Total synthesis of carbazole alkaloid clausamine E
Introduction
Naturally occurring carbazole alkaloids display a wide variety of biological activities such as antitumor, antibacterial, antimicrobial, and anti-inflammatory activities [1]. Additionally, various carbazole derivatives serve as building blocks for potential electroluminescent materials[2] and host materials [3].
As mentioned above, because of their unique structures, characters, and biological activities, developing a convenient and efficient synthetic route to construct the carbazole ring has attracted considerable attention from organic and medicinal chemists. Therefore, various synthetic strategies using the cyclization of arylhydrazones, [4] thermal cyclization of 1-phenylbenzotriazole, [5] cyclization of biarylnitrenes, [6] iron-mediated arylamine cyclization, [7] palladium(II)-catalyzed oxidative cyclization, [8] and electrocyclization [9] of hexatriene have been developed.
In 2000, four new clausamines, D, E, F, and G, were isolated along with some known carbazoles by Furukawa and co-workers from Clausena anisata (Fig. 1) [10]. These newly isolated carbazole alkaloids belong to the class of 1-oxygenated 3-methoxycarbonylcarbazoles having a prenyl group or its analogous moiety at the C4 position. Clausamine E (1) was found to exhibit cytotoxicity against the human leukemia cell line, HL-60 [11]. In 2015, the first total synthesis of clausamine E (1) was reported by Mal and co-workers, which used anionic annulation of a furoindolone and selective bromination as the key steps [12].
We are interested in the unique structure and pharmacological action of carbazole and carbazolequinone alkaloids. To date, we have achieved the total synthesis of carbazoles (hyellazole, [9b] carazostatin, [9b] furostifoline, [13] and carbazomadurins [14]) and carbazolequonones (murrayaquinone A, [15] koeniginequinones, [16] carbazomycin G, [17] carquinostatin A, [18] carbazoquinocins, [9b] calothrixins, [19] and ellipticine quinone [20]) based on our original two methods of allene-mediated electrocyclization [9]b), [13], [14], [15]a), [15]b), [17], [18], [19] of a 6π-electron system or tandem RCM and dehydrogenation reaction [15]c), [16], [20]. Furthermore, we have been searching for stronger biologically active compounds using these natural compounds and their derivatives [20,21].
Recently, we reported the one-pot synthesis of carbazole-1,4-quinone by the consecutive Pd-catalyzed cyclocarbonylation, desilylation, and oxidation (Scheme 1) [22]. This reaction occurred between 3-iodo-2-propenylindole 5 and CO (1 atm) in the presence of tributyl(vinyl)tin and PdCl2(dppf), and the formed acyl palladium intermediate (A) was coupled directly to the terminal alkene moiety intramolecularly, followed by β-elimination to obtain carbazole 6. Subsequently, treatment with tetrabutylammonium fluoride (TBAF) in O2 atmosphere produced carbazole-1,4-quinone 7 by desilylation and then oxidation.
By tuning the nature of the protecting group of propenylindole 5 in place of the TBS group, we considered that it can synthesize carbazoles that possess different oxygen functional groups at the 1- and 4-positions by performing the cyclocarbonylation reaction. Furthermore, we thought that this was applicable to various poly-substituted carbazole syntheses by using two oxygen functional groups selectively. Thus, we decided to apply this method to the synthesis of the 1,3,4-trisubstituted carbazole alkaloid, clausamines.
Section snippets
Results and discussion
Our retrosynthetic analysis of the 1,3,4-trisubstituted carbazoles on the basis of Pd-catalyzed cyclocarbonylation in the presence of CO (1 atm) and tributyl(vinyl)tin is shown in Scheme 2. The synthesis of clausamines requires the introduction of the C4 substituent that can be achieved by introducing an alkenyl group by utilizing its oxygen functional group [23]. The key precursor 9 required for constructing 1,3,4-trisubstituted carbazole 8 by cyclocarbonylation could be synthesized by the
Conclusion
Total synthesis of the carbazole alkaloid, clausamine E (1), was newly achieved by applying our cyclocarbonylation procedure between 3-iodo-2-(prop-2-enyl)indole 24 and CO via an eight-step sequence with an 8.6% overall yield. This new synthetic route could be used as a versatile method to synthesize clausamine derivatives and other polysubstituted carbazoles. The biological activity of clausamine E and their derivatives is under evaluation.
General information
All non-aqueous reactions were carried out under an atmosphere of nitrogen in dried glassware unless otherwise noted. Solvents were dried and distilled according to standard protocols. Analytical thin-layer chromatography was performed with Silica gel 60PF254 (Merck). Silica gel column chromatography was performed with Silica gel 60 (70–230 mesh, Kanto Chemical Co. Lit.). All melting points were determined on Yanagimoto micro melting point apparatus and are uncorrected. Proton nuclear magnetic
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References (25)
- et al.
Heterocycles
(1993)et al.J. Org. Chem.
(1997)et al.J. Chem. Soc., Perkin Trans.
(1993) - et al.
J. Nat. Prod.
(2009) - et al.
Tetrahedron
(2015) - et al.
Chem. Pharm. Bull.
(2001) - et al.
Chem. Pharm. Bull.
(2012) - et al.
J. Org. Chem.
(2011) - et al.
Molecules
(2015)et al.Chem. Rev.
(2012) - et al.
J. Am. Chem. Soc.
(2001)et al.Macromolecules
(2002)et al.Macromolecules
(2004) - et al.
J. Am. Chem. Soc.
(2004)et al.Macromolecules
(2005)et al.J. Org. Chem.
(2009) - et al.
Tetrahedron Lett.
(2011)
J. Chem. Soc.
Tetrahedron
Cited by (6)
Trends in carbazole synthesis - an update (2013-2023)
2023, Organic and Biomolecular ChemistrySynthesis of N-acyl carbazoles, phenoxazines and acridines from cyclic diaryliodonium salts
2024, Beilstein Journal of Organic Chemistry