FROM COLCHICINE AND SOME OF ITS DERIVATIVES TO 1,2,3,9,10-PENTAMETHOXYBENZO[A]HEPTALENES

A two-step synthesis of 4-methylcolchicine (13), starting from colchicine (2), has been developed (Scheme 5). In three steps, 4-ethylcolchicine (28) is also accessible from 2 (Scheme 8). Colchicine (2) and its derivatives 13 and 28 have been transformed into the benzo[a]heptalene derivatives 9, 18, and 34, respectively, by Hofmann degradation of the corresponding deacetylcolchiceine 3, 19, and 29, respectively, followed by methylation of the two O-functions first with diazomethane and then with trimethoxonium tetrafluoroborate (Scheme 2 and 6). The thus formed tropylium salts gave, on deprotonation with Me(3)N in CHCl3, the expected pentamelhoxybenzo[a]heptalenes 9, 18, and 34, respectively. X-Ray crystal-structure analysis of 9 (Fig. 3) and 18 (Fig. 7), determination of the vicinal coupling constants of the H-atoms at the heptalene skeleton as well as the measurement of the racemization rate of the new benzo[a]heptalenes revealed a marked influence of the substituent at C(4) on the degree of twisting of the heptalene skeleton. The absolute configuration of the resolved heptalenes was deduced from their long-wavelength CD maxima around 350 nm. The heptalenes with a negative maximum in this range possess (7aP)-configuration.