Total Synthesis of (±)-Fasicularin through Double Consecutive Epimerizations

Abstract

The total synthesis of tricyclic marine alkaloid fasicularin (1b) has been accomplished from a novel sterically well-defined α-aminonitrile 7, featuring a novel double consecutive epimerization process and Ir-catalyzed reductive functionalization of a tertiary γ-lactam. The required configuration is obtained through the thermodynamically stereoselectively driven isomerization of a readily available 8a-cyanodecahydroquinoline framework. The strategy allows us to achieve the tricyclic core structures efficiently from affordable starting materials through simple operations.

Discovery and Mechanism Study of SARS-CoV-2 3C-like Protease Inhibitors with a New Reactive Group

“…Compound 18 has been described as an intracellular covalent ligand for CCR2 (CC Chemokine Receptor 2), which has been investigated as a potential drug target in inflammation and immuno-oncology . Compound 19 (fasicularin), a thiocyanate-containing natural product, was found to be selectively active against an organism with DNA repair deficiencies. , Several compounds structurally related to compound 20 (4-phenoxyphenoxyethyl thiocyanate) were investigated as inhibitors of Trypanosoma cruzi, which is responsible for American trypanosomiasis. − We retested the inhibitory activity of compounds 3a and 3h on 3CL pro in the presence of 1 mM GSH, and the results showed that the introduction of reducing agents significantly reduced the inhibitory activity of the compound (Table S9). However, this does not indicate a nonspecific binding between the compounds and 3CL pro , as disruption of the disulfide bond can lead to similar results.…”

“…66 Compound 19 (fasicularin), a thiocyanate-containing natural product, was found to be selectively active against an organism with DNA repair deficiencies. 92,93 Several compounds structurally related to compound 20 (4-phenoxyphenoxyethyl thiocyanate) were investigated as inhibitors of Trypanosoma cruzi, which is responsible for American trypanosomiasis. 99−101 We retested the inhibitory activity of compounds 3a and 3h on 3CL pro in the presence of 1 mM GSH, and the results showed that the introduction of reducing agents significantly reduced the inhibitory activity of the compound (Table S9).…”

“…In addition to being used in clinics, there are a number of thiocyanate groups are being explored in the different stages of the drug development process, e.g., antitumor, ,,− anti-HIV, antimicrobial, − and antiparasitic − activities of thiocyanate-containing compounds. Several thiocyanate-containing compounds are shown in Figure S8.…”

Collective Asymmetric Total Synthesis of Cylindricines

“…7 A number of asymmetric and racemic total syntheses of cylindricines, fasicularin, and lepadiformines have been described to date. 8 Nonetheless, the synthetic development and biological evaluation of a collection of marine tricyclic alkaloids are yet to be achieved. Moreover, the biological activity of cylindricines has not been described so far except that a mixture of 1 and 2 was found to be toxic in a brine shrimp bioassay.…”