1
Targeted Organic Synthesis Lecture 1
1
Introduction
Why bother with organic synthesis?
Organic molecules are required for:
Pharmaceuticals and agrochemicals
Polymers
Dyes
Food colourings
Dyes
Etc.
Most of the required molecules are not available from nature
and for those that are, most are not available in sufficient
quantities.
Chemists need to make them!
Retrosynthetic Analysis
When presented with a "target" compound, how to chemists decide how to make it?
AcO
O
Me
NH
Me
NHBz O
Me
O
OH
O
omuralide
(moderate complexity)
Ph
OH
Me
Me
Me
O
O OH
Me
O
H
OH OBz OAc
taxol
(high complexity)
These two molecules are derived
from natural sources, and exhibit
high biological activities.
Even for a molecule of only moderate complexity (e.g. omuralide), it is not easy to "imagine" a complete
synthesis from scratch.
The best way is to start from the target molecule, and to work backwards with a series of disconnections
until we get back to readily available starting materials.
This procedure is known as retrosynthetic analysis.
Targeted Organic Synthesis Lecture 1
2
Retrosynthetic Analysis
The principles behind retrosynthetic analysis are best explained with a simple example:
Retrosynthesis:
Target molecule (TM)
O
Me
retrosynthetic
arrow
OEt
disconnection
Synthons:
(Work backwards
from target)
Me
O
3
OEt
donor synthon
(nucleophile)
acceptor synthon
(electrophile)
Synthetic equivalents:
O
O
Br
Me
Forward synthesis:
O
Br
O
Zn
OEt
OEt
BrZn
Me
OEt
Reformatsky reagent
(a nucleophilic zinc enolate)
Michael reaction
Me
OEt
Targeted Organic Synthesis Lecture 1
Terminology
Definition of terms used (Warren p. 15)
Retrosynthetic analysis: Process of breaking down a target molecule (TM) into available starting materials
by disconnections and/or functional group interconversions (FGI).
Disconnection:
The reverse operation to a reaction. The imagined cleavage of a bond to "break"
the molecule into possible starting materials.
Synthons:
Imaginary fragments (usually a cation or anion) from which the TM might be made
Synthetic equivalents:
Real reagents carrying out the function of a synthon.
Retrosynthetic arrow:
) Backwards arrow used to show a retrosynthetic step.
Targeted Organic Synthesis Lecture 1
4
Donor Synthons
Some common donor synthons (carbon nucleophiles):
Synthon
Synthetic equivalent(s)
Ar-H, Ar M
(M = Li, MgBr, CuR)
Ar
R
R2
O
R
R
R3
O
R
Me
O
CN
OR
O
S
Li
M
EtO
OEt
R3
O
MgBr
(R = H)
R1
R1
R3
R3
(masked C=O)
NR22
O
H
R2
Synthetic equivalent(s)
Synthon
S
R
EtO
O
Br
EtO
OEt
(Reformatsky)
NO2
R
(masked C=O)
MgBr
MeO
OMe
MgBr
The only real way to learn the information presented in this table is to practice example questions again and again!
Targeted Organic Synthesis Lecture 1
5
Acceptor Synthons
Some common acceptor synthons (carbon electrophiles):
Synthon
Ar
Synthetic equivalent(s)
Ar-N2
R1
R2
3
R1
R1
O
X = Cl, OEt
EtO
OR
OR
CO2
Br
EtO
Hal
R2
O
Hal
(masked C=O)
O
R2
Hal
R
OH
Synthetic equivalent(s)
OH
R1
R2
R
Synthon
MeO OMe
R
Br
The only real way to learn the information presented in this table is to practice example questions again and again!
Targeted Organic Synthesis Lecture 1
6
Disconnection Guidelines
How to choose a good disconnection? What follows are some guidelines:
See Warren, p. 86-92
Make disconnections corresponding to known, reliable reactions.
Use two-group disconnections - e.g. between two C=O groups, or other pairs of groups.
