HETEROCYCLES

Paper | Special issue | Vol. 80, No. 2, 2010, pp. 1067-1079
Received, 30th July, 2009, Accepted, 31st August, 2009, Published online, 3rd September, 2009.
DOI: 10.3987/COM-09-S(S)86

■ Synthetic Study on Clutiolide Based on a Remote Chelation Controlled Ireland-Claisen Rearrangement

Jun Ishihara,* Okihisa Tokuda, Kazunori Shiraishi, Yukihiro Nishino, Keisuke Takahashi, and Susumi Hatakeyama*

Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

A methodology feasible for the stereoselective synthesis of clutiolide, a secolabdane diterpene from Clutia abyssinica, was developed based on a remote chelation controlled Ireland-Claisen rearrangement.

INTRODUCTION
The Ireland-Claisen rearrangement often proceeds in high stereoselectivity in consequence of the reaction process via a chairlike transition state. In particular, Claisen rearrangement of protected allylic glycolates 1 affords the syn-products 3 in high stereoselectivity via a chelated lithium enolate 2 with E-geometry (Scheme 1).1) The chelated enolates derived from amino acid esters also undergo Claisen rearrangement in highly diastereoselective fashion.2)

Previously, we reported that Ireland-Claisen rearrangement of 4 using LHMDS, Me2SiCl2, and Et3N in toluene proceeded stereoselectively. To explain the observed high stereoselectivity, we proposed the reaction mechanism where the coordination of the silyl group to the lactone carbonyl at the γ-position controlled the geometry of the silyl ketene acetal and we referred this reaction as a remote chelation controlled Ireland-Claisen rearrangement.3) To further demonstrate the synthetic utility of this methodology, we attempted to synthesize clutiolide (6).
The shrub Clutia abyssinica is distributed to the dry regions of Africa. Extracts of the aerial parts are popularly used to treat skin diseases and its root is used for the kidney cleansing as well as the extermination of roundworms. There are several characteristic secolabdane diterpenes isolated from the genus Clutia, namely clutiolide (6), 4a) dihydroclutiolide, 4a) isodihydroclutiolide, 4a) saudin, 4b) cluytene A4c) and richardianidin-1 and 24d) etc. (Figure 1). This family of compounds has attracted much attention as a target for synthesis because of their intriguing molecular architectures and biological activities. For example, saudin was known to possess a significant hypoglycemic effect in nonalloxanized, rather than alloxanized fasting mice.5,6) Clutiolide (6) were isolated from Clutia abyssinica by Euerby et al. in 1990 and structurally consists of a bicylic lactone and a δ-lactone attached to the furan moiety. Here we describe the study toward the synthesis of clutiolide (6) by taking advantage of our remote chelation controlled Ireland-Claisen rearrangement which we have previously developed.

Our synthetic strategy leading to clutiolide (6) centers around the construction of the quaternary center by Ireland-Claisen rearrangement. Thus, the target molecule can be divided to the left-hand segment 9 and the right-hand segment 12 (Scheme 2). It is assumed that the bicyclic framework in 9 would be assembled by intramolecular Diels-Alder reaction of 10, which is easily prepared by the esterification of 11 with methyl fumarate. On the other hand, the allylic alcohol 12 could be obtained by ring-closing metathesis of ester 13, which is easily obtained from 14.

RESULTS AND DISCUSSION
Our synthesis of the left hand segment 9 commenced with Wittig reaction of acrolein with Ph3P=C(Me)CO2Et to generate 15 in 91% yield (Scheme 3). Reduction of 15 with LiAl(OEt)H3 gave allyl alcohol 11 in 91% yield,7) which was esterified with mono-methyl fumarate to afford triene 10 in 85% yield. The intramolecular Diels-Alder reaction of 10 was performed under heating at 230 °C in 1,2,4-trichlorobenzene to afford the desired 16 in 77% yield as the sole product. Hydrolysis of 16 gave carboxylic acid 9 in 97% yield. Initially we attempted to separate the enantiomers by chromatography of the corresponding esters and amides derived from chiral alcohols and chiral amines. Optical resolution of 9 using a chiral resolving agents, such as quinidine and cinchonidine was also examined. However all attempts were fruitless. Therefore, we proceeded further using racemic compound 9.

