HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 9, 2009, pp. 2295-2314
Received, 30th March, 2009, Accepted, 15th May, 2009, Published online, 19th May, 2009.
DOI: 10.3987/COM-09-11720

■ Trisubstituted Double Bond in the Cyclooctene Ring. Preparation Using the RCM Reaction

Reiko Mizutani, Takuo Miki, Katsuyuki Nakashima, Masakazu Sono, and Motoo Tori*

Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihamabouji, Yamashiro-machi, Tokushima, 770-8514, Japan

Abstract

Cyclization to eight-membered rings with a trisubstituted double bond was attempted using ring closing metathesis (RCM) reactions. Although simple substrates were not good candidates, the triene with a proper configuration cyclized to the cyclooctene with a tri-cycle (5-8-6 membered) in moderate yield. The formation of one-carbon smaller rings was also observed.

INTRODUCTION
We have prepared the seven-membered carbocycles present in terpenoids using the ring closing metathesis (RCM) reaction.1,2 This method was applied to the synthesis of tormesol and other liverwort terpenoids with a sphenolobane-type skeleton.1 At the same time we were also interested in the synthesis of eight-membered carbocycles by applying the RCM reaction. Eight-membered carbocycles are frequently found in terpenoids, especially those with trisubstituted double bonds, for example ophiobolin,3 fusicoccin,4 ceroplastrol,5 serpendione,6 dactylol,7 and YW3699.8,9 It is well known that it can be difficult to cyclize to eight-membered carbocycles.10 Recently, papers on the synthesis of these molecules have accumulated in the series of carbocycles and heterocycles.11-25 However, there is no report of systematic work in this area.
We tested simple examples (Scheme 1) to compare the reactivity of the substrates 1a and 1b with those for seven-membered carbocycles as a continuation of the systematic studies. Diene 1a afforded compound 2a using Grubbs catalyst26 in CH2Cl2 (14% yield), while diene 1b produced compound 2b27 using Grubs II catalyst (28% yield). These simple examples show that the RCM reaction is capable of constructing eight-membered carbocycles, although the double bonds are di-substituted. Therefore, we prepared several substrates and attempted the RCM reaction. The result confirmed the importance of the conformation of the diene substrate. We now describe the details of our results.

RESULTS AND DISCUSSION
Cyclization of dienes 4 and 7
Our work started with simple diene substrates, which cyclize to bicyclic compounds bearing eight- and six-membered carbocycles. The C-6 alkyl chain unit was introduced to enone 328,29 in the presence of a cuprous bromide-dimethyl sulfide complex to afford diene 4 in 93% yield. The RCM cyclization was carried out using the Grubbs second generation catalyst30 in CH2Cl2 under reflux (Table 1). However, the desired product 5 was produced only in a minute quantity, and dimer 6 was formed instead in 68% yield (entry 2).

When the carbonyl group was protected as a ketal, compound 7 did not give an eight-membered carbocycle 9 in CH2Cl2, benzene, or toluene. Surprisingly, the seven-membered compound 8 was formed in benzene or toluene as a solvent (Table 2). In entries 2 and 3, microwave was used to get a high temperature. It is known that at higher temperatures the terminal vinyl group is susceptible to rearrangement into di-substituted olefin.2 It is then cyclized to the one-carbon smaller product 8.31 This type of rearrangement has been reported in the literature.32-38 Simple dienes are not good candidates for construction of trisubstituted cyclooctenes. This is presumably due to the conformational freedom of the vinyl alkyl side chain by free rotation.

Cyclization of triene 15
We next introduced an sp2 carbon adjacent to the cyclohexane ring, which might assist the conformation close to the isopropenyl group by keeping the plane around the sp2 carbon. The 1,4-addition of a vinyl group was accomplished in the presence of a cuprous reagent. However, the stereoselectivity was not as high as expected.39 Therefore, an ethynyl group was introduced to enone 3 (Scheme 2). The TMS protected acetylene was converted to the ate complex using Me2AlCl, Ni(acac)2, and DIBAL and was reacted with enone 3.40,41 The TMS group was removed by TBAF. The bromide was prepared by reductive bromination using B-Br-9-BBN in 85% yield.42 After protection of the carbonyl group as a ketal,43 the metal exchange of bromine with the lithium atom and addition of 4-pentenal afforded enol 14 as a mixture of the diastereoisomers (the ratio was 5:4 from 13C NMR) in 56% yield.44 The hydroxy group was protected as a TES ether 15, which was treated with the Grubbs II catalyst in CH2Cl2 under reflux to give compounds 16 and 17 in 41% and 33% yield, respectively (Scheme 2). Compound 16 was converted to alcohol 18 and its structure was analyzed, because it gave better resolution in its NMR spectra. The eight-membered carbocycle was shown by the HMBC correlations, from the methyl group at the C-7 position to the carbon atoms at the C-6 and 7 positions. The configuration of the hydroxy group was established as β-orientation by the NOESY correlation between H-1 and H-3. Unfortunately, compound 17 proved to be a five-membered carbocycle45 formed as a result of competitive reaction with the isopropenyl group.

