Meroterpenoid Synthesis via Sequential Polyketide Aromatization and Cationic Polyene Cyclization: Total Syntheses of (+)-Hongoquercin A and B and Related Meroterpenoids.

(+)-Hongoquercin A and B were synthesized from commercially available trans, trans-farnesol in six and eleven steps, respectively, using dual biomimetic strategies with polyketide aromatization and subsequent polyene functionalization from a common farnesyl-resorcylate intermediate. Key steps involve Pd(0)-catalyzed decarboxylative allylic rearrangement of a dioxinone β,δ-diketo ester to a β,δ-diketo dioxinone, which was readily aromatized into the corresponding resorcylate, and subsequent polyene cyclization via enantioselective protonation or regioselective terminal alkene oxidation and cationic cyclization of enantiomerically enriched epoxide to furnish the tetracyclic natural product cores. Analogues of the hongoquercin were synthesized via halonium-induced polyene cyclizations, and the meroterpenoid could be further functionalized via saponification, hydrolytic decarboxylation, reduction, and amidation reactions.

Introduction

(+)-Hongoquercin A (1) and B (2) were isolated from the fermentation broths produced by an unidentified fungus in 1998 independently by Roll and Abbanat (Figure ).[1] They exhibited modest antibacterial activity against methicillin-resistant n class="Species">Staphylococcus aureus and vancomycin-resistant Enterococcus faecium.[1] These natural products are meroterpenoids which have a mixed biosynthetic origin involving polyketide and terpenoid pathways. (−)-Siccanin (3) and (−)-austalide K (4) are additional examples of such structurally diverse bioactive meroterpenoids.[2]

Figure 1

Bioactive meroterpenoid natural products.

Over the last two decades, several total syntheses of hongoquercins 5 have been reported.[3] The common synthetic strategy involves the coupling of two synthons, an enantiopure synthesized n class="Chemical">drimene 6 coupled with a substituted resorcinol derivative 7 (Scheme ). However, this conventional approach often requires extensive use of protecting groups on the resorcinol unit 7 and multistep transformations for the synthesis of the precursor drimene 6. Most of the reported processes for the preparation of the resorcinol rely on extensive derivatization of an aromatic precursor, while alternative synthetic strategies to prepare resorcinol, such as benzannulation, have been shown to be more concise and flexible.[4] Therefore, we considered that a dual biomimetic approach for elaborating the arene ring and tricyclic terpenoid residues from acyclic precursor 9 sequentially via cascade cyclizations would simplify the syntheses of these natural products. Additionally, if the farnesyl residue was functionalized after aromatization to construct the resorcylate entity, a diverse range of hongoquercin analogues 8 should be available by variation of the electrophilic reagents used in such derivatizations.

Scheme 1

Synthetic Strategies of the Hongoquercins 5

Inspired by the pioneering work of the Harris group and Hyatt group, respectively, on the biomimetic synthesis of β-resorylate and on the generation of acyl ketenes by the thermolysis of n class="Chemical">dioxinones,[5,6] our group has developed a biomimetic route to β-resorylate natural products that utilizes β,δ-diketo dioxinones as masked triketo ketenes.[7] In 2009, we additionally discovered a regioselective palladium(0)-catalyzed decarboxylative rearrangement during the synthesis of aigialomycin D.[8] Application of this reaction greatly facilitated the synthesis of meroterpenoid resorcylate natural products.[9] More recently, we developed an efficient methodology for the synthesis of dioxinone β-keto esters 12 using dioxane-4,6-dione keto dioxanones 10 as the masked dioxinone acylketene 11 (Scheme ).[10] Application of this reaction provided an efficient route for the synthesis of β-resorylates, and its utility has been showcased in the total syntheses of several bioactive meroterpenoid natural products.[10] Herein we report further extensive studies on the dual biomimetic total synthesis of the hongoquercins 5, which we initially published as a communication.[9e]

Scheme 2

Thermolysis of Dioxane-4,6-dione Ketodioxanones 10

Results and Discussion

We considered that the key meroterpenoids 13 should be available using a n class="Chemical">polyene cyclization from resorcylate 14 by enantioselective electrophilic reactions with chiral Brønsted acids (E = H), epoxidation, and subsequent reaction with a Lewis acid (E = OH) or halogenations with reagents that provide halonium ion intermediates (E = Br and I) (Scheme ). The common resorcylate intermediate 14 should be available from the cycloaromatization of β,δ-diketodioxinone 9, which could be synthesized via palladium(0)-catalyzed decarboxylative allylic rearrangement of dioxinone β,δ-diketo ester 15. Dioxinone β,δ-diketo ester 15, in turn, should be available via C-acylation of dioxinone β-keto ester 16, which, in turn, is available from trapping a dioxinone acylketene with trans,trans-farnesol (17).[10]

Scheme 3

Retrosynthetic Analyses of Hongoquercins A (1) and B (2)

Following our recently published methods,[10] thermolysis of dioxane-4,6-dione keto dioxanone 19 at 55 °C generated the n class="Chemical">dioxinone acyl ketene 11, which was trapped with trans,trans-farnesol (17) to provide dioxinone β-keto ester 21 (79%) (Scheme ). Magnesium chloride mediated regioselective C-acylation of β-keto ester 21 with acetyl chloride gave dioxinone β,δ-diketo ester 23, which on reaction with Pd2(dba)3 and tri(2-furyl)phosphine resulted in a highly regioselective decarboxylative allylic rearrangement giving the β,δ-diketo dioxinone 9 and readily aromatized in situ to produce farnesyl resorcylate 14 (55% overall from 21). A geranyl-substituted analogue 24 was also synthesized, using the same reaction sequence, from geraniol (18) in three steps with an overall yield of 57%.

Scheme 4

Synthesis of the Terpene Resorcylates 14 and 24

We first investigated the synthesis of (+)-hongoquercin A (1) via n class="Chemical">enantioselective protonation of farnesyl resorcylate 14 (Scheme ) using the Lewis acid enhanced chiral Brønsted acids derived from antimony pentachloride with binol 25 and stannic chloride with binol 26 as introduced by Corey et al.[11] and Yamamoto et al.[12] Enantioselective protonation with SbCl5·25 gave a mixture of partially cyclized products from which the desired meroterpenoid 23 was isolated in 15% yield and with an enantiomeric excess of 20% as determined by chiral HPLC. Fortunately, the cyclization using SnCl4·26 as the dual Brønsted and Lewis acids was highly enantioselective and gave the desired meroterpenoid 27 (61%, 81% dr and 90% ee as determined by chiral HPLC) on sequential reaction with SnCl4·26 and SnCl4 and trifluoroacetic acid. Finally, saponification[13] of meroterpenoid 27 gave (+)-hongoquercin A (1) (75%) with an overall yield of 20% over five5 steps from trans,trans-farnesol 17. The spectroscopic data were in full agreement with that reported for the isolated natural product,[1] and the structure was unambiguously confirmed by single-crystal X-ray crystallography.

Scheme 5

Total Synthesis of (+)-Hongoquercin A (1)

Next, we focused on the synthesis of (+)-hongoquercin B, which utilized n class="Chemical">enantioselective epoxidation (Scheme ). While we had reported the synthesis of this natural product from the farnesyl derivative 33,[9e] we wished to reinvestigate this synthesis with late-stage oxidation of the terminal alkene on the pendant farnesyl side chain since this should greatly facilitate the synthesis and bioassay of a focused library of novel hongoquercin analogues with the late-stage introduction of terpene structural diversity. In order to effect such electrophilic functionalization of the terminal alkene unit, we needed to suppress phenol-directed oxidation.[14] We found that protection by phenol allylation was suitable for this purpose. Allylation of farnesyl resorcylate 14 gave allyl ether 28 (77%), which was subjected to dihydroxylation in the presence of the Corey dihydroquinidine ligand 29, thus producing the (R)-diol 30 (58%, 78% brsm, 88% ee as determined by Mosher ester analysis).[15] Diol 30 was subsequently converted into the (S)-epoxide 31 (93%) via mesylation and potassium carbonate mediated cyclization. The allyl protecting group was selectively removed by reaction with dimethylbarbituric acid 32 catalyzed by Pd(PPh3)4 to provide epoxide 33 (91%).[16] After screening a variety of different Lewis acids with epoxide 33, it was found that ferric chloride hydrate was a superior Lewis acid catalyst to boron trifluoride etherate,[9e] which we previously reported for this cyclization of epoxide 33 to provide meroterpenoid 34. The use of boron trifluoride etherate often led to the formation of undesired byproducts such as bicyclic ethers and partially cyclized products. Such side reactions and irreproducibility were substantially suppressed using ferric chloride hydrate.[17] Thus, treatment of epoxide 33 with FeCl3·6H2O resulted in biomimetic cationic cyclization to give meroterpeonoid 34 (56%, 92% ee as determined by chiral HPLC) as a single diastereoisomer. Saponification of meroterpenoid 34 gave acid 35 (69%),[13] which was subjected to acetylation to provide diacetate 36. Subsequent selective deacetylation of the phenolic acetate gave (+)-hongoquercin B (66%) with an overall yield of 3.7% over 11 steps. The analytical data for this synthetic material are in full agreement with that reported for the isolated natural product.[1]

