UC Berkeley

Abstract

Studies toward the Cyathane and Cyanthiwigin Diterpenes

by

Laura Carolyn Miller

Doctor of Philosophy in Chemistry

University of California, Berkeley

Professor Richmond Sarpong, Chair

The cyathanes and cyanthiwigins are a large family of natural products isolated from terrestrial and marine sources. The compounds share a [5-6-7] fused-ring structure, with two all-carbon quaternary centers at the ring junctions and a trans-B-C ring fusion. There is a variety of oxygenation and unsaturation patterns about the tricyclic skeleton, leading to a wide range of biological activity for the natural products, including antibiotic, anti-inflammatory, anticancer and neurotrophic indications. The exciting biological activity and unique structure of the cyathane diterpenoids has inspired much synthetic interest following the isolation of these natural products.

Rather than targeting a single cyathane diterpenoid, we planned to develop a general strategy to provide access to many of the natural products. We divided the cyathane family of natural products into two main categories, the cyanthiwigins and other cyathane diterpenes, on the basis of the syn- or anti-relationship of the angular methyl groups at the ring fusion positions. From a common dienol precursor derived from the Hajos-Parrish ketone, we successfully forged the cores of the cyanthiwigin and cyathane natural products through a divinylcyclopropane Cope rearrangement. We were also able to install the second all-carbon quaternary center through an atom-transfer method.

In a second-generation approach, we streamlined the strategy using a rhodium-mediated cyclopropanation of a central diene precursor to perform a cyclopropanation/Cope rearrangement cascade to form the tricyclic core of the cyanthiwigin and cyathane natural products. Using the Rh₂[DOSP]₄ catalysts, we were able to effect a resolution of the racemic diene, furnishing two enantioenriched diastereomeric tricycles that are applicable to the total syntheses of cyanthiwigin G and cyathin A₃.

Finally, we developed a strategy for the stereoselective installation of the second all-carbon quaternary center in the [3,3] sigmatropic rearrangement. This approach involves application of the cyclopropanation/Cope rearrangement cascade to a diene with the second methyl group in place prior to cyclopropanation, or incorporation of the requisite cyclopropyl derivative through a Suzuki coupling. Either method should provide a powerful strategy to stereoselectively install the second all-carbon quaternary center of the cyathane and cyanthiwigin natural products.