Substituent Effects on the Reactivity of Cyclic Tertiary Sulfamidates.

The reactivity of cyclic tertiary sulfamidates derived from α-methylisoserine strongly depends on the substitution at the C and N termini. These substrates are one of the very few examples able to undergo nucleophilic ring opening at a quaternary carbon with complete inversion of the configuration, as demonstrated both experimentally and computationally. When the sulfonamide is unprotected, the characteristic ring-opening reaction is completely silenced, which explains that the majority of the ring-opening reactions reported in the literature invoke N-alkyl or N-carbonyl-protected sulfamidates. Accumulation of negative charge at the NSO3 moiety in the transition state, especially when the sulfonamide NH is deprotonated, drastically raises the activation barrier for the nucleophilic attack. On the other hand, ester groups at the carboxylic position favor ring opening, whereas amides allow competition between the substitution and elimination pathways. Using pyridine as a nucleophilic probe, we have demonstrated both experimentally and computationally that a proper selection of the substitution scheme can enhance the synthetic scope of α-methylisoserine-derived sulfamidates, switching off and on the nucleophilic ring-opening in a controlled manner. This is particularly convenient for hybrid α/β-peptide synthesis, as demonstrated recently by our group.