These results indicate that the introduction of the sp2 carbon predominated in the formation of the eight-membered carbocycle as expected. It is very interesting to note that both products 16 and 17 were isolated in a pure form (from 13C NMR). That is to say, a β-OH isomer cyclized to an eight-membered carbocycle, while an α-OH isomer cyclized to a five-membered compound. Unfortunately, we could not verify the configuration of the hydroxy group in compound 17. Although this is speculation, it is very likely that this is the case, and is presumably attributed to the difference in the conformation of both isomers of substrate 15.

Cyclization of trienes 19a and 19b
We next planned to construct the tri-cyclic substance which appeared in YW3699.8,9 The lithio-derivative of bromide 13 was reacted with 2-allylcyclopentanone to afford separable alcohols 19a and 19b (Table 3). A better yield was obtained in Et2O at -50˚C for 8 h (entry 2). A low yield was attributed to the rapid formation of debrominated compound 20. The stereochemistry was later established based on the 2D NMR of the cyclized products.

TES-ether 21a, derived from alcohol 19a by protection (TESOTf, iPr2NEt), was treated with the Grubbs II catalyst under the conditions listed in Table 4. The use of CH2Cl2 at rt gave almost full recovery (entry 1), however at higher temperatures the reaction proceeded to afford cyclized compounds. Compounds 22a and 24 were isolated by chromatographic separation. However, compound 23 was not easy to purify, therefore, was converted to alcohol 26. Compound 22a was the desired eight-membered product, while compound 26 was a seven-membered substance, which was presumably produced through a rearranged olefin 24. As previously discussed, the use of benzene as a solvent resulted in the formation of a large amount of rearranged olefin 24 (entry 4). When 30 mol% of the catalyst was used (entry 5), the yield of compound 22a was 28%. Therefore, this condition may be used in the cyclization reaction for eight-membered carbocycles.
The structures of these products are shown in Figure 1. The 1H NMR spectrum of compound 22a showed a broad triplet signal at δ 5.37 as well as a singlet methyl group at δ 1.56, being comparable to those of compound 18. Since the NMR spectrum of compound 22a did not give good resolution, it was not easy to see the stereochemistry in detail. This phenomenon was also observed at the stage of alcohol 25a. Compound 26 gave good resolution in its NMR spectra. Therefore, compound 26 was thoroughly analyzed, because the configurations at C-1 and 11 should be the same in the products. The HMBC correlations between the methyl group at C-9 and the carbons at the C-9 and 10 positions indicated the presence of the cyclized ring. The proton of H-10 appeared at δ 5.40 as a broad doublet with J=2.4 Hz. These observations as well as the MS spectrum clearly indicated that compound 26 had a seven-membered carbocycle. The NOE between H-8 and H-11 showed the β-orientation of both protons. Because the anion attacked the carbonyl group of 2-allylcyclopentanone from the back side of the allyl group, the hydroxy and the allyl groups were always on the same side. Therefore, the structure of compound 26 was established as depicted in the formula. The structure of compound 22a was thus suggested as 1α-OTES,11β-H following the discussion above. Compound 24 showed the quasi-molecular ion peak at m/z 447 [M+H]+ and the formula C27H46O3Si by HRCIMS, being the isomer of the starting material 21a. The olefinic proton of H-1046 was detected at δ 5.43 (dd, J=15.6 and 8.6 Hz) showing that the double bond rearranged into the 10,10´-position with the trans stereochemistry (JH10,10´ = 15.6 Hz). This was further confirmed by the NOE between H-10 and H-10´´.

TES-ether 21b, prepared by protection of alcohol 19b, was subjected to the reaction with Grubbs II catalyst (30 mol%) in CH2Cl2 (0.5 mM), and the desired eight-membered compound 22b was isolated in 61% yield (Scheme 3). Compound 22b exhibited a molecular ion peak at m/z 418 and the molecular formula was determined to be C25H42O3Si by HRMS. It was obvious that this compound had the eight-membered ring, because the HMBC spectrum indicated the correlations between the methyl group at C-9 and C-9 and 10, and the proton at C-10 appeared at δ 5.39 as a triplet (J = 8.4 Hz). The stereochemistry was deduced by the NOESY correlations between H-8 and H-11β, H-10 and H-12, and H-12 and H-16a. Therefore, the structure of 22b was established as depicted in the formula (Scheme 3).

CONCLUSION
In summary, we have demonstrated some examples of synthesizing eight-membered carbocycles with a trisubstituted double bond present in the terpenoids. Although simple examples such as compounds 4, 7 and 15 did not necessarily give satisfactory results, more complex examples such as compounds 21a and 21b afforded the cyclized products in low or moderate yield under the correct conditions. Compound 21b gave a higher yield of the eight-membered carbocycle than compound 21a. This result confirmed the importance of the conformation of the diene substrate, although the relative stability of the transition states is not clear at this stage.

