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A Total Synthesis of (+)-Ryanodol


Chuang, Kangway V. (2016) A Total Synthesis of (+)-Ryanodol. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z95X26ZV.


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.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:ryanodol, total synthesis, chemical synthesis
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Reisman, Sarah E.
Thesis Committee:
  • Fu, Gregory C. (chair)
  • Gray, Harry B.
  • Stoltz, Brian M.
  • Reisman, Sarah E.
Defense Date:1 June 2016
Funding AgencyGrant Number
NSF Graduate Research FellowshipDGE-1144469
Record Number:CaltechTHESIS:06082016-142725994
Persistent URL:
Chuang, Kangway V.0000-0002-0652-8071
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:9865
Deposited By: Kangway Chuang
Deposited On:08 Mar 2017 19:19
Last Modified:04 Oct 2019 00:14

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