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Disconnection Approach: Retrosynthetic Principles and Synthetic

Applications

Presentation · February 2009

DOI: 10.13140/RG.2.2.28229.55526

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 DISCONNECTION APPROACH:
Retrosynthetic Principles and Synthetic
Applications
XV Summer School in Pharmaceutical and
Medicinal Chemistry
Rio de Janeiro, Brasil 09-13 February 2009

Pier Giovanni Baraldi

Department of Pharmaceutical Siences
Ferrara University, Italy
 Disconnection Approach
Retrosynthetic Analysis: the logical process of analysing the structure of
a target molecule to discern a possible synthesis step by step

Retrosynthetic arrow is: A B (B is a precursor of A)

( Means “can be made from”)

Functional group interconversion (FGI)

Functional group addiction (FGA)
Functional group removal (FGR)
Disconnection: the formal reverse of a bond forming reaction (conceptual
cleavage of a bond to break the molecule into possible starting materials)
dn synthon: Functionalized nucleophile (d, donor) with the heteroatom of
the functional group joined to the nth carbon atom
an synthon: Functionalized electrophile (a, acceptor) with the heteroatom of
the functional group joined to the nth carbon atom
Reagent: A chemical compound used in practice for a synthon
 Disconnection Approach
Synthons and Reagents
dn synthon: Functionalized nucleophile (d, donor) with the heteroatom of
the functional group joined to the nth carbon atom.

d1 CN
d2 CH2CHO

an synthon: Functionalized electrophile (a, acceptor) with the heteroatom of

the functional group joined to the nth carbon atom.

a1 CH2OH
a2 CH2CHO
a3 CH2CH2CHO

Reagent: A chemical compound used in practice for a synthon.

Synthon Reagent
CH3 CH3I or CH3oTs
CH3 CH3MgBr
CH2CH2CHO CHO
 Retrosyhthesis of Benzocaine
Retrosynthetic Pathway: Benzocain from toluene
O O O

OEt C-O OH FGI OH

H2N H2N O2N

FGI
Benzocaine
•Toluene is a readily available starting material
• Me is activating and ortho/para- directing Me Me
• We know reagents for the synthon NO2+ C-N
O2N

Toluene

Synthesis O
O
Me OH
Me OH
H2SO4, HNO3 KMnO4 H2 Pd/C
H2N
O2N Oxidation O N Chemoselective
2
reduction
EtOH/ H+

OEt

H2N
 Eletrophilic Aromatic Substitution
How to identify the most suitable synthons and reagents?

Which disconnection and which sense of polarity?

O
O

MeO
or
O Synthons
MeO

MeO

O
Reagents +
Cl Me
MeO

O
O
AlCl3
Synthesis + Me

MeO Cl Me
MeO
o/p directing and activating
 Eletrophilic Aromatic Substitution
How to identify the suitable synthons and reagents?
Key reactions and Reagents for FGI in the contest of Aromatic Chemistry

Synthon Reagent Reaction

R+ RBr with Lewis acid Friedel Craft alkylation

ROH/H+
RCO+ RCOCl with Lewis Acid Friedel Craft acylation
NO2+ HNO3/H2SO4 Nitration
Cl+ Cl2/FeCl3 Chlorination
Br+ Br2 and Lewis Acid Bromination
SO3 H2SO4 Sulfonation
 Eletrophilic Aromatic Substitution
How to identify the most suitable synthons and reagents?
Key reactions and Reagents for FGI in the contest of Aromatic Chemistry

Y X Reagent

NO2 NH2 H2
COR CH(OH)R NaBH4
COR CH2R Zn/Hg
CH3 COOH KMnO4
COR OCOR RCO3H
CN COOH Hydrolysis
 Eletrophilic Aromatic Substitution
Retrosynthesis of BHT
OH
Retrosynthesism of BHT = Buthylated Hydroxy Toluene
BHT ia an antioxidant and is used as a food preservative

Cl OH
Cl

OH OH
Reagents

OR

Synthons OH

Reagents
 Eletrophilic Aromatic Substitution
Friedel-Craft alkylation or acylation

C-C Cl

NOT SUITABLE
Problems:
1. Rearrangement of alkyl for more stable carbocation.
2. problem of polyalkylation

Synthesis
O
O O

FGI C-C
Cl

SUITABLE
 Nucleophilic Aromatic Substitution
SN1 for nucleophilic aromatic substitution: Diazonium Chemistry

X NH2 X Reagent

+ X OH H2O
OR ROH
CN CuCN
Cl CuCl
NH2 Br CuBr
N2 + X
NaNO2/HCl -N2 I KI
Ar ArH
H H3PO2

Addition-Elimination
F Cl Br I

X Nu O2 N O2N O2 N O 2N

O2N O2 N >> ∼ >>

Nu-
+ X-
More reactive Less reactive
 Aromatic Substitution
Retrosynthesis of Trifluoralin B Herbicide
N Cl Cl Cl Cl

O2N NO2 O2N NO2

C-N FGI FGI C-Cl

CF3 CF3 CF3 CCl3 CH3 CH3

Retrosynthesis of biphenyl derivative

COOH CN NH2 NH2 NO2

Cl Cl Cl

FGI C-C FGI C-N

 Aromatic Substitution
The use of removable group to control selectivity
Retrosynthesis
of Propoxycaine Problem of
Regiocontrol
Local anaesthetic

