Topic:-Methodology in organic synthesis

ExamplesNatural products e.g.. steroids, prostaglandins, alkaloids

HO

HOOH

CO2MeHN

N

Cl

15-Methyl PGF2α (prostaglandin) Epibatidine (South American frog alkaloid

Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions

Alkaloid)

Each step of a synthesis involves a chemical reaction, and reagents and conditions for each of these reactions must be designed to give an adequate yield of pure product, with as little work as possible

METHODOLOGY IN ORGANIC CHEMISTRY

In chemistry a convergent synthesis is a strategy that aims to improve the efficiency of multi-step chemical synthesis.

In linear synthesis the overall yield quickly drops with each reaction step

A → B → C → D

Suppose the yield is 50% for each reaction, the overall yield of D is only 12.5% from A.

Convergent synthesis

Convergent synthesis is applied in the synthesis of complex molecules and involve fragment coupling and independent synthesis.

In a convergent synthesis A → B (50%) C → D (50%)B + D → E (25%)

the overall yield of E (25%) looks much better.

o An example of its use in total synthesis is the final step (photochemical [2+2]cycloaddition) towards the compound Biyouyanagin A:

o Proteins of up to 300 amino acids are produced by a convergent approach using chemical ligation.

Examples:

In chemistry a divergent synthesis is a strategy with the aim to improve the efficiency of chemical synthesis

In another strategy divergent synthesis starts from a molecule as a central core from which successive generations of building blocks are added.

Divergent synthesis

In one strategy divergent synthesis aims to generate a library of chemical compounds by first reacting a molecule with a set of reactants

o A good example is the divergent synthesis of dendrimers.

oThe next generation of compounds is generated by further reactions with each compound in generation 1.

o This methodology quickly diverges to large numbers of new compoundso A generates A1, A2, A3, A4, A5 in generation 1o A1 generates A11, A12, A13 in generation 2 and so on

Schematic of divergent and convergent method synthesis of dendrimers

Functional group interconversionwriting of one functional group for another so that disconnection becomes possible to get a starting material available in the market.

FGI is necessary for functional group protection..

-CH2OHFGI

-COOet

-COOH -CNFGI

C6H5COOHFGI

C6H5CN

Functional group addition (FGA): acyclic or alicyclic saturated hydrocarbons are usually unreactive. Disconnection of such hydrocarbons are difficult because the hydrocarbon is a compound having no functional group which is guiding signal for disconnection.

H OH

FGA CH3-CH2-

++

OH

CH3CH2MgBr CH3CHO

FGA NH2

NO2

FGA

FGI

This FGA is two types:

1. Type1: FGA to the TM first and DIX done which gives recognizable SE

2. Type2: DIX is done to target molecule first and then FGA to the SN so that recognizable SE is possible.

O

H

O

COOetFGA

O

-COOet

+ CH3 +

TM

DIX

SN

CH3io COOet

oDIX CH3+

CH3I

FGAFGA

O COOet

O

-

SE

+

TM

Disconnection rules:1) Dix is done mainly adjacent to the functional group i:e especially –OH

and C=O. CH3CH2-OH- CH2CHO CH3CHOH + CH2CHO(Synthons). 2) a c-c double bond may be converted to c(OH)-CH before dix if c=c

is a part of a conjugated system involving hetero atom. .

+ -

CH2OH ++ -

FGI

• 3) In a conjugated or non conjugated system the dix of = carbons of c=c may also be done without adding H2O to c=c part.

• (CH3)2 C=CH CH3 (CH3)2 COH + CH2CH3• 4) The branch point is to be disconnected to get unbranched C- synthons

which are more likely to be available.

• . . + CH2CH2CH3

• 5) It is better to DIX towords middle of the target molecule rather than cutting off one or 2 carbon atoms from the end.

• CH3CH2CH2CH2CH2CH3 CH3CH2CH2 +CH2CH2CH3

+ -

- +

_ +

• 6) Branches may be disconnected from rings.

+ +

7) Symmetric target molecules may be DIX symmetrically:

+

- +

8) It is worth to disconnnect a c-c bond between two functional groups separated by not more than 3 other carbons.

++ -

• C-C bond DIX should be according to fragmentations in target molecule• The DIX should be done in such a way that the synthetic route will be as

short as possible.• ONE GROUP DISCONNECTIONS: disconnection of target molecule aiming

one particular functional group i:e DIX in which involve only one functional group is called one group disconnection.

+ +

Cl-ALCL3

• TWO GROUP DISCONNECTIONS: when a target molecule contain two functional groups and if DIX is done using the two together i:e using of one functional group to help disconnection of another is called two group disconnection.

CH3CH2-OH- CH2CHO CH3CHOH + CH2CHO(Synthons)+ -

CH3CHO CH3CHO

NO2 C

H

OH

C

H

CH2OH

NHCOCHCl2

NO2 C

H

OH

C

H

CH2OH

NH2

ClCOCHCl2

NO2 C

H

OH

CH2 NH2

CH2O

NO2 C CH2 NH2

O

NO2 C

O

CH3

C

O

CH3

NO2ClCOCH3

ClCOCH3

CH3COOH

D(-)chloramphenicol

disconnection

disconnection

disconnection

disconnection

disconnection

acetic acid

benzeneacetyl chloride

nitro benzene

acetophenone

acetyl chloride

FGI

Example of retrosynthetic analysis:

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