Evidence for facile atropisomerism and simple (non-nucleophilic) biradical-forming cycloaromatization within kedarcidin chromophore aglycon.
The kinetics and thermodynamics of atropisomerism within the protected kedarcidin chromophore aglycon 8, as well as a series of ansa-bridged synthetic intermediates leading to 8, were determined by 1H NMR spectroscopy. The data show that the ratio of atropisomeric forms of chloropyridine-bridged ansa intermediates is subject to wide variation with seemingly subtle structural variation. The vinyl bromide 4, for example, in the first X-ray structure determination of a kedarcidin ansa-bridged system, was found to exist as a single atropisomer in the solid state, but a nearly equal mixture (K = 0.70) of isomers in solution (t1/2 for isomer interconversion approximately 0.2 s at 20 degrees C). The aglycon 8, a 2.2:1 mixture of atropisomers, was found to undergo direct unimolecular biradical-forming cycloaromatization at ambient temperature in a mixture of 1,4-cyclohexadiene-benzene, without nucleophilic activation. The product 9 was formed as a single atropisomer (k = 2 x 10-4 s-1, t1/2 = 58 min, 81% yield), suggesting that the rate of atropisomerism within 8 is rapid with respect to cycloaromatization. The rate of cycloaromatization of 8 was found to be highly solvent-dependent, being more rapid in the presence of a good hydrogen-atom donor, consistent with the earlier model studies of Hirama et al. that showed that certain nine-membered cyclic (Z)-enediynes may equilibrate with their biradical cycloaromatization products. Incubation of 8 with beta-mercaptoethanol, under conditions mimicking experiments leading to DNA cleavage with kedarcidin, showed no evidence for nucleophilic activation. The product of direct cycloaromatization (9) was isolated instead. The evidence suggests that kedarcidin, like the enediyne agent C-1027, is capable of spontaneous thermal biradical formation without prior chemical activation.
Myers
Andrew G
AG
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA. myers@chemistry.harvard.edu
Hurd
Alexander R
AR
Hogan
Philip C
PC
D000480:Alkynes; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism; D003516:Cycloparaffins; D053281:Enediynes; D007536:Isomerism; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides
D000480:Alkynes; D000900:Anti-Bacterial Agents; D003516:Cycloparaffins; D053281:Enediynes; D009281:Naphthalenes; D010455:Peptides; C080542:kedarcidin chromophore