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Published in final edited form as: ChemistryEurope. 2025 Apr 26;3(3):ceur.202500020. doi: 10.1002/ceur.202500020

Evolution of a Strategy for the Total Synthesis of the Ganoderma Meroterpenoid Ganoapplanin

Nicolas Müller 1, Ondřej Kováč 2, Alexander Rode 3, Daniel Atzl 3, Clemens Dietrich 3, Ana V Serna 4, Sebastian Schaar 5, Antonio Paparesta 5, Julian Lichtenegger 5, Thomas Magauer 5,✉
PMCID: PMC7618469  EMSID: EMS211543  PMID: 41393789

Abstract

Herein, a detailed account of the efforts leading to the recently published synthesis of the Ganoderma meroterpenoid ganoapplanin, a natural product identified as an inhibitor of T-type voltage-gated calcium channels, is provided. Ganoapplanin, which was isolated as a racemate from the fungus Ganoderma applanatum in 2016, features a complex structure, including a characteristic spiro bisacetal structure, a highly functionalized tetra-ortho-substituted biaryl motif, and a propellane-like dioxatricyclo[4.3.3.0]dodecane scaffold. While the southern terpenoid fragment is available via a diastereoselective titanium-mediated iodolactonization, considerable efforts are required to fuse this fragment with various aromatic fragments. The breakthrough was achieved by a highly efficient two-component coupling strategy that simultaneously fuses the fragments and establishes the crucial biaryl bond. This transformation involves an intramolecular 6-exo-trig radical addition of a quinone monoacetal, followed by an intermolecular aldol addition. Finally, strategic late-stage oxidations enabled the formation of the characteristic spiro bisacetal motif and the completion of the synthesis of ganoapplanin.

Keywords: Ganoderma, meroterpenoids, natural products, radicals, total synthesis

1. Introduction

Ganoderma, a genus of wood decay fungi frequently used in traditional Chinese medicine, has been a subject of intense research due to its diverse array of bioactive compounds.[1] Among the various classes of compounds isolated from Ganoderma species, meroterpenoids are particularly noteworthy for their structural complexity and significant bioactivity profiles including antioxidant, antifibrotic, and antimicrobial activities. Ganoderma meroterpenoids (GMs) can be classified based on their structural complexity into three distinct subclasses: linear, polycyclic, and dimeric GMs (Figure 1).[1]

Figure 1. Selected structures of GMs and their classification.

Figure 1

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Linear GMs are characterized by a hydroquinone group linked to a linear terpenoid chain, as exemplified by ganodercin D (1).[2] In contrast, polycyclic GMs, such as lingzhilactone B (2),[3] feature a hydroquinone motif connected to a polycyclic ring system. Dimeric GMs, including ganoapplanin (3),[4] consist of two hydroquinone units attached to a terpenoid backbone, resulting in greater structural complexity.

From a biosynthetic perspective, GMs are constructed from 4-hydroxybenzoic acid (4) and GPP (geranyl diphosphate, 5), with the former originating from the shikimic acid pathway. In the first step, 4 is attached to GPP by a geranyltransferase, followed by oxidative decarboxylation to yield the hydroquinone intermediate 6.[5] This compound can then undergo allylic oxidation to form linear GMs, such as ganodercin D (1). In addition, oxidative processes can trigger cyclization reactions leading to a wide range of structurally diverse polycyclic meroterpenoids.

For instance, lingzhilactone B (3) is thought to form via the oxidation of intermediate 6 to precursor 7, which then undergoes an intramolecular conjugate addition to generate cyclopentyl carbocation I. Further transformations, including esterification and interception from water, lead to the bicyclic structure of lingzhilactone B (2).[5] In the later stages of the proposed biosynthesis of ganoapplanin (3), methanol and anthranilic acid 9 react with lingzhilactone B (2) to form acetal 10. To construct the aryl–aryl bond, a diazotization of the aniline group followed by a Pschorr–Gomberg–Bachmann radical cyclization was proposed.[6,7] The biosynthesis is completed through aromatization and lactonization, culminating in the formation of ganoapplanin (3) (Scheme 1).[4]

Scheme 1. Proposed biosynthetic pathway to lingzhilactone B (2) and ganoapplanin (3).

Scheme 1

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The unique structural features and compelling biological activities of GMs make them highly appealing targets for total synthesis.[8] Polycyclic GMs, such as cochlearol B[9–12] and lingzhiol,[13–19] have been synthesized multiple times. Recently, we also reported the total synthesis of lingzhilactone B (2), meroapplanin B, lingzhiol, and other related polycyclic GMs.[19] The synthesis of dimeric GMs remains relatively underexplored, with only a few examples reported, such as cochlearoid B.[20]

Ganoapplanin (3), first isolated in racemic form by Qiu from Ganoderma applanatum in 2016,[4] is particularly remarkable from a structural standpoint. It contains five contiguous stereocenters, including two quaternary centers, and features a unique spiro bisacetal framework. This intricate structure is composed of a 6/6/6/6 tetracyclic system, incorporating a tetra-ortho-substituted biaryl motif and a dioxatricyclo[4.3.3.0]dodecane propellane-like scaffold (Scheme 2A). Given the traditional use of Ganoderma fungi extracts in Chinese medicine as an adjuvant for central nervous system disorders,[21] the neuroprotective potential of ganoapplanin (3) was also investigated. In the course of this study, inhibition of T-type voltage-gated calcium channels was revealed for a racemic mixture of 3 (IC50 of 36.6 μM).[4] Based on these results, ganoapplanin (3) shows potential as a lead compound for the development of novel therapeutics against neurodegenerative diseases such as epilepsy or Parkinson’s disease.[22,23] In recent years, our group has developed various synthetic methods for constructing highly functionalized arenes[24] and heteroarenes.[25] We have also successfully completed the total syntheses of natural products featuring similar polysubstituted aromatic frameworks.[24,26,27] As these methods were unsuitable for the unique structure of ganoapplanin (3), in particular its highly congested central region, including the tetra-ortho-substituted biaryl motif, we set out to develop new synthetic strategies.

Scheme 2. Structural features of ganoapplanin (3) and attempted key-steps: A) structural features and B) key bond disconnections.

Scheme 2

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Herein, we report a full account of these attempts and present the development of a synthetic strategy that enabled us to accomplish the first total synthesis of ganoapplanin (3).[28]

2. Results and Discussion

2.1. Retrosynthetic Analysis

Considering the potential instability of the spiro bisacetal moiety, we opted for its late-stage construction and therefore traced back ganoapplanin (3) to hydroquinone 12 (Scheme 2B). To build up the latter, we designed several key steps, relying on (A) [4 + 2]-cycloadditions, (B) umpolung reactions of aldehydes, (C) alkylations of lactones, (D) late-stage biaryl formations, (E) nucleophilic additions, and (F) Fries rearrangements/cationic cyclizations. The precursors for these key transformations can be traced back to lactone 13, which resembles the southern fragment of ganoapplanin (3). Inspired by seminal work of Taguchi,[29,30] we envisioned the construction of this lactone by a titanium(IV)-mediated iodolactonization of alkene 14.

2.2. Synthesis of the Southern Fragment of Ganoapplanin

We commenced our synthetic endeavors toward ganoapplanin (3) with a Nozaki–Hiyama–Kishi reaction[31] between aldehyde 15[32,33] and vinyl iodide 16[34,35] followed by in situ TBS protection of the formed secondary alcohol gave access to silyl ether 14 (Scheme 3A). To forge the bicyclic lactone structure, we relied on an iodocarbocyclization reaction, using titanium(IV) tert-butoxide, copper(ll) oxide, and iodine.[29,30] Under these conditions, 14 underwent a 5-exo-trig cyclization followed by lactonization, resulting in the formation of the bicyclic lactone 17 as a single diastereomer on a decagram scale in 61% yield. The reaction effectively established two quaternary centers during the 5-exo-trig cyclization (IV to V), achieving the desired relative configuration at C6′. Moving forward, we carried out a Krapcho decarboxylation (LiCl, H2O, DMSO, 140 °C) to remove the methyl ester of 17.[36] An attempt to perform the debenzylation of 18 with palladium on charcoal under a hydrogen atmosphere resulted in low reactivity. However, upon increasing the pressure to 40 bar and using Pearlman’s catalyst, we were able to realize the desired transformation. The resulting intermediate 19 was then subjected to a Swern oxidation, yielding aldehyde 20 in 64% over two steps.[37,38] With aldehyde 20 in hand, we proceeded to attempt the protection of the carbonyl function as a dimethyl acetal. Surprisingly, this step proved more difficult than expected, as commonly used methods involving Brønsted or Lewis acids in the presence of methanol led either to decomposition or failed to initiate the reaction (see the Supporting Information for details). To our satisfaction, using the acidic resin Dowex 50WX4 in combination with trimethyl orthoformate yielded the desired dimethylacetal 21 in 70% yield.[39]

Scheme 3. Syntheses of the southern fragments 13 and 24: A) synthesis of aldehyde 13 and B) synthesis of aldehyde 24.

