Meroterpenoid Synthesis via Sequential Polyketide Aromatization and Radical Anion Cascade Triene Cyclization: Biomimetic Total Syntheses of Austalide Natural Products.

The first total synthesis of five austalide natural products, (±)-17 S-dihydroaustalide K, (±)-austalide K, (±)-13-deacetoxyaustalide I, (±)-austalide P, and (±)-13-deoxyaustalide Q acid, was accomplished via a series of biomimetic transformations. Key steps involved polyketide aromatization of a trans, trans-farnesol-derived β,δ-diketodioxinone into the corresponding β-resorcylate, followed by titanium(III)-mediated reductive radical cyclization of an epoxide to furnish the drimene core. Subsequent phenylselenonium ion induced diastereoselective cyclization of the drimene completed the essential carbon framework of the austalides to access (±)-17 S-dihydroaustalide K, (±)-austalide K, and (±)-13-deacetoxyaustalide I via sequential oxidations. Furthermore, (±)-13-deacetoxyaustalide I could serve as a common intermediate to be derivatized into other related natural products, (±)-austalide P and (±)-13-deoxyaustalide Q acid, by functionalizing the cyclic lactone moiety.

Introduction

The austalides (Figure ) are a diverse group of meroterpenoid natural products featuring a trans,transoid,cis-fused ring system. The first 12 members were isolated from the whole maize cultures of Aspergillus ustus, strain MRC 1163 in the 1980s.[1] Additional new members were isolated recently from the metabolites of the fungi Aspergillus aureolatus, Penicillium thomii, and Penicillium lividum.[2] Initial profiling of the isolated natural products showed them to possess a broad spectrum of bioactivity such as cytotoxic and antibacterial properties as well as inhibiting endo-1,3-β-d-glucanase.[2]

Figure 1

Representative austalide natural products.

The biosynthesis of austalide K (2) was first proposed in 1987 (Scheme ).[3a] It was postulated that 6-[(2E,6E)farnesyl]-5,7-dihydroxy-4-methylphthalide (6), a key intermediate in the biogenesis of mycophenolic acid, first undergoes cyclization via a stereospecific attack of the phenol on the 11si,21si-face of the alkene to provide chromene 7. Subsequent epoxidation of the terminal alkene gives epoxide 8, which could undergo cationic polyene cyclization to furnish the trans,transoid,cis-fused ring motif. However, further investigations on the fate of the hydrogen atom incorporation using 13C,2H- and 2H-labeled mevalonolactones provided evidence to exclude the intermediacy of chromene 7.[3b] This has led to an alternative proposal on the biosynthesis of the austalides involving polyene cyclization of epoxide 9 to generate carbocation intermediate 10, followed by enzyme-controlled stereospecific cyclization of the phenolic oxygen to furnish the chromane structure with the cis-fused ring. It is important to note that concerted polyene cyclization of epoxide 9 would lead to the formation of a stereoisomer of austalide K (2), featuring an all-trans-fused ring system.

Scheme 1

Proposed Biosynthesis of Austalides K (2)

Inspired by the pioneering work of Hyatt and co-workers and Harris and co-workers on dioxinone thermolysis and biomimetic polyketide aromatization,[4] our group focused on the biomimetic synthesis of β-resorcylate-derived natural products utilizing β,δ-diketodioxinones.[5] Recently, we disclosed a scalable and efficient synthesis of dioxinone β-ketoesters 13 with the use of regioselective thermolysis of dioxane-4,6-dione ketodioxanones 11 (Scheme ).[6] Utilization of our recent findings with sequential polyketide aromatization and polyene cyclization greatly facilitated concise syntheses of hongoquercin A and B.[7] Herein, we report further studies on the biomimetic total syntheses of the austalide natural products via a series of biomimetic transformations.

Scheme 2

Thermolysis of Dioxane-4,6-dione Ketodioxanones 11

Results and Discussion

We considered that austalide P (4) and 13-deoxyaustalide Q acid (5) could be derived from 13-deacetoxyaustalide I (3) by functionalizing the cyclic lactone moiety (Scheme ). Late-stage arene methylation and deacetylation of acetate 14 would allow access to 17S-dihydroaustalide K (1), followed by sequential oxidations of the alcohol functionality to give austalide K (2) and 13-deacetoxyaustalide I (3). In order to construct the trans,transoid,cis-fused ring motif, we envisioned the use of two sequential diastereoselective cyclizations. First, a titanium(III)-mediated radical triene cyclization of epoxide 16 would give drimene 15 to furnish the first trans-fused ring with an exocyclic alkene, acting as an equivalent of carbocation 10. Subsequent phenylselenonium ion induced diastereoselective cyclization of the drimene 15 should provide the desired cis-fused ring to complete the essential carbon framework. Epoxide 16 should be available from a farnesol-derived β-resorcylate, which was accessible via sequential cycloaromatization and lactonization of β,δ-diketodioxinones 17. Dioxinone β,δ-diketoester 18, synthesized via C-acylation of dioxinone β-ketoester 19, should undergo palladium(0)-catalyzed decarboxylative allylic rearrangement to provide β,δ-diketodioxinone 17. Finally, dioxinone β-ketoester 19 is available by trapping a dioxinone acylketene 12 with trans,trans-farnesol (20) following our recently published protocols.[6]

Scheme 3

Retrosynthetic Analysis of the Austalides

The synthesis of β-resorcylate 22 (Scheme ) was undertaken by trapping dioxinone acylketene 12, generated in situ from 4,6-dione ketodioxanone 21, with trans,trans-farnesol (20) to provide dioxinone β-ketoester 19 (87%).[6] Subsequent MgCl-mediated regioselective C-acylation of the dioxinone β-ketoester 19 with acetoxyacetyl chloride gave dioxinone β,δ-diketoester 18, which was allowed to react with a catalytic amount of Pd2(dba)3 in the presence of tri(2-furyl)phosphine to induce a decarboxylative allylic rearrangement to provide β,δ-diketodioxinone 17, which was directly aromatized by treatment with triethyl amine to provide β-resorcylate 22 (39% over two steps from dioxinone β-ketoester 19).

