ACID-DEPENDENT ELECTROPHILICITY OF CYCLOPROPYLPYRROLOINDOLES - NATURES MASKING STRATEGY FOR A POTENT DNA ALKYLATOR

Pseudo-first-order rate constants were determined for the solvolysis o f adozelesin (2) and of several related cyclopropylpyrroloindoles (CPI s) as a function of pH and buffer concentration in mixed organic-aqueo us solvents. Rate constants were proportional to the hydronium ion con centration at pH > 2, and the slope of the log k(obs) vs pH plot was - 1. Both the pyrrolidinoindole (2a) and piperidinoindole (2b) alcohols (ca. 4:1) were produced upon acid-catalyzed solvolysis of 2. The produ cts and kinetic behavior are consistent with rate-determining solvent attack on the protonated CPI and competing carbocation rearrangement. Reaction of 2 with HCl afforded predominantly the pyrrolidinoindole ch loride 2e, with only a trace amount (<5%) of the piperidinoindole chlo ride 2f. Pseudo-first-order rate constants were proportional to both c hloride and hydronium ion concentration. The products and kinetic beha vior are consistent with attack of chloride ion on the protonated CPI. Comparison to the reported reactivity of spiro[2.5]octa-1 ,4-dien-3-o ne (6) and bis(trifluoromethyl) quinone methide 8 suggests that the co njugated cyclopropyl ring of the CPI imparts a strong acid dependence to its reactivity with nucleophiles. This property may be relevant to the exceptional reactivity of the parent CPI antibiotic, CC-1065, towa rd duplex DNA.