Retrosynthetic analysis of a substituted caprolactam, highlighting the Beckmann rearrangement, Michael addition, and protecting group chemistry using the THP group.
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The 7-membered ring in this molecule can be a challenging motif to synthesise by conventional ring closing synthetic strategies, for example here an intramolecular amidation, as transannular strain disfavours the reactive conformation in such systems. However, this 7-membered ring cyclic amide - also known as a lactam, specifically here a caprolactam - can be made by a rearrangement reaction that can expand a 6-membered ring cyclic ketone into the required amide. The Beckmann rearrangement is a reaction sequence in which a ketone is transformed into the corresponding oxime by condensation with hydroxylamine. It is important that there is some stereoselectivity achieved in this condensation reaction on the C=N double bond and, given reversibility in the mechanism, some steric differentiation between the two sides of the parent carbonyl is required. The oxime has a weak N-O sigma bond which contributes to the driving force for the Beckmann rearrangement. When the oxime is treating with strong acid or when the hydroxyl group is converted into a good leaving group such as a tosylate, the alkyl group that is antiperiplanar across the C=N double bond is able to migrate (1,2-migration) leaving a carbocation behind on the carbon that was originally part of the parent carbonyl. This carbocation is quickly trapped by water and then tautomerises to the much more stable amide functional group. Hence the thermodynamically tricky 7-membered ring is constructed by a ring expansion method not reliant on the rules for ring closure.
The 6-membered ring ketone intermediate has two branching points on either side, one alpha and one beta, which are good points for further disconnections. The ethyl group in the alpha position can be installed by enolate alkylation by, for example, generating the lithium enolate by reaction with LDA (LiNiPr2) at -78°C and performing an SN2 reaction with bromoethane (ethyl bromide). The branch point with an alkyne in the beta position can be synthesised by Michael addition (conjugate addition) of an acetylide type nucleophile, the deprotonated alkyne being made softer by the use of a Cu(I) catalyst. A hydrogen directly attached to an alkyne triple bond is rather acidic, pKa 25 ish, and so is deprotonated by a base such as NaNH2 or BuLi more simply than you might expect for something that generates a carbanion. The carbanion is in an sp-hybridised molecular orbital which has 50% s-character and is quite low in energy as a result.
The alkyne nucleophile used has a protected alcohol functional group using the THP protecting group, which itself is a reasonably stable acetal due to the anomeric effect. The starting material for the synthesis is therefore propargyl alcohol which is cheap and readily available. The THP protecting group (tetrahydropyran acetal) can be installed by reacting the free hydroxyl group with DHP (dihydropyran) in the presence of an acid catalyst. The enol ether functional group in DHP is, in equilibrium, converted to the oxycarbenium ion that is then trapped by the alcohol.
Негізгі бет Retrosynthesis 10 - Organic Chemistry
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