Scheme 4

Synthesis of Terpene Resorcylate 22

With the β-resorcylate 22 in hand, attention was focused on the functionalization of the aromatic core as well as installing the terminal epoxide for the triene cyclization reaction (Scheme ). The phenol group of β-resorcylate 22 was first protected as the MOM ether 23 (75%), followed by lactonization under basic conditions to give phthalide 24 (93%). Methylation of the resulting phenol of phthalide 24 gave methyl ether 25 (98%), which was allowed to react with N-bromosuccinimide with regioselective electrophilic addition at the terminal alkene of the terpene chain to form bromohydrin 26 (77%). Subsequent potassium carbonate (K2CO3)-mediated cyclization of bromohydrin 26 gave the desired racemic epoxide 16 (97%).

Scheme 5

Synthesis of Epoxide 16

Next, the terpene side chain of epoxide 16 was functionalized (Scheme ). Treatment of the epoxide 16 with a titanocene(III) catalyst, generated from titanocene(IV) dichloride, manganese, trimethylsilyl chloride, and 2,4,6-collidine,[8] initiated a radical anion cascade cyclization, producing alcohol 27 (40% over two steps) after desilylation with tetrabutylammonium fluoride. Acetylation of the alcohol 27 yielded acetate 28 (98%), followed by MOM deprotection with pyridinium p-toluenesulfonate (PPTS) and BuOH to furnish phenol 15 (86%). The relative stereochemistry of phenol 15 was unambiguously determined by X-ray crystallography, confirming the formation of the trans-fused ring system. Reaction of N-(phenylseleno)phthalimide and stannic chloride with phenol 15 resulted in the formation of a selenonium ion intermediate, which was intramolecularly trapped by the phenolic group to provide the 6-exo-trig cyclized phenylselenide 29 (58%).[9] After removal of the phenylselenyl group by reaction with tri-n-butylstannane in the presence of 2,2-azobis(isobutyronitrile), meroterpenoid 14 (94%) was isolated as a single diastereoisomer with the desired trans,transoid,cis-fused ring system, the relative stereochemistry of which was confirmed by additional NOESY experiments.

Scheme 6

Synthesis of Meroterpenoid 14

With the key meroterpenoid 14 in hand after establishing the correct relative stereochemistry, we directed our attention to the arene methylation and sequential oxidation reactions to complete the synthesis of (±)-17S-dihydroaustalide K (1), (±)-austalide K (2), and (±)-13-deacetoxyaustalide I (3) (Scheme ). Electrophilic aromatic substitution reaction of meroterpenoid 14 with N-bromosuccinimide gave bromide 30 (93%), which was subjected to the palladium-catalyzed Suzuki–Miyaura cross-coupling reaction with potassium methyltrifluoroborate to furnish the hexa-substituted arene 31 (88%).[10] Finally, selective acetate deprotection with magnesium methoxide completed the synthesis of (±)-17S-dihydroaustalide K (1) (88%).[11] Furthermore, Dess–Martin periodinane-mediated oxidation of (±)-17S-dihydroaustalide K (1) gave (±)-austalide K (2) (83%), and subsequent Baeyer–Villiger oxidation with mCPBA gave (±)-13-deacetoxyaustalide I (3) (96%). The analytical data for these synthetic materials were in substantial agreement with those reported for the isolated natural product.[1b,2c]

Scheme 7

Synthesis of (±)-17S-Dihydroaustalide K (1), (±)-Austalide K (2), and (±)-13-Deacetoxyaustalide I (3)

(±)-13-Deacetoxyaustalide I (3) was also used in alternative derivatization reactions for the synthesis of additional austalide natural products (Scheme ). Reaction of (±)-13-deacetoxyaustalide I (3) with sodium methoxide resulted in transesterification to provide (±)-austalide P (4) (80%).[12] Under acidic conditions at elevated temperature, the cyclic lactone moiety of (±)-13-deacetoxyaustalide I (3) was hydrolyzed accompanied by elimination of the resulting tertiary alcohol to give (±)-13-deoxyaustalide Q acid (5) (71%).[13] The analytical data of the synthetic products were compared with data reported for the isolated natural products and were found to be in substantial agreement.[2a,2c]

Scheme 8

Synthesis of (±)-Austalide P (4) and (±)-13-Deoxyaustalide Q Acid (5)

Conclusion

In conclusion, the first total synthesis of five austalide natural products, (±)-17S-dihydroaustalide K (1), (±)-austalide K (2), (±)-13-deacetoxyaustalide I (3), (±)-austalide P (4), and (±)-13-deoxyaustalide Q acid (5), was completed in 17–20 steps. A series of biomimetic transformations were employed to construct the carbon skeleton of these natural products. The aromatic core was synthesized by biomimetic polyketide aromatization, whereas the fused ring motif was constructed by sequential reductive radical anion triene cyclization of an epoxide, followed by phenylselenium-mediated diastereoselective cyclization reaction. Further studies on the synthesis of novel meroterpenoids using such biomimetic approaches are ongoing in our laboratory.

Experimental Section

General Methods

All reagents and solvents were used directly without further purification unless otherwise specified. The syntheses of malonate, dioxinone acid, and dioxinone β-ketoesters 19 were carried out according to Barrett et al.[6,7] All solvents were purified and dried by distillation under an atmosphere of N2 before use. THF was redistilled from Na-Ph2CO. CH2Cl2, Et3N, MeOH, and pyridine were redistilled from CaH2. PhH and PhMe were redistilled from Na. Me2CO and BuOH were dried over 4 Å activated molecular sieves under N2 for 24 h. 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 were visualized under UV light and stained with an acidic vanillin solution. Flash column chromatography was performed employing silica gel 60 Å, with a particle size of 40–63 μm. All 1H and proton-decoupled 13C NMR spectra were recorded at 400 and 101 MHz, respectively, at ambient temperature in deuterated solvents as noted. NMR spectra are 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), and chemical shifts are reported in parts per million. IR spectra are reported in cm–1. 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 were uncorrected. X-ray diffraction data were recorded by the Imperial College X-ray Crystallography Facility.

