Chapter 4 Retrosynthesis_ GUIDELINES.pdf

Organic
Chemistry II
UNIT 4.Retrosynthesis
Main guidelines

Re t ro synt he t i c a n a ly s is
Cl
Cl
O
O
OH
2-(2,4-dichlorophenoxy)acetic acid
Target molecule
Choosing a disconnection
Synthons Equivalent reagents
Reliable reactions

Cl
Cl
O
O
OH
2-(2,4-dichlorophenoxy)acetic acid
Target molecule
Synthons

Which reagent should we
use?? Only experiments
can tell us which is the
better option
Synthons
Synthon Equivalent reagents
Synthon
Equivalent reagents
Reliable reactions

Which reagent should we use?? Only
experiments can tell us which is the
better option

Synthons
Equivalent reagents

Synthons Equivalent reagents

Reliable reactions

PROBLEM 1. HOW WOULD YOU MAKE THESE TWO COMPOUNDS? GIVE YOUR DISCONNECTIONS.
BRIEFLY , EXPLAIN WHY YOU CHOSE THEM AND THEN GIVE REAGENTS FOR THE SYNTHESIS.
MOODLE PLATFORM

Multiple step synthesis
Chemoselectivity problem
Alkylation of phenol in presence of basic nitrogen
Alkylation of phenol in presence of basic nitrogen
Not a good option: next disconection
should be next to the oxigen and then
the same problem like in red or green
We want to introduce
reactive group late in the
synthesis in order to avoid
chemoselectivity problems
ICI-D7114 potential
antiobesity drug

ICI-D7114 potential
antiobesity drug
Requires alkylation of a compound
that is itself an alkylation agent

ICI-D7114 potential
antiobesity drug
O
HO
Ph
Br
Br

Funcional group interconversion
Which disconection choose first
Next disconection:
We need to prepare
amide in the presence of
NH2
Next disconection:
We need to prepare
amine in presence of acyl
chloride
NH
OH
O
N
antihipertensivo / vasodilatador

Retrosynthetic transformation of acyl chloride to carboxylic acid is not really a disconnection.
We call it instead functional group interconversion FGI
FGI often aid disconnection because the sort of reactive functional groups (acyl chlorides, alkyl halides) we want in
starting materials are not desirable in compounds to be disconnected – chemoselectivity problems
Funcional group interconversion

Amine synthesis FGI
Reminder - when alkylation of primary amine can produce multiple alkylated product
There are 2 better approximations
1. By amide reduction

Reminder when alkylation of primary amine can produce multiple alkylated product
2. By imine reduction
Amine synthesis FGI
1. By amide reduction

Reminder when alkylation of primary amine can produce multiple alkylated product
2. By imine reduction
Amine synthesis FGI

Amine synthesis FGI
PROBLEM 2. HOW WOULD YOU MAKE THESE TWO AMINE DERIVATIVES USING AMINE FGI? GIVE
YOUR DISCONNECTIONS. BRIEFLY , EXPLAIN WHY YOU CHOSE THEM AND THEN GIVE REAGENTS
FOR THE SYNTHESIS.

Disconnections with carbonyl group
1,2-disconnection 1,3-disconnection

1,2-disconnection with carbonyl group
Alpha-halocarbonyl
Synthesis:
α-halocarbonyl compound are easly made by halogenation of a keton, ester or carboxylic acid and they are good
equivalent for synthon B

1,3-disconnection with carbonyl group
Reminder:
Disconnection:
Example:

C-C disconection
Disconnection:
Reaction:
Alkynes are valuable as
synthetic intermediates
Can be reduce either to cis
or trans double bonds

C-C Disconnections
C-C 1,2-disconnection
C-C 1,1-disconection on alcohols
C-C 1,3-difunctionalized compounds
C-C 1,5-related functional groups

Example:
C-C disconnection

1,2 C-C disconnection, 2
carbons away of the
carbonyl group
Carotene precursor If you think of enolate of
acetone stop right here
Remember that beta-ketoester can be
easily decarboxylate
Enolates once again

Carotene precursor If you think of enolate of
acetone stop right here
Enolates once again

C-C 1,1-disconection on alcohols Grignard to carbonyl

C-C 1,1-disconection on alcohols Grignard to carbonyl
To synthesis this compound rout “c”
has been chosen because is the
cheapest way to obtain the perfume
Which rout would you
choose?

