Concise Total Synthesis of (±)-Makaluvamine F and Its Derivatives

Abstract

A concise gram-scale total synthesis of (±)-makaluvamine F was accomplished. The left segment, 2-aminodihydrobenzothiophene possessing an N,S-acetal moiety, was prepared using commercially available 2-fluoro-4-methoxybenzaldehyde in 6 steps via Curtius rearrangement. Subsequent condensation of the 2-aminodihydrobenzothiophene segment with a pyrroloiminoquinone segment completed the total synthesis of makaluvamine F, which was achieved in a 23% overall yield via a longest linear sequence of 7 steps. The versatility of the synthetic route involving the Curtius rearrangement was demonstrated by applying it to synthesize several unnatural makaluvamine F derivatives.

Introduction

Pyrroloiminoquinone (PIQ) alkaloids are a class of marine and fungal natural products characterized by a tryptamine-derived pyrrolo[4,3,2-de]quinoline skeleton. In addition to their structural diversity stemming from the presence of a variety of functional groups on the PIQ core, their broad range of biological activities attract considerable interest from the synthetic community. Among the PIQ alkaloids, makaluvamines are a family of compounds bearing an amino group at the C7 position of the PIQ core¹⁾ (Chart 1). These compounds exhibit cytotoxicity against several tumor cell lines and topoisomerase II inhibitory activity.^2–9) In addition, Quinn and colleagues reported that several congeners of the makaluvamine family demonstrated promising activity against both chloroquine-sensitive and multidrug-resistant strains (3D7 and Dd2) of Plasmodium falciparum, a parasite causing human malaria, with good therapeutic indices (TIs).¹⁰⁾ Recently, Vanderwal and colleagues found that an appropriately modified makaluvamine derivatives possess potent antiprotozoal activity with a good TI.¹¹⁾

Chart 1. Structures of Makaluvamines

Owing to the structural diversity and remarkable biological activities of makaluvamine alkaloids, considerable efforts have been devoted to their synthesis. The most convergent and versatile synthetic strategy developed so far for the divergent synthesis of makaluvamines having a broad range of C7 amino groups is the later-stage introduction of the amino group at the C7 position of orthoquinone 2 or 7-methoxypyrroloiminoquinone 3^11–28) (Chart 2a). On the basis of this synthetic strategy, Velu and Jaskula-Sztul synthesized DHN-II-84 and DHN-III-14 and demonstrated their potent cytotoxicity against neuroendocrine tumor cells⁹⁾ (Chart 2b). Moreover, in their work on the synthesis of a broad range of makaluvamine derivatives, Vanderwal and colleagues conducted systematic structure–activity relationship (SAR) studies, revealing the importance of methylation of the imine moiety and the presence of a lipophilic tryptamine motif to achieve potent antimalarial activity with a good TI¹¹⁾ (Chart 2c).

Chart 2. General Strategy for the Synthesis of Makaluvamines and Examples of Unnatural Makaluvamine Derivatives

However, despite the advances made on the synthesis of compounds of the makaluvamine family, the synthetic difficulty of the left segment of the most cytotoxic congener makaluvamine F (1), 2-amino-5-bromo-6-hydroxy-2,3-dihydrobenzothiophene (6) having a labile N,S-acetal moiety, has hindered SAR studies (Chart 3a). Only Kita and colleagues successfully synthesized left segment 6 by constructing the N,S-acetal moiety via oxidative azidation of dihydrobenzothiophene 4 using a combination of PhI = O and TMSN₃, followed by hydrogenation.^29–32) However, the oxidative azidation proceeded in low yield owing to the generation of benzothiophen byproduct 8 via aromatization of cyclic thionium ion 9 (Chart 3b). The first total synthesis of makaluvamine F (1)^29–31) was accomplished by condensing left segment 6 with pyrroloiminoquinone 7 according to the general strategy depicted in Chart 2a (vide infra). After Kita’s pioneering synthesis, no example of the construction of 2-aminodihydrobenzothiophene has been reported to date.

Chart 3. Kita’s Total Synthesis of Makaluvamine F (1)

To circumvent the problematic construction of the 2-aminodihydrobenzothiophene segment 6, we developed an alternative route during our synthetic studies on discorhabdin B, which were proposed to be biosynthetically derived from makaluvamine F (1) by Munro.^33,34) Specifically, Curtius rearrangement of 6-methoxydihydrobenzothiophene-2-carboxylic acid (11) using diphenylphosphoryl azide (DPPA) in t-BuOH as the solvent to trap the isocyanate intermediate furnished N-tert-butoxycarbonyl (Boc)-2-amino-6-methoxydihydrobenzothiophene (12) in high yield (92%) without generation of the corresponding benzothiophene byproduct³⁵⁾ (Chart 4). Motivated by this result, we envisioned that the total synthesis of makaluvamine F (1) could be substantially improved by adopting our Curtius rearrangement strategy for the preparation of segment 6. In this study, we developed a gram-scale total synthesis of makaluvamine F (1) and a divergent synthesis of unnatural makaluvamine F derivatives.