(7-Hydroxy-2,2-dimethyl-4-oxo-8-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)-4H-benzo[d][1,3]dioxin-5-yl)methyl Acetate (22)

MgCl2 (7.12 g, 74.8 mmol) and pyridine (23 mL, 288 mmol) were added with stirring to β-ketoester 19 (24.9 g, 57.6 mmol) in CH2Cl2 (200 mL) at 0 °C. After 15 min, AcCH2COCl (7.40 mL, 69.1 mmol) was added dropwise, and the reaction mixture was further stirred for 2 h at 0 °C. Saturated aqueous NH4Cl (100 mL) was added, 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 × 150 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give the crude dioxinone β,δ-diketoester 18. P(2-furyl)3 (2.67 g, 11.5 mmol) and Pd2dba3 (2.64 g, 2.88 mmol) were added sequentially with stirring to this crude dioxinone β,δ-diketoester 18 in THF (300 mL) at 25 °C. After 3 h, Et3N (24.0 mL, 173 mmol) was added, and the resulting mixture was stirred for an additional 18 h. Reaction was quenched with aqueous HCl (1 M; 200 mL); the two phases were separated, and the aqueous layer was extracted with CH2Cl2 (3 × 150 mL). The combined organic layers were dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (pentane/EtOAc 19:1 to 10:1) to give β-resorcylate 22 (10.7 g, 22.7 mmol, 39% over two steps) as a yellow oil: R 0.26 (pentane/Et2O 2:1); 1H NMR (400 MHz, CDCl3) δ 6.64 (s, 1H), 5.53 (s, 2H), 5.23–5.12 (m, 1H), 5.11–5.00 (m, 2H), 3.33 (d, J = 7.2 Hz, 2H), 2.15 (s, 3H), 2.16–1.90 (m, 8H), 1.79 (s, 3H), 1.69 (s, 6H), 1.66 (s, 3H), 1.58 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 160.8, 160.5, 156.1, 139.8, 138.7, 135.5, 131.3, 124.3, 123.5, 120.3, 114.5, 109.8, 105.3, 103.6, 64.1, 39.7, 39.6, 26.7, 26.3, 25.7 (2C), 21.9, 21.0, 17.7, 16.2, 16.0; IR νmax (neat) 3290, 1724, 1699, 1597, 1422, 1377, 1274, 1207, 1029 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C28H39O6 471.2747; found 471.2731.

(7-(Methoxymethoxy)-2,2-dimethyl-4-oxo-8-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)-4H-benzo[d][1,3]dioxin-5-yl)methyl Acetate (23)

MOMCl (1.03 mL; 13.6 mmol) was added with stirring to Pr2EtN (5.92 mL; 34.0 mmol) and β-resorcylate 22 (3.19 g, 6.79 mmol) in CH2Cl2 (60 mL). After 3 h, saturated aqueous NH4Cl (30 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 under reduced pressure, and chromatographed (pentane/EtOAc 9:1) to give MOM ether 23 (2.61 g, 5.07 mmol, 75%) as a colorless oil: R 0.17 (pentane/EtOAc 9:1); 1H NMR (400 MHz, CDCl3) δ 6.90 (s, 1H), 5.54 (s, 2H), 5.26 (s, 2H), 5.15–5.03 (m, 3H), 3.48 (s, 3H), 3.30 (d, J = 7.5 Hz, 2H), 2.16 (s, 3H), 2.08–1.89 (m, 8H), 1.76 (s, 3H), 1.69 (s, 6H), 1.66 (s, 3H), 1.58 (s, 3H), 1.56 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.5, 160.24, 160.17, 155.8, 139.7, 135.7, 135.1, 131.3, 124.3, 124.0, 121.0, 118.2, 107.2, 105.3, 105.0, 94.1, 64.2, 56.4, 39.74, 39.66, 26.7, 26.6, 25.70 (2C), 25.66, 21.9, 20.9, 17.6, 16.1, 16.0; IR νmax (neat) 2968, 2918, 2856, 1728, 1609, 1582, 1376, 1293, 1222, 1151, 1044, 964 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C30H43O7 515.3009; found 515.2994. Anal. Calcd for C30H42O7: C, 70.01; H, 8.23. Found: C, 69.75; H, 8.37.

7-Hydroxy-5-(methoxymethoxy)-6-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)isobenzofuran-1(3H)-one (24)

K2CO3 (3.51 g, 25.4 mmol) was added with stirring to ether 23 (2.61 g, 5.07 mmol) in MeOH (70 mL) at 25 °C. After 18 h, aqueous citric acid (1 M) was added to pH ∼3, and the mixture was diluted with CH2Cl2 (100 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 2:1) to provide lactone 24 (1.96 g, 4.73 mmol, 93%) a colorless oil, which solidified upon standing: R 0.44 (pentane/Et2O 2:1); mp 61–62 °C; 1H NMR (400 MHz, CDCl3) δ 6.75 (s, 1H), 6.21 (s, 1H), 4.75 (s, 2H), 4.71 (s, 2H), 4.71–4.66 (m, 1H), 4.58–4.53 (m, 2H), 2.97 (s, 3H), 2.88 (d, J = 7.2 Hz, 2H), 1.61–1.37 (m, 8H), 1.28 (s, 3H), 1.16 (s, 3H), 1.07 (s, 3H), 1.05 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.7, 162.1, 154.7, 145.5, 135.8, 135.0, 131.3, 124.3, 124.1, 121.2, 117.7, 104.8, 99.1, 94.2, 70.4, 56.3, 39.8, 39.7, 26.7, 26.5, 25.7, 21.8, 17.6, 16.1, 16.0; IR νmax (neat) 3414, 1730, 1627, 1610, 1151, 1064, 1036, 959 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C25H35O5 415.2484; found 415.2482. Anal. Calcd for C25H34O5: C, 72.44; H, 8.27. Found: C, 72.31; H, 8.35.

7-Methoxy-5-(methoxymethoxy)-6-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)isobenzofuran-1(3H)-one (25)

MeI (0.86 mL, 13.8 mmol) was added dropwise with stirring to a suspension of Cs2CO3 (4.50 g, 13.8 mmol) and lactone 24 (1.91 g, 4.60 mmol) in THF (46 mL) at 25 °C. After 16 h, saturated aqueous NH4Cl (30 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/Et2O 2:1) to provide methyl ether 25 (1.94 g, 4.53 mmol, 98%) as a colorless oil: R 0.34 (pentane/Et2O 2:1); 1H NMR (400 MHz, CDCl3) δ 6.88 (s, 1H), 5.27 (s, 2H), 5.17 (s, 2H), 5.16–5.10 (m, 1H), 5.09–5.02 (m, 2H), 4.06 (s, 3H), 3.48 (s, 3H), 3.42 (d, J = 7.1 Hz, 2H), 2.09–1.88 (m, 8H), 1.79 (s, 3H), 1.66 (s, 3H), 1.58 (s, 3H), 1.56 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.8, 161.3, 158.0, 148.2, 135.5, 135.0, 131.3, 124.8, 124.3, 124.0, 122.0, 110.5, 101.9, 94.2, 68.8, 62.6, 56.3, 39.8, 39.7, 26.7, 26.5, 25.7, 22.7, 17.6, 16.1, 16.0; IR νmax (neat) 1752, 1604, 1232, 1151, 1078, 1041, 926 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C26H37O5 429.2641; found 429.2650. Anal. Calcd for C26H36O5: C, 72.87; H, 8.47. Found: C, 72.79; H, 8.55.

