Strategies for Synthesis and Retrosynthesis | Organic Chemistry 1
Protection - Deprotection
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
Alcohol Protecting Groups
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:
Carbonyl Protecting Groups
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
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:
- 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
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)