A New Synthetic Route to Indoloquinones: Formal Synthesis of Ellipticine

Abstract

The anionic [4+2] cycloaddition of furoindolones with arynes and quinol ethers is introduced as an efficient strategy for the synthesis of indoloquinones. The utility of the strategy is exemplified by a very short synthesis of elipticine. Ellipticine (1), a representative member of pyrido [4,3-b]carbazole alkaloids, was isolated in 1959 from the stems of Ochrosia elliptica Labill. 1 In 1967, this alkaloid and its derivatives were reported to possess promising antitumour activities. 2 Since then, a large number of investigations of the structure-activity have been made concomitantly with the development of efficient synthetic routes to ellipticines and structurally allied derivatives. 3 Several ellipticine analogs are in phase II clinical trials, though the parent ellipticine is too toxic to be useful. However, elliptium, an ellipticine analog is used for treatment of thyroid, breast and kidney cancer. 4 Calothrixins (e.g., calothrixins A, 2), a newer class of alkaloids with an indolo[3,2-j]phenanthridine ring system were isolated from the cyanobacteria Calothrix in 1999. 5 They exhibit potent activity against both malaria parasites and human cancer cell lines at nanomolar scales. The striking structural resemblance between ellipticines and calothrixins provoked us to develop a common strategy for their synthesis. More interestingly, both calothrixin A (2) and ellipticine quinone (3, Figure 1) have very similar EC 50 values to HeLa cell lines. 6 Several indolonaphthoquinones also have shown promising antileukemic activity, but pharmacological studies are inhibited by the lack of easy accessibility. 7 Above all, simple indoloquinones are useful synthetic intermediates for the total synthesis of alkaloids. 8 Herein, we report our preliminary finding that the anionic [4+2] cycloaddition of furoindolones with arynes, quinol ethers and quinone monoketals provides a straightforward route for the preparation of indoloquinones. We also report that ellipticine (1) can be synthesized in only three steps from the known furoindolone 4, which, in turn, is obtainable in two steps from commercially available inexpensive starting materials.The established synthetic avenues to indoloquinones commonly entail Friedel-Crafts acylation or carbolithiation as one of the key steps. 9 Alternative methods rely upon use of 2-phenylamino-1,4-napthoquinones and formation of the heterocyclic ring as the last crucial step. 10 Our continued interest in the application of anionic [4+2] cycloaddition 11 of isobenzofuranones led us to undertake a study on anionic reactivity of furoindolones (e.g. 5). Moreover, anionic [4+2] cycloaddition has never been investigated in the context of heterocyclic quinone compounds. 12 Accordingly, we devised Scheme 1 for the direct entry to indoloquinones.Scheme 1 Proposed methodology for the synthesis of indoloquinones.

Total Synthesis of Carbazole Alkaloids – Ekeberginine, Harmandianamine A, and Furanoclausamine B

“…The key step is presumed to be characteristic loss of CO 2 from the β‐lactone intermediate 40 by retro [2+2] cycloaddition. The formation of 40 is a consequence of cis stereochemistry in 38 22. During the initial Michael addition of 31 to dimethyl maleate, two diastereomeric intermediates 38 and 39 are formed through in situ deprotection 22.…”

“…The formation of 40 is a consequence of cis stereochemistry in 38 22. During the initial Michael addition of 31 to dimethyl maleate, two diastereomeric intermediates 38 and 39 are formed through in situ deprotection 22. Of the two intermediates 38 and 39 , the cis orientation of the alkoxy group and the ester group in 38 perhaps leads to facile formation of the tetracyclic intermediate 40 .…”

“…The loss of CO 2 by retro [2+2] cycloaddition leads to the carbazole 33 . We presume that the formation of the uncommon product 33 is due to the electron‐donating effect of the NH group that is formed in situ by cleavage of the Boc group 22…”

Synthesis of a New Pyrido[3,2-b]carbazole as an Ellipticine-Makaluvamine Hybrid

“…The combined organic layers were dried (MgSO 4 ) and concentrated in vacuo to afford the crude product, which were purified by column chromatography (cyclohexane-EtOAc, 8:2) to give compound 12 as a brown solid; yield: 210 mg (99%); mp 186-188°C. 1 13 …”

“…[3][4][5][6][7] As a consequence ellipticine has proven to be a popular synthetic target, and a wide variety of routes have been reported. [8][9][10][11][12][13] Similarly, the structurally related aryl-and heteroaryl-annulated carbazoles have also received considerable synthetic attention. [14][15][16][17][18] Despite the great synthetic work developed around ellipticine, very little attention has been focused on its fusion with other biologically important molecules such as makaluvamine derivatives, which could lead to promising biological activities ( Figure 1).…”