6-((2E,6E)-10-Bromo-11-hydroxy-3,7,11-trimethyldodeca-2,6-dien-1-yl)-7-methoxy-5-(methoxymethoxy)isobenzofuran-1(3H)-one (26)

N-Bromosuccinimide (959 mg, 5.39 mmol) was added with stirring to methyl ether 25 (2.10 g, 4.90 mmol) in THF (46 mL) and H2O (23 mL) at 0 °C. After 2 h, Na2S2O5 (0.5 M; 30 mL) and EtOAc (30 mL) were added, and the two phases were separated. The aqueous layer was extracted with EtOAc (3 × 50 mL), and the combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/EtOAc 2:1) to provide bromohydrin 26 (1.99 g, 3.79 mmol, 77%) as a colorless oil: R 0.14 (pentane/Et2O 1:1); 1H NMR (400 MHz, CDCl3) δ 6.88 (s, 1H), 5.28 (s, 2H), 5.17 (s, 2H), 5.17–5.11 (m, 2H), 4.07 (s, 3H), 3.95 (dd, J = 11.4, 1.9 Hz, 1H), 3.48 (s, 3H), 3.42 (d, J = 7.1 Hz, 2H), 2.33–2.22 (m, 1H), 2.19–1.88 (m, 6H), 1.79 (s, 3H), 1.78–1.68 (m, 1H), 1.55 (s, 3H), 1.33 (s, 3H), 1.31 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.8, 161.4, 158.0, 148.2, 135.3, 133.1, 125.8, 124.8, 122.1, 110.5, 102.0, 94.3, 72.4, 70.8, 68.8, 62.6, 56.3, 39.7, 38.1, 32.1, 26.6, 26.5, 25.8, 22.7, 16.1, 15.8; IR νmax (neat) 3484, 1752, 1605, 1233, 1151, 1118, 1077. 1042, 978, 943 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C26H37BrO6 525.1852; found 525.1865.

6-((2E,6E)-9-((S)-3,3-Dimethyloxiran-2-yl)-3,7-dimethylnona-2,6-dien-1-yl)-7-methoxy-5-(methoxymethoxy)isobenzofuran-1(3H)-one (16)

K2CO3 (1.56 g, 2.96 mmol) was added with stirring to bromohydrin 26 in Me2CO (60 mL) at 25 °C. After 18 h, H2O (50 mL) and CH2Cl2 (100 mL) were 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/Et2O 1:1) to provide epoxide 16 (1.28 g, 2.88 mmol, 97%) as a colorless oil: R 0.38 (pentane/Et2O 1:1); 1H NMR (400 MHz, CDCl3) δ 6.88 (s, 1H), 5.27 (s, 2H), 5.17 (s, 2H), 5.16–5.02 (m, 2H), 4.06 (s, 3H), 3.47 (s, 3H), 3.41 (d, J = 7.1 Hz, 2H), 2.66 (t, J = 6.3 Hz, 1H), 2.29–1.89 (m, 6H), 1.78 (s, 3H), 1.63–1.58 (m, 1H), 1.57 (s, 3H), 1.56–1.50 (m, 1H), 1.28 (s, 3H), 1.23 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.7, 161.3, 158.0, 148.2, 135.4, 134.1, 124.8, 124.7, 122.1, 110.5, 102.0, 94.2, 68.8, 64.1, 62.6, 58.2, 56.3, 39.7, 36.2, 27.4, 26.5, 24.9, 22.7, 18.7, 16.1, 16.0; IR νmax (neat) 1752, 1604, 1232, 1117, 1077, 1041, 978 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C26H37O6 445.2590; found 445.2598.

6-(((1S,4aR,6S,8aR)-6-Hydroxy-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methyl)-7-methoxy-5-(methoxymethoxy)isobenzofuran-1(3H)-one (27)

Cp2TiCl2 (197 mg, 0.792 mmol) and Mn powder (1.74 g, 31.7 mmol) were added with stirring to THF (50 mL) at 25 °C. After 30 min, when the solution changed from red to green, 2,4,6-collidine (3.67 mL, 27.7 mmol) and Me3SiCl (2.01 mL, 15.8 mmol) were added sequentially with stirring. After 5 min, epoxide 16 (1.76 g, 3.96 mmol) in THF (50 mL) was added dropwise with stirring. After 16 h, aqueous citric acid (1 M; 100 mL) was added with stirring, and when effervescence ceased, Et2O (100 mL) was added, and the two phases were separated. The aqueous layer was extracted with Et2O (3 × 50 mL), and the combined organic layers were dried (MgSO4), filtered, concentrated, and dissolved in THF (50 mL). Bu4NF (1 M in THF; 16.0 mL, 16.0 mmol) was added, and the resulting mixture was stirred for 2 h at 25 °C. The reaction mixture was concentrated and chromatographed (pentane/Et2O 1:4) to provide alcohol 27 (697 mg, 1.57 mmol, 40%) as a white foam: R 0.17 (pentane/Et2O 1:4); 1H NMR (400 MHz, CDCl3) δ 6.87 (s, 1H), 5.31–5.23 (m, 2H), 5.15 (s, 2H), 4.96 (s, 1H), 4.70 (s, 1H), 4.06 (s, 3H), 3.51 (s, 3H), 3.27 (dd, J = 11.5, 4.6 Hz, 1H), 2.92 (dd, J = 13.8, 9.7 Hz, 1H), 2.73 (dd, J = 13.8, 3.7 Hz, 1H), 2.50 (dd, J = 10.0, 3.4 Hz, 1H), 2.39–2.22 (m, 1H), 1.94–1.87 (m, 2H), 1.79–1.59 (m, 3H), 1.46–1.39 (m, 1H), 1.40–1.32 (m, 1H), 1.15 (dd, J = 12.5, 2.8 Hz, 1H), 1.00 (s, 3H), 0.83 (s, 3H), 0.80 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.9, 161.6, 158.5, 148.7, 148.1, 125.2, 110.6, 106.9, 102.1, 94.6, 78.9, 68.7, 62.4, 56.6, 55.3, 54.8, 40.1, 39.2, 38.4, 36.5, 28.3, 28.0, 24.1, 19.6, 15.4, 14.2; IR νmax (neat) 3489, 1748, 1606, 1463, 1323, 1077, 1042, 732 cm–1; HRMS (ES) m/z [M + H]+ calcd for C26H37O6 445.2590; found 445.2592.