Scheme 6

Total Synthesis of (+)-Hongoquercin B (2)

Additional meroterpenoids analogues were prepared via epoxidation (Scheme ) and halogenations (Scheme ). First, the n class="Chemical">geranyl-substituted resorcylate 24 was protected as its silyl ether 37 (76%) and epoxidized with the dioxirane derived from the Shi chiral ketone 38 to give epoxide 39 (69%).[18] Subsequent deprotection gave epoxide 40 (92%), which was cyclized using boron trifluoride etherate to give meroterpenoid 41 (77%, 84% ee as determined by chiral HPLC) as a single diastereoisomer. The (S)-enantiomer of meroterpenoid 41 (98% ee as determined by chiral HPLC) was obtained by recrystallization to enhance chiral purity. Second, we examined the halonium-induced polyene cyclization of the resorcylates to produce additional analogues (Scheme ).[19] Reaction of the geranyl resorcylate 24 with the Snyder reagents Et2SBr·SbCl5Br (BDSB, 46) and (Et2SI)2Cl·SbCl6 (IDSI, 47) resulted in bromo- and iodo-cyclizations to produce the racemic bromo-meroterpenoid 42 (64%) and racemic iodo-meroterpenoid 43 (88%) as single diastereoisomers, respectively. Racemic bromide 44 (45%, 2:1 dr) and racemic iodide 45 (54%, 2:1 dr) were also successfully synthesized from farnesyl-substituted resorcylate 14 using the BDSB- (46) and IDSI-mediated (47) halocyclizations.[20]

Scheme 7

Synthesis of Meroterpenoid 41

Scheme 8

Halocyclizations To Produce Meroterpenoids 42–45[20]

The 2,2-dimethyl-1,3-benzodioxan-4-one moiety of the n class="Chemical">meroterpenoids intermediates was also used in alternative derivatization reactions (Scheme ). Thus, reaction of the geranyl-substituted resorcylate 24 with boron trifluoride etherate at 25 °C gave the racemic meroterpenoid 48 (89%, 3:1 dr), and the desired pure trans-fused ring product was obtained by recrystallization from n-hexane.[21] Saponification[13] of meroterpenoid 48 gave racemic carboxylic acid 49 (69%), while hydrolytic decarboxylation gave racemic phenol 50 (97%). Furthermore, reduction of meroterpenoid 48 with LiAlH4 gave racemic diol 51 (95%), and racemic Weinreb amide 52 (96%) was obtained following Grignard reagent mediated amidation.[22]

Scheme 9

Synthesis and Functionalization of Meroterpenoid 48

Conclusion

In conclusion, the total syntheses of (+)-hongoquercins A (1) and B (2) were completed in five and eleven steps, respectively with an overall yield of 20% and 3.7% via a dual biomimetic approach involving sequential n class="Chemical">polyketide and late-stage electrophile-mediated polyene cyclizations. Several analogues were synthesized by epoxidation or bromo- and iodo-cyclizations. The meroterpenoids were additionally functionalized using saponification, hydrolytic decarboxylation, reduction, and Grignard reagent mediated amidation reactions. Further studies on the synthesis of novel meroterpenoids adopting such dual biomimetic approach are ongoing in our laboratory.

Experimental Section

General Methods

All reagents and solvents were used directly without further purification unless otherwise stated. The preparation of malonate and dioxinone acid was performed according to the method of Barrett et al.[10b] n class="Chemical">Binol 25 and binol 26 were prepared, respectively, according to the procedures reported by Corey et al.[11] and Yamamoto et al.[12] Dihydroquinidine ligand 29 was prepared according to the procedure reported by Corey et al.[15] Et2SBr·SbCl5Br (BDSB, 46) and (Et2SI)2Cl·SbCl6 (IDSI, 47) were prepared according to the method published by Snyder et al.[19] All solvents were purified and dried by distillation under an atmosphere of N2 before use. The chiral ketone 38 was prepared from l-fructose according to the established method by Shi et al.[18] Et2O and THF were redistilled from Na–Ph2CO. CH2Cl2, Et3N, MeOH, PrNO2, MeNO2, and pyridine were redistilled from CaH2, and PhMe was redistilled from Na. All air- and moisture-sensitive reactions were carried out under an atmosphere of N2 using standard Schlenk techniques in oven-dried glassware equipped with a magnetic stirring bar. The progress of reactions was monitored by analytical thin-layer chromatography (TLC) on silica gel coated aluminum oxide F254 plates. Developed TLC was visualized under UV light and stained with acidic vanillin solution. Flash column chromatography was performed by employing silica gel 60 Å, particle size 40–63 μm. The enantiomeric excesses of the compounds were determined by chiral HPLC analysis on Chiralpak IE column with n-hexane and PrOH as the mobile phase. All 1H and proton-decoupled 13C NMR spectra were recorded at 400 and 101 MHz, respectively, at ambient temperature in deuterated solvent as noted. NMR spectra were referenced to residual solvent peaks (CDCl3: δ = 7.26 for 1H NMR and δ = 77.0 for 13C NMR; CD3OD δ = 3.31 and 4.87 for 1H NMR and δ = 49.0 for 13C NMR; (CD3)2CO: δ = 2.05 for 1H NMR and δ = 29.8 for 13C NMR) and chemical shifts were reported in ppm. IR spectra are reported in cm–1. Optical rotations were recorded with a polarimeter with the specified concentration and temperature. Mass spectra were obtained from the Imperial College Mass Spectrometry Service with the use of TOF and magnetic analyzers for ESI and EI techniques, respectively. Melting points are uncorrected. X-ray diffraction data were recorded at the Imperial College X-ray Crystallography Facility.

General Procedures for the Synthesis of Dioxinone β-Keto Esters

2-Phenyl-1,3-dioxane-4,6-dione (6.91 g, 36.0 mmol), DCC (7.43 g, 36.0 mmol), and DMAP (4.40 g, 36.0 mmol) were dissolved in n class="Chemical">CH2Cl2 (300 mL), and the resulting mixture was stirred for 5 min at 25 °C. 2-(2,2-Dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetic acid (6.70 g, 36.0 mmol) was added with stirring at 25 °C. After 18 h, the mixture was cooled to 0 °C, and the insoluble solid was filtered off and washed with CH2Cl2 (15 mL). The filtrate was washed with aqueous HCl (1 M; 2 × 200 mL), the two phases were separated, and the organic layer was dried MgSO4), filtered, and concentrated under reduced pressure to give the crude delicate dioxane-4,6-dione keto dioxinone 19 as a yellow foam, which was used directly without further purification. Crude dioxane-4,6-dione keto dioxinone 19 and geraniol (18) or trans,trans-farnesol (17) (20.0 mmol) were dissolved in PhMe (150 mL) and stirred at 55 °C for 4 h. The reaction mixture was concentrated under reduced pressure, and the brown residue was chromatographed (pentane/EtOAc 9:1–4:1) to provide the dioxinone β-keto esters 20 and 21, respectively.

(E)-3,7-Dimethylocta-2,6-dienyl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (20)

Dioxinone β-keto ester 20 (6.92 g, 19.0 mmol, 95%), prepared from n class="Chemical">geraniol (18) (3.47 mL, 20.0 mmol), was obtained as a pale yellow oil: R 0.20 (pentane/EtOAc 4:1); 1H NMR (400 MHz, CDCl3) δ 5.36 (s, 1H), 5.34–5.30 (m, 1H), 5.09–5.04 (m, 1H), 4.67 (d, J = 7.2 Hz, 2H), 3.51 (s, 2H), 3.50 (s, 2H), 2.14–2.01 (m, 4H), 1.71 (s, 6H), 1.68 (s, 3H), 1.67 (s, 3H), 1.59 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 195.6, 166.3, 163.5, 160.4, 143.6, 132.0, 123.5, 117.3, 107.3, 97.1, 62.6, 49.1, 46.9, 39.5, 26.2, 25.6, 25.0, 17.7, 16.5; IR νmax (neat) 1720, 1375, 1272, 1201, 1015 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C20H29O6 365.1964, found 365.1977.

(2E,6E)-3,7,11-Trimethyldodeca-2,6,10-trienyl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (21)

Dioxinone β-keto ester 21 (6.81 g, 15.7 mmol, 79%), prepared from n class="Chemical">trans,trans-farnesol (17) (5.02 mL, 20.0 mmol), was obtained as a pale yellow oil: R 0.36 (pentane/Et2O 1:1); 1H NMR (400 MHz, CDCl3) δ 5.34 (s, 1H), 5.33–5.28 (m, 1H), 5.11–5.02 (m, 2H), 4.65 (d, J = 7.2 Hz, 2H), 3.49 (s, 2H), 3.48 (s, 2H), 2.13–1.99 (m, 6H), 1.99–1.91 (m, 2H), 1.69 (s, 6H), 1.66 (s, 3H), 1.65 (s, 3H), 1.57 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 195.6, 166.3, 163.5, 160.4, 143.5, 135.5, 131.2, 124.2, 123.4, 117.3, 107.2, 97.0, 62.5, 49.0, 46.9, 39.6, 39.4, 26.6, 26.1, 25.6, 24.9, 17.6, 16.4, 15.9; IR νmax (neat) 2922, 1722, 1639, 1375, 1272, 1202, 1015, 901, 806 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C25H37O6 433.2590, found 433.2598. Anal. Calcd for C25H36O6: C, 69.42; H, 8.39. Found: C, 69.49; H, 8.24.

