Total synthesis of cruciferane via epoxidation/tandem cyclization sequence

Abstract

The total synthesis of alkaloid cruciferane is performed in three steps with an overall yield of 60.3%. The key step involves the in situ epoxidation of indole followed by tandem Cyclization via epoxide ring opening to furnish the 3-hydroxypyrroloindoline skeleton. This methodology gave a step economical and protecting group free total synthesis of cruciferane.

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Nitrogen based alkaloids have always been a major constituent of nature.¹ Among them, particularly indole based natural products come with a broad skeleton diversity, which might be one of the reasons for their wide bioactivity spectrum.^2,3 Thus, indole natural products have always been a fascinating target to synthetic chemists.³ Quinazolinone is another class of heterocycle, which shows vital biological properties, such as anti-inflammatory, diuretic, anticancer, anticonvulsant and anti-hypertensive propoerties.⁴ Examples for a indoloquinazolinone based natural product are scarce.⁵ In 2012, the Shi group isolated 17 new alkaloids from the root of the Isatis indigotica plant, among which cruciferane is the first racemic natural product that contains a pyrrolo[2,3-b]indolo[5,5-a,6-b,a]quinazoline skeleton (Fig. 1).⁶ Isatis indigotica Fortune is a biennial plant in the cruciferae family, also known as Chinese woad. The dried root of Isatis indigotica is used ethnomedically to treat erysipelas, influenza, carbuncles, epidermic hepatitis and encephalitis B, as an antipyretic. A large number of compounds have been isolated from this plant, which include indigotin, indrubin, isatin, isatan A, isatan B, trytanthrin, purin, isaindigotidione, organic acids and many amino acids.⁷ As a part of our ongoing research on indoloquinazolinone based natural products and also due to its biological importance, we have chosen cruciferane as the target molecule.⁸ So far, two reports are available, which demonstrate the total synthesis of cruciferane.⁹ The first report was from Nair et al. in 2013, where they synthesized the alkaloids using condensation followed by an aldol reaction.^9a The other report was from the same year by the Argade group, where they synthesized cruciferane using benzyne Cyclization.^9b

Fig. 1 Structure of naturally occurring cruciferane alkaloids.

Later, Ji reported the formal synthesis of this alkaloid.¹⁰ However, these syntheses were carried out with same intermediate core tryptanthrin, which was prepared from either complicated starting materials or expensive reagents.

Thus our initial objective was to simplify the route with easy and inexpensive starting materials. Thus, we planned our synthesis for this alkaloid from the 3-hyroxypyrroloindoline intermediate (Fig. 2), which was not used thus far. There are some noteworthy reports for the construction of 3-hydroxypyrroloindoline, such as iodine(III)-mediated intramolecular annulation,¹¹ selenocyclization/oxidative deselenation sequence,¹² photosensitized oxygenation,¹³ and metal catalyzed radical Cyclization.¹⁴ Another well-known approach was the epoxidation of indole as the key step with dioxirane, but for most of the cases it needs an array of protecting groups or complicated reaction conditions.¹⁵ Thus, we intended to synthesize the molecule devoid of any protecting group and under simplified conditions, which will lead to a step economical¹⁶ total synthesis of cruciferane. Thus, in this paper, we wish to report a three step total synthesis of racemic cruciferane via an epoxidation/tandem cyclization strategy.

Fig. 2 Strategies for the synthesis of cruciferane.

The retrosynthetic approach is depicted in Scheme 1. We envisioned that the late stage C–N bond formation of the 3-hydroxypyrroloindoline skeleton (4) would lead to cruciferane. The 3-hydroxypyrroloindoline skeleton (4) would be acquired from the intermediate, which contains an epoxide at C2–C3 (see transition structure 3) of the indole core. This key intermediate (3) could stem from the epoxidation on the C2–C3 bond of the corresponding 3-substituted indole (2), which would be prepared in a one-pot procedure from corresponding indole acid and amino ester.

Scheme 1 Retrosynthetic representation of cruciferane.

As we envisioned the retrosynthetic approach, we started our venture by synthesizing the starting materials. Thus, we synthesized methyl anthranilate (1b) from anthranilic acid following a procedure from the literature¹⁷ and another starting material, indole 3-acetic acid (1a), was obtained from a commercial source. Next, we focused on the C–N bond formation between 1a and methyl anthranilate. We have chosen the most conventional and simple method for the synthesis of compound 2, via acid chloride formation followed by base mediated amidation in a one-pot sequence. Thus, we transformed indole 3-acetic acid to its corresponding acid chloride with oxalyl chloride. Without further purification of the acid chloride, it was used for the subsequent amidation reaction in a solution of methyl anthranilate and triethylamine (base) in dry DCM at 0 °C. The successive reactions gave the amidation product (2) in 78% yield (Scheme 2). With compound 2 in hand, we next focused on the epoxidation step, which was supposed to be the key reaction step in the total synthesis. As we envisaged, because of its chemoselective nature particularly on indole C2–C3, the reaction with dimethyldioxirane (DMDO) is one of the convenient methods to synthesise the 3-hydroxypyrroloindoline core. It was shown in the literature (vide supra) that the DMDO method was mostly applied to tryptophan derivatives. The derivative (2) contains an adjacent carbonyl group (C9) next to the nucleophilic nitrogen, and an aromatic ester as substitution, which makes it a little different compared to other conventional tryptophan derivatives. The DMDO solution in acetone was first prepared using the reported procedure by Taber et al.,¹⁸ which was added dropwise to compound 2 in dry acetone at −78 °C, stirred at the same temperature for 6 h, and then stirred at rt for an additional 2 h.

Scheme 2 Synthesis of racemic cruciferane.

However, after 1 h of reaction, TLC shows the formation of some complex mixtures, which might be due to the intermediate epoxide. After completion of the reaction (checked by TLC) a polar intense spot was shown. This in situ epoxidation, followed by tandem Cyclization, gave the step economy for this total synthesis. Next, we sought after the conditions to form the C–N bond between N1–C7′ of compound 4. We found that freshly prepared NaOMe (base)/MeOH (solvent) at −10 °C for 5 h and then at rt for 1 h gave the cyclised product in 91% yield. This C–N formation led to our final target molecule, racemic cruciferane. Thus, we have completed the total synthesis for racemic cruciferane via three graceful steps with an overall yield of 60.31%. The spectral data and HRMS data are consistent with the data of the isolated natural product as well as the synthetic product.

In summary, we have developed a new step economical and protecting group free strategy to synthesize racemic cruciferane in three steps. The main features of this total synthesis are easily available and preparable starting materials under mild conditions, devoid of any protecting groups and with a good overall yield.

Acknowledgements

We are grateful to DST for the financial support (project number: SR/S1/OC-70/2008) and S.K.G also thanks UGC for the Senior Research Fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra10309b

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