A Concise Total Synthesis of Dictyodendrins F, H, and I Using Aryl Ynol Ethers as Key Building Blocks

Abstract

We report a concise total synthesis of dictyodendrin F and the first total syntheses of dictyodendrins H and I in six steps. In these syntheses, aryl ynol ethers were employed as the key building blocks to introduce aryl and heteroaryl rings in the dictyodendrins. This rapid synthesis utilized a novel hetero-[2+2]-cycloaddition reaction between two aryl ynol ethers to yield a cyclobutenone ring. The cyclobutenone was sequentially converted into a highly substituted carbazole via a retro-4π/6π-electrocyclization-N-acylation cascade reaction to provide the dictyodendrin core. Consecutive intramolecular oxidative coupling and deprotection gave dictyodendrins F, H, and I.

Total Synthesis of Dictyodendrins A–F by the Gold‐Catalyzed Cascade Cyclization of Conjugated Diyne with Pyrrole

“…In ar ecent report, Ready showedt hat dictyodendrinsF ,H ,a nd Id isplay cytotoxicity against severalh uman cancerc ell lines. [3] Interestingly,t he DNA cleavage activity of dictyodendrin derivatives is highly dependento nt he methylation level of the phenol moieties, as reported by Fürstner and co-workers. [4] As dictyodendrins F, H, and Ie xhibit inhibitory activity towards bsite amyloid-cleaving enzyme 1( BACE1), they are also recognized as potential lead compounds for the treatment of Alzheimer'sdisease.…”

“…[5] In 2005, the Fürstner group disclosed the first total syntheses of dictyodendrins B, C, E, and Ft hrough ac arefully designed stepwise constructiono ft he fused carbazole core (Scheme 1). [6,7] Subsequently,s everal total syntheses of dictyodendrinsh ave been established by the research groupso f Ishibashi (dictyodendrin B), [8,9] Tokuyama( A-E), [10,11] Jia (B, C, and E), [12,13] Gaunt (B), [14] Yamaguchi/Itami/Davies (A and F), [15] Ready (F,H ,a nd I), [3] andH e( F, G, H, and I). [16] Most reported syntheses used strategies based on introducing the requisite substituents prior to construction of the pyrrolo[2,3-c]carbazole core.…”

Total Synthesis of Dictyodendrins by the Gold‐Catalyzed Cascade Cyclization of Conjugated Diynes with Pyrroles

“…In 2005, the Fürstner group reported the first total synthesis of dictyodendrins B, C, E, and F through a carefully devised process involving the stepwise construction of the complex ring systems of these compounds . Subsequently, the research groups of Ishibashi, Tokuyama, Jia, Gaunt, Yamaguchi/Itami/Davies, and Ready disclosed total syntheses of these interesting natural products. A common feature of these strategies was the introduction of several optimally placed substituents prior to the construction of the pyrrolo[2,3‐ c ]carbazole core.…”

Total Synthesis of Dictyodendrins by the Gold‐Catalyzed Cascade Cyclization of Conjugated Diynes with Pyrroles

“…[1] These compounds belong to af amily of marine indole alkaloids and have been reported to inhibit the activity of telomerase,t hus making them potential anticancer agents.D ictyodendrins F-J were first isolated by Capon and co-workers in 2012 from the southern Australian marine sponge Ianthella sp.T hese compounds exhibited inhibitory activity towards b-site amyloidcleaving enzyme 1(BACE1), and are therefore recognized as potential targets for the treatment of Alzheimersd isease. [3] Subsequently, the research groups of Ishibashi, [4] Tokuyama, [5] Jia, [6] Gaunt, [7] Yamaguchi/Itami/Davies, [8] and Ready [9] disclosed total syntheses of these interesting natural products.A common feature of these strategies was the introduction of several optimally placed substituents prior to the construction of the pyrrolo[2,3-c]carbazole core.W ee nvisaged that the development of ad iversity-oriented synthesis for the construction of these natural products on the basis of the earlystage construction of the core structure,f ollowed by the introduction of the different substituents,w ould be more amenable to medicinal applications. [3] Subsequently, the research groups of Ishibashi, [4] Tokuyama, [5] Jia, [6] Gaunt, [7] Yamaguchi/Itami/Davies, [8] and Ready [9] disclosed total syntheses of these interesting natural products.A common feature of these strategies was the introduction of several optimally placed substituents prior to the construction of the pyrrolo[2,3-c]carbazole core.W ee nvisaged that the development of ad iversity-oriented synthesis for the construction of these natural products on the basis of the earlystage construction of the core structure,f ollowed by the introduction of the different substituents,w ould be more amenable to medicinal applications.…”

“…[2] In terms of their structural characteristics,dictyodendrins consist of ah ighly substituted pyrrolo [2,3-c]carbazole core, the complexity of which has attracted the interest of synthetic chemists.I n2 005, the Fürstner group reported the first total synthesis of dictyodendrins B, C, E, and Fthrough acarefully devised process involving the stepwise construction of the complex ring systems of these compounds. [3] Subsequently, the research groups of Ishibashi, [4] Tokuyama, [5] Jia, [6] Gaunt, [7] Yamaguchi/Itami/Davies, [8] and Ready [9] disclosed total syntheses of these interesting natural products.A common feature of these strategies was the introduction of several optimally placed substituents prior to the construction of the pyrrolo[2,3-c]carbazole core.W ee nvisaged that the development of ad iversity-oriented synthesis for the construction of these natural products on the basis of the earlystage construction of the core structure,f ollowed by the introduction of the different substituents,w ould be more amenable to medicinal applications.…”