Synthesis of <i>N</i> -Betsylated Amino Acids Using Aqueous Buffered Sodium Hypochlorite Solution

We report a new method for the synthesis of <i>N</i>-benzo[<i>d</i>]thiazol-2-sulfonyl (Bts, betsyl)-protected amino acids, yielding building blocks amenable to solid-phase peptide synthesis (SPPS) in one step from their corresponding free amino acids. The procedure uses sodium benzo[<i>d</i>]-thiazol-2-sulfinate (sodium betsylate) and buffered aqueous oxidative conditions to generate unstable benzo[<i>d</i>]-thiazol-2-sulfonyl chloride (Bts-Cl) in situ. This epimerization-free method was used to generate a library of betsylated amino acids containing various protected and unprotected side chains. Further utility was demonstrated by incorporating an <i>N</i>-terminal betsylated residue on a linear pentapeptide as a means of preparing a macrocycle via an on-resin Mitsunobu reaction. Additionally, betsylated amino acids proved to be suitable for peptide synthesis in solution with newer coupling reagents such as COMU and TCFH/NMI. Deprotection can be performed under basic or reductive conditions, allowing for orthogonality with other commonly used protecting groups.