SELECTIVE NUCLEOPHILIC-ATTACK OF TRISULFIDES - AN AB-INITIO STUDY

The nucleophilic substitution reactions of three trisulfides by thiola te were evaluated at MP2(full)/6-31+G and MP4SDTQ(fc)/6-311+G**//MP2( full)/6-31+G. The results show that the gas-phase mechanism at MP2/6- 31+G is addition-elimination. Kinetically, there is a 2-5 kcal mol(-1 ) preference for attack at a terminal sulfur over a central sulfur in the same trisulfide. This preference for the terminal sulfur is due to more steric hindrance encountered when the nucleophile attacks the ce ntral sulfur versus attacking a terminal sulfur. Hydrogen bonding betw een the nucleophile and the trisulfide also assists in directing attac k to the terminal position. Attack at the terminal sulfur is also ther modynamically favored, a result of the thiosulfenate being a better le aving group than the thiolate. These results provide theoretical suppo rt to the findings of Myers et al. that the trigger mechanism for acti vation of calichaemicin and related enediyne antitumor agents occurs b y a multistep process, with a displacement at the terminal sulfur of t he trisulfide followed by nucleophilic substitution of a disulfide.