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. 2022 Dec 22;10:1103554. doi: 10.3389/fchem.2022.1103554

Total synthesis of justicidin B, justicidin E, and taiwanin C: A general and flexible approach toward the synthesis of natural arylnaphthalene lactone lignans

Kai Wei 1,2,†, Yucui Sun 1,†, Yiren Xu 1,†, Wen Hu 1, Ying Ma 1, Yi Lu 1, Wen Chen 1,*, Hongbin Zhang 1,*
PMCID: PMC9815507  PMID: 36618865

Abstract

Lignans are widely present in traditional medicinal plants. Many natural arylnaphthalene lactone lignans (NALLs) isolated from the genera Justicia, Haplophyllum, and Phyllanthus possess interesting biological activities. Herein, we report a general strategy for the total synthesis of this kind of lignans. Features of this new approach are an aryl–alkyl Suzuki cross-coupling to introduce the dioxinone unit, a cation-induced cyclization to construct the aryl dihydronaphthalene, and base-mediated oxidative aromatization to furnish the arylnaphthalene core. By incorporating these key transformations, the total syntheses of justicidins B and E and taiwanin C covered type I and type II NALLs were accomplished.

Keywords: total synthesis, natural products, arylnaphthalene lactone lignans, Suzuki cross-coupling, cation-induced cyclization

1 Introduction

Natural arylnaphthalene lactone lignans (NALLs) are widely isolated from the plant family Acanthaceae (Day et al., 1999; Shen et al., 2004; Zhang et al., 2007; Jin et al., 2014; Jiang et al., 2017; Jin et al., 2017; Lv et al., 2021; Liu et al., 2022), Euphorbiaceae (Anjaneyulu et al., 1981; Wu et al., 2006) and Rutaceae (Gözler et al., 1984; Sheriha et al., 1984; Hesse et al., 1992; Ulubelen et al., 1994; Gözler et al., 1996), especially from the genera Justicia, Haplophyllum, and Phyllanthus. Many of these lignans possess a broad range of biological activities, including antimicrobial (Kawazoe et al., 2001), antifungal (Ashraf et al., 1995), anti-cancer (Wang et al., 2019), antiplatelet (Chen et al., 1996; Weng et al., 2004), antiprotozoal (Gertsch et al., 2003), antimetastatic (Hajdu et al., 2014), antiviral (Sagar et al., 2004; Yeo et al., 2005; Janmanchi et al., 2010), cytotoxic (Day et al., 2002; Chang et al., 2003; Susplugas et al., 2005; Vasilev et al., 2006), and neuroprotective activities (Chun et al., 2017) in cell-based assays or animal models. For instance, justicidin B exhibits powerful antimicrobial activity (El-Gendy et al., 2008) and inhibitory activity against the Sindbis virus (Charlton, 1998). Meanwhile, taiwanin C exhibits important antiplatelet activity (Daron et al., 2022) and was found to be a potent COX inhibitor (Ban et al., 2002). Some representative natural arylnaphthalene lactone lignans (1–9) are shown in Figure 1.

FIGURE 1.

FIGURE 1

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Representative NALLs.

Because of their important pharmacological properties, NALLs have attracted attention from the organic synthetic community since the pioneering synthetic work on these lignans in 1895 by Michael et al. (1895). Synthetic efforts have resulted in many impressive approaches toward these highly substituted 1-arylnaphthalenes and culminated in the total synthesis of a series of arylnaphthalene lactone-type lignans (Chen et al., 2018; Zhao et al., 2018; Park et al., 2020). Methodologies for the construction of 1-arylnaphthalenes could be roughly classified into five categories: Diels–Alder type cycloaddition (Brown et al., 1964; Holmes et al., 1971; Klemm et al., 1971; Takano et al., 1985; Stevenson et al., 1989; Padwa et al., 1996; Xiong et al., 2012; Kudoh et al., 2013; Kocsis et al., 2014; Park et al., 2014; Meng et al., 2016), benzannulation (Ogiku et al., 1995; Flanagan et al., 2002; Nishii et al., 2005; Ishikawa et al., 2021; Moriguchi et al., 2021), Garratt–Braverman-type cyclization (Mondal et al., 2011; Mondal et al., 2012), transition metal-mediated cyclization (Murakami et al., 1998; Mizufune et al., 2001; Sato et al., 2004; Sato et al., 2007; Gudla et al., 2011; Patel et al., 2013; Wong et al., 2014; Kao et al., 2015; Naresh et al., 2015; Xiao et al., 2018), and other type of annulations (Ogiku et al., 1990; Kamal et al., 1994; Ogiku et al., 1995; Harrowven et al., 2001; Foley et al., 2010; He et al., 2014; Hayat et al., 2015; Yamamoto et al., 2015).

