Tetracyclic Diterpenoid Synthesis Facilitated by ODI-Cascade Approaches to Bicyclo[3.2.1]octane Skeletons

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Tetracyclic diterpenoids (C 20 ) mainly refer to the plant terpenoids bearing biogenetically related carbon skeletons derived from copalyl diphosphates (ent-CPP and syn-CPP). This large family contains over 1600 known members that can be categorized into 11 major structural types. Among them, more than three-quarters share a bridged bicyclo[3.2.1]octane subunit, which is also an important branching point in biosynthesis en route to the other types of bicyclic scaffolds, such as bicyclo[2.2.2]-, bicyclo[3.3.0]-, and tricyclo[3.2.1.0]octanes. Combined with the significance of its stereochemical importance in biological activity, the assembly of the bicyclo[3.2.1]octane skeletons is critical to the success of the whole synthesis blueprint toward tetracyclic diterpenoids. Although a number of inspiring methodologies have been disclosed, general approaches by the incorporation of innovative cascade reactions permitting access to diverse structural types of tetracyclic diterpenoids remain limited and in urgent demand. Because of the long-standing interest in the synthesis of bridged diterpenoids, we have recently developed two complementary types of oxidative dearomatization induced (ODI) cascade approaches to the rapid and efficient construction of bicyclo[3.2.1]octane skeletons. In this Account, we summarize our original synthesis design, methodology development, and the application of these two strategies in tetracyclic diterpenoid synthesis during the past few years in our laboratory. First, we detail our preliminary investigation of the ODI-[5 + 2] cycloaddition/pinacol rearrangement cascade reaction, which showed a wide scope of vinylphenol substrates and led to cyclopentane and cyclohexane-fused bicyclo[3.2.1]octanes in good yields with excellent dr values. Next, we describe the utilization of this ODI-[5 + 2] cascade reaction which resulted in the asymmetric total syntheses of four highly oxygenated ent-kauranoids. The strategy concerning accurate stereochemical control in the ODI-[5 + 2] cycloaddition was then successfully transplanted to the total syntheses of three stemaranoids, thus providing a straightforward and diastereoselective route to C9-ethano-bridged tetracyclic diterpenoids. To access more complex diterpenoid rhodomollanol A, we exploited two additional biomimetic rearrangements, namely, the retro-Dieckmann fragmentation/vinylogous Dieckmann cyclization cascade and the photo-Nazarov cyclization/intramolecular cycloetherification cascade. Taken together with the ODI-[5 + 2] cascade, the asymmetric total synthesis of the target molecule was realized, which shed light on the biogenetic pathway of the unprecedented rhodomollane-type carbon framework. Finally, we describe an ODI-Diels−Alder/Beckwith−Dowd cascade approach as a valuable supplement to the ODI-[5 + 2] cascade for the fabrication of cycloheptane-fused bicyclo[3.2.1]octane skeletons.Its versatility was also demonstrated by the total syntheses of two challenging grayanane diterpenoids. In view...

Divergent Total Syntheses of (−)-Crinipellins Facilitated by a HAT-Initiated Dowd–Beckwith Rearrangement

“…9 We envisioned that the steric encumbrance surrounding the tertiary carbon-centered radical at C10 in 9 might retard the rate of premature reduction, thus permitting reversible formation of the exocyclic β-keto radical 7 (7.7 kcal/mol more stable than 9 by DFT calculations) with the release of ring strain. In connection with our previous studies, 10 the construction of 10 containing two quaternary carbons at C7 and C11 could be traced back to vinylphenol 11 through an oxidative dearomatization-induced (ODI) [5+2] cycloaddition/pinacol rearrangement cascade. However, we were uncertain of the feasibility, especially the inherent diastereocontrol of this transformation when it employs a more complicated conjugate dienone functionality.…”

“…10,20 -alkene of 5/5/6/5 tetracycle 10 generates 9, which would undergo subsequent Dowd−Beckwith rearrange-…”

Total Synthesis of the Alleged Structure of (+)-Fimbricalyxoid A

“…Polycyclic diterpenoids, widely distributed among a variety of medicinal plants, constitute a large family of structurally fascinating natural products with remarkable biological activities . The intriguing structural complexity and potential bioactivities of diterpenoids have long attracted a great deal of attention from synthetic chemists . However, due to the lack of efficient methods, enantioselective total synthesis of these complex diterpenoids, especially those bearing all-carbon quaternary stereocenters, remains a formidable challenge in organic synthesis .…”

Reductive Radical Annulation Strategy toward Bicyclo[3.2.1]octanes: Synthesis of ent-Kaurane and Beyerane Diterpenoids

“…There are more than 1600 known tetracyclic diterpenoid natural products, more than three-quarters of which possess a bicyclo[3.2.1]­octane moiety, including, for example, the well-known ent -kauranoids, gibberellins, and grayananoids (Scheme A). Studies over many decades have demonstrated a broad spectrum of bioactivities for these diterpenoids (e.g., antitumor, antibacterial) .…”

“…6,7 The recent admirable achievements of the Ding group have helped address this challenge by using oxidative dearomatization-induced cycloaddition/1,2-migration cascades. 1,8 Nonetheless, the development of more straightforward approaches toward the construction of bicyclo[3.2.1]octane scaffolds and especially approaches that are applicable for the synthesis of structurally diverse tetracyclic diterpenoids is still in high demand to accelerate syntheses in support of biomedical investigations. Herein we report a collective synthesis of entkaurane-and beyerane-type diterpenoids using a [3 + 2] radical annulation strategy that can directly install the bridged D rings onto the easily accessible fused A/B/C ring systems.…”