Synthetic Route
to Propoxycaine

Solution:
Introduction of a temporary group
that will be removed at a later stage
of the synthesis
 Aromatic Substitution
The importance of order of events- disconnection
Retrosinthesis of Dinocap (Fungicide)
hex hex

O OH
HO
C-O
+
O O
O2N NO2 O2N NO2

hex

OH OH
OH
C-C 2x C-N Good disconnection-
Correct order of events
O2N NO2 O2N NO2

hex hex

OH OH OH
2x C-N C-C Poor disconnection-
Wrong order of events
O2N NO2

Para position not blocked to force alkylation ortho

 One Group and Two Groups Disconnection
One Group C-X Disconnection
For compounds consisting of two parts joined by a heteroatom (X), disconnet next
to the heteroatom. This guideline works for esters,
O
amides, ethers, sulfides etc.
Retrosynthesis of HN NH2 NO2
Propanil Weed killer
C-N FGI

Disconnection Cl
Cl Cl Cl
Cl
Cl Cl Cl

Synthons Reagents
Cl S Cl
SH
+
Cl
Cl
C-S +
S Disconnection
Retrosynthesis of Cl Cl
+
Chlorbenside S
Cl
Cl
Cl
 One Group and Two Groups Disconnection
Chemoselectivity
Chemoselectivity arising from two groups of different reactivity.
The preferential retrosynthetic route should avoid chemoselectivity problems.
In pratice, this means that one should disconnect reactive groups first.
To solve chemoselectivity problems, it is very often critical to choose carefully
reaction condictions for the foreward synthetic step.
O O NR2 O OH O OH
Retrosynyhesis of I

Cyclomethycaine C-O C-O

Disconnection Disconnection
(anaesthetic) +

O O OH

Chemoselectivity
O OH O O O OH O O NR2
Synthesis of
Cyclomethycaine excess base SOCl2

HOCH2CH2CH2NR2

OH O O O

pKa phenol ~ 10
Both groups ionised pH> 10 pKa benzoic acid ~ 4.2
 One Group and Two Groups Disconnection
Chemoselectivity
Retrosynthesis of Paracetamol (Analgesic)
O

HN NH2 NO2

C-N C-N
Disconnection FGI Disconnection

OH OH OH OH
O

Synthesis of Paracetamol
NH2 HN More Nucleophilic
NH2 NH2

1.HNO3/ H2SO4 Ac2O

2. H2 Pd/C

OH OH
Under conditions that OH OH O-
pKa phenol ~ 10
keep phenol unionised pKa aniline ~ 30 More Nucleophilic
 Two Groups C- X Disconnection
1,1-Difunctionalised compounds
Example 1

Cl 1,1 diX HO OH
Cl +
O O
acidic conditions O

Example 2
R FGI R 1,1 diX RCHO

H2N COOH Strecker Synthesis NH3 HCN

H2N CN

Example 3
OH OH
CN OH O
NH2 FGI
1,1 diX CN + KCN/H+

a1 d1
 Two Groups C- X Disconnection
1,2-difunctionalised compounds

ALCOHOLS 1,2 diX

O
NR2
HO HO a2 NR2

Important synthon Reagent is epoxide

Example 1: Phenyramidol (muscle relaxant)

1,2 diX Ph O
Ph + +
N N HN N H2N N
H OH Ph
OH

Example 2: Propranolol (beta-blocker reduces blood pressure)

O N O OH O
H
OH O
1,2 diX
Cl
Epichlorhydrin
Propranolol allows for two possible 1,2-diX readily available
but it is best to disconnect the more reactive amine group first.
 Two Groups C-X Disconnection
1,2-difunctionalised compounds

CARBONYLS O
1,2 diX O O

Nu
Nu Cl
R R a2 R

Important synthon Reagent

N
O
O O
N
Cl
1,2 diX

Reagent
N

HN
k rel
Note: α-chloro or bromo highly reactive electrophiles Me-Cl 200
and Control of mono-versus polyhalogenation. iPrCl 0.02
allylCl 80
MeOCH2Cl 920
PhCOCH2Cl 10000
 Two Groups C- X Disconnection
1,3-difunctionalised compounds

CARBONYLS O O O
1,3 diX
Nu
R Nu R a3 R

Important synthon Reagent

Example 1: Atropine (Muscle relaxant)

O O

1,3 diX Ph Ph
N O

Ph
Reagent
N
H
 Two Groups C- X Disconnection
1,3-difunctionalised compounds

NITRILES

FGI
O O

NH2 CN

1,3 diX

OH +
N
 Protecting Group Chemistry
To avoid if you can…Each protection event adds two steps:
protection-deprotection
Synthesis requiring protecting group chemistry
O

Br
HO
C-Br HO FGI HO
Salicylic acid
HO HO HO
O
Synthesis: Br
HO LiAlH4 HO Br2 HO O

HO HO HO HO

Revised Synthesis: Side-product

Br2 ia also an oxydant
O

HO O O
HO acetone
LiAlH4 Br2
pTosOH
HO O O
HO
H+/H2O

Br
HO

HO
Amines and One Group C-C Disconnections
Synthesis of secondary amines
O
FGI +
N
NH2

O
HN or

FGI COCl
HN H2N
+

Retrosynthesis of Fenfluramine (Drug CNS)

NHEt NHCOMe NH2
FGI C,N-amide

F3C F3C F3C

FGI
Reagent for reductive amination:
Carbonyl dervative, amine and
NaBH4 NaOAc/HOAc pH 6 O NOH

F3C F3 C
Amines and One Group C-C Disconnections
Synthesis of primary amines

These targets are not conveniently prepared from unsubstituted

imines [unstable] or primary amides.