(2S,4aR,5S,8aR)-5-((4-Methoxy-6-(methoxymethoxy)-3-oxo-1,3-dihydroisobenzofuran-5-yl)methyl)-1,1,4a-trimethyl-6-methylenedecahydronaphthalen-2-yl Acetate (28)

DMAP (9 mg, 0.0704 mmol), Et3N (108 μL, 0.774 mmol) and Ac2O (74 μL, 0.774 mmol) were added sequentially with stirring to alcohol 27 (313 mg, 0.704 mmol) in CH2Cl2 (3 mL) at 25 °C. After 2 h, saturated aqueous NaHCO3 (2 mL) was added, and the two phases were separated. The aqueous layer was extracted with CH2Cl2 (3 × 3 mL), and the combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/Et2O 1:1) to provide acetate 28 (337 mg, 0.693 mmol, 98%) as a white solid: R 0.33 (pentane/Et2O 1:1); mp 155–158 °C; 1H NMR (400 MHz, CDCl3) δ 6.88 (s, 1H), 5.29–5.25 (m, 2H), 5.16 (s, 2H), 4.95 (s, 1H), 4.70 (s, 1H), 4.52 (dd, J = 11.6, 4.6 Hz, 1H), 4.06 (s, 3H), 3.51 (s, 3H), 2.92 (dd, J = 13.8, 9.6 Hz, 1H), 2.73 (dd, J = 13.8, 3.9 Hz, 1H), 2.57–2.48 (m, 1H), 2.36–2.27 (m, 1H), 2.06 (s, 3H), 1.93–1.83 (m, 2H), 1.81–1.59 (m, 3H), 1.49–1.32 (m, 2H), 1.22 (dd, J = 12.5, 2.7 Hz, 1H), 0.87 (s, 6H), 0.85 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.1, 168.9, 161.6, 158.4, 148.5, 148.2, 125.0, 110.5, 107.1, 102.1, 94.5, 80.8, 68.7, 62.6, 56.6, 55.0, 54.8, 39.9, 38.3, 38.1, 36.2, 28.3, 24.4, 24.0, 21.3, 19.8, 16.6, 14.2; IR νmax (neat) 1753, 1729, 1606, 1463, 1234, 1078, 1043, 978, 920, 732 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C28H39O7 487.2696; found 487.2674.

(2S,4aR,5S,8aR)-5-((6-Hydroxy-4-methoxy-3-oxo-1,3-dihydroisobenzofuran-5-yl)methyl)-1,1,4a-trimethyl-6-methylenedecahydronaphthalen-2-yl Acetate (15)

Pyridinium p-toluenesulfonate (842 mg, 3.35 mmol) was added with stirring to acetate 28 (326 mg, 0.670 mmol) in BuOH (25 mL), and the mixture was heated to 100 °C for 36 h. After being cooled, brine (30 mL) and CH2Cl2 (40 mL) were added, 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 chromatographed (pentane/EtOAc 3:2) to provide phenol 15 (225 mg, 0.580 mmol, 86%) as a white solid: R 0.12 (pentane/Et2O 1:1); mp 222–223 °C; 1H NMR (400 MHz, CDCl3) δ 6.55 (s, 1H), 6.15 (s, 1H), 5.13 (s, 2H), 5.03 (s, 1H), 4.81 (s, 1H), 4.51 (dd, J = 11.6, 4.6 Hz, 1H), 4.08 (s, 3H), 2.90–2.75 (m, 2H), 2.42–2.32 (m, 2H), 2.06 (s, 3H), 2.02–1.87 (m, 2H), 1.78–1.62 (m, 3H), 1.48–1.36 (m, 2H), 1.23 (dd, J = 12.5, 2.8 Hz, 1H), 0.87 (s, 6H), 0.85 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.1, 168.9, 160.9, 158.8, 149.4, 148.1, 122.8, 109.6, 107.3, 103.8, 80.8, 68.4, 62.7, 55.2, 54.8, 40.2, 38.2, 38.1, 36.2, 28.2, 24.3, 24.0, 21.3, 19.2, 16.5, 14.2; IR νmax (neat) 3295, 1730, 1605, 1429, 1235, 1077, 1027 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C26H35O6 443.2434; found 443.2434.

((3S,4aR,6aS,13aR,13bS)-12-Methoxy-4,4,13b-trimethyl-11-oxo-6a-((phenylselanyl)methyl)-1,3,4,4a,5,6,6a,9,11,13,13a,13b-dodecahydro-2H-benzo[a]furo[3,4-i]xanthen-3-yl Acetate (29)

Phenol 15 (100 mg, 0.226 mmol) in CH2Cl2 (10 mL) was added dropwise with stirring to N-(phenylseleno)phthalimide (410 mg, 1.36 mmol) and SnCl4 (1 M in CH2Cl2; 1.13 mL, 1.13 mmol) in CH2Cl2 (20 mL) at −78 °C. After 7 h, NaOH (2 M; 1 mL) was added and the reaction mixture was filtered through Celite. NaOH (2 M; 10 mL) was added; 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 1:1) to provide phenylselenide 29 (79 mg, 0.132 mmol, 58%) as a colorless oil: R 0.26 (pentane/Et2O 1:1); 1H NMR (400 MHz, CDCl3) δ 7.45–7.40 (m, 2H), 7.23–7.16 (m, 3H), 6.39 (s, 1H), 5.09 (s, 2H), 4.53 (dd, J = 11.8, 4.6 Hz, 1H), 4.08 (s, 3H), 3.12 (d, J = 12.6 Hz, 1H), 2.95 (d, J = 12.6 Hz, 1H), 2.77 (d, J = 18.9 Hz, 1H), 2.44 (dd, J = 18.9, 8.4 Hz, 1H), 2.30 (dt, J = 14.0, 3.0 Hz, 1H), 2.05 (s, 3H), 1.94–1.57 (m, 7H), 1.19 (td, J = 13.2, 3.9 Hz, 1H), 1.03 (dd, J = 11.3, 2.7 Hz, 1H), 0.92 (s, 3H), 0.85 (s, 3H), 0.66 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.0, 168.8, 160.7, 157.3, 147.4, 133.3 (2C), 130.2, 129.1 (2C), 127.3, 116.0, 108.2, 105.3, 80.4, 79.1, 68.6, 62.1, 53.9, 45.5, 38.03, 37.97, 37.8, 37.7, 37.3, 28.4, 23.4, 21.3, 17.5, 17.4, 16.8, 14.4; IR νmax (neat) 1751, 1734, 1613, 1592, 1429, 1366, 1238, 1131, 1027, 1078, 733 cm–1; HRMS (ESI) m/z [M + H]+ calcd for C32H38O6Se 599.1912; found 599.1913.

