Total Synthesis of Stipiamide and Designed Polyenes as New Agents for the Reversal of Multidrug Resistance

The synthesis of (−)-stipiamide (1) is reported together with the designed enynes 2 (6,7-dehydrostipiamide) and 3 that are now shown to reverse the multidrug resistance (MDR) of human breast cancer cells (MCF-7adrR). Stipiamide was assembled using a Stille coupling with (E)-vinyl iodide 17 and (Z)-stannyl amide 16 in 78% yield. (E)-Vinyl iodide 17 was made using a Takai reaction and a selective dihydroxylation of the terminal olefin of nonconjugated diene 7 using the Sharpless AD-mix reagent. The precursor to 16, (E,Z)-stannyl diene ester 13, was assembled with high selectivity in a single operation using a tandem syn-addition of tributyltin cuprate to acetylene followed by conjugate addition to ethyl propiolate. Structural variants 2 and 3 were assembled using palladium-catalyzed Sonogashira couplings with vinyl iodides 17 and 35 and acetylenes 22 and 26 in high yield at near 1:1 stoichiometry. Compound 2 was found to be far less toxic than stipiamide and performed much better as an MDR reversal agent. Compound 3 was better still due to even lower toxicity.