RETROSYNTHETIC APPROCH APPROCH

TOTOORGANIC SYNTHESISORGANIC SYNTHESIS

Prof. Dr. Shaikh S. NizamiProf. Dr. Shaikh S. NizamiDepartment of ChemistryDepartment of Chemistry

University of KarachiUniversity of Karachi

BASIC BASIC CONCEPTS

(Part 1)

CONTENTS

1. Definition of synthesis2. Importance of synthesis3. Polarity of bonds4. Arrow notations5. Basic concepts of

Retrosynthesis

READINGREADING MATTERIALS

DEFINATION

The preparation of a The preparation of a desireddesired organic compoundorganic compound from a a readily available readily available starting starting materialmaterial is is known as organic as organic synthesissynthesis

[Synthesis---- singular][Synthesis---- singular]

[Syntheses--- plural][Syntheses--- plural]

DESIRED ORGANIC ORGANIC COMPOUNDCOMPOUND

The compound we wish to prepare

It is called Target MoleculeDesired Organic Compound is denoted by TM

STARTINGSTARTING MATERIALMATERIAL

Readily availableCommercialInexpensivecontains five carbon atoms or less apart from aromatic ring ring

OBJECTIVEOBJECTIVE

To get a pure sample of To get a pure sample of the desired organic the desired organic compoundcompound

To avoid the reactions To avoid the reactions that will produce a that will produce a mixture of productsmixture of products

PURE COMPOUNDPURE COMPOUND

To studyTo study

1.1. Physical propertiesPhysical properties

2.2. Chemical propertiesChemical properties

3.3. Pharmacological Pharmacological propertiesproperties

Reasons for synthesizing Reasons for synthesizing Organic CompoundOrganic Compound

1. Proof of structure of a natural 1. Proof of structure of a natural compoundcompound

2. To prepare compounds that are 2. To prepare compounds that are useful to mankind e.g. useful to mankind e.g. pharmaceutical, polymers, dyes pharmaceutical, polymers, dyes etc.etc.

Reasons for synthesizing Reasons for synthesizing Organic CompoundOrganic Compound

3. To prepare specific compounds to study reaction mechanisms or biological metabolism e.g. labelled compounds

4. For the intellectual challenges – new problems demand new solutions and can lead to the development of NEW CHEMISTRY, reagents, etc.

SOME FASCINATING SOME FASCINATING COMPOUNDSCOMPOUNDS

BOND POLARITYBOND POLARITY(Polar covalent bond)(Polar covalent bond)

Most heteroatom are more Most heteroatom are more electronegative than electronegative than carbon carbon i.e.i.e. O, N, Br, Cl, O, N, Br, Cl,

Partial positive charge Partial positive charge appears on carbon (appears on carbon (+)+)

BOND POLARITYBOND POLARITY(Polar covalent bond)(Polar covalent bond)

Si, Mg,Li are electropositive Si, Mg,Li are electropositive compared with the carboncompared with the carbon

The polarity in these case is The polarity in these case is reversedreversed

partial negative charge partial negative charge appears on carbon (appears on carbon (-)-)

ARROW NOTATIONARROW NOTATION

Simple reaction arrow “reacts to give”Delocalisation arrow

“two different ways to draw the same delocalised structures”Equilibrium arrow

Curved arrow“two structures are interconverting”

“motion of two electrons”Fish-hook arrow “motion of one electron”Retrosynthesis arrow

“could be made from”

RETROSYNTHESISRETROSYNTHESIS

It is reverse of the synthetic steps

We have a reliable reaction in mind

RETROSYNTHETIC ANALYSISRETROSYNTHETIC ANALYSIS

1.1.The process of WORKING The process of WORKING BACKWARD from the TM in order to BACKWARD from the TM in order to devise suitable synthetic routedevise suitable synthetic route

2. Retrosynthetic Analysis can be done by two methods

a) Disconnection

b) Functional Group Interconversion

DISCONNECTIONDISCONNECTION

1.A paper operation involving an imagined cleavage of a bond.

