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 ecteinascidin 743. A key step in this synthesis is the use of 1-fluoro-3,5-dichloropyridinium triflate to oxidize a phenolic ring to a 1,4-benzoquinone unit while simultaneously cleaving a methoxymethyl ether of a different phenolic ring to the corresponding phenol (4 --> 5). The common intermediate (2) for the synthesis of saframycin A (1) and ecteinascidin 743 also allowed the synthesis of two hybrids of these structures (6 and 7), Whole cell bioassays for antitumor activity using lung, colon, melanoma, and prostate derived tumor cell lines allowed a clear correlation of structure with biological activity in this series.