Synthesis of Captopril - Biochemistry - Lecture Slides, Slides of Biochemistry

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Module 10:

White Biotechnology

Lecture40:

White Biotechnology

(Contd.)

(R)-

β

-hydroxy-isobutyric acid is used as a chiral

synthon for the synthesis of captopril, an ACE inhibitor

O H

CO

H 2

Cl

CO

H 2

(b)-hydroxy-isobutyric acid

SOCl

Cl

SOCl COCl

2

hydrolysis

NaSHAc

O 2

COCl

AcS

CO

H 2

NaOHL-proline

SOCl

2

Cl

O

N

CO

H 2

AcS

COCl NaOHL-proline

O

2

AcS

N

NH

SH 4

p o

e

base

S H

O

N

CO

H 2

O

CO

H 2

captopril

Malease

O

HO

C 2

HO

C 2

OH

H

O 2

E

O O

HO

C 2

HO

C 2

(R) Malic acid(R)-Malic acid

subs conc: 93 g/L; pH = 7.0; temp: 25

o C

reaction type: addition of watercatalyst: immobilized whole cellscatalyst: immobilized whole cellsstrain:

Pseudomonas pseudoalcaligenes

developer: DSM; yield = 99%; ee = 99%

(R)-Malic acid is used as a chiral synthon in asymmetric organic synthesis

Nitrile hydratase

NC

CN

NC

O

NH

2

E

+H O

2

+H

O 2

adiponitrile

5-cyano-valeramide

subs conc: 108.14g/mol; pH = 7.0; temp: 5

o C

reaction type: hydration of nitrilecatalyst: immobilized whole cellsstrain:

Pseudomonas chlororaphis

developer: DuPont; yield = 93%developer:

DuPont; yield = 93%

• 5-Cyanovaleramide is used as an intermediate for the synthesis of the DuPont herbicide azafenidine (Drauz)

azafenidine

Carnitine dehydratase

N

CO

H 2

OH

E

N

CO H

N

CO

H 2

E

+H

O 2

(R) C

i i

crotonobetaine (1)

N

CO

H 2

(R)-Carnitine

4-butyrobetaine (2)

subs conc: 70 g/L for both 1 and 2; pH = 7.0; temp: 30

o C

reaction type: C-O bond formationcatalyst: whole cellt

i^

t^

t^

t^

i^

f^

A

b

t^

i^

/ Rhi

bi

strain: mutant strain of

A

grobacterium

/ Rhizobium

sp.

developer: Lonza AG; yield = 99.5%; ee = 99.9%

* L Carnitine is used as thyroid inhibitor and in infant foods and geriatric nutrition* L-Carnitine is used as thyroid inhibitor and in infant foods and geriatric nutrition

Aspartase

CO

H 2

HO

C 2

CO

H 2

HO

C 2

E +NH+NH

3

Fumaric acid

L-aspartic acid

b

174 1

/L

H

8 5

35

C

subs conc: 174.1 g/L; pH = 8.5, temp: 35

o C

reaction type: C-N bond formationcatalyst: immobilized enzymeenzyme: L-aspartic acid ammonia lyase

i^

E

li

strain:

E

coli

developer: Biocatalytics Inc.; yield = 99%; ee = 99%

*** The product is used as a precursor for the synthesis of aspartame, an artificial sweetener.* It is also used as an acidulant, as a food additive and chiral synthon in organic synthesis.**

L-phenylalanine ammonia lyase

CO

H 2

NH

CO 2

H 2

E

+NH

3

E-cinamic acid

L-phenylalanine

subs conc: 13.02 g/L; pH = 10.6; temp: 25

o^ C

reaction type: C-N bond formation

t l

t^

d d

h l

ll

catalyst: suspended whole cellsenzyme: L-phenylalanine ammonia lyase (PAL)strain:

Rhodococcus rubra

developer: Genex Corporation; yield = 86%

*** L-Phenylalanine is used in the manufacture of aspartame and also as a chiron in organic synthesis**

GlcNAc 2 epimerase

O H

NHAc

O H

E

GlcNAc

2-epimerase

O

OH

NHAc

O OH H

O

OH

O OH H

NHAc

E

N-acetyl-D-glucosamine

N-acetyl-D-mannosamine

N acetyl D glucosamine

y

subs conc: 177 g/L; pH = 7.2, temp: 30

o C

reaction type: epimerization

t l

t^

l bili

d

catalyst: solubilized enzymeenzyme: N-acyl-D-glucosamine 2-epimerasestrain:

E coli

developer: Marukin Shoyu Co. Ltd.

*** N-acetyl-D-mannosamine serves as in situ generated substrate for the synthesis of N-acetyl-neuraminic acid**