SYNTHETIC AND MECHANISTIC STUDIES ON THE ANTITUMOR ANTIBIOTICS ESPERAMICIN-A1 AND CALICHEAMICIN-GAMMA-1 - SYNTHESIS OF 2-KETOBICYCLO[7.3.1] ENEDIYNE AND 13-KETOCYCLO[7.3.1] ENEDIYNE CORES MEDIATED BY ETA-2 DICOBALT HEXACARBONYL ALKYNE COMPLEXES - CYCLOAROMATIZATION RATE STUDIES

A general strategy for the construction of the bicyclo[7.3.1]tridecenediyne core structure of the antitumor antibiotics esperamicin and calicheamicin can be realized provided the 10, 11-acetylenic bond is complexed as its derived eta-2 CO2(CO)6 adduct. The 10,11-eta-2-ketobicyclo[7.3.11 enediyne dicobalt hexacarbonyl adduct 38 was synthesized using eta-2 dicobalt hexacarbonyl propargyl cation alkylation to form the crucial 10-membered ring. Oxidative decomplexation of 38 in 1,4-cyclohexadiene gave the cycloaromatized adduct 49, presumably via the uncomplexed 2-ketobicyclo[7.3.1] enediyne 27. The keto isomer 10,11-eta-2-13-ketobicyclo[7.3.11 enediyne dicobalt hexacarbonyl adduct 39 was synthesized in a similar manner and its structure secured by single-crystal X-ray crystallography. Oxidative decomplexation of 39 gave the 13-ketobicyclo[7.3.1] enediyne 32 as a stable crystalline solid. The five-membered-ring analogue, 12-ketobicyclo[7.2.11 enediyne 94, was readily made in the same way. The relative rates of cycloaromatization of 32 compared to the derived alcohol 86 and the five-membered-ring analogue 94 (and 97) demonstrate that the distance (r) between the bonding acetylenes (leading to the 1,4-diyl) in the ground state does not control the rate of cycloaromatization. Strain release in the transition state predicts the relative rates of cycloaromatization.