Total Synthesis of Complex Molecules

We develop novel strategies and methodologies in pursuit of
constructing complex synthetic targets with intriguing biological activity.

NATURAL PRODUCTS TOTAL SYNTHESIS 

The diterpenoid alkaloids including liljestrandinine and weisaconitine are architecturally complex secondary metabolites that have remained formidable targets for synthesis for over half a century. Using a ‘network-analysis’ approach, we have recently accomplished the total syntheses of these compounds. This work has now set the stage for the synthesis of additional congeners as well as studies into the biological activity of these compounds, which includes modulation of voltage-gated sodium ion channels and potential applications to ameliorating chronic pain.

Reversed-prenylated indole alkaloids including the stephacidins, citrinalins, and cyclopiamines are intriguing natural products that demonstrate a range of skeletal diversity as well as biological activity.  A unified strategy to prepare all the different skeletons of these molecules is highly desired. We have accomplished an important advance toward this eventual goal by identifying a tricycle that can be advanced to molecules that contain (as well as those that lack) a characteristic bicyclo[2.2.2]diazaoctane structural motif. Recently, we accomplished a unified approach to all members of the reverse-prenylated indole alkaloids. Our syntheses of these metabolites now provide opportunities for bioactivity studies, which are ongoing with collaborators.

Development of Synthetic Methods

We leverage C–C bond cleaving and forming processes to access
new organic frameworks for application in total synthesis or drug development.

CARBON–CARBON CLEAVAGE METHODODOLOGY  

The ubiquity of C–H bonds in organic molecules makes them attractive as potential functional groups that may be employed in the synthesis of complex organic molecules. While many methods have been described for selective C–H bond activation and functionalization, their applications in complex molecules have only begun to emerge. Our laboratory demonstrated some of the earliest examples of these applications and we continue in this vein with many challenging targets where the focus is on late-stage C–H bond activation/functionalization using functional groups innate in the target molecule.

Organic compounds by their very definition consist of a predominantly carbon skeleton. As such, it would be advantageous if this carbon skeleton could be manipulated by C–C bond activation in order to access value-added compounds from much more readily available starting inputs. In this regard, we have become increasingly interested in the utilization of carvone to accomplish the synthesis of more complex organic molecules. Efforts in this regard are currently focused on the synthesis of the phomactin natural products and taxoids related to paclitaxel.

Completed Targets