The right hand segment 12 was prepared from 3-furaldehyde as shown in Scheme 4. Allylation of 3-furaldehyde afforded 14, which was then subjected to enzymatic kinetic resolution. Initially, we examined acetylation of 14 with vinyl acetate using various lipases; however, the results were unsatisfactory. Fortunately, it was found that lipase-catalyzed hydrolysis of acetate 17 furnished better results.8) Thus, treatment of 17 with PS Amano in pH 7.0 buffer afforded (R)-14 (99% ee) and (S)-17 (87% ee) in 44% and 55% yields, respectively. The resulting (S)-17 (87% ee) was again subjected to the second enzymatic hydrolysis. As a result, (R)-14 (>95% ee) and (S)-17 (99% ee) were obtained in 49% and 46% yields, respectively. Hydrolysis of 17, followed by esterification gave phosphonate 18,

which was then converted to compound 13 by the reaction with formalin in the presence of DABCO. For the ring-closing metathesis of 13, 13 was first treated with Grubbs 2nd generation catalyst in toluene (0.01 M). However, in this case, the corresponding dimer was obtained as a major product. After exploring various conditions, we were pleased to find that reaction of 13 with Hoveyda-Grubbs 2nd catalyst9) at 80 °C in toluene furnished desired 12 in 58% yield, along with unreacted 13 (19%) and the dimer (6%). Reduction of 12 with DIBAL and subsequent acetalization gave methyl acetal 19 as a single isomer in good yield.
Esterification of racemic 9 with 19 under the conditions using EDCI and DMAP gave ester 20 in 66% yield as a diastereoisomeric mixture (Scheme 5). With 20 in hand, we then investigated the key Claisen rearrangement under various conditions.10) When 20 was reacted with Me2SiCl2 in the presence of LHMDS and heated at 80 °C in toluene, the desired compound 7 and its unidentified diastereoisomer were obtained in 36% and 4% yields, respectively. This result suggested that, provided the pure (3aR,4S,7aS)-isomer is used, the desired 7 could be obtained selectively in ca. 70% yield. The stereochemistry of the major product was characterized by NOESY spectra of the corresponding iodolactonization product 21 derived from 7. In contrast, the rearrangement under the conditions using KHMDS, TMSCl, and Et3N turned out to be sluggish to afford a complex mixture including compound 7 (5%).

The possible reaction courses of the Claisen rearrangement of 20 are shown in Scheme 6. Under the conditions employing LHMDS and Me2SiCl2, the coordination of the silyl group to the lactone carbonyl oxygen forces the silyl ketene acetal to take a Z-geometry. Regarding (3aR,7aS)-compound, there are two possible transition states, TS-A and TS-B. However, in TS-A taking a boat conformation, there can be the significant steric repulsion between the methoxy group and the silyl substituent, whereas such an interaction would not be observed in TS-B. On the other hand, as for transition states from (3aS, 7aR)-compound, both TS-C and TS-D would have experienced severe steric repulsion between the furyl group and the 7aR-methyl group and between the furyl group and the silyl substituent, respectively. Consequently, TS-B would be the most favorable transition state which leads to the desired 7.

CONCLUSION
We succeeded in the stereoselective synthesis of compound 7, a promising precursor for the synthesis of clutiolide (6), utilizing a remote chelation controlled Ireland-Claisen rearrangement we have previously developed. The synthesis of clutiolide is now ongoing in our laboratory.

