Synthesis of a Biomimetic Tetracyclic Precursor of Aspochalasins and Formal Synthesis of Trichoderone A

Abstract

Aspochalasins are leucine-derived cytochalasins. Their complexity is associated to a high degree of biosynthetic oxidation, herein inspiring a two-phase strategy in total synthesis. We thus describe the synthesis of a putative biomimetic tetracyclic intermediate. The constructive steps are an intramolecular Diels-Alder reaction to install the isoindolone core of cytochalasins, whose branched precursor was obtained from a stereoselective Ireland-Claisen rearrangement performed from a highly unsaturated substrate. This also constitutes a formal synthesis of trichoderone A.

Synthesis of cytochalasan analogues with aryl substituents at position 10

“…This journal is © The Royal Society of Chemistry 2024 Methyl (1S,3aR,4S,7S,7aR)-6,7-dimethyl-3-oxo-1-( phenanthren-9-ylmethyl)-4-(2-phenethoxyethyl)-1,2,3,4,7,7a-hexahydro-3aH-isoindole-3a-carboxylate (26). By following the general procedure, the cross-coupling reaction was carried out with Fe (acac) 3 (38 mg, 108 µmol), 19 (50 mg, 108 µmol) in dry THF…”

“…Since their discovery, chemists have been pursuing the total synthesis of cytochalasans due to their intricate structure, which poses a persistent challenge. [25][26][27][28][29] However, none of the total syntheses have involved the late-stage introduction of substituents into position 10, so far. Only a synthesis of cytochalasan analogues based on desymmetrization reactions of succinimide derivatives has been reported.…”

Sharpless Asymmetric Dihydroxylation: An Impressive Gadget for the Synthesis of Natural Products: A Review

“…Owing to their biologically active nature, efforts towards their total synthesis were inevitable. Gayraud et al [ 75 ] in 2021 reported the total synthesis of these cyclic cytochalasin natural products, i.e., aspochalasins, leading to the synthesis of trichoderone. Their synthetic approach included Sharpless asymmetric dihydroxylation, Ireland–Claisen rearrangement, Diels–Alder reaction and Suzuki–Miyaura cross-coupling reaction as the main steps.…”

Recent advances in the total synthesis of cytochalasan natural products using bioinspired strategies

“…By taking advantage of this biomimetic transformation, Nay and co-workers achieved the formal synthesis of trichoderone A through a “cyclase-oxidase” two-phase strategy in 2021 (Scheme 9). 23 In the “cyclase” phase, they synthesized the key tetracyclic intermediate 95 through an Ireland–Claisen rearrangement and an intramolecular Diels–Alder reaction.…”