Scheme 3

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The installation of the adjacent quaternary stereocenter was completed by treating the lactone 21 with potassium bis(trimethylsilyl)amide (KHMDS) and allyl iodide at 23 °C, yielding alkene 22 in 64% yield. The final step toward aldehyde 13 involved the oxidative cleavage of alkene 22 (O3, then PPh3), which provided aldehyde 13 in 95% yield. Similarly, we were able to access alkene 23 and aldehyde 24 via direct allylation of lactone 18, followed by ozonolysis (Scheme 3B).

2.2.1. Construction of the Biaryl Moiety via [4 + 2]-Cycloadditions

After establishing a synthetic route to aldehyde 13, we were eager to explore our first proposed strategy for the synthesis of the biaryl moiety of ganoapplanin (3), which involved a couple of [4 + 2]-cycloadditions of a diyne moiety with 2-methoxyfuran (Scheme 4A).[40–43]

Scheme 4. [4 + 2]-Cycloaddition approaches: A) retrosynthetic analysis for strategy A; B) [4 + 2]-cycloaddition employing a diyne, and C) [4 + 2]-cycloaddition employing an enyne.

Scheme 4

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We commenced this synthetic approach with the preparation of diyne 27 (see the Supporting Information for details). Upon deprotonation using n-BuLi, the corresponding lithium acetylide was formed, which was then transmetalated with cerium(lll) tri-chloride, forming a suitable nucleophile to attack aldehyde 13 to give secondary alcohol 28 as an inconsequential diastereomeric mixture (1.4:1). Oxidation with manganese(IV) oxide gave access to ketone 29 and set the stage for the first [4 + 2]-cycloaddition. Treating acetylenic ketone 29 with 2-methoxyfuran allowed us to obtain hydroquinone 30 in good yields (57%). In order to activate the remaining aldehyde moiety for the upcoming second [4 + 2]-cycloaddition, we decided to install an electron-withdrawing group on the terminal alkyne position. To this end, desilylation using 3 HF·NEt3 provided propargylic alcohol 31 in 76% yield. Even though the oxidation of 31 with MnO2 was successful, the desired aldehyde 32 turned out to be unstable and was, therefore, isolated in only low yield (27%). Unfortunately, the key [4 + 2]-cycloaddition of 32 with 2-methoxyfuran proved to be fruitless under several screened conditions, including treatment with excess diene at elevated temperatures (60 °C) and/or applying high pressure (14 kbar)[44] as decomposition of the starting material was observed (Scheme 4B).

Surprisingly, an attempt to realize an analogous [4 + 2]-cycloaddition of 2-methoxyfuran and enyne 36, accessible via a comparable 1,2-addition/oxidation sequence, resulted in no reaction despite the similarity of the dienophiles 29 and 36.

2.2.2. Aldehyde Umpolung

As the construction of the biaryl motif of ganoapplanin (3) turned out to be more difficult than expected, we considered an alternative approach, which is based on the synthesis of an aromatic fragment, substituted with an aldehyde moiety, via cross-coupling reactions. Subsequent umpolung of aldehyde 38,[45] followed by alkylation with alkyl iodide 39, should forge the C2-linker (C−C bond between C1′ and C2′) between both fragments (Scheme 5A). To investigate this strategy, we commenced with the synthesis of alkyl iodide 39, which was conducted in five steps starting from lactone 23 (Scheme 5B). The process began with an isomerization of the terminal olefin of 23 to internal olefin 40 using Pd(MeCN)2Cl2 in toluene at 100 °C.[46] Ozonolysis of the double bond yielded aldehyde 41, which was then reduced to the corresponding alcohol 42 using the borane–tetrahydrofuran complex. The desired alkyl iodide 39 was accessed upon tosylation and iodination with potassium iodide. Having achieved the synthesis of alkyl iodide 39, we turned our focus to the synthesis of the aromatic fragment. Thus, we designed tricycles 49 and 50 with the desired substitution pattern including a protected benzylic alcohol, which could then be further elaborated to the corresponding benzaldehyde 38 required for the umpolung/alkylation approach.

Scheme 5. Retrosynthetic analysis of the umpolung/alkylation approach and synthesis of the southern component 39: A) retrosynthetic analysis for strategy B and B) synthesis of alkyl 39.

Scheme 5

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We initiated this campaign with the synthesis of phenols 44 and 45 and treated them with benzyl bromide 46 under basic conditions to access the bis-halogenated ethers 47 and 48 (see the Supporting Information for details). To construct the crucial aryl–aryl bond, we investigated several metal catalyzed cross-coupling reactions. Unfortunately, these attempts exclusively resulted in decomposition of 47 and 48 and were unsuitable to form either 49 or 50 (Scheme 6A). We reasoned that the systems we used were challenging substrates for cross-coupling reactions for two reasons: first, due to the steric hindrance caused by a total of four ortho substituents next to the bromine substituents, and second, due to the electron richness caused by several electron donating substituents.

Scheme 6. Attempted intramolecular coupling reactions: A) attempted intramolecular coupling of ethers 47 and 48; B) Stille–Kelly coupling of ether 52; C) Stille–Kelly coupling of ester 56; and D) C–H functionalization of ester 60.

Scheme 6

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To overcome the issue regarding sterical hindrance, we decided to synthesize bis-halogenated ether 52 (see the Supporting Information for details), which is lacking the phenol group at C4a, from phenol 45 and benzyl bromide 51. Unfortunately, attempts to form the aryl–aryl bond, using Stille–Kelly cross-coupling conditions (Pd(PPh3)4, Sn2Bu6, 140 °C), only gave trace amounts of biaryl 53 (Scheme 6B).[26,47,48]

We then set out to reduce electron richness of the system and synthesized ester 56 (see the Supporting Information for details) from phenol 54 and acyl chloride 55. Surprisingly, when subjecting 56 to the same conditions, only decomposition was observed, presumably due to instability of the aldehyde moiety (Scheme 6C). A C–H functionalization approach involving the treatment of ester 60 (see the Supporting Information for details) with Pd(OAc)2, PCy3·HBF4 and potassium carbonate at elevated temperatures (130 °C) in DMA[49] led to a regioisomeric mixture of biaryl 62 and 61 in 3:1 ratio favoring the undesired sterically less hindered regioisomer (Scheme 6D). From these results, we concluded that ester 63 might be a suitable substrate, as it features the electron-withdrawing ester moiety, a sturdy MOM-protected benzylic alcohol and two bromo substituents, to avoid the formation of regioisomers. We therefore synthesized ester 63 by treating phenol 45 and acyl chloride 55 with DMAP in pyridine in almost quantitative yields (97%).

Having this substrate in hand, we screened several Stille–Kelly cross-coupling conditions (see the Supporting Information for details) and found that treatment of 63 with Pd(PPh3)4 with Sn2Bu6 in benzene at elevated temperatures (140 °C) led to the formation of biaryl 61 in around 20% yield (Scheme 7A).

Scheme 7. Synthesis of benzaldehyde 57 and umpolung/alkylation attempt: A) Stille–Kelly coupling of ester 63 and B) attempted umpolung/alkylation sequence.

Scheme 7

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Moving on with protected biaryl 61, we attempted the chemoselective deprotection of the MOM-ether; however, the PMB proved to be more labile. Therefore, we opted for a global deprotection with trifluoroacetic acid (TFA) to give benzylic alcohol 64, which was then oxidized by treatment with pyridinium chlorochromate (PCC) to benzaldehyde 65. Subsequently, the PMB protecting group was reinstalled to give 57. As the construction of benzaldehyde 57 proved to be more challenging and inefficient than anticipated, the synthetic sequence yielded only small amounts of the target compound. Consequently, we decided to explore the key umpolung/alkylation transformation using a model substrate instead. Therefore, we synthesized cyanohydrin 67[50] from commercially available ortho-anisaldehyde (66). Attempts to deprotonate 67 with lithium bis(trimethylsilyl)amide (LHMDS) followed by exposure to alkyl iodide 39 at various temperatures failed to produce either 68 or ketone 69. We hypothesized that the desired reaction was prevented by the steric hindrance of the neopentylic alkyl iodide (Scheme 7B).

