Stereocontrolled Radical Bicyclizations of Oxygenated Precursors Enable Short Syntheses of Oxidized Abietane Diterpenoids

Abstract

The power of cation-initiated cyclizations of polyenes for the synthesis of polycyclic terpenoids cannot be overstated. However, a major limitation is the intolerance of many relevant reaction conditions toward the inclusion in the substrate of polar functionality, particularly in unprotected form. Radical polycyclizations are important alternatives to bioinspired cationic variants, in part owing to the range of possible initiation strategies, and in part for the functional group tolerance of radical reactions. In this article, we demonstrate that Co-catalyzed MHAT-initiated radical bicyclizations are not only tolerant of oxidation at virtually every position in the substrate, oftentimes in unprotected form, but these functional groups can also contribute to high levels of stereochemical control in these complexity-generating transformations. Specifically, we show the effects of protected or unprotected hydroxy groups at six different positions and their impact on stereoselectivity. Further, we show how multiply oxidized substrates perform in these reactions, and finally, we document the utility of these reactions in the synthesis of three aromatic abietane diterpenoids.

Total Synthesis of Natural Terpenoids Enabled by Cobalt Catalysis

“…As shown in Figure 2E-VII , Vanderwal ( Vrubliauskas et al, 2021 ) systematically studied that Co-catalyzed MHAT-initiated (metal-catalyzed hydrogen atom transfer, MHAT) radical bicyclization was uniquely effective in synthesizing polycyclic terpenoids from polyene. The authors researched the utility of these reactions in synthesizing three aromatic abietane diterpenoids.…”

Cyclization Strategies for the Concurrent Installation of Multiple Quaternary Stereogenic Centers

“…Exotic variants of biomimetic polycyclizations that proceed via radical intermediates have been known for decades [28–30] . Very recently, innovative new methods to generate such radicals have also garnered attention [31] . One such example, applied to this problem of multiple QSC installation during the polycyclization, was illustrated in the 2010 study by MacMillan and coworkers [32] .…”

Stereocontrolled Synthesis and Structural Revision of Plebeianiol A

“…Our group recently disclosed the total syntheses of related oxidized abietane diterpenoids via cobalt-catalyzed hydrogen-atom-transfer-induced radical bicyclizations that were inspired by cationic biogenetic cyclizations known to produce abietanes and related diterpenoids . We surmised that we could avail ourselves of a similar approach to access the proposed revised structure of plebeianiol A ( 5 ) and in doing so correct its structure.…”

“…On the basis of our previous work, we aimed to use the cobalt-catalyzed, MHAT-induced bicyclization to access the tricyclic core of 5 and 6 (Scheme ). The corresponding polyene precursor 8 would arise from suitably protected fragments 9 and 10 via Horner–Wadsworth–Emmons alkenylation. The key architecture-building bicyclization event would feature a more oxidized A-ring than that in any of our previous studies.…”

“…One potential advantage of this protecting group is the rigid chairlike configuration that might help enforce a reactive conformation for cyclization, and we therefore initially chose it over the more-often-used acetonide. Additionally, previous work had indicated that whereas unprotected carbinols are tolerated under the cyclization conditions, free alcohols at C3 were associated with only moderate levels of diastereoselectivity (∼3:1), and we were thus unable to predict the outcome of a free C2/C3 diol. To probe this question, we prepared slightly simpler model substrates 21a – c (Figure ) containing a dimethyl resorcinol terminating group in place of the protected catechol needed for the total synthesis.…”