SYNTHESIS OF ALKALOID STRUCTURE ppt _ HÓA HỮU CƠ

SYNTHESIS OF ALKALOID STRUCTUREBài giảng pptx các môn ngành Y dược hay nhất có tại “tài liệu ngành dược hay nhất”; https://123doc.net/users/home/user_home.php?. ELECTROPHILIC SUBSTITUTIO

SYNTHESIS OF ALKALOID STRUCTURE

Bài giảng pptx các môn ngành Y dược hay nhất có tại “tài liệu ngành dược hay nhất”;

https://123doc.net/users/home/user_home.php?

use_id=7046916

1 INTRODUCTION

2 SYNTHESIS OF 5-SUBSTITUTED AND 5-UNSUBSTITUTED

PYRIDOCARBAZOLONES, TETRAHYDROPYRIDOCARBAZOLONES

3 ELECTROPHILIC SUBSTITUTION REACTIONS AT C-5 POSITION

4 RINGCLOSURE REACTION OF AZIDES AND AMINE

5 RING CONTRACTION OF 5-HYDROXYPYRIDOCARBAZOLONES

6 CONCLUSION

3 NUCLEOPHILIC SUBSTITUTION REACTIONS AT C-4 POSITION

Pyridocarbazoles in Bioactive Structures

Seeds of Strychnos nux-vomica.

Tonic in tincture.

Powerful peristaltic action.

Stimulate the spinal cord.

N

R

R

O O

N

Strychnine (R = H) Brucine (R = OMe)

Strychnos nux vomica tree

Pyridocarbazoles in Bioactive Structures

3-hydroxy quinolinediones Alkaloids from several plants(e.g

Haplophytin) Contents from bacteria (Pseudomonas aeruginosa) antibiotic

Alkaloids: e.g Swietidine A, Daurine, Folidine, Glycolone A, Glycocitridine, Flindersine, Almein

Bioactivity: antiallergic, herbicidic, antiinflammatoric, antiosteoporotic, tranquilizer

N O

R R

R

N O

R OAc

Retrosynthesis of Pyridocarbazoles

N O O

H

N H

OR RO

O O

Carbazole

Malonate

Synthetic Approach and Reactivity

Electrophilic attack

Nucleophilic attack

C-H acidic

N O O

H

R

N O O

R H

N O

Cl

R

N O O

R Cl

N 3 , TosO, Amines N

3 , OH, NO 2 , Amines

Literature Known Reaction of Carbazoles with

R1

O H

R1

O H

Cl

Cl

Cl

OH Cl

Reaction of Carbazoles with Diethyl Malonates

N H

O O

R1O

O

R2

R2

N O

R1

O H

N O O

R1 H

6 R1 R2

a b c d e f g

Me Et Bu Heptyl Nonyl Bn Ph

Et Me Et Me Me Me Et

a b c d e f g

Me Et Bu Heptyl Nonyl Bn Ph

Ph2O

60-80%

Reaction of Tetrahydrocarbazoles with

Diethyl Malonates

Tetrahydrocarbazoles

Tetrahydro Pyridocarbazoles

N H

N

O O

R 2

O O

Et Et

R 2

N

O O

Synthesis of Tetrahydrocarbazoles with

Substituents in Benzene and Cyclohexene Ring

Reaction of 2-Hydroxycarbazoles with Malonates

N H

O H

N

O O

R 1

O H

H

R 1

O H

N H

Reaction of 2-Hydroxycarbazoles with Malonates

N H

O

H

N

O O

R 1

O H

H

N

O O

OH O

N

O O

H

N

O O

H

CH 3 O

N O O

H

Cl Cl

O

N O

O

Cl Cl

N O O

OH O

N O O

H

N O

O

N O O

H

R

N O O

N O O

H

N O O

H

NO 2

N O O

H

R

N O

O

NO 2

R

[HNO 2 ] HNO 3

AcOH r.t.

[HNO 2 ] HNO 3

AcOH r.t.

Nitration at the CH-acidic Position

Amination and Azidation at the CH-acidic Position

N O

O

R Cl

N H

X

N

X

N O

O R

NHR1

N O

O R

N O

Amination and Azidation at the CH-acidic Position

N O

O

R Cl

N H

X

N

X

N O

O R

NHR1

N O

O R

N O

Amination with Primary Amines at the

Hydroxy Position

N O

N

R2

N O

R1

O

H

N O

N

R2

N O Me

O

H

R 2 NH 2 reflux, 6 h 62-75%

R 2 NH 2 reflux, 6 h 63- 65%

Amination with Secondary Amines at the

Hydroxy Position

N O R

X

N O

N Y

N H R O

Amination with Primary Amines at the Hydroxy

Position

N O

R1

N

H2

N O

R1

O H

N O

R1

N H

R2

N O

Chlorination and Tosylation at the Hydroxy Position

N O

O

H

R

N O R

Cl

N O R

O Tos

POCl 3

R = alkyl, aryl, NO 2 , Cl, acetyl

reflux

Acetonitril TosCl

MeTHPC

MeTHPC

N O

X

R

N O O

H

R

N O

N O N

P

R

N O R

N 3

N O

N O

Cl

NO 2

N O O

H

NO 2

N O

NO 2

C

H 2 O

N H

150 °C

DSC diagram HeatFlow

[mW]

Temp [°C]

Peak: 173.68 °C

Heat: 180 J/g

Cyclization of Azides

HeatFlow [mW]

Temp [°C] Azido compound

After refluxing in toluene

N O

mp: 223.6 °C

mp: 227.9 °C

N O

N

O N

O

N O

N 3

NO 2

153 °C

+ -

Hydroxylation of the CH-acidic Position

Kitamura S et al., J Antibiot 39 (1986) 1160-66.

analogs of contents of Pseudomonas aeruginosa

N O O

H

R

N O O

R OH

N O O

R NO 2

N O O

Hydroxylation of the CH-acidic Position

Kitamura S et al., J Antibiot 39 (1986) 1160-66.

N

O

Me OHO

N O

Me OH

N

O

Me OHO

N O O

H OH

aq KOH, PhMe

Hydroxylation of the CH-acidic Position

Kitamura S et al., J Antibiot 39 (1986) 1160-66.

N O

R1 OHO

N O

R1OH

N

OH

N H

N X

N

N

O O

CH 3

N O X

R 1

N O O

N O

I would like to thank Vietnamese Government for Ph.D scholarship

This work was performed at the Institute of Chemistry, Graz (Austria)

Under the Supervision of Uni.-Prof Dr STADLBAUER

I would like to express my sincere thanks to everybody in Institute

of Chemistry, Karl Franzens University Graz

THANK YOU FOR YOUR ATTENTION