2.2.3. Lactone Alkylation

Since our attempt to construct the C1′−C2′ bond between the aromatic motif and terpenoid fragment via an umpolung strategy was unsuccessful, we decided to discontinue this approach. Instead, we moved on to investigate the alkylation of lactone 18. This approach builds on our prior success with allylating lactone 18 using allyl iodide and LHMDS. We reasoned that aromatic fragment 70, substituted with a leaving group in the allylic position, should serve as a suitable electrophile for addition to the enolate derived from lactone 18. This strategy would yield ketone 12 through oxidative cleavage of the olefin and oxidation at C4a to form the hydroquinone motif. 70 can be traced back to ketone 71 via olefination and functionalization of the allylic position (Scheme 8A).

Scheme 8. Lactone alkylation strategy: A) retrosynthetic analysis for strategy C; B) attempted formation of styrene 75; and C) synthesis of styrene 79 and attempted functionalization of the allylic position.

Scheme 8

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To access ester 73 (see the Supporting Information for details), we performed an esterification of phenol 72 with acyl chloride 55 in the presence of 4-dimethylaminopyridine and pyridine. With 73 in hand, we were poised for another Stille–Kelly cross-coupling reaction. To our delight, the reaction conditions previously employed for synthesizing biaryl 61 also proved effective for the preparation of biaryl 74. Notably, replacing the electron-donating MOM-protected alcohol (as in 63) with an electron-withdrawing ketone group (as in 73) increased the yield from 20 to 50%. Moving forward, we explored various conditions for the methenylation of ketone 74. However, all olefination attempts (e.g., Wittig, Nysted)[51] were unsuccessful, and we consistently reisolated the starting material. We suspect that steric hindrance around the ketone moiety may prevent the desired transformation (Scheme 8B).

To address the challenges with the olefination, we synthesized ester 78 (see the Supporting Information for details), which already carries the propene moiety. By applying our optimized Stille–Kelly cross-coupling conditions to this substrate, we were able to obtain the biaryl 79 in 11% yield. We attributed the low yield to the more electron-rich nature of the styrene moiety compared to the previously used ketone. With a limited supply of 79, we attempted an allylic oxidation under modified Riley conditions;[52,53] however, only decomposition of biaryl 79 was observed (Scheme 8C).

Since the preparation of 80 proved more challenging than anticipated, we decided to explore the feasibility of the alkylation strategy using a less functionalized aromatic electrophile (Scheme 9). We went back to phenol 76, protected the phenolic hydroxyl group as a TBS ether, and oxidized the allylic position using modified Riley conditions (SeO2, tert-butyl hydroperoxide (TBHP), 40 °C)[52] to obtain alcohol 82. After successful mesylation, we proceeded with the planned alkylation of lactone 18. To this end, we generated the enolate from 18 upon treatment with LHMDS followed by addition of 83. Unfortunately, the resulting enolate (not shown) did not react with mesylate 83 over a range of different temperatures.

Scheme 9. Synthesis of mesylate 83 and attempted alkylation of 18.

Scheme 9

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2.2.4. Late-Stage Biaryl Formation

Despite the various difficulties in merging the aromatic and terpenoid fragments, we achieved considerable success in synthesizing highly functionalized biaryl compounds using the Stille–Kelly cross-coupling described in the previous chapters. Building on this, we planned to implement this strategy as the key transformation in our next approach. Retrosynthetically, we envisioned biaryl 12 arising from an intramolecular cross-coupling reaction of bis-halogenated ester 85 (Scheme 10A). To access 85, we planned to perform an esterification of acyl chloride 77 with phenol 86. Based on our earlier approach, we decided to construct brominated phenol 86 through a Diels–Alder reaction between 2-methoxyfuran and a suitable brominated alkyne.

Scheme 10. Retrosynthetic analysis and synthesis of biaryl 90: A) retrosynthetic analysis for strategy D and B) synthesis of biaryl 90.

Scheme 10

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To install the alkyne moiety, we carried out a 1,2-addition of trimethylsilylacetylene, yielding a diastereomeric mixture of the corresponding secondary alcohol (not shown). Oxidation with Dess–Martin periodinane (DMP) converted this mixture to ketone 87 in 45% yield over two steps. The alkyne was brominated with N-bromosuccinimide (NBS), yielding an almost quantitative amount of bromo alkyne 88. With bromo alkyne 88 in hand, we investigated the [4 + 2]-cycloaddition. To our satisfaction, heating 88 with 2-methoxyfuran at 60 °C gave phenol 86 in acceptable yields, probably via intermediate VI, which aromatizes spontaneously. The observed regioselectivity of the cycloaddition is in accordance with reported findings from Sonoda and is attributed to the electronic effects of the bromo substituent.[40] Esterification was subsequently achieved by treating 86 with acyl chloride 77, DMAP, and pyridine at elevated temperatures, yielding bis-halogenated ester 85. With synthetic access to ester 85, we were eager to attempt the envisioned Stille–Kelly cross-coupling. To our surprise, the previously used conditions (Pd(PPh3)4, Sn2Bu6, 140 °C) resulted only in a complex mixture, while conditions reported by Cramer (NiCl2(PPh3)2, Zn, 100 °C)[54] failed to consume ester 85. Fortunately, using Hosokawa’s conditions (Ni(cod)2, EtAlCl2, 80 °C)[55] successfully provided biaryl 89 in high yield (81%).

Having constructed the crucial aryl–aryl bond, we next set out to investigate oxidation at the C4a position to form the hydroquinone motif. For this, we performed a global debenzylation (Pearlman’s catalyst Pd(OH)2/C, H2, 1 atm), which afforded phenol 90 (Scheme 10B). To install the missing C4a oxidation, we planned to oxidize the phenol moiety to its corresponding quinone 91, followed by reduction to the corresponding hydroquinone.

To achieve the oxidation of compound 90 to the quinone, we screened several commonly used oxidants, such as PIDA, CAN, salcomine/O2, Fremy’s salt (potassium nitrosodisulfonate)[56] and manganese(III) acetate.[57] Unfortunately, those attempts resulted in no reaction (see the Supporting Information for details).

When 90 was subjected to PCC, the phenol moiety remained unaffected, while the primary alcohol was oxidized to the corresponding aldehyde (not shown). We hypothesized that the electron-withdrawing lactone group decreases the reactivity of the phenol moiety toward oxidation, thus impeding the desired transformation. Literature reports for phenol oxidation with an ortho-substituted carbonyl group are scarce, indicating that our target reaction may indeed be challenging to accomplish. To address this issue, we revisited earlier steps in our synthetic approach and decided to modify the intramolecular coupling precursor 85.

Therefore, we synthesized ester 92 and ether 94 (see the Supporting Information for details), which already include the additional phenol group at C4a. Unfortunately, when treating either 92 or 94 with Ni(cod)2 and EtAlCl2 at 80 °C, we only observed decomposition (Scheme 11A). We attributed this outcome to increased steric hindrance from the additional substituent at C4a, which created a system with four ortho substituents around the reactive sites, making cross-coupling reactions particularly challenging. Similarly, subjecting ether 96 (see the Supporting Information for details) to the same conditions (Scheme 11B) led to formation of a complex mixture.

Scheme 11. Intramolecular coupling attempts: A) attempted syntheses of 93 and 95 via intramolecular couplings and B) attempted intermolecular coupling of ether 96 and synthesis of fluorinated biaryl 99.

Scheme 11

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Additionally, we also envisioned the synthesis of fluorinated biaryl 99, which could be a suitable substrate for an SNAr reaction to introduce the hydroxy group at C4a. The intramolecular coupling reaction of 98 (see the Supporting Information for details) furnished the desired aryl fluoride 99 in low yields. For this specific reaction it was also important to lower the temperature from 80 to 60 °C as we observed decomposition otherwise. With this substrate in hand, we then set out to attempt the SNAr reaction. Given that these types of reactions typically require harsh reaction conditions[58] or are limited to electron-deficient arenes, we opted for a rhodium catalyzed SNAr hydroxylation. Unfortunately, conditions reported by Shi,[59] which proved to be applicable for the synthesis of electron-rich phenols, were found to be incompatible with our substrate, as we observed the formation of a complex mixture when aryl fluoride 99 was treated with [Cp*RhCl2]2 and water at 150 °C.