Synthons
Example 1
O
O
Me
Me
Forward synthesis:
OEt
OEt
Me
Example 2
Me
OEt
O
Synthons
O
OH
Me
Me
Me
Me
Me
Forward synthesis:
OH
Me
Me
Me
Me
Me
Me
Aldol reaction
Me
Me
Me
Me
O
Me
Me
Me Me
OH
Me
NaOH
Synthetic equivalents
O
O
Me
OEt
OEt
Me
O
OEt
Claisen condensation
Me
O
OEt Me
Me
OEt
Synthetic equivalents
O
O
NaOEt
H3O
Me
Me
Me
Me
In each case, disconnecting between two functional groups is a simplifying operation, and is often the easiest way to
get back to simple starting materials.
Targeted Organic Synthesis Lecture 1
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Disconnection Guidelines
For compounds consisting of two parts joined by a heteroatom, disconnect next to the heteroatom.
Why? Carbon-heteroatom bonds are almost always easier to make (usually by nucleophilic substitution
reactions such as alkylation or acylation) than carbon-carbon bonds.
Synthons
Cl
Forward synthesis:
S
Cl
Cl
Cl
Cl
SH
Synthetic equivalents
Cl
SH
Cl
Cl
Cl
Cl
S
Cl
Cl
NaOEt
Cl
Disconnect towards the middle of a molecule to make two reasonably equal halves.
Disconnect at branch points, as this strategy is more likely to give straight chain fragments.
Synthons
OH
Ph
Me
Me
Forward synthesis:
OH
Me
Ph
Br
Me
BrMg
Mg
Me
Me
O
OH
BrMg
H
Me
Me
Synthetic equivalents
Ph
Simplifying operations
that are more likley to
give reasonable
starting materials
Me
Me
Ph
Ph
(after work-up) Me
Me
Targeted Organic Synthesis Lecture 1
8
Disconnection Guidelines
Disconnect back to readily available starting materials.
Use symmetry if possible in a helpful way.
Synthetic equivalents
OH
Ph
Forward synthesis:
O
Ph
Me
O
OEt
Me
OEt
2 x PhMgBr
Me
PhMgBr
Me
Ph
This ketone is more reactive than the
starting ester (do you know why?),
and reacts with more PhMgBr as soon
as it is formed.
Disconnect twice at
branch points
OH
PhMgBr
Ph
Ph
Me
Use a convergent strategy, rather than a linear strategy if possible.
Consider:
Linear strategy:
Convergent
strategy:
A
C
A target molecule (TM) made up of four fragments A, B, C, D
90%
90%
90%
90%
90%
B
A
C
B
90%
3 steps, 73% overall yield
(0.90 x 0.90 x 0.90)
2 steps longest linear sequence,
80% overall yield (0.90 x 0.90)
Some of the previous guidelines amount to a convergent strategy (disconnecting towards the middle
of molecules and at branch points).
Targeted Organic Synthesis Lecture 2
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An Example of the Disconnection Approach
The disconnection approach applied to a perfumery compound:
O
O
Me
Me
Disconnect at ester first (disconnection at a
carbon-heteroatom bond and towards the
middle of the molecule).
Me
Disconnect at branch point
O
+
OH
HO
Me
Me
Me
Not commercially
available
O
Synthons
Synthons
OH
Me
A branched alcohol. This is actually commercially
available but we can simplify further for illustrative
purposes.
Me
HO
Me
use: CO2 = C
O
Synthetic equivalents
O
Me
Synthetic equivalents
Me
Br
acetylene
BrMg
H
Me
Me
Grignard reagent
Make Grignard from:
Br
Me
Me
10
Targeted Organic Synthesis Lecture 2
10
An Example of the Disconnection Approach
Forward synthesis:
Preparation of alcohol:
Br
Me
Mg
O
1.
BrMg
Me
Me
Me
HO
Me
Me
2. H3O
Preparation of carboxylic acid:
1. BuLi
1. BuLi
Br
Me
Me
OH
2. CO2
3. H3O
Me
Preparation of final target:
O
O
OH +
Me
HO
Me
Me
(cat.)