Inspired by these well-designed processes and our previous efforts on cation-induced cyclization (Chen et al., 2017; Chen et al., 2019; Wei et al., 2021; Chen et al., 2022; Li et al., 2022), we recently developed an intramolecular cation-induced reaction to synthesize the highly substituted 1-aryl dihydronaphthalene unit, an advanced precursor of natural arylnaphthalene lactone lignans. In this paper, we report a general and flexible strategy toward the synthesis of justicidin E (type II NALLs), justicidin B, and taiwanin C (type I NALLs) based on this efficient cation-induced cyclization.

2 Results and discussion

2.1 Retrosynthetic analysis

Our retrosynthetic analysis for both type I and type II NALLs is shown in Scheme 1. Type I NALLs could be achieved by a Stille cross-coupling between common intermediates (10) and tributylstannyl methanol followed by lactonization (Zhang et al., 2019). Type II NALLs could be accessed via carbonylative lactonization (Crisp et al., 1995) of triflate 18, which could be obtained via a reduction from common intermediates (10). Ring opening of dioxinone 11 followed by subsequent base-mediated oxidation (Zhao et al., 2020) and triflation would lead to methyl ester 10. Dihydronaphthalene 11 could be accessed through the intramolecular cation-induced cyclization of alcohol 12, which could be prepared by a selective nucleophilic addition of aryl lithium generated in situ from aryl bromide 13 to aldehyde 14. Aldehyde 14 was expected to be formed by an aryl–alkyl Suzuki cross-coupling between pinacolyl borate 15 and commercially available alkyl bromide 16 followed by a deprotection of the ketal moiety. Borate 15 could be obtained from commercially available bromide 17 via functional group protection, halogen–lithium exchange reaction, and borylation.

SCHEME 1.

SCHEME 1

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Retrosynthetic analysis for both type I and II NALLs.

2.2 Total synthesis of justicidin B

We chose justicidin B, a type I NALL, as the first target of our synthetic journey. Our synthesis began with the preparation of pinacolyl borate 15a (Scheme 2). Treatment of commercially available bromo-aldehyde 17a with ethylene glycol provided its acetal, after subsequent halogen–lithium exchange by exposing it with n-butyllithium followed by borylation (Nagaki et al., 2012) provided 15a in 85% yield.

SCHEME 2.

SCHEME 2

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Gram-scale synthesis of pinacolyl borate 15a. Bu: butyl, THF: tetrahydrofuran, and Ts: p-toluenesulfonyl.

With pinacolyl borate in hand, we next explored aryl–alkyl Suzuki cross-coupling between borate 15a and commercially available alkyl bromide 16 (Table 1). Although numerous conditions for Suzuki cross-coupling reactions between alkyl halide and aryl boric acid or borate have been developed, using alkyl bromide 16 as a coupling partner to accomplish this cross-coupling reaction is still challenging due to the thermosensitive and base-sensitive dioxinone unit present in substrate 16 (Reber et al., 2009; Katsuki et al., 2017).

TABLE 1.

Optimization for the aryl–alkyl Suzuki cross-coupling a .

graphic file with name FCHEM_fchem-2022-1103554_wc_tfx1.jpg
Entry Catalyst Ligand Base Solvent Yield [%] b
1 Pd(PPh3)4 - K3PO4 1,4-Dioxane Trace
2 Pd(OAc)2 PPh3 K3PO4 1,4-Dioxane 2
3 Pd(dppf)Cl2 PPh3 K3PO4 1,4-Dioxane 3
4 Pd2(dba)3 PPh3 K3PO4 1,4-Dioxane 4
5 Pd(dba)2 PPh3 K3PO4 1,4-Dioxane 8
6 Pd(dba)2 PPh3 K2CO3 1,4-Dioxane 3
7 Pd(dba)2 PPh3 Na2CO3 1,4-Dioxane 0
8 Pd(dba)2 PPh3 Cs2CO3 1,4-Dioxane 5
9 Pd(dba)2 PPh3 KOAc 1,4-Dioxane 2
10 Pd(dba)2 t-Bu3P K3PO4 1,4-Dioxane 20
11 Pd(dba)2 PCy3 K3PO4 1,4-Dioxane 26
12 Pd(dba)2 X-Phos K3PO4 1,4-Dioxane Trace
13 Pd(dba)2 S-Phos K3PO4 1,4-Dioxane 51
14 Pd(dba)2 S-Phos K3PO4 DMF Trace
15 Pd(dba)2 S-Phos K3PO4 THF 71
16 Pd(dba)2 S-Phos K3PO4 CPME 51
17 Pd(dba)2 S-Phos K3PO4 TBME 63
18 Pd(dba)2 S-Phos K3PO4 DME 77
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a

