A Total Synthesis of (+)-Ryanodol

Citation

Chuang, Kangway V. (2016) A Total Synthesis of (+)-Ryanodol. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z95X26ZV. https://resolver.caltech.edu/CaltechTHESIS:06082016-142725994

Abstract

Highly oxygenated, architecturally complex terpenoids constitute a biologically important class of natural products, yet their development into medicinally relevant analogs and effective biological probes are obstructed by their synthetic accessibility. Ryanodine is a unique diterpenoid that exhibits high affinity to a class of intracellular calcium ion channels bearing its name: ryanodine receptors. Structure-activity relationship studies have demonstrated how peripheral structural modifications affect binding affinity and selectivity among receptor isoforms, but to date have been limited to analogs prepared via chemical derivatization of natural material due to the intractability of total chemical synthesis.

This thesis details synthetic efforts culminating in a total synthesis of ryanodol that proceeds in only 15-steps from commercially available (–)-pulegone. Early stage oxygen atom incorporation is strategically implemented to facilitate key, stereoselective carbon-carbon bond formation. In particular, a rhodium-catalyzed, intramolecular Pauson–Khand reaction is utilized to rapidly assemble the tetracyclic ABCD-ring system that constitutes the anhydroryanodol core. A novel, selenium-dioxide mediated oxidation to install three oxidation states and three oxygen atoms was discovered, enabling the rapid oxidative functionalization of the ryanodol A-ring. The modular route described herein allows for the preparation of synthetic structural analogs not readily accessible via chemical degradation, and is anticipated to enable rapid construction and evaluation of biologically active ryanodine analogs.

Thesis Files