2.2.5. Nucleophilic Addition

Due to the difficulties encountered in realizing the oxidation of phenol 90 or forming the biaryl bond in compounds 93, 95, or 97, we decided to explore an alternative approach. Since we successfully achieved a 1,2-addition with metalated trimethylsilylacetylene to the terpenoid fragment, we based our next key transformation on this reactivity. Specifically, we aimed to prepare aryl halides 101, 102, or 103, which would undergo halogen/metal exchange followed by a nucleophilic 1,2-addition to aldehyde 24 to give access to 12 (Scheme 12A). Since 101 and 102 feature tetra-ortho-substituted biaryl bonds, typically challenging to form through transition metal-catalyzed cross-coupling reactions, we sought an alternative strategy. Inspired by the work of Barrett[60] and Buchwald,[61] we envisioned a three-component reaction to form these biaryls, utilizing aryne intermediate VII. Treatment of 2-fluoro-1,4-dimethoxybenzene (104) with n-BuLi followed by addition of the Grignard reagent 105 (prepared from commercially available 3-bromoanisole, not shown) led to formation of VIII, which was subjected to carbon dioxide to yield benzoic acid 106. To simplify the purification by column chromatography on silica gel, we converted the acid 106 to methyl ester 107 (43% over 2 steps). Subsequent saponification followed by oxidative lactonization, under conditions reported by Wei (N-iodosuccinimide (NIS), 75 °C),[62] afforded the desired biaryl lactone 108 in 63% yield. Alternative conditions such as PIDA/Pd(OAc)2[63] or K2S2O8/AgNO3[64] only led to decomposition. Photochemical (CeCl3, 419 nm)[65] and electrochemical conditions (Pt electrodes, 23 mA, 5 V)[66] also failed to form the desired product 108.

Scheme 12. Retrosynthetic analysis and attempted preparation of organometallic compound 112: A) retrosynthetic analysis for strategy E and B) synthesis of halogenated biaryls 109 and 111.

Scheme 12

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With a synthetic route to compound 108 established, we then focused on halogenating the C2 position. Attempted bromination using NBS failed to react at 23 °C and produced complex mixtures at elevated temperatures. Using 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TBCO) as the bromine source yielded the undesired regioisomer 111 in 44% yield. Chlorination of the C2 position, however, proved more successful: treatment with N-chlorosuccinimide (NCS) in acetic acid at 80 °C gave aryl chloride 109 as the only isolable regioisomer in 45% yield. We hypothesize that the C2 position is indeed the most reactive site for electrophilic halogenation but may be sterically too hindered for bromination (Scheme 12B).

To fuse aryl chloride 109 and aldehyde 24 we planned a metalation, followed by nucleophilic 1,2-addition.

Unfortunately, attempts to form the corresponding organometallic intermediate by treatment of 109 with magnesium, magnesium and lithium chloride,[67] zinc and lithium chloride, lithium or 4,4’-di-tert-butyldiphenylide (LiDBB)[68,69] failed and either decomposition or no reaction was observed (see the Supporting Information for details). Attempts of a halogen/metal exchange using either n-BuLi or t-BuLi resulted in complex mixtures. Additionally, the lactone moiety of 109 may be incompatible with nucleophilic organolithium reagents like n-BuLi or t-BuLi. To address this, we chose to reduce the lactone moiety in 109 by treating it with triethylsilane and catalytic indium(III) bromide,[70] yielding the cyclic ether 110 in 88% yield. With this substrate in hand, we set out to investigate the metalation as well; however, in this case neither treatment with magnesium, LiDBB, n-BuLi or t-BuLi led to formation of 112, and only unreacted starting material was recovered.

To reduce steric hindrance, we synthesized a less encumbered biaryl compound 116 by slightly adapting our established synthetic route. Starting from commercially available 1-fluoro-3-methoxybenzene (113), we generated the corresponding benzyne intermediate IX, which was subsequently treated in situ with Grignard reagent 105 and carbon dioxide. This yielded crude benzoic acid 114, which was transformed into methyl ester 115 with an overall yield of 35% over two steps to simplify purification by column chromatography. Saponification afforded pure benzoic acid 114, which was then treated with NIS to induce oxidative lactonization, to lactone 116. With this substrate in hand, we screened various conditions for halogenation at the C2 position. However, under all investigated conditions, we observed exclusively the formation of undesired regioisomers (Scheme 13).

Scheme 13. Synthesis of biaryl 116 and halogenation attempts.

Scheme 13

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2.2.6. Cationic Cyclization/Fries Rearrangement

After reaching a dead end, we decided to reconsider our strategy and design a new strategy involving a cationic cyclization. We envisioned that exposure of ester 119 to a Lewis or Brønsted acid would activate the acetal group and generate the oxocarbenium ion XI and XII. This would then trigger a nucleophilic attack of the benzene ring, leading to the formation of the spiro bisacetal structure (Scheme 14A).

Scheme 14. Synthesis of bromoester 127 and attempted alkylation of lactone 21: A) retrosynthetic analysis for strategy F and B) synthesis of phenol 126.

Scheme 14

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To investigate this key step, we initially set out to synthesize α-bromoester 127 and then attach it to lactone 21 via deprotonation followed by alkylation. We commenced our synthetic endeavor with an initial esterification step (N,N′-dicyclohexylcarbodiimide (DCC), DMAP) between propiolic acid (120) and 4-methoxyphenol to yield ester 121. The terminal alkyne was brominated employing silver nitrate and NBS to afford bromoalkyne 122 (Scheme 14B). When alkyne 122 was treated with 2-methoxyfuran, a cycloaddition adduct was formed and subsequently transformed into bromobenzoate 123 upon exposure to silica gel.[40] The hydroxyl group was then protected as a benzyl ether to yield 124. To form the tricyclic structure, various C–H activation conditions were screened: We found that exposure of 124 to Pd(PPh3)2Cl2, triphenylphosphine, and sodium acetate in dimethyl acetamide (DMA) at 130 °C furnished desired product 125 in 41% yield.[71] Hydrogenolysis of the benzyl group, followed by esterification of phenol 126 with bromoacetyl bromide, yielded bromoester 127. Unfortunately, an attempt to alkylate lactone 21 with α-bromoester 127 was unsuccessful. While the lactone 21 remained intact under the reaction conditions, the α-bromoester 127 decomposed. It is likely that 127 is more acidic than 21, resulting in its deprotonation by the enolate generated from lactone 21. The resulting anion may undergo decomposition pathways.

To overcome the seemingly challenging alkylation step, we aimed for a synthesis of phenol 133 and carbonylimidazole 135 and a subsequent esterification to access 136.

We commenced our synthetic approach toward phenol 133 with the formation of bis-brominated ether 131 by treatment of a mixture of benzyl bromide 130 (see the Supporting Information for details) and phenol 129 with potassium carbonate. After screening various conditions for the crucial aryl–aryl bond formation, we found that Lipshutz’s conditions afforded the desired biaryl 132 in acceptable yields.[72,73] The MOM-protected phenol was then deprotected with aqueous hydrochloric acid, yielding phenol 133 (Scheme 15A).

Scheme 15. Attempted cationic cyclization: A) synthesis of phenol 133 and B) synthesis of amide 135 and ester 136.

Scheme 15

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With the synthesis of 133 completed, we turned our attention to the formation of ester 136. Aldehyde 13 was oxidized to the corresponding carboxylic acid 134 using the Pinnick–Lindgren–Kraus oxidation (Scheme 15B).[74] To form 136, we activated carboxylic acid 134 using Staab’s reagent (CDI) under basic conditions to obtain carbonylimidazole 135[75] and treated it with phenol 133 to give ester 136 in a 40% yield.

With the cyclization precursor 136 prepared, we tested several Lewis and Brønsted acids to initiate the cationic cyclization. However, we only observed deprotection of the acetal and desilylation upon exposure to various acids. Notably, this result was unaffected by the substituents on the hydroxyl groups, as a debenzylated intermediate also failed to form the desired product by treatment with Lewis and Brønsted acids (see the Supporting Information for details). As a result of the failure of this approach, we decided to slightly modify our synthetic strategy.

Given our recent success in synthesizing related GMs through a Fries rearrangement as the pivotal step, we chose to apply this method to ganoapplanin (3) as well.[19] This approach led us to trace key intermediate 138 back to ester 139 (Scheme 16A), which should be attainable via the esterification of phenol 140 with carboxylic acid 141.

Scheme 16. Fries rearrangement approach: A) retrosynthetic analysis for strategy F; B) synthesis of phenol 140; and C) Fries rearrangement.

