An efficient synthetic strategy for obtaining 4-methoxy carbon isotope labeled combretastatin a-4 phosphate and other Z-combretastatins

Human cancer and other clinical trials under development employing combretastatin A-4 phosphate (1b, CA4P) should benefit from the availability of a [¹¹C]-labeled derivative for positron emission tomography (PET). In order to obtain a suitable precursor for addition of a [¹¹C]methyl group at the penultimate step, several new synthetic pathways to CA4P were evaluated. Geometrical isomerization (Z to E) proved to be a challenge, but it was overcome by development of a new CA4P synthesis suitable for 4-methoxy isotope labeling.