HETEROCYCLES

Paper | Special issue | Vol. 80, No. 2, 2010, pp. 1003-1012
Received, 27th July, 2009, Accepted, 31st August, 2009, Published online, 2nd September, 2009.
DOI: 10.3987/COM-09-S(S)75

■ Synthesis of (±)-Heliannuol D Based on Platinum Catalyzed Regioselective Addition of Arylboronic Acids to Allenes

Mayu Osaka, Makoto Kanematsu, Masahiro Yoshida, and Kozo Shishido*

Graduate School of Pharmaceutical Sciences, University of Tokushima, Sho-machi, Tokushima 770-8505, Japan

Abstract

An alternative total synthesis of (±)-heliannuol D has been achieved in 13 steps and 6.9% overall yield from the arylboronic acid 9. The synthesis applies the previously developed regiocontrolled addition of arylboronic acids to allenes using a platinum catalyst to install the C5 carbon chain on the aryl ring.

INTRODUCTION
In our previous paper, we reported the regiocontrolled addition of arylboronic acids 1 to allenes 2 using the platinum catalyst 3 leading to the formation of exo-olefinic products 4 with high yields and regioselectivity (>20:1).1 The procedure would be useful for the synthesis of natural products with a tertiary stereogenic center at the benzylic position by hydrogenation of the products. (Scheme 1)

RESULTS AND DISCUSSION
During the course of our projects directed towards an efficient synthesis of allelochemicals for the development of a new type of environmentally benign herbicides,2 we planned to apply this cross coupling reaction to the synthesis of heliannuol type sesquiterpenoids isolated from the aqueous extracts of fresh sunflower leaves (Helianthus annuus var. SH-222).3 As a target allelochemical, we chose heliannuol D (5),3b which has a unique carbon skeleton made up of an oxygen-containing seven-membered heterocycle fused to the aryl ring and two stereogenic centers whose absolute configurations were determined to be C-7R and C-10R, respectively, by our enantioselective total synthesis of (–)-5.4a Because of the intriguing structural features and the allelopathic activity of 5, three enantioselective total syntheses4 and six racemic syntheses5 have been reported so far. Herein we report a new approach to the total synthesis of (±)-heliannuol D using the cross coupling methodology for the application to the allelochemical synthesis. Approaching the synthesis from a retrosynthetic perspective, we envisioned the following scheme: (±)-5 would be derived from the phenolic epoxide 6 employing the intramolecular etherification we previously developed. The epoxide 6 would be prepared via curcuhydroquinone 7,6 which can be made by catalytic hydrogenation followed by demethylation of 8. The exo-olefinic compound 8 could in turn be synthesized by the platinum catalyzed cross coupling reaction of the boronic acid 9 with the allene 10. (Scheme 2)

Treatment of a mixture of the boronic acid 97 and the allene 108 with a catalytic amount of the platinum complex, [Pt2(OH)2(Ph3P)4][BF4]2 (3),1 and KOH in dioxane/H2O (20/1) at 100 °C for 0.5 h furnished in 77% yield the coupled product 8, which was subjected to catalytic hydrogenation to give the alcohol 11.9 Swern oxidation and Julia-Kocienski olefination of the aldehyde with the sulfone 1210 in the presence of LHMDS provided the alkene 134a in good overall yield. Oxidation of 13 with ceric ammonium nitrate (CAN) in aqueous THF followed by immediate reduction of the resulting quinone with Na2S2O4 provided (±)-curcuhydroquinone (7),6 which was treated with TBSCl, imidazole and 4-DMAP to give the bis-TBS ether 144a in 57% yield for the 3 steps. Desilylation of 14 with K2CO3 in MeOH furnished a separable mixture of the mono-TBS ethers 15 (the desired), 16 (the undesired but which can be recycled11) and the recovered 14 in 60%, 17% and 12% yield, respectively. The desired 15 was converted to the methoxymethyl (MOM) ether 17, which was oxidized with mCPBA to give the epoxide 184a as an inseparable 1:1 mixture of diastereomers. (Scheme 3)