EXPERIMENTAL
Where appropriate, reactions were performed in flame-dried glassware under argon atmosphere. All extracts were dried over MgSO4 and concentrated by rotary evaporation below 30 °C at 25 Torr unless otherwise noted. Commercial reagents and solvents were used as supplied with following exceptions. N,N-Dimethyformamide (DMF), dichloromethane (CH2Cl2), triethylamine, benzene and toluene (PhMe) were distilled from CaH2. Methanol (MeOH) was distilled from sodium. Thin-layer chromatography (TLC) was performed using glass-packed silica gel plates (0.2 or 0.5 mm thickness). Column chromatography was performed using silica gel (particle size 100-210 mm (regular), 40-50 mm (flash)). Optical rotations were recorded on a digital polarimeter at ambient temperature, JEOL DIP-370 or P-2200. Infrared spectra were measured on a Fourier transform infrared spectrometer, JEOL FT/IR-230. 1H NMR (400 and 500 MHz) and 13C NMR (100 and 75 MHz) spectra were measured using CDCl3 as solvent, and chemical shifts are reported as δ values in ppm based on internal CHCl3 (7.26 ppm, 1H; 77.0 ppm, 13C). HRMS spectra were taken in EI or FAB mode.
(E)-Ethyl 2-methylpenta-2,4-dienoate (15): To a stirred solution of acrolein (6.2 g, 0.11 mol) in CH2Cl2 (150 mL) was added (carbethoxyethylidene)triphenylphosphorane (40 g, 0.11 mol), and the reaction mixture was refluxed for 4 h. The mixture was allowed to cool to room temperature and diluted with pentane (100 mL). The resulting solid was filtered off, and the filtrate was concentrated in vauo. Addition of pentane and filtration were repeated three times to give compound 15 (14.1 g, 0.101 mol, 91%) as pale yellow oil: FT-IR (neat) ν 2977, 1714, 1575, 1448, 1245, 1099, 912 cm-1; 1H-NMR (300 MHz, CDCl3) δ 7.16 (d, J = 9.9 Hz, 1H), 6.66 (ddd, J = 9.9, 10.2, 16.5 Hz, 1H), 5.56 (d, J = 16.5 Hz, 1H), 5.44 (d, J = 10.2 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 1.95 (s, 3H), 1.31 (t, J = 6.9 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 168.3, 138.2, 132.2, 128.1, 124.3, 60.6, 14.2, 12.6; HRMS (EI) calcd for C8H12O2: 140.0837, found: 140.0812.
(E)-2-Methylpenta-2,4-dien-1-ol (11): To an ice-cooled suspension of LiAlH4 (0.83 g, 21.9 mmol) in Et2O (66 mL) was added EtOH (1.27 mL, 22.5 mmol), and the mixture was stirred for 15 min. To this suspension was added dropwise a solution of compound 15 (4.0 g, 28.6 mmol) in Et2O (5.0 mL) over 5 min. After stirring for 2.5 h, the reaction was quenched by addition of H2O (4 mL), 3 M aqueous NaOH (4 mL), and H2O (12 mL) in that order. The resulting solid was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (SiO2 150 g, hexane/EtOAc = 5/1 to 2/1) to afford compound 11 (2.56 g, 26.1 mmol, 91%) as a colorless oil: FT-IR (neat) ν 3332, 2917, 1654, 1600, 1428, 1214, 1141, 1066, 997, 900 cm-1; 1H-NMR (300 MHz, CDCl3) δ 6.63-6.54 (m, 1H), 6.08 (d, J = 10.8 Hz, 1H), 5.21 (d, J = 16.5 Hz, 1H), 5.11 (d, J = 9.9 Hz, 1H), 4.13 (s, 2H), 1.79 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 137.7, 132.5, 125.3, 117.0, 68.1, 14.0.
Methyl (E)-2-methylpenta-2,4-dienyl fumarate (10): To an ice-cooled solution of 11 (3.0 g, 30.6 mmol) in CH2Cl2 (100 mL) were added EDCI (7.0 g, 36.7 mmol), mono-methyl fumarate (4.78 g, 36.7 mmol), and DMAP (373 mg, 3.06 mmol). After stirring at rt for 2 h, the reaction mixture was diluted with sat. aq. NaHCO3 (100 mL) and extracted with EtOAc (100 mL x 3). Combined organic layer was dried, concentrated, and chromatographed (SiO2 120 g, hexane/EtOAc = 5/1) to give compound 10 (5.47 g, 26.0 mmol, 85%) as colorless oil: FT-IR (neat) ν 2952, 1727, 1650, 1438, 1376, 1301, 1159, 987, 910, 775 cm-1; 1H-NMR (300 MHz, CDCl3) δ 6.89 (s, 2H), 6.64-6.52 (m, 1H), 6.11 (d, J = 10.5 Hz, 1H), 5.27 (d, J = 16.8 Hz, 1H), 5.19 (d, J = 10.2 Hz, 1H), 4.66 (s, 2H), 3.82 (s, 3H), 1.86 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 165.3, 164.6, 133.5, 133.4, 131.9, 129.0, 128.0, 118.5, 70.2, 52.3, 14.3; HRMS (EI) calcd for C11H14O4: 210.0892, found: 210.0869.
