Formal total synthesis of calothrixin B and its N-benzyl analogues

Abstract

A formal total synthesis of calothrixin B and its N-benzyl analogues has been accomplished from (2-chlorophenyl)boronic acid, 8-bromophenanthridine-7,10-dione and benzylamines. The synthesis involves Suzuki cross-coupling and copper-catalyzed domino reactions to generate N-benzylcalothrixins in good to moderate yields.

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Calothrixin A (1) and B (2) are pentacyclic quinones which belong to the family of quinolino[4,3-b]carbazole alkaloids (Fig. 1).¹ These alkaloids were isolated from the strain of Calothrix cyanobacteria in 1999 by Rickards and co-workers.² They show potent activity against malaria parasites and human cancer cells.^2,3 Due to their valuable biological activities as well as their unique structural scaffold, novel among natural products, calothrixins have drawn much attention from medicinal and synthetic chemists.⁴

Fig. 1 Structures of calothrixin A (1) and B (2).

In 2009, Hibino and co-workers extensively reviewed the synthesis of calothrixins in which they described six total syntheses and two biomimetic routes.⁵ Several synthetic routes have been developed later for the synthesis of calothrixins and its analogues, comprising of Pd-catalyzed tandem cyclization/cross-coupling reaction followed by copper-catalyzed electrocyclization,⁶ Pd-mediated intramolecular arylation,⁷ FeCl₃-mediated domino reaction,⁸ thermal electrocyclization,⁹ oxidative radical reaction,¹⁰ Pb(OAc)₄-mediated rearrangement¹¹ and Pd-mediated multiple cross-coupling reaction.¹² We have also reported two total syntheses of calothrixin B using Pd-catalyzed cross-coupling/C–H activation¹³ and Friedel–Crafts hydroxyalkylation followed by a ketone directed ortho-lithiation strategies.¹⁴

The Suzuki coupling reaction has been frequently used in syntheses of complex natural products.¹⁵ Copper-catalyzed domino reactions are one of the most useful synthetic method for the construction of heterocyclic compounds.¹⁶ Benzylamines are widely used as a starting material in several copper-catalyzed domino reactions for the production of various N-heterocycles.¹⁷ N-Alkylated calothrixins show a promising antimalarial activity.¹⁸ In particular, the activity of N-benzylcalothrixins has never been reported till date due to the lack of synthetic routes available for their direct synthesis. Therefore, we herein report a facile route to synthesize a series of N-benzylcalothrixins by exploiting Suzuki cross-coupling and copper-catalyzed domino reaction through Ullmann type N-arylation and C–H amination, starting from readily available starting materials (2-chlorophenyl)boronic acid, benzylamines and 8-bromophenanthridine-7,10-dione.

The retrosynthetic approach for the synthesis of N-benzylated calothrixins is described in Scheme 1. Two key reactions are utilized to construct the target compounds; (i) copper-catalyzed domino reaction of intermediate 7 with benzylamines, (ii) Suzuki cross-coupling reaction of (2-chlorophenyl)boronic acid 6 and 8-bromophenanthridine-7,10-dione 5. The compound 5 could be synthesized from a known synthetic precursor 8-bromo-7,10-dimethoxy-5-(methoxymethyl)phenanthridin-6(5H)-one 3 which was previously used for the synthesis of calothrixin B.¹⁹

Scheme 1 Retrosynthetic analysis to N-benzylcalothrixins.

The synthesis of a starting material 8-bromophenanthridine-7,10-dione 5 began from a known derivative, 8-bromo-7,10-dimethoxy-5-(methoxymethyl)phenanthridin-6(5H)-one 3 which was synthesized according to the procedure reported by Chai and co-workers (Scheme 2).¹⁹ In turn, the compound 3 was converted into 5 in two steps by standard transformations. Reduction of 3 with LiAlH₄ in THF at 0 °C for 2 h afforded 4, which was not isolated from the reaction mixture. After the work up process, the crude mixture containing 4 was treated with CAN in CH₃CN/H₂O (2 : 1) at room temperature for 2 h gave required 8-bromophenanthridine-7,10-dione 5 in 78% yield over 2 steps. With required starting compound 5 in hand, we proceeded Suzuki cross-coupling reaction with commercially available (2-chlorophenyl)boronic acid 6 as a coupling partner (Scheme 2). The coupled product 7 was obtained in 84% yield, on carrying out this reaction using 10 mol% Pd(PPh₃)₄, K₂CO₃ (2 equiv.) in DMF at 140 °C for 8 h.

Scheme 2 Synthesis of 8-(2-chlorophenyl)phenanthridine-7,10-dione (7).

Next, we focused on copper-catalyzed domino reaction of the coupled product 7 with benzylamines (Scheme 3). Initially, we tried out various reaction conditions to find out an optimal, high yielding catalyst system for the copper-catalyzed domino reaction. In order to obtain a suitable reaction condition, different copper salts like CuBr, CuCl, CuCl₂, CuBr₂, CuO, Cu₂O, CuI, Cu(OAc)₂·H₂O, Cu(OTf)₂ and combination of Cu powder (electrolytic) with these copper salts as catalysts, and K₂CO₃, Cs₂CO₃, AcOK, K₃PO₄, NaOH and t-BuOK as bases, and DMF, DMA, DMSO, NMP, ethylene glycol, toluene and dioxane as solvents at different temperatures under inert atmosphere were examined. Out of which, we found that the reaction of 7 with benzylamine 8a proceeded smoothly in the presence of 10 mol% Cu powder and 20 mol% CuO as a catalyst, t-BuOK (2 equiv.) as a base and NMP as a solvent at 140 °C for 6 h under nitrogen atmosphere, which gave N-benzylcalothrixin 9a in 78% yield.

Scheme 3 Copper-catalyzed domino synthesis of N-benzylcalothrixins (9a–i).

With this optimized condition, we were able to synthesize a series of N-benzylcalothrixins 9b–i by varying substituents in benzylamines 8b–i. The compound 9f was obtained in a maximum yield of 86% and the compound 9g in moderate yield of 46%, when we used benzylamines 8f and 8g respectively. Finally, calothrixin B 2 was obtained by the N-deprotection of the derivative 9f using 5 equiv. of AlCl₃ in anisole at 100 °C with an overall yield of 36.1% in 5 steps from the known precursor 3 (Scheme 4).

Scheme 4 Synthesis of calothrixin B (2).

Conclusions

In summary, we have developed a simple and efficient route for the synthesis of N-benzylcalothrixin derivatives. This can be the first example of constructing a series of N-benzylcalothrixins using Suzuki cross-coupling and copper-catalyzed domino reaction protocols, starting from commercially available benzylamines, (2-chlorophenyl)boronic acid, and 8-bromophenanthridine-7,10-dione in good yields.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and copies of ¹H, ¹³C NMR and mass spectra for all compounds. See DOI: 10.1039/c5ra18120h

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