methodology of organic synthesis
TRANSCRIPT
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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