PLANNING OF ORGANIC SYNTHESIS

By

Bapu R. Thorat M.Sc. SET. NET

Assit. Professor

Dept of Chemistry & Dept of Biotechnology,

Government of Maharashtra,
Ismail Yusuf College of Arts, Science and Commerce, Jogeshwari (East),
Mumbai - 60

Planning of organic synthesis

The major goal of the organic synthesis is the construction of organic
molecules (target molecule) and their synthesis by applying various
synthetic strategies. The choice of target molecule is the starting of
synthesis.

Research

Selection
of Target
molecule

During the selection of target molecule, Scientist

suggested that- what is most important is not a choice
of a given target, but how the goal is going to be
achieved is important.

Why this molecule is

choose as target or
final molecule?

How it can be
synthesized?

1. Why this molecule was chosen as a target molecule? And

2. Where do I begin? How?

Planning of organic synthesis

The answer of the question (1) is
1.
The need and interest of the synthetic
chemist.
2.
It may have challenging stereochemical problems or functional
group combinations.
3.
The molecule may possess unique
chemical and or biological properties.
4.
The challenging problem in the total
synthesis of given target molecule
provides many opportunities to find new
reactions, process or strategies which
may be of value to other reactions.
5.
The learning opportunity.
6.
More global and important regarding
the destination and usefulness of pure
science.
7.
Does not immediate benefits to
humanity, but in foreseable feature.
Industrial application.
8.
Necessary to eliminate toxic effect,
explosive material, minimize the
hazardous effect, etc

Need
and
Interest

Selection
of target
molecule

Challenging
Stereochemical
& Functional gr.
Combination

Unique
chemical &
biological
property
Provides opportunities to
find new reactions, process
& strategies

Learning
opportunity

Global &
important in
pure science

To eliminate
side effect

Useful in feature
& industrial
applications

Planning of organic synthesis

The chemical reaction can be

viewed in two directions the
synthetic direction corresponding
to laboratory operations and the
retrosynthesis (or antithetic).
Retrosynthesis gives the answer of
the second question- Where do I
begin?
These simple molecules are
obtained by the degradation of the
molecule which will be synthesized
is called as retrosynthesis.
It is a technique completely
theoretical and used for solving
problems in synthesis planning,
especially those represented for
complex problems.
Required well trained eyes of
professional to identify the
fragment(s) present in the complex
target molecule which is to be
derived.
Elias James Corey (Nobel Price in Chemistry 1990)

OH

Where do I begin?
HO
T.M.
O

These simple molecules are

obtained by the degradation
of the molecule which will
be synthesized.
Retrosynthesis

HO

O
O

Theoretical and used

for solving problems in
synthesis planning

Planning of organic synthesis

The target molecule can be fragmented to by more than one way to
gives simple starting molecule by starting disconnection from
any site of the complex molecule.
The starting molecule is- simple, small, easily available (fossile
sources, nature, leaving organism), chief.
This starting material was converted into product by applying your
knowledge of reactions, reagents, synthetic and analytical
methods.
For transforming one to another intermediate, following parameters
are considered i. The selection of chemical reaction for transforming one
synthetic intermediate to next in the synthesis.
ii. The selection of specific reagent.
iii. The design of experiment.
iv. Experimental conditions and analysis.

O
Ph

O2N
O

O
Target Molecule

O
Ph

O2N
OH

O
Ph

O2N

O2N

O
TM

H
O

O
O2N

H
O
OH

O2N
O
OH

H
OH

O2N

For all these stages- observations, discoveries (experimental results taken

for references), inventions, and theorems are very important.
Therefore someone can achieve their target in small period or even longer
term basis.

Ref: Elias James Corey brought a more formal approach to synthesis design based on
retrosynthesis analysis for which he won the noble prize for chemistry in 1990.

C2 H5
HO

C2 H5
H

OH

H
O

The organic synthesis has been designed by the concept

retro-synthesis.
Retrosynthesis is used to developed synthetic route to a target
molecule. Multistep synthesis of the complex target molecule
from specified starting material becomes one of the most
challenging problem. The design of the synthesis of simple
molecule is very simple.
E.g.- Synthesis of meso-3,4-hexanediol from 3-hexyne, most
of students realized that alkyne was reduced to cis or trans-3hexene and then undergoes glycol formation. Therefore, there
is more than one procedure for the synthesis of desired
product.

3-Hexyne

transH

CaC2

Na/liq.NH3
H3O+

3-Hexyne

m-CPBA

H
O

Lindlar cat.
or
9-BBN/AcOH

H3O+

C2H5
HO

C2H5
H H

OH

cis-

1 OsO4
2 NaHCO3

Planning of Organic Synthesis

Organic synthesis is the construction of a organic molecule via chemical processes or
reaction. The synthesis of a organic molecule is difficult as compared to inorganic
molecules in various aspects such as yield, purity, time etc. There are two areas of
research in general of organic synthesis are- Total synthesis and methodology.

Construction of
carbon skeleton of
target molecule

Carried out the

synthesis in minimum
number of steps

Construct the
synthesis before
carried out actual
synthesis

Introducing, removing
& transforming
functional groups

Principles of
Organic
Synthesis

Try to maintain
stereochemistry of
product of each step

Functional group is
less reactive, increase
yield by using
activating group

To avoid side product

or to protect the
group use protecting
groups

Planning of Organic Synthesis

Recovery or recycling of
expensive reagents/
catalyst and less number
of side products

Starting compounds &

reagents are cheaf &
easily available.

