Total Synthesis and Structure Revision of (−)-Illisimonin A, a Neuroprotective Sesquiterpenoid from the Fruits of Illicium simonsii

Abstract

Illisimonin A was isolated from Illicium simonsii and has a previously unreported tricyclic carbon framework. It displayed neuroprotective effects against oxygen-glucose deprivation-induced cell injury in SH-SY5Y cells. It incorporates a highly strained trans-pentalene ring system. We report the first synthesis of (±)-illisimonin A. Notable steps in the route include a 1,3-dioxa-2-silacyclohexene templated Diels–Alder cycloaddition and type-3 semipinacol rearrangement to generate the trans-pentalene. The final step is an iron-catalyzed C–H oxidation. The synthetic route is robust, with 94 mg of racemic material prepared in a single pass. Resolving an intermediate enabled the synthesis of natural (−)-illisimonin A. The absolute configuration of (−)-illisimonin A was revised to 1S,4S,5S,6S,7R,9R,10R based on the X-ray structure of a heavy-atom analogue.

Synthesis of bridged tricyclo[5.2.1.01,5]decanes via nickel-catalyzed asymmetric domino cyclization of enynones

“…Despite their importance, the bridged tricyclo[5.2.1.0 1,5 ] decane remain an elusive skeleton, and the development of which has been clearly underexploited [5][6][7] . Only recently, Rychnovsky's group reported the first total synthesis of Illisimonin A, in which the key tricyclic core was constructed by Diels-Alder reaction, and enantioselective control of this transformation has not yet been achieved 8 . The limited output for these challenging molecules may be due to the difficulty in asymmetric synthesis of the bridged tricyclo[5.2.1.0 1,5 ]decane core [9][10][11][12] , which hinders any further study on their potential bioactive properties.…”

Contiguous Quaternary Carbons: A Selection of Total Syntheses

“…In mid-2019, less than two years after the reported isolation and structure elucidation [ 18 ], Rychnovsky and Burns published the first total synthesis of the pentacyclic sesquiterpene illisimonin A ( 72 ) [ 8 ].…”

“…Retrosynthetically, Rychnovsky and Burns’ first key transformation is the disconnection of the central gamma-lactone, which they planned to form via a carboxylic acid-directed C-H oxidation of CH-4. They stated that the “gamble” [ 8 ] to implement this transformation at such a late stage in the synthesis was motivated by Synder’s scaparvin B-D syntheses and Maimone’s pseudoanisatin synthesis in which a comparably congested methine group was selectively oxidized using White and Chen’s method [ 8 , 22 , 23 ]. Disconnection of the ketol ring to the corresponding ketone and protected alcohol reduced the natural product to precursor 74 , featuring its complete carbon backbone ( Scheme 15 ) [ 8 ].…”

“…In their thorough analysis of ring connectivity, Rychnovsky and Burns reported that the tricyclo[5.2.1.0 1,5 ]decane carbon-framework, as present in the natural product, features a trans -fused pentalane substructure ( 74′ , Scheme 15 b), which is thought to burden the ring system with a significant amount of strain. In contrast, the stereoisomeric tricyclodecane 75′ containing a cis -fused pentalane substructure has been shown to be significantly less strained [ 8 , 24 ].…”

“…Finally, a total synthesis of musabalbisiane A, mentioned in Hanessian and Overman’s review, is still not published [ 1 ]. Furthermore, this review covers a recent synthesis of (±)-11- O -debenzoyltashironin ( 55 ) by Wang and coworkers [ 7 ] and the first synthesis of illisimonin A ( 72 ) published by Rychnovsky and Burns [ 8 ].…”