Deprotection of the TBS ether in 18 was realized by treatment with CsF in DMF at 0 °C to give a chromatographically separable mixture of the phenolic epoxides 64a and 19 in 45% and 47% yield, respectively. Finally, 6 was treated with 5% aqueous NaOH to produce the 7-membered cyclized product 20, which was hydrolyzed with 6N HCl (aq.) to give (±)-heliannuol D (5) quantitatively. The spectroscopic properties of the synthesized compound 5 were completely identical with those for the natural product.3-5 Similarly, 19 was transformed to (±)-10-epi-heliannuol D (22)5a,c in 69% yield for the 2 steps. (Scheme 4)

In conclusion, an alternative total synthesis of (±)-heliannuol D (5) has been achieved in 13 steps and 6.9% overall yield from the arylboronic acid 9. This synthesis highlights the utility of the regiocontrolled addition of arylboronic acids to allenes using platinum catalyst developed in our laboratories. The synthetic route developed here is efficient and flexible for obtaining a variety of derivatives (e.g. 10-epi-heliannuol D), which can be supplied for evaluation of the allelopathic activity.

EXPERIMENTAL
Solvents were dried and distilled according to standard protocols. The phrase ‘residue upon workup’ refers to the residue obtained when the organic layer was separated and dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure.

1-{5-(Benzyloxy)pent-1-en-2-yl}-2,5-dimethoxy-4-methylbenzene (8)
To a stirred solution of 5-benzyloxy-1,2-pentadiene 108 (222 mg, 1.28 mmol) in 1,4-dioxane (12.3 mL) and H2O (0.61 mL) were added 2,5-dimethoxy-4-methylphenylboronic acid 97 (500 mg, 2.55 mmol), [Pt2(OH)2(PPh3)4][BF4]2 (3)1 (105 mg, 0.064 mmol) and KOH (358 mg, 0.37 mmol) at rt, and stirring was continued at 100 °C for 0.5 h. The reaction mixture was diluted with minimum amount of AcOEt and dried over MgSO4. After filtration through a pad of silica gel, the residue upon workup was chromatographed on silica gel with hexane-AcOEt (97:3, v/v) as eluent to give 8 (320 mg, 77%, exo:endo = >20:1) as a colorless oil. IR (neat): 2935, 2852, 1503, 1465, 1396, 1211, 1104, 1045, 901, 737, 698 cm-1; 1H-NMR (400 MHz, CDCl3) δ 1.70 (quint., J = 6.8 Hz, 2H), 2.21 (s, 3H), 2.57 (t, J = 7.6 Hz, 2H), 3.47 (t, J = 6.4 Hz, 2H), 3.74 (s, 3H), 3.76 (s, 3H), 4.47 (s, 2H), 5.02 (s, 1H), 5.13 (s, 1H), 6.61 (s, 1H), 6.68 (s, 1H), 7.26-7.33 (m, 5H); 13C-NMR (100 MHz, CDCl3) δ 16.1 (CH3), 28.2 (CH2), 32.9 (CH2), 55.9 (CH3), 56.2 (CH3), 70.0 (CH2), 72.7 (CH2), 112.6 (CH), 114.0 (CH2), 114.4 (CH), 126.1 (Cq), 127.4 (CH), 127.5 (CH), 128.2 (CH), 129.7 (Cq), 138.7 (Cq), 148.5 (Cq), 150.1 (Cq), 151.5 (Cq); HRMS (ESI) m/z calcd for C21H26O3Na [M++Na+] 349.1780, found 349.1780.

4-(2,5-Dimethoxy-4-methylphenyl)pentan-1-ol (11)9
To a stirred suspension of Pd-C (79.4 mg, 25 wt%) in EtOH (2.3 mL) was added ether 8 (317 mg, 0.97 mmol) at rt, and stirring was continued for 12 h at the same temperature under 5 atm of hydrogen gas. The resulting solution was filtered and the solvent was evaporated to give a residue, which was chromatographed on silica gel with hexane-AcOEt (75:25, v/v) as eluent to give the alcohol 11 (203 mg, 88%) as a colorless oil. IR (neat): 3363, 2937, 1505, 1464, 1398, 1209, 1046 cm-1; 1H-NMR (400 MHz, CDCl3) δ 1.21 (d, J = 6.8 Hz, 3H), 1.44 (s, 1H, OH, D2O exchangeable), 1.44-1.65 (m, 2H), 2.20 (s, 3H), 3.17 (sext., J = 6.8 Hz, 1H), 3.61 (t, J = 6.4 Hz, 2H), 3.76 (s, 3H), 3.79 (s, 3H), 6.67 (s, 1H), 6.68 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ 16.0 (CH3), 21.0 (CH3), 30.7 (CH2), 31.5 (CH), 33.4 (CH2), 56.1 (CH3), 56.3 (CH3), 62.9 (CH2), 109.6 (CH), 114.3 (CH), 124.3 (Cq), 133.5 (Cq), 150.6 (Cq), 151.9 (Cq); HRMS (ESI) m/z calcd for C12H14ONa [M++Na+] 261.1467, found 261.1467.

