Studies on C20-diterpenoid alkaloids: synthesis of the hetidine framework and its application to the synthesis of dihydronavirine and the atisine skeleton.

The full details of a synthesis of the hetidine framework of the C20-diterpenoid alkaloids and its conversion to the atisine core structure are reported. The application of the hetidine framework to the synthesis of dihydronavirine, which is the formal reduction product of the natural product navirine, is also described. Key to the success of these studies is the use of a Ga(III)-catalyzed cycloisomerization reaction of alkynylindenes to prepare a [6-7-6] framework that was advanced to the hetidine skeleton. Furthermore, a Michael/aldol sequence was developed for the construction of the bicyclo[2.2.2] framework that is characteristic of the hetidines and atisines.

Synthetic strategies toward hetidine and hetisine-type diterpenoid alkaloids.

Within the diterpenoid alkaloid family of natural products, the hetidine and hetisine structural types have been the targets of a number of synthetic studies. Various strategies have been pursued to access the azacyclic moiety of these natural products as well as the characteristic [2.2.2] bicyclic structural motif. This perspective article examines the different disconnections and approaches that have been applied to the synthesis of these natural products to date.

Synthetic studies on the icetexones: enantioselective formal syntheses of icetexone and epi-icetexone.

Two strategies for the synthesis of the icetexane diterpenoids icetexone and epi-icetexone that rely on Ga(III)-catalyzed cycloisomerization of alkynyl indene substrates to yield fused [6-7-6] tricycles have been explored. In the first approach, access to a tricycle bearing a gem-dimethyl group paved the way for explorations of C-H functionalization of one of the methyl groups in close proximity to a hydroxyl-directing group. This approach was ultimately unsuccessful and led only to ring cleaved products. In the second approach, an alkynyl indene substrate bearing a cyano substituent was utilized, which was effective in providing a functional handle to access the icetexone subclass of diterpenoids. A key epoxide opening/diazene rearrangement sequence was utilized to complete a formal synthesis of icetexone and epi-icetexone, which is discussed in detail. Furthermore, the cyano-containing substrate has been prepared in enantioenriched form using a Rh-catalyzed conjugate addition reaction, which now provides a route to the enantioselective synthesis of these natural products.