Studies on C₂₀-Diterpenoid Alkaloids: Synthesis of the Hetidine Framework and Its Application to the Synthesis of Dihydronavirine and the Atisine Skeleton

Abstract

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.

Magnesiate Addition/Ring-Expansion Strategy To Access the 6–7–6 Tricyclic Core of Hetisine-Type C20-Diterpenoid Alkaloids

“…6 Despite these initial successes, the synthesis of more highly oxygenated hetisine- type alkaloids remains elusive, and new strategies to access these secondary metabolites with suitable functional group handles are required. The synthesis of the related hetidine-type core, which lacks the N-C6 bond (Figure 1), has seen more recent success, with routes from our group 7 as well as the laboratories of Baran 8 and Qin. 9 While early work by Okamoto suggested a final N-C6 bond could be formed at a late stage through HLF-type chemistry, 10 this transformation has not been successfully realized by other investigators, suggesting the need for novel strategies that incorporate the formation of this N-C6 bond into the synthetic plan.…”

“…7 While this reaction proceeds in a high 89% yield, alkyne 7 takes 13 steps to synthesize (longest linear sequence), and the resulting tricycle is relatively unfunctionalized (Scheme 2). Several steps are then required to introduce key functional groups for both the C—N bond forming reactions and the [4 + 2] cycloaddition.…”

A Unified Approach for the Assembly of Atisine‐ and Hetidine‐type Diterpenoid Alkaloids: Total Syntheses of Azitine and the Proposed Structure of Navirine C

“…Considering the practical and divergent transformations of nitriles, we decided to undertake the retrosynthetic analysis as shown in Figure . Based on Sarpong's method to install the hordenine part, we envisioned that navirine C ( 2 ) could arise from the hetidine skeleton 8 , which could be generated by reductive cyclization of imine 10 . Another target molecule, azitine, could be assembled through functional group manipulation of imine 9 .…”

“…Deprotection of the ketal group in 32 provided ketone 33 in 72 % yield, whose structure was confirmed by X‐ray analysis of its HCl salt (see the Supporting Information). Finally, we incorporated the hordenine part according to Sarpong's procedures . Treatment of ketone 33 with LiHMDS and Comins’ reagent furnished the corresponding triflate, which underwent palladium‐catalyzed Stille coupling with (tributylstannyl)methanol to give the allylic alcohol 34 in a moderate yield.…”

Ongoing Pursuit of Diterpenoid Alkaloids: A Synthetic View

“…Concerning further pursuit of the natural product navirine (40), introduction of an endocyclica lkene and an imine was required. [45] Specifically,aseven-step procedure mainly involving Barton-McCombie radicald eoxygenation, [46] enol triflate formation and cross-coupling with tributylstannyl methanol, installation of the hordenine moiety,a nd cleavage of the cyclic carbamate led to dihydronavirine (47). The final task would be the forge of imine at C19p osition.…”