Don't see why the above should be cleaved in the stomach. I don't think this is a good prodrug for the following reason: I think most ester hydrolysis reactions happen in the liver where the most esterases are. Why do you expect the above molecule to cleave even faster, and why does it even cleave itself?
This needs 2 metabolic steps to cleave. The first metabolic reaction would be to hydrolyse the cyclic ester, and this would be more unfavourable relative to an acyclic ester. Cyclic esters (lactones) are more stable because their formation is more entropically favourable; when they are hydrolysed, there is only one product rather than 2 with normal acyclic hydrolysis. The latter procedure would increase entropy (2 molecules from one means a more disordered system) thus pushing the equilibrium to the hydrolysis side, but as one can see this is not the case with the lactones. And this is the product:
Then the enzymes would now need to cleave the N-hydroxymethyl group (probably CYP mediated) to finally give N-acetylcysteine. In fact, the enzymes might actually oxidise the alcohol instead of cleave that group so you might not even get any NAC at all.
Last but not least, the cyclic molecule would have a lower logP than NACET reducing absorption. I just don't see how the above could be a good prodrug.
What you want for this prodrug is a high logP and obviously the masked carboxylic acid which should be easy to unmask in the liver only. And finally the leaving group should be non-toxic and polar enough to be easily excretable therefore. So you want something kind of reactive but not too reactive. Here is my idea:
Rationale: very high logP. Good absorption from the stomach. A nitro group instead of the chloro would make for a pretty good leaving group (4-nitrophenoxide) but at the cost of a much reduced logP (nitro groups are pretty polar). Also, I thought the nitro derivative might just be too reactive and start reacting with water as it is in the stomach itself. But that can't be too bad as you'll just get NAC and the possibly toxic leaving group.
So the compromise is the chlorine derivative instead. Significantly increases logP on the ring while also withdrawing electron density from the ring to make it a better leaving group, although less so than nitro. Hopefully this one will only react with the help of liver esterases.
If you'd want to go further then just design many ester analogues but the key points to keep in mind here are:
1. High logP derivative
2. Once in the liver, the moiety gets cleaved easily, but it can't be too reactive such that it reacts in the stomach.
3. The moiety must be non-toxic and therefore have metabolical labilities which result in increased polarity for easy excretion and must not pose any obvious toxicity risks (e.g alkylating agent though I doubt this would happen here as the leaving moiety would anyway have to be a weak base and thus a weak nucleophile).