Alternative and better solutions are available and include:

• the reduction of cyano group
• the reduction of azido group
• the reduction of oximes
• alkylation and reduction of nitro compounds
• the Ritter reaction followed by hydrolysis
• the Gabriel synthesis
 Amines and One Group C-C Disconnections
The synthesis of amines is slightly more complicated in comparison
with the synthesis of e.g. ethers or sulfides because the product of
an N-alkylation is at least as reactive as the starting material,
therefore leading to complex reaction mixtures.
X
C-N
N R2 + Bad disconnection
R1 NH2
H
R2
The problem of polyalkylation
X X X

+
R2 R2 R2
R1 NH2 R1 N R2 R1 N R2 R1 N R2

H X-
Secondary amine R2 R2 R2
More reactive than primary amine
Suitable FGI involved amides,
The solution: FGI prior to disconnection imines or oximas.
H H
RNH2 R1COCl N R1 LiAlH4 N R1
R R

O H
LiAlH4 N R1
RNH2 R1COR2 N R1 R
R or
NaBH3CN R2
R2
Amines and One Group C-C Disconnections
Example 1 AMINES
NH2
FGI C C-C
N + CN-

Synthons

Reagent for reduction of cyano into amine is LiAl H4

Br
+ NaCN or KCN
Example 2 Reagents
OH OH OH
FGI 1,2 diX O
NH2 NH2
R R R
R
Reagent for reduction of azide into amine: PPh3 + NaN3

Example 3

2x alkylation H2 cat
R1CH2NO2 R1R2R3CNO2 R1R2R3CNH2
 Amines and One Group C-C Disconnections
AMINES
Example 4 Ritter Reaction

R1R2R3COH MeCN/ H+ R1R2R3CNHCOCH3 Hydrolisis R1R2R3CNH2

Ritter Reaction: VIA CARBOCATION R1R2R3C+

Example 5 Gabriel Reaction

O
O O O RNH2

NH3 KOH/ EtOH NH

O NH NR
then NH2NH2 NH
RBr
O O O
O
Amines and One Group C-C Disconnections
One Group C-C Disconnection
SYNTHONS REAGENTS

R1 R1
1,1 CC OH
-
OH
R RMgBr + R1COR2
R2 R3 R2

OH OH
O
1,2 CC RMgBr +
R-
R R1 R1 R1

O O
1,2 CC
R+ RBr + R1COMe
R R1 R1

OH
OH
1,3 CC
R- RMgBr/ CuX + CH2=CHCOR1
R R1
R1
 Amines and One Group C-C Disconnections
One Group C-C Disconnection- Alcohols
1,2CC Disconnections leading to alcohols
O
1,2 CC
Ph + PhMgBr
Ph

OH OH Reagents

Example
1,2 CC O FGI

OH
OH Br OH

1,1 CC

MgBr +

Reagents: PBr3 or the Apple Reaction [PPh3 /CBr4]

Amines and One Group C-C Disconnections
One Group C-C Disconnection- Alcohols
1,1CC Disconnection leading to alcohols

OH 1,1 CC OEt + 2eq MeMgBr

Retrosynthesis of Pirindol- Muscle Relaxant

NH
1,1 CC 1,3CX
N OH N OEt
OEt

Ph Ph O
O
1,1CC Disconnection leading to carboxylic acid
Synthons Reagents
OH 1,1 CC
MgBr + CO2 COOH CO2
O COOH NaCN
Amines and One Group C-C Disconnections
One Group C-C Disconnection- Carbonyl Compound as Target

1,1 CC 1) The use of ester and Grignard as double

O 1,1CC O
addition will generate the alcohol
R1 R2 R1 R2 2) The use of less reactive organocadmium
Synthons like R1CdR2

Alternative routes are: ketones from nitriles,from acids and from Weinreb amides

1,2CC COOEt
COOH
1,2CC COOH
Br
COOEt

Example:
Br
O

O O
EtO O

Synthons Reagents
 Amines and One Group C-C Disconnections
One Group C-C Disconnection- Carbonyl Compound as Target

1,3CC
R1 R1
R R
R + RMgX/CuI

O O O

OH O
Example: O

FGI 1,3 CC
a3 +

COOEt COOEt
COOEt Synthons
Keys aspects for the synthesis:
• organocopper chemistry O O
• stereoselectivity of Michael Hagemann’s Ester
addition and reduction
O