General Procedure for the Synthesis of Resorcylates 14 and 24

MgCl2 (476 mg, 5.00 mmol) and pyridine (0.810 mL, 10.0 mmol) were added with stirring to β-keto ester 20 or 21 (5.00 mmol) in n class="Chemical">CH2Cl2 (25 mL) at 0 °C. After 15 min, AcCl (0.540 mL, 7.50 mmol) was added dropwise, and the reaction mixture was further stirred for 1 h at 0 °C. The reaction was quenched by addition of saturated aqueous NH4Cl (20 mL), and the pH was adjusted to ∼2 with aqueous HCl (1 M). The two phases were separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give the crude dioxinone β,δ-diketo ester 22 or 23. P(2-furyl)3 (232 mg, 1.00 mmol) and Pd2dba3 (229 mg, 0.250 mmol) were added sequentially with stirring to this crude material in THF (30 mL) at 25 °C. After 1 h, CsOAc (2.88 g, 15.0 mmol) in PrOH (30 mL) was added, and the resulting mixture was stirred for an dditional 1.5 h. The reaction was quenched with aqueous HCl (1 M; 30 mL), the two phases were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (pentane/EtOAc 19:1–10:1) to give resorcylate 24 or 14.

(E)-8-(3,7-Dimethylocta-2,6-dienyl)-7-hydroxy-2,2,5-trimethyl-4H-benzo[d][1,3]dioxin-4-one (24)

Resorcylate 24 (1.03 g, 3.02 mmol, 60% over two steps), prepared from dioxinone β-keto ester 20 (1.83 g, 5.00 mmol), was obtained as a white solid. An analytically pure sample was obtained by recrystallization from n class="Chemical">MeNO2: R 0.37 (pentane/EtOAc 4:1); mp 102.9–103.0 °C; 1H NMR (400 MHz, CDCl3) δ 6.42 (s, 1H), 6.06 (s, 1H), 5.19 (t, J = 7.4 Hz, 1H), 5.04 (t, J = 6.3 Hz, 1H), 3.33 (d, J = 7.2 Hz, 2H), 2.59 (s, 3H), 2.14–1.98 (m, 4H), 1.79 (s, 3H), 1.69 (s, 6H), 1.67 (s, 3H), 1.59 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 161.2, 160.2, 156.0, 142.8, 138.5, 132.0, 123.7, 120.8, 113.7, 112.8, 105.3, 104.8, 39.7, 26.4, 25.7, 25.6, 22.0, 21.9, 17.7, 16.2; IR νmax (neat) 3199, 1694, 1608, 1300, 1282, 1210, 1177, 1106, 1045, 754 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C21H29O4 345.2066, found 345.2067. Anal. Calcd for C21H28O4: C, 73.32; H, 8.19. Found: C, 73.35; H, 8.31.

7-Hydroxy-2,2,5-trimethyl-8-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienyl)-4H-benzo[d][1,3]dioxin-4-one (14)

Resorcylate 14 (1.14 g, 2.75 mmol, 55% over two steps), prepared from dioxinone β-keto ester 21 (2.17 g, 5.00 mmol), was obtained as a yellow oil, which solidified upon standing: R 0.24 (n class="Chemical">pentane/EtOAc 9:1); mp 72.2 °C; 1H NMR (400 MHz, CDCl3) δ 6.41 (s, 1H), 6.15 (s, 1H), 5.19 (t, J = 6.7 Hz, 1H), 5.13–5.00 (m, 2H), 3.32 (d, J = 7.2 Hz), 2.58 (s, 3H), 2.14–1.90 (m, 8H), 1.79 (s, 3H), 1.68 (s, 6H), 1.67 (s, 3H), 1.58 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.0, 160.0, 156.0, 142.8, 138.6, 135.6, 131.3, 124.3, 123.5, 120.8, 113.6, 112.7, 105.3, 104.8, 39.7, 39.7, 26.7, 26.3, 25.7, 25.7, 22.0, 21.9, 17.7, 16.2, 16.0; IR νmax (neat) 3209, 2971, 2926, 1738, 1704, 1964, 1606, 1590, 1376, 1284, 1217, 1170, 1107, 1046, 858, 751 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C26H37O4 413.2692, found 413.2680. Anal. Calcd for C26H36O4: C, 75.69; H, 8.80. Found: C, 75.56; H, 8.96.

(7aR,9aS,13aS,13bR)-2,2,5,7a,10,10,13a-Heptamethyl-7a,8,9a,10,11,12,13,13a,13b,14-decahydro-4H,9H-benzo[a][1,3]dioxino[5,4-j]xanthen-4-one (27)

SnCl4 in n class="Chemical">heptane (1 M; 0.750 mL, 0.750 mmol) was added with stirring to binol 26 (463 mg, 0.900 mmol) in PhMe (9 mL) at 25 °C. After 10 min, the mixture was cooled to −78 °C, when resorcylate 14 (124 mg, 0.300 mmol) in PhMe (1.5 mL) was added dropwise and the reaction mixture was further stirred for 48 h at −78 °C. The reaction was quenched with NaHCO3 (15 mL) and the mixture diluted with Et2O (10 mL). The two phases were separated, and the aqueous layer was extracted with CH2Cl2 (4 × 15 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/Et2O 9:1 to PhMe/Et2O 12:1) to recover the binol 26. The crude mixture of products was then dissolved in 2-nitropropane (6 mL) and cooled to −78 °C. SnCl4 in heptane (1 M; 0.750 mL, 0.750 mmol) and CF3COOH (0.230 mL, 3.00 mmol) were sequentially added dropwise with stirring at −78 °C. After 24 h, the reaction was quenched with saturated aqueous NaHCO3 (10 mL) and diluted with Et2O (10 mL). The two phases were separated, and the aqueous layer was extracted with Et2O (4 × 15 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/Et2O 9:1) to provide meroterpenoid 27 (78 mg, 0.189 mmol, 63%, 80% dr, 90% ee, measured by chiral HPLC, Chiralpak IE column, n-hexane/PrOH 19:1, 5 mL/min, tR = 15.9 [(+)-enantiomer], 14.9 [(−)-enantiomer] min) as a colorless oil containing a mixture of diastereoisomers. An analytical sample was purified by preparative chiral HPLC: R 0.75 (pentane/EtOAc 9:1); [α]D20 +80.3 (c 0.57, MeOH); 1H NMR (500 MHz, CDCl3) δ 6.33 (s, 1H), 2.57 (s, 3H), 2.53 (dd, 1H), 2.24 (dd, J = 16.8, 13.2 Hz, 1H), 2.08 (dt, J = 12.5, 3.2 Hz, 1H), 1.82–1.77 (m, 1H), 1.77–1.74 (m, 1H), 1.72 (s, 3H), 1.69 (s, 3H), 1.68–1.65 (m, 1H), 1.65–1.62 (m, 1H), 1.53 (d, J = 5.3 Hz, 1H), 1.52–1.45 (m, 1H), 1.45–1.39 (m, 1H), 1.39–1.34 (m, 1H), 1.19 (s, 3H), 1.16 (dd, J = 13.5, 4.3 Hz, 1H), 1.02 (dd, J = 12.2, 2.3 Hz, 1H), 0.98 (dd, J = 12.8, 3.8 Hz, 1H), 0.91 (s, 6H), 0.85 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.9, 158.7, 156.1, 142.0, 114.3, 108.3, 104.8, 103.9, 78.4, 56.1, 51.3, 41.8, 40.8, 39.2, 36.9, 33.4, 33.2, 26.2, 25.5, 22.0, 21.6, 20.7, 19.7, 18.5, 16.5, 14.9; IR νmax (neat) 2928, 2867, 1728, 1616, 1575, 1452, 1388, 1285, 1127 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C26H37O4 413.2696, found 413.2698.