Methyl (3aR*,4S*,7aS*)-1,3,3a,4,5,7a-hexahydro-7a-methyl-3-oxoisobenzofuran-4-carboxylate (16): A mixture of 10 (2.7 g, 12.8 mmol) and BHT (0.28 g, 1.28 mmol) in 1,2,4-trichlorobenzene (642 mL) was degassed, and stirred at 230 °C for 39 h. The reaction mixture was concentrated and chromatographed (SiO2 150 g, hexane/EtOAc = 5/1) to afford compound 16 (2.08 g, 9.9 mmol, 77%) as a yellow oil: FT-IR (neat) ν 2921, 2854, 1774, 1444, 1369, 1261, 1205, 1024, 740 cm-1; 1H-NMR (300 MHz, CDCl3) δ 5.85-5.80 (m, 1H), 5.47 (dt, J = 7.5, 0.9 Hz, 1H), 4.04 (d, J = 6.6 Hz, 1H), 3.97 (d, J = 6.6 Hz, 1H), 3.73 (s, 3H), 3.25-3.22 (m, 1H), 3.12 (d, J = 1.6 Hz, 1H), 2.59-2.52(m, 1H), 2.22 -2.15 (m, 1H), 1.17 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 177.1, 173.9, 129.8, 128.2, 77.4, 51.9, 46.1, 39.1, 35.0, 23.2, 21.4; HRMS (EI) calcd for C11H14O4: 210.0892, found: 210.0861.
(3aR*,4S*,7aS*)-1,3,3a,4,5,7a-hexahydro-7a-methyl-3-oxoisobenzofuran-4-carboxylic acid (9): To a stirred solution of compound 16 (1.7 g, 8.10 mmol) in MeOH (17 mL) was added 3 M aq. NaOH (17.0 mL), and the mixture was stirred for 10 h. After the mixture was washed with Et2O (20 mL x 3), the aqueous layer was adjusted to pH 2 by addition of HCl and extracted with Et2O (20 mL x 3). Organic extracts were washed with brine (3 mL), dried, and concentrated to afford a carboxylic acid (9), which was subjected to next reaction without further purification. 1H-NMR (400 MHz, CDCl3) δ 5.90-5.82 (m, 1H), 5.51-5.49 (m, 1H), 4.05 (d, J = 9.0 Hz, 1H), 3.99 (d, J = 9.0 Hz, 1H), 3.32-3.28 (m, 1H), 3.18-3.16 (m, 1H), 2.56 (dd, J = 5.1, 17.0 Hz, 1H), 2.23-2.17 (m, 1H), 1.23 (s, 3H).
1-(Furan-3-yl)but-3-en-1-ol (14): To a stirred solution of 3-furaldehyde (1.00 g, 10.4 mmol) in THF (34.7 mL) at -78 °C was added allylmagnesium chloride (1.38 M solution in THF, 18.9 mL, 26.0 mmol), and the mixture was stirred for 2 h. The reaction mixture was diluted with sat. aq. NH4Cl (30 mL), extracted with EtOAc (30 mL x 3), dried, and concentrated. The residue was purified by chromatography (SiO2 40 g, hexane/EtOAc = 10/1) to give compound 14 (1.2 g, 8.81 mmol, 85%). FT-IR (neat) ν 3407, 2924, 1641, 1502, 1430, 1301, 1161, 1028, 920, 868, 798 cm-1; 1H-NMR (300 MHz, CDCl3) δ 7.40 (s, 2H), 6.41 (s, 1H), 5.89-5.75 (m, 1H), 5.21-5.15 (m, 2H), 4.72 (t, J = 6.0 Hz, 2H), 2.59-2.44 (m, 2H); 13C-NMR (75 MHz, CDCl3) δ 143.2, 139.0, 134.1, 128.4, 118.4, 108.5, 66.0, 42.3; HRMS (EI) calcd for C8H9O2: 137.0603, found: 137.0573.
1-(Furan-3-yl)but-3-enyl acetate (17): To a stirred solution of 14 (9.27 g, 57.0 mmol) in CH2Cl2 (66 mL) were added Et3N (33 mL, 230 mmol), Ac2O (10.2 mL, 108 mmol) and DMAP (0.69 g, 5.6 mmol). After stirring at 15 h, the mixture was washed with 2 M HCl (50 mL), sat. aq. NaHCO3 (50 mL), and brine (50 mL). Organic extracts were dried, concentrated, and chromatographed (SiO2 300 g, hexane/EtOAc = 30:1) to give 17 (9.27 g, 51.4 mmol, 90%) as an yellow oil: FT-IR (neat) ν 1739, 1504, 1373, 1240, 1162, 1025, 931, 875, 800 cm-1; 1H-NMR (300 MHz, CDCl3) δ 7.42 (s, 1H), 7.37 (s, 1H) 6.39 (s, 1H), 5.83 (t, J = 6.9 Hz, 1H), 5.79- 5.65 (m, 1H), 5.14 -5.05 (m, 2H) 2.68 -2.51 (m, 2H) 2.04 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 170.2, 143.1, 140.1, 133.1, 124.4, 118.0, 108.9, 67.6, 39.1, 21.1; HRMS (EI) calcd for C10H12O3: 180.0786, found: 180.0780.