1-(1,5-Dimethylhex-4-enyl)-2,5-dimethoxy-4-methylbenzene (13)4a
To a solution of oxalyl chloride (1.63 mL, 18.7 mmol) in CH2Cl2 (17.6 mL) was added DMSO (1.8 mL, 23 mmol) in CH2Cl2 (8.8 mL) at –78 °C. A solution of 11 (1.78 g, 7.5 mmol) in CH2Cl2 (17.6 mL) was added dropwise, and after 30 min, Et3N (8.14 mL, 58.4 mmol) was added. After being stirred for 10 min at –78 °C, the reaction mixture was allowed to warm to 0 °C over 15 min and the reaction mixture was diluted with water and concentrated in vacuo. The residue was extracted with Et2O and the combined extracts were washed with brine. The residue upon workup was the corresponding aldehyde, a colorless oil, which was used to the next reaction without further purification. To a solution of sulfone 12 10 (4.3 g, 17 mmol) in THF (100 mL) at –78 °C was added dropwise LHMDS (1.6 M in THF, 10.8 mL, 17 mmol). The yellow solution was stirred at –78 °C for 30 min and the solution was added in one portion with a precooled syringe to a solution of the crude aldehyde in THF (100 mL) at –78 °C. The reaction mixture was stirred at –78 °C for 3 h, then the mixture was slowly warmed to rt and stirred for 10 min. The reaction mixture was quenched with H2O and concentrated in vacuo. The residue was extracted with Et2O and the extracts were washed with brine. The residue upon workup was chromatographed on silica gel with hexane-AcOEt (95:5, v/v) as eluent to give 13 (1.73 g, 88% for the 2 steps) as a colorless oil. IR (neat): 2927, 2852, 1504, 1465, 1398, 1208, 1049 cm-1; 1H-NMR (400 MHz, CDCl3) δ 1.18 (d, J = 7.2 Hz, 3H), 1.54 (s, 3H), 1.48-1.67 (m, 2H), 1.67 (s, 3H), 1.92 (dt, J = 16.6 Hz and 8.4 Hz, 2H), 2.20 (s, 3H), 3.14 (sext., J = 7.6 Hz, 1H), 3.76 (s, 3H), 3.78 (s, 3H), 5.12 (t, J = 7.2 Hz, 1H), 6.67 (s, 2H); 13C-NMR (100 MHz, CDCl3) δ 16.0 (CH3), 17.5 (CH3), 21.2 (CH3), 25.6 (CH3), 26.3 (CH2), 31.9 (CH), 37.3 (CH2), 55.9 (CH3), 56.2 (CH3), 109.7 (CH), 114.2 (CH), 124.1 (Cq), 124.8 (CH), 130.9 (Cq), 133.9 (Cq), 150.8 (Cq), 151.9 (Cq); HRMS (ESI) m/z calcd for C17H26O2Na [M++Na+] 285.1831, found 285.1839.