EXPERIMENTAL
General. All reactions were carried out under an argon (Ar) atmosphere. Anhydrous solvents were purchased from Kanto Chemical Co., Inc. Reagents were purchased at the highest commercial quality and were used without further purification. The IR spectra were measured on a JASCO FT/IR 500 spectrophotometer. Mass spectra, including high-resolution spectra, were recorded on a JEOL JMS-700 MStation. 1H and 13C NMR spectra were measured on a Varian Unity 600 (600 MHz and 150 MHz, respectively) and a Varian Unity 200 (200 MHz and 50 MHz, respectively) spectrometer. Silica gel 60 (70-230 mesh, Fuji Silysia) was used for column chromatography. Silica gel BW-300 (200-400 mesh, Fuji Silysia) was used for column chromatography and a silica-gel 60F254 plate (0.25mm, Merck) was used for TLC.

Preparation of dimethyl 2-allyl-2-(hex-5-enyl)malonate (1a)
Dimethyl allylmalonate (263 mg, 1.23 mmol) in DMF (5 mL) was treated with NaH (26.0 mg, 0.65 mmol) for 30 min at rt. 6-Bromohexene (0.14 mL 1.35 mmol) was added and the mixture was stirred overnight at rt. 1M HCl (5 mL) was added and the mixture was extracted with Et2O. The organic layer was washed with brine, dried (MgSO4) and then evaporated to give a residue. The residue was purified by silica-gel column chromatography (hexane-EtOAc, 0-100%) to afford 1a (285 mg, 73%). FTIR 1740 cm-1; 1H NMR (200 MHz, CDCl3) δ 5.5-5.9 (2H, m), 4.8-5.2 (4H, m), 3.71 (6H, s), 2.64 (2H, d, J=7.6 Hz), 2.05 (2H, m), 1.8-1.9 (2H, m), 1.39 (2H, m), 1.1-1.3 (2H, m); 13C NMR (50 MHz, CDCl3) δ 171.8 (C × 2), 138.6 (CH), 132.5 (CH), 118.9 (CH2), 114.6 (C), 57.6 (C), 52.3 (CH3 × 2), 37.0 (CH2), 33.4 (CH2), 32.1 (CH2), 28.9 (CH2), 23.3 (CH2); MS (CI) m/z 255 [M+H]+, 229, 191, 165, 123, 111, 87 (base); HRCIMS Found m/z 255.1596 [M+H]+ C14H23O4 requires 255.1596.

Preparation of dimethyl 2-(but-3-enyl)-2-(pent-4-enyl)malonate (1b)
A mixture of dimethyl 3-butenylmalonate (1 g, 5.37 mmol), NaH (240 mg, 5.9 mmol), and 5-bromopentene (0.73 mL 5.9 mmol) in DMF (20 mL) was stirred at rt overnight. 6M HCl was added and the mixture was extracted with Et2O. The organic layer was washed with brine, dried (MgSO4) and then evaporated to give a residue. The residue was purified by silica-gel column chromatography (hexane-EtOAc, 0-2%) to afford 1b (653.7 mg, 48%). FTIR 1740, 1640 cm-1; 1H NMR (200 MHz, CDCl3) δ 5.77 (2H, ddt, J = 15, 11, 6.8 Hz), 5.03 (2H, br d, J = 15 Hz), 4.96 (2H, br d, J = 11 Hz), 3.71 (5H, s), 2.15-1.85 (5H, m), 1.33-1.18 (2H, m); 13C NMR (50 MHz, CDCl3) δ 172.0 (C × 2), 137.9 (CH), 137.4 (CH), 114.9 (CH2 × 2), 57.1 (C), 52.2 (CH3 × 2), 33.6 (CH2), 31.9 (CH2), 31.6 (CH2), 28.3 (CH2), 23.2 (CH2); MS (CI) m/z 255 [M+H]+, 223, 213, 191, 163, 145 (base), 132, 113, 93, 81; HRMS (CI) Found m/z 255.1577 [M+H]+, C14H23O4 requires 255.1596.

Preparation of dimethyl cyclooct-3-ene-1,1-dicarboxylate (2a)
To a stirred solution of ester 1a (45.5 mg, 0.18 mmol) in CH2Cl2 (12 mL) Grubbs II was added (7.6 mg, 5 mol%) in CH2Cl2 (5 mL) and the solution was refluxed for 15 h under Ar atmosphere. The reaction was quenched by bubbling air and the solvent was evaporated. The residue was purified by silica-gel column chromatography (hexane-EtOAc, 0-25%) to afford 2a (11.4 mg, 28%). FTIR 1730 cm-1; 1H NMR (200 MHz, CDCl3) δ 5.8-5.9 (1H, m), 5.4-5.5 (1H, m), 3.72 (6H, s), 2.73 (2H, d, J = 8 Hz), 2.0-2.2 (4H, m), 1.5-1.6 (4H, m); 13C NMR (50 MHz, CDCl3) δ 172.3 (C × 2), 134.0 (CH), 125.7 (CH), 52.5 (CH3 × 2), 59.0 (C), 30.9 (CH2), 29.8 (CH2), 29.4 (CH2), 26.7 (CH2), 23.5 (CH2); MS (CI) m/z 227 [M+H]+, 195, 166, 127, 89 (base), 61; HRCIMS Found m/z 227.1267 [M+H]+ C12H19O4 requires 227.1283.

