Total Synthesis of Dysifragilones A and B and Dysidavarone C

Abstract

The concise synthesis of dysifragilones A and B and dysidavarones has been accomplished for the first time in a divergent way from a common intermediate. The synthetic route features an intramolecular reductive Heck reaction to construct the 6/5/6/6/-tetracycle of dysifragilones A and B and an intramolecular palladium-catalyzed α-arylation of a sterically hindered ketone to forge the tetracyclo­[7.7.1.02,7.010,15]­heptadecane core structure of dysidavarone C. The late-stage introduction of amino and ethoxy groups is effective.

Modular total syntheses of trans-clerodanes and sesquiterpene (hydro)quinones via tail-to-head cyclization and reductive coupling strategies

“…1a ) feature the same trans -decalin core structure ( 1 or ent - 1 , Fig. 1a ) 4 – 26 . It suggests that these might have a similar biosynthetic pathway in Nature.…”

Marine natural products

“…484 Two separate groups have reported the total synthesis of various oxo-aplysinopsin alkaloids. 485,486 Other compounds that have been synthesised include hyrtioseragamine A, 487 7-hydroxylamellarin A, 488 and ma'edamines C and D. 489 Three Dysidea-derived merosesquiterpenoids have been synthesised, 490 while three groups have independently revised the structure of dysiherbol A to 1167; the latter two groups also report the total synthesis of dysideanone B. [491][492][493] The structure of halioxepine 1168 has also been revised following its synthesis, 494 while the structures of diterpenoid metabolites cyclobutastellettolide B and hamigeran M have been conrmed following their rst total syntheses.…”

Practical and Scalable Total Syntheses of (+)-Dysidavarones A–C

“…Subsequent Dess-Martin periodinane (DMP) oxidation of the hydroxy functionality rendered tetracyclic diketone 13 in 84% yield. While Wittig methylenation of the tetracyclic diketone 13 proceeded smoothly (92%), the direct oxidation of the resulting product 14 with CrO3 or other tested oxidating reagents only gave around 35% yield of (+)-dysidavarone "E" (5). This problem was solved by first removal of the O5' ethyl group with n-BuSLi, 15 after which oxidation of the resulting phenol with O2 and salcomine afforded (+)-dysidavarone "E" (5) in 75% overall yield over the two steps.…”

“…3 In 2016 and 2021, the groups of Shen and Qin achieved total syntheses of dysidavarones A and C (1 and 3) by using the same strategy as Menche, but with different benzylic bromides. 4,5 In 2022, Yang and co-workers developed a tail-to-head cyclization strategy for the synthesis of the trans-decalin unit, introducing the side-chain by nickel-catalyzed reductive coupling, to achieve divergent total syntheses of dysidavarones A-C. 6 In 2023, we also completed divergent total syntheses of dysidavarones A-C by a one-pot intermolecular diastereoselective alkylation and intramolecular arylation reaction of a Wieland-Miescher ketone derivative without the protection of the C4 carbonyl group and a benzylic bromide to establish the central bridged bicyclo[3.3.1]nonane ring and a late-stage introduction of the ethyl group onto the key common intermediate predysidavarone. 7 However, the synthetic routes of Menche, Katoh, Shen, and Qin all involved a steric-hindrance-sensitive reductive alkylation reaction of a Wieland-Miescher ketone derivative in liquid ammonia.…”

“…[3] In 2016 and 2021, Shen and Qin's groups achieved the total synthesis of dysidavarones A and C (1 and 3) using the same strategy as Menche's with different benzyl bromides. [4,5] In 2022, Yang and co-workers developed a tail-to-head cyclization strategy for the synthesis of the trans-decalin unit, introduced the side chain by nickel-catalyzed reductive coupling, and achieved the divergent total synthesis of dysidavarones A-C. [6] In 2023, we also completed the divergent total synthesis dysidavarones A-C by a one-pot intermolecular diastereoselective alkylation and intramolecular arylation reaction of a Wieland-Miescher ketone This article is protected by copyright. All rights reserved.…”