Scheme 16

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To access phenol 140 we employed an oxidative dearomatization of phenol 142 (see the Supporting Information for details) using (diacetoxyiodo)benzene (PIDA), affording quinone monacetal 143 in 82% yield[76] (Scheme 16B). To construct the aryl–aryl bond, we then explored various conditions to facilitate an intramolecular 1,4-addition of aryl iodide 143 to its enone system (Table 1). Treatment of 143 with t-BuLi at -78 °C resulted in a complex mixture (entry 1). Adding hexamethylphosphoramide (HMPA) or N,N′-Dimethylpropyleneurea (DMPU) did not change the reaction outcome (entries 2 and 3). Attempts to generate an organomagnesium intermediate for 1,4-addition, using Turbo–Grignard (i-PrMgCl·LiCl) at 0 °C also resulted in the decomposition of 143 (entry 4).

Shifting away from anionic conditions, we then explored radical conditions and found that treating 143 with AIBN and tributyltin hydride at elevated temperatures yielded tricycle 144 in high yield (entry 5).[77] Further optimization by using triethylborane (BEt3) and tributyltin hydride ((n-Bu3)SnH) improved the reaction, providing the desired product 144 as a single diastereomer in 90% yield (entry 6).[78] Enone 144 was then aromatized by treatment with p-TsOH at 23 °C affording phenol 140.[79]

With the successful synthesis of phenol 140, we shifted our focus to the preparation of ester 139 (Scheme 16C). This was achieved by converting aldehyde 24 into carboxylic acid 141 under Pinnick–Lindgren–Kraus conditions, followed by treatment with Yamaguchi’s reagent,[80] 140, and NEt3, which afforded ester 139 in 69% yield.

With ester 139 in hand, we proceeded to screen conditions for the key Fries rearrangement to afford 145 (Table 2).[81] Treatment with Lewis acids such as (Sc(OTf)3, AlCl3, BF3.OEt2; entries 1–3) resulted in no reactions at lower temperatures (<100 °C) and decomposition at 150 °C. We reasoned that conditions employing Lewis acids might be too harsh for our substrate. Building on our prior work using photochemical conditions for Fries rearrangements,[19] we irradiated 139 at 254 nm.[82]

In acetonitrile or cyclohexane, only complex mixtures were formed (entries 4 and 5), while irradiating 139 in methanol gave the desired product 145 in ≈8% yield (entry 6).

Unfortunately, we were unable to establish a protocol to obtain ketone 145 in synthetically useful yields, leading us to abandon this approach. However, the remarkable efficiency of the triethylborane-mediated radical 1,4-addition of aryl iodide 143 to form the biaryl motif captured our interest. Thus, we decided to further explore the potential of incorporating this step into the total synthesis of ganoapplanin (3). The results of those investigations are presented in the next section.

2.2.7. Radical 1,4-Addition/Aldol Sequence

Building on the findings described in the previous section, we devised a new strategy to access ganoapplanin (3). For this purpose, we traced 3 back to phenol 146 through late-stage oxidation and spiro bisacetalization. 146 could arise from ß-hydroxyketone 147 via aromatization. To construct 147, we envisioned an intermolecular aldol addition of enolate XIV and aldehyde 24 (Scheme 17A). To investigate this strategy, we set out to synthesize phenol 148 (see the Supporting Information for details), which was subsequently oxidatively dearomatized to form quinone monoacetal 149. Radical initiation with triethylborane, tributyltin hydride, and air generated the corresponding aryl radical, which underwent an intramolecular 1,4-addition to form enone 150 (Scheme 17B).

Scheme 17. Retrosynthetic analysis and fusion of the components: A) retrosynthetic analysis for strategy G; B) attempted aldol addition; and C) radical 1,4-addition/aldol cascade.

Scheme 17

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With enone 150 in hand, we proceeded to screen conditions for the aldol addition to aldehyde 24 to form hydroxyketone 151. Surprisingly, treatment with bases like LDA, KHMDS, or LHMDS failed to consume the starting materials at both low temperatures (−78 °C) and 23 °C. Attempts to generate boron enolates[83] using either n-Bu2BOTf or Cy2BOTf also did not yield hydroxyketone 151 (see the Supporting Information for details). As our envisioned two step sequence including an intramolecular radical 1,4-addition followed by an intermolecular aldol addition failed, we took a closer look into literature. Reports by Utimoto[84] and Inoue[85] describe the triethylborane-mediated radical 1,4-additions of alkyl radicals into enones, followed by in situ boron enolate formation and aldol additions to aldehydes. Inspired by these intriguing results, we decided to apply these conditions to our substrates 24 and 149.

We ultimately found that radical initiation using triethylborane and oxygen in the presence of tributyltin hydride successfully induced both the intramolecular radical 1,4-addition of 149 and the intermolecular aldol reaction with aldehyde 24, yielding 151 as a mixture of diastereomers in 74% yield. Triethylborane serves a dual function in this process: (1) initiating the radical reaction to enable the 6-exo-trig cyclization of aryl radical XV,[86] and (2) forming boron enolate XVI, which facilitates the aldol addition with 24.[84,85] This sequence efficiently joined both fragments in high yield, establishing the key C3−C3a and C1−C2 bonds in a single step. Notably, the presence of both triethylborane and tributyltin hydride was essential, as omitting either reagent resulted in no desired reactivity (Scheme 17C). To construct the biaryl motif, we proceeded with the aromatization of enone 151. This sequence started by oxidizing the secondary alcohol to the ketone using DMP, followed by treatment with p-toluenesulfonic acid (p-TsOH) to obtain 152 in 80% yield. However, this method was inconsistent and difficult to reproduce. While optimizing this process, we discovered that exposing the formed ketone to 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) generated a mixture of diastereomers, which then underwent smooth aromatization when treated with p-TsOH. We then continued our synthetic route with a benzyl protection of phenol 152 yielding benzyl ether 153 almost quantitatively (92%).

To achieve the C4a oxidation and form the hydroquinone motif, we envisioned an oxidation of phenol 154 to its quinone. Therefore, we aimed for a selective deprotection of the methoxyether, which, unfortunately, turned out to be very challenging. Initial screening of conditions, including BiCl3 at −78 °C and Ph2PLi[87] at 70 °C, led to the liberation of the benzyl protected phenol through debenzylation. Treatment with either BBr3 or AlCl3 and t-BuSH, however, resulted in decomposition. When 153 was subjected to LiCl[88] or Na2S[89] at elevated temperatures, no reaction was observed (see the Supporting Information for details).

Since we were unable to remove the protecting group from 153, we slightly modified our key radical addition/aldol reaction cascade, opting to use quinone monoacetal 143 with a MOM protected phenol that could be removed in later stages (Scheme 18A). To our satisfaction, the key cascade reaction with aldehyde 24 and quinone monoacetal 143 proceeded smoothly, yielding hydroxyketone 155 in 81%. Next, we oxidized the secondary alcohol to the corresponding ketone (not shown) and carried out the aromatization of the enone moiety under previously used conditions (DMP, DBU, and p-TsOH) to obtain biaryl 145 in 49% yield. This yield was somewhat lower than that of biaryl 152 (80% over three steps), likely due to the acid sensitivity of the MOM protecting group.

Scheme 18. Sequence leading to bisphenol 157 and synthesis of aldehyde 161: A) synthesis of phenol 157 and B) synthesis of aldehyde 161.

Scheme 18

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To continue, the unprotected C1 phenol group was masked as a MOM ether, the benzyl ether was cleaved from the primary and subsequently oxidized to aldehyde 156 using DMP. The following cleavage of the MOM ethers was realized by treatment with an excess of TMSBr and was followed by desilylation using HF·pyridine and dimethylacetalization of the aldehyde moiety using p-TsOH, CH(OMe)3, and methanol.

With bis-phenol 157 synthesized, we proceeded to attempt the C4a oxidation. Using hypervalent iodine reagents, such as (bis(trifluoroacetoxy)iodo)benzene (PIFA) and PIDA, only led to complex mixtures. Other commonly used quinone-forming oxidants, including Fremy’s salt, CAN, salcomine/O2, K2CO3/O2, and CrO3, showed no reactivity, as 157 was not consumed in any of these attempts (see the Supporting Information for details).

From these C4a oxidation attempts, we concluded that a protecting group on the C1 phenol is necessary to prevent undesired side reactions. We opted for a PMB protecting group and treated phenol 159 with PMBCl and K2CO3 leading to ether 160 in nearly quantitative yield. Oxidation to aldehyde 161 was achieved using DMP (83% yield). However, attempts to cleave the MOM ether proved challenging due to the greater lability of the PMB protecting group on the C1 phenol. Conditions involving either Lewis or Brønsted acids selectively removed the PMB group or simultaneously cleaved both the PMB and MOM protecting groups, ultimately yielding phenol 157 (Scheme 18B).

