An efficient approach to angular tricyclic molecular architecture via Nazarov-like cyclization and double ring-expansion cascade

Abstract

A modular and efficient method for constructing angular tri-carbocyclic architectures containing quaternary carbon center(s) from 1,3-dicycloalkylidenyl ketones is established, which involves an unconventional synergistic cascade of a Nazarov cyclization and two ring expansions. It features high selectivity, mild conditions and convenient operation, wide scope and easy availability of substrate. Substitution with R1 and R2 at the 4πe-system with electron-donating group favors this reaction, while that with electron-withdrawing group or proton disfavors. The electron-donating group as R1 directs the initial ring expansion at its own site, while the p-π- or n-π- associated substituent as R2 favors selectively the later ring expansion near its location because of the beneficial maintenance of an original conjugated system. The stereoselectivity has proved to be governed by either the steric effect of R3 and R4 at the expanded rings, or the migration ability of the migrating atom. Density Functional Theory calculation suggests the initial Nazarov cyclization would be the rate-determining step. A racemic total synthesis of the natural (±)-waihoensene is realized in 18 steps by use of this methodology.

Finding activity through rigidity: syntheses of natural products containing tricyclic bridgehead carbon centers

“…To date, ve total syntheses of waihoensene (100) have been reported; each will be discussed here. [60][61][62][63][64] In 2017, Lee and co-workers disclosed a total synthesis of (±)-waihoensene (100) that employed a cycloaddition-fragmentation-cyclization cascade to construct the carbon skeleton (Scheme 14). 60 The allene 102 was prepared in twelve steps and 35% yield from the known ketoester (±)-101.…”

“…To date, five total syntheses of waihoensene ( 100 ) have been reported; each will be discussed here. 60–64…”

“…In 2022, Tu and co-workers reported a total synthesis of (±)-waihoensene ( 100 ) that employed a Nazarov cyclization and a double ring expansion cascade as key steps (Scheme 18). 64 The synthesis began with a Horner–Wadsworth–Emmons olefination of the silylated cyclobutanone (±)- 131 ( 132 , sodium hydride). Ester hydrolysis followed by a Dieckmann condensation (lithium hydroxide; oxalyl chloride; lithium diisopropylamide, methyl acetate) then furnished the β-ketoester 133 (82%, three steps).…”

“…The configuration of C5a was relayed to the C9a and C3a TBCCs. Both the Lee 60 and the Tu 64 syntheses took advantage of novel cyclization strategies to construct these centers. In the Lee synthesis, 60 a linear precursor 102 was first prepared.…”

Synthesis of Polycyclic n/5/8 and n/5/5/5 Skeletons Using Rhodium-Catalyzed [5 + 2 + 1] Cycloaddition of Exocyclic-ene-vinylcyclopropanes and Carbon Monoxide

“…If the above-mentioned idea of the synthesis of angular tricycles containing eight-membered carbocycles can be accomplished using exocyclic ene-vinylcyclopropanes, we then envisioned that the cycloadducts from the [5 + 2 + 1] reactions could also be converted to 5/5/5/5 and 6/5/5/5 tetracyclic skeletons (Scheme b), some of which are found in natural products shown in Figure d . Importantly, these natural products have significant biological activities (listed also in Figure d) and have attracted intensive attention from many leading total synthetic chemists . Therefore, the synthesis of these multicyclic rings by the present strategy would provide new and step-economic ways to access related natural products and analogues, which could then be beneficial for future drug discovery.…”