
NH2
SMe C C
C
Cl -
MeS
Cl: Cl
Cl
O
O O
O

16. COOMe COOMe
COOMeCOOMe
COOMe COOMe
Raney Ni, MeOH, H2O
NH HN HN
NH
NH HN
MeS Desulfuration Me
O O O O Me
O O SMe MeS
COOMe O
Me
H SMe
N
N Me
H
O COOMe
Penultimate
Exhaustive reduction
LiAlH4, THF
COO H O
Me
H
Me N
N Me
H
O
COOH
Me
Ethambutol

17. Synthesis of Atenolol
O O O
O N S
O O
N
OH H
OH
S-Glycidylnosylate O
O O
N
OH H
CH2CONH2
2-(4-Hydroxyphenyl)acetamide
CH2CONH2
CH2CONH2
O O O
O N S
Atenolol OH

18. O O O
O N S
O O
O
CH2CONH2
O O O CH
S.
2
O N
-.O
.. O
+ H..O +
CH2CONH2

19. Synthesis of Atenolol
O O O
O N S O
O O O
N O
OH H O O
OH
S-Glycidylnosylate +
O N S
OH
CH2CONH2 CH2CONH2
H3C
2-(4-Hydroxyphenyl)acetamide NH2
Isopropyl amine H3C
O N
OH H
Atenolol
CH2CONH2

20. CH3
+
.N
..
.+ CH3
CH2 H
.
.
O O-
O N
OH H
CH2CONH2
CH2CONH2