1,4-Bis-(tert-butyldimethylsiloxy)-2-(1,5-dimethylhex-4-enyl)-5-methylbenzene (14)4a
To a solution of 13 (31.7 mg, 0.121 mmol) in THF (1.12 mL) and H2O (0.38 mL) was added CAN (159 mg, 0.29 mmol) at 0 °C. After being stirred at the same temperature for 5 min, the reaction mixture was diluted with H2O and extracted with Et2O. The combined extracts were washed with brine and the residue upon workup was curcuquinone,6 a yellow oil, which was used to the next reaction without further purification. To a solution of curcuquinone in THF (0.6 mL) was added and Na2S2O4 (63.5 mg, 0.36 mmol) in H2O at 0 °C. After being stirred at rt for 3 h, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with Et2O. The extracts were washed with brine and the residue upon workup was curcuhydroquinone 76, a yellow oil, which was used to the next reaction without further purification. To a solution of curcuhydroquinone, imidazole (29.6 mg, 0.435 mmol) and TBSCl (40.1 mg, 0.27 mmol) in CH2Cl2 (0.6 mL) was added 4-DMAP (1.5 mg, 12.1 mmol) at 0 °C. After being stirred for 0.5 h at rt, the reaction mixture was quenched with water and extracted with CH2Cl2. The extracts were washed with brine and the residue upon workup was chromatographed on silica gel with hexane-AcOEt (95:5, v/v) as eluent to give 14 (31.9 mg, 57% for the 3 steps) as a colorless oil. IR (neat): 2958, 2930, 2859, 1499, 1472, 1463, 1399, 1255, 1203 cm-1; 1H-NMR (400 MHz, CDCl3) δ 0.16-0.19 (m, 12H), 1.00 (s, 18H), 1.11 (d, J = 6.8 Hz, 3H), 1.46-1.53 (m. 5H), 1.66 (s, 3H), 1.88-1.96 (m, 2H), 2.11 (s, 3H), 3.10 (sext., J = 7.2 Hz, 1H), 5.09 (t, J = 6.4 Hz, 1H), 6.53 (s, 1H), 6.55 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ -4.3 (CH3), -4.1 (CH3), 16.6 (CH3), 17.6 (CH3), 18.2 (Cq), 18.2 (Cq), 21.3 (CH3), 25.7 (CH3), 25.8 (CH3), 26.1 (CH2), 30.8 (CH), 37.4 (CH2), 116.8 (CH), 120.6 (CH), 124.8 (CH), 125.8 (Cq), 131.1 (Cq), 135.7 (Cq), 146.6 (Cq), 147.8 (Cq); HRMS (ESI) m/z calcd for C29H58O2NaSi2 [M++Na+] 517.3873, found 517.3872.

4-(tert-Butyldimethylsiloxy)-5-(1,5-dimethylhex-4-enyl)-2-methylphenol (15) and 4-(tert-Butyldimethylsiloxy)-2-(1,5-dimethylhex-4-enyl)-5-methylphenol (16)
To a solution of 14 (40.7 mg, 87.9 µmol) in MeOH (2.9 mL) was added K2CO3 (36.5 mg, 0.26 mmol) at rt. After being stirred for 4 h, the reaction mixture was quenched with water and extracted with AcOEt. The extracts were washed with brine and the residue upon workup was chromatographed on silica gel with CHCl3 as eluent to give the recovered 14 (9.2 mg, 22%), compound 16 (5.3 mg, 17%) as a colorless oil, and compound 15 (18.5 mg, 60%) as a colorless oil.
Compound 16: IR (neat): 3414, 2958, 2928, 2857, 1510, 1412, 1256, 1195 cm-1; 1H-NMR (400 MHz, CDCl3) d 0.17 (s, 6H), 1.01 (s, 9H), 1.19 (d, J = 6.8 Hz, 3H), 1.53 (s, 3H), 1.53-1.60 (m. 2H), 1.68 (s, 3H), 1.93 (q, J = 7.2 Hz, 2H), 2.12 (s, 3H), 2.92 (sext., J = 7.2 Hz, 1H), 4.31 (s, 1H, OH, D2O exchangeable), 5.11 (t, J = 7.2 Hz, 1H), 6.55 (s, 2H); 13C-NMR (100 MHz, CDCl3) d -4.2 (CH3), -4.2 (CH3), 16.4 (CH3), 17.7 (CH3), 18.2 (Cq), 21.2 (CH3), 25.7 (CH3), 25.8 (CH3), 26.0 (CH2), 31.4 (CH), 37.4 (CH2), 117.0 (CH), 117.8 (CH), 124.6 (CH), 126.6 (Cq), 130.8 (Cq), 132.0 (Cq), 146.8 (Cq), 147.7 (Cq); HRMS (ESI) m/z calcd for C21H37O2Si [M++H+] 349.2563, found 349.2559.
Compound 15: IR (neat): 3353, 2958, 2928, 2858, 1503, 1462, 1408, 1196 cm-1; 1H-NMR (400 MHz, CDCl3) δ 0.19 (s, 3H), 0.20 (s, 3H), 1.00 (s, 9H), 1.12 (d, J = 6.8 Hz, 3H), 1.47-1.60 (m. 2H), 1.54 (s, 3H), 1.66 (s, 3H), 1.86-2.00 (m, 2H), 2.16 (s, 3H), 3.10 (sext., J = 6.8 Hz, 1H), 4.26 (s, 1H, OH, D2O exchangeable), 5.09 (tt, J = 7.2 Hz and 1.2 Hz, 1H), 6.53 (s, 1H), 6.58 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ -4.2 (CH3), -4.1 (CH3), 15.6 (CH3), 17.6 (CH3), 18.2 (Cq), 21.2 (CH3), 25.7 (CH3), 25.8 (CH3), 26.1 (CH2), 30.9 (CH), 37.4 (CH2), 113.3 (CH), 120.6 (CH), 121.0 (Cq), 124.7 (CH), 131.1 (Cq), 136.6 (Cq), 146.4 (Cq), 147.8 (Cq); HRMS (ESI) m/z calcd for C21H37O2Si [M++H+] 349.2563, found 349.2560.

