Multigram Scale Synthesis and Anti-Influenza Activity of 3-Indoleacetonitrile Glucosides

Abstract

Indole-3-acetonitrile-6- O-β-d-glucopyranoside 1 is a simple alkaloid with anti-influenza A virus activity extracted from Radix isatidis. Herein, a concise and practical total synthetic route of 1 was presented, starting from 6-benzyloxyindole on a multigram scale. The pivotal reaction sequence involved the Mannich reaction, the fluoride ion-induced elimination-addition reaction, and phase-transfer-catalyzed glycosylation reaction as key steps. In addition, compounds 1 and two modified derivatives 8 and 16 were tested for anti-influenza efficacy and cytotoxicity in vitro performed on Madin-Darby canine kidney cells. The results revealed that the compounds exerted antiviral activity against the influenza A virus to a certain extent and displayed no cytotoxicity. These findings could contribute to the development of traditional Chinese medicine R. isatidis for treating the influenza virus.

A Method for the Synthesis of Thioindoles through Copper-Catalyzed C–S Bond Coupling Reaction

“…The synthetic route of isatindigotindoside IV was outlined in Scheme b. Using commercially available compound 11 as starting material, compound 15 was obtained in five steps according to a slightly improved method with a yield of 22% . The reaction of 15 with N -(thioglycoside)succinimide 10 was performed, and the desired product 16 was obtained in 51% yield after deprotection of the OAc group by NaOMe to provide isatindigotindoloside IV .…”

“…2-(4-(Benzyloxy)-1H-indol-3-yl)acetonitrile (12). 30 A solution of 4-(benzyloxy)-1H-indole 11 (245.6 mg, 1.1 mmol) in MeCN (5.0 mL) was added over 20 min to a suspension of N,Ndimethylmethyleneammonium iodide (244.3 mg, 1.32 mmol) in a mixture of MeCN/AcOH (5.0/2.5 mL) at room temperature. The solution was stirred for 5 min and monitored by TLC.…”

“…(2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-((3-(cyanomethyl)-1Hindol-4-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl Triacetate (15). 30 Compound 13 (60.3 mg, 0.35 mmol), 2,3,4,6-tetra-O-acetyl-α-Dglucopyranosyl bromide 14 (287.8 mg, 0.7 mmol), anhydrous K 2 CO 3 (338.6 mg, 2.45 mmol), tetrabutylammonium bromide (22.6 mg, 0.07 mmol), CHCl 3 (0.5 mL), and H 2 O (0.5 mL) were added in turn into a 25 mL glass reaction flask. The reaction mixture was stirred at room temperature for 4 h and monitored by TLC.…”