(+)-Hongoquercin A [(4aS,6aR,12aR,12bS)-11-Hydroxy-4,4,6a,9,12b-pentamethyl-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-2H-benzo[a]xanthene-10-carboxylic Acid (1)]

H2O (7 μL, 0.383 mmol) was added with stirring to a suspension of n class="Chemical">meroterpenoid 27 (79.0 mg, 0.191 mmol) and KOBu (172 mg, 1.53 mmol) in Et2O (3 mL) at 25 °C. After 2 h, ice was added until two layers were formed, and the two phases were separated. The organic layer was extracted with H2O (5 × 5 mL), and the combined aqueous layers were acidified with HCl (4 M) to pH ∼1. The two phases were separated, and the aqueous layer was extracted with Et2O (5 × 5 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/EtOAc/AcOH 9:1:0.01) to afford (+)-hongoquercin A (1) (53 mg, 0.142 mmol, 75%) as white solid. An analytical sample was prepared by recrystallization (pentane/CH2Cl2): R 0.25 (pentane/EtOAc/AcOH 9:1:0.01); mp 146.1–148.5 °C; [α]D24 +90.5 (c 0.57, MeOH); 1H NMR (400 MHz, CDCl3) δ 11.86 (s, 1H), 6.21 (s, 1H), 2.69 (dd, J = 16.9, 5.0 Hz, 1H), 2.51 (s, 3H), 2.29 (dd, J = 16.9, 13.2 Hz, 1H), 2.08 (dt, J = 12.5, 3.1 Hz, 1H), 1.86–1.72 (m, 2H), 1.69 (dd, J = 13.1, 4.8 Hz, 1H), 1.66–1.58 (m, 1H), 1.55 (dd, J = 13.1, 5.0 Hz, 1H), 1.52–1.45 (m, 1H), 1.44–1.42 (m, 1H), 1.42–1.34 (m, 1H), 1.20 (s, 3H), 1.15 (dd, J = 13.4, 4.0 Hz, 1H), 1.03 (dd, J = 12.2, 2.2 Hz, 1H), 1.00–0.94 (m, 1H), 0.92 (s, 3H), 0.91 (s, 3H), 0.85 (s, 3H). 1H NMR (500 MHz, CD3OD) δ 6.11 (s, 1H), 2.65 (dd, J = 16.9, 5.0 Hz, 1H), 2.46 (s, 3H), 2.27 (dd, J = 16.7, 13.2 Hz, 1H), 2.05 (dt, J = 12.5, 3.2 Hz, 1H), 1.81–1.76 (m, 2H), 1.72 (dt, J = 13.7, 3.6 Hz, 1H), 1.69–1.61 (m, 1H), 1.52 (dd, J = 13.2, 5.2 Hz, 1H), 1.50–1.40 (m, 3H), 1.26–1.21 (m, 1H), 1.19 (s, 3H), 1.08 (dd, J = 12.2, 2.3 Hz, 1H), 1.05–0.98 (m, 1H), 0.96 (s, 3H), 0.92 (s, 3H), 0.89 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 175.3, 163.9, 158.8, 141.3, 112.6, 108.1, 104.9, 78.4, 56.1, 51.5, 41.8, 40.8, 39.2, 37.0, 33.4, 33.2, 24.1, 21.6, 20.8, 19.7, 18.5, 16.7, 14.9); 13C{1H} NMR (126 MHz, CD3OD) δ 175.6, 164.5, 158.9, 141.7, 112.8, 108.8, 104.9, 79.0, 57.5, 53.2, 43.0, 42.1, 40.4, 38.1, 34.2, 33.9, 24.2, 22.0, 21.1, 20.8, 19.6, 17.7, 15.4; IR νmax (neat) 2927, 1621, 1574, 1454, 1378, 1262, 1126 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C23H33O4 373.2383, found 373.2379. Anal. Calcd for C23H32O4: C, 74.16; H, 8.66. Found: C, 74.22; H, 8.78.

7-(Allyloxy)-2,2,5-trimethyl-8-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)-4H-benzo[d][1,3]dioxin-4-one (28)

Allyl bromide (0.65 mL, 7.50 mmol) was added with stirring to a suspension of n class="Chemical">K2CO3 (1.38 g, 10.0 mmol) and resorcylate 14 (2.06 g, 5.00 mmol) in Me2CO (50 mL). The resulting suspension was heated to 60 °C with stirring for 18 h, when the mixture was concentrated and diluted with H2O (50 mL) and CH2Cl2 (50 mL). The two phases were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/Et2O 9:1) to provide allyl ether 28 (1.61 g, 3.56 mmol, 71%) as a pale yellow oil: R 0.33 (pentane/Et2O 9:1); 1H NMR (400 MHz, CDCl3) δ 6.41 (s, 1H), 6.04 (ddt, J = 17.3, 10.3, 5.1 Hz, 1H), 5.42 (dd, J = 17.3, 1.6 Hz, 1H), 5.30 (dd, J = 10.6, 1.4 Hz, 1H), 5.13 (tq, J = 7.3, 1.3 Hz, 1H), 5.07 (tdd, J = 6.9, 3.1, 1.4 Hz, 2H), 4.60 (dt, J = 5.1, 1.6 Hz, 2H), 3.29 (d, J = 7.3 Hz, 2H), 2.63 (s, 3H), 2.10–1.89 (m, 8H), 1.75 (s, 3H), 1.68–1.66 (m, 9H), 1.58 (s, 3H), 1.56 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.9, 155.6, 142.5, 135.2, 134.9, 132.6, 131.2, 124.3, 124.1, 121.6, 117.6, 116.0, 109.3, 105.7, 104.7, 68.9, 39.74, 39.66, 26.7, 26.5, 25.73, 25.66, 22.5, 21.8, 17.6, 16.1, 16.0; IR νmax (neat) 2969, 3925, 2856, 1729, 1606, 1575, 1376, 1278, 1207, 1169, 1115, 1046, 980, 908 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C29H41O4 453.3005, found 453.2983. Anal. Calcd for C29H40O4: C, 76.95; H, 8.91. Found: C, 76.84; H, 8.87.

7-(Allyloxy)-8-((R,2E,6E)-10,11-dihydroxy-3,7,11-trimethyldodeca-2,6-dien-1-yl)-2,2,5-trimethyl-4H-benzo[d][1,3]dioxin-4-one (30)

Allyl ether 28 (1.53 g, 3.38 mmol) was dissolved in BuOH (17 mL) and n class="Chemical">H2O (17 mL) and cooled to 0 °C. Ligand 29 (35 mg, 33.8 μmol), MeSO4NH2 (322 mg, 3.39 mmol), K3Fe(CN)6 (3.34 g, 10.1 mmol), K2CO3 (1.40 g, 10.1 mmol), and K2OsO4·2H2O (6.3 mg, 17.1 μmol) were added sequentially with stirring at 0 °C. After 24 h, solid Na2SO3 (3.00 g) was added, and the mixture was further stirred for 30 min. The reaction mixture was diluted with H2O (25 mL) and EtOAc (25 mL), the two phases were separated, and the aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/EtOAc 4:1–1:1 to EtOAc/EtOH 4:1) to afford unreacted allyl ether 28 (400 mg, 0.88 mmol, 26%), tetraol (204 mg, 0.392 mmol, 12%), ligand 29 (33 mg, 32.3 μmol, 96% recovered), and diol 30 (956 mg, 1.96 mmol, 58%, 78% corrected for recovered allyl ether 28, 88% ee as determined by Mosher ester analysis)[15] as a colorless oil: R 0.36 (pentane/EtOAc 1:1); [α]D23 +10.4 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.42 (s, 1H), 6.05 (ddt, J = 17.3, 10.4, 5.1 Hz, 1H), 5.42 (dd, J = 17.3, 1.6 Hz, 1H), 5.30 (dd, J = 10.6, 1.4 Hz, 1H), 5.19–5.10 (m, 2H), 4.61 (dt, J = 5.1, 1.6 Hz, 2H), 3.33 (dd, J = 10.5, 2.0 Hz, 1H), 3.29 (d, J = 7.4 Hz, 2H), 2.63 (s, 3H), 2.25–1.92 (m, 6H), 1.75 (s, 3H), 1.71 (s, 2H), 1.67 (s, 6H), 1.59 (s, 3H), 1.56–1.45 (m, 1H), 1.46–1.32 (m, 1H), 1.18 (s, 3H), 1.14 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.14, 161.08, 155.7, 142.7, 135.2, 135.1, 132.8, 125.1, 121.9, 117.9, 116.1, 109.5, 105.9, 104.9, 78.4, 73.1, 69.1, 39.9, 36.9, 29.8, 26.7, 26.6, 25.9 (2C), 23.4, 22.6, 21.9, 16.2, 16.0; IR νmax (neat) 3443, 2931, 2972, 1729, 1606,1576, 1451, 1377, 1329, 1281, 1209, 1170, 1117 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C29H43O6 487.3060, found 487.3051. Anal. Calcd for C29H42O6: C, 71.57; H, 8.70. Found: C, 71.69; H, 8.73.

7-(Allyloxy)-8-((2E,6E)-9-((S)-3,3-dimethyloxiran-2-yl)-3,7-dimethylnona-2,6-dien-1-yl)-2,2,5-trimethyl-4H-benzo[d][1,3]dioxin-4-one (31)

Pyridine (2.20 mL, 27.3 mmol) and n class="Chemical">MsCl (0.28 mL, 3.62 mmol) were added sequentially with stirring to diol 30 in CH2Cl2 (20 mL). After 15 h, the mixture was diluted with Me2CO (50 mL), K2CO3 (20.0 g, 0.145 mol) was added, and stirring was continued for 24 h. H2O (30 mL) was added, and the two phases were separated. The aqueous layer was extracted with CH2Cl2 (3 × 40 mL), and the combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/EtOAc 19:1 to 5:1) to give epoxide 31 (767 mg, 1.64 mmol, 90%) as a colorless oil: R 0.25 (pentane/EtOAc 19:1); [α]D25 −1.8 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.41 (s, 1H), 6.16–5.90 (m, 1H), 5.46–5.36 (m, 1H), 5.32–5.26 (m, 1H), 5.17–5.05 (m, 2H), 4.60 (d, J = 5.0 Hz, 2H), 3.28 (d, J = 7.3 Hz, 2H), 2.66 (t, J = 6.3 Hz, 1H), 2.62 (s, 3H), 2.17–1.91 (m, 6H), 1.74 (s, 3H), 1.66 (s, 6H), 1.57 (s, 3H), 1.67–1.48 (m, 2H), 1.28 (s, 3H), 1.23 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.9 (2C), 155.5, 142.5, 135.0, 134.0, 132.6, 124.7, 121.7, 117.6, 115.9, 109.3, 105.7, 104.6, 68.9, 64.1, 58.2, 39.7, 36.2, 27.4, 26.5, 25.7 (2C), 24.9, 22.4, 21.8, 18.7, 16.1, 15.9; IR νmax (neat) 2961, 2923, 1727, 1606, 1575, 1450, 1376, 1327, 1279, 1207, 1169, 1115 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C29H41O5 469.2954, found 469.2960.