1,4-Bis-(tert-butyldimethylsiloxy)-2-(1,5-dimethylhex-4-enyl)-5-methylbenzene (14)4a

To a solution of 16 (5.1 mg, 14.63 µmol) and TBSCl (3.3 mg, 21.95 µmol) in CH2Cl2 (0.1 mL) was added 4-DMAP (0.2 mg, 1.46 µmol) at rt. After being stirred for 10 min, the reaction mixture was quenched with water and extracted with CH2Cl2. The extracts were washed with brine and the residue upon workup was chromatographed on silica gel with hexane-AcOEt (98:2, v/v) as eluent to give the olefin 14 (5.9 mg, 87%) as a colorless oil.

6-(2-tert-Butyldimethylsiloxy-5-methoxymethoxy-4-methylphenyl)-2-methyl-2-heptene (17)
To a solution of 15 (57.9 mg, 0.17 mmol) in CH2Cl2 (1.0 mL) was added iPr2NEt (0.35 mL, 1.99 mmol) and methoxymethyl chloride (0.13 mL, 1.66 mmol) at rt. The reaction mixture was stirred for 9 h at the same temperature, then quenched with water and extracted with Et2O. The extracts were washed with brine and the residue upon workup was chromatographed on silica gel with hexane-AcOEt (92.5:7.5, v/v) as eluent to give the MOM ether 17 (63.1 mg, 97%) as a colorless oil. IR (neat): 2957, 2928, 2857, 1501, 1391, 1255, 1215, 1193, 1151 cm-1; 1H-NMR (400 MHz, CDCl3) δ 0.20 (s, 3H), 0.21 (s, 3H), 1.01 (s, 9H), 1.13 (d, J = 6.8 Hz, 3H), 1.48-1.60 (m, 2H), 1.54 (s, 3H), 1.66 (s, 3H), 1.93 (quint., J = 7.2 Hz, 2H), 2.17 (s, 3H), 3.11 (sext., J = 6.8 Hz, 1H), 3.50 (s, 3H), 5.08-5.12 (m, 1H), 5.10 (s, 2H), 6.55 (s, 1H), 6.82 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ -4.2 (CH3), -4.1 (CH3), 16.0 (CH3), 17.6 (CH3), 18.2 (Cq), 21.2 (CH3), 25.7 (CH3), 25.8 (CH3), 26.2 (CH2), 31.2 (CH), 37.2 (CH2), 56.0 (CH3), 95.8 (CH2), 113.7 (CH), 120.5 (CH), 124.8 (CH), 125.2 (Cq), 131.1 (Cq), 136.0 (Cq), 147.4 (Cq), 149.9 (Cq); HRMS (ESI) m/z calcd for C23H41O3Si [M++H+] 393.2825, found 393.2823.