MgBr/CuI
O O

COOEt COOEt COOEt Reagents

 Synthesis and Use of alkenes and Alkynes
OH
FGI Ph
Synthesis of R
Ph Ph
Alkenes R or
Ph
via elimination FGI Ph
R
EtO
R + PhMgBr
HO 2 x 1,1 CC O
Ph

Synthesis of Alkenes via Wittig Olefination

PPh3 + base
Wittig Reagent R1CH2Br R1CH2PPh3 R1CHPPh3 phosphorus Ylide
Phosphorus Ylide Br-

Wittig Reaction R1CHPPh3 + R2CHO R1CH=CHR2 + OPPh3

PPh3 + O=CH2
Decision making:

O + Ph3P=CH2
 Synthesis and Use of alkenes and Alkynes
Ph3P
Elimination or O this approach may not lead
to single geometrical isomer

Wittig Olefination?
Problem of elimination: product selectivity
+
OH OH
or
OH OH
+

Stereochemistry of the Wittig Reaction

E/Z geometry is a function of the structural features of the phpsphorus ylid
STABILISED YLIDE E ALKENES
UNSTABILISED YLIDE Z ALKENES
O
PPh3 O O
stabilised ylids R Horner-Wadswoth-
R PO(OEt)2 Emmons variant

unstabilised ylids PPh3

R
Synthesis and Use of alkenes and Alkynes
Stereochemistry of the Wittig Reaction
E/Z geometry is a function of the structural features of the phosphorus ylid
Z selective Wittig IRREVERSIBLE
PPh3
Ph3P O
R PHPh3 + R'CHO O
R' R
R'
R R'
R

E selective Wittig REVERSIBLE

Ph3P O

EtOOC R' SLOW R' R

O
PPh3 + R'CHO
EtO
Ph3P O R
FAST R'
EtOOC R'
oxaphosphetane formation
is reversible
 Synthesis and Use of Alkenes and Alkynes
Synthesis of E,E or E,Z Diene
Solution needs to take into account E,Z or E,E geometry of the diene

Wittig
E-stabilised ylid + O
PPh3

Wittig
Z-unstabilised ylid PPh3 + O

Synthesis Alkenes upon reduction of Alkenes

For Z isomer Hydrogenation [Lindlar's catalyst]

For E isomer Na/NH3 reduction

Revision: Mechanism of Na-ammonia reduction SET - origin of E selectivity

 Synthesis and Use of Alkenes and Alkynes
Problem for trisubstituted alkenes: Control over E/Z geometry

One solution to the problem: Synthesis involving a cyclic intermediate

OH OH O

OH Double O O
FGI OEt FGI OEt

OEt OEt

Revise Birch reduction:

the Mechanism and the issue of Product Selectivity
 Synthesis and Use of Alkenes and Alkynes
pKa and key transformations R H pKa 25

R Na
R H
R MgBr + RH

RX R R alkylation
OH
O addition onto carbonyl
R R
derivatives
O
R
R epoxide ring opening
OH
R

Conversion of terminal Alkynes into Carbonyl Derivatives

O
R H Hg2+ / H2SO4
R Me
O O
H
Me d1 H2C d2 t-hexyl2BH
R H H
H2O2/ NaOH R
O
 Synthesis and Use of Alkenes and Alkynes
Example 1

O + CH2=CHMgBr

OH or acrolein readily
available
O
MgBr

FGI FGI
OH
Br OH OH

Example 2
O
FGI HO FGI HO 1,1 C-C
+ H
Synthesis and Use of Alkenes and Alkynes
Multistriatin Retrosynthesis
Br
O 1,1-diX HO 1,2-CC + HO
O O
O OH OH

Br HO
FGI HO Me OH
HO
OH HO OH
OH

Reagents
Me OH 1,2-CC OH O
MeMgBr
HO OH HO OH HO OH

O
FGI FGI HO
HO OH HO OH
OH
 Two Group Disconnections
1,3-, 1,5- and 1,2- Difunctionalised Compounds
• 1,3-Dicarbonyl Compounds and their derivatives
Synthons Reagents
O O O O O O

R R R d2 a1 R EtO

O O O O O

2
EtO EtO d2 a1 EtO
Note: Mechanism of Claisen condesation
• Example 1: Synthesis of Pival [Rat Poison]
O O

O O

+
O EtO tBu
tBu

O O O

O O O
tBu
COOEt O
tBu
O
tBu
COOEt COOEt

O
 Two Group Disconnections
1,3-Difunctionalised Compounds
O O O
OEt
O
COOEt COOEt
• Example 2 +
EtO OEt
B A
• A and B are the two
possible disconnections
O O
• Example 3 Ph OCOR
• B corresponds to the
C-C NH2
+ Dickmann cyclisation
Me
N N unstable

Me
FGA Add a group!