(3S,4aR,6aS,13aR,13bS)-12-Methoxy-4,4,6a,13b-tetramethyl-11-oxo-1,3,4,4a,5,6,6a,9,11,13,13a,13b-dodecahydro-2H-benzo[a]furo[3,4-i]xanthen-3-yl Acetate (14)

Phenylselenide 29 (46 mg, 0.0770 mmol), AIBN (13 mg, 0.0770 mmol), and HSnBu3 (62 μL, 0.231 mmol) in PhH (2 mL) were purged with Ar for 5 min and heated to 100 °C for 5 h. The reaction mixture was directly purified by chromatography (pentane/Et2O 1:1) through a pad of KF to give meroterpenoid 14 (31 mg, 0.0700 mmol, 91%) as a white solid: R 0.29 (pentane/Et2O 1:1); mp 212–213 °C; 1H NMR (400 MHz, CDCl3) δ 6.50 (s, 1H), 5.13 (s, 2H), 4.49 (dd, J = 11.7, 4.7 Hz, 1H), 4.13 (s, 3H), 2.88 (d, J = 18.7 Hz, 1H), 2.71 (dd, J = 18.6, 8.0 Hz, 1H), 2.23–2.14 (m, 1H), 2.04 (s, 3H), 1.87 (dt, J = 13.3, 3.7 Hz, 1H), 1.74–1.50 (m, 5H), 1.40 (d, J = 8.1 Hz, 1H), 1.17 (s, 3H), 1.13 (dd, J = 13.4, 4.0 Hz, 1H), 1.00 (dd, J = 11.3, 2.1 Hz, 1H), 0.89 (s, 3H), 0.84 (s, 3H), 0.66 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.9, 168.9, 161.6, 157.4, 147.4, 116.0, 107.9, 105.2, 80.5, 76.6, 68.6, 62.0, 54.2, 48.1, 40.1, 37.9, 37.8, 37.6, 28.4, 27.0, 23.4, 21.2, 17.7 (2C), 16.8, 14.3; IR νmax (neat) 1730, 1752, 1612, 1592, 1366, 1238, 1130, 1081, 1025, 901, 731 cm–1; HRMS (ES) m/z [M + H]+ calcd for C26H34O6 443.2434; found 443.2419.

(3S,4aR,6aS,13aR,13bS)-8-Bromo-12-methoxy-4,4,6a,13b-tetramethyl-11-oxo-1,3,4,4a,5,6,6a,9,11,13,13a,13b-dodecahydro-2H-benzo[a]furo[3,4-i]xanthen-3-yl Acetate (30)

N-Bromosuccinimide (19 mg, 0.105 mmol) and H2SO4 (13 μL,0.244 mmol) were added sequentially with stirring to meroterpenoid 14 (31 mg, 0.0700 mmol) in THF (0.4 mL). After 17 h, saturated aqueous NaHCO3 (0.4 mL) and Na2S2O3 (50 mg, 0.316 mmol) were added, and the two phases were separated. The aqueous layer was extracted with CH2Cl2 (3 × 0.5 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/Et2O 7:3) to provide bromide 30 (34 mg, 0.0652 mmol, 93%) as a white foam: R 0.19 (pentane/Et2O 7:3); 1H NMR (400 MHz, CDCl3) δ 5.07 (s, 2H), 4.50 (dd, J = 11.8, 4.5 Hz, 1H), 4.15 (s, 3H), 2.90 (d, J = 18.8 Hz, 1H), 2.75 (dd, J = 18.8, 8.1 Hz, 1H), 2.38–2.29 (m, 1H), 2.04 (s, 3H), 1.86 (dd, J = 13.5, 3.7 Hz, 1H), 1.79–1.51 (m, 5H), 1.44 (d, J = 8.2 Hz, 1H), 1.19 (s, 3H), 1.17–1.08 (m, 1H), 1.01 (d, J = 11.0 Hz, 1H), 0.90 (s, 3H), 0.85 (s, 3H), 0.63 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.9, 168.4, 157.4, 156.4, 146.9, 117.5, 109.2, 98.3, 80.4, 78.1, 69.3, 62.2, 54.1, 48.0, 39.9, 37.9, 37.8, 37.7, 28.4, 27.1, 23.3, 21.3, 18.3, 17.8, 16.8, 14.2; IR νmax (neat) 1759, 1733, 1603, 1465, 1436, 1366, 1246, 1135, 1029, 904, 732 cm–1; HRMS (ES) m/z [M + H]+ calcd for C26H34O6Br 521.1539; found 521.1549.

