In my opinion  under DBU/HOBT conditions phenyl ester going to be very stable for the hydrolysis. Even if there is a plenty of moisture still phenyl ester going to be retained in the FMoc removal cycle

Generally bulkier protecting groups tend to be used, t-butyl, or phenylisopropyl which are only particularly labile in acid. However with DBU/HOBT the only nucleophiles about will be adventitious water and HOBT so it should be fine.

Do you need to retain the phenyl ester on resin cleavage?

Thank you for your answers.

Dear Eric

The final product is a C terminal aldehyde generated via acidic hydrolysis of the corresponding oxazolidine, but for that i do expect the phenyl ester to be stable under Tfa cleavage conditions.

My concern is whether the phenolic ester is stable under the fmoc depo steps, with DBU.

Over the past week i read an article where my concern found confirmation, though in such paper they didn't use HOBT, which i think to be able to prevent the unwanted hydrolysis due to its acidic character.

Thank you for the clarification. DBU/HOBT should be fine at the relative concentrations you have listed. The phenyl ester itself is not inherently base labile and requires a nucleophile for transesterification, I would not expect HOBT to transesterify even under repeated exposure, however water could potentially be a problem.

TBAF could be a viable alternative and has literature precedence in Fmoc SPPS. It would be less basic but water would be more of an issue.

Dear Herris

The DBU was indeed chosen to prevent any transesterification.....but still it could promote the phenyl ester hydrolysis via alpha hydrogen elimination, as reported previously.....this is related to the steric hindrance of both the base used and of the substrate, and therefore on its substituents.....in general it was shown that electron withdrawing substituents promote the hydrolysis, which in my case would not be a concern...thank you for your interest, and wish me luck :)