The next compound was an intermediate in the synthesis of the potential anti-obesity drug ICI-D7114. You can spot that, with two ethers and an amine functional group, it requires several disconnections to take it back to simple compounds. The question is, which do we do first? One way to solve the problem is to write down all the possibilities and see which looks best. Here there are four reasonable disconnections: one at each of the ether groups (a and b) or on either side of the amine (c and d).
Both (a) and (b) pose problems of chemoselectivity as it would be hard to alkylate the phenol in the presence of the basic nitrogen atom. Between (c) and (d), (c) appears to be the better choice because the next disconnection after (d) will have to be an alkylation of O in the presence of an NH2 group. To avoid chemoselectivity problems like this, we want to try to intro duce reactive groups late in the synthesis. In terms of retrosynthetic analysis, then, we can formulate another guideline.
●Guideline 3 Consider alternative disconnections and choose routes that avoid chemoselectivity problems— often this means disconnecting reactive groups fi rst.
This guideline helps us in the next retrosynthetic step for the ICI-D7114 intermediate. Disconnection (c) gave us a compound with two ethers that might be disconnected further by disconnection (e) or (f).
Disconnection (e) requires alkylation of a compound that is itself an alkylating agent. Disconnection (f) is much more satisfactory and leads to a compound that is easily disconnected to 4-hydroxyphenol and 1,2-dibromoethane. Using Guideline 3, we can say that it’s best to disconnect the bromoethyl group (f) before the benzyl group (g) because the bromo ethyl group is more reactive and more likely to cause problems of chemoselectivity.