Preparation of dimethyl cyclooct-4-ene-1,1-dicarboxylate (2b)27
To a stirred solution of ester 1b (127.0 mg, 0.5 mmol) in CH2Cl2 (40 mL) Grubbs catalyst was added (12 mg, 3 mol%) in CH2Cl2 (10 mL) and the solution was refluxed overnight under Ar atmosphere. The reaction was quenched by bubbling air and the solvent was evaporated. The residue was purified by silica-gel column chromatography (hexane-EtOAc, 0-5%) to afford 2b (16.0 mg, 14%). FTIR 1730 cm-1; 1H NMR (200 MHz, CDCl3) δ 5.73-5.20 (2H, m), 3.72 (6H, s), 2.39-2.11 (6H, m), 1.63-1.51 (4H, m); 13C NMR (50 MHz, CDCl3) δ 173.0 (C × 2), 131.5 (CH), 126.3 (CH), 58.3 (C), 52.4 (CH3 × 2), 31.2 (CH2), 28.0 (CH2), 25.7 (CH2), 24.3 (CH2), 24.2 (CH2); MS (CI) m/z 227 [M+H]+, 195, 163 (base), 139, 119, 107, 99, 79; HRMS (CI) Found m/z 227.1282 [M+H]+, C12H19O4 requires 227.1283.

Preparation of (3R*,4R*)-3-(hex-5-enyl)-4-(prop-1-en-2-yl)cyclohexanone (4)
To a Grignard reagent prepared from 6-bromo-1-hexene (1.84 g, 11.3 mmol) and Mg (271.2 mg, 11.3 mmol) in THF (2 mL) a suspension of CuBr•Me2S was added (348 mg, 1.70 mmol) in THF (15 mL). Compound 3 (768.7 mg, 5.65 mmol) in THF (5.0 mL) was slowly added to this solution at -30 °C. The mixture was kept at -30~0 °C for 1 h. Sat. NH4Cl soln. and aq. ammonia were added and the mixture was stirred for 30 min. The solvent was evaporated and the mixture was extracted with Et2O. The organic layer was washed with water and brine, dried (MgSO4), and was then evaporated to afford a residue. The residue was purified by silica-gel column chromatography (hexane-EtOAc, 0-30%) to afford 4 (1.21 g, 93%). FTIR 1720, 1640 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.79 (1H, ddt, J = 17.1, 10.3, 6.3 Hz), 4.99 (1H, br d, J = 17.1 Hz), 4.93 (1H, br d, J = 10.3 Hz), 4.82 (2H, m), 2.52 (1H, dd, J = 13.8, 4.2 Hz), 2.39 (2H, m), 2.18 (1H, ddd, J = 11.7, 10.3, 3.3 Hz), 2.02-1.90 (4H, m), 1.81-1.68 (2H, m), 1.62 (3H, s), 1.54-1.28 (4H, m), 1.32-1.04 (2H, m); 13C NMR (75 MHz, CDCl3) δ 211.1 (C), 146.7 (C), 138.8 (CH), 114.4 (CH2), 112.4 (CH2), 50.4 (CH), 46.2 (CH2), 41.2 (CH2), 40.2 (CH), 33.9 (CH2), 33.6 (CH2), 31.6 (CH2), 29.0 (CH2), 25.3 (CH2), 18.8 (CH3); MS (Cl) m/z 221 [M+H]+ (base), 203, 165, 137, 111, 97, 68; HRMS (CI) Found m/z 221.1889 [M+H]+, C15H25O requires 221.1906.

Attempted RCM reaction of (3R*,4R*)-3-(hex-5-enyl)-4-(prop-1-en-2-yl)cyclohexanone (4)
To a stirred solution of 4 (61.4 mg, 0.28 mmol) in CH2Cl2 (270 mL) Grubbs II was added (25.0 mg, 0.028 mmol) in CH2Cl2 (10 mL). The mixture was heated under reflux for 1 h. The reaction mixture was quenched by bubbling air and was then evaporated. The residue was purified by silica-gel column chromatography (hexane-AcOEt 0-50%) to give dimer 6 (19.2 mg, 33%). FTIR 1720 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.34 (2H, dd, J = 3.9, 1.8 Hz), 4.81 (2H, d, J = 1.5 Hz), 4.80 (2H, s), 2.51 (2H, dd, J = 13.8, 3.6 Hz), 2.41-2.36 (4H, m), 2.17 (2H, dt, J = 10.8, 3.0 Hz), 2.06-1.89 (8H, m), 1.81-1.70 (4H, m), 1.55 (6H, s), 1.45-1.06 (10H, m); 13C NMR (75 MHz, CDCl3) δ 214.6 (C), 146.8 (C), 130.3 (CH), 112.4 (CH2), 50.5 (CH), 46.2 (CH2), 41.2 (CH2), 40.2 (CH), 34.0 (CH2), 32.5 (CH2), 31.6 (CH2), 29.7 (CH2), 25.3 (CH2), 18.8 (CH3); MS (Cl) m/z 413 [M+H]+ (base), 395, 137, 58; HRMS (CI) Found m/z 413.3392 [M+H]+, C28H45O2 requires 413.3420.