O
Me
Me
Me
11
Targeted Organic Synthesis Lecture 2
11
Available Starting Materials
Warren p.90
What follows is not a comprehensive list, but to just give a basic idea:
Straight chain aliphatic compounds: C1 to about C8
alcohols, alkyl halides, acids, aldehydes, amines
Branched aliphatic compounds: X = functional group (as above)
Me
Me
x
Me
Me
Me
X
Me
Me
Me
Me
Me
X
Me
Me
Me
X
Me
Me
Me
X
Me
Cyclic alcohols and ketones: C4 to C8
Acyclic ketones:
O
Me
O
Me
Me
O
Me
Me
Me
Me
Me
O
Me
Me
Monomers used to make plastics etc:
H (or Me)
Me
Ph
butadiene
isoprene
styrene
CO2Me
methyl acrylate
methyl methacrylate
H (or Me)
CN
acrylonitrile
methacrylonitrile
H (or Me)
CHO
acrolein
methacrolein
12
Targeted Organic Synthesis Lecture 2
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Available Starting Materials
Chiral pool compounds:
Hydroxy acids
Amino acids
NH2
Me
CO2H
NH2
Ph
Me
valine
OH
CO2H
Me
Sugars
Ph
CO2H
CO2H
HO2C
OH
tartaric acid
mandelic acid
Terpenes
OH
HO
HO
CO2H
lactic acid
phenylalanine
OH
OH
HO
HO
OH
OH
O
OH OH
glucose
Me
Me
Me
OH
mannose
Me
Me
Me
camphor
OH
geraniol
13
Targeted Organic Synthesis Lecture 2
13
Summary of Useful Reactions
Transformation
Reagents
H
OH
Reagents
Transformation
R2
PCC
R1
R2
R1
1. O3
2. PPh3
ozonolysis
alcohol oxidation
OH
R
OH
Jones reagent
[CrO3, H2SO4]
alcohol oxidation
R2
1
1. BH3
2. NaOH, H2O2
Jones reagent
or PCC
R2
R2
Me
OH
hydroboration-oxidation
alcohol oxidation
R2
1
R
R2
OH
R2
HgSO4, H2O
m-CPBA
R1
R1
epoxidation
alkyne hydration
R2
1
R2
NO2
Nef reaction
R2
O
TiCl3, H2O
R2
1
dihydroxylation
OH
OH
OsO4
14
Targeted Organic Synthesis Lecture 2
14
Summary of Useful Reactions
Transformation
Reagents
R2
R2
R1
R1
H
OH
NaBH 4
or LiAlH 4
carbonyl reduction
H
O
OH
LiAlH4
R1
OH
ester reduction
R1
LiAlH 4
or DIBAL
(iBu2 AlH)
H
R1
nitrile reduction
(Pd/C, BaSO 4)
Li, NH 3
H
alkyne "semi-reduction"
LiAlH4
R1
H 2, Lindlar's catalyst
R2
R2
amide reduction
alkyne "semi-reduction"
OR 2
O
DIBAL
carboxylic acid reduction
R1
nitrile reduction
OH
R
Reagents
Transformation
R1
NH 2
LiAlH4
R2
R1
alkene reduction
R2
H 2, Pd/C (c at.)
15
Targeted Organic Synthesis Lecture 3
15
Latent Polarity
Latent polarity is the imaginary pattern of alternating positive and negative charges
used to assist in the choice of disconnections and synthons. Sticking to latent polarity
usually gives the best choice of synthons. However, this is not always possible!
Willis p. 15
For example:
Addition of a nucleophile:
O
O
or
R
Nu
so:
"natural" synthons
Nu
Deprotonation to give an enolate:
O
O
R
R
H
R 1
or
So:
R 1
R 1
R
H
B
"natural" synthons
Applying this to different functional groups:
OH
O
R
Ph
latent polarity of a carbonyl
Br
Ph
get both of these from carbonyl
Ph
16
Targeted Organic Synthesis Lecture 3
16
Functional Group Interconversions
Must recognise functional group relationships!
Willis p. 27-32
Most complex molecules contain many more functional groups than simply the carbonyl group.
Many of these can often be prepared from carbonyl-containing functional groups.
