Synthesis and Retrosynthesis Strategies | Organic Chemistry 1

The strategies in retrosynthesis are studied in this chapter: protection / deprotection of chemical functional groups, retrosynthetic analysis, summary of the chemical transformations seen so far

Protecting Groups

A molecule generally has more than one chemical function. In order to obtain chemoselectivity in a subsequent chemical reaction, a protecting group is introduced into a molecule by chemical modification of a functional group. At the end of the specific reaction, a deprotection step gives back the original function

Alcohol Protecting Groups

Protection: convert alcohol to ether using another alcohol​​​​​​​ in acidic condition
Deprotection: protecting group removed by an acid or a base​​​​​​​
 

 

 

Grignard reaction on unprotected 4-hydroxycyclohexan-1-one:


 

Grignard reaction on protected 4-hydroxycyclohexan-1-one:

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Carbonyl Protecting Groups

Protection: convert aldehyde / ketone to acetal / ketal using diol​​​​​​​ in acidic condition
Deprotection: protecting group removed by an acid
 

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Retrosynthetic Analysis

Always work backwards (retrosynthetic direction). Look at the final product and find the immediate precursor(s), keeping in mind the compounds you have in your toolbox. Count the number of carbons and determine the disconnections you need

At this point, you have 2 different types of goals:
- modification or formation of a chemical function⇒ you can use deprotonation, substitution, elimination, oxidation or reduction reactions
- formation of carbon-carbon bond ⇒ so far we have only seen one possibility: the reaction between organometallics and carbonyls

Follow the same process with the precursors until you get to the starting reagents

 

Propose a strategy to synthesize heptan-3-ol, using propanal, butan-1-ol and any inorganic reagents:


​​​​​​​Retrosynthetic analysis:


1st goal: formation of a carbon-carbon bond between the blue and the green alkyl chains ⇒ organometallics + carbonyls
2nd goal: chemical function modification to form organometallics starting from alkyl halide
3rd goal: chemical function modification to form alkyl halide starting from butan-1-ol​​​​​​​


Proposed Synthesis:

Retrosynthesis Strategies

Carbon-Carbon bond formation:

- Organometallics + Carbonyls (chapter 8)
- Organometallics + Epoxides (chapter 9)
 

Chemical Function formation/modification:

- Alkene formation (chapter 7) - Elimination reaction
- Aldehyde to Alcohol (chapter 8) - NaBH4 or LiAlH4
- Ketone to Alcohol (chapter 8) - LiAlH4
- Alcohol to Ketone (chapter 8) - Na2Cr2O7 or PCC
- Alcohol to Aldehyde (chapter 8) - PCC
- Alcohol to Carboxylic acid (chapter 8) - Na2Cr2O7
- Alcohol to Alkyl Halide (chapter 9) - PBr3, SOCl2, HBr
- Alcohol to Ether (chapter 9) - NaOR
- Alcohol to Epoxide (chapter 9) - NaOH
- Alkyl Halide to Ether (chapter 9) - NaOR