(3S,4aR,6aS,13aR,13bS)-12-Methoxy-4,4,6a,8,13b-pentamethyl-11-oxo-1,3,4,4a,5,6,6a,9,11,13,13a,13b-dodecahydro-2H-benzo[a]furo[3,4-i]xanthen-3-yl Acetate (31)

A degassed solution of bromide 30 (65 mg, 0.125 mmol), Pd(dppf)Cl2·CH2Cl2 (21 mg, 0.0257 mmol), CH3BF3K (23 mg, 0.187 mmol), and Cs2CO3 (122 mg, 0.375 mmol) in THF (1.5 mL) and H2O (75 μL) was heated to 80 °C for 18 h. After being cooled to 25 °C, H2O (1 mL) and Et2O (1 mL) were added, and the two phases were separated. The aqueous layer was extracted with Et2O (3 × 1 mL), and the combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/Et2O 7:3) to provide arene 31 (50 mg, 0.110 mmol, 88%) as a white foam: R 0.26 (pentane/Et2O 7:3); 1H NMR (400 MHz, CDCl3) δ 5.11 (s, 2H), 4.50 (dd, J = 11.7, 4.6 Hz, 1H), 4.09 (s, 3H), 2.90 (d, J = 18.6 Hz, 1H), 2.74 (dd, J = 18.6, 8.1 Hz, 1H), 2.33–2.16 (m, 1H), 2.04 (s, 3H), 2.03 (s, 3H), 1.95–1.81 (m, 1H), 1.72–1.54 (m, 5H), 1.40 (d, J = 7.8 Hz, 1H), 1.21–1.16 (m, 1H), 1.16 (s, 3H), 1.01 (d, J = 9.9 Hz, 1H), 0.90 (s, 3H), 0.85 (s, 3H), 0.63 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.9, 169.5, 158.8, 155.3, 145.3, 115.7, 114.3, 107.2, 80.5, 76.4, 68.2, 61.9, 54.2, 47.9, 40.2, 37.9, 37.8, 37.7, 28.5, 27.3, 23.4, 21.3, 17.9, 17.8, 16.8, 14.3, 10.7; IR νmax (neat) 1754, 1609, 1368, 1245, 1146, 1135, 1041, 1029, 904, 732 cm–1; HRMS (ES) m/z [M + H]+ calcd for C27H37O6 457.2590; found 457.2594.

(±)-17S-Dihydroaustalide K [(3S,4aR,6aS,13aR,13bS)-3-Hydroxy-12-methoxy-4,4,6a,8,13b-pentamethyl-1,2,3,4,4a,5,6,6a,9,13,13a,13b-dodecahydro-11H-benzo[a]furo[3,4-i]xanthen-11-one (1)]

Magnesium turnings (4 mg, 0.164 mmol) were added with stirring to a solution of arene 31 (15 mg, 0.0329 mmol) in MeOH (1 mL) and THF (0.1 mL), and the resulting suspension was heated at reflux for 1 h. When the reaction mixture had turned into a milky solution and effervescence has ceased, it was cooled to 25 °C and stirred for an additional 20 h. Aqueous HCl (1 M) was added until pH ∼1, and the two phases were separated. The aqueous layer was extracted with CH2Cl2 (3 × 1 mL), and the combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/Et2O 1:1) to provide (±)-17S-dihydroaustalide K (1) (13 mg, 0.0314 mmol, 95%) as a white solid: R 0.12 (pentane/Et2O 1:1); mp 198–200 °C; 1H NMR (400 MHz, CDCl3) δ 5.11 (s, 2H), 4.09 (s, 3H), 3.24 (dd, J = 11.7, 4.5 Hz, 1H), 2.91 (d, J = 18.6 Hz, 1H), 2.73 (dd, J = 18.7, 8.2 Hz, 1H), 2.29–2.22 (m, 1H), 2.03 (s, 3H), 1.89 (dt, J = 13.1, 3.5 Hz, 1H), 1.62–1.52 (m, 5H), 1.39 (d, J = 8.2 Hz, 1H), 1.18 (d, J = 6.2 Hz, 1H), 1.15 (s, 3H), 1.09 (td, J = 13.2, 3.8 Hz, 1H), 1.03 (s, 3H), 0.93 (d, J = 11.5 Hz, 1H), 0.78 (s, 3H), 0.61 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.5, 158.9, 155.3, 145.3, 115.7, 114.3, 107.2, 78.8, 76.4, 68.2, 61.9, 54.1, 48.0, 40.3, 38.8, 38.1, 38.0, 28.5, 27.3, 27.1, 18.0, 17.9, 15.7, 14.2, 10.7; IR νmax (neat) 3494, 1752, 1610, 1477, 1368, 1148, 1135, 1040, 904, 732 cm–1; HRMS (ES) m/z [M + H]+ calcd for C25H35O5 415.2484; found 415.2486.

(±)-Austalide K [(5aR,7aS,14aR,14bS)-13-Methoxy-5,5,7a,9,14b-pentamethyl-1,2,5a,6,7,7a,10,14,14a,14b-decahydro-5H-furo[3,4-i]oxepino[4,3-a]xanthene-3,12-dione (2)]

Dess–Martin periodinane (52 mg, 0.123 mmol) was added with stirring to (±)-17S-dihydroaustalide K (1) (34 mg, 0.0820 mmol) in CH2Cl2 (2 mL) at 25 °C. After 1 h, the mixture was concentrated and chromatographed (pentane/Et2O 1:1) to give (±)-austalide K (2) (28 mg, 0.0679 mmol, 83%) as a white solid: R 0.34 (pentane/Et2O 1:1); mp 160–164 °C; 1H NMR (400 MHz, CDCl3) δ 5.12 (s, 2H), 4.11 (s, 3H), 2.93 (d, J = 18.5 Hz, 1H), 2.81 (dd, J = 18.6, 8.2 Hz, 1H), 2.54 (ddd, J = 16.1, 11.7, 7.0 Hz, 1H), 2.47–2.36 (m, 1H), 2.31–2.25 (m, 1H), 2.11 (ddd, J = 13.4, 6.9, 3.8 Hz, 1H), 2.05 (s, 3H), 1.88–1.74 (m, 1H), 1.72–1.60 (m, 1H), 1.57–1.47 (m, 4H), 1.19 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H), 0.73 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 216.6, 169.4, 158.6, 155.4, 145.52, 115.3, 114.4, 107.3, 76.2, 68.2, 62.0, 54.2, 47.3, 47.1, 39.7, 38.4, 37.6, 34.1, 27.1, 26.7, 21.7, 19.1, 18.3, 14.2, 10.7; IR νmax (neat) 1754, 1702, 1610, 1477, 1367, 1141, 904 cm–1; HRMS (ES) m/z [M + H]+ calcd for C25H33O5 413.2328; found 413.2327.