Principles of
Organic
Synthesis

Used named reported reactions and

reagents for the synthesis of new
compounds because the yield, reaction
conditions, by-products, reagents, etc
are known.
Functional groups are altered, without change the carbon skeleton of starting material or
change both functional group and carbon skeleton or without affecting the functional
group, carbon skeleton can be changed.

OH

Et
H

NH
NH

Et
H

OH

OH

Et
NH

NH

Et
H

OH

(S,S) -isomer
Tuberculostatic

(R,R)-isomer
Cause blindness
Ethambutol

OH

OH
OH

OH

HNCOCHCl2

HNCOCHCl2

O2N

O2N

(R,R)-isomer
antibacterial

Chloromycetin

(S,S)-isomer
inactive
O

NH

R
O

OH

R CO2H
HS
H2N

S
HS
H2N

Anti-arthritic Penicillamine Toxic

CO2H
H

S - isomer,
beta -blocker

Propranalol

OH

R - isomer,
Contraceptive

NH

Area of research in Organic Synthesis

Total
Synthesis

Methodology

A total synthesis is the complete chemical synthesis of complex organic molecules from
simple, commercially available (petrochemical) or natural precursors. The choice of
target molecule is the starting of synthesis.
The target molecule can be synthesized in a series of steps which are performed one
after another until the molecule is made is called as linear synthesis. It is applied for
the synthesis of simple structure molecules. The chemical compounds made in each
step are usually referred to as synthetic intermediate.
For the synthesis of more complex molecules, convergent synthesis is often preferred.
In this synthesis, several key intermediates are synthesized separately and then coupled
together to give final product.
The father of modern organic synthesis is regarded as Robert Burns Woodward who
received Nobel Price for chemistry in 1965 for several brilliant examples of total
synthesis such as synthesis of strychnine in 1954.

Convergent synthesis

Divergent synthesis

Diversity oriented synthesis

(DOS)
Total synthesis

Carbon-carbon bond formation

Polar functions and Umpolung

Cascade reaction sequences

Multistep Transformation

1. Convergent synthesis

In chemistry, a convergent synthesis is a strategy that aims to improve the efficiency of

multi-step chemical synthesis. It is more convenient than the linear synthesis.
Linear synthesis:-

80%

80%

80%

80%

80%

Overall yield is 32.8%

(3.1% if 50% each step)

Convergent synthesis:-

80%

A
80%

80%

80%

80%

Overall yield is 51.2%

(12.5% if 50% each step)

2. Divergent synthesis

Divergent synthesis is a strategy with the aim to improve the efficiency of

chemical synthesis. It is an alternative to convergent or linear synthesis.
In one strategy, divergent synthesis aims to generate a library of chemical
compounds by first reacting a molecule with a set of reactants. The next
generation of compounds is generated by further reactions of another reagent
with each compound in generation first. This methodology gives large number
of new compounds.
A generates A1, A2, A3, A4, A5, in generation first.
A1 generates A11, A12, A13, A14, A15, in generation 2 and so on.
In another strategy, divergent synthesis starts from a molecule as a central core
from which generation of building blocks are added.

e.g.:- Synthesis of dendrimers (in each generation new monomer reacts to the growing
surface of the sphere).

3. Diversity oriented synthesis (DOS)

DOS is a strategy for quick access to molecular libraries with an emphasis on skeleton
diversity. In following example- A Petasis reaction product (1) is functionalized with
propargyl bromide leading to starting compound (2) having five functional groups. This
molecule can be subjected to whole set of reagents, each reaction yielding a unique
skeleton already in generation one.
Ph
Ph

During this synthesis, in a

majority of reactions
involving a functional group
modifications, proceeding or
following smaller number of
carbon-carbon bond forming
reactions because functional
group chemistry consist of
such a vast number of
addition, elimination,
substitution, rearrangement,
free radical, pericyclic, redox,
etc reactions.

Ph
N

EtOOC
N O

COOEt

Ph
OH

Ph

H
Ph

3.81%

OH

OH
9.87%

4.89%

Ph
Ph

Ph
COOEt

HN

COOEt

Br

EtOOC
Ph

Ph

Ph

OH
OH

OH

5.85%

Ph
Ph
O

Ph

O
H
Ph

8.88%

EtOOC
Ph

OH

COOEt

O
Ph

6.85%

7.85%

During the synthesis, a stereochemistry of a product try to maintain along with regio- and
stereo-control is important during this functional group modification.

4. Carbon-carbon bond formation

Numbers of useful and well tested reactions are reported for the effective carbon-carbon
bond formation, ideally in regio and stereospecific fashion. These reactions are relatively
small as compared with the reactions used to modify the functional groups.

Friedel-Craft alkylation
and acylation.

Robinson
Annulation

Addition of
organometallic
compounds to
unsaturated compounds

Diels-Alder
cycloaddition

C-C bond formation

Wittig and other ylide

reactions

Alkylation of
Acetylide anions

Claisen, Aldol,
Dickmann
condensation,
Reimer-Tiemann
reaction, etc

Alkylation of enolate
anions

4. Carbon-carbon bond formation

Coupling reactions carried out
by using transition metal
catalysts

Addition of carbon radicals to

multiple bonds

C-C bond formation

Photochemical cycloaddition
and rearrangement reactions

Reaction of transition metal

alkylidene complexes e.g. Olefin
metathesis

In addition to development of these and other new reactions, many classic procedures
have been modified and enhanced in scope byControl of regio and stereo-selectivity during the formation of reaction intermediates.
Charge inversion in polar reactants, Umpolung.
Applications of Tandem, Domino or Cascade reaction sequences.

IF ONE CAN DO, I CAN ALSO DO,

IF NONE CAN DO, I MUST DO