Strategies for Synthesis and Retrosynthesis | Organic Chemistry 1

A molecule usually has more than one chemical function. In order to obtain chemoselectivity during a reaction, the chemical functions that may react to form side products must be protected. At the end of the desired reaction, a deprotection step allows to regenerate the initial chemical function
 

Protecting group:

A blocking group that renders a reactive functional group unreactive so that it does not interfere with another reaction
 

Protection - Deprotection:

• Protection: the reaction that blocks a reactive functional group with a protecting group
• Deprotection: a reaction that removes a protecting group, regenerating a functional group

Conversion to silyl ether

• Protection: the OH group is converted into an silyl ether using silylchloride in a basic solvent (imidazole, pyridine ...). The most widely used silyl ether protecting group is the tert-butyldimethylsilyl ether, abbreviated as TBDMS ether
• Deprotection: the protecting group is removed with a fluoride salt

Conversion to ether

• Protection: the OH group is converted into an ether using another alcohol under acidic conditions
• Deprotection: the protecting group is removed by an acid or a base

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

Unprotected:

Protected:

Conversion to acetal or ketal

• Protection: the aldehyde or ketone is converted respectively into acetal or ketal with a diol under acidic conditions
• Deprotection: the protecting group is removed by an acid

Retrosynthetic analysis:

Working backwards from a product to determine the starting material from which it is made
 

Retrosynthetic process:

• Count the number of carbons in the product and reagents, and determine the disconnects you need
• Find the immediate precursor(s), keeping in mind the compounds you have in your toolbox
• At this point, you have 2 different possibilities:
  - formation of a carbon-carbon bond
  - the synthesis of a particular chemical function by deprotonation, substitution, elimination, oxidation or reduction reactions

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

Strategy to synthesize heptan-3-ol, using propanal, butan-1-ol and any inorganic reagents

Retrosynthetic analysis:

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

Proposed Synthesis:

How to form a carbon-carbon bond

• Reaction of an aldehyde or ketone with a Grignard or organolithium reagent (chapter 8)
• Reaction of an alkyl halide with a Gilman reagent (chapter 8)
• Reaction of an organometallic reagent with an epoxide (chapter 9)
   

How to synthesize particular functional groups

Alcohols:

• Nucleophilic substitution of an alkyl halide with HO^- or H₂O (chapter 6)
• Reduction of an aldehyde with NaBH₄ (chapter 8)
• Reduction of a ketone with LiAlH₄ (chapter 8)
• Reaction of an aldehyde or ketone with a Grignard or organolithium reagent (chapter 8)
• Reaction of an organometallic reagent with an epoxide (chapter 9)

Aldehydes:

• Oxidation of a primary alcohol with PCC (chapter 8)

Alkenes:

• β Elimination of an alkyl halide or an alkyl tosylate with base (chapter 7)
• Dehydration of an alcohol with acid (chapter 9)
• Dehydration of an alcohol using POCl₃ and pyridine (chapter 9)

Alkyl halides:

• Radical halogenation of an alkane with X₂ (chapter 3)
• Reaction of an alcohol with SOCl₂ or PBr₃ (chapter 9)
• Reaction of an alcohol with HX (chapter 9)

Carboxylic acids:

• Oxidation of a primary alcohol with Na₂Cr₂O₇ (chapter 8)

Epoxides:

• Intramolecular SN2 reaction of a haloalcohol using base (chapter 8)

Ethers:

• Williamson ether synthesis: SN2 reaction of an alkyl halide with an alkoxide (chapter 8)
• Reaction of an alkyl tosylate with an alkoxide

Ketones:

• Oxidation of a secondary alcohol with PCC or Na₂Cr₂O₇ (chapter 8)