Enantioselective synthesis of saframycin A and evaluation of antitumor activity relative to ecteinascidin/saframycin hybrids

A short synthesis of saframycin A is described which begins with a readily available intermediate previously utilized for the total synthesis of ectei nascidin 743. A key step in this synthesis is the use of 1-fluoro-3,5-dichl oropyridinium triflate to oxidize a phenolic ring to a 1,4-benzoquinone uni t while simultaneously cleaving a methoxymethyl ether of a different phenol ic ring to the corresponding phenol (4 --> 5). The common intermediate (2) for the synthesis of saframycin A (1) and ecteinascidin 743 also allowed th e synthesis of two hybrids of these structures (6 and 7), Whole cell bioass ays for antitumor activity using lung, colon, melanoma, and prostate derive d tumor cell lines allowed a clear correlation of structure with biological activity in this series.