Preparation of (7R*,8R*)-7-(hex-5-enyl)-8-(prop-1-en-2-yl)-1,4-dioxaspiro[4.5]decane (7)
Ketone 4 (263 mg, 1.19 mmol) was treated with ethylene glycol (0.1 mL, 1.79 mmol) and TsOH (26 mg) in PhH (40 mL) under reflux with the aid of the Dean-Stark water separator for 12 h. The mixture was washed with sat. aq. NaHCO3 soln. and brine and then evaporated. The residue was purified by silica-gel column chromatography (hexane-EtOAc, 0-20%) to afford 7 (193.7 mg, 73%). FTIR 1640 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.79 (1H, m), 4.99 (1H, d, J = 16.7 Hz), 4.95 (1H, d, J = 10.0 Hz), 4.75 (2H, m), 3.96 (4H, m), 2.10-1.80 (4H, m), 1.80-1.50 (8H, m), 1.61 (3H, s), 1.40-1.10 (4H, m); MS (CI) m/z 265 [M+H]+, 181 (base), 99; HRMS (CI) Found m/z 265.2157 [M+H]+, C17H29O2 requires 265.2168.

Attempted RCM reaction of (7R*,8R*)-7-(hex-5-enyl)-8-(prop-1-en-2-yl)-1,4-dioxaspiro[4.5]decane (7)
To a stirred solution of ketal 7 (32.7 mg, 0.12 mmol) in PhH (10 mL) Grubbs II was added (11.8 mg, 0.012 mmol) in PhH (2 mL). The mixture was heated at 60 overnight. The mixture was quenched by bubbling air and was then evaporated. The residue was purified by silica-gel column chromatography (hexane-AcOEt 0-50%) to give 7 (9.5 mg) and 8 (4.2 mg, 15%). 1H NMR (300 MHz, CDCl3) δ 5.46 (1H, t, J = 9.9 Hz), 3.96 (4H, s), 1.85-1.62 (5H, m), 1.67 (3H, s), 1.64-1.36 (9H, m); 13C NMR (75 MHz, CDCl3) δ 138.5 (C), 124.0 (CH), 109.3 (C), 64.3 (CH2), 64.2 (CH2), 48.7 (CH), 43.5 (CH2), 35.3 (CH), 35.0 (CH2), 33.4 (CH2), 27.8 (CH2), 24.5 (CH2), 24.2 (CH2), 23.1 (CH3); MS (Cl) m/z 223 [M+H]+ (base), 222, 203, 160, 121, 89, 44; HRMS (CI) Found m/z 223.1690 [M+H]+, C14H23O2 requires 223.1698.

Preparation of (3R*,4R*)-4-(prop-1-en-2-yl)-3-((trimethylsilyl)ethynyl)cyclohexanone (10)
A solution of trimethylsilylacetylene (136.5 mg, 1.39 mmol) in Et2O (2 mL) was treated with nBuLi (in hexane, 1.59 M, 0.87 mL, 1.39 mmol) at 0 °C for 1.5 h. Me2AlCl (in hexane, 1 M, 1.33 mL, 1.33 mmol) was added to this solution at -40 °C and the mixture (A) was stirred for 4 h. In another flask (B), a solution of Ni(acac)2 (35.5mg, 0.14 mmol) in Et2O (1.5 mL) was treated with DIBAL (in toluene, 1 M 0.14 mL, 0.14 mmol) at 0 °C for 10 min. The mixture (A) was added to the flask (B) at -25 °C followed by the addition of a solution of 3 (94.2 mg, 0.67 mmol) in Et2O (4 mL) over 1 h at -30 °C and then the mixture was stirred for 3 h. Saturated aq. KH2PO4 soln. was added at rt and the mixture was stirred for 15 min. Sulfuric acid (10%) was added and the mixture was extracted with Et2O. The organic layer was washed with saturated NaHCO3 and brine, dried (MgSO4), and was then evaporated to afford a residue. The residue was purified by silica-gel chromatography (hexane-EtOAc, 0-5%) to give (10) (112.9 mg, 72%). FTIR 2160, 1720, 1640 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.89 (1H, s), 4.86 (1H, s), 2.70 (1H, m), 2.50-2.36 (4H, m), 2.01 (1H, m), 1.75 (3H, s), 1.72 (2H, m), 0.12 (9H, s); MS (Cl) m/z 235 [M+H]+, 211 (base), 89, 73; HRMS (CI) Found m/z 235.1523 [M+H]+, C14H23OSi requires 235.1518.