Hydration of double bonds
O
FGI
Ph
Ph
Ph
N.B. NOT
O
Ph
Ph
Oxidations
H
O
benzaldehyde
aldehyde
carboxylic acid
Reductions
Esters:
Ph
Ox
R
alcohol
Me
OH
Ox
OH
benzophenone
OH
does not fit with "normal" reactivity pattern
Ph
Ph
Ph
OH
Ph
Ph
FGI
Ph
OH
O
LiAlH4
Amides:
O
OR
LiAlH4
R
R1
OH
NH2
NH2
O
2
R1
N
H
LiAlH4
N
H
R2
17
Targeted Organic Synthesis Lecture 3
17
Functional Group Interconversions
Reductions continued
Me
Nitriles:
R
NH2
LiAlH4
1. DIBAL
2. H3O
Me
H
via
Me
N
Al
H
We can use the chemoselectivity of different reducing agents in a useful way:
O
R1
NaBH4
OR2
O
R1
no reaction (most
of the time)
NaBH4
R2
OH
So:
R1
OH
Compare with LiAlH4 reactivity!
OH
R2
LiAlH4
O
R
OH
1. LiAlH4
2. H3O
O
R
OEt
HO
OH
NaBH4
O
OEt
OH , H
Use acetal formation to protect ketone
OEt
Me
18
Targeted Organic Synthesis Lecture 3
18
Functional Group Interconversions
Aldehydes/ketones
R3O OR3
1
R3OH, H
HS
SH , H
S
H3O
HgCl2, H2O
R1
R2
dithioacetals
acetals
Acetals serve as carbonyl
protecting groups.
Dithioacetals can serve as carbonyl
protecting groups and are also used when
Umpolung chemistry is required (see later).
Alcohols
Br
CBr4, PPh3
OH
PCl5
or SOCl2
Cl
To convert a complex alcohol into a
bromide/chloride for use in alkylation
reactions.
Carboxylic acids
O
R1
R2OH, H
OR2
H3O
R1
SOCl2
OH
H2O
R1
Cl
or OH
NH3
H3O
O
R1
R2OH
NH2
R1
OR2
19
Targeted Organic Synthesis Lecture 3
19
1,3-Difunctional Compounds
Warren, Chapter 19
Recognise different oxidation levels:
OH
O
R
(-H2O)
1,3-Dicarbonyls
O
O
3
Ph
Ph
Me
Use:
Me
Ph
O
Me
EtO
Me
Forward synthesis
O
Ph
OEt
NaOEt
Ph
EtO
O
Me
Ph
Me
OEt
Ph
Claisen condensation
O
Me
20
Targeted Organic Synthesis Lecture 3
20
1,3-Difunctional Compounds
The cyclic case:
O
A
CO2Et
O
OEt
Path A
Use
EtO
OEt
B
Path B
O
O
CO2Et
Use
symmetrical 1,6-diester readily available
OEt
OEt
O
Path B
Forward synthesis:
Path A
Forward synthesis:
O
+
NaOEt
EtO
OEt
CO2Et
NaOEt
OEt
CO2Et
OEt
Dieckmann Cyclisation
21
Targeted Organic Synthesis Lecture 3
21
1,3-Difunctional Compounds
-Hydroxyketones
Same disconnection at a lower oxidation level
Synthons
O
O
OH
Me
OH
Me
Forward synthesis:
O
Me
Me
Use:
Me
Me
Me
O
Me
Me
O
Me
Me
Me
, -Unsaturated carbonyl compounds
O
OH
acid or base
Me
Me
Me
H
acidic proton
to carbonyl
elimination
(-H2O)
Me
Me
Me
proceeds via
enolate/enol formation
Hence
O
Me
Me
FGI
Me
Me
OH
Me
Me
O
2 x
Me
NaOEt
Me
Me
OH
Me
Me
Aldol
reaction
22
Targeted Organic Synthesis Lecture 4
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1,4-Difunctional Compounds
disconnect in
the middle
O
O
OEt
R
O
Umpolung:
O
2
normal reactivity;
use enolate
OEt
'Umpolung'
synthon required
Warren Chapter 25
German word used to describe cases in which a
synthon of opposite polarity to that normally
associated with a required functional group must
be used.
Some umpolung acceptors
-Halocarbonyls
Good strategy for C=O oxidation state (but avoid haloaldehydes because they are unstable).
Br
Need an enolate equivalent which is "soft" and will displace the halogen rather than reacting
with the C=O group.
