Toward a total synthesis of (+)-Amphidinolide P and related studies

The progress toward a stereoselective total synthesis of (+)-Amphidinolide P is discussed. The work highlights the use of chiral allenylmetal reagents to set the intrinsic propionate domains of the cytotoxic natural product. A Stille coupling provides the carbon backbone. The macrolactone is closed using a traditional Yamaguchi macrolactonization and the pyran is established by using a novel gold-catalyzed conjugate addition.;A novel preparation of enantiopure butynol mesylates is presented. This approach features a Noyori hydrogen transfer reaction and can be used to supply gram-quantities of propargyl alcohols which can be directly converted to their corresponding mesylates without workup. Chiral butynol mesylates are precursors of allenylmetal reagents.;Finally, novel palladium-catalyzed conjugate additions of organozinc reagents to alpha,beta-unsaturated aldehydes are discussed. This methodology can be diastereoselective and can be used for the selective preparation of (E)-silyl enol ethers. The palladium-catalyzed reaction is also compared to its copper-catalyzed counterpart.