(S)-1-(Furan-3-yl)but-3-enyl acetate ((S)-17) and (R)-1-(Furan-3-yl)but-3-en-1-ol ((R)-14): To a stirred solution of 17 (30 g, 165 mmol) in DMSO (81 mL) and Na-K phosphate buffer (pH 7.0, 822 mL) was added lipase PS Amano (1.85 g), and the mixture was stirred at rt for 43 h. The reaction mixture was extracted with Et2O (1.0 L x 3), washed with sat. NaHCO3 (1.0 L) and brine (1.0 L), dried, and concentrated. The residue was purified by chromatography (SiO2 800 g, hexane/EtOAc = 30/1 to 5/1) to give (S)-17 (16.4 g, 91 mmol, 55 %) and (R)-14 (10 g, 72.5 mmol, 44 %). The resulting (S)-17 was treated with PS Amano analogously. Totally (R)-14 (11.1 g, 80.4 mmol, 49%, >95%ee) and (S)-17 (13.6 g, 75.5 mmol, 46%, 99%ee) were obtained. (S)-17; [α]D24 -60.6 (c 0.97, CHCl3): (R)-14; [α]D24 +31.6 (c 1.09, CHCl3).
(S)-1-(Furan-3-yl)but-3-en-1-ol ((S)-14). To an ice-cooled solution of (S)-17 (3.08 g, 16.6 mmol) in EtOH (55 mL) was added K2CO3 (4.58 g, 33.2 mmol) and the mixture was stirred at 0 °C for 10 h. The reaction mixture was diluted with sat. NH4Cl (50 mL), extracted with EtOAc (55 mL x 3), dried, and concentrated to give (S)-14 (2.17 g, 15.7 mmol, 94%): (S)-14; [α]D24 -28.0 (c 1.43, CHCl3).
(S)-1-(Furan-3-yl)but-3-enyl diethylphosphonoacetate (18): To an ice-cooled solution of (S)-14 (3.0 g, 32.6 mmol) in THF (60 mL) were added DMAP (265 mg, 2.17 mmol), EDCI (6.25 g, 32.6 mmol), and diethyl phosphonoacetate (5.2 mL, 32.6 mmol) . After stirring at rt for 3.5 h, DMAP (100 mg, 0.82 mmol) and EDCI (2.0 g, 10.4 mmol) were added and stirring was continued at rt for additional 2 h. The mixture was diluted with sat. aq. NaHCO3 (100 mL), extracted with EtOAc (100 mL x 3), and washed with brine (100 mL). Organic extracts were dried, concentrated, and chromatographed (SiO2 600 g, hexane/EtOAc = 1/1) to give compound 18 (12.6 g, 39.8 mmol, 95%) as colorless oil: [α]D24 -37.5 (c 0.995, CHCl3); FT-IR (neat) ν 3466, 3126, 3078, 2982, 1733, 1504, 1394, 1259, 1162, 1113, 1021, 957, 875, 602 cm-1; 1H-NMR (300 MHz, CDCl3) δ 7.47 (s, 1H), 7.38 (s, 1H), 6.43 (s, 1H), 5.87 (t, J = 6.8 Hz, 1H), 5.77 (ddt, J = 7.1, 10.0, 17.4 Hz, 1H), 5.12 (d, J = 17.6 Hz, 1H), 5.09 (d, J = 11.2 Hz, 1H), 4.13 (dq, J = 7.5, 15.0 Hz, 4H), 2.96 (d, J = 20.5 Hz, 2H), 2.71-2.56 (m, 2H), 1.34-1.28 (m, 6H); 13C-NMR (75 MHz, CDCl3) δ 165.0, 143.1, 140.5, 132.8, 123.9, 118.2, 108.8, 69.1, 62.5, 38.9, 35.0, 33.7, 16.2; HRMS (EI) calcd for C14H21O6P: 316.1076, found 316.1075.
(S)-1-(Furan-3-yl)but-3-enyl 2-(hydroxymethyl)acrylate (13): To an ice-cooled solution of 18 (6.70 g, 21.2 mmol) in THF (106 mL) were added formalin (35% aqueous solution, 106 mL, 1.30 mol) and DABCO (3.56 mL, 31.8 mmol). After stirring at rt for 18 h, the mixture was diluted with sat. NaHCO3 (200 mL), and extracted with EtOAc (200 mL x 3). Combined extracts were dried, concentrated, and chromatographed (SiO2 250 g, hexane/EtOAc = 3/1 to 2/1) to give compound 13 (3.97 g, 17.9 mmol, 84%) as colorless oil: [α]D24 -38.3 (c 1.09, CHCl3); FT-IR (neat) ν 3442, 1712, 1643, 1504, 1263, 1157, 1022, 874, 796, 601 cm-1; 1H-NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.39 (s, 1H), 6.41 (s, 1H), 6.27 (s, 1H), 5.93 (t, J = 6.8 Hz, 1H), 5.83 (s, 1H), 5.75 (ddt, J = 9.8, 17.0, 4.4 Hz, 1H), 5.13 (d, J = 17.0 Hz, 1H), 5.10 (d, J = 9.8 Hz, 1H), 4.32 (s, 2H), 2.73-2.59 (m, 2H), 2.44 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ 165.4, 143.2, 140.3, 139.4, 132.9, 125.9, 124.2, 118.4, 108.8, 68.3, 62.4, 39.1; HRMS (EI) calcd for C12H14O4: 222.0892, found 222.0890.
