ALPHA-DIAZO KETONES AS PHOTOCHEMICAL DNA CLEAVERS - A MIMIC FOR THE RADICAL GENERATING-SYSTEM OF NEOCARZINOSTATIN CHROMOPHORE

The alpha-diazo ketones 1, 10, and 11 were designed as mimics for the radical-generating system of neocarzinostatin chromophore (7). These a lpha-diazo ketones are able to generate diradicals under thermal or ph otoirradiation conditions in toluene via the cyclization of the ene-yn e-ketene intermediates. Ab initio MO calculations revealed that the ef ficiency of the radical generation is highly dependent on the conforma tion of the alpha-diazo ketones which is controlled by the substituent on the carbon directly attached to the diazo group. Two alpha-diazo k etones 10 and 11 having a DNA binding group considerably improved the DNA-cleaving activity compared to that for 1 under photoirradiation at 366 nm. The absence of an appreciable amount of cyclized indanol 23 i n the photoirradiated solution of 10 in the presence of pBR322 DNA str ongly suggests that the diradical is not responsible for the observed DNA cleavage. Likewise, photoirradiation of 1 in a 50% aqueous acetoni trile solution did not produce indanol 5 but gave a novel furan deriva tive 33. The increased yield of 33 under aerobic conditions suggested that the mechanism producing 33 involves the trapping of photogenerate d alpha-keto carbene 29 with molecular oxygen. These experiments toget her with theoretical calculations indicated that alpha-keto carbenes g enerated by photoirradiation of alpha-diazo ketones may be the princip al DNA-cleaving species.