COOEt EtOOC COOEt COOEt

NH2
+
Me
N N

Me Me

• Example 4 Route to symmetrical ketones

O O O

COOEt COOEt
Add a group!
OEt

R R
FGA R R R R
 Two Group Disconnections
1,3-Difunctionalised: β –Hydroxycarbonyl and α,β -Unsatured carbonyls
• Example 1
O OH O

N OH OH O

• Example 2 Oxanamide (tranquilliser)

O
O
FGI FGI
C-N CHO
CONH2 COOH CHO

• Example 3 Doxpicomine (analgesic)

O OH
COOEt COOEt

N O N OH N N
C. O acetal
COOEt COOEt
FGI
H
N N N N
H3 C CH3 H 3C CH3 H 3C CH3 H 3C CH3

COOEt
N
COOEt
O
 Two Group Disconnections
1,3-Difunctionalised Compounds – Amino alcohols
• Reduction of nitriles
O R R'
HO
R' R' HO reduction
R CN CN
C-C formation R' NH2
R'
R' R
Example Venlafaxine (Antidepressant)
MeO MeO MeO MeO

Me CN CN MeO
N NH2
HO HO HO
Me O
Br

• Mannich Reaction
R' R' R'
O
FGI
HO NR2 O NR2 O
NHR2
R R R

Example Clobutinol (Cough Medicine)

O
MgBr
H
N
OH N O N O
 Two Group Disconnections
1,3-Difunctionalised Compounds – Summary

O OH O O O

FGI
ALDOL and Variants
R R' R R' R R'

O O O O

CLAISEN and Variants

R OEt R OEt OEt

R' R' R'

O
FGI
HO NH2 O NH2 O MANNICH and Variants
RNH2
R R R

R' R'
R' CN
FGI CN
HO NH2 HO
O R NITRILE and Variants
R R
 Two Group Disconnections
1,5-Difunctionalised Compounds
• 1,5-Dicarbonyl Derivatives
O O O O O
1,5diCO

d2 a3

Example
O O O O

O Add a group! O OEt

+
COOEt
OH OEt

COOEt

Example Rogletimide (Sedative)

N N O O N O O N O
O N O
H OEt NH2 OEt NH2 OEt
 Two Group Disconnections
1,5-Difunctionalised Compounds
• Robinson Annulation
O O O O

1,5 diCO

O O O O O O
OH

• Synthesis of Coccinelline
COOMe
O

N N O O
FGI CH(OMe)2 CHO
CH(OMe)2 CHO
COOEt

COOEt O

• Synthesis involving an intermediate featuring a 1,5-Difunctionality

H2 N
FGI H 2N O
H 2N
NH2 NO2 + MeNO2
FGA pKa = 10

1,5 diCO
O O

N N
 Two Group Disconnections
1,2-Difunctionalised Compounds
• 1,2-Diols via alkenes
OH
O R'
R' FGI R' FGI
R R
R PPh3
OH
• 1,2-Diols via cyanhydrins
Cl Cl Cl Cl
O
FGI
CN
OH OEt
OH OH OH

• α-Hydroxyketones via benzoin condensation

O

O O
Ph
Ph
Ph Ph
Also Revise: acyloin condensation
d1 OH a1
OH
• α-Functionalisation of carbonyl compounds
OH O
Ph
PhOC
Ph Ph

Diphepanol N N
PhOC
PhOC
spasmolytic
Br
 Two Group Disconnection
1,4-Difunctionalised Compounds: Strategy 1
O O
R2 or R2
R1 R1
O OH

O O O X
a2
R2 R2 R2
R1 R1 R1
O d2 O O

Example: Precursor of antibiotic methylenomycin

O O O O O
Br
O
COOEt COOEt
COOH COOEt OH COOEt
O O

O O
METHYLENOMYCIN
COOEt
base cyclisation
O O
Synthesis: Br COOEt COOEt
O
 Two Group Disconnection
1,4-Difunctionalised Compounds: Strategy 2
O O O
a2
R2 R2 R2
R1 R1 R1
d2 O
OH OH

Example:
COOH
O CH2(COOEt)2

OH

1,4-Difunctionalised Compounds: Strategy 3

Reagents
O O O
d1
R2 R2
R1 R1 R1
O a3 O
With nitrile or
nitro derivative
 Two Group Disconnection
1,4-Difunctionalised Compounds: Strategy 3 Nitrile
Ph
Ph
Ph Ph CN

O O HOOC COOH
N NC COOH COOH
H

Synthesis: H+/H2O Ph
NaOEt Ph CN
PhCHO + NCCH2COOEt
Then MeNH2 O O
Then KCN NC COOEt N
H
1,4-Difunctionalised Compounds: Strategy 3 Nitro
base NO2 O
R2 R2
R1 NO2 R2 R1 R1
O O
O
O O O NO2

FGI

OH
O O
 Two Group Disconnection
1,4-Diols and derivatives: Strategy 4 Alkynes
OH
HO OH O O
R2
R1
R1 R2 R1 R2
OH
O
Example: FGI
OH HO
O COOH
R O R
OH

HO O

R R

1,4-Difunctionalised Compounds: Strategy 5 Allylation

O FGI Br

CO2Et CO2Et CO2Et

 Two Group Disconnection
1,6-Difunctionalised Compounds: Ozonolysis
“Reconnection” is a reliable strategy for synthesising 1,6-difunctionalised
compounds since the cyclohexenes required for the oxidative cleavage are
easily accessible
O
OH
HO
“Reconnection”
Example: O
O
O O
1
reconnect
6
O