The reactions were performed with 15a (0.2 mmol), 16 (0.26 mmol), catalyst (10 mol%), ligand (20 mol%), base (2.5 eq.), and solvent (3 ml) at 40°C for 7 h.

b

Yields represent isolated yields. Ac: acetyl, Bu: butyl, CPME: cyclopentyl methyl ether, Cy: cyclohexyl, dba: dibenzylideneacetone, DME: 1,2-dimethoxyethane, DMF: N,N-dimethylformamide, dppf: 1,1′-bis(diphenylphosphino)ferrocene, Ph: phenyl, S-Phos 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, TBME: tert-butyl methyl ether, X-Phos 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl.

In order to optimize the yield of this cross-coupling reaction, a systematic screening of reaction conditions was conducted (Table 1). Initially, we used the regular catalyst Pd(PPh3)4 employed in Suzuki cross-coupling (Miyaura et al., 1979). Not surprisingly, Pd(PPh3)4 was completely ineffective for the desired cross-coupling (Table 1, entry 1). Reactions were then conducted at a 0.2-mmol scale with several commercially available palladium catalysts (10 mol%) in the presence of PPh3 (20 mol%) and K3PO4 in 1,4-dioxane (Table 1, entries 2–5). We found that Pd(dba)2 served as an efficient Pd source for this coupling process (Table 1, entry 5). Next, the bases were screened, and the yield of the desired product 19a was not increased with a number of bases (Table 1, entries 5–9). A number of ligands were then used. We found that a ligand has a significant impact on the efficiency of this cross-coupling reaction (Table 1, entries 9–13). When the S-Phos ligand was used, the desired product 19a could be obtained with 51% yield (Table 1, entry 9). With the catalytic system in hand, we next screened the solvents, and DME gave the best results (Table 1, entries 13–18). Finally, the optimum reaction conditions for this coupling reaction (Table 1, entry 18) were established.

Next, the acetal protecting group of compound 19a was removed with HCl in acetone to produce aldehyde 14a (Scheme 3). The treatment of 13a with n-BuLi followed by the addition of aldehyde 14a unfortunately failed to yield the desired benzhydrol 12a. To promote the desired reaction, a number of additives were used including hexamethylphosphoric acid triamide (HMPA), N,N-dimethyl propylene urea (DMPU), and N,N,N′,N′-tetramethylethylenediamine (TMEDA). The addition of TMEDA provided benzhydrol 12a at 71% yield.

SCHEME 3.

SCHEME 3

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Synthesis of benzhydrol 12a. TMEDA: N,N,N′,N′-tetramethylethylenediamine.

With benzhydrol 12a in hand, we next focused on the proposed cation-induced cyclization (Table 2). A number of Brønsted acids and Lewis acids (Table 2, entries 1–6) were used. Although the cyclization could be promoted by Brønsted acids, BF3·Et2O provided the best yield (Table 2, entry 6). The yield of the targeted product could be further improved when the reaction was conducted at a lower temperature (Table 2, entry 8). This cation-induced cyclization could be scaled up to 2.1 mmol (Table 2, entry 8, 0.90 g, and 68% yield).

TABLE 2.

Optimization for the intramolecular cation-induced cyclization a .

graphic file with name FCHEM_fchem-2022-1103554_wc_tfx2.jpg
Entry Acid Temperature [oC] Yield [%] b
1 TfOH 0 Trace
2 TFA 0 40
3 CSA 0 19
4 TsOH 0 43
5 TMSCl 0 46
6 BF3·Et2O 0 50
7 BF3·Et2O -30 60
8 BF3·Et2O -40 69
9 BF3·Et2O -50 61
10 BF3·Et2O -40 68 c
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a

The reactions were performed with 12a (0.2 mmol), acid (2.0 eq.), and solvent (3 ml) for 3 h.

b

Yields represent isolated yields.

c

The reaction was conducted at a 2.1-mmol scale. CSA: camphorsufonic acid, DCM: dichloromethane, Et: ethyl, and TFA: trifluoroacetic acid.

