An adjacent thioester provides apical-directed stabilization to 3-isothiazolidinone 1-oxide heterocycles

The structural and energetic features of the attractive intramolecular thro ugh-space S-X interaction [X being oxygen (O) or sulfur (S)] of thioester c ontaining 3-isothiazolidinone 1-oxide heterocycles are described. Density f unctional theoretical and semiempirical calculations are used to explain th e previous X-ray data on 3-isothiazolidinone 1-oxides 5 and 6 [Kanda, Y., A shizawa, T., Kakita, S., Takahashi, Y., Kono, M., Yoshida, M., Saitoh, Y., and Okabe, M. (1999) J. Med. Chem. 42, 1330-1332] and implicate a mechanism where the adjacent thioester participates in an apical-directed stabilizat ion of the sulfur heterocycle. A key factor that distinguishes the S-O inte raction from the S-S interaction is the stronger through-space interaction of the former, which is a consequence of the greater electronegativity of a pical O compared to apical S. Reaction field theory reveals that the conver sion of the S-O interaction to the S-S interaction is more facile compared to gas phase computations, which suggest a reduced importance of the 1,5-S- X interactions in solution. The conversion of the S-O interaction to the S- S interaction gives an isothiazolidinone oxide that places the reacting sul furs in proximity with an orientation presumably suitable for bond formatio n and access to the dithiolanone oxide surface. Factors that influence the through-space S-X interactions may represent important issues in identifyin g target 3-isothiazolidinone 1-oxide prodrugs capable of rearranging to 1,2 -dithiolan-3-one 1-oxide drugs.