O
e.g.
O
1
CO2Et
CO2Et
2
O
CO2Et
O
N ,H
H
Br
an enamine
(soft nucleophile)
CO2Et
CO2Et
H3O
Use of an enamine of the ketone as an enol/enolate
equivalent here gives good results.
CO2Et
23
Targeted Organic Synthesis Lecture 4
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1,4-Difunctional Compounds
Epoxides
e.g.
R
R1
use
OH
1 CO2H
Synthons
CO2H
2
3
epoxide
OH
OH
use:
Forward synthesis:
EtO2C
CO2Et
EtO2C
CO2Et
1. NaOEt
2.
CO2H
1. NaOH
CO2Et
O
CO2Et
OH
enolate attacks epoxide on
opposite face from
epoxide oxygen (SN2)
2. H3O, heat
(-CO2)
OH
Unnatural nucleophilic synthons
How about?
O
O
OR2
OR
R2
2
1
24
Targeted Organic Synthesis Lecture 4
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1,4-Difunctional Compounds
We need an umpolung synthon that will add in a Michael fashion:
OH
If we need
OR2
or
O
O
R2
If we need
R2
we can use
NO2
base
Me
FGI
aldol
Me
O
Me
Me
Forward synthesis:
O
O
Me
O
Me
NO2
Me
Me
O2N
iPr2NEt
Me
Me
NO2
NO2
Resonance stabilised
For example:
Me
H
very acidic proton
pKa ~ 10
Me
CN
we can use
Me
TiCl3
H2O
Me
Nef reaction
Me
O
Me
O
cyclisation gives the most
substituted double bond
Me
Me
NaOH
25
Targeted Organic Synthesis Lecture 4
25
1,2-Difunctional Compounds
X
Use: RCHO
R1
R2
R1
unusual (umpolung) synthon
Problem: unusual reactivity requireds an umpolung nucleophilic synthon
Solution: devise a reagent for the required synthon or avoid problem altogether by a different strategy
Acyl anion equivalents
HO
HO
Me
O
Me
R
Use: RCHO
Use appropriate acyl anion equivalent
Acetylide anions
1.
O
R
OH
OH
Li
Hg(II), H2O
2. H3O
oxymercuration
Me
of acetylene
Thioacetals
O
Me
HS
H
SH
H
Me
BuLi
Me
Li
OH
H
OH
Me
HgCl2
H2O
Me
thioacetal hydrolysis
26
Targeted Organic Synthesis Lecture 4
26
1,2-Difunctional Compounds
Acyl anion equivalents continued
Nitro compounds
We have already seen that nitro compounds serve as nucleophilic umpolung synthons.
R2
R2
NO2
O
Cyanide ion
CO2H
CN
For example:
CO2H
Me
CO2H
Me
OH
OH
Use:
Forward synthesis:
H
Me
O
1. NaCN
2. H
CN
aldehyde
CN
Me
OH
H3O
CO2H
Me
OH
hydrolysis of cyano group
27
Targeted Organic Synthesis Lecture 4
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1,5-Difunctional Compounds
O
O
3
R2
R2
R1
Soft enolate required
Use:
Use activating group to
ensure enolisation and
Michael addition
Often made in situ
Example:
O
1
Warren Chapter 21
Esters function well
as activating groups
O
CO2H
2
3
CO2H
disconnect at
branch point
needs activating group,
requires more acidic -H
EtO2C
Use:
CO2Et
diethyl malonate
Forward synthesis:
O
O
+ EtO2C
CO2Et
NaOEt
1. KOH
CO2Et 2. H O
3
CO2Et
CO2H
Ester hydrolysis and decarboxylation
28
Targeted Organic Synthesis Lecture 4
28
1,5-Difunctional Compounds
CO2Me
Me
CO2Me
Me
CHO
CHO
disconnect at
branch point
aldehyde enolate too reactive,
would self-condense
Use enamine!
Me
Use:
CO2Me
N
O
Forward Synthesis:
Me
O
Me
+
CHO
N
H
1.
N
O
2. H3O
CO2Me
CO2Me
Me
CHO
29
Targeted Organic Synthesis Lecture 5
29
1,6-Difunctional Compounds
O
5
Me
O
6
Me
Me
Me
Difficult synthon
based on carbonyl
chemistry (C=O is
electrophilic).
