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. 2024 Oct 11;26(42):9017–9021. doi: 10.1021/acs.orglett.4c03192

A General Entry to Ganoderma Meroterpenoids: Synthesis of Applanatumol E, H, and I, Lingzhilactone B, Meroapplanin B, and Lingzhiol

Alexander Rode †, Nicolas Müller †, Ondřej Kováč †,‡, Klaus Wurst §, Thomas Magauer †,*
PMCID: PMC7616716  EMSID: EMS199349  PMID: 39392896

Abstract

graphic file with name ol4c03192_0006.jpg

Ganoderma meroterpenoids are fungal derived hybrid natural product class containing a 1,2,4-trisubstituted benzene ring and a polycyclic terpenoid part. The representatives applanatumol E, H and I, lingzhilactone B, and meroapplanin B share the same bicyclic lactone moiety connected to the arene. Employing photo-Fries rearrangements as the key step enabled a general entry to these natural products. For the synthesis of the tetracyclic framework of lingzhiol, we made use of a powerful photoredox oxidative decarboxylation/Friedel–Crafts sequence.

Ganoderma is genus of wood decay fungi that has been used in traditional Chinese medicine to treat a variety of medical conditions such as hypertension, chronic bronchitis and diabetes.1−3 The secondary metabolites from these fungi cover the classes of polysaccharides, (mero)terpenoids, steroids and fatty acids of which polysaccharides were found to be the main bioactive component. To date, more than 100 meroterpenoids belonging to this natural product class have been isolated including applanatumol A (1),4 applanatumol E (2),5 lingzhilactone B (3),6 meroapplanin B (4),7 lingzhiol (5),8 and ganoapplanin9 (6, Figure 1).

Figure 1.

Figure 1

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Selected polycyclic Ganoderma meroterpenoids

These natural products have a common bicyclic lactone moiety (highlighted in blue), connected to a 1,2,4-trisubstituted benzene ring. In the case of lingzhiol (5), the aromatic core is further linked to the bicycle to give a unique tetralone subunit. Bioactivity assays revealed lingzhilactone B (3) and lingzhiol (5) to protect against renal injuries by increasing the activity of antioxidants and hence might be beneficial for antikidney disease drug design.6,8 Ganoapplanin (6) was reported to be an inhibitor for T-type voltage-gated calcium channels (IC50 = 36.6 μM), positioning it as a potential lead compound for the development of treatments for neurodegenerative diseases.10,11

Owing to their structural complexity and medicinal relevance, meroterpenoids from the Ganoderma genus constitute an attractive target for total synthesis. While syntheses for lingzhilactone B (3),12 lingzhiol (5)13−18 and ganoapplanin (6)19 were previously reported, synthetic strategies to access the applanatumol natural product family and meroapplanin B (4) are still unknown.

Here, we report a general entry to this natural product class involving two photochemical reactions as the key steps.20 We began our endeavor with the retrosynthetic analysis of applanatumol E (2) for which a photo-Fries retron was found (Scheme 1). Disconnecting the ketone from the arene revealed ester 7 as the required precursor. Further dissection gave commercially available hydroquinone (not shown) and the corresponding acid 8. The functional group pattern of 8 was derived from bicyclic lactone 9 via Krapcho decarboxylation of the methyl ester followed by allylation and sequential oxidation. For the installation of the crucial bicyclic lactone component 9, we identified a highly diastereoselective iodocarbocyclization employing malonate 10.

Scheme 1. Retrosynthetic Analysis.

Scheme 1

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As depicted in Scheme 2A, our synthesis commenced with the lithiation and 1,2-addition of vinyl iodide 12(21,22) to commercially available aldehyde 11 to give the corresponding allylic alcohol. Silylation (TBSCl, imidazole, DMAP) provided ester 13 in 53% over two steps. Sequential treatment of ester 13 with LDA and methyl chloroformate at −78 °C gave the prerequisite malonate 10 in 56% yield.23 Alternatively, 10 can also be accessed via a one-pot Nozaki–Hiyama–Kishi (NHK) reaction between aldehyde 14 and vinyl iodide 12 to form the corresponding secondary alcohol, which was protected in-situ to give TBS ether 10.19

Scheme 2. Synthesis of Lingzhilactone B (3), Applanatumol E (2), H (28), and I (29), and Meroapplanin B (4).

