Retrosynthesis: 123.312

.Retrosynthetic
.analysis
©gareth j rowlands

123.312 gareth j rowlands: massey university

Retrosynthetic analysis

©gareth j rowlands

This ﬁle does not contain my lecture notes.
This ﬁlenot contain all the my lecture notes. lectures.
It does does not contain information in my
It does not contain all the information in my lectures.
Itisis not intended to be printed (so no complaints that it is 400 pages long).
It not intended to be printed.


OH

The idea of this ﬁle is to allow you to look at the retrosynthesis of a
variety of molecules at your own pace and for me to experiment with
methods of communicating the material. If you click on the arrow you’ll
get the general idea...
terminology guidelines aromatics aliphatics two group patterns C–C bonds


OH

I have attempted to make various bonds (in this case adjacent to the
alcohol) interactive thus allowing you to see potential disconnections. It
may be helpful, it may not...we will have to wait and see.
Funnily enough, I like to experiment...


general speciﬁc www.massey.ac.nz/~gjrowlan/teaching.html

All the information you need can be found from these sources.
Of course, to actually pass the course, you need to understand the
material...

Terminology

target molecule retrosynthetic analysis
reverse step disconnection
synthon synthetic equivalent
functional group interconversion

Terminology
O
The target molecule (TM) is the
H2N
goal, the target, the molecule
you are trying to make...


Terminology
target starting
precursor 1 precursor 2
molecule material

Retrosynthetic analysis (or retrosynthesis) is the idea of working
backwards, one step at a time, to simplify a molecule. It is the logical
approach to planning a synthesis. Each precursor becomes the target
for further analysis. -EXAMPLE-


Terminology
A logical backwards steps. This arrow
effectively means “can be made from.”

To be of any value, there must be a
real reaction that corresponds to the
forward reaction


Terminology
A retrosynthetic (reverse) step
involving the breaking of a bond X Y
to form two (or more) synthons.
X Y
X Y X Y
The more reactions you know the X• Y•
more possibilities you can invoke.


Terminology
X Y A synthon is an idealised fragment.

It does not have to exist. It aids
X Y thought/retrosynthesis. It should have a
synthetic equivalent to be of any use.

X• Y• -EXAMPLE-


Terminology
H
The synthetic equivalent is a real ≡
compound that corresponds to the
synthon. Ideally, a commercially O O
available reagent (or the next target in
your retrosynthesis)
≡
Cl
(& AlCl3)


Terminology
O O
H2N FGI O2N

The imaginary conversion of one functional group into another in order to
aid simpliﬁcation, help planning or uncover a disconnection. There must
be a good ‘forward’ (real) reaction. -EXAMPLE-


.Retrosynthetic
.analysis: planning

©Tom Coates@Flickr

Guidelines
O
H2N

Where do we start when we plan a synthesis?

Below are a set of guidelines to help you logically approach
retrosynthesis or the planning stage. They are not rules, the only rule is
that you want to simplify the problem whilst using chemically allowable
transformations!

identify functional groups identify patterns
examine disconnections identify problems
consider FGI repeat

.....identify functional groups
O
ketone
amine H2N

Functional groups are the signposts to retrosynthesis. Without
functionality, we have a very limited range of reactions at our disposal.
Frequently, they control where we can apply disconnections.

consider FGI repeat

.....identify patterns
O
ketone
amine H2N

ortho/para meta
directing directing
The pattern or connections between functional groups often reveal
which reactions you can employ. Learning to recognise patterns of
functional groups is very important for retrosynthesis. The pattern of
functional groups frequently indicates the order reactions should be
approached.
consider FGI repeat

.....examine disconnections
H2N O
a O b
O C–N a b C–C
H2N
H2N

To begin with, you need to examine all possible disconnections. With
practice you will learn that some can readily be ignored. You must also
remember not to look at backwards just one step but to go further back.
Shortsightedness has ruined many a retrosynthesis.
consider FGI repeat

.....identify problems
route a route b
H2N H2N
o,p-directing,
no synthetic NOT meta-directing
equivalent

Are all the disconnections chemically allowable? Will the reaction
proceed with the correct regio-, stereo- or chemoselectivity? Does the
disconnection simplify the problem? Try and answer these questions
before you proceed.
consider FGI repeat