6-(2-tert-Butyldimethylsiloxy-5-methoxymethoxy-4-methylphenyl)-2-methyl-2,3-epoxyheptane (18)4a
To a mixture of 17 (19.9 mg, 50.7 µmol) and sodium bicarbonate (21.3 mg, 0.25 mmol) in CH2Cl2 (0.5 mL) was added mCPBA (20.2 mg, 76.0 µmol) at 0 °C. After being stirred at rt for 0.5 h, the reaction mixture was quenched with saturated aqueous NaHCO3 and concentrated in vacuo. The residue was extracted with CH2Cl2, the extracts were washed with brine and the residue upon workup was chromatographed on silica gel with hexane-AcOEt (90:10, v/v) as eluent to give a 1:1 diastereomeric mixture of 18 (16.2 mg, 78%) as a colorless oil. IR (neat): 2958, 2930, 2859, 1503, 1391, 1255, 1215, 1194, 1151 cm-1; 1H-NMR (400 MHz, CDCl3) δ 0.19-0.21 (m, 6H), 1.00 (s, 4.5H), 1.00 (s, 4.5H), 1.17 (d, J = 6.8 Hz, 3H), 1.19 (s, 3H), 1.25 (s, 1.5H), 1.26 (s, 1.5H), 1.35-1.73 (m, 4H), 2.17 (s, 3H), 2.65-2.71 (m, 1H), 3.16 (sext., J = 6.4 Hz, 1H), 3.49 (s, 1.5 H), 3.50 (s, 1.5H), 5.08-5.12 (m, 2H), 6.56 (s, 1H), 6.82 (s, 0.5H), 6.83 (s, 0.5H); 13C-NMR (100 MHz, CDCl3) δ -4.2 (CH3), -4.0 (CH3), 16.1 (CH3), 18.3 (Cq), 18.6 (CH3), 21.1 (CH3), 21.4 (CH3), 24.9 (CH3), 25.9 (CH3), 27.0 (CH2), 27.4 (CH2), 31.5 (CH), 31.7 (CH), 33.7 (CH2), 34.1 (CH2), 56.0 (CH3), 58.2 (Cq), 64.3 (CH), 64.6 (CH), 95.7 (CH2), 113.5 (CH), 113.6 (CH), 120.6 (CH), 120.7 (CH), 125.5 (Cq), 135.2 (Cq), 147.4 (Cq), 150.0 (Cq); HRMS (ESI) m/z calcd for C23H40O4NaSi [M++Na+] 431.2594, found 431.2596.

6-(2-Hydroxy-5-methoxymethoxy-4-methylphenyl)-2-methyl-2,3-epoxyheptane (6)4a and 3-epi-6-(2-hydroxy-5-methoxymethoxy-4-methylphenyl)-2-methyl-2,3-epoxyheptane (19)
To a mixture of CsF (6.8 mg, 0.04 mmol) in DMF (0.62 mL) was added 18 (15.3 mg, 37.4 mmol) in DMF (0.62 mL) at 0 °C. The reaction mixture was stirred at rt for 15 min, then quenched with water and extracted with Et2O. The extracts were washed with brine and the residue upon workup was chromatographed on silica gel with hexane-AcOEt (90:10, v/v) as eluent to give 19 (5.2 mg, 47%) as a colorless oil and 6 (4.9 mg, 45%) as a colorless oil.
Compound 19: IR (neat): 3379, 2960, 2927, 1514, 1455, 1399, 1191, 1150 cm-1; 1H-NMR (400 MHz, CDCl3) δ 1.06-1.17 (m, 1H), 1.21 (s, 3H), 1.25 (d, 6.8 Hz, 3H), 1.33 (s, 3H), 1.67-1.76 (m, 2H), 1.80-1.87 (m, 1H), 2.17 (s, 3H), 2.85 (dd, J = 9.2 Hz and 1.6 Hz, 1H), 3.14-3.18 (m, 1H), 3.50 (s, 3H), 5.08-5.11 (m, 2H), 6.61 (s, 1H, OH, D2O exchangeable), 6.66 (s, 1H), 6.80 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ 15.9 (CH3), 18.4 (CH3), 22.4 (CH3), 24.7 (CH3), 25.9 (CH2), 30.5 (CH), 36.4 (CH2), 56.0 (CH3), 58.9 (Cq), 66.2 (CH), 95.9 (CH2), 113.3 (CH), 119.3 (CH), 126.4 (Cq), 130.5 (Cq), 148.3 (Cq), 149.9 (Cq); HRMS (ESI) m/z calcd for C17H27O4 [M++H+] 295.1909, found 295.1913.
Compound 6: IR (neat): 3375, 2960, 1456, 1191, 1149, 1058 cm-1; 1H-NMR (400 MHz, CDCl3) δ 1.21 (s, 3H), 1.24 (d, J = 7.2 Hz, 3H), 1.28 (s, 3H), 1.44-1.69 (m, 3H), 1.77-1.86 (m, 1H), 2.17 (s, 3H), 2.72 (t, J = 6.4 Hz, 1H), 3.07 (sext., J = 6.8 Hz, 1H), 3.50 (s, 3H), 4.58 (s, 1H, OH, D2O exchangeable), 5.10 (s, 2H), 6.56 (s, 1H), 6.83 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ 15.8 (CH3), 18.6 (CH3), 20.8 (CH3), 24.8 (CH3), 26.7 (CH2), 32.0 (CH), 33.6 (CH2), 56.0 (CH3), 58.8 (Cq), 64.6 (CH), 95.9 (CH2), 114.2 (CH), 117.8 (CH), 126.1 (Cq), 130.9 (Cq), 147.9 (Cq), 149.6 (Cq); HRMS (ESI) m/z calcd for C17H27O4 [M++H+] 295.1909, found 295.1911.

