I'm trying to do an alkylation of an amine on a natural product and ideally I would like to add "some bulk" and then a carboxylic acid. I've tried a few things, including using tert-butyl bromoacetate. The alkylation proceeds with moderate yield and I can then purify the protected ester.

However, the deprotection is causing problems. The tert-butyl group seems to require harsh enough conditions that my SM is breaking down. I have tried 45:50:5 H2O:TFA:TIS, as well as a more mild 3eq H3PO4 in DCM, but no luck on either of those.

So, I'm considering switching PGs to something more labile than the tert-butyl group. I may be able to use a benzyl PG and hydrogenate it off, but I'm not sure my natural product is stable to hydrogenation conditions. Also, it is not stable to moderately basic conditions, especially those containing hydroxide.

So, it seems like it is fairly stable in acidic conditions, though maybe not strong acid conditions like a high percent of TFA. It is likely to be somewhat stable to hydrogenation if I have to go that route.

Any other straightforward ideas? Thanks!