Total Synthesis of Astellatol

Abstract

A nearly-30-year-old unanswered synthetic puzzle, astellatol, has been solved in an enantiospecific manner. The highly congested pentacyclic skeleton of this rare sesterterpenoid, which possesses a unique bicyclo[4.1.1]octane motif, ten stereocenters, a cyclobutane that contains two quaternary centers, an exo-methylene group, and a sterically encumbered isopropyl trans-hydrindane motif, makes astellatol arguably one of the most challenging targets for sesterterpenoid synthesis. An intramolecular Pauson-Khand reaction was exploited to construct the right-hand side scaffold of this sesterterpenoid. An unprecedented reductive radical 1,6-addition, mediated by SmI , forged the cyclobutane motif. Last, a strategic oxidation/reduction step provided not only the decisive solution for the remarkably challenging late-stage transformations, but also a highly valuable unravelling of the notorious issue of trans-hydrindane synthesis. Importantly, the synthesis of astellatol showcases a rapid, scalable strategy to access diverse complex isopropyl trans-hydrindane sesterterpenoids.

A Concise Total Synthesis of (−)‐Himalensine A

“…[7c-e] Thet riethylsilyl group was cleaved concomitantly.I nterestingly,w hen this reaction was scaled up to 150 mg or higher scale,the diastereoselectivity was somehow decreased (5:1). Other hydrogenation attempts,u sing for example,C rabtreesc atalyst [24] or Wilkinsonsc atalyst, [25] resulted in either undesirable diastereoselectivity or no reaction. Subsequent addition of 2-hydroxy-2-azaadamantane (AZADOL) and (diacetoxyiodo)benzene( PIDA) to the reaction mixture led to ao ne-pot oxidation, affording enone 18 in 82 %y ield.…”

Metathesis Reactions in Natural Product Fragments and Total Syntheses

“…Xu and co‐workers reported the first enantiospecific total synthesis of astellatol 273 (Scheme 28), [207] a fascinating sesterterpenoid with sterically congested trans ‐hydrindane framework, extracted from Aspergillus stellatus . Biological properties of astellatol are still undisclosed and only limited synthetic studies have been reported by Xu [208] and Trauner's [209] groups.…”

Application of Pauson–Khand reaction in the total synthesis of terpenes

“…As a result, the total synthesis of the rare sesterterpenoid, astellatol 544, was achieved in twenty-ve steps and 0.63% overall yield starting from chiral synthon 524 (Scheme 42). 366,371 A concise and asymmetric total synthesis of A-ring component of nitiol 559 including diastereoselective Pauson-Khand cycloaddition was reported by Dake in 2001. 372 It was actually an attempt towards the total synthesis of the natural product, nitiol 558.…”

“… 365 In 2018, Xu et al also accomplished 536 (ref. 366 ) and reported a brief and asymmetric synthesis of astellatol 544. That was including a SmI 2 -catalyzed reductive radical 1,4-addition.…”

“…As a result, the total synthesis of the rare sesterterpenoid, astellatol 544, was achieved in twenty-five steps and 0.63% overall yield starting from chiral synthon 524 ( Scheme 42 ). 366,371 …”