We were then keen to investigate the usability of a benzyl protecting group on the C1 phenol. For this purpose, we conducted a chemoselective benzylation of the phenol group of 159, followed by the oxidation of the primary alcohol to corresponding aldehyde 163. At this stage, we removed the MOM and TBS protecting groups through sequential treatment with TMSBr[90] and HF·pyridine and the aldehyde group was then transformed into a dimethyl acetal under acidic conditions, providing 164 in 67% yield. For the critical oxidation of the C4a position, we converted the phenol to the corresponding quinone 165, which was immediately reduced with sodium dithionite. Unexcitedly, the spiro bisacetal structure was not formed under these conditions. Instead, we identified enol ether 166 as the sole component in the crude 1H-NMR. Unfortunately, enol ether 166 was unstable on silica gel, making isolation challenging. We assume 166 forms through the elimination of the corresponding hemiacetal XVIII. Subjecting 166 to concentrated sulfuric acid at elevated temperatures (60 °C) produced trace amounts of spiro bisacetal 167 (Scheme 19). We were surprised to find that the alcohol group of the formed hemiacetal XVIII did not react with the dimethyl acetal to yield the desired spiro bisacetal structure. We hypothesize that this outcome may be due to steric hindrance from the benzyl protecting group on the C1 phenol. To test this hypothesis, we attempted the C4a oxidation using an acetyl protecting group at the C1 phenol.

Scheme 19. Synthesis of acetal 165.

Scheme 19

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Phenol 159 was treated with acetic anhydride and triethylamine to give the corresponding acetyl ester, which was then subjected to DMP, which smoothly oxidized the primary alcohol to aldehyde 168 in 99% yield.[28] The MOM and TBS protecting groups were subsequently removed using TMSBr and HF·pyridine to give phenol 169. We then turned our attention to the C4a oxidation followed by reductive spiro bisacetalization. Oxidation with PIFA generated quinone 170, which proved to be unstable and was therefore used directly in the next step without purification. Treating a solution of crude quinone 170 in ethyl acetate with sodium dithionite resulted in a mixture of hydroquinone XIX and hemiacetal XX, which was then converted into spiro bisacetal 171 using trimethyl orthoformate and p-TsOH in methanol. Interestingly, in this case, we did not observe the elimination of water from the formed intermediate as we did not detect formation of the corresponding enol ether. To ensure efficient oxidation at the benzylic position, we protected the phenol moiety as its acetyl ester, followed by treatment with tert-butyl hydroperoxide and catalytic copper(I) chloride to yield the corresponding lactone.[91] In the final step, the acetyl protecting groups were removed with potassium carbonate in methanol, completing the synthesis of ganoapplanin (3) (Scheme 20).

Scheme 20. Synthesis of ganoapplanin (3).

Scheme 20

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This culminated in the first published total synthesis of the dimeric Ganoderma natural product, ganoapplanin (3), achieved in 25 steps (20 steps in the longest linear sequence).[28] The spectroscopic data of synthetic ganoapplanin (3) were in full agreement with the literature values.[4] To further enhance the efficiency of our synthetic sequence for ganoapplanin (3), we focused on improving the key radical 1,4-addition/aldol cascade. Using quinone monoacetal 143 in this cascade requires introducing the hydroquinone motif later in the synthesis via oxidation of phenol 169. We wondered whether it would be possible to use a highly oxidized aromatic fragment, already containing the hydroquinone motif, for the cascade reaction, thereby eliminating the need for the C4a oxidation step. To explore this, we set out to synthesize quinone monoacetal 172 (see the Supporting Information for details). Unfortunately, when we attempted the radical 1,4-addition/aldol sequence with aldehyde 24 and quinone monoacetal 172 at −78 °C, the aldol product 173 did not form. However, we did observe the formation of tricycle 174, indicating that the 1,4-addition step was successful, but the aldol addition failed. Increasing the reaction temperature to −50 or 0 °C did not change the outcome, while running the reaction at 23 °C led to decomposition of the starting materials (Scheme 21).[92]

Scheme 21. Attempted radical 1,4-addition/aldol sequence employing quinone monoacetal 172.

Scheme 21

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3. Conclusion

In conclusion, we have reported the development of the first synthetic access to the GM ganoapplanin (3). Our studies explored the convergent assembly of a range of aromatic fragments with the southern terpenoid component. A key step in constructing the latter was a highly efficient and diastereoselective titanium-mediated iodolactonization. Our initial strategy utilized two consecutive [4 + 2]-cycloadditions of a diyne motif with 2-methoxyfuran to generate the highly functionalized biaryl core. While the first cycloaddition was successful, attempts to achieve the second failed. We then pivoted to the synthesis of functionalized biaryl lactones, accessed through the Stille–Kelly reaction, and investigated several methods to link these to the southern terpenoid fragment. As these attempts were unsuccessful, we employed a nickel-mediated coupling to forge the aryl–aryl bond at a later stage, successfully synthesizing a biaryl lactone with the complete carbon skeleton of ganoapplanin (3). Unfortunately, attempts to install the missing phenol moiety at C4a via late-stage oxidations were unsuccessful. We next turned to halogenated biaryls, aiming to add them to the southern fragment via nucleophilic additions. This strategy involved the addition of an organomagnesium reagent to an aryne, followed by reaction with carbon dioxide to form a benzoic acid, which underwent oxidative lactonization. While selective chlorination of the biaryl lactone was achieved, subsequent metalation proved unfeasible. This led us to investigate new strategies based on Fries rearrangements and cationic cyclizations. Here, phenol-containing biaryls were esterified with the southern fragment, followed by a Lewis acid or light-mediated acyl migration. Unfortunately, these methods either resulted in decomposition or lacked efficiency (Scheme 16). A breakthrough was achieved with a two-component coupling strategy involving a 6-exo-trig radical addition of a quinone monoacetal, followed by an intermolecular aldol reaction cascade. This cascade simultaneously constructed the C3−C3a bond and fused the northern and southern fragments. Two late-stage oxidations then facilitated the critical C4a oxidation and the introduction of both the spiro bisacetal skeleton and the lactone moiety. This strategy culminated in the first total synthesis of ganoapplanin (3) (Scheme 22).

Scheme 22. Synthetic route to ganoapplanin (3).

Scheme 22

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Table 1. Screened reaction conditions for intramolecular 1,4-addition of 143.

graphic file with name EMS211543-i001.jpg
Entry Conditions Solvent T [°C] Observation
1 t-BuLi THF –78 Decomposition
2 t-BuLi, HMPA THF –78 Decomposition
3 t-BuLi, DMPU THF –78 Decomposition
4 i-PrMgCl.LiCl THF 0 Decomposition
5 AIBN, (n-Bu3)SnH Toluene 50 70%
6 BEt3, (n-Bu3)SnH Toluene –50 90%
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Table 2. Screened reaction conditions for the Fries rearrangement of 139.

graphic file with name EMS211543-i002.jpg
Entry Conditions Solvent T [°C] Observation
1 Sc(OTf)3 1,2-dichlorobenzene 150 Decomposition
2 AlCl3 1,2-dichlorobenzene 150 Decomposition
3 BF3.OEt2 1,2-dichlorobenzene 150 Decomposition
4 254 nm MeCN 23 Traces of 145
5 254 nm Cyclohexane 23 Traces of 145
6 254 nm MeOH 23 8%
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Acknowledgements

N.M., O.K., and A.R. contributed equally to this work. This research was funded in whole or in part by the Austrian Science Fund (FWF) [10.55776/P33894] and the Tyrolean Science Fund TWF (F.33842/7-2021 to N.M.). For open access purposes, the author has applied for a CC BY public copyright license to any author accepted manuscript version arising from this submission. The authors 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. O.K. received financial support from the Experientia Foundation, while Ana Victoria Serna is grateful for funding provided by the Wagoner Fellowship. The authors are grateful to Immanuel Plangger (University of Innsbruck) for assistance in the preparation of this manuscript, and Prof. Christoph Kreutz (University of Innsbruck) and Prof. Thomas Müller (University of Innsbruck) for NMR and HRMS studies.

Footnotes

Conflict of Interest

The authors declare no conflict of interest.

Supporting information for this article is available on the WWW under https://doi.org/10.1002/ceur.202500020

Contributor Information

Nicolas Müller, Department of Organic Chemistry and Center for Molecular Biosciences, University of Innsbruck, Innrain 80–82, 6020 Innsbruck, Austria.