Preparation of (3R*,4R*)-3-ethynyl-4-(prop-1-en-2-yl)cyclohexanone (11)
To a stirred solution of 10 (145.0 mg, 0.62 mmol) in THF (2 mL) TBAF was added (in THF, 1 M, 1.24 mL, 1.24 mmol) at 0 °C and the mixture was stirred for 3 h. Water was added and the mixture was extracted with Et2O. The organic layer was washed with brine, dried (MgSO4), and was then evaporated to afford a residue. The residue was purified by silica-gel column chromatography (hexane-EtOAc, 0-10%) to give 11 (75.3 mg, 75%). FTIR 3300, 2120, 1720, 1640 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.95 (1H, s), 4.93 (1H, s), 2.72 (2H, m), 2.55-2.39 (4H, m), 2.17 (1H, d, J = 2.1 Hz), 2.03 (1H, m), 1.77 (3H, s), 1.72 (1H, m); 13C NMR (75 MHz, CDCl3) δ 208.3 (C), 145.5 (C), 112.6 (CH2), 84.6 (C), 70.7 (CH), 49.6 (CH), 46.3 (CH2), 40.6 (CH2), 33.6 (CH), 30.4 (CH2), 19.7 (CH3); MS (Cl) m/z 163 [M+H]+ (base), 145, 121, 89; HRMS (CI) Found m/z 163.1078 [M+H]+, C11H15O requires 163.1081.

Preparation of (3R*,4R*)-3-(1-bromovinyl)-4-(prop-1-en-2-yl)cyclohexanone (12)
To a stirred solution of 11 (147.0 mg, 0.91 mmol) in CH2Cl2 (2.7 mL) and hexane (2.7 mL), B-Br-9-BBN was added (in hexane, 1 M, 1.82 mL, 1.82 mmol) at -25 °C over 1 h and the mixture was stirred at 0 °C for 6 h. AcOH was added and the mixture was stirred for 1 h at 0 °C. H2O2 (30%) was added and the mixture was then extracted with Et2O. The organic layer was washed with saturated aq. Na2SO3 soln. and brine, dried (MgSO4), and was then evaporated to afford a residue. The residue was purified by silica-gel column chromatography (hexane-EtOAc, 0-5%) to give 12 (187.2 mg, 85%). FTIR 1720, 1640 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.61 (1H, d, J = 1.5 Hz), 5.42 (1H, d, J = 1.5 Hz), 4.88 (1H, s), 4.86 (1H, s), 2.73-2.60 (2H, m), 2.47-2.38 (2H, m), 1.92-1.84 (2H, m), 1.68 (3H, s), 1.58-1.52 (2H, m); 13C NMR (75 MHz, CDCl3) δ 209.2 (C), 144.6 (C), 136.7 (C), 117.9 (CH2) , 113.3 (CH2), 51.0 (CH), 47.6 (CH2), 41.8 (CH2), 40.7 (CH2), 30.0 (CH2), 27.1 (CH3) MS (Cl) m/z 245, 243 [M+H]+, 189, 187, 163 (base), 121; HRMS (CI) Found m/z 243.1402 [M+H]+, C11H16OBr requires 243.1410.

Preparation of (7R*,8R*)-7-(1-bromovinyl)-8-(prop-1-en-2-yl)-1,4-dioxaspiro[4.5]decane (13)
To a stirred solution of 12 (664 mg, 2.66 mmol) in CH2Cl2 (26 mL), TMSOTf (0.02 mL, 0.08 mmol) and 1,2-bis(trimethylsilyloxy)ethane (0.65 mL, 2.26 mmol) were added at -78 °C. The mixture was stirred for 2 h before quenching by the addition of pyridine (3 drops) at rt. The mixture was extracted with Et2O. The organic layer was washed with saturated aq. NaHCO3 and brine, dried (MgSO4) and then evaporated to afford a residue. The residue was purified by silica-gel column chromatography (hexane-EtOAc, 0-2%) to give 13 (605 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 5.59 (1H, d, J = 1.5 Hz), 5.38 (1H, d, J = 1.5 Hz), 4.80 (1H, s), 4.78 (1H, s), 3.96 (4H, s), 2.54 (1H, td, J = 9.9, 4.8 Hz), 2.21 (1H, td, J = 9.9, 6.0 Hz), 1.82-1.74 (4H, m), 1.70-1.57 (2H, m), 1.66 (3H, s); 13C NMR (75 MHz, CDCl3) δ 146.3 (C), 138.5 (C), 117.0 (CH2), 112.4 (CH2), 108.3 (C), 64.4 (CH2), 64.3 (CH2), 48.6 (CH2), 48.1 (CH), 40.1 (CH2), 34.5 (CH2), 28.4 (CH2), 22.2 (CH3); MS (Cl) m/z 289, 287 [M+H]+, 207, 205, 203, 99 (base), 86; HRMS (CI) Found m/z 287.0631 [M+H]+, C13H20O2Br requires 287.0646.