.....consider FGI
O O
H2N FGI O2N

reduction

(note: I have written the forward reaction
under the arrow; this shows the FGI is
possible & highlights potential problems)

Functional group interconversions do not simplify a structure, but they
do overcome problems and/or allow disconnections that will simply the
target
consider FGI repeat

.....repeat 1-5 (until you have simple SM)
O O
H2N FGI O2N

reduction

Just keep repeating the steps until C–C
you have a commercially available
starting material. Approached O2N
O
logically, and with a good working
knowledge of reactions,
retrosynthesis can be both fun & easy. -synthetic equivalents-

consider FGI repeat

O O
H2N FGI O2N

reduction

C–C

-ﬁnish retrosynthesis- O2N O

Cl

consider FGI repeat

O O
H2N FGI O2N

reduction

-Synthesis-
C–C

C–N O2N O
O2N
Cl

consider FGI repeat

O O
H2N FGI O2N
reduction
Sn
HCl C–C
-Synthesis- AlCl3
C–N O2N O

HNO3 Cl
H2SO4
consider FGI repeat

.Retrosynthetic
.analysis: examples
©lennox_mcdough@Flickr

.Retrosynthesis of a benzene derivative

The synthesis of aromatic compounds is relatively simple; we have a
limited number of reliable reactions and a well-deﬁned set of guiding
principles.

Therefore, we will start here...

.Simple retrosynthesis
NH2

Br
How could you make this compound?
Consider our guidelines...

amine NH2 o,p-directing

identify FG & patterns Which bond C–N or
connecting them C–Br would you
(guidelines 1 & 2) disconnect?

bromide Br o,p-directing
(just)

NH2

Br
Choose a bond! I’m not doing all the work for you...


NH2

Br
Are there any other approaches to this molecule?



NH2 NO2

FGI

reduction

Br Br
Change order of events & perform FGI ﬁrst.
Do we disconnect C–N or C–Br next?


NH2 NO2

FGI

reduction

Br Br
Now you are just being lazy. Choose a bond!


NH2

Br
Which route is best?
Really depends on your
deﬁnition of best...

-next example-
©carbonNYC@Flickr


.Simple aromatic retrosynthesis

OH

Br


secondary
alcohol OH

alkyl
bromide Br
o,p-directing
o,p-directing
identify FG & patterns connecting them (guidelines 1 & 2).
Which bond, C–Br or C–C would you disconnect ﬁrst?

OH O
FGI

reduction
Br Br

FGI introduces a ketone. This aids simpliﬁcation by permitting
standard Friedel Crafts chemistry.

Which bond, C–Br or C–C would you disconnect ﬁrst?


OH O
FGI

reduction
Br Br

C–C

C–Br O

bromination Br Cl

and the synthesis


OH O
FGI

reduction
Br Br

NaBH4 C–C AlCl3

C–Br O

bromination Br Cl

Br2/Fe


.Retrosynthesis of a benzene derivatives

Aromatic chemistry limits your choices (but allows some very reliable
reactions). It was a good place to start but now lets turn our attention to
more complex systems...


.Retrosynthetic analysis:
aliphatic examples ©Horia Varian@Flickr

How would you make chlorbenside (anti-tick/mite)?
Cl

S

Cl

©graftedno1@Flickr


chloride
sulﬁde
Cl

chloride S

Cl reactive benzylic
position
Identify FG & patterns connecting them (guidelines 1 & 2)
C–heteroatom bonds are easy to identify & wide range of reactions
available to form them. These disconnections are our starting point...


d
Cl
b c
S
a
Cl

Which C–heteroatom bond would you disconnect ﬁrst?
Remember we want to simplify the problem & use reliable reactions.

SH Cl

Br
Cl

NaOEt

Cl

S

Cl



O
O OMe
OH N
H H
O N
O

ICI-D7114
©Peter Keyngnaert@Flickr
(anti-obesity drug)

How would you make this intermediate from the synthesis of ICI-D7114?