Ondřej Kováč, Department of Organic Chemistry and Center for Molecular Biosciences University of Innsbruck, Innrain 80–82, 6020 Innsbruck, Austria; Department of Organic Chemistry, Palacký University Olomouc, tř. 17. listopadu 1192/12, 77900 Olomouc, Czech Republic.

Ana V. Serna, Department of Organic Chemistry and Center for Molecular Biosciences University of Innsbruck, Innrain 80–82, 6020 Innsbruck, Austria; Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104, USA

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.

References

  • [1].Peng X, Qiu M. Nat Prod Bioprospect. 2018;8:137. doi: 10.1007/s13659-018-0164-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [2].Qin F-Y, Zhang J-J, Wang D-W, Xu T, Cai D, Cheng Y-X. J Funct Foods. 2021;87:104758 [Google Scholar]
  • [3].Yan Y-M, Wang X-L, Zhou L-L, Zhou F-J, Li R, Tian Y, Zuo Z-L, Fang P, Chung ACK, Hou F-F, Cheng Y-X. J Ethnopharmacol. 2015;176:385. doi: 10.1016/j.jep.2015.11.024. [DOI] [PubMed] [Google Scholar]
  • [4].Li L, Li H, Peng X-R, Hou B, Yu M-Y, Dong J-R, Li X-N, Zhou L, Yang J, Qiu MH. Org Lett. 2016;18:6078. doi: 10.1021/acs.orglett.6b03064. [DOI] [PubMed] [Google Scholar]
  • [5].Luo Q, Tian L, Di L, Yan Y-M, Wei X-Y, Wang X-F, Cheng Y-X. Org Lett. 2015;17:1565. doi: 10.1021/acs.orglett.5b00448. [DOI] [PubMed] [Google Scholar]
  • [6].Gomberg M, Bachmann WE. J Am Chem Soc. 1924;46:2339 [Google Scholar]
  • [7].Rüchardt C, Merz E. Tetrahedron Lett. 1964;5:2431 [Google Scholar]
  • [8].Kawamoto Y, Ito H. Asian J Org Chem. 2024;13:e202300633 [Google Scholar]
  • [9].Mashiko T, Shingai Y, Sakai J, Kamo S, Adachi S, Matsuzawa A, Sugita K. Angew Chem Int Ed. 2021;60:24484. doi: 10.1002/anie.202110556. [DOI] [PubMed] [Google Scholar]
  • [10].Mashiko T, Shingai Y, Sakai J, Adachi S, Matsuzawa A, Kamo S, Sugita K. Org Lett. 2023;25:8382. doi: 10.1021/acs.orglett.3c03572. [DOI] [PubMed] [Google Scholar]
  • [11].Richardson AD, Vogel TR, Traficante EF, Glover KJ, Schindler CS. Angew Chem Int Ed. 2022;61:e202201213. doi: 10.1002/anie.202201213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Zhou Q, Ma X, Qiao J, He W, Jiang M, Shao H, Zhao Y. Chem Eur J. 2024;30:e202400084. doi: 10.1002/chem.202400084. [DOI] [PubMed] [Google Scholar]
  • [13].Long R, Huang J, Shao W, Liu S, Lan Y, Gong J, Yang Z. Nat Commun. 2014;5:5707. doi: 10.1038/ncomms6707. [DOI] [PubMed] [Google Scholar]
  • [14].Chen D, Liu H-M, Li M-M, Yan Y-M, Xu W-D, Li X-N, Cheng Y-X, Qin H-B. Chem Commun. 2015;51:14594. doi: 10.1039/c5cc05680b. [DOI] [PubMed] [Google Scholar]
  • [15].Li X, Liu X, Jiao X, Yang H, Yao Y, Xie P. Org Lett. 2016;18:1944. doi: 10.1021/acs.orglett.6b00542. [DOI] [PubMed] [Google Scholar]
  • [16].Sharmah Gautam K, Birman VB. Org Lett. 2016;18:1499. doi: 10.1021/acs.orglett.5b03212. [DOI] [PubMed] [Google Scholar]
  • [17].Mehl L-M, Maier ME. J Org Chem. 2017;82:9844. doi: 10.1021/acs.joc.7b01416. [DOI] [PubMed] [Google Scholar]
  • [18].Riehl PS, Richardson AD, Sakamoto T, Schindler CS. Org Lett. 2020;22:290. doi: 10.1021/acs.orglett.9b04322. [DOI] [PubMed] [Google Scholar]
  • [19].Rode A, Müller N, Kováč O, Wurst K, Magauer T. Org Lett. 2024;26:9017. doi: 10.1021/acs.orglett.4c03192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Zhang W, Xiao D, Wang B. Org Biomol Chem. 2018;16:3358. doi: 10.1039/c8ob00615f. [DOI] [PubMed] [Google Scholar]
  • [21].Paterson RRM. Phytochemistry. 2006;67:1985. doi: 10.1016/j.phytochem.2006.07.004. [DOI] [PubMed] [Google Scholar]
  • [22].Zaichick SV, McGrath KM, Caraveo G. Dis Models Mech. 2017;10:519. doi: 10.1242/dmm.028738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Rajakulendran S, Hanna MG. Cold Spring Harbor Perspect Med. 2016;6:a022723. doi: 10.1101/cshperspect.a022723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Unzner TA, Grossmann AS, Magauer T. Angew Chem Int Ed. 2016;55:9763. doi: 10.1002/anie.201605071. [DOI] [PubMed] [Google Scholar]
  • [25].Feierfeil J, Magauer T. Chem Eur J. 2018;24:1455. doi: 10.1002/chem.201705662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Zamarija I, Marsh BJ, Magauer T. Org Lett. 2021;23:9221. doi: 10.1021/acs.orglett.1c03530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Röder L, Wurst K, Magauer T. Org Lett. 2024;26:3065. doi: 10.1021/acs.orglett.4c00695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Müller N, Kováč O, Rode A, Atzl D, Magauer T. J Am Chem Soc. 2024;146:22937. doi: 10.1021/jacs.4c08291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Kitagawa O, Inoue T, Taguchi T. Tetrahedron Lett. 1994;35:1059 [Google Scholar]
  • [30].Inoue T, Kitagawa O, Oda Y, Taguchi T. J Org Chem. 1996;61:8256. doi: 10.1021/jo961076+. [DOI] [PubMed] [Google Scholar]
  • [31].Okude Y, Hirano S, Hiyama T, Nozaki H. J Am Chem Soc. 1977;99:3179 [Google Scholar]
  • [32].Morrill C, Péter Á, Amalina I, Pye E, Crisenza GEM, Kaltsoyannis N, Procter DJ. J Am Chem Soc. 2022;144:13946. doi: 10.1021/jacs.2c05972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Kohara K, Trowbridge A, Smith MA, Gaunt MJ. J Am Chem Soc. 2021;143:19268. doi: 10.1021/jacs.1c09445. [DOI] [PubMed] [Google Scholar]
  • [34].Wollnitzke P, Essig S, Gölz JP, Von Schwarzenberg K, Menche D. Org Lett. 2020;22:6344. doi: 10.1021/acs.orglett.0c02188. [DOI] [PubMed] [Google Scholar]
  • [35].Riaz MT, Pohorilets I, Hernandez JJ, Rios J, Totah NI. Tetrahedron Lett. 2018;59:2809 [Google Scholar]
  • [36].Krapcho AP, Mundy BP. Tetrahedron. 1970;26:5437 [Google Scholar]
  • [37].Mancuso AJ, Huang S-L, Swern D. J Org Chem. 1978;43:2480 [Google Scholar]
  • [38].Omura K, Swern D. Tetrahedron. 1978;34:1651 [Google Scholar]
  • [39].Taylor EC, Palmer DC, George TJ, Fletcher SR, Tseng CP, Harrington PJ, Beardsley GP, Dumas DJ, Rosowsky A, Wick M. J Org Chem. 1983;48:4852 [Google Scholar]
  • [40].Shinohara H, Sonoda M, Hayagane N, Kita S, Tanimori S, Ogawa A. Tetrahedron Lett. 2014;55:5302 [Google Scholar]
  • [41].Zhu G-D, Staeger MA, Boyd SA. Org Lett. 2000;2:3345. doi: 10.1021/ol0064359. [DOI] [PubMed] [Google Scholar]