Grignard to carbonyl
Do you know why is that
possible ?
C-C 1,1-disconection on alcohols

Aldol reaction
Two group disconnection
Do you remember?
Part that attacks is enolate and where is hydroxyl is a
place that have been attacked
Now it would be easier: close to oxygen is + and other
part need to be -

Aldol reaction
Aldol product can be dehydrated
To simplify we can say alpha, beta

Aldol reaction
A good equivalent for the ester enolate d2 synthon is beta-dicarbonyl compound
because it can easily be disconnected to diethyl malonate and an alkylation agent
Hydrolysis and decarboxylation

Aldol style with N and O
Nitriles can be reduce to
amines
CN – is electro
withdrawing group so
it’s alpha proton is
enolizable
1,3 and 1,2 relations
Aldol like reaction
Addition to the carbonyl

Aldol style with N and O

C-C 1,5-related functional groups

Retrosynthesis Problems 3
MOODLE PLATFORM

Protecting groups – an necessary evil
If only exists something
that allowed us to block
this very reactive
ketone….

Protecting groups – an necessary evil
Protecting group
But why is evil?
• We need to add two reactions protecting/deprotecting – we will lost some
material – lower global yield
• Atom economy

Protecting aldehydes and ketones
PG - ACETAL

Protecting Alcohols
PG – silyl ether
What can we do then?
PG - TBDMS

PG – silyl ether
PG - TBDMS
Silicon has a strong affinity for electronegative elements – FLUOR ion. TBAF (Tetra-n-ButylAmmonium Fluoride –
soluble in organic solvents is normally used to remove TBDMS (TertButylDiMethylSylil) group
Protecting Alcohols

PG – silyl ether
Other silyl ether protecting groups
When the group is bigger more stable protecting group – can be
advantage and disadvantage
Not stable under acidic conditions!
Protecting Alcohols

PG – acetal
Protecting Alcohols

PG – acetal
THP-acetal protecting group
Not stable under acidic conditions!
Protecting Alcohols

PG – ether
Bn-benzyl ether protecting group
How we remove it?
• Pd/C + H2 typical conditions
• Do not confuse with Pt – hydrogenation of aromatic ring
Protecting Alcohols

Protecting amines and carboxylic acids
Peptide synthesis
Because of effectiveness of the
protecting groups peptides can be
synthetize by machine!!!!!!!!!
Amines:
• Cbz
• Boc
• Fmoc
Carboxylic acids:
• t-butyl ester
Would be a mess!!

Peptide synthesis
Amines:
• Cbz
• Boc
• Fmoc
Carboxylic acids:
• t-butyl ester

Peptide synthesis
Amines:
• Cbz
• Boc
• Fmoc
Carboxylic acids:
• t-butyl ester
This is preferable way to make tert-butyl ester
• If we use alcohol – this is very hindered so reaction is very slow even with acid chloride or anhydride
isobutene

Peptide synthesis
Amines:
• Cbz
• Boc
• Fmoc
Carboxylic acids:
• t-butyl ester
But why is stable in presence of hydroxyl group??
• Bulky tert butyl group makes it very hindered for nucleophilic attack
Removal of t-butyl ester

Protecting amines
Peptide synthesis
Amines:
• Cbz
• Boc
• Fmoc
Carboxylic acids:
• t-butyl ester
Removal of Cbz (carboxybenzyl)
Carbamic acid not stable – suffer decarboxylation to give amine

Protecting amines
Peptide synthesis
Amines:
• Cbz
• Boc
• Fmoc
Carboxylic acids:
• t-butyl ester
Removal of Boc (tert-butoxycarbonyl)
For Boc removal we can use diluted aqueous acid like 3M HCl for Cbz we need to use stronger conditions

Protecting amines
Peptide synthesis
Amines:
• Cbz
• Boc
• Fmoc
Carboxylic acids:
• t-butyl ester
Removal of Fmoc (fluorenylmethyloxycarbonyl)
Nonnucleophilic base is used
This protecting group cannot be lost by
substitution in the manner of Cbz or t-Boc
because neither SN1 nor SN2 mechanisms can
operate at the ringed carbon atom: it is both
primary and hindered.

Protecting groups

Fmoc/t-Bu Boc/Bn

O
OH
Ph Ph
Problems 4
OEt
O
How would you make the following compound starting from ethyl benzoate?

O
OH
Ph Ph
Problems 4

O
OH
Ph Ph
Problems 4
OEt
O
O
OEt
O
Ph MgBr
2
I need to protect ketone
OEt
O
Cl
O

Chapter 4 Retrosynthesis_ GUIDELINES.pdf

Chapter 4 Retrosynthesis_ GUIDELINES.pdf

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Chapter 4 Retrosynthesis_ GUIDELINES.pdf