O Ph
H
Ph N
O


C–X no simple
disconnections aromatic
disconnections
O Ph
H
Ph N
O
amine ether

C–heteroatom (C–X) bonds are easy to identify.
These disconnections are our starting point...


a
O Ph
d H c b
Ph N
O


.Remove reactive functionality

Removing reactive functionality early limits side reactions & increases
the chance of selectivity.
The rest of the retrosynthesis... ©Alexandra Polido@Flickr


.Simple retrosynthesis continued
e
O Ph
f
Br
O

Which C–heteroatom bond should we disconnect next?

OH OBn
base
BnCl
HO HO
excess
base
Br
Br
excess
NHBn OBn Br OBn
BnNH2

O O

A simple understanding of basic reactions (& the principles behind them)
allows a rapid synthesis of this precursor.

.Retrosynthesis

HN

F3C
fenfluramine
neuroactive drug
©alancleaver_2000@Flickr
appetite surpressant

.Retrosynthesis
amine

HN

F3C
C–X
disconnections
C–heteroatom (C–X) bonds are easy to identify.

.Retrosynthesis

HN C–N H2N

F3C F3C

≡

≡
NH2
Br
F3C

The obvious disconnection does NOT work.
Why?
Think about the chemistry/reactivity of primary vs. secondary amines...


.Problem
NH2 Br HN

F3C F3C
more reactive

Br

N Br N
Br
F3C F3C
MORE reactive
Over alkylation can be a serious problem.
The solution to which is...

.Solution
O
HN FGI
HN
F3C amide
reduction F3C

C–N
amide

NH2 O

F3C Cl

...Functional Group Interconversion
An amide is deactivated compared to an amine, so get single addition.
The synthesis is...

.Synthesis
O
HN FGI
HN
F3C amide
reduction F3C
LiAlH4
C–N
base amide

NH2 O

F3C Cl

...Functional Group Interconversion
An amide is deactivated compared to an amine, so get single addition.
The synthesis is...

.Solution
HN FGI N

F3C imine F3C
reduction
C–N
imine

O
H2N
F3C

There are many other FGI for the formation of amines.
A common solution is given on the next page...

.Synthesis
HN FGI N

F3C imine F3C
reduction
C–N
NaBH4 or H+ imine
NaBH3CN

O
H2N
F3C

And now for an example...

.Retrosynthesis

O
OMe
N

N
F

Ph Ocfentanil
painkiller


.Retrosynthesis
amide ether
O
amine OMe C–N
N amide

N
F

Ph C–N
amine
C–N bonds are easy to identify.

.Retrosynthesis

O
OMe
c
a
N
b
N
F

Ph


.Retrosynthesis
O
O OMe
OMe
Cl
N H
C–N N
N amide
F N
F
Ph
Ph
FGI
imine
reduction
O
N
N
C–N
N
F
Ph H2N amine
condensation
Ph
F ...and the synthesis...

.Retrosynthesis
O
O OMe
OMe
Cl
N H
C–N N
N amide
F N
F
Ph base
Ph
FGI
NaBH3CN imine
H+ reduction
O
N
N
C–N
N
F
Ph H2N amine
condensation
Ph
F

.Two group disconnections

OH
O
Ph


allyl ether
group
OH alcohol
{ O
Ph
C–X
at centre of
molecule
C–X bonds are easy to identify.


OH
a b
O
Ph

Which would be the better disconnection?


OH OH O
≡ Br ≡ Ph
Ph Ph

Epoxides are relatively stable.
Epoxides are easy to prepare (and control stereochemistry)
Therefore...

.1,2-diX

X2 1,2-diX
X2

X 1
2 R2
R R2
1

X1≠ (or =) X2= O, N, S
Forwards - 1 functional group gives 2 new ones.
Backwards - look for two functional groups next to each other & we
know we can make them from a single functional group.

So the synthesis is...

.Retrosynthesis

O OH
OH
≡
b C–O
O
Ph OH
O
≡ Ph
Ph

NaH

lets look at an example...

.Retrosynthesis
O N
H
OH

propranolol
beta blocker
stress relief

©non-partizan@Flickr


.Retrosynthesis
ether alcohol amine

C–O 1 1
phenolic 2
ether O N
H
OH 1,2-diX
C–N
amine

C–X bonds are easy to form & our new 1,2-diX pattern is visible twice.