(S)-6-(Furan-3-yl)-5,6-dihydro-3-(hydroxymethyl)pyran-2-one (12): To a stirred solution of compound 13 (1.50 g, 6.75 mmol) in degassed toluene (135 mL) was added 2nd generation Hoveyda-Grubbs catalyst (60 mg, 0.101 mmol). After 10 h and 15 h, the catalysts (30 mg, 0.050 mmol) were added respectively and the mixture was stirred at 80 °C for additional 18 h. The reaction mixture was concentrated, and chromatographed (SiO2 45 g, hexane/EtOAc = 2:1 to 1:1) to give compound 12 (752 mg, 3.88 mmol, 58%) as colorless oil, unreacted 13 (283 mg, 0.189 mmol, 19%), and dimer (93 mg, 0.22 mmol, 6%): 12; [α]D24 -68.0 (c 1.18, CHCl3); FT-IR (neat) ν 3407, 1697, 1503, 1379, 1220, 1126, 1019, 873, 792, 599, 493 cm-1; 1H-NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.42 (s, 1H), 6.93 (s, 1H), 6.46 (s, 1H), 5.43 (dd, J = 4.9, 10.7 Hz, 1H), 4.33 (s, 2H), 3.40 (s, 1H), 2.75-2.60 (m, 2H); 13C-NMR (75 MHz, CDCl3) δ 164.8, 143.7, 140.0, 139.6, 131.7, 123.5, 108.5, 72.5, 61.1, 30.0.
((2S,6S)-6-(Furan-3-yl)-5,6-dihydro-2-methoxy-2H-pyran-3-yl)methanol (19): To a stirred solution of 12 (53 mg, 0.273 mmol) in CH2Cl2 (2 mL) at -78 °C was added DIBAL (1.02 M in hexane, 0.53 mL, 0.546 mmol) and the mixture was stirred for 2 h. The reaction was quenched by addition of potassium sodium tartrate (20% aqueous solution, 2 mL). After stirring for 12 h, the mixture was extracted with EtOAc (100 mL x 3), washed by brine (20 mL), dried, and concentrated to afford a crude hemiacetal. To an ice-cooled solution of crude hemiacetal in methanol (2 mL) was added CSA (6.3 mg, 0.0273 mmol). After stirring at 0 °C for 16 h, the reaction mixture was diluted with sat. aq. NaHCO3 (2 mL), and extracted with EtOAc (5 mL x 3). Organic extracts were washed with brine (2 mL), dried, concentrated, and chromatographed (SiO2 2 g, hexane/EtOAc = 1:1) to give compound 19 (50 mg, 0.238 mmol, 87%) as colorless oil: [α]D24 -24.5 (c 1.00, CHCl3); FT-IR (neat) ν 3411, 2898, 1503, 1394, 1156, 1024, 956, 875, 777, 601 cm-1; 1H-NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.41 (s, 1H), 6.44 (s, 1H), 6.01 (d, J = 5.4 Hz, 1H), 5.00 (s, 1H), 4.85 (dd, J = 3.4, 11.2 Hz, 1H), 4.14 (d, J = 12.7 Hz, 1H), 4.09 (d, J = 12.2 Hz, 1H), 3.49 (s, 3H), 2.58 (s, 1H), 2.42-2.33 (m, 1H), 2.28-2.21 (m, 1H); 13C-NMR (75 MHz, CDCl3) δ 143.2, 139.3, 135.8, 126.0, 125.1, 108.8, 97.3, 63.6, 61.6, 55.2, 30.7; HRMS (EI) calcd for C11H14O4: 210.0892, found 210.0864.
(3aR*,7aS*)-((2S,6S)-6-(Furan-3-yl)-5,6-dihydro-2-methoxy-2H-pyran-3-yl)methyl 1,3,3a,4,5,7a-　hexahydro-7a-methyl-3-oxoisobenzofuran-4-carboxylate (20): To an ice-cooled solution of compound 9 (1.36 g, 6.92 mmol) and compound 19 (1.45 g, 6.92 mmol) in CH2Cl2 (35 mL) were added EDCI (2.0 g, 10.4 mmol) and DMAP (83.8 mg, 0.69 mmol). After stirring at rt for 2.5 h, EDCI (0.40 g, 2.1 mmol) and DMAP (83.8 mg, 0.69 mmol) were added, and stirring was continued for 11.5 h. To the mixture was added sat. aq. NaHCO3 (50 mL), extracted with EtOAc (50 mL x 3). Organic extracts were washed with brine (50 mL), dried, concentrated, and chromatographed (SiO2 75 g, hexane/EtOAc = 3:1) to give compound 20 (1.77 g, 4.557 mmol, 66%) as colorless oil and recovered compound 19 (180 mg, 0.853 mmol, 12%): 