2.As a result of disconnection usually negative ion and positive ion are formed which are called ‘SYNTHONS’

3.Disconnection is shown by a wavy line like ~ or VVVVVVVV

JIGSAW PUZZLEJIGSAW PUZZLE(Target Puzzle)(Target Puzzle)

PUZZLEPUZZLE(Disconnection)(Disconnection)

DISCONNECTION OF C-CDISCONNECTION OF C-C

R1 C C

H

H

R2

H

H

TM

PATH 1

PATH 2

R1 C

H

H

+ + C R2

H

H_

R1 C

H

H

_+ C R2

H

H+

SYNTHONS

FUNCTIONAL GROUP FUNCTIONAL GROUP INTERCONVERSION (INTERCONVERSION (FGIFGI))

The process of writing The process of writing one functional group one functional group for another to help for another to help synthetic planning is synthetic planning is known as known as FGIFGI

FUNCTIONAL GROUP FUNCTIONAL GROUP INTERCONVERSION (INTERCONVERSION (FGIFGI))

FGI can be done by FGI can be done by ADDITION ADDITION SUBSTITUTIONSUBSTITUTION ELIMINATIONELIMINATION OXIDATION / REDUCTIONOXIDATION / REDUCTION FREE RADICAL REACTIONFREE RADICAL REACTION

SYNTHONSSYNTHONS

These are idealized fragmentsThese are idealized fragmentsSynthonsSynthons are shown by a are shown by a ++ or or

–– sign like anion or cation sign like anion or cation (Not real anion or cation)(Not real anion or cation)

May or may not be May or may not be intermediate in the intermediate in the corresponding reactionscorresponding reactions

SYNTHETIC EQUIVALENT

The actual compound used The actual compound used toto

function as synthon function as synthon Denoted by a triple line Denoted by a triple line Known as REAGENTKnown as REAGENT

Retrosynthetic analysis,Retrosynthetic analysis,Synthons & Synthetic Synthons & Synthetic

equivalentsequivalents

R—R ………………………………………………………………………

R+

+

R-

R-

+

R+

TM

RBr,RI,ROMe,ROTs

RMgBr, RLi, LiCuR2

SynthonsSynthetic equivalents

DESIGNING A SYNTHESISDESIGNING A SYNTHESIS

Recognize the functional Recognize the functional groups in the target moleculegroups in the target molecule

Disconnect by methods Disconnect by methods corresponding to known and corresponding to known and reliable reactionsreliable reactions

Repeat as necessary to reach Repeat as necessary to reach available starting materialavailable starting material

SYNTHESISSYNTHESIS

Write out the plan Write out the plan according to the analysis, according to the analysis, adding reagents and adding reagents and conditionsconditions

Modify the plan according Modify the plan according to unexpected failure in to unexpected failure in the laboratorythe laboratory

RETOSYNTHETIC ANALYSISRETOSYNTHETIC ANALYSIS Hawthorn perfumeHawthorn perfume

MeO

O

TM

_

MeO+

+

O

H

MeO

Cl

O

Path 1

---------------------------------------------------------------------

Path 2

+

MeO+

_O

?

?

EFFECTIVE SYNTHESIS

An understanding of An understanding of reaction mechanismreaction mechanism

A working knowledge A working knowledge of reliable reactions of reliable reactions

EFFECTIVE SYNTHESIS

An appreciation that An appreciation that some compounds are some compounds are available available

An understanding of An understanding of stereochemistrystereochemistry

11stst RETROSYNTHETIC ANALYSISRETROSYNTHETIC ANALYSIS CHCH33CHCH22OHOH

CH3 CH2 OH

TM

Path 1

CH3+

+-CH2OH

CH3Br

?---------------------------------------------------------------------

Path 2 CH3-

++CH2OH

CH3MgBr

H2C O

SYNTHESISSYNTHESIS

CH3MgBr

CH3CH2OMgBr TMH3O

+

22ndnd RETROSYNTHETIC RETROSYNTHETIC ANALYSISANALYSIS

CH CH33CHCH22OH & OH & SYNTHESISSYNTHESIS

CH3 CH2 OHFGI

CH3CHOreductionTM

SYNTHESIS

CH3CHONaBH4

TM

33rdrd RETROSYNTHETIC ANALYSIS RETROSYNTHETIC ANALYSIS

CH CH33CHCH22OH & OH & SYNTHESISSYNTHESIS

CH3 CH2 OHFGI

hydrationSYNTHESIS

H2C CH2

H2C CH2H3O

+

TM

TM

44thth RETROSYNTHETIC RETROSYNTHETIC ANALYSISANALYSIS

CH CH33CHCH22OH & OH & SYNTHESISSYNTHESIS

CH3 CH2 OHTM

FGI

SN2CH3CH2Br

CH3CH2Br-OH TM

SYNTHESIS