.Retrosynthesis

a b
]
O N
H
OH

Which C–X bond would you disconnect ﬁrst?

.Retrosynthesis
O
O N C–N O
H
OH
H2N

C–O

Cl
O
≡
O
OH O

≡

Looks good but can you see a potential problem?

.There is a problem!

stereochemistry!
Don’t care? Go to next -retrosynthesis-
Want to know what is going on? -here-
©tibchris@Flickr


.Retrosynthesis
O

H2N
N O

N O

intermediate towards
moxnidazole (anti-parasitic)

©limowreck666@Flickr


.Retrosynthesis
hydrazone
O
carbamate
H2N
N O amine
2 x C–X 1 2 1
carbamate N O

2 x 1,2-diX
C–X bonds & two possible 1,2-diX disconnections.

.Retrosynthesis

O
ab c
H2N
N O
1 2
d
1 O
N

Where would you start?

.Retrosynthesis

H2N
NH OH
e
1 2
f
1 O
N

Which order to we add the ‘amines’? (both are 1,2-diX disconnections)

.Retrosynthesis
O
b c H2N
2 x C-X NH OH
H2N e
N O
N O
N O

1,2-diX

O
O O C–X
H2N f
Cl NH2 O
HN N

Here is the complete retrosynthesis and here is the synthesis

.Retrosynthesis
O
b c H2N
2 x C-X NH OH
H2N e
N O
O N O
N O
MeO OMe

hydrazine
Base 1,2-diX

O
O O C–X
H2N f
Cl NH2 O
HN N

Now lets look at another useful pattern to identify

.Retrosynthesis
N O

Ph

atropine
mimic

©shellgreenier@Flickr


.Retrosynthesis

amine N O ketone

3 2 1
Ph
1,3-diX
New pattern has heteroatoms three carbons apart (1,3-diX).
Why is this a useful pattern?

.1,3-diX

C–X N
N O
O
Ph
Ph

≡
O Br O
3

Ph
2
1
≡ Ph

too reactive
Conjugate addition is a reliable reaction. So the pattern is...

.1,3-diX

X O O ≡ O

3 1 3 1
2 2

Conjugate addition or Michael addition or 1,4-addition.
Good disconnection as it is a reliable forward reaction and there are
many methods for the formation of the enone.

so the synthesis would be...

.1,3-diX
O
N O
Ph
N
H Ph

HOO
Note: the proton could be replace by
other electrophiles to make more
complex compounds
Note: in this case the mechanism is
N O
probably more complicated (look up
iminium ion activation)
Ph

Remember, it’s not just ketones that can
activate alkenes...

.1,3-diX

X .X .X ≡ .X

3 1 3 1
2 2

Conjugate addition or Michael addition or 1,4-addition.
alkene can be activated by carbonyl group, sulfones, nitriles, nitro
groups or any strongly electron-withdrawing group.

Lets look at an example

.Retrosynthesis

O NH2

How would you make this compound?
Follow our normal thought process...

Look for patterns

.Retrosynthesis
ether amine
3 2
O 1
NH2

1,3-diX

Two heteroatoms (1,3-diX) but neither are electron-withdrawing groups.

Do we know any FGI that could convert one into a EWG?

.Retrosynthesis
FGI
O NH2 O
reduction N

1,3-diX

OH
≡ O
N N

FGI allows amine to be converted to nitrile (reduction in a forward
reaction). Nitrile strong electron-withdrawing group & sets up 1,3-diX.

-Synthesis-

.Retrosynthesis
FGI
O NH2 O
reduction N

LiAlH4
1,3-diX
base

OH
≡ O
N N

1,3-diX disconnection is very useful. It allows molecules to be rapidly
divided.

-Now the biggy-

.C–C Bond Formation

©the albino@Flickr


.Retrosynthesis

carnation perfume
intermediate

©Somalia ya swan@Flickr


.Retrosynthesis
alkyne

C–C
next to FG

Only FG is alkyne.
C–C bonds next to functional groups are good starting points.

-Retrosynthesis-

.Retrosynthesis
C–C

≡

≡
H Br

H

Alkynes can be deprotonated with strong base and make good
nucleophiles.

-Synthesis-

.Retrosynthesis
C–C

≡

≡
i. NaNH2
ii. R–Br
H Br

H

Alkynes can be deprotonated with strong base and make good
nucleophiles.

