De novo Assembly of the Benzenoid Ring as a Core Strategy for Synthesis of the Isoindolinone Natural Products Isohericerin, Erinacerin A, and Sterenin A

Abstract

Here we describe the use of the hexadehydro-Diels–Alder (HDDA) reaction for the de novo construction of the isoindolinone scaffold and its application to the synthesis of the title natural products. The key isoindolinone-forming HDDA reaction involved an unprecedented substrate motif in which an amide carbonyl group was conjugated to the 4π 1,3-diyne component. In addition, a dimethylsilyl (−SiMe2H) substituent was exploited to trigger a Fleming–Tamao–Kumada oxidation for the installation of an essential phenolic hydroxyl group.

Total Synthesis of Isohericerinol A and Its Analogues to Access Their Potential Neurotrophic Effects

“…The crude product was purified by silica gel column chromatography (Hex/EtOAc = 3/1) to obtain 6 (1.34 g, 87%) as a white solid. 1 [1,3]oxazine-5-carboxylate (13, 3.21 g, 9.82 mmol) was taken in 10 ml EtOH at room temperature. Then, HCl was added dropwise to the reaction mixture to bring the pH at 2−3.…”

“…1 H NMR (400 MHz, CDCl 3 ): δ 7.27 (d, J = 7.3 Hz, 2H), 7.25−7.20 (m, 3H), 7.14 (s, 1H), 5.97−5.87 (m, 1H), 4.99 (s, 2H), 4.97 (d, J = 1.7 Hz, 1H), 4.94 (dt, J = 7.1, 1.8 Hz, 1H), 4.24 (s, 2H), 3.87 (s, 3H), 3.83 (d, J = 7.4 Hz, 2H), 3.47 (s, 3H), 3.45 (t, J = 1.8 Hz, 2H), 2.98 (t, J = 7.3 Hz, 2H). ; 13 [1,3]oxazine-5-carboxylate (13). To a solution of methyl 3-hydroxy-5methoxybenzoate (9b, 4.0 g, 21.98 mmol) in MeOH (10 mL), phenylethylamine (4.0 mL, 33.03 mmol) and 30% formaldehyde solution (4.0 mL) was added dropwise at room temperature.…”

“…Hericium erinaceus, an edible mushroom belonging to the Hericiaceae family, is broadly found in East Asian countries. It is widely used in traditional medicines for the treatment of gastrointestinal diseases, dyspepsia, and enervation. − Natural products isolated from the fruiting body of the mushroom constitutes diverse chemical constituents such as diterpenoids, alkaloids, sterols, polysaccharides, aromatic compounds, and so forth. − In particular, isohericenone, , hericenones, − erinacerine, − corallocins, − and isohericerin , (Figure ) exhibit a broad spectrum of biological activities such as anti-cancer, anti-hypertensive, hypolipidemic, and neuronal disease protecting activities. ,− The isolated metabolites of H. erinaceus have diversity on chemical structures and biological activities, making these metabolites attractive targets for synthetic and medicinal chemists.…”

Total Synthesis of Geranyl-Resorcinols Isolated from Mushrooms of Genus Hericium

“…In 2021, Hoye and co-workers reported a unique approach to the isoindolinone framework of Type 3 and Type 4 geranyl-resorcinols from an acyclic amide-triyne intermediate utilizing a hexadehydro-Diels-Alder reaction (Scheme 12). 75 Their synthesis began with introduction of the alkyne part to geranyl bromide (121) by a Grignard reaction. The resulting dienyne 157 was subjected to a Cadiot-Chodkiewicz cross-coupling reaction with 3-bromoprop-2-yn-1-ol (158) to provide the conjugated diyne 159.…”

Bioinspired Total Synthesis of Bipolarolides A and B

“…The singlet-oxygen ene reaction of 44 by using methylene blue followed by Babler-Dauben oxidation gave enone 45. [31] Finally, removal of the TBS group in 45 with TBAF provided bipolarolide A (1). All analytical data ( 1 H NMR, 13 C NMR, HRMS, IR and a ½ � 25:0 D ) of the synthesized 1 and 2 matched with that reported for the natural products.…”