A retrosythesis of this organic molecule using classic disconnection approach methods. The retrosynthetic analysis highlights some key strategies in organic synthesis and organic chemistry reactivity.

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The molecule has a fair amount of functionality and so a good first disconnection would be somewhere in the middle. For something simple to do as the last step in the forward synthesis, disconnecting the ester is a good place to start as that can be made from the corresponding acid chloride and a simple alcohol. The alcohol component is an example of a 1,2difunctionalised compound (1,2diX) and those can usually be easily synthesised by using epoxides. Here a simple SN2 reaction using an amine nucleophile on ethylene oxide (the epoxide, also known as epoxyethane).

Next turning to the acid chloride half of the target molecule – some functional group interconversions can disconnect it back to a more easy to handle methyl ester. The alpha,beta unsaturated ester is easy to retrosynthesis back using either an aldol condensation or a Wittig type reaction for C=C double bond formation (olefination/alkenylation). Here, there is a simple benchstable ylid (ylide) that can be used so a Wittig reaction looks simple here. This should also give the required E geometry of trisubstituted alkene. If the stereoselectivity wasn’t good enough, an HWE reaction (HornerWadsworthEmmons reaction) would probably give better E selectivity and would use the corresponding beta ketophosphonate.

The bicyclic ring system can be quickly formed by cycloaddition (a pericyclic reaction) and specifically here a DielsAlder reaction. The DielsAlder reaction is great for forming cyclohexenes but also require a dienophile component to have an appropriate electron withdrawing group attached to the C=C double bond. Careless disconnection would lead to suggesting using ketene with cyclopentadiene, but this does not fulfil the criterion of having an appropriately placed pi electron withdrawing group for LUMO lowering purposes. A functional group interconversion of the target ketone to a nitro (RNO2) functional group is a clever way to fix this problem. The nitro group is an electron withdrawing group that doesn’t contain any carbon atoms, and it can be converted into the ketone in the forward synthesis by Nef reaction. The Nef reaction would use reaction conditions such as titanium trichloride in water (TiCl3, H2O), although many other alternative reagents are available in organic chemistry for this transformation.

So then the final DielsAlder reaction disconnection is set up and this ends the retrosynthetic analysis. At the end of the video, I have proposed a forwards synthesis for assembling the pieces described above.