1

Introduction to Organic

Synthesis

#2

Multistep synthesis

2

Stratagy

SM TM

retrosynthetic analysis

E. J. Corey

3

retrosynthetic analysis

• The transformation of a molecule to a synthetic precursor is accomplished by– Disconnection: the reverse operation to a synthetic reaction,

the imagined cleavage of a bond,

– Functional Group Interconversion (FGI): the process of converting

– one functional group into another by substitution, addition, elimination, reduction, or oxidation.

• Synthetic Strategies: Choosing the way along the retrosynthetic tree, synthetic planning.

• Synthetic Tactics: How a specific bond or set of bonds at a given site can be efficiently created.

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Synthetic versus retrosynthetic analysis

RetronReacting

functionality

Substructure required for

operation

Precursor (SM)Product`Resulting' structure

Target (TM)Reactant`Starting' structure

graphical depiction

Transform or

Retro-reactionReactionStep

Retrosynthetic or Antithetic

SyntheticDirection

Tactics of synthesis

• Retron – The minimal substructural element in a target structure which keys the direct application of a disconnection to generate a synthetic precursor. For instance, in Diels-Alder reaction the retron, a minimal keying element, is 6-membered ring with a π-bond:

• Synthon – An idealised fragment, usually cation or anion, resulting from a disconnection. May or may not be an intermediate in the corresponding reaction.

• Reagent – compound used in practice for a synthon.

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Retrosynthetic analysis

6

TM

TM

7

Disconecting...OH

DISCONNECT

A B

SYNTHONS

Syntheticequivalents

SYNTHONS

Syntheticequivalents

Br

OH OH

?PhCHOBrMg

8

OH

Ph Ph

OH

Ph

O

BrMg

OH

PhPh

OBrMg

synthesis

OH

Ph

O

Ph

FGI

DISCONNECT

O

Ph

O

Ph

Br

(as enolate)

O

Ph

Br

i) base

ii)

O

Ph

LiAlH4

T.M.

∴ synthesis

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CO2Et

H2N

benzocaine (painkiller)

from toluene

H2N

CO2H

O2N

CO2H

H2N

HNO3

H2SO4

KMNO4

NO2

CO2H

NO2

H2 Pd/C

CO2H

NH2

EtOH

H+T.M.

benzocaine

OH OHBr

I

building block for homogeneous catalyst synthesis

HO2C CO2H

Br

I

Br

I

Br

NH2NH2

HO2C CO2H

Br

I

Br

INH2

Br

NH2

Br

NHAc

i) Ac2O/AcOH

ii) Br2

NaOH

57% EtOH

i) NaNO2/HCl

ii) KI

aq. t-BuOH

KMnO4BH3·SMe2

T.M.

nb// acetanilide prevents polybromination

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O

CO2H

discon.

FGI

O

O

O

+

AlCl3

O

HO2CHO2C

Zn-Hg/HCl

Clemmensen

OOO

i) SOCl2ii) AlCl3

O

tetralone

RR

i) RMgx

ii) H3O+

Pd/C

∆

via enamineRBr

O

R

i) LiAlH4

ii) H3O+

R

Pd/C

∆R

1-subtitution (aka αααα-)

2-subtitution (aka ββββ-)

tactical combination

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2,7-dimethyl-4-octanone

12

Taxol

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Precursor synthesis

The ethyl ester of propionic acid 1 is brominated (2) and then converted to the Wittig

reagent 3 with triphenylphosphine.

This compound reacts with the aldehyde 6 in a Wittig reaction.

This aldehyde is obtained from allyl alcohol 4, with the alcohol group protected as a

silyl ether 5 with tert-butyldiphenylsiliyl chloride and the allyl group oxidized by

ozonolysis (6).

The Wittig reaction product 7 is deprotected to the allyl alcohol 8

Precursor synthesis

Synthesis of the diene precursor in ring A:

acetone 1 and acetylacetonate 2 react in an aldol condensation to the β-keto-ester 3.

The ketone group is reacted with methylmagnesium bromide derived from methyl

bromide in a Grignard reaction to the alcohol 4.

The final three steps are an acid catalyzed elimination reaction to the diene 5 , ester

reduction to 6 and acylation to 7

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Synthesis C ring

Synthesis C ring

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Synthesis A ring

Synthesis B ring

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Synthesis of D ring

Tail addition

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• http://www.cem.msu.edu/~reusch/VirtTxtJml/synth1.htm

• http://www.cem.msu.edu/~reusch/VirtTxtJml/react1.htm#rx2b

• http://cheminf.cmbi.ru.nl/cheminf/ira/index.shtml

• http://www.chem.gla.ac.uk/staff/amalkov/Retrosynthesis%20part%201.pdf

• http://www.uea.ac.uk/~c286/notes/retrosynthesis.htm

• http://www.uea.ac.uk/~c286/Interactive/start.htm

• http://www.dq.fct.unl.pt/cadeiras/docinf/main/Trabalhos2003%20PDF/Ana%20margaridaGinkgo.PDF

• http://www.chem.gla.ac.uk/staff/stephenc/OrganicSynthesis2(Clark).pdf

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Pros & Cons of...

...blocking

Misturando conceitos

• Blocos

• Regime intensivo

– Novo regime lectivo

– Não obrigatório

– Não regulamentado

– Específico (UAlg)

• Bolonha

• Estratégia europeia

– Novo paradigna

– Obrigatório

– Regulamentado

– Geral

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Blocos

• Vantagens– Nova abordagem

– Estudo contínuo

– Estudo acompanhado

– Focado (2 disciplinas)

– Obriga a estudar

• Desvantagens– Adaptação e problemas de regulamentação

– Saturação

– Falta de tempo para consolidação de conceitos

Problemas em Química Orgânica

• Adaptação ao método (QO I)

• Interferências externas

• Falta de tempo de consolidação (QO I)

• Falta de aulas TP

• Horários

• Aulas práticas

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Propostas

• Regulamentação dos blocos

• Horários e épocas de exame optimizadas

• Aulas TP

• Aulas práticas independentes das teóricas

• Alterações ao programa

– Espectroscopia deve passar para QO II

obrigado

boa sorte!