(±)-Heliannuol D (5)5
A solution of 6 (10.1 mg, 34 µmol) in 5% aqueous NaOH (1.1 mL) was stirred at rt for 31 h. The reaction mixture was diluted with CHCl3, acidified with 1% aqueous HCl (pH<7) and extracted with CHCl3. The extracts were washed with brine and the residue upon workup was the alcohol 20, a colorless oil, which was used to the next reaction without further purification. To a solution of the crude 20 in THF (0.1 mL) was added 6 N HCl aq. (0.1 mL). After being stirred at rt for 2 h, the mixture was extracted with Et2O. The extracts were washed with brine and the residue upon workup was chromatographed on silica gel with hexane-AcOEt (70:30, v/v) as eluent to give the (±)-heliannuol D 5 (8.7 mg, quant. for 2 steps) as a colorless crystalline solid. mp 157-158 °C (lit.,5a,c 161-162 °C); IR (KBr): 3362, 2931, 2360, 1508, 1456, 1417, 1375, 1192, 1065 cm-1; 1H-NMR (400 MHz, CDCl3) δ 1.27-1.29 (m, 9H), 1.72-2.05 (m, 4H), 2.16 (s, 3H), 2.66 (s, 1H, OH, D2O exchangeable), 2.88-2.91 (m, 1H), 3.30 (dd, J = 11.2 Hz and 1.2 Hz, 1H), 4.54 (s, 1H, OH, D2O exchangeable), 6.54 (s, 1H), 6.73 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ 15.3 (CH3), 18.6 (CH3), 24.5 (CH3), 25.6 (CH2), 26.1 (CH3), 31.8 (CH2), 38.5 (CH), 72.6 (Cq), 90.5 (CH), 115.8 (CH), 122.1 (Cq), 123.5 (CH), 138.2 (Cq), 149.6 (Cq), 151.7 (Cq); HRMS (ESI) m/z calcd for C15H23O3 [M++H+] 251.1647, found 251.1643.

(±)-10-epi-Heliannuol D (22)5a,c
According to the same procedure as for the preparation of 5, 22 was obtained from 19 as a colorless crystalline solid in 69% yield for the 2 steps. mp 155-157 °C (lit.,5c 158-159 °C); IR (KBr): 3262, 2973, 1506, 1456, 1374, 1187, 1152, 1062 cm-1; 1H-NMR (400 MHz, CDCl3) δ 1.27 (s, 3H), 1.28 (s, 3H), 1.30 (d, J = 7.2 Hz, 3H), 1.87-1.93 (m, 3H), 2.18 (s, 3H), 2.63 (s, 1H, OH, D2O exchangeable), 3.02 (quint., J = 8.0 Hz, 1H), 3.24 (dd, J = 10.0 Hz and 3.2 Hz, 1H), 4.62 (s, 1H, OH, D2O exchangeable), 6.61 (s, 1H), 6.76 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ 15.3 (CH3), 20.2 (CH3), 24.4 (CH3), 26.3 (CH3), 30.9 (CH2), 34.3 (CH), 65.9 (CH2), 72.5 (Cq), 89.7 (CH), 112.7 (CH), 121.5 (Cq), 122.8 (CH), 138.5 (Cq), 149.8 (Cq), 152.6 (Cq); HRMS (ESI) m/z calcd for C15H23O3 [M++H+] 251.1647, found 251.1645.

ACKNOWLEDGEMENTS
This work was supported financially by the Program for the Promotion of Basic and Applied Research for Innovations in the Bio-oriented Industry (BRAIN).

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