Having established the procedure for advanced intermediate 11a, research focus was then directed toward the total synthesis of justicidin B 1). The treatment of 11a with sodium methoxide in MeOH under air followed by the addition of Tf2O and DIPEA in DCM produced the first common intermediate 10a in 45% yield (Scheme 4). It is noteworthy that an oxidative (by air) aromatization occurred under strong basic conditions. Next, a Pd-catalyzed Stille cross-coupling of triflate 10a with tributylstannyl methanol in the presence of Pd(PPh3)4, Cs2CO3, and LiCl followed by spontaneous lactonization provided natural justicidin B (Zhang et al., 2019). The NMR spectra of our synthetic sample were in full agreement with those reported in the literature (Okigawa et al., 1970; Borges et al., 2018).

SCHEME 4.

SCHEME 4

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Total synthesis of justicidin B (1). DIPEA: diisopropylethylamine, Me: methyl.

2.3 Total synthesis of taiwanin C and justicidin E

To demonstrate the generality and flexibility of our strategy, the total syntheses of naturally occurring arylnaphthalene lignans taiwanin C (type I) and justicidin E (type II) were conducted accordingly. Treatment of commercially available piperonyl bromide 17b with ethylene glycol in the presence of TsOH followed by a halogen–lithium exchange and borylation afforded the pinacolyl borate 15b in 74% yield (Scheme 5). Suzuki cross-coupling of bromide 16 with 15b under the optimum reaction conditions afforded the corresponding dioxinone 19b. Deprotection of the acetal of 19b with HCl in acetone followed by a selective 1,2-addition with the 3,4-methylenedioxyphenyllithium, which was generated in situ from the halogen–lithium exchange between bromide 13a and n-BuLi, yielded the benzhydrol 12b in 59% for two steps.

SCHEME 5.

SCHEME 5

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Total synthesis of taiwanin C (4) and justicidin E (7). DMAP: 4-dimethylaminopyridine, dppf: 1,1′-bis(diphenylphosphino)ferrocene.

Aryl dihydronaphthalene 11b was obtained successfully in 70% yield through our intramolecular cation-induced cyclization from benzhydrol 12b. The treatment of 11b with NaOMe in MeOH under air followed by triflation with Tf2O afforded the common intermediate 10b in 46% yield for two steps. Reaction of 10b with tributylstannyl methanol in the presence of Pd(PPh3)4, Cs2CO3, and LiCl produced the natural taiwanin C 4). Reduction of 10b with DIBAL-H provided the alcohol 18a in 90% yield. Natural justicidin E (7) was furnished in 38% isolated yield via an improved Pd-catalyzed carbonylative lactonization of triflate 18a with Co(CO)6. The NMR spectra of these two synthetic samples agree well with the reported literature (Anjaneyulu et al., 1981; Subbaraju et al., 1996; Flanagan et al., 2002).

3 Conclusion

We have developed a general and flexible strategy for the synthesis of justicidin B, taiwanin C, and justicidin E from commercially available materials. Key transformations to the success of the synthesis were an aryl–alkyl Suzuki cross-coupling, an intramolecular cation-induced cyclization, and a base-mediated oxidative aromatization. Our new approach paves the way toward the synthesis of biologically active natural arylnaphthalene lactone lignans and could be used for the preparation of their analogues.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Author contributions

HZ conceived the synthetic design. WC and HZ supervised the project. KW, YS, YX, WH, YM, and YL conducted the experimental work and data analysis. WC and HZ wrote the manuscript.

Funding

This work was supported by grants from the Natural Science Foundation of China (U1702286, 21901224, 22261054, and 22271247), the Program for Changjiang Scholars and Innovative Research Team in University (IRT17R94), Ling-Jun Scholars of Yunnan Province (202005AB160003), YunLing Scholar Programs, Yunnan Fundamental Research Projects (202201AT070141 and 2019FI018), the Talent Plan of Yunnan Province (YNWR-QNBJ-2018-025), the Project of Yunnan Characteristic Plant Screening and R&D Service CXO Platform (2022YKZY001), and the National Key Research and Development Program of China (2019YFE0109200).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fchem.2022.1103554/full#supplementary-material

Click here for additional data file. (3.1MB, PDF)

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