Ready access to seven-membered rings systems will facilitate the synthesis of biologically important compounds possessing this ring system. Three carbocyclic cores of three targets, thapsigargin, grayanotoxin III and guanacastepene J, will be synthesized to demonstrate the synthetic utility, efficiency, and flexibility of the allenic cyclocarbonylation reaction. Realization of the goals of this proposal will provide a more general understanding of allenes and transition-metal catalyzed cyclocarbonylation reactions. Moreover, the long-term goals of this project are the application of this strategy to the total synthesis of thapsigargin, guanacastepene J and grayanotoxin III that will feature access to novel intermediates and analogs enabling new biological studies. The long-term goals are not within the scope of this proposal.
The specific aims of this proposal include: 1) Extending the scope of the allenic Pauson-Khand reaction to include more densely functionalized precursors including, but not limited to allenol esters. Cyclocarbonylation of allenol esters provides rapid access to ?-acetoxy cyclopentadienones. The rapid isomerization of allenol acetates under the Rh(I)-catalyzed conditions will be explored for the enantioselective preparation of ?-acetoxy cyclopentadienones using dynamic kinetic asymmetric transformation (DYKAT). 2) Synthesizing the carbocyclic framework of thapsigargin using the Pauson-Khand reaction of an allenol ester. Thapsigargin is a highly oxygenated carbocycle that is particularly well suited for this method that features well-timed introductions of oxygen functionality limiting the number of protection and deprotection steps. Moreover, the DYKAT protocol developed in Aim 1 will be exploited as a potential means of achieving a diastereoselective allenic Pauson-Khand reaction. Thapsigargin posseses interesting biological activity functioning as a subnanomolar inhibitor of sarcoplasmic and endoplasmic reticulum Ca+2 ATPase (SERCA). 3) Synthesizing the carbocyclic core of guanacastepene J, a member of the guanacastepene family, but a compound in which the biological activity has not been established due to very limited quantities. The synthesis features an allenic Pauson- Khand reaction using an unusual ?-allenylidene butenolide. 4) Synthesizing the carbocyclic core of grayanotoxin III via a route that features a highly functionalized allene-yne precursor to generate a molecularly complex skeleton. Grayanotoxin is an important molecular tool for deciphering the mechanism for gating functions of the sodium ion channels.
Efficient and flexible ways to synthesize compounds are important to the drug discovery process and ultimately, medical discoveries. Synthetic methods developed in our research program provide access to substructures not previously available using known protocols and are complementary to approaches to substructures previously synthesized. Particularly relevant to this proposal is use of the allenic Pauson-Khand reaction to prepare seven-membered rings.