-Lets try something harder-

.Retrosynthesis
OH

violet oil
component

©{ pranav }@Flickr


.Retrosynthesis
alkene alcohol

OH

C–C
next to FG
Two functional groups makes life a little easier but still some potential
problems...

-Retrosynthesis-

.Retrosynthesis

b
a OH

FGI

Where would you start this retrosynthesis?

.Retrosynthesis

OH
FGI OH C–C
OH
H2
Lindlar's
i. NaNH2
catalyst
NaNH2 ii. oxirane

≡
H C–C
Br
H H

-another example-

.Retrosynthesis
O

O
pea moth pheromone

this is not a pea moth ©Dell’s Pics@Flickr


.Retrosynthesis
alkene ester
O

O

C–C reactive
next to FG functionality

-Retrosynthesis-

.Retrosynthesis

O
a b
O
FGI


.Retrosynthesis
Na
( )7 OTHP
Br O O
i. NaNH2
ii. MeI
Na(s),
NH3(l)
( )7 OTHP
( )7 OTHP

i. HO
ii. AcCl

O

O

In the actual synthesis the THP protecting group was used.
Make sure you understand each step (and know all the mechanisms)
Next a -key disconnection-

.How would you make?

OH
Ph
©vitroid@Flickr


.Retrosynthesis
alcohol

OH
Ph
C–C
next to FG
New pattern is called 1,1-C–C

-1,1-C–C-

.1,1-C–C
OH 1,1-C–C OH
R'
R R' R

≡

≡
O
BrMg R'
R
If you see an alcohol, the ﬁrst disconnection you should think about is
the addition of a nucleophile to a C=O bond (but not the only disconnection).

-Retrosynthesis-

.Retrosynthesis

b
OH
Ph c
a


.Retrosynthesis

OH

Ph N
Ph

fenpiprane precursor
(anti-histamine)

©jeffreyklassen.com


.Retrosynthesis
alcohol OH amine

1 3
Ph 2 N
Ph
1,1-C–C 1,3-diX
next to FG (if we form C=O)
The alcohol group allows 1,1-C–C disconnections.
two heteroatoms indicates that we should look to set up 1,3-diX (in
other words this is going to inﬂuence the order of steps)
-retrosynthesis-

.Retrosynthesis
OH
a b
Ph N
Ph

So, which way around should we perform the disconnections?

.Retrosynthesis
OH 2x OH
1,1-C–C Ph
Ph N N
Ph Ph

≡
2 x Ph MgBr O

MeO N
mix
together
1,3-diX

O HN ≡ O N

MeO MeO

Now that was easy. Want another example?

.Retrosynthesis

Cl O

precursor to
chlophedianol
(cough suppressant)

©tranchis@Flickr


.Retrosynthesis

Cl O ketone
aryl ring aryl ring

1,1-C–C
next to FG

Looks straightforward? No way I could be trying to trick you?
-retrosynthesis-

.Retrosynthesis
Cl O Cl O
1,1-C–C

≡

≡
Cl O
BrMg
OEt

1,1-C–C disconnection removes aryl ring.
Can you see why this will not work?

.Problem

Cl O Cl OH
BrMg
OEt Ph
Ph

Multiple addition will occur (ketones normally more reactive than esters)

Solution? Functional group interconversion

.Retrosynthesis
Cl O Cl OH
FGI

oxidation

1,1-C–C

Cl O Cl OH
MgCl ≡

FGI gives the precursor for a single addition (or 1,1-C–C disconnection)
-synthesis-

.Retrosynthesis
Cl O Cl OH
MgCl

Jones
reagent

Cl O

How else could we make this compound
(with reactions you have been taught)?

.Retrosynthesis

Cl O
a b

Think about aromatic substitution and the Friedel-Crafts reaction.

Which side would you disconnect?

.Retrosynthesis

Cl O Cl O
FeCl3
Cl

Synthesis is a simple Friedel-Crafts reaction.

Now a more complex example involving the carbonyl group...

.Retrosynthesis

O O

How would we make this compound?