Chart 4. Synthesis of 2-Aminodihydrobenzothiophene via Curtius Rearrangement Developed by Our Group

Results and Discussion

Our synthetic plan for makaluvamine F (1) is depicted in Chart 5. According to the general strategy (Chart 2a) and Kita’s first total synthesis (Chart 3a), makaluvamine F (1) would be obtained by coupling of segment 6 with pyrroloiminoquinone segment 7 at the final stage of the synthesis. We selected dihydrobenzothiophene-2-carboxylic acid (14) as a precursor of 6. Carboxylic acid 14 would be synthesized from dihydrobenzothiophene-2-methyl ester (15)³⁶⁾ via ester hydrolysis, reduction of the C2–C3 double bond, and regioselective bromination at the C5 position. Meanwhile, a known 5-step sequence starting from 2,3-dimethoxyaniline (13) would provide access to pyrroloiminoquinone segment 7.¹¹⁾

Chart 5. Synthetic Plan for Makaluvamine F (1)

As shown in Chart 6, our synthesis of makaluvamine F (1) commenced with the construction of 6-methoxybenzothiophene-2-carboxylic acid methyl ester 15 by performing the cyclocondensation of benzaldehyde 16 with methyl thioglycolate.³⁶⁾ Then, after reduction of the C2–C3 double bond of benzothiophene, hydrolysis of the methyl ester, and regioselective bromination of the resultant carboxylic acid 11 with Br₂, the crude brominated compound was subjected to the key Curtius rearrangement using DPPA in t-BuOH to furnish the desired N-Boc-2-amino-5-bromo-6-methoxy-2,3-dihydro benzothiophene (17) in good yield (2 steps, 62%, 1 g scale) without generation of the corresponding benzothiophene. Removal of the methyl group on the phenolic hydroxyl group and the Boc group using BBr₃, followed by additions of MeOH and trifluoroacetic acid (TFA) to quench excess BBr₃ and to convert the resultant primary amine to the TFA salt, afforded 2-amino-6-hydroxydihydrobenzothiophene 6 while leaving the N,S-acetal moiety intact. Finally, coupling of 2-amino-5-bromo-6-hydroxy-2,3-dihydrobenzothiophene (6) (945 mg) with pyrroloiminoquinone segment 7 (497 mg) completed the gram-scale (1.15 g) total synthesis of makaluvamine F (1) in a 23% overall yield via a longest linear sequence of 7 steps.²⁾

Chart 6. Total Synthesis of Makaluvamine F (1)

Next, we turned our attention to the divergent synthesis of unnatural makaluvamine F derivatives 19a–d (Chart 7). Curtius rearrangement of 6-methoxydihydrobenzothiophene-2-carboxylic acid (11) gave N-Boc-2-amino-6-methoxy dihydrobenzothiophene (12) in 92% yield.³³⁾ After deprotection of the methyl group on the phenolic hydroxyl group and the Boc group with BBr₃, the resultant 2-aminodihydrobenzothiophene segment 18 was condensed with pyrroloiminoquinone segment 7 to complete the synthesis of debromomakaluvamine F (19a). Furthermore, regioselective bromination of 6-methoxydihydrobenzothiophene-2-carboxylic acid (11) followed by Curtius rearrangement and removal of the Boc group furnished 2-amino-5-bromo-6-methoxydihydrobenzothiophene (20), which was coupled with pyrroloiminoquinone segment 7 to give makaluvamine F methyl ether (19b). Meanwhile, Curtius rearrangement of 5-methoxydihydrobenzothiophene-2-carboxylic acid (21)³⁷⁾ gave N-Boc-2-amino-5-methoxydihydrobenzothiophene (22) in 58% yield. Subsequent deprotection of the 2 protecting groups in 22 and condensation with pyrroloiminoquinone segment 7 afforded makaluvamine F derivative 19c, albeit a modest yield. The low yield is probably due to instability of 19c caused by electron donating effect of free phenolic hydroxy group on the p-position of sulfur atom, that also made complete purification of 19c difficult. Finally, the Curtius rearrangement strategy was applied to simple dihydrobenzothiophene-2-carboxylic acid (24)³⁸⁾ to obtain N-Boc-2-aminodihydrobenzothiophene (25) in 77% yield. Subsequent removal of Boc group and coupling of 26 with pyrroloiminoquinone segment 7 furnished debromodehydroxymakaluvamine F (19d). For stabilities of the 2-aminodihydrobenzothiophenes, all of N-Boc derivatives and TFA salt of free amines were found to be stable. However, the deprotection of the two protecting groups in 22 provided inseparable byproducts due to instability of 22 or 23 under the reaction conditions. Therefore, condensation between 7 and 23 was conducted without purification of 23.

Chart 7. Divergent Syntheses of Makaluvamine F Derivatives

Conclusion

In summary, we accomplished a gram-scale total synthesis of makaluvamine F (1) via a facile and efficient assembly of 2-amino-5-bromo-6-hydroxy-2,3-dihydrobenzothiophene segment (6) possessing an N,S-acetal moiety by means of Curtius rearrangement. The generality of the Curtius rearrangement strategy was fully demonstrated by performing the divergent synthesis of unnatural makaluvamine F derivatives 19a–d via the highly efficient preparation of 2-aminodihydrobenzothiophene derivatives. Further studies including the biological evaluations of the synthesized compounds are ongoing and will be reported in due course.

Acknowledgments

This work was supported by a Grant-in-Aid for Transformative Research Areas (A) “Latent Chemical Space” [JP24H01744] the Ministry of Education, Culture, Sports, Science and Technology, Japan. This work was also financially supported by KAKENHI (JP24H00591, JP21K15217, and JP24K09704) from JSPS, Research Support Project for Life Sciences Research and Drug Discovery (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED (JP25ama121040), and JSPS pre-doctoral fellowship (19J20732 for M.S. and 22KJ0284 for K.I.).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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