Efficient assembly of the tricyclic core of the 1-alkyldaphnanes: Progress toward the total synthesis of gnidimacrin.

摘要

The Euphorbiaceae and Thymelaeaceae plant families have been recognized for thousands of years thanks to the myriad of biological effects they produce in humans and animals. Many diterpene natural products isolated from these plants now hold promise for the treatment of such scourges as Alzheimer's disease, chronic pain and cancer. Gnidimacrin, a 1-alkyldaphnane first isolated nearly three decades ago from the leaves of the Kenyan plant Gnidia subcordata (Thymelaeaceae), has exhibited promising activity against a number of cancers. Unfortunately, the development of gnidimacrin as a therapeutic agent has been severely hampered by poor isolation yields (0.0005--0.001%). Nevertheless, organic chemistry offers a unique opportunity for the synthesis of gnidimacrin and its analogs, which will help solve the supply problem as well as expand our knowledge of gnidimacrin's interaction with cellular targets such as its putative receptor, protein kinase C.; This dissertation details the development of an efficient route to the 1-alkyldaphnanes, compounds that have received no attention from the synthetic community due to their highly complex structures. Access to advanced precursors of gnidimacrin incorporating its tricyclic core and much of its functionality has been provided through this work. A room temperature oxidopyrylium-alkene [5+2] cycloaddition was utilized for the construction of the B,C core of gnidimacrin. Several synthetic transformations then set the stage for a highly diastereoselective palladium-catalyzed enyne cyclization. This reaction closed the A ring with a suitably functionalized C1 appendage, which was then extended to include a protected alpha-hydroxy carboxylic acid as a precursor to gnidimacrin's macrocyclic orthoester. These and other manipulations resulted in the construction of the des-isopropenyl carbon skeleton of gnidimacrin. Subsequent work with related substrates resulted in optimization of key synthetic sequences. As a result, nine out of the thirteen stereogenic centers that decorate the fourteen-carbon 5,7,6-tricyclic core of gnidimacrin have been established, and adequate functionality has been installed to accommodate the other four, as well as the remainder of the total synthesis of gnidimacrin.