8-((2E,6E)-9-((S)-3,3-Dimethyloxiran-2-yl)-3,7-dimethylnona-2,6-dien-1-yl)-7-hydroxy-2,2,5-trimethyl-4H-benzo[d][1,3]dioxin-4-one (33)

Dimethylbarbituric acid (32) (217 mg, 1.39 mmol) and n class="Chemical">Pd(PPh3)4 (29 mg, 0.0251 mmol) were added sequentially with stirring to epoxide 31 (589 mg, 1.26 mmol) in CH2Cl2 (10 mL). After 1 h, the reaction mixture was concentrated and purified by chromatography (pentane/EtOAc 4:1) to afford epoxide 33 (491 mg, 1.15 mmol, 91%) as a colorless oil: R 0.30 (pentane/EtOAc 4:1); [α]D26 +13.8 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 6.90 (s, 1H), 6.42 (s, 1H), 5.19–5.13 (m, 1H), 5.12–5.05 (m, 1H), 3.29 (d, J = 7.3 Hz, 2H), 2.77 (dd, J = 7.4, 4.9 Hz, 1H), 2.58 (s, 3H), 2.19–1.98 (m, 6H), 1.74 (s, 3H), 1.73–1.69 (m, 1H), 1.68 (s, 6H), 1.57 (s, 3H), 1.56–1.49 (m, 1H), 1.33 (s, 3H), 1.29 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.1, 160.4, 155.9, 142.6, 136.8, 134.0, 124.5, 121.9, 113.5, 113.2, 105.0, 104.7, 64.6, 59.5, 39.3, 36.2, 27.0, 25.7, 25.7 (2C), 24.9, 22.0, 21.8, 18.7, 16.0 (2C); IR νmax (neat) 3258, 2964, 2927, 1727, 1693, 1609, 1514, 1452, 1377, 1327, 1276, 1210, 1107 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C26H37O5 429.2641, found 429.2645.

(7aR,9aR,11S,13aS,13bR)-11-Hydroxy-2,2,5,7a,10,10,13a-heptamethyl-7a,8,9a,10,11,12,13,13a,13b,14-decahydro-4H,9H-benzo[a][1,3]dioxino[5,4-j]xanthen-4-one (34)

FeCl3·6H2O (892 mg, 3.30 mmol) was added with stirring to n class="Chemical">epoxide 33 (470 mg, 1.10 mmol) in MeNO2 (220 mL), and the resulting mixture was further stirred at 25 °C for 15 min. Saturated aqueous NaHCO3 (150 mL) was added, and the two phases were separated. The aqueous layer was extracted with CH2Cl2 (3 × 50 mL), and the combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/EtOAc 3:1) to give meroterpenoid 34 (263 mg, 0.614 mmol, 56%, 92% ee, measured by chiral HPLC, Chiralpak IE column, n-hexane/PrOH 17:3, 5 mL/min, tR = 18.9 [(−)-enantiomer], 25.8 [(+)-enantiomer] min) as a white foam: R 0.19 (pentane/EtOAc 3:1); [α]D24 +52.2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.33 (s, 1H), 3.26 (dt, J = 11.0, 5.3 Hz, 1H), 2.56 (s, 3H), 2.56–2.49 (m, 1H), 2.25 (dd, J = 16.7, 13.1 Hz, 1H), 2.10 (dt, J = 12.5, 3.2 Hz, 1H), 1.86–1.76 (m, 2H), 1.72 (s, 3H), 1.68 (s, 3H), 1.73–1.60 (m, 3H), 1.52 (dd, J = 13.1, 5.0 Hz, 1H), 1.47–1.41 (m, 1H), 1.40 (d, J = 5.9 Hz, 1H), 1.19 (s, 3H), 1.12 (td, J = 13.0, 4.3 Hz, 1H), 1.03 (s, 3H), 1.02–0.98 (m, 1H), 0.92 (s, 3H), 0.82 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.8, 158.6, 156.1, 142.1, 114.3, 108.0, 104.8, 104.0, 78.6, 78.1, 55.0, 51.1, 40.7, 38.8, 37.4, 36.7, 28.1, 27.1, 26.1, 25.5, 22.0, 20.7, 19.4, 16.5, 15.5, 15.0; IR νmax (neat) 3440, 2930, 2867, 1713, 1616, 1574, 1452, 1388, 1286, 1207, 1126, 1043 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C26H37O5 429.2641, found 429.2646.

(3S,4aR,6aR,12aR,12bS)-3,11-Dihydroxy-4,4,6a,9,12b-pentamethyl-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-2H-benzo[a]xanthene-10-carboxylic Acid (35)

H2O (10 μL, 0.552 mmol) was added to a suspension of KOBu (124 mg, 1.10 mmol) in n class="Chemical">Et2O (1 mL) at 0 °C and stirred for 5 min. Meroterpenoid 34 (59 mg, 0.138 mmol) in Et2O (1 mL) was added with stirring at 25 °C. After 3 h, ice was added until two layers were formed, and the two phases were separated and diluted with Et2O (2 mL). The pH was adjusted to ∼1 with aqueous HCl (4 M). The two phases were separated, and the aqueous layer was extracted with Et2O (3 × 2 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/EtOAc/AcOH 3:1:0.01) to give the carboxylic acid 35 (37 mg, 0.0952 mmol, 69%) as a white solid: R 0.14 (pentane/EtOAc/AcOH 4:1:0.01); mp 153–155 °C; [α]D24 +104.3 (c 0.3, CH3OH); 1H NMR (400 MHz, CD3OD) δ 6.08 (s, 1H), 3.18 (dd, J = 11.3, 5.0 Hz, 1H), 2.61 (dd, J = 16.8, 5.0 Hz, 1H), 2.45 (s, 3H), 2.26 (dd, J = 16.7, 13.0 Hz, 1H), 2.03 (dt, J = 12.4, 3.2 Hz, 1H), 1.84–1.73 (m, 2H), 1.72–1.59 (m, 3H), 1.54–1.41 (m, 2H), 1.16 (s, 3H), 1.15–1.08 (m, 1H), 1.04–1.01 (m, 1H), 1.00 (s, 3H), 0.94 (s, 3H), 0.81 (s, 3H); 13C{1H} NMR (101 MHz, CD3OD) δ 175.6, 164.4, 158.7, 141.7, 112.7, 108.6, 105.2, 79.4, 78.7, 56.5, 52.9, 42.1, 39.9, 38.8, 37.8, 28.7, 27.9, 24.2, 21.0, 20.5, 17.8, 16.2, 15.5; IR νmax (neat) 3445, 2972, 2934, 2865, 1621, 1579, 1453, 1379, 1265, 1178, 1126, 1038 cm–1; HRMS (ESI) m/z [M – H]− Calcd for C23H31O5 387.2171, found 387.2180.

(+)-Hongoquercin B [(3S,4aR,6aR,12aR,12bS)-3-Acetoxy-11-hydroxy-4,4,6a,9,12b-pentamethyl-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-2H-benzo[a]xanthene-10-carboxylic Acid (2)]

