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

Pseudo-first-order rate constants were determined for the solvolysis of adozelesin (2) and of several related cyclopropylpyrroloindoles (CPIs) as a function of pH and buffer concentration in mixed organic-aqueous solvents. Rate constants were proportional to the hydronium ion concentration 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 products 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 chloride 2e, with only a trace amount (<5%) of the piperidinoindole chloride 2f. Pseudo-first-order rate constants were proportional to both chloride and hydronium ion concentration. The products and kinetic behavior 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-one (6) and bis(trifluoromethyl) quinone methide 8 suggests that the conjugated 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, toward duplex DNA.