Total Synthesis and Anti-Tobacco Mosaic Virus Activity of the Furofuran Lignan (±)-Phrymarolin II and Its Analogues

Abstract

Phrymarolin II, a furofuran lignan isolated from Phryma leptostachya L., features a 3,7-dioxabicyclo[3.3.0]octane skeleton. Herein, we report an alternative total synthesis of (±)-phrymarolin II (2), which was performed in 9 steps from commercially available sesamol. The key steps of the synthesis included a zinc-mediated Barbier-type allylation and a coppercatalyzed anomeric O-arylation. Our total synthesis allowed the synthesis of analogues of (±)-phrymarolin II. Most derivatives displayed good to excellent in vivo activity against tobacco mosaic virus (TMV). (±)-Phrymarolin II (2) and compounds (±)-31d and (±)-31g exhibited similar or higher activity than commercial ningnanmycin, which indicated that phrymarolin lignans are a promising new class of plant virus inhibitors.

Furofuran Lignans for Plant Protection: Discovery of Sesamolin and Its Derivatives as Novel Anti-Tobacco Mosaic Virus and Antibacterial Agents

“…Then, treatment of the triol ( 3a or 3b ) with catalytic d -camphorsulfonic acid (CSA) provided the corresponding alkene ( 4a or 4b ) as a single diastereomer. This phenomenon could be explained by an initial protonation of benzylic alcohol and formation of a carbonium ion reaction intermediate. , With the alkenes 4a and 4b in hand, the oxidative cleavage of the terminal alkene with KMnO 4 and H 5 IO 6 in isopropanol/H 2 O afforded the lactols A0 and B0 ( dr > 19:1). Using Cu­(OAc) 2 as the catalyst, the Chan–Lam–Evans cross-coupling reactions of lactol A0 or B0 with varieties of arylboronic acid provided compounds A1 – A31 and B1 – B4 in 43–80% yields.…”

“…Overall, the sesamolin and its derivatives were synthesized in 4–5 steps and high yields from the substituted benzaldehydes and β-vinyl-γ-butyrolactone. Due to the simplified structure of the target compounds, this newly developed synthetic approach is more concise and efficient than that of the lead compound (±)-phrymarolin II . The structures of all synthesized compounds were identified using NMR ( 1 H, 13 C) and HRMS and can be found in the Supporting Information.…”

“…38,39 General Synthetic Procedure of Compounds A1−A31 and B1−B4. According to the literature method, 29,40 to a dried flask were added sequentially activated 4 Å molecular sieves (600 mg), Cu(OAc) 2 (1.5 mmol, 1.5 equiv), 4-dimethylaminopyridine (DMAP, 2.0 mmol, 2.0 equiv), and DCM (15 mL), and the reaction mixture was stirred for 5 min. Then, arylboronic acid (3.0 mmol, 3.0 equiv) was added, and the mixture was further stirred for 5 min.…”

“…26,28 To discover its full potential, recently we developed a concise total synthesis of (±)-phrymarolin II from commercial sesamol. 29 Bioactivity evaluation revealed that (±)-phrymarolin II displayed good anti-TMV activity. However, there are still some shortages in the present synthetic strategy; particularly, long steps were required to introduce the acetoxy group (−OAc) at the C-1 position in the 3,7-dioxabicyclo[3.3.0]octane core structure.…”

Discovery of Novel α-Methylene-γ-Butyrolactone Derivatives Containing Vanillin Moieties as Antiviral and Antifungal Agents

“…Natural products play a significant role in the development of green pesticides with novel structure and unique mechanism of action. − In recent decades, several natural product-based antiviral agents, such as dufulin, NK-007, and xiangcaoliusuobingmi, (Figure ) have been developed. In addition, many natural products or their analogues, such as (tetrahydro)­harmine, , coumarin, phenols, gossypols, flavonoids, limonoids, , and lignans, − have also been found to possess significant antiviral activities.…”