Ac2O (63 μL, 0.666 mmol) was added with stirring to n class="Chemical">carboxylic acid 35 (37 mg, 0.0952 mmol) in pyridine (0.5 mL) at 25 °C. After 24 h, CH2Cl2 (2 mL) was added, and the pH was adjusted to ∼1 with aqueous HCl (4 M). The two phases were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 2 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to give diacetate 36. Crude diacetate 36 was dissolved in MeOH (2 mL) and H2O (0.2 mL), and K2CO3 (20 mg, 0.143 mmol) was added at 25 °C. The resulting mixture was stirred for 5 h, when CH2Cl2 (2 mL) was added, and the pH was adjusted to ∼1 with aqueous HCl (4 M). The two phases were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 1 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/EtOAc/AcOH 3:1:0.01) to give (+)-hongoquercin B (2) (27 mg, 0.0627 mmol, 66% over two steps from carboxylic acid 35) as white solid: R 0.29 (pentane/EtOAc/AcOH 3:1:0.01); mp 155–157 °C; [α]D30 +91.0 (c 0.52, CH3OH); 1H NMR (400 MHz, CDCl3) δ 11.85 (s, 1H), 6.21 (s, 1H), 4.52 (dd, J = 11.6, 4.7 Hz, 1H), 2.66 (dd, J = 16.8, 4.8 Hz, 1H), 2.52 (s, 3H), 2.30 (dd, J = 16.8, 13.1 Hz, 1H), 2.13–2.07 (m, 1H), 2.07 (s, 3H), 1.86 (dt, J = 13.3, 3.6 Hz, 1H), 1.81–1.60 (m, 4H), 1.53 (dd, J = 13.1, 5.0 Hz, 1H), 1.47–1.42 (m, 1H), 1.24–1.18 (m, 1H), 1.20 (s, 3H), 1.10 (dd, J = 12.1, 2.2 Hz, 1H), 0.96 (s, 3H), 0.91 (s, 3H), 0.90 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 175.9, 171.0, 163.8, 158.6, 141.6, 112.6, 107.7, 102.7, 80.4, 78.0, 55.1, 51.3, 40.6, 37.7, 37.1, 36.6, 28.1, 24.1, 23.5, 21.3, 20.7, 19.3, 16.8, 16.7, 15.0; IR νmax (neat) 3063, 2972, 2941, 1731, 1623, 1580, 1454, 1371, 1263, 1178, 1126, 1035, 1007 cm–1; HRMS (ESI) m/z [M – H]− calcd for C25H33O6 429.2277, found 429.2284.

(E)-7-(tert-Butyldimethylsilyloxy)-8-(3,7-dimethylocta-2,6-dienyl)-2,2,5-trimethyl-4H-benzo[d][1,3]dioxin-4-one (37)

NEt3 (1.08 mL, 7.72 mmol) was added with stirring to resorcylate 24 (806 mg, 2.34 mmol) in n class="Chemical">CH2Cl2 (50 mL) at 25 °C, when BuMe2SiCl (1.16 g, 7.72 mmol) and DMAP (5.72 mg, 0.0468 mmol) were added. The resulting mixture was stirred for 2 h, when 10% aqueous citric acid (30 mL) and CH2Cl2 (20 mL) were added. The two phases were separated, and the organic layer was washed with 10% citric acid solution (2 × 30 mL), H2O (30 mL), and brine (30 mL). The organic layer was dried (MgSO4), filtered, concentrated, and chromatographed (pentane/EtOAc 19:1) to give silyl ether 37 (815 mg, 1.78 mmol, 76%) as a colorless oil: R 0.59 (pentane/Et2O 10:1); 1H NMR (400 MHz, CDCl3) δ 6.36 (s, 1H), 5.13–5.00 (m, 2H), 3.24 (d, J = 7.0 Hz, 2H), 2.58 (s, 3H), 2.07–1.99 (m, 2H), 1.98–1.90 (m, 2H), 1.73 (s, 3H), 1.65 (s, 6H), 1.63 (s, 3H), 1.55 (s, 3H), 1.01 (s, 9H), 0.28 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.9, 158.9, 156.4, 141.7, 134.9, 131.3, 124.1, 121.8, 118.4, 116.1, 105.9, 104.6, 39.6, 26.5, 25.7 (2C), 25.6 (4C), 22.2, 22.1, 18.2, 17.6, 16.2, −4.1 (2C); IR νmax (neat) 2930, 2859, 1733, 1606, 1569, 1292, 1209, 1169, 1044, 841, 782 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C27H43O4Si 459.2931, found 459.2938. Anal. Calcd for C27H42O4Si: C, 70.70; H, 9.23. Found: C, 70.52; H, 9.10.

(S,E)-7-((tert-Butyldimethylsilyl)oxy)-8-(5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-en-1-yl)-2,2,5-trimethyl-4H-benzo[d][1,3]dioxin-4-one (39)

Silyl ether 37 (334 mg, 0.75 mmol) and the chiral n class="Chemical">ketone 38 (58 mg, 0.225 mmol) were dissolved in CH2Cl2 (6 mL), CH3CN (3 mL), EtOH (3 mL), and aqueous buffer (2 M K2CO3; 4 × 10–3 M EDTA; 6 mL) and cooled to 0 °C. H2O2 (0.42 mL) was added dropwise with stirring. After 15 h, Na2SO3 (200 mg) was added, and the phases were separated. The aqueous layer was extracted with Et2O (3 × 15 mL), and the combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/EtOAc 10:1) to afford epoxide 39 (244 mg, 0.514 mmol, 69%) as a colorless oil: R 0.22 (pentane/EtOAc 19:1); [α]D23 +2.8 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.35 (s, 1H), 5.12 (tq, J = 7.1, 1.3 Hz, 1H), 3.24 (d, J = 7.0 Hz, 2H), 2.65 (t, J = 6.2 Hz, 1H), 2.58 (s, 3H), 2.20–1.98 (m, 2H), 1.74 (s, 3H), 1.65 (s, 6H), 1.61–1.53 (m, 2H), 1.24 (s, 3H), 1.21 (s, 3H), 1.00 (s, 9H), 0.28 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.8, 158.9, 156.3, 141.9, 134.1, 122.5, 118.1, 116.1, 105.9, 104.6, 64.0, 58.2, 36.2, 27.3, 25.8 (2C), 25.6 (3C), 24.8, 22.2, 22.1, 18.6, 18.3, 16.2, −4.0 (2C); IR νmax (neat) 2959, 2930, 2859, 1732, 1605, 1570, 1279, 842 cm–1; HRMS (FTMS + p APCI) m/z [M + H]+ calcd for C27H43O5Si 475.2874, found 475.2870. Anal. Calcd for C27H42O5Si: C, 68.31; H, 8.92. Found: C, 68.21; H, 9.03.

(S,E)-8-(5-(3,3-Dimethyloxiran-2-yl)-3-methylpent-2-en-1-yl)-7-hydroxy-2,2,5-trimethyl-4H-benzo[d][1,3]dioxin-4-one (40)

K2CO3 (2.33 g, 16.9 mmol) was added with stirring to n class="Chemical">epoxide 39 (160 mg, 0.337 mmol) in Me2CO (20 mL) at 25 °C. After 2 h, CH2Cl2 (30 mL) and H2O (50 mL) were added, and the two phases were separated. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL), and the combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/EtOAc 5:1) to give epoxide 40 (112 mg, 0.311 mmol, 92%) as a colorless oil: R 0.29 (pentane/EtOAc 5:1); [α]D24 −9.4 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.40 (s, 1H), 6.17 (s, 1H), 5.30–5.15 (m, 1H), 3.31 (dd, J = 7.0, 2.1 Hz, 2H), 2.69 (dd, J = 6.8, 5.6 Hz, 1H), 2.58 (s, 3H), 2.26–2.07 (m, 2H), 1.80 (s, 3H), 1.68 (s, 6H), 1.69–1.55 (m, 2H), 1.28 (s, 3H), 1.25 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.9, 159.8, 156.0, 142.8, 136.8, 121.7, 113.6, 113.0, 105.4, 104.8, 64.2, 58.6, 36.5, 27.2, 25.8, 25.7, 24.8, 22.0, 21.8, 18.7, 16.2; IR νmax (neat) 3235, 2928, 1727, 1696, 1609, 1277 cm–1; HRMS (FTMS + p APCI) m/z [M + H]+ calcd for C21H29O5 361.2010, found 361.2016.

(7aS,10S,11aS)-10-Hydroxy-2,2,5,7a,11,11-hexamethyl-7a,8,10,11,11a,12-hexahydro-4H,9H-[1,3]dioxino[4,5-a]xanthen-4-one (41)

BF3OEt2 (0.2 mL, 0.139 mmol) was added with stirring to n class="Chemical">epoxide 40 (110 mg, 0.305 mmol) in CH2Cl2 (30 mL) at −78 °C. After 5 min, Et3N (5 mL) and H2O (20 mL) were added, the mixture was allowed to warm to 25 °C, and the two phases were separated. The aqueous layer was extracted with CH2Cl2 (3 × 30 mL), and the combined organic layers were dried (MgSO4), filtered, concentrated, and purified by chromatography (pentane/EtOAc 5:2) to give the meroterpenoid 41 (85 mg, 0.236 mmol, 77%, 84% ee, measured by chiral HPLC, Chiralpak IE column, n-hexane/PrOH 9:1, 5 mL/min, tR = 22.0 [(−)-enantiomer], 26.6 [(+)-enantiomer] min) as a white foam: R 0.29 (pentane/EtOAc 5:2); [α]D24 −71.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.33 (s, 1H), 3.41 (dd, J = 11.4, 4.2 Hz, 1H), 2.63 (dd, J = 16.8, 4.9 Hz, 1H), 2.56 (s, 3H), 2.31 (dd, J = 16.9, 13.2 Hz, 1H), 2.00 (dt, J = 12.5, 3.3 Hz, 1H), 1.91–1.81 (m, 1H), 1.78–1.74 (m, 1H), 1.73 (s, 3H), 1.69 (s, 3H), 1.64–1.52 (m, 2H), 1.20 (s, 3H), 1.12 (s, 3H), 0.89 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.8, 158.6, 156.0, 142.2, 114.3, 107.9, 104.8, 104.1, 77.8, 77.6, 46.1, 38.5, 37.4, 28.1, 27.3, 26.1, 25.4, 21.9, 19.8, 17.2, 14.3; IR νmax (neat) 3433, 2942, 1708, 1617, 1573, 1287, 1128 cm–1; HRMS (ESI) m/z [M – H]− calcd for C21H27O5 359.1858, found 359.1853. Anal. Calcd for C21H28O5: C, 69.98; H, 7.83. Found: C, 69.86; H, 7.94.