(±)-13-Deacetoxyaustalide I [(5aR,7aS,14aR,14bS)-13-Methoxy-5,5,7a,9,14b-pentamethyl-1,2,5a,6,7,7a,10,14,14a,14b-decahydro-5H-furo[3,4-i]oxepino[4,3-a]xanthene-3,12-dione (3)]

NaHCO3 (9 mg, 0.107 mmol) and m-CPBA (18.4 mg, 0.107 mmol) were added with stirring to (±)-austalide K (2) (22 mg, 0.0533 mmol) in CH2Cl2 (1 mL) at 25 °C. After 19 h, saturated aqueous NaHCO3 (1 mL) was added, and phases were separated. The aqueous layer was extracted with CH2Cl2 (3 × 1 mL), and the combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (Et2O) to provide (±)-13-deacetoxyaustalide I (3) (22 mg, 0.0513 mmol, 96%) as a white solid: R 0.37 (Et2O); mp 93–95 °C; 1H NMR (400 MHz, CDCl3) δ 5.14 (s, 2H), 4.13 (s, 3H), 2.96 (d, J = 18.6 Hz, 1H), 2.84 (dd, J = 18.7, 8.1 Hz, 1H), 2.69 (ddd, J = 15.6, 11.2, 3.1 Hz, 1H), 2.60 (ddd, J = 15.6, 8.3, 2.7 Hz, 1H), 2.25 (dt, J = 14.2, 3.1 Hz, 1H), 2.06 (s, 3H), 2.02–1.84 (m, 3H), 1.75–1.62 (m, 2H), 1.56 (d, J = 7.8 Hz, 1H), 1.54–1.53 (m, 1H), 1.52 (s, 3H), 1.42 (s, 3H), 1.21 (s, 3H), 0.83 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 175.1, 169.3, 158.3, 155.3, 145.6, 115.1, 114.3, 107.4, 85.8, 76.0, 68.2, 62.0, 53.6, 47.3, 40.4, 39.3, 37.3, 32.5, 31.8, 27.1, 25.8, 22.1, 18.7, 16.7, 10.6; IR νmax (neat) 1749, 1609, 1477, 1372, 1282, 1142, 1112, 905, 731 cm–1; HRMS (ES) m/z [M + H]+ calcd for C25H33O6 429.2277; found 429.2291.

(±)-Austalide P [Methyl 3-((5aS,8R,9S,9aR)-8-(2-hydroxypropan-2-yl)-11-methoxy-4,5a,9-trimethyl-1-oxo-3,5a,6,7,8,9,9a,10-octahydro-1H-furo[3,4-b]xanthen-9-yl)propanoate (4)]

NaOMe (0.5 M; 0.50 mL; 0.250 mmol) was added with stirring to (±)-13-deacetoxyaustalide I (3) (10.8 mg, 0.0252 mmol) in MeOH (0.50 mL) at 25 °C. After 1 h, saturated aqueous NH4Cl (1 mL) and Et2O (2 mL) were added; the phases were separated, and the aqueous layer was extracted with Et2O (3 × 1 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (pentane/Et2O 1:1) to provide (±)-austalide P (4) (9.3 mg, 0.0202 mmol, 80%) as a white foam: R 0.21 (pentane/Et2O 1:1); 1H NMR (400 MHz, CD3OD) δ 5.20 (s, 2H), 4.04 (s, 3H), 3.67 (s, 3H), 3.01 (d, J = 18.6 Hz, 1H), 2.76 (dd, J = 18.6, 7.9 Hz, 1H), 2.65–2.55 (m, 1H), 2.42 (tdd, J = 11.5, 4.8, 2.5 Hz, 1H), 2.37–2.27 (m, 1H), 2.15–2.10 (m, 1H), 2.05 (s, 3H), 1.88–1.75 (m, 2H), 1.68 (d, J = 8.0 Hz, 1H), 1.66–1.57 (m, 1H), 1.57–1.48 (m, 2H), 1.27 (s, 3H), 1.20 (s, 3H), 1.19 (s, 3H), 0.70 (s, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 176.9, 171.8, 160.4, 156.6, 147.5, 117.3, 115.8, 108.2, 78.3, 75.7, 69.8, 62.2, 52.1, 52.0, 42.8, 41.4, 40.5, 34.9, 33.2, 30.1, 28.1, 27.7, 22.6, 19.5, 18.8, 10.6; IR νmax (neat) 3514, 2971, 1740, 1610, 1436, 1368, 1141, 1045, 898, 732 cm–1; HRMS (ES) m/z [M + H]+ calcd for C26H37O7 461.2539; found 461.2531.

(±)-13-Deoxyaustalide Q Acid [3-((5aS,8S,9S,9aR)-11-Methoxy-4,5a,9-trimethyl-1-oxo-8-(prop-1-en-2-yl)-3,5a,6,7,8,9,9a,10-octahydro-1H-furo[3,4-b]xanthen-9-yl)propanoic Acid (5)]

(±)-13-Deacetoxyaustalide I (3) (14 mg, 0.0327 mmol) was dissolved in THF (1 mL), and p-TsOH·H2O (56 mg, 0.327 mmol) was added. The resulting mixture was heated to 70 °C for 1 h. After being cooled back to 25 °C, H2O (1 mL) and Et2O (1 mL) were added and the two phases separated, and the aqueous layer was extracted with Et2O (3 × 1 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and chromatographed (Et2O) to provide (±)-13-deoxyaustalide Q acid (5) (10 mg, 0.0233 mmol, 71%) as a white foam: R 0.42 (Et2O); 1H NMR (400 MHz, CDCl3) δ 5.12 (s, 2H), 4.90 (s, 1H), 4.69 (s, 1H), 4.11 (s, 3H), 2.89 (d, J = 18.5 Hz, 1H), 2.77 (dd, J = 18.4, 7.8 Hz, 1H), 2.52–2.26 (m, 2H), 2.23–2.06 (m, 3H), 2.04 (s, 3H), 1.74 (s, 3H), 1.74–1.70 (m, 2H), 1.68–1.61 (m, 1H), 1.57 (d, J = 7.8 Hz, 1H), 1.49–1.44 (m, 1H), 1.20 (s, 3H), 0.60 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.1, 169.5, 158.6, 155.5, 146.7, 145.5, 115.2, 114.4, 114.2, 107.3, 76.5, 68.3, 62.0, 50.1, 40.0, 39.6, 39.0, 32.9, 28.5, 27.4, 23.8, 23.6, 18.1 (2C), 10.7; IR νmax (neat) 3261, 2933, 1749, 1705, 1610, 1369, 1148, 1131, 910, 732 cm–1; HRMS (ES) m/z [M + H]+ calcd for C25H33O6 429.2277; found 429.2285.