| Total synthesis and structural revision of the marine natural product callipeltoside C is described. A highly convergent fragment based approach facilitated rapid access to the natural product. Three of the four fragments were constructed utilizing asymmetric organocatalytic methodologies developed in our laboratory. Specifically, a double stereodifferentiating anti -aldol coupling, alpha-oxyamination, and de novo carbohydrate synthesis establish much of the requisite callipeltoside stereochemistry, all using proline as an organocatalyst. Additional highlights include a palladium-catalyzed Semmelhack alkoxycarbonylation to close the central tetrahydrofuran ring, chelation-controlled vinyl Grignard addition and Yamaguchi lactonization furnish the macrocyclic core, and a pi-facial selective methyl Grignard addition introduces a key tertiary alcohol stereocenter.;Also described in this work is the total synthesis of the natural product diazonamide A. The linchpin of our diazonamide A synthesis was an iminium-catalyzed addition/cyclization to stereoselectively assemble the tetracyclic furanoindoline core and central C(10) quaternary carbon stereocenter. A strategically innovative magnesium-mediated macroaldolization and novel DAST-mediated cyclodehydration close the left-hand macrolactam, while either a Stille-Kelly coupling or tandem Miyaura boration/intramolecular Suzuki cross-coupling represent viable strategies to forge a key biaryl bond and close the right-hand macrocycle. We also present two approaches to installation of the peripheral chlorine atoms, each of which utilize bromine as a protecting group. |