-retrosynthesis-

.Retrosynthesis
(alcohol?)
(acid?)
1,1-C–C
next to FG
lactone
O O
1,1-C–C
next to FG
Technically only a lactone but this could be derived from an alcohol & an
acid. Such a disconnection permits 1,1-C–C to be used.
-retrosynthesis-

.Retrosynthesis

b c
a
O O
e d

Which bond would you disconnect ﬁrst?
(please remember what I have just written)

.Retrosynthesis

FGI
b c
a
CO2H
OH

Which bond would you disconnect next?
(think about selectivity and how easy it is form the nucleophile)

.Retrosynthesis
CO2H
C–O FGI
CO2H
O O OH
lactonisation reduction
OH

1,1-C–C

O C O O C OH

1,1-C–C
≡
O
OH OH

Once the alkyne is installed the rest of the retrosynthesis is ok.
-synthesis-

.Retrosynthesis
i. 2 x BuLi HO O
i. NaNH2 ii. CO2
ii. PrCHO iii. HO
H H
OH
OH

i. H2, Pd/C
ii. HO

O O

The synthesis is quite simple. Just note we need two equivalents of
butyllithium for the second deprotonation due to the relatively acidic
alcohol.
-next pattern-

.Retrosynthesis
Cl Et
O
( )5 O

Et O
OMe
arildone
(anti-polio & herpes
simplex virus)

not the correct virus...©groovelock@Flickr


.Retrosynthesis
ether malonate
(1,3-dicarbonyl)
Cl Et
O
( )5 O

Et O
OMe C–X
next to FG
(1,2-C–C)
The new pattern is 1,2-C–C and corresponds to enolate chemistry
-pattern-

.1,2-C–C
O 1,2-C–C O

R R2 R R2

≡

≡
O
Br R2
R
A carbonyl group should always be one of the ﬁrst places you look to
simplify a molecule, either by 1,1-C–C disconnections and oxidation or
1,2-C–C disconnection.
-retrosynthesis-

.Retrosynthesis

Cl Et
a b
O
O

Et O
OMe

Which bond would you disconnect ﬁrst?

.Retrosynthesis
alkene allylic ketone

O
allylic next to FG
(activated (1,2-C–C)
electrophile)
The new pattern is 1,2-C–C and corresponds to enolate chemistry
-retrosynthesis-

.Retrosynthesis
1,2-C–C

O O

≡

≡
O

Br

Looks fairly straight forward.
Are there any problems with this in the forward sense?
-yes- -no-

.Retrosynthesis

a
O
b FGI

So where would you start your retrosynthesis?
Disconnection or functional group interconversion?

.Retrosynthesis

Br
NaOEt
O
O O
CO2Et
OEt NaOH

H+
heat
O
O
CO2H

The synthesis is quick and efﬁcient.
-next pattern-

.1,3-diO (aldol)
O OH O
1,3-diO OH
2 3
R 1
R3 R
R3
R2 R2

≡

≡
O
O

As soon as you see an alcohol 1 R
carbon from a carbonyl group you
R3
should think about the aldol reaction.
R2
-example-

.Retrosynthesis

alcohol OH O ketone
OMe

1,3-diO OH
(aldol)

The new pattern is 1,3-diO and corresponds to aldol chemistry
-retrosynthesis-

.Retrosynthesis

OH O
OMe
a b
OH

So, where would you start your retrosynthesis?

.Retrosynthesis
O OTMS
i. (TMS)2NLi
OMe ii. TMSCl OMe

OH OH

hexanal
TiCl4

OH O
OMe

OH
Readily prepared by the Mukiayama aldol reaction.
-another example-

.Retrosynthesis

EtO2C

HO

MeO
thromboxane
antagonist intermediate

.Retrosynthesis

ester EtO2C allyl

alcohol HO 1,2-C–C
1,3-diO
(aldol) MeO

Ester is key but remember the problem of self-condensation
-retrosynthesis-

.Retrosynthesis
FGI
a
EtO2C
b
HO
c
MeO

Where would you start your retrosynthesis?

.Retrosynthesis

CO2Et
EtO2C
b a
HO

MeO

What would be the next step of the retrosynthesis?