1,6-Difunctionalised Compounds: Baeyer-Villiger

O OH reconnect O O

OMe OMe O

O O
“Revision”: mechanism of Baeyer-Villiger reaction and migratory aptitude
 Two Group Disconnection
1,6-Difunctionalised Compounds

“Reconnect”
O
or Br
O O O
EtO

O
EtOOC
Synthesis O
EtO
COOEt
Br O
O HCl
O
Then
Polyphosphoric O O
O EtOOC COOEt acid
 Two Group Disconnection
1,6-Difunctionalised Compounds
O O O “Reconnect”
EtO O

Retrosynthesis- Solution 1
O O O O
EtO O
CN Br
COOEt
O O

COOEt
COOEt
COOEt
COOEt
Retrosynthesis- Solution 2
O OH OH
EtO O EtO O

E/Z O
 Dithianes are d1 Reagents
Acyl anion equivalents
Which dithiane?

BuLi BuLi
S S S S but S S S S

S S
Li Li
Not stable
Example

Br Br

O O
O O O O

Revision: pKa and mechanism/reagents to transform dithianes into

aldehydes or ketones HgCl2, oxidation or alkylation
 Ring Synthesis
Three-membered rings

• Three-membered rings
OEt
a
O
Mechanisms
O O

b O
Epoxidation
O
OEt
: Ring closure
OEt

OEt
Synthesis a: H2O2, base
O
O O

Cl O OEt
EtO- /acetone
Synthesis b:
OEt
 Ring Synthesis
Three-membered rings

• Three-membered rings
O
O O O
C-C FGI
+ O

R Br R HO R

EtOOC R

• Three-membered rings
Br

Br O
O O
Br
COOEt
O : + O HO
Br
EtOOC
HO
 Ring Synthesis
Four-membered rings

O O
R R R
BuLi R1 R2
S S S
R1 R2
R R R

R1
O
R
O H+ R2
S

R R1
R1 R2
O
R2
 Ring Synthesis
Five-membered rings
• Five-membered rings: chemoselectivity ozonolysis, control over recyclisation step

O
O Limonene
Natural Product

• Acyloin condesation as a key step for the synthesis of 5-membered rings

O O O O O
EtO EtO
OH OH OH O O

OEt OEt

Corylone NMe2 NMe2

Spicy coffee
O

COOEt
• Favorskii Ring Contraction
 Ring Synthesis
Six-membered rings
• Six-membered rings via Diels-Alder Cycloaddition

O O
• Six-membered rings via complete Reduction
O OH OH

• Six-membered rings via partial Reduction

O
O MeO MeO

O O
 Synthesis of Nuciferal
Bisbolane type sesquiterpene isolated from wood oil of
Torreya Nucifera
BrMg

OH
O

A ?
O STAGE 1 O
Nuciferal
CHO
O

STAGE 2 ?
1. Suggest a synthesis for the
starting material A
2. Suggest reagents for stages 1, 2
and 3
3. Draw out the retrosynthetic ?
analysis with suitable labelling STAGE 3
for all retrosynthetic steps CHO
4. Which synthon does the starting Nuciferal
material A represent?
CHO
 Synthesis of Coccinelline
O
Ladybird compound COOMe

N N O O
FGI CH(OMe)2 CHO
CH(OMe)2 CHO
COOEt

COOEt O
H O H OMe OMe O OMe
OMe
NaOMe MeOH/H+
MeOOC COOMe
CH2=CHCHO MeO OMe
then decarboxylation NaOMe
COOMe

MeOOC MeOOC
OMe O OMe OMe NH2 OMe
NaCl, DMSO NH4OAc
Krapcho MeO OMe NaB(CN)H3 MeO OMe
dealkoxy-
decarboxylation
H

O NH2 O H
pH 5, H2O
N O
H
MeO2C CO2Me
H H N O
O
H
MeOOC COOMe

OH MeOOC COOMe
N
N
O

COOEt
MeOOC COOMe
COOEt O
O
 Retrosynthesis of Terfenadine
Ph NaBH4 Ph
Me Me
H
Ph C N (CH2)3 C C Me Ph C N (CH2)3 C C Me
Me Me
OH OH FGI OH O

K2CO3
DMF
Antagonist H1 ∆

Ph
Ph C OH
O
Me
Cl (CH2)3 C C Me
Me
N
H

1) PhMgBr FGI, AlCl3 RETRO ACILAZIONE

2) NaOH, BuOH RETRO GRIGNARD CHCl3 FRIEDEL CRAFT
∆

CO2Et ClCO2Et CO2Et Cl Me

TEA (CH2)3 C Me
COCl Me

N FGI N
H
COOEt
 Retrosynthesis of Minaprine -Antidepressant

5 O FGI FGI
4
6 N
Ph N Ph Cl Ph O
3 H POCl3
N N RNH2, ∆ N N ∆ N N
1 2
H

FGI Br, AcOH, ∆

O FGI
1
Ph O
Ph CO2H NH2NH2 N N
2 ∆
H

FGI RETRO ACILAZ.

