Mòdul MD2301 - Formació general; 564497 – Química orgànica i inorgànica

MASTER ON DRUGS, COSMETICS AND FOOD QUALITYMASTER ON DRUGS, COSMETICS AND FOOD QUALITY

Dr. Antonio DelgadoUniversitat de BarcelonaOctober 2009

2

Session 3

Electrophilic aromatic substitution. Benzene, substituted benzenes and their reactivity with electrophiles. Directing groups.

Organic synthesis. Linear versus convergent synthesis. Protecting groups in organic synthesis. Retrosynthetic analysis. Enantiopure compounds: chemical resolution of racemates.

3

Hückel’s rule: (4n+2) electrons delocalized (conjugated) in a cyclic system

Electrophilic aromatic substitution

4

Heterocyclic aromatic systems

5

6

Stability of aromatic systems

7

8

9

10

Electrophilic aromatic substitution

Halogenation

11

Electrophilic aromatic substitution

Nitration

12

Electrophilic aromatic substitution

Sulfonation

13

Electrophilic aromatic substitution

Alkylation

14

15

Electrophilic aromatic substitution

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Electrophilic aromatic substitution on benzene derivatives

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18

19

20

21

22

23

24

• Construction of the carbon skeleton• Functional group transformations• Functional group protection• Stereochemical control (stereogenic

centers)

Planning an organic synthesis

Basic steps

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Planning an organic synthesis Construction of the carbon skeleton

Linear vs convergent synthesis

Linear synthesis

Convergent synthesis

AB ABC ABCD ABCDE

ABCDEF ABCDEFG ABCDEFGH

E

G

rendimiento de cada etapa 80%

rendimiento global:0,87 x 100 = 21%

A

B C D

F H

E G

AB EF GH

ABCD EFGH

ABCDEFGHrendimiento de cada etapa 80%

rendimiento global:0,83 x 100 = 51%

(80%)

(80%)

(80%)A B C D F H

CD

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CH3

CH3C

OH

Nretrosíntesis

desconexión

CH3

CH3C

OH

N

sintones

CH3

CH3

O

reactivos

síntesis KCN

H

ReagentReal species

Synthon (“virtual”)Ionic or radical fragment arising from a disconnection

Construction of the carbon skeletonRetrosynthetic analysis:

Strategic disconnections and synthon generation

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CE2

CX

PR2

OR

O

R

O

CH3Li / CH3MgBr

MgBr

NC CH2 CN

EtOOC CH2 COOEt

OR

O

R

O

Cl

Sintón Reactivo Sintón Reactivo

C1

CN

CH3

KCN

CH3Br

(CH3)3S Br

(CH3)2PCl

Equivalence between synthons and reagents

28

Functional group transformationReduction of carbonyl derivatives

29

Functional group protection: protecting groups in peptide synthesis: Reactivity control

ROH

O

NH2

H

RO

O

NH3

H

zwitterion

R1 O

O

NH3

H

R2 O

O

NH3

H

R1 OH

O

NHH

P

R1 X

O

NHH

P

protección NH2

activación COOH

R2 O

O

NH2

HY

R1

O

NHH

P

NH

O

O

R2H

Y

protección COOH

AA1 AA2

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R1

O

NHH

P

NH

O

O

R2H

Y

R1

O

NH2

HNH

O

O

R2H

YR1

O

NHH

P

NH

OH

O

R2H

elongación

desprotección NHPdesprotección COOY

Protecting groups in peptide synthesisDirectionality in peptide bond formation

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Enantiomers and chirality

Stereochemical control

32

Enantiomers can show different biological activity

33

Resolution of racemic mixtures

Chiralchromatography

EnzymaticChemical

Diastereomeric saltformation

Kineticresolution

Racemic mixtures

Preferentialcrystallization

34

Chemical resolution(diastereomeric salt formation)

35

An example of diastereomeric salt formation

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Resolution of racemic mixtures Diastereomeric salt formation in “high throughput format”

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Resolution of racemic mixturesChiral chromatography