General Procedure for BDSB (46)-Induced Halocyclization

BDSB (46) (604 mg, 1.10 mmol) was added with stirring to resorcylate 24 or 14 (1.00 mmol) in MeNO2 (50 mL) at −25 °C. After 10 min, saturated aqueous n class="Chemical">NaHCO3 (15 mL) and aqueous Na2SO3 (0.5 M; 5 mL) were added, and stirring was continued for 15 min. The two phases were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/Et2O 9:1) to give the bromo-meroterpenoid 42 or 44.

10-Bromo-2,2,5,7a,11,11-hexamethyl-7a,8,10,11,11a,12-hexahydro-4H,9H-[1,3]dioxino[4,5-a]xanthen-4-one (42)

Bromide 42 (272 mg, 0.642 mmol, 64%), prepared from resorcylate 24 (344 mg, 1.00 mmol), was obtained as a white solid: R 0.29 (n class="Chemical">pentane/Et2O 9:1); mp 225.3–225.7 °C; 1H NMR (400 MHz, (CD3)2CO) δ 6.36 (s, 1H), 4.26 (dd, J = 11.8, 4.8 Hz, 1H), 2.80–2.77 (m, 1H), 2.52 (s, 3H), 2.50–2.43 (m, 1H), 2.30–2.13 (m, 2H), 2.00 (dt, J = 13.0, 3.5 Hz, 1H), 1.90–1.79 (m, 2H), 1.70 (s, 3H), 1.67 (s, 3H), 1.27 (s, 3H), 1.19 (s, 3H), 1.06 (s, 3H); 13C{1H} NMR (101 MHz, (CD3)2CO) δ 160.7, 159.1, 157.0, 142.6, 115.1, 109.3, 105.8, 105.4, 78.2, 66.9, 47.9, 41.0, 40.1, 32.3, 29.9, 26.3, 25.6, 22.1, 20.2, 19.5, 17.4; IR νmax (neat) 2975, 2924, 2865, 1715, 1616, 1575, 1380, 1286, 1128, 1044 cm–1; HRMS (EI) m/z [M]•+ calcd for C21H27BrO4 422.1093, found 422.1110. Anal. Calcd for C21H27BrO4: C, 59.58; H, 6.43. Found: C, 59.45; H, 6.57.

11-Bromo-2,2,5,7a,10,10,13a-heptamethyl-7a,8,9a,10,11,12,13,13a,13b,14-decahydro-4H,9H-benzo[a][1,3]dioxino[5,4-j]xanthen-4-one (44)

Bromide 44 (219 mg, 0.446 mmol, 45%, 2:1 dr), prepared from resorcylate 14 (413 mg, 1.00 mmol), was obtained as a white solid containing a minor amount of a diastereoisomer: R 0.24 (n class="Chemical">pentane/Et2O 9:1); mp 234.0–237.4 °C; 1H NMR (400 MHz, CDCl3) δ 6.33 (s, 1H), 4.00 (dd, J = 12.6, 4.7 Hz, 1H), 2.57 (s, 3H), 2.51 (dd, J = 16.8, 5.1 Hz, 1H), 2.37–2.13 (m, 3H), 2.13–2.07 (m, 1H), 1.91–1.84 (m, 1H), 1.84–1.78 (m, 1H), 1.72 (s, 3H), 1.71–1.69 (m, 1H), 1.69 (s, 3H), 1.59–1.46 (m, 2H), 1.20 (s, 3H), 1.20–1.11 (m, 2H), 1.12 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.8, 158.5, 156.1, 142.2, 114.3, 107.8, 104.8, 104.1, 77.8, 68.4, 56.3, 51.1, 40.7, 40.5, 39.6, 37.0, 30.7, 30.6, 26.1, 25.5, 22.0, 21.1, 20.6, 18.3, 16.5, 14.9; IR νmax (neat) 2949, 1718, 1613, 1575, 1376, 1288, 1131, 1042, 902, 844, 693 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C26H36BrO4 491.1797, found 491.1807. Anal. Calcd for C26H35BrO4: C, 63.54; H, 7.18. Found: C, 63.49; H, 7.07.

General Procedure for IDSI (47)-Induced Halocyclization

IDSI (47) (884 mg, 1.10 mmol) was added with stirring to resorcylate 24 or 14 (1.00 mmol) in MeNO2 (50 mL) at −25 °C. After 10 min, saturated aqueous n class="Chemical">NaHCO3 (15 mL) and aqueous Na2SO3 (0.5 M; 5 mL) were added, and stirring was continued for 15 min. The two phases were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/Et2O 9:1) to give the iodo-meroterpenoid 43 or 45.

10-Iodo-2,2,5,7a,11,11-hexamethyl-7a,8,10,11,11a,12-hexahydro-4H,9H-[1,3]dioxino[4,5-a]xanthen-4-one (43)

Iodide 43 (415 mg, 0.882 mmol, 88%), prepared from resorcylate 24 (344 mg, 1.00 mmol), was obtained as a white solid: R 0.29 (n class="Chemical">pentane/Et2O 9:1); mp 221.6–222.4 °C; 1H NMR (400 MHz, (CD3)2CO) δ 6.36 (s, 1H), 4.46 (dd, J = 11.9, 4.8 Hz, 1H), 2.82 (dd, J = 23.3, 6.7 Hz, 1H), 2.52 (s, 3H), 2.50–2.44 (m, 1H), 2.46–2.30 (m, 2H), 1.91 (dd, J = 13.2, 5.0 Hz, 1H), 1.87–1.82 (m, 2H), 1.70 (s, 3H), 1.67 (s, 3H), 1.28 (s, 3H), 1.16 (s, 3H), 1.09 (s, 3H); 13C{1H} NMR (100 MHz, (CD3)2CO) δ 160.5, 158.9, 156.7, 142.4, 114.9, 109.3, 105.6, 105.2, 78.2, 50.1, 46.2, 42.5, 39.6, 34.9, 32.3, 26.1, 25.4, 21.9, 20.3, 20.0, 19.9; IR νmax (neat) 2970, 1715, 1616, 1575, 1379, 1285, 1127, 1044, 902 cm–1; HRMS (EI) m/z [M]•·+ Calcd for C21H27IO4 470.0954, found 470.0947. Anal. Calcd for C21H27IO4: C, 53.63; H, 5.79. Found: C, 53.55; H, 5.86.

11-Iodo-2,2,5,7a,10,10,13a-heptamethyl-7a,8,9a,10,11,12,13,13a,13b,14-decahydro-4H,9H-benzo[a][1,3]dioxino[5,4-j]xanthen-4-one (45)

Iodide 45 (293 mg, 0.544 mmol, 54%, 2:1 dr), prepared from resorcylate 14 (413 mg, 1.00 mmol), was obtained as a white solid containing a minor diastereoisomer: R 0.24 (n class="Chemical">pentane/Et2O 9:1); mp 189.5–192.0 °C; 1H NMR (400 MHz, CDCl3) δ 6.33 (s, 1H), 4.24 (dd, J = 13.0, 3.2 Hz, 1H), 2.57 (s, 3H), 2.50 (dd, J = 16.4, 5.0 Hz, 1H), 2.46–2.29 (m, 2H), 2.24 (dd, J = 16.8, 13.1 Hz, 1H), 2.10–2.03 (m, 1H), 1.95–1.87 (m, 1H), 1.72 (s, 3H), 1.69 (s, 3H), 1.68–1.55 (m, 2H), 1.55–1.51 (m, 1H), 1.51–1.45 (m, 1H), 1.26–1.20 (m, 1H), 1.20 (s, 3H), 1.20–1.10 (m, 1H), 1.10 (s, 3H), 1.01 (s, 3H), 0.98 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.8, 158.5, 156.1, 142.2, 114.3, 107.8, 104.8, 104.1, 77.3, 54.9, 52.9, 51.2, 42.2, 40.8, 39.3, 37.3, 33.6, 33.2, 26.1, 25.5, 22.2, 22.0, 21.1, 20.6, 16.5, 14.9; IR νmax (neat) 2946, 1726, 1615, 1576, 1371, 1285, 1124, 1038, 902 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C26H36IO4 539.1658, found 539.1664.