Use:
O
Two possible electrophilic sites.
Need to control Michael addition.
Alternative Strategy:
We can use a functional group reconnection, rather than a disconnection
O
R
R1
O
R1
R2
Me
30
Targeted Organic Synthesis Lecture 5
30
1,6-Difunctional Compounds
How?
By using an ozonolysis reaction - using O3 (ozone)
Me
Me
O
rapid
rearrangement
Me
O
O
O
Clayden p. 938-939
ozonide
molozonide
A 1,3-dipolar cycloaddition
The intermediate ozonide can be treated in a number of ways:
Me
O
Me
NaBH4
reducing: generates diol
OH
O
Me2S
OH
KMnO4
Me
Me
oxidising: keto-acid
O
CO2H
O
CHO
mildly reducing: keto-aldehyde
31
Targeted Organic Synthesis Lecture 5
31
1,6-Difunctional Compounds
Example:
Me
Me
FGI, then
1,3-diO
Me
Me
Me
Me
Me
Me reconnect
Me
CHO
Me
Me
Me
FGI
Me
OH
Me
Forward Synthesis:
MeMgBr
Me
Me
Me
Me
Me
Me
Me
OH
H3O ,
Me
Me
Me
Me
Me
Me
O
Me
Grignard
Me
Me
OH
Me
Me
Me
Me
1. O3 , -78 oC
2. Me2S
O
O
NaOH
Me
Me
Me
Me
Me
CHO
33
Targeted Organic Synthesis Lecture 5
32
Regioselective Enolate Formation
When several sites are available for deprotonation in a substrate, how can we control which enolate is formed?
For example:
Willis p. 60-63
O
Me
O
base
Me
Me
and/or
kinetic enolate
proton removed more
rapidly from less
hindered position
thermodynamic enolate
double bond more stable
(more highly substituted)
We can exhibit control over which enolate is formed by altering the reaction conditions.
Using a bulky non-nucleophilic base such as LDA at low temperatures (conditions that favour irreversible
deprotonation), we can generate kinetic enolates with high selectivity.
Me
Me
Me
N
Me
Li
Me
LDA, -78 C
lithium
diisopropylamide (LDA)
Me
Me
MeI
Me
Nitrogen atom sterically shielded
by bulky isopropyl groups.
Non-nucleophilic.
Removes least hindered
proton in irreversible (kinetic)
deprotonation.
Li
O
Me
LDA, -78 C
Me
O
Me
Li
O
Ph
Me
OH
Ph
34
Targeted Organic Synthesis Lecture 5
33
Regioselective Enolate Formation
In contrast, heating a ketone with a weak base such as Et3N in the presence of Me3SiCl promotes reversible
enolisation to generate the thermodynamic enolate preferentially:
Kinetic product
O
OSiMe3
Me
Me3SiCl, Et3N, heat
Compare with:
Thermodynamic product
1. LDA, -78 C
2. Me3SiCl
OSiMe3
Me
Me
+
1
12
99
The silyl enol ethers can be isolated,
purified and used in further reactions.
Regeneration of lithium enolate:
OSiMe3
Me
MeLi
Me
O
Me
Li
SiMe3
O
Me
Li
Ph
Br
Ph
Me
35
Targeted Organic Synthesis Lecture 5
34
Regioselective Enolate Formation
We can also control the regioselectivity of enolisation by the introduction of an additional electron-withdrawing (and
hence "acidifying") group. Esters serve as good activating groups, and can be removed later by hydrolysis and
decarboxylation.
e.g.
O
O
O
EtO2C
CO2Et
CO2Et
Me
OH
Me
acetoacetate
O
O
Me
malonate ester
CO2Et
1. NaOEt
Br
2.
CO2Et
Me
1. NaOEt
2. Ph
Br
Me
O
CO2Et 1. NaOH
Ph
Me
Me
Me
The above sequence equates to a regioselective
controlled dialkylation of an acetone equivalent.
2. H3O
Me
H
Ph
Me
hydrolysis and
decarboxylation
(2nd Year carbonyl
chemistry!)
