The Retrosynthetic Analysis Approach to Designing Organic Syntheses-1
A. Introduction:
The retrosynthetic approach to organic synthesis starts from the product and attempts to
determine what reactant molecules might be used to synthesize the target molecule (The
desired product) in one reaction step. We will consider the synthetic utility of Grignard
reactions for synthesizing alcohols. Note that both of the following Grignard reactions form
the same product but use different starting materials.
O
1. Ether
+
a.
CH3
CH2 Mg Cl
H
2. H3O+ H2O
O
H
H
H
O
1. Ether
+
b.
O
Mg Br
2. H3O+ H2O
H
H
1. What bonds are made in reaction a? Mark them on the product structure.
2. What bonds are made in reaction b? Mark them on the product structure.
3. How are the bonds made in the two reactions similar? How are they different?
4. What is the relationship between the C-C bond formed in each reaction and the OH group
of the alcohol in the product?
5. If the new C-C bonds were removed (disconnected), what additional changes would be
required to convert the product molecule back into the starting materials for each
reaction?
6. Considering your discoveries in 1->5, suggest structures for starting materials that would
produce the target alcohol given below. Explain the logic you used to devise your
starting materials
H
O
3-ethyl-2-methyl-3-hexanol
Retrosynthetic Analysis-1
2
B. Synthesis of Alcohols: C-C Disconnections
1. Retrosynthetic Analysis
Look at the product molecule, find the alcohol OH and identify the bonds around the
carbon holding the OH. These are the bonds that could have been made by a Grignard
reaction. Disconnect each bond (C-C disconnections) in turn to reveal potential
precursors for the product. Then identify the reaction that will reveal the precursors of
the Grignard reagent. In the terminology of Retrosynthetic Analysis, a process such as
the formation of the Grignard reagent is a Functional Group Interconversion (FGI) since
it changes the nature of the functional group but does not change the carbon structure. So
the retrosynthetic step for formation of an organometallic reagent is symbolized by FGI
Grig, since it is the formation of a Grignard reagent.
Full Retrosynthetic Analysis for the synthesis of 3-ethyl-2-methyl-3-hexanol
(Starting materials in bold)
H
O
b.
O
a.
a.
c.
synthon
synthon
C-C
Disconnection
O
Mg Cl
FGI Grig
Cl
+ MgÞ
c.
C-C
Disconnections
b.
C-C
Disconnections
O
O
synthon
O
synthon
CH3
Mg Br
synthon
FGI Grig
Br + MgÞ
CH2
synthon
O
FGI Grig
CH3
CH2 Mg Cl
CH3
CH2 Cl + MgÞ
2. Synthesis based on retrosynthetic analysis b:
O
H
O
Br + MgÞ
Dry
Ether
1. Dry Ether
Mg Br
2. H2SO4/H2O
Retrosynthetic Analysis-1
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3. An Additional C-C Disconnection Example
b.
a.
O
a.
c.
CH3
Mg Cl
FGI Grig
CH3 Cl + MgÞ
C-C
Disconnection
O
H
b.
C-C
Disconnections
c.
C-C
Disconnections
O
FGI Grig
CH3
CH2 Mg Cl
CH3
CH2 Cl + MgÞ
O
FGI Grig
Mg
+ MgÞ
Cl
Cl
4. Synthesis based on retrosynthetic analysis c:
O
1. Dry Ether
Dry
+
Cl
MgÞ
Ether
Mg
2. H2SO4/H2O
Cl
O
H
5. Class Discussion Problem on Alcohol Synthesis:
Use Retrosynthetic Analysis to devise a synthetic pathway for the following compound
from smaller molecules.
O
H
Then write a complete synthetic path, including reagents and reaction conditions based
on your retrosynthetic analysis.
Retrosynthetic Analysis-1
4
6. Out of Class Exercises on C-C disconnections in alcohol syntheses.
For our next lab discussion period, use retrosynthetic analysis to devise at least two
syntheses for the following compounds.
H
O
CH3
N
CH3
O
H
Then write complete synthetic paths, including reagents and reaction conditions based on
your retrosynthetic analyses.
Be prepared to discuss both the retroanalysis and the synthesis.