Total synthesis and preliminary evaluation of (+)- and ent-(-)-duocarmycin SA

Article abstract of DOI:10.1021/ja00073a019

Concise total syntheses of natural (+)- and ent-(-)-duocarmycin SA (1) are detailed based on sequential regioselective nucleophilic substitution reactions of the unsymmetrical p-quinone diimine 3 in the preparation of a dihydropyrroloindole precursor to the left-hand subunit. In addition to constituting a new synthetic strategy for the preparation of natural or synthetic duocarmycins and related agents, both enantiomers of 2 (N-BOC-DSA) and its immediate synthetic precursors are made available by the approach. This provides access to synthetic analogs incorporating either enantiomer of the exceptionally stable and potent duocarmycin SA alkylation subunit. The comparative chemical properties of the agents are detailed in studies which reveal that N-BOC-DSA (t_1/2 = 177 h, pH = 3; stable, pH = 7) is 4.8× more stable to chemical solvolysis than N-BOC-CPI (t_1/2 = 37 h, pH = 3), the authentic alkylation subunit of CC-1065, and that the agents participate in a stereoelectronically-controlled solvolysis reaction with nucleophilic addition to the least hindered cyclopropane carbon. Consistent with this enhanced stability, (+)-N-BOC-DSA (2) proved to possess the most potent inherent cytotoxic activity of all natural and synthetic alkylation subunits examined to date including (+)-N-BOC-CPI, and its relative cytotoxic potency predictably follows a fundamental relationship between chemical stability and cytotoxic potency established in prior studies. In contrast to expectations based on past observations, the unnatural enantiomers of 1 and 2 as well as the natural enantiomers were found to constitute potent cytotoxic agents whose further examination should prove exceptionally interesting.