20; FT-IR (neat) ν 2899, 1773, 1735, 1254, 1190, 1097, 1050, 961, 876 cm-1; 1H-NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.42 (s, 1H), 6.44 (s, 1H), 6.09 (t, J = 5.4 Hz, 1H), 5.86-5.81 (m, 1H), 5.48 (d, J = 8.8 Hz, 1H), 4.95 (s, 1H), 4.86 (dd, J = 3.7, 11.0 Hz, 1H), 4.73-4.69 (m, 1H), 4.60 (d, J = 12.2 Hz, 1H), 4.03 (d, J = 8.8 Hz, 1H), 3.98 (d, J = 8.8 Hz, 1H), 3.46 (s, 3H), 3.28-3.24 (m, 1H), 3.12 (t, J = 3.4 Hz, 1H), 2.86 (dd, J = 5.2, 18.3 Hz, 1H), 2.43-2.36 (m, 1H), 2.30-2.17 (m, 2H), 1.18 (d, J = 5.4 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 177.1, 172.6, 143.3, 139.3, 131.8, 129.9, 128.2, 126.8, 125.9, 108.8, 96.3, 65.0, 61.2, 55.5, 52.0, 46.2, 39.2, 36.3, 30.9, 23.3, 22.1; HRMS (EI) calcd for C21H24O7: 388.1523, found 388.1530.
(3aS,4S,7aS)-4-((2S,4S,6S)-6-(Furan-3-yl)-tetrahydro-2-methoxy-3-methylene-2H-pyran-4-yl)-1,3,-
3a,4,5,7a-hexahydro-7a-methyl-3-oxoisobenzofuran-4-carboxylic acid (7): To a stirred solution of 20 (85 mg, 0.215 mmol) in PhMe (2 mL) at -78 °C was added a solution of LHMDS (1.0 M in hexane, 0.64 mL, 0.64 mmol) and the mixture was stirred for 30 min. A mixture of dichlorodimethylsilane (1.0 mL, 8.24 mmol) and Et3N (1.0 mL, 7.17 mmol) was centrifuged at 3000 rpm for 5 min and the supernatant (0.3 mL), regarding to include dichlorodimethylsilane (1.24 mmol) and Et3N (1.08 mmol), was added to the reaction mixture. After stirring at –78 °C for 1 h, the mixture was allowed to warm gradually to 80 °C and stirring was continued at 80 °C for an additional 10 h. The mixture was diluted with sat. aq. NH4Cl (2 mL), extracted with EtOAc (10 mL x 3), washed with brine, dried, and concentrated. The residue was purified by chromatography (SiO2 10 g, hexane-EtOAc, 3/1 to 1/1) afforded compound 7 (31 mg, 80 µmol, 36%) as colorless oil and diastereoisomer (3 mg, 8 µmol, 4%) and 20 (12 mg, 0.031 mmol, 14%); 7: 1H-NMR (400 MHz, CDCl3) δ 7.36 (s, 2H), 6.36 (s, 1H), 5.86-5.82 (m, 1H), 5.61 (s, 1H), 5.56 (s, 1H), 5.43 (d, J = 10.2 Hz, 1H), 5.19 (s, 1H), 4.73 (dd, J = 3.7, 11.5, 1H), 4.34 (dd, J = 6.8, 9.2 Hz, 1H), 3.96 (d, J = 8.8 Hz, 1H), 3.90 (d, J = 8.8 Hz, 1H), 3.37 (s, 3H), 3.28 (s, 1H), 2.86 (dd, J = 6.8, 18.2 Hz, 1H), 2.12-1.99 (m, 3H), 1.14 (s, 3H); HRMS (EI) calcd for C21H24O7: 388.1523, found 388.1530.
Iodolactonization of 7: To an ice-cooled solution of 7 (14 mg, 0.036 mmol) in THF (0.5 mL) were added iodine (27 mg, 0.108 mmol) and sat. aq. NaHCO3 (0.5 mL), and a mixture was stirred for 2 h. The reaction mixture was diluted with sat. aq. Na2S2O3 (1 mL), and stirring was continued for 30 min. The mixture was extracted with Et2O (5 mL x 3), washed with brine (1 mL), dried, and concentrated. The residue was purified by flash chromatography (SiO2 1g, hexane/EtOAc = 3/1) to afford compound 41 (10 mg, 0.0195 mmol, 56%) as colorless oil. [α]D24 +14.0 (c 0.8, CHCl3); FT-IR (neat) ν 3149, 2927, 2251, 1766, 1208, 1149, 1027, 735, 602 cm-1; 1H-NMR (400 MHz, CDCl3) δ 7.42 (s, 2H), 6.39 (s, 1H), 5.78-5.73 (m, 1H), 5.59 (dt, J = 1.3, 10.2 Hz, 1H), 4.95 (dd, J = 4.2, 10.2 Hz, 1H) 4.84 (s, 1H), 4.06 (d, J = 8.8 Hz, 1H), 4.00 (d, J = 8.8 Hz, 1H), 3.83 (d, J = 11.2 Hz, 1H), 3.53-3.48 (m, 5H), 3.27 (s, 1H), 2.37-2.31 (m, 1H), 2.24 (dt, J = 2.6, 17.8 Hz, 1H), 2.11 (dd, J = 5.4, 17.6 Hz, 1H), 2.05-1.93 (m, 1H), 1.36 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 176.3, 175.9, 143.6, 138.9, 130.2 , 126.8, 125.1 108.2, 100.0, 80.7, 77.2, 65.2, 56.8, 50.8, 44.5, 42.6, 28.7, 28.2, 21.4, 11.5, HRMS (EI) calcd for C21H23IO7: 514.0488, found 514.0507.

