New strategies for the synthesis of bioactive natural and unnatural products via palladium catalyzed asymmetric allylic alkylation

New strategies for the enantioselective synthesis of bioactive targets via palladium-catalyzed asymmetric allylic alkylations (Pd-AAA) are described. The palladium- and boron-cocatalyzed chemo-, regio-, and enantioselective opening of racemic vinyl epoxides in a dynamic kinetic asymmetric transformation (DYKAT) provides a valuable and flexible entry to versatile chiral building blocks. The DYKAT of vinyl epoxides nicely accommodates the rather bulky nonyl group in the synthesis of naturally occurring antibiotic-malyngolide. In the synthesis of LY333531, a selective protein kinase C inhibitor, the ability to employ bromo-substituted alkyl alcohols in the DYKAT process without complications demonstrates the exquisite chemoselectivity the reaction possesses. These two syntheses not only demonstrate the utility of this methodology but also expand the scope of the electrophiles and nucleophiles for the DYKAT process. A divergent synthetic strategy was developed for the syntheses of galanthamine, an amaryllidaceae alkaloid that is useful for the treatment of Alzheimer's patients, and morphine, an opium alkaloid with broad spectrum of analgesic properties. From a common precursor prepared by deracemization of a chiral racemic allyl carbonate using phenol as nucleophile in the Pd-AAA, galanthamine and its analogues are available in two steps while morphine is available in seven steps. These represent the most efficient asymmetric syntheses of these two families of alkaloids without using resolution. The hydroamination reaction discovered in the synthesis of morphine created a simple asymmetric synthesis of synthetic analgesics with diminished addictive properties, the benzomorphans. A diastereoselective olefin migration was also accomplished under the condition for hydroamination. In this case, all the stereochemistry was derived from a Pd-AAA in which the enantiodiscrimination is at the nucleophile. Efforts to expand the scope of Pd-AAA to eight-membered ring in the context of synthesis of 8,9-seco-kaurene led to a facile entry into highly functionalized bicyclo[7.2.IIdodecene carbon skeleton. A new catalyst was developed for the diastereoselective and enantioselective monoepoxidation of 6,7-disubstituted 1,3-cyclooctadiene. An enyne metathesis was performed efficiently in the presence of PtCl2 catalyst on a highly functionalized substrate.