Total Synthesis Of Bioactive Natural Products By Palladium Catalyzed Domino Cyclization Of Allenes And Related Compounds PDF Download

Transition metal-catalyzed transformations of allenes are underexplored compared to other unsaturated functional groups. However, the consecutive, orthogonal double bonds of allenes represent an extremely valuable functional handle that can be manipulated to rapidly build molecular complexity. The first section of this work (Chapter 2) describes how targeted changes to the reaction conditions enable control over the mechanism of Pd-catalyzed allene cross-coupling/cyclization and cycloisomerization, irrespective of the allene substitution pattern. Both enantioenriched cyclopropanes and cyclopentenes can be obtained through axis-to-center chirality transfer from the allene precursor at room temperature. The next section (Chapter 4) demonstrates a highly stereoselective Pd-catalyzed Heck-type reaction of allenes to form 1,3-dienes in which the stereochemistry of both olefins is set simultaneously. The stereodetermining factors and a plausible mechanism for this work are proposed and both inter- and intramolecular trapping of the Ï0-allyl intermediate with an oxygen nucleophile are demonstrated. The final portion of this work will be focused on progress towards the total synthesis of Nogalamycin (NOG) (Chapter 6). NOG is a member of the glycosidic anthracyclines and shows a unique dumbbell type binding to DNA. Toxicity and relatively low antineoplastic activity have prevented NOG from clinical use, but semisynthetically accessed derivatives have shown great potential, leading to the need for a highly modular synthetic approach to access new analogs and further probe SARs. A complex bicyclic aminosugar motif creates a significant challenge for the synthesis of NOG, as there are no reliable synthetic methods to install the C℗Ơaryl-Cglycoside bond late stage. In this section, we propose a late-stage chemoenzymatic installation of the C℗Ơaryl-Cglycoside bond inspired by the biosynthetic pathway. The synthesis of the tetracyclic anthracycline core includes a key boron-directed cycloaddition, a novel SmI2 mediated ring opening of an oxanorbornadiene, and a proposed Ni-catalyzed cross electrophile coupling.