Preparation of 2-((7R*,8R*)-8-(prop-1-en-2-yl)-1,4-dioxaspiro[4.5]decan-7-yl)hepta-1,6-dien-3-ol (14)
A solution of 13 (150 mg, 0.52 mmol) in Et2O (6 mL) was treated with tBuLi (in hexane, 1.59 M, 0.98 mL, 1.58 mmol) at -78 °C. The mixture was stirred for 15 min and 4-pentenal (66 mg, 0.79 mmol) was added. The reaction temperature was raised to -30 °C for 3 h with stirring. Saturated aq. NaHCO3 soln. was added and the mixture was extracted with Et2O. The organic layer was washed with brine, dried (MgSO4), and then evaporated to afford a residue. The residue was purified by silica-gel column chromatography (hexane-EtOAc, 0-30%) to give 14 (13 mg, 56%). FTIR 3450, 1640 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.84 (m), 5.18 (m), 5.14 (m), 5.08-4.92 (m), 4.97 (m), 4.92 (m), 4.74 (m), 4.66 (s), 4.03 (dd, J = 5.1, 2.7 Hz), 3.96 (s), 2.48 (m), 2.30-2.01 (m), 1.88-1.69 (m), 1.67 (s), 1.65-1.45 (m); 13C NMR (75 MHz, CDCl3) δ 155.5 (C), 154.4 (C), 149.4 (C), 147.9 (C), 138.5 (CH), 138.4 (CH), 114.7 (CH × 2), 111.9 (CH2), 111.7 (CH2), 109.1 (CH2), 108.6 (C), 74.0 (CH), 72.7 (CH), 64.3 (CH2), 64.2 (CH2), 50.7 (CH), 49.2 (CH), 42.5 (CH2), 42.2 (CH2), 42.2 (CH). 41.9 (CH), 35.4 (CH2), 34.9 (CH2), 34.7 (CH2), 34.6 (CH2), 30.2 (CH2), 30.1 (CH2), 29.6 (CH2), 29.4 (CH2), 20.3 (CH3), 20.0 (CH3) [signals overlapped due to the presence of the diastereoisomers]; MS (Cl) m/z 293 [M+H]+, 275, 231, 213, 181, 147, 99 (base), 86; HRMS (CI) Found m/z 293.2133 [M+H]+, C18H29O3 requires 293.2117.

Preparation of 2-((7R*,8R*)-8-(prop-1-en-2-yl)-1,4-dioxaspiro[4.5]decan-7-yl)-3-triethylsilyloxy-hepta- 1,6-diene (15)
To a stirred solution of 14 (31.5 mg, 0.11 mmol) in CH2Cl2 (5.0 mL) iPr2NEt was added (71.1 mg, 0.55 mmol) followed by TESOTf (87.2 mg, 0.33 mmol) at 0 °C. The temperature was gradually raised to rt with stirring overnight. Saturated aq. NaHCO3 soln. was added and the mixture was extracted with Et2O. The organic layer was washed with brine, dried (MgSO4), and then evaporated to afford a residue. The residue was purified by silica-gel column chromatography (hexane-EtOAc, 0-5%) to give 15 (41.6 mg, 94%). 1H NMR (300 MHz, CDCl3) δ 5.82 (m), 5.17 (m), 5.14 (m), 5.03 (m), 4.95 (m), 4.90 (m), 4.87 (m), 4.71 (m), 4.68 (m), 4.03 (dd, J = 5.7, 5.4 Hz), 3.98-3.93 (m), 2.25-2.14 (m), 2.11-1.98 (m), 1.98-1.86 (m), 1.82-1.77 (m), 1.74-1.67 (m), 1.65 (s), 1.51-1.34 (m), 0.94 (t, J = 7.8 Hz), 0.57 (q, J = 7.8 Hz); 13C NMR (75 MHz, CDCl3) δ 153.6 (C), 153.0 (C), 147.8 (C), 147.7 (C), 139.0 (CH), 144.1 (CH2), 109.8 (CH2), 109.4 (CH2), 108.8 (C), 108.6 (C), 75.7 (CH), 73.4 (CH), 64.4 (CH2), 64.2 (CH2), 50.3 (CH), 48.2 (CH), 43.6 (CH2), 43.2 (CH2), 40.9 (CH), 40.4 (CH), 35.5 (CH2), 35.0 (CH2), 34.9 (CH2), 34.7 (CH2), 30.2 (CH2), 29.0 (CH2), 21.4 (CH3), 20.5 (CH3), 7.0 (CH3 × 3), 4.9 (CH2 × 3) [signals overlapped due to the presence of the diastereoisomers]; MS (Cl) m/z 406 [M]+, 377, 351, 275 (base), 199, 155, 99, 87; HRMS (CI) Found m/z 406.2913 [M]+, C24H42O3Si requires 406.2904.

