Total Synthesis of Olivacine and Ellipticine via a Lactone Ring-Opening and Aromatization Cascade

Abstract

Effective preparation of olivacine and ellipticine via late-stage D-ring cyclization is described. Key features of the synthetic routes include trifluoroacetic acid-mediated formation of a lactone that is fused to a tetrahydrocarbazole derivative and its one-pot two-step ring opening and aromatization mediated by para-toluenesulfonic acid and palladium on carbon, respectively.

Divergent Synthesis of Indolo[3,2- c]quinolines, Neocryptolepines and Related Tetracyclic Ring-Systems Containing Promising Biological Activities

“…The pyridocarbazole scaffold is present in several natural products, the two most prominent examples being olivacine (51) and ellipticine (52) (Figure 2.1). [108,109] Being regioisomers of the bioactive indoloquinoline compounds, the pyridocarbazoles are also known for possessing a range of biological activities, but are first and foremost known for their potent anticancer properties. First isolated from the tropical evergreen tree Ochrosia elliptica in 1959, ellipticine (52) was quickly determined to contain significant antiproliferative activities.…”

“…[110] In a relatively recent work, Ertürk's group described the synthesis of both olivacine (51) and ellipticine (52) from a common lactone intermediate using a high-yielding and practical, though somewhat step-heavy, synthetic cascade (Scheme 5). [109] The key features required include a trifluoroacetic acid-mediated lactone formation (not included in the reaction scheme), followed by a one-pot two-step lactone ring-opening and finally Pd/C-catalyzed dehydrogenative rearomatization, to give the desired carbazole intermediate 53. With carbazoles 53 in hand, D-ring cyclizations was realized through application of a previously published reaction sequence, [117] affoarding the two natural products olivacine (51) and ellipticine (52) in 78 and 50% yields, respectively.…”

“…With carbazoles 53 in hand, D-ring cyclizations was realized through application of a previously published reaction sequence, [117] affoarding the two natural products olivacine (51) and ellipticine (52) in 78 and 50% yields, respectively. [109] Scheme 5: Synthesis of olivacine (51) and ellipticine (52) from a common intermediate 53 as presented by Ertürk and coworkers; DCC = N,N'-dicyclohexylcarbodiimide; HOBt = 1hydroxylbenzotriazole hydrate. [109] The pyridoacridine scaffold is well detailed in the literature due to its presence in certain natural products, [118] while its regioisomeric pyridophenanthridines have never been observed naturally and thus remain largely unexplored.…”

“…[109] Scheme 5: Synthesis of olivacine (51) and ellipticine (52) from a common intermediate 53 as presented by Ertürk and coworkers; DCC = N,N'-dicyclohexylcarbodiimide; HOBt = 1hydroxylbenzotriazole hydrate. [109] The pyridoacridine scaffold is well detailed in the literature due to its presence in certain natural products, [118] while its regioisomeric pyridophenanthridines have never been observed naturally and thus remain largely unexplored. To present date, there are only two examples of the synthesis of a pyridophenanthridine in the published literature, the first reported being the accidental synthesis of pyridophenanthridine 54A by Beauchard and colleagues (Scheme 6).…”

Anticancer and Immunomodulatory Activities of a Novel Water-Soluble Derivative of Ellipticine

“…Ellipticine derivatives such as 9-hydroxy-2-methylellipticinium acetate (NHME) had been introduced into the market, but were later withdrawn. [6] The search for other ellipticine derivatives is under way [10][11][12][13][14][15][16]. However, low water solubility of ellipticine derivatives is a crucial obstacle for the wide practical application in cancer therapies.…”