1 FRIEDEL - CRAFT
AlCl3
2
CH2Cl2

PhCO O
O Ph O

HO
CN OR
Ph C
H2C C CO2R O
N
CH3
O
O

O
 Retrosynthesis of (+)-Norgestrel
19-Nor Steroid
OH OH H O
H

RETRO
17
FGI ETINILAZIONE
H H H H

H+, ∆ H H 1) LiC CH H H
H H
2) NH4Cl / H2O
O MeO MeO

1) Li / NH2(l) FGI
2) Al (OiPr)3, ∆ RETRO
BIRCH

O
H
RETRO OAc
OH
KNOEVENAGEL
FGI FGA, FGI
*

*
1) H2,Pd / CaCO3 H
1) Ac2O, Py 2) KOH, MeOH
O 2) TosOH, ∆
MeO
MeO
MeO

RID. FGI
ENZ.

O
O
RETRO
TORGOR
a d
d a

O KOH, MeOH
∆ OH
O
MeO

MeO
 Retrosynthesis of Avenaciolide
C8H17 C8H17
O O
O O C8H17 O O O
C8H17
RETRO OH
FGI
METILENAZ. H H
H H
a d O
O O O
H 2C

O
O O O

FGI
CHO C8H17
O C6H13 O
O
RETRO
WITTIG FGA
O Me O Me
O Me
O O
Me O Me
RO2C Me RO2C
RO2C

CON

Me O Me O D-GLUCOSIO
HO Me O Me O HO
O O FGI
HO RETRO O
O FGI WITTIG
OH
O Me O Me

O Me FGA H O OH OH
O O
Me Me
OH
O CO2R
Me
RO2C
 Retrosynthesis of Pentenomicina
d Me
O O
O O a CHO
RETRO
FGI FGI ALDOLIC

AcO BuO O O
O O BuO O O
HO OH OH
(-)-Pentenomicina
Me Me Me Me
Me Me

FGI

Me O OMe
TsO OMe O
TsO O H2C
O
Me O
O

O Me
BuO O O
O Me BuO O O
BuO OH O Me
BuO OH O Me Me Me
Me Me

FGI

Me O Me Me O

RETRO RETRO Me O
Me O Me O HENRY
O NEF O
O D-GLUCOSIO

d a
OHC O Me O Me O Me

O2 N O O Me
OH O Me OH O Me
 Retrosynthesis of 11-Deoxy-8-aza-PGE1
O
O O O
(CH2)6-CO2R
(CH2)6-CO2R (CH2)6-CO2R (CH2)6-CO2R
RETRO N
N FGI N WITTIG FGI N

C5H11 C5H11
CHO
1) K2CO3 CO2R
Zn(BH4)2
2) ClCO2Et, TEA
11-Deoxy-8-aza-PGE1 O R = Me, H
OH NaBH4
3) CrO3. 2Py

RX
NaH

O
NH2 O
∆ FGI
NH
HO NH
CO2H
H CO2H CH2N2
O FGI
H CO2R
(R)-Acido Glutammico

Baraldi,P.G. et al. J.Org.Chem.,1979,10,1734

 Retrosynthesis of ±4 –oxocyclopentane-
1,2-dicarboxylic acid

O O
FGA
FGI
1 RO2C CO2R
CO2R RETRO 1
DIECKMANN CO2R
∆, DMSO
160°C CO2R RO2C 2 CO2R
HO2C CO2H RO2C CO2R ∆

2
RETRO ∆
MICHAEL

a CO2R
CO2R Br 3 CO2R
3
CH2 CH2
d
CO2R CO2R CO2R
EtONa RO2C RO2C
Retrosynthesis of cis-3-oxabicyclo[3.3.0]octan-7-one

RETRO 1
FGA DIECKMANN
RO2C
O O O O
O
RO2C
∆
1 EtONa, ∆
cis-3-Ossabiciclo
3.3.0 -Ottan-7-one RO2C

1) CrO3 FGI, FGI

2) CH2N2

FGI RETRO
OZONOLYSIS
OTos OHC
O
O
OH OHC
TEA
O3

TosCI
TEA FGI
O
O
RETRO
FGI DIELS - ALDER
OH
O
O
OH
LiAlH4
∆
O
O

Baraldi,P.G. et al.,Tetrahedron,1984,40,761
 Retrosynthesis of Diidroiasmone
O
O

RETRO O
ALDOLIC FGA

OH- Fe(CO)5 O
O OH- / H2O

1) H2, PtO2
2) PhCOCl, Py
3) NaBH4
4) H+

O
O
O O O
NO2
NO2

PhNCO
(CH2OH)2 TEA
H+ 1-Esino
N O
TMG

CH3NO2
Baraldi,P.G. et al..J.Org.Chem.,1979,44,105
 Retrosynthesis of PGF2α
HO THPO

CO2H CO2R
FGI

HO PGF2α THPO
HO O

RETRO
WITTIG

FGI

O
O

O
O O

CO2R FGI
1-Eptino
a d
NO2 NO2

THPO C5H11
THPO THPO N
O

RETRO
MICHAEL

O
O O
O
CO2R
CO2R CO2R N
CO2R CHO

FGI FGI FGR CO2Me

THPO
HO Br
 Synthetic scheme of PGE2α
O
1) CHO O O

CO2R H+ H2 O
N NBS
CO2R
∆ CO2R BuOH, ∆ CO2R Diossano
CCl4, ∆
2) H+ ∆

Br

O O O
O
CH3NO2 LiAlH(OtBut)3 PhNCO
DHP
CO2R CO2R CO2R
TMG, 0°C THF, ∆ 1-Eptino
pTsOH
NO2
HO THPO THPO NO2

THPO

OH
O
THPO

DIBAH, -78°C O 1) Na, NH3 (l)