Scheme 2

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For the following iodocarbocyclization reaction we relied on the conditions reported in seminal work of Taguchi and recently employed by us for the synthesis of ganoapplanin (6) (Scheme 2B).19,24,25 Following the established protocol, 10 was converted via a 5-exo-trig cyclization/lactonization sequence to the bicyclic lactone 9 as a single diastereomer on decagram scale in 61% yield. The two quaternary centers are set in the 5-exo-trig cyclization of I to II with the desired relative configuration at C5.26 A Krapcho decarboxylation27 using LiCl in DMSO/water at elevated temperature (140 °C) allowed for clean removal of the ester group of 9 to furnish 15 in 87% yield. The use of NaCl instead of LiCl under otherwise similar reaction conditions gave 15 in slightly lower yields (68%). For the subsequent debenzylation of 15 Pearlman’s catalyst28 and a hydrogen pressure of 40 bar proved to be the conditions of choice. At lower pressure or when employing Pd/C, only slow conversion of 15 to alcohol 16 was observed. Oxidation of 16 was accomplished under Swern conditions29,30 to provide aldehyde 17 in 64% yield over two steps. Surprisingly, for the subsequent conversion of 17 to dimethyl acetal 18 most standard conditions failed (see Supporting Information for details). After extensive experimentation, we found that the use of acidic Dowex resin in combination with trimethyl orthoformate was highly effective to give 18 in 70% yield. Subsequent treatment with KHMDS and allyl iodide at 23 °C completed the installation of the vicinal quaternary stereocenters in 64% yield. Noteworthy, at standard cryogenic temperatures either no reaction took place, or an intermolecular Claisen-type addition was observed.31 Finally, aldehyde 21 was obtained in 95% yield by oxidative cleavage (O3, then PPh3) of remote alkene 19. With robust access to aldehyde 21, we continued our synthesis by first performing a Pinnick–Lindgren–Kraus oxidation32 to access acid 8. Subsequent treatment of 8 with Yamaguchi’s reagent,33 NEt3 and TBS-hydroquinone 24 afforded ester 7 in 97% yield over 2 steps. To access the 1,2,4-trisubsituted phenyl group inherent to the Ganoderma meroterpenoids we resorted to a Fries rearrangement.34 Since the use of standard conditions involving Lewis acids (e.g., AlCl3, BF3·OEt, TiCl4) was considered to be too harsh for both the silyl and the acetal protecting groups we opted for the rare photochemical variant.35−37 To our delight, irradiation of 7 at 254 nm in n-hexane (see Supporting Information for details) afforded the rearranged product 26 in 50% yield despite competing substrate decomposition. To complete the synthesis of applanatumol E (2), 26 was treated with NEt3·3HF to give 2 in 95% yield. The analytical data for 2 (1H NMR, 13C NMR, HRMS) fully matched those reported for the natural compound.5 We were also able to convert applanatumol E (2) to lingzhilactone B (3) in 55% yield by means of acetal removal employing p-TsOH in the presence of aqueous acetone. Lingzhilactone B (3) was further oxidized under Pinnick–Lindgren–Kraus conditions to deliver applanatumol I (29) in 78% yield. To access applanatumol H (28) we performed a direct allylation of lactone 15 to give alkene 20, followed by ozonolysis to afford aldehyde 22.19 Following the established conditions ester 25 was obtained in two additional steps. The photo-Fries reaction of 25 to 27 and the subsequent deprotection sequence proceeded with the same efficiency and high yields, ultimately enabling the synthesis of applanatumol H (28). In addition, meroapplanin B (4) was accessible in 85% yield when a solution of 3 in methanol was treated with NH4OAc at 50 °C. It might be noteworthy, that attempts to form the meroapplanin B (4) scaffold from 26 failed under those conditions.

With access to applanatumol I (29), we wondered if transformation to lingzhiol (5) would be feasible by means of an oxidative decarboxylation/Friedel–Crafts sequence. For the investigation of this transformation in the chemical laboratory, we first prepared phenol 32 from acid 8 (49% yield over two steps) through the well-established esterification/photo-Fries sequence (Scheme 3). To reduce the risk of overoxidation of the delicate phenol during the key-step, we protected the remaining phenolic hydroxy group as a methyl ether (K2CO3, MeI, 96%) to give 33. Acetal removal with p-TsOH gave aldehyde 34 which was further oxidized to acid 35 (81%). Based on recent work by Doyle on the photocatalytic fluorination of redoxactive esters,38 the intermediate acid 35 was converted to the N-hydroxyphthalimide ester 36 (92%). Fortunately, by employing the Ir(dFppy)3 catalyst (10 mol %) in combination with a catalytic amount of NEt3•3 HF at 419 nm (blue light), 36 was cleanly converted to tetralone 37 in 71% yield. According to the mechanistic proposal, an initial single electron reduction forms an intermediate carboxyl radical IV. After extrusion of carbon dioxide, a single electron oxidation gives a stabilized tertiary carbocation V. This is then attacked by the arene in a Friedel–Crafts reaction to give tetralone 37.

Scheme 3. Synthesis of Lingzhiol (5) via a Photo-Fries Rearrangement and an Oxidative Decarboxylation/Friedel–Crafts Sequence.

Scheme 3

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Global deprotection of the silyl protecting group (TBAF) and the methyl ethers (BBr3) afforded the natural product lingzhiol (5) in 50% yield over 2 steps. The spectroscopic data (1H and 13C NMR, HRMS) for 5 were in full agreement with those reported for the naturally occurring substance.8

In conclusion, we accomplished the total synthesis of six Ganoderma meroterpenoids. The robust route features the formation of the 1,2,4-trisubstituted benzene ring by employing a powerful, yet rare photo-Fries rearrangement. The natural product lingzhiol (5) was synthesized by photoredox catalysis that enabled an efficient oxidative decarboxylation/Friedel–Crafts sequence. The realization of this sequence highlights the synthetic potential of oxidative decarboxylation processes and constitutes a valuable starting point to access related Ganoderma natural products. Studies in this direction are currently underway in our laboratories and will be reported in due course.

Acknowledgments

We acknowledge the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 101000060), the Austrian Academy of Sciences (OeAW), and the Center for Molecular Biosciences CMBI. We are grateful to Prof. Christoph Kreutz (University of Innsbruck) and Prof. Thomas Müller (University of Innsbruck) for NMR and HRMS studies.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.4c03192.

  • Experimental procedures and characterization data for all new compounds as well as optimization tables and X-ray data (PDF)

The authors declare no competing financial interest.

Supplementary Material

ol4c03192_si_001.pdf (8.7MB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ol4c03192_si_001.pdf (8.7MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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