This presentation is very useful for post graduate students from different universities and I covers all the basic aspects of Retrosynthesis.

1. Shri Shivaji Education Society, Amravati
SHRI SHIVAJI COLLEGE OF ARTS, COMMERCE & SCIENCE, AKOLA
• Reaccredited by NAAC with "A" Grade with a CGPA of 3.24
* Awarded CPE status(College with Potential for Excellence) by UGC
2 March 2020 Retrosyntesis by Zamir Shekh 1
Designing synthesis based on Retro
synthetic analysis
Mr. Zamir Shekh
Assistant Professor
Department of Chemistry

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4. Syllabus - Organic Synthesis Unit No.II
Designing the synthesis based on retrosynthetic
analysis
• A disconnection approach to the synthesis of organic
compound. Different consideration in designing target
molecule, concept of synthons, FGI, Chemoselectivity,
regioselectivity, specificity, stereoselectivity, general
strategy choosing a disconnection.
• Types of bond disconnection, some of the applications
of these concepts in designing the synthesis of
commonimpotant class of the compounds.
• C-X, C-C one group, C-C two FGs
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5. • Concepts of synthesizing organic molecules.
Definition of the terms :
• Synthetic Plan
• Retrosynthesis
• Disconnection
• Target molecule (TM)
• Synthon
• Functional group interconversion (FGI)
• Functional group addition (FGA)
• Chemoselectivity, Regioselectivity.
• Stereo selectivity and Stereospecificity
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Important Terms in Stratagic
Analysis

6. • The Construction of synthetic tree by working backword from
the target molecule (TM) is called retrosynthetis analysis or
antithesis.
• The symbol  signifies a reverse synthetic step i.e. → and is
called transform.
• The main transforms are disconnection, cleavage of C-C bond
and Functional Group Interconversion (FGI).
• Retrosynthetic analysis involves the disassembly of TM in to
available starting materials (sms) by sequential disconnection
and function group interconversion (FGI).
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Basic Concepts

7. • Actual substrate used for the forward synthesis are the
synthetic equivalents (SE)
• Synthetic design involves two distincts steps
1.Retrosynthetic analysis
2. Chemical Synthesis
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Cleavages of Bonds
Chemical bonds can be cleaver heterolytically, homolytically or
through concerted transform (in to two neutral, closed-shell
fragments).

9. Heterolytic retrosynthesis disconnection of a
carbon carbon bond in a molecule breaks the TM
in to an acceptor synthons carbocations and
donor synthons a carbanions.
In the formal sense the reverse reaction is
formation of C-C bond which involves the union
of electrophilic acceptor synthon and nucleophilic
donor synthons.
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Donor and
Acceptor Synthons

10. Here I listed out important Donor and acceptor synthons
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Synthons Synthetic equivalent

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Synthons Synthetic equivalent
Common Donor
Synthons
Synthon Derived Reagent Equivalent

12. • The question is how one can choose the appropriate
C-C bond disconnection of in molecule which is
determined by the presence of functional group in
Target molecule.
• The presence of heteroatom in molecule imparts a
pattern of electrophilicity and nucleophilicity to
atom of the molecule.
• The concept of alternating polarity (imaginary
charges) identifies the best position to make the
disconnection in complex molecule.
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Alternating Polarities
Disconnection

13. • E-Class:- Groups conferring Electrophilic
character to attached Carbon (+)
• G-Class :- Groups conferring Nucleophilic
character to attached Carbon (-)
• A-Class :- The Functional groups that exhibit ambivalent
character (+/-)
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Classification of Functional
Groups

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One Functional Group
Analysis

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Synthesis

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Two FGs in 1,3 Relationship
Analysis

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Synthesis Route A

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Synthesis Route B

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Two FGs in 1,4 Relationship
Analysis

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Synthesis

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Analysis

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Synthesis

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Introduction
 Technical terms
Why to do synthesis?
History of synthesis
Designing synthetic strategy
Retrosynthetic analysis
 Practice of total synthesis (analysis and synthesis)
 Linear and convergent synthesis
Examples
Synthesis: An Ever Challenging
and Exciting Science

26. • Concepts of synthesizing organic molecules.
Definition of the terms :
• Synthetic Plan
• Retrosynthesis
• Disconnection
• Target molecule (TM)
• Synthon
• Functional group interconversion (FGI)
• Functional group addition (FGA)
• Chemoselectivity, Regioselectivity.
• Stereo selectivity and Stereospecificity
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Important Terms in Stratagic
Analysis

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R B Woodward
(1917-1979)

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E J Corey
(1928 )

