An introductory level video for retrosynthesis using 1,5diX disconnections in organic chemistry. These disconnections often involved conjugate addition (Michael addition) using enamines or 1,3dicarbonyl reagents.

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A cyclic ester (lactone) is used as an example in this video and so that functional group is a standard one for a first disconnection. There is branching alpha to the carbonyl group that would allow for an enolate alkylation type disconnection if there were a complicated substituent there – but in this example, there is just a methyl group which doesn’t add complexity later when choosing cheap and readily available starting materials. Opening the sixmembered ring gives a 1,5hydroxyester. The 1,5diX functional group relationship lends itself to conjugate addition (Michael addition) chemistry. This is a soft reactivity for the nucleophile and electrophile pairing using an a3 synthon and a d2 synthon.

A functional group interconversion (FGI) is useful for setting up the d2 synthon because enolate equivalents are generally versatile things to use as controlled nucleophiles. Here, an enamine is particularly useful for the key carboncarbon bond forming reaction, taking us quickly back to cheap starting materials in methyl methacrylate and butanal.

I also comment on some other useful reagents that come up when you encounter a 1,5diX disconnection, and specifically when you have a 1,5dicarbonyl system. These are 1,3dicarbonyl reagents, that act as good soft nucleophiles and can then be quickly manipulated by decarboxylation to the usually intended reactive fragment required. This is a common technique in organic chemistry and synthesis in general.