Goniomitine: An Overview on the Chemistry of This Indole Alkaloid

This paper reports an overview on the chemistry of the indole alkaloid goniomitine focusing, mainly, on the methods of synthesis related to this natural product and analogs.


Introduction
The indole alkaloids belong to the class of natural substances displaying biological activities as well as a broad structural diversity. In view of these important properties, these products are target of study in the areas of isolation, identification, and synthesis [1][2][3][4][5]. Goniomitine (1) (Figure 1) is an indole alkaloid that was isolated and identified by Randriambola et al. [6] and Hashimoto and Husson [7]. The unique structure and biological activity of goniomitine have attracted the attention of several groups. This review describes the isolation, biogenesis hypothesis, chemical transformations, and syntheses of this alkaloid and analogs.

Isolation of Goniomitine
In the course of studies of the alkaloids of the genus Gonioma, Randriambola et al. [6]  The structure of goniomitine was initially proposed as indicated in Figure 1, with 20S, 21R configuration, based on its NMR spectra. Its absolute structure was deduced through the correlation with other alkaloids from Aspidosperma found in the same plant from where goniomitine had been isolated. The relative structure of goniomitine (1) was soon after confirmed by Takano et al. [8] through the total enantioselective synthesis of the natural form of this alkaloid. It could be evidenced that the absolute structure of the compound 1 is enantiomeric to the one that had been initially proposed for 20S, 21R configuration.

Biogenesis of Goniomitine
Randriambola et al. [6] proposed that goniomitine (1) may be derived from the Aspidosperma skeleton of vincadifformine (2) by the successive steps depicted in Scheme 1.

Chemical Transformations of Goniomitine.
For the occasion of the structural determination of goniomitine (1) [6], this compound was transformed into the N-acetyl derivative 5 upon treatment with Ac 2 O in MeOH and into the N,Odiacetyl derivative 6 upon treatment with Ac 2 O in pyridine (Scheme 2). The formation of the acetylated compounds 5 and 6 confirmed the presence of the groups OH and NH in the structure of 1.

The First Biomimetic
Approach to the Skeleton of Goniomitine from an Aspidosperma Alkaloid. The results from the study of biomimetic transformation of an Aspidosperma alkaloid (2) into the substances 39-40, with the skeleton of goniomitine (1), were published in 1995 by Lewin et al. [9]. The sequences of reactions for the discovery of a new biomimetic in vitro rearrangement are depicted in Scheme 5. Scheme 6 displays the proposed mechanism [9] for the transformation of compound 36 into the alkaloids 39 and 40.

Synthesis of the Goniomitine Analogs 52-55 by Cycloaddition Reactions.
In the year 1996, Gürtler et al. [11] published the synthesis of the goniomitine analogs 52-55 by [4 + 2] cycloaddition reactions between 2-vinylindoles and substituted cyclic enamines, via anodic oxidation (Scheme 8). Alves. In the year 2000, Alves [12] presented his qualification exam of doctorate about a plan of synthesis of the indole alkaloid goniomitine (1). The convergent strategies and synthetic routes for the synthesis of this alkaloid, idealized on that occasion, are described in the supplementary material of this review, available online at http://dx.doi.org/10.1155/2013/292396.

Syntheses of Cytotoxic Bisindole Alkaloids.
In the year 2000, Lewin et al. [13] published an article about a slight modification of the Borch reductive amination method (delayed addition of NaBH 3 CN) [14,15], applied to compound 40, analog of the natural alkaloid goniomitine (1). As a result of this reaction, a series of new cytotoxic bisindole alkaloids was prepared, as depicted in Scheme 9 .  In continuation to the studies of synthesis of cytotoxic bisindole alkaloids, Raoul et al. [16] published, in the year 2001, an article with a novel series of these alkaloids prepared by reductive amination of the compound 40 with various anilines, using the modified Borch amination conditions described in Scheme 9 (delayed addition (20 min) of NaBH 3 CN) [15]. The influence of substitution of the starting aniline on the reaction and on cytotoxicity of produced dimers is discussed in the paper.

Total Synthesis of (+/−)-Goniomitine by Waser. De
Simone et al. [18] published the synthesis of racemic goniomitine (1) with the first study of its bioactivity, revealing significant cytotoxicity against several cancer cell lines [18,  19]. The strategy of this synthesis is based on cyclization of aminocyclopropanes [20], applied to cyclopropyl ketone 83 to lead to compound 84 with tetracyclic skeleton of goniomitine (Scheme 11).

Total Syntheses of (+/−)-, (−)-, and (+)-Goniomitine by Mukay.
In the year 2011, Mizutani et al. [21] published the syntheses of both racemic and optically active goniomitine, whose principal steps are the preparation of the indole skeleton by their own developed procedure [22] and alkene crossmetathesis. The synthesis of racemic (+/−)-goniomitine (1) was performed, as a preliminary study, by the sequence of reactions depicted in Scheme 12.
The convergent total synthesis of the natural (−)-goniomitine (1) [21] was completed by the sequence of reactions depicted in Scheme 13.
Using the synthetic route described in Scheme 13, but starting from the enantiomer of the lactam 97 (ent-97) Mizutani et al. [21] synthesized the unnatural (+)-goniomitine (ent-1). With the racemic, natural, and unnatural goniomitine in hand, the authors [21] executed the preliminary bioactive assays, which revealed that natural (−)-goniomitine has stronger antiproliferative activity in Mock and MDCK/MDR1 cells than its enantiomer.

Conclusions
In summary, it may be concluded that this brief survey on the chemistry of goniomitine has covered the literature relative to this alkaloid and analogs from 1987 to the first semester of the year 2013. Taking into account the results published in this period, a considerable progress on the synthesis of this alkaloid has been verified in the last years (2008-2013) with the publications of five racemic and two enantiomeric syntheses. It is also important to emphasize the recent pioneering works on the bioactive assays performed with the racemic mixtures as well as both enantiomers of goniomitine. In spite of these progresses, the development of new efficient enantioselective synthetic strategies for this indole alkaloid, with low operational costs, is still a target to be reached.