29. What is a synthesis?
A rational plan to construct a complex molecule from its less
complex components by interlacing a series of organic reactions
Preparation vs Synthesis
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30. For a specific target molecule – a synthetic route designed must lead to
• a pure sample of desired product in a convenient and efficient procedure
• With required carbon skeleton with all substituents and functional groups
in correct position
• with appropriate three dimensional orientation (stereochemistry)
• Ideally shortest synthetic route to get better yield
• Each step of the synthesis should give the desired product ( if the mixture
is obtained it should be separated)
• To satisfy all these concepts a logical approach of the synthesis is needed -
Retrosynthesis
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32. Some definitions
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33. •Retro synthetic analysis (Retrosynthesis) is a technique for planning a
synthesis, especially of complex organic molecules.
• whereby the complex target molecule (TM) is reduced into a sequence of
progressively simpler structures along a pathway
• which ultimately leads to the identification of a simple or commercially
available starting material (SM) from which a chemical synthesis can then be
developed.
Retro synthetic analysis is based on known reactions (e.g the Wittig reaction,
oxidation, reduction etc). The synthetic plan generated from the retro synthetic
analysis will be the roadmap to guide the synthesis of the target molecule.
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Retro synthetic Analysis
Definition

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36. • The molecule whose
synthesis is being planned
• Usually written as TM
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Target molecule

37. • An analytical operation, which breaks a bond and converts a
molecule into a possible starting material(s) during retro
synthetic analysis
• The reverse of a chemical reaction, and the symbol is
• A curved line is drawn thro’ the bond being broken
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Disconnection

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Functional group inter-
conversion (FGI)

39. CH3 CH2 OH CH3 CH2OH
SN SN
dix
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Synthon

40. • A compound which reacts to give an intermediate
in the planned synthesis or to give the target
molecule itself.
• It is the synthetic equivalent of a Synthon
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i) H LiAlH4
ii) Br NBS
iii) CH3
CH3MgBr
iv) -CH2 Ph3P-CH2-
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Reagent

41. • A reagent carrying out the function of a synthon
which cannot itself be used
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CH3 CH2 OH CH3 CH2OH
SN SN
CH3MgBr CH2O
SE SE
dix
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Synthon equivalent

42. PhPh
OH
(A)
OH
Ph
CH2
Ph
PhBr
? Reagent
(B)
Ph
OH
Ph
CH2
Ph H
O
Ph
BrMg
(synthons)
(synthons)
(Reagents)
Example:
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Retro synthesis

43. Synthesis is a construction process that
involves converting simple or commercially
available molecules into complex molecules
using specific reagents associated with known
reactions in the retrosynthetic scheme
Syntheses can be grouped into two broad
categories:
(i) Linear syntheses
(ii)Convergent syntheses
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Synthetic Planning
Definition

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Synthesis
Retrosynthetic
Route 1

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Retrosynthetic
Route 2
Synthesis B

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Question 1.
Propose a retrosynthetic analysis of the following two
compounds. Your answer should include both the
synthons, showing your thinking, and the reagents
that would be employed in the actual synthesis.

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Compound B

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Answer

56. • Molecular size
• Carbon skeletal complexity
• Functionality
• Stereo-chemical considerations
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Concepts that make up a
synthetic plan

57. The synthesis of a target molecule begins with
two questions
1. why was this molecule chosen as a
target?
2. where do I begin?
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Target selection

58. • Structural verification
• Important biological activity
• Analog generation and studies
• Structural or topological challenge
• Development of new reactions or reagents
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Criteria for target
selection

59. • Periplanone-B - the sex pheremone of the
American cockroach, periplanita americana –
isolated 200 ug from 75,000 virgin female
cockroaches.
OO
O
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Structural verification

60. • Importance in medicine, agriculture or other commercial and
humanitarian ventures
• Prostaglandins have diverse biological activity
• Widely distributed in mammals
• Total production is only 1-2 mg /24h,
• Require large amounts for evaluation of biological activity
COOH
20
1
5
6
9
11 13 15 17
Prostanoic acid
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Biological activity

61. Chlorothiazide
• Diuretic – also used to treat
hypertension
Chlorexolone
• Improved hypotensive
activity and diuretic action
N
NH
S
Cl
O O
H2NO2S 2NO2SH
Cl
N
O
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Analog studies

62. • Potential anti-tumor agent • Enhanced anti-tumor activity
O
O
HOOC
O
O
X
HOOC
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Flavone-8-acetic acid

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Structural and topological
challenge

64. • Vit-B12 synthesis –
hydrolysis of amide bonds
• New reagent
N
CO2H
NH2
O
N
O
Cl
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New reactions and new
reagents

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