A vast rate increase in the Mitsunobu reaction of phenols with alcohols where either or both are sterically hindered has been achieved by the use of high concentration combined with sonication.

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.

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The addition of carbamate nitrogen to a non-conjugated carbon-carbon triple bond is catalyzed by an ammonium salt leading to a cyclic product. Studies in homogeneous systems suggest that the ammonium agent facilitates nitrogen-carbon bond formation through a cation-π interaction with the alkyne unit that, for the first time, is directly observed by Raman spectroscopy.