Uploaded September 2021 | Updated September 2026, 2 weeks ago
Retrosynthetic analysis of a spirocyclic unsaturated ketone to showcase 1,6-diX disconnections and the pinacol rearrangement as synthesis strategies in organic chemistry.
More retrosynthesis videos here: youtube.com/watch?v=lD02HC4h6yw&list=PLavaRHHaRimVhyZD79H8g08cfhxrZMcB1
#chemistry #organicchemistry #orgo #ochem #stemeducation #education #science #stem #synthesis
The molecule has an alpha beta unsaturated ketone (enone) and an all carbon quaternary centre as a spiro centre joining two five-membered rings. The enone is the ketone functionality in the middle of the molecule, making it a good choice for a first disconnection in any retrosynthesis. Enones are often most easily constructed by some type of aldol reaction/condensation or by Wittig type chemistry. Here, as the disconnection across the C=C double bond does not break the whole molecule into two pieces, an intramolecular aldol condensation is very easy to set up using the general selectivity of ring closures for 5-membered rings over 7-membered rings. The aldehyde component is also usefully non-enolisable in this proposed intermediate. This intramolecular aldol condensation should proceed smoothly by the use of an equilibrating base such as sodium ethoxide (NaOEt).
The next intermediate in the retrosynthesis displays two carbonyl groups in a 1,6 relationship, and a standard disconnection approach for such a 1,6-diX system is to perform a reconnection – as in deliberately reform a 6-membered ring. Here, reconnection to an alkene is sensible as it could be oxidatively cleaved easily using ozonolysis to return the required carbonyl groups if a neutral work-up is used to break down the intermediate ozonide.
Alkenes can be formed by elimination reaction (E1 or E2) and so a functional group interconversion (FGI) is used as the next disconnection back to a tosylate, derived from its parent alcohol. There is a regioselectivity concern here depending on which of the carbon atoms the tosylate/hydroxyl group is installed. In one case, there are three possible eleimination products and the most likely one, by both E1 mechanism or E2 mechanism, is not the desired one, but one where the C=C double bond ends up in conjugation with a phenyl substituent. Installing the hydroxyl group adjacent to the spiro centre prevents these issues entirely.
Next, a functional group interconversion is performed on the alcohol to give the more versatile ketone. The alpha branching of this ketone, particularly as it’s coming off a ring, is a good clue to take the next disconnection as an alkylation to disconnect off the benzyl group. This alkylation reaction would be easily performed by using the lithium enolate (formed by using LDA) and reacting it with benzyl bromide to do an SN2 reaction (substitution reaction).
Finally the spirocyclic ketone is perfectly set up as the product of a pinacol rearrangement of a diol derived from the radical coupling of cyclopentanone. Cyclopentanone is reacted with magnesium metal, which can react to transfer single electrons to the carbonyl groups and affect a reduction mechanism. As the magnesium has two readily transferable electrons for reduction, and the fact that Mg2+ as an ion is great at coordinating to oxygen, two singly reduced cyclopentanone molecules are held in close proximity and the carbinol radicals can couple to form a new C-C bond, and hence a diol on work-up. Treatment of this diol with strong acid and heat makes one of the hydroxyl groups into a group leaving group on a tertiary carbon. Rather than forming explicitly a high energy tertiary carbocation, it is observed that one of the adjacent alkyl groups migrates first as the resulting oxycarbenium ion is much more stable (essentially can be seen as lone pair donation stabilisation of a carbocation).
Retrosynthetic analysis of a spirocyclic unsaturated ketone to showcase 1,6-diX disconnections and the pinacol rearrangement as synthesis strategies in organic chemistry.
More retrosynthesis videos here: youtube.com/watch?v=lD02HC4h6yw&list=PLavaRHHaRimVhyZD79H8g08cfhxrZMcB1
#chemistry #organicchemistry #orgo #ochem #stemeducation #education #science #stem #synthesis
The molecule has an alpha beta unsaturated ketone (enone) and an all carbon quaternary centre as a spiro centre joining two five-membered rings. The enone is the ketone functionality in the middle of the molecule, making it a good choice for a first disconnection in any retrosynthesis. Enones are often most easily constructed by some type of aldol reaction/condensation or by Wittig type chemistry. Here, as the disconnection across the C=C double bond does not break the whole molecule into two pieces, an intramolecular aldol condensation is very easy to set up using the general selectivity of ring closures for 5-membered rings over 7-membered rings. The aldehyde component is also usefully non-enolisable in this proposed intermediate. This intramolecular aldol condensation should proceed smoothly by the use of an equilibrating base such as sodium ethoxide (NaOEt).
The next intermediate in the retrosynthesis displays two carbonyl groups in a 1,6 relationship, and a standard disconnection approach for such a 1,6-diX system is to perform a reconnection – as in deliberately reform a 6-membered ring. Here, reconnection to an alkene is sensible as it could be oxidatively cleaved easily using ozonolysis to return the required carbonyl groups if a neutral work-up is used to break down the intermediate ozonide.
Alkenes can be formed by elimination reaction (E1 or E2) and so a functional group interconversion (FGI) is used as the next disconnection back to a tosylate, derived from its parent alcohol. There is a regioselectivity concern here depending on which of the carbon atoms the tosylate/hydroxyl group is installed. In one case, there are three possible eleimination products and the most likely one, by both E1 mechanism or E2 mechanism, is not the desired one, but one where the C=C double bond ends up in conjugation with a phenyl substituent. Installing the hydroxyl group adjacent to the spiro centre prevents these issues entirely.
Next, a functional group interconversion is performed on the alcohol to give the more versatile ketone. The alpha branching of this ketone, particularly as it’s coming off a ring, is a good clue to take the next disconnection as an alkylation to disconnect off the benzyl group. This alkylation reaction would be easily performed by using the lithium enolate (formed by using LDA) and reacting it with benzyl bromide to do an SN2 reaction (substitution reaction).
Finally the spirocyclic ketone is perfectly set up as the product of a pinacol rearrangement of a diol derived from the radical coupling of cyclopentanone. Cyclopentanone is reacted with magnesium metal, which can react to transfer single electrons to the carbonyl groups and affect a reduction mechanism. As the magnesium has two readily transferable electrons for reduction, and the fact that Mg2+ as an ion is great at coordinating to oxygen, two singly reduced cyclopentanone molecules are held in close proximity and the carbinol radicals can couple to form a new C-C bond, and hence a diol on work-up. Treatment of this diol with strong acid and heat makes one of the hydroxyl groups into a group leaving group on a tertiary carbon. Rather than forming explicitly a high energy tertiary carbocation, it is observed that one of the adjacent alkyl groups migrates first as the resulting oxycarbenium ion is much more stable (essentially can be seen as lone pair donation stabilisation of a carbocation).