O 1) Wittig
CO2H 2) Si O2
1-Eptino 3) NaBH4
2) DHP, pTsOH PGF2α
4) H+
C5H11
C5H11
THPO
N O
THPO N O
THPO N O

Baraldi,P.G. et al. Tetrahedron,1987,43,4669

 Retrosynthetic Route to Geiparvarin
O
O
3
4
2 FGI
5 O O O OH O O O
O
1 O
AcOH, 0°C

Geiparvarin

AcOH,0°C FGI

TMSO N NH2 O
O FGI

O O O TMSO O O O

Mo(CO)6
∆

PhNCO RETRO
TEA CICLOADDIZIONE
3+2 DIPOLARE

O O O H
HO O O
FGI
NO2
OH
TMSO

DEAD
FGI Ph3P

NO2 O CH3NO2
HO

Baraldi,P.G. et al. Tet.Lett.1985, 43, 5319

 Retrosynthesis of Sarcomycin
O O
FGI FGA, FGI O O
FGI
O O
O
H+, RT, 5d O CO2H O CH2OH
H+, RT, 6 h. CrO3, H+
HC2O 0°C
O

O O
Sarcomicina

1) O3, -78°
FGI
2) NaBH4

O O

O
O
O
RETRO
DIELS-ALDER FGI
Br

∆, 3 d MED
CO2R TosOH CO2R

CO2R

Baraldi,P.G. et al. J.Chem.Soc.Chem.Com.1984,1049

 Retrosynthesis of Carbaprostacycline
CO2H

O O

FGI
FGI

RETRO
WITTIG C5H11
C5H11 C5H11

OTHP OTHP
OH OH OTHP O

Carbaprostacycline
RETRO
WITTIG

O
O O O O

FGI
FGI

CO2R CHO
CO2R

O OTHP
O
 Retrosynthesis of a intermediate for
Carbaprostacycline
O O
O
RETRO OH
RETRO CLAISEN
MICHAEL
FGI

K2CO3 1) Im2CO
2) CO2Et Jones
CO2R CO2R
CH2
CO2H CO2H
O O CO2H
Mg(OEt)2

NaOH FGI

RETRO
BAYER-WILLIGER
O
O
NaOH, H2O2
O

Baraldi,P.G. et al. J.Org.Chem.,1980,45,4776

 Synthesis and Retrosynthesis A2B Agonists
O
O R
N
H I NH2
HN N N
N N
N N
H N N H N N
H N N O N O
N
N O O O
O O O NH2
O O Isopentylnitrite, O O
OH OH 1) R NH CH2I2
2) TFA, H2O
R = Ph
hA1 Ki= 8.5nM
hA2A Ki= >1000nM 1) SOCl2
2) EtNH2
hA2B EC50= 7.3nM
hA3 Ki= 38.4nM
NH2 NH2
N N N
N
NH2
N N N N N
N HO HO O
O O
N N
HO
O p-TsOH, O O KMnO4, O O
2,2-dimethoxypropane KOH
OH OH

P. G. Baraldi et al., Bioorg. Med. Chem., 15, 2007, 2514-2527

Synthesis and Retrosynthesis A2B Antagonists
O
H
N
hA1 Ki >1000nM
N Cl
O hA2A Ki >1000nM
N N
N hA2B IC50 = 7nM
O N
N
H
hA3 Ki >1000nM

O
NH2
N
1: , EDC
O N NH2 O

OEt
2: NaOH
Cl
O N
N
+
O N2-alkylated product
N
N N KOH O
H
OH
O
HN

OEt
Cl
N EtONa,
N p-Cl-acetanilide
H

P. G. Baraldi et al., Bioorg. Med. Chem., 16, 2008, 2419-2430

 Synthesis and Retrosynthesis of sulphur Duocarmycins
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X TEMPO

NBoc
NBoc NBoc

S
14 DBU S Zn powder S TEMPO,
O
(2 steps) 10 (Me3Si)3SiH
OR OBn
R = Bn, X = OH, 11
PPH3, CCl4
Chiral column R = Bn, X = Cl, 12
Pd/C, H2CO2NH4 N
R = H, X = Cl, 13
O
I X

NBoc R COOEt

S S LiOH S
NaH, allyl bromide AcONa, Ac2O
9
(2 steps)
OBn OBn OR
R = COOH, X = H, 6 R = Ac, 3
DPPA K2CO3
R = NHBoc, X = H, 7 R = H, 4
NIS BnBr
R = NHBoc, X = I, 8 R = Bn, 5

COOEt CHO

S
2 COOH
t-BuOK,
S 1 Baraldi P.G., Boger D.L., et al.
diethyl
succinate
JACS., 2007, 129, 14092-14099