ACKNOWLEDGEMENTS
This work was financially supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (17590009) and by a Grant-in-Aid for Scientific Research from the President of Nagasaki University.

References

1. a) P. A. Bartlett, D. J. Tanzella, and J. F. Barstow, J. Org. Chem., 1982, 47, 3941; CrossRef b) T. J. Gould, M. Balestra, M. D. Wittman, J. A. Gary, L. T. Rossano, and J. Kallmerten, J. Org. Chem., 1987, 52, 3889; CrossRef c) T. Sato, K. Tajima, and T. Fujisawa, Tetrahedorn Lett., 1983, 24, 729. CrossRef
2. U. Kazmaier, Angew. Chem., Int. Ed. Engl., 1994, 33, 998. CrossRef
3. T. Fukuzaki, S. Kobayashi, T. Hibi, Y. Ikuma, J. Ishihara, N. Kanoh, and A. Murai, Org. Lett., 2002, 4, 2877. CrossRef
4. a) R. D. Waigh, B. Zerihun, and M. R. Euerby, Phytochemistry, 1990, 29, 2935; CrossRef b) J. S. Mossa, J. M. Cassady, M. D. Antoun, S. R. Byrn, A. T. McKenzie, J. F. Kozlowski, and P. Main, J. Org. Chem., 1985, 50, 916; CrossRef c) I. Muhammad, J. S. Mossa, M. A. Al-Yahya, H. H. Mirza, F. S. El-Feraly, and A. T. McPhail, J. Nat. Prod., 1994, 57, 248; CrossRef d) J. S. Mossa, J. M. Cassady, J. F. Kozlowski, T. M. Zennie, M. D. Antoun, M. G. Pellechia, A, T, McKenzie, and S. R. Byrn, Tetrahedron Lett., 1988, 29, 3627. CrossRef
5. J. S. Mossa, E. S. M. El-Denshary, R. Hindawi, and A. M. Ageel, Int. J. Crude Drug Res., 1988, 26, 81.
6. Total synthesis of saudin; a) J. D. Winkler and E. M. Doherty, J. Am. Chem. Soc., 1999, 121, 7425; CrossRef b) R. K. Boeckman Jr., M. D. R. R. Ferreira, L. H. Mitchell, and P. Shao, J. Am. Chem. Soc., 2002, 124, 190. CrossRef
7. E. Piers and E. H. Ruediger, J. Org. Chem., 1980, 45, 1725. CrossRef
8. a) C. Held, R. Fröhlich, and P. Metz, Angew. Chem. Int. Ed., 2001, 40, 1058; CrossRef b) A. Bierstedt, J. Stölting, R. Fröhlich, and P. Metz, Tetrahedron: Asymmetry, 2002, 12, 3399. CrossRef
9. a) J. S. Kingsbury, J. P. A. Harrity, P. J. Bonitatebus, Jr., and A. H. Hoveyda, J. Am. Chem. Soc., 1999, 121, 791; CrossRef b) S. B. Garber, J. S. Kingsbury, B. L. Gray, and A. H. Hoveyda, J. Am. Chem. Soc., 2000, 122, 8168; CrossRef Example for RCM to form α-substituted δ-lactone, see; H. Mizutani, M. Watanabe, and T. Honda, Tetrahedron, 2002, 58, 8929. CrossRef
10. The Claisen rearrangement of the ester coupled with 9 and 12 afforded a complex mixture.