2,2,5,7a,11,11-Hexamethyl-7a,8,10,11,11a,12-hexahydro-4H,9H-[1,3]dioxino[4,5-a]xanthen-4-one (48)

BF3·OEt2 (0.31 mL, 2.50 mmol) was added dropwise with stirring to resorcylate 24 (172 mg, 0.50 mmol) in CH2Cl2 (50 mL) at −78 °C. The resulting mixture was warmed to 25 °C and further stirred for 1.5 h, when saturated aqueous n class="Chemical">NaHCO3 (25 mL) and H2O (25 mL) were added and the phases were separated. The aqueous layer was extracted with CH2Cl2 (3 × 25 mL), and the combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/Et2O 9:1) to provide meroterpenoid 48 (154 mg, 0.447 mmol, 89%, 3:1 dr) as a white solid containing a minor diastereoisomer. Recrystallization from n-hexane provided the pure trans-fused ring product: R 0.48 (pentane/EtOAc 19:1); mp 139.5–141.3 °C; 1H NMR (400 MHz, CDCl3) δ 6.34 (s, 1H), 2.62 (dd, J = 16.8, 4.8 Hz, 1H), 2.57 (s, 3H), 2.22 (dd, J = 16.8, 13.3 Hz, 1H), 2.01–1.94 (m, 1H), 1.74 (s, 3H), 1.70 (s, 3H), 1.68–1.64 (m, 1H), 1.60 (dd, J = 13.4, 4.8 Hz, 1H), 1.60–1.55 (m, 2H), 1.54–1.47 (m, 1H), 1.37–1.28 (m, 1H), 1.21 (s, 3H), 1.03 (s, 3H), 0.93 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.9, 158.8, 156.0, 142.1, 114.4, 108.6, 104.8, 104.0, 78.7, 47.4, 41.4, 39.7, 33.5, 32.1, 26.2, 25.5, 22.0, 20.6, 19.8, 19.7, 17.3; IR νmax (neat) 2969, 2901, 2921, 1720, 1618, 1576, 1390, 1286, 1043 cm–1; HRMS (ESI) m/z [M]•+ calcd for C21H28O4 344.1988, found 344.1990. Anal. Calcd for C21H28O4: C, 73.32; H, 8.19. Found: C, 73.17; H, 8.22.

8-Hydroxy-1,1,4a,6-tetramethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-7-carboxylic Acid (49)

H2O (8 μL, 0.4 mmol) was added with stirring to a suspension of KOBu (180 mg, 1.60 mmol) in n class="Chemical">Et2O (3 mL) at 0 °C. After 5 min, meroterpenoid 48 (69 mg, 0.200 mmol) was added, and the resulting mixture was further stirred at 25 °C for 2 h. The pH was adjusted to ∼2 with aqueous HCl (1 M), the two phases were separated, and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/EtOAc/AcOH 9:1:0.01) to give the carboxylic acid 49 (42 mg, 0.138 mmol, 69%) as a white solid: R 0.30 (pentane/EtOAc/AcOH 9:1:0.01); mp 176.7–178.6 °C; 1H NMR (400 MHz, CDCl3) δ 11.84 (s, 1H), 11.17 (s, 1H), 6.22 (s, 1H), 2.77 (dd, J = 17.0, 4.8 Hz, 1H), 2.52 (s, 3H), 2.28 (dd, J = 16.9, 13.4 Hz, 1H), 2.01–1.94 (m, 1H), 1.72–1.64 (m, 1H), 1.64–1.55 (m, 3H), 1.55–1.45 (m, 1H), 1.40–1.27 (m, 1H), 1.22 (s, 3H), 1.04 (s, 3H), 0.94 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 175.5, 163.7, 158.9, 141.4, 112.7, 108.4, 102.4, 78.7, 47.6, 41.5, 39.7, 33.6, 32.1, 24.1, 20.6, 19.8, 19.7, 17.6; IR νmax (neat) 2694, 2919, 2865, 1619, 1578, 1454, 1268, 1151, 1100 cm–1; HRMS (EI) m/z [M]•+ Calcd for C18H24O4 304.1675, found 304.1679. Anal. Calcd for C18H24O4: C, 71.03; H, 7.95. Found: C, 71.17; H, 8.11.

1,1,4a,6-Tetramethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-8-ol (50)

Aqueous KOH (5 M; 1 mL) was added with stirring to n class="Chemical">meroterpenoid 48 (69 mg, 0.200 mmol) in 1,4-dioxane (2 mL), and the resulting mixture was heated at 110 °C for 23 h. After the reaction mixture was cooled to 25 °C, the pH was adjusted to ∼2 with aqueous HCl (4 M). The two phases were separated, and the aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/EtOAc 15:1) to give the phenol 50 (40 mg, 0.194 mmol, 97%) as a white foam: R 0.33 (pentane/EtOAc 15:1); 1H NMR (400 MHz, (CD3)2CO) δ 8.00 (s, 1H), 6.21 (s, 1H), 6.05 (s, 1H), 2.71 (dd, J = 16.7, 5.0 Hz, 1H), 2.26 (dd, J = 16.6, 13.5 Hz, 1H), 2.12 (s, 3H), 1.92–1.81 (m, 1H), 1.68–1.53 (m, 4H), 1.52–1.44 (m, 1H), 1.40–1.27 (m, 1H), 1.17 (s, 3H), 1.01 (s, 3H), 0.94 (s, 3H); 13C{1H} NMR (100 MHz, (CD3)2CO) δ 156.2, 155.0, 137.2, 109.7, 107.7, 107.6, 77.0, 48.8, 42.3, 40.8, 34.0, 21.3, 20.9, 20.4, 20.0, 18.6; IR νmax (neat) 3398, 2935, 2866, 1627, 1587, 1516, 1457, 1101, 1063, 1040 cm–1; HRMS (EI) m/z [M]•+ calcd for C17H24O2 260.1776, found 260.1786.

7-(Hydroxymethyl)-1,1,4a,6-tetramethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-8-ol (51)

LiAlH4 in n class="Chemical">THF (1 M; 0.8 mL, 0.800 mmol) was added with stirring to meroterpenoid 48 (69 mg, 0.200 mmol) in THF (4 mL) at 0 °C. After 1 h, H2O (65 μL) and NaOH (1 M; 150 μL) were added dropwise sequentially, and the mixture was further stirred for 30 min. Solid NH4Cl (100 mg) was added, and the solids were filtered and eluted with Et2O (5 mL). The filtrate was concentrated and chromatographed (pentane/EtOAc 4:1) to afford diol 51 (55 mg, 0.189 mmol, 95%) as white foam: R 0.22 (pentane/EtOAc 9:1); 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 6.19 (s, 1H), 4.88 (s, 2H), 2.75 (dd, J = 16.6, 5.0 Hz, 1H), 2.37–2.27 (m, 1H), 2.17 (s, 3H), 1.99–1.90 (m, 1H), 1.69–1.54 (m, 4H), 1.52–1.40 (m, 1H), 1.38–1.25 (m, 1H), 1.20 (s, 3H), 1.02 (s, 3H), 0.92 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.0, 153.4, 133.6, 113.6, 110.2, 109.0, 77.1, 60.8, 47.8, 41.6, 39.9, 33.5, 32.1, 20.6, 19.8, 19.6, 19.2, 17.7; IR νmax (neat) 3344, 2934, 2865, 1627, 1583, 1102 cm–1; HRMS (ESI) m/z [M – H]− calcd for C18H25O3 289.1804, found 289.1807. Anal. Calcd for C18H26O3: C, 74.45; H, 9.02. Found: C, 74.59; H, 9.13.

8-Hydroxy-N-methoxy-N,1,1,4a,6-pentamethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthene-7-carboxamide (52)

MeNH(OMe)·HCl (59 mg, 0.605 mmol) was added dropwise with stirring to n class="Chemical">meroterpenoid 48 (69 mg, 0.200 mmol) in THF (4 mL) and cooled to 0 °C, followed by dropwise addition of PrMgCl in THF (2 M; 0.6 mL, 1.20 mmol). The resulting mixture was stirred at 0 °C for 3 h, when the reaction was quenched with saturated NH4Cl (2 mL) and the mixture was acidified to pH ∼ 1 with aqueous HCl (1 M). The two phases were separated, and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/EtOAc 7:3) to give the amide 52 (67 mg, 0.193 mmol, 96%) as a white solid: R 0.43 (pentane/EtOAc 7:3); mp 178.9–182.7 °C; 1H NMR (400 MHz, CDCl3) δ 6.20 (s, 1H), 3.57 (s, 3H), 3.33 (s, 3H), 2.74 (dd, J = 16.7, 5.0 Hz, 1H), 2.28 (dd, J = 16.7, 13.4 Hz, 1H), 2.23 (s, 3H), 1.98–1.93 (m, 1H), 1.71–1.64 (m, 1H), 1.61 (dd, J = 13.2, 4.9 Hz, 1H), 1.59–1.54 (m, 2H), 1.54–1.45 (m, 1H), 1.37–1.24 (m, 1H), 1.20 (s, 3H), 1.02 (s, 3H), 0.92 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.9, 155.5, 154.5, 135.3, 111.1, 110.7, 108.5, 77.7, 61.3, 47.7, 41.6, 39.9, 34.2, 33.5, 32.1, 20.6, 19.9, 19.8, 19.7, 17.8; IR νmax (neat) 3110, 2933, 1616, 1578, 1456, 1389, 1120, 732 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C20H30NO4 348.2175, found 348.2188. Anal. Calcd for C20H29NO4: C, 69.14; H, 8.41; N, 4.03. Found: C, 69.11; H, 8.49; N, 3.97.