  • [42].Moreno A, Gómez MV, Vázquez E, De La Hoz A, Díaz-Ortiz A, Prieto P, Mayoral JA, Pires E. Synlett. 2004;1259 [Google Scholar]
  • [43].Nawrotek A, Benabdi S, Niyomchon S, Kryszke M-H, Ginestier C, Cañeque T, Tepshi L, Mariani A, Onge RP, St, Giaever G, Nislow C, et al. Nat Chem Biol. 2019;15:358. doi: 10.1038/s41589-019-0228-3. [DOI] [PubMed] [Google Scholar]
  • [44].Hugelshofer C, Magauer T. Synthesis. 2014;46:1279 [Google Scholar]
  • [45].Seebach D. Angew Chem Int Ed Eng. 1979;18:239. [Google Scholar]
  • [46].Koshimizu M, Nagatomo M, Inoue M. Tetrahedron. 2018;74:3384 [Google Scholar]
  • [47].Ross Kelly T, Li Q, Bhushan V. Tetrahedron Lett. 1990;31:161. [Google Scholar]
  • [48].Yue WS, Li JJ. Org Lett. 2002;4:2201. doi: 10.1021/ol0260425. [DOI] [PubMed] [Google Scholar]
  • [49].Halder P, Mondal K, Jash A, Das P. J Org Chem. 2024;89:9275. doi: 10.1021/acs.joc.4c00234. [DOI] [PubMed] [Google Scholar]
  • [50].Schnur RC, Morville M. J Med Chem. 1986;29:770. doi: 10.1021/jm00155a030. [DOI] [PubMed] [Google Scholar]
  • [51].Wang Z. Comprehensive Organic Name Reactions And Reagents. John Wiley & Sons; Hoboken, New Jersey, USA: 2010. pp. 2081–2083. [Google Scholar]
  • [52].Zhuang Z, Li C-L, Xiang Y, Wang Y-H, Yu Z-X. Chem Commun. 2017;53:2158. doi: 10.1039/c6cc09925d. [DOI] [PubMed] [Google Scholar]
  • [53].Riley HL, Morley JF, Friend NAC. J Chem Soc. 1932;1875 [Google Scholar]
  • [54].Duchemin C, Smits G, Cramer N. Organometallics. 2019;38:3939 [Google Scholar]
  • [55].Tatsuta K, Furuyama A, Yano T, Suzuki Y, Ogura T, Hosokawa S. Tetrahedron Lett. 2008;49:4036 [Google Scholar]
  • [56].Moser W, Howie RA. J Chem Soc, A. 1968;3039 [Google Scholar]
  • [57].Munive L, Gómez-Calvario V, Olivo HF. Tetrahedron Lett. 2017;58:2445 [Google Scholar]
  • [58].Zoratti M, Bunnett JF. J Org Chem. 1980;45:1769 [Google Scholar]
  • [59].Kang Q, Lin Y, Li Y, Xu L, Li K, Shi H. Angew Chem Int Ed. 2021;60:20391. doi: 10.1002/anie.202106440. [DOI] [PubMed] [Google Scholar]
  • [60].Larrosa I, Da Silva MI, Gómez PM, Hannen P, Ko E, Lenger SR, Linke SR, White AJP, Wilton D, Barrett AGM. J Am Chem Soc. 2006;128:14042. doi: 10.1021/ja0662671. [DOI] [PubMed] [Google Scholar]
  • [61].Tomori H, Fox JM, Buchwald SL. J Org Chem. 2000;65:5334. doi: 10.1021/jo000691h. [DOI] [PubMed] [Google Scholar]
  • [62].Gao P, Wei Y. Synthesis. 2013;46:343. [Google Scholar]
  • [63].Li Y, Ding Y-J, Wang J-Y, Su Y-M, Wang X-S. Org Lett. 2013;15:2574. doi: 10.1021/ol400877q. [DOI] [PubMed] [Google Scholar]
  • [64].Wang Y, Gulevich AV, Gevorgyan V. Chem Eur J. 2013;19:15836. doi: 10.1002/chem.201303511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [65].Wadekar K, Aswale S, Yatham VR. Org Biomol Chem. 2020;18:983. doi: 10.1039/c9ob02676b. [DOI] [PubMed] [Google Scholar]
  • [66].Zhang L, Zhang Z, Hong J, Yu J, Zhang J, Mo F. J Org Chem. 2018;83:3200. doi: 10.1021/acs.joc.8b00089. [DOI] [PubMed] [Google Scholar]
  • [67].Piller FM, Appukkuttan P, Gavryushin A, Helm M, Knochel P. Angew Chem Int Ed. 2008;47:6802. doi: 10.1002/anie.200801968. [DOI] [PubMed] [Google Scholar]
  • [68].Hill RR, Rychnovsky SD. J Org Chem. 2016;81:10707. doi: 10.1021/acs.joc.6b01748. [DOI] [PubMed] [Google Scholar]
  • [69].Shen Z-L, Sommer K, Knochel P. Synthesis. 2015;47:2617 [Google Scholar]
  • [70].Sakai N, Moriya T, Fujii K, Konakahara T. Synthesis. 2008;2008:3533 [Google Scholar]
  • [71].Chen G-Q, Lin B-J, Huang J-M, Zhao L-Y, Chen Q-S, Jia S-P, Yin Q, Zhang X. J Am Chem Soc. 2018;140:8064. doi: 10.1021/jacs.8b03642. [DOI] [PubMed] [Google Scholar]
  • [72].Spring DR, Krishnan S, Blackwell HE, Schreiber SL. J Am Chem Soc. 2002;124:1354. doi: 10.1021/ja017248o. [DOI] [PubMed] [Google Scholar]
  • [73].Lipshutz BH, Siegmann K, Garcia E. J Am Chem Soc. 1991;113:8161 [Google Scholar]
  • [74].Lindgren BO, Nilsson T, Husebye S, Mikalsen Ø, Leander K, Swahn C-G. Acta Chem Scand. 1973;27:888. [Google Scholar]
  • [75].Staab HA. Angew Chem Int Ed Eng. 1962;1:351. [Google Scholar]
  • [76].Imbos R, Minnaard AJ, Feringa BL. J Am Chem Soc. 2002;124:184. doi: 10.1021/ja017200a. [DOI] [PubMed] [Google Scholar]
  • [77].Clive DLJ, Fletcher SP, Liu D. J Org Chem. 2004;69:3282. doi: 10.1021/jo030364k. [DOI] [PubMed] [Google Scholar]
  • [78].Liu J-Y, Jang Y-J, Lin W-W, Liu J-T, Yao C-F. J Org Chem. 2003;68:4030. doi: 10.1021/jo020681b. [DOI] [PubMed] [Google Scholar]
  • [79].Clive DLJ, Fletcher SP, Zhu M. Chem Commun. 2003;526 doi: 10.1039/b212223e. [DOI] [PubMed] [Google Scholar]
  • [80].Inanaga J, Hirata K, Saeki H, Katsuki T, Yamaguchi M. Bull Chem Soc Jpn. 1979;52:1989 [Google Scholar]
  • [81].Fries K, Finck G. Ber Dtsch Chem Ges. 1908;41:4271 [Google Scholar]
  • [82].Anderson JC, Reese CB. J Chem Soc. 1963;1781 [Google Scholar]
  • [83].Evans DA, Nelson JV, Vogel E, Taber TR. J Am Chem Soc. 1981;103:3099 [Google Scholar]
  • [84].Nozaki K, Oshima K, Utimoto K. Tetrahedron Lett. 1988;29:1041 [Google Scholar]
  • [85].Nagatomo M, Kamimura D, Matsui Y, Masuda K, Inoue M. Chem Sci. 2015;6:2765. doi: 10.1039/c5sc00457h. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [86].Curran DP, McFadden TR. J Am Chem Soc. 2016;138:7741. doi: 10.1021/jacs.6b04014. [DOI] [PubMed] [Google Scholar]
  • [87].Ireland RE, Walba DM. Org Synth. 1977;56:44. [Google Scholar]
  • [88].Bernard AM, Ghiani MR, Piras PP, Rivoldini A. Synthesis. 1989;1989:287. [Google Scholar]
  • [89].Newman MS, Sankaran V, Olson DR. J Am Chem Soc. 1976;98:3237. doi: 10.1021/ja00427a031. [DOI] [PubMed] [Google Scholar]
  • [90].Huffman JW, Zhang X, Wu MJ, Joyner HH, Pennington WT. J Org Chem. 1991;56:1481 [Google Scholar]
  • [91].Tanaka H, Oisaki K, Kanai M. Synlett. 2017;28:1576 [Google Scholar]
  • [92].Müller N, Kováč O, Rode A, Atzl D, Magauer T. Synlett. 2024 doi: 10.1055/a-2501-4079. [DOI] [PMC free article] [PubMed] [Google Scholar]

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Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.

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