.Retrosynthesis
EtO2C CO2Et EtO2C CO2Et
NaOEt

Br
NaOEt
O

MeO

EtO2C CO2Et
i. NaOH EtO2C
ii. H+, heat
HO HO

MeO MeO

-next example-

.α,β
.the aldol condensation

.α,β (the aldol condensation)
O FGI O OH 1,3-diO O O

R R" R R" R R"
this is the same as

O α,β O O

aldol
R R" condensation
R R"

Enones can readily be formed form the dehydration of 1,3-
hydroxyketones (and related molecules)...
Or we can perform the disconnection in one step...
-example-

.Retrosynthesis
enone

{
alkene O aldehyde

H
α,β

Enone is key to simplifying this problem
-retrosynthesis-

.Retrosynthesis
O OH O
FGI
H H
dehydration

1,3-diO

O O
OH
2x H ≡ H

FGI allows aldol reaction (or 1,3-diO)...
Alternatively...
-one step-

.Retrosynthesis

O O
α,β
O
H H
aldol
condensation

α,β disconnection gives us the two aldehydes in one go.
It is the same thing but misses out some of the thought processes (so
for advanced students only?)
-synthesis-

.Retrosynthesis

O O
NaOEt
O H H

Simple really!
-example-

.Retrosynthesis

H
N
F
O
cinflumide
(muscle relaxant)

.Retrosynthesis
α,β-unsaturated

{
H amide
N
F
α,β O C–N
amide
Remove reactive functionality and then look at unsaturated system
-retrosynthesis-

.Retrosynthesis

a b H
N
F
O


.Retrosynthesis

heat
HO2C CO2H OH
O F
F
O
SOCl2

H2N
H
N Cl
F F
O O

The synthesis requires a malonate to prevent self-condensation.
Otherwise, it is fairly straightforward.
-another example-


O

N O

N
doxpicomine
(analgesic)

.Retrosynthesis
amine acetal
O 2 x C–O
acetal
N O
C–N
N

These are the obvious patterns but there is another we should consider.
-hidden pattern-

.Retrosynthesis
amine acetal
O

N O
2
1 3
N

The 1,3-diX relationship between heteroatoms suggests that we should
consider conjugate addition and hence formation of an α,β-system.
-hidden pattern-

.Retrosynthesis

O

N O

N O

The 1,3-diX relationship between heteroatoms suggests that we should
consider conjugate addition and hence formation of an α,β-system.
-retrosynthesis-

.Retrosynthesis

O
a e
N O
c
b d
N


.Retrosynthesis

EtO O
c
N O
b
N OEt

Which should be the next disconnection?

.Retrosynthesis

EtO O H EtO O
EtO2C CO2Et
N
base
N N O N O

O OEt N OEt

LiAlH4

O OH
CH2=O
BF3
N O N OH

N N

And the complete synthesis.
There are other ways of making amines as we shall see...
-new pattern-

.1,3-aminoalcohols
.nitrile chemistry

.1,3-aminoalcohols (nitrile chemistry)
OH NH2 OH NH2
1,3-aminoalcohol

R R
R" R"

≡

≡
key: no substituent
O N

R R"

Unsubstituted methylene amines can be readily prepared from nitriles
-example-


MeO

N
HO

Venlafaxine
(anti-depressant)

.Retrosynthesis
MeO amine

alcohol HO
2
1
3 { N

1,3-
aminoalcohol

It contains 1,3-aminoalcohol pattern so we should know what to do...
-retrosynthesis-

.Retrosynthesis
a
MeO
b e
N
HO c f
d


.1,3-aminoketones
.the Mannich reaction

.1,3-aminoketones (Mannich reaction)

R R 1,3-aminoketone O R R
O N N

Mannich reaction R'
R' R" R"

≡

≡
O O O R R
R R N
N
H
≡
R' R" R' R"

Three-component coupling reaction to form 1,3-aminoketones
-example-


MeO

O

Ph N

nisoxetine analogue
(anti-depressant)

.Retrosynthesis
MeO

ether O
1 2 3
Ph N amine

{ 1,3-
aminoketone
Disconnections should lead to 1,3-aminoketone pattern
-retrosynthesis-

.Retrosynthesis

MeO
a
b
O
c e
Ph N
d f


Retrosynthesis: 123.312

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Retrosynthesis: 123.312