RCM reaction of 2-((7R*,8R*)-8-(prop-1-en-2-yl)-1,4-dioxaspiro[4.5]decan-7-yl)-3-triethylsilyloxy- hepta-1,6-diene (15)
A solution of 15 (32.9 mg, 0.082 mmol) in CH2Cl2 (160 mL) was treated with Grubbs II (14.7 mg, 0.016 mmol) in CH2Cl2 (4 mL) under reflux for 1 h. The solvent was evaporated and the residue was purified by silica-gel column chromatography (hexane-toluene, 0-90%) to give 16 (12.6 mg, 41%), 17 (10 mg, 32%).
16; 1H NMR (300 MHz, CDCl3) δ 5.32 (1H, br t, J = 7.2 Hz), 5.13 (1H, s), 4.82 (1H, d, J = 1.8 Hz), 4.03-4.00 (1H, m), 3.97 (4H, s), 2.50-2.37 (2H, m), 2.19-2.16 (2H, m), 1.93-1.90 (1H, m), 1.85-1.77 (3H, m), 1.72-1.63 (2H, m), 1.55 (3H, s), 1.52-1.34 (2H, m), 0.93 (9H, t, J = 8.1 Hz), 0.55 (6H, q, J = 8.1 Hz); 13C NMR (75 MHz, CDCl3) δ 156.3 (C), 138.9 (C), 124.5 (CH), 112.7 (C), 108.8 (C), 70.9 (CH), 64.4 (CH2), 64.2 (CH2), 47.5 (CH), 42.6 (CH2), 40.7 (CH2), 40.0 (CH2), 34.7 (CH2), 26.5 (CH2), 23.5 (CH2), 18.9 (CH3), 6.9 (CH3 × 3), 5.0 (CH2 × 3); MS (Cl) m/z 379 [M+H]+, 349, 247, 210 (base), 99, 87, 59; HRMS (CI) Found m/z 379.2668 [M+H]+, C22H39O3Si requires 379.2668.
17; 1H NMR (300 MHz, CDCl3) δ 5.48 (1H, br s), 4.67 (1H, d, J = 1.5 Hz), 4.63 (1H, s), 3.94 (1H, m), 3.93 (4H, s), 2.46 (1H, td, J = 8.7, 3.3 Hz), 2.39-2.31 (1H, m), 2.21-2.08 (3H, m), 2.01 (1H, dt, J = 8.7, 3.3 Hz), 1.77 (1H, m), 1.71-1.62 (4H, m), 1.57 (3H, s), 1.55-1.46 (1H, m), 0.99 (9H, t, J = 7.8 Hz), 0.63 (6H, q, J = 7.8 Hz); 13C NMR (75 MHz, CDCl3) δ 148.7 (C), 148.6 (C), 126.4 (CH), 110.8 (CH2), 108.6 (C), 80.5 (CH), 64.3 (CH2 × 2), 50.4 (CH), 41.9 (CH2), 38.0 (CH2). 35.1 (CH2), 34.3 (CH2), 30.1 (CH), 29.7 (CH3), 20.4 (CH2), 6.9 (CH3 × 3), 5.0 (CH2 × 3); MS (Cl) m/z 378 [M]+, 349, 289, 247 (base), 210, 155, 99, 89, 75, 61; HRMS (CI) Found m/z 378.2590 [M]+, C22H38O3Si requires 378.2590.

Preparation of (1R*,3S*,8R*)-11-ethylenedioxy-2-exomethylene-7-methylbicyclo[6.4.0]-6-dodecen-3-ol (18)
A solution of 16 (7.8 mg, 0.021 mmol) in THF (1 mL) was treated with TBAF (in THF, 1 M, 0.06 mL, 0.06 mmol) at 0 °C for 6 h. Water was added and the mixture was extracted with Et2O. The organic layer was washed with brine, dried (MgSO4), and then evaporated to afford a residue. The residue was purified by silica-gel column chromatography (hexane-EtOAc, 0-50%) to give 18 (4.7 mg, 89%). FTIR 3440, 1640 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.33 (1H, br t, J = 7.8 Hz), 5.15 (1H, s), 4.90 (1H, s), 4.14 (1H,
dd, J = 10.8, 7.8 Hz), 3.99-3.97 (4H, m), 2.48-2.35 (2H, m), 2.27-2.18 (1H, m), 2.06-1.97 (2H, m), 1.86-1.76 (3H, m), 1.72-1.58 (4H, m), 1.56 (3H, s), 1.49-1.40 (1H, m); 13C NMR (100 MHz, CDCl3) δ 158.3 (C), 139.2 (C), 124.4 (CH), 111.8 (CH2), 108.6 (CH), 70.9 (CH), 64.5 (CH2), 64.3 (CH2), 47.3 (CH), 40.5 (CH2), 40.2 (CH2), 39.9 (CH), 34.7 (CH2), 26.3 (CH2), 23.6 (CH2), 18.9 (CH3); MS (Cl) m/z 264 [M+H]+, 247 (base), 202, 169, 99, 86, 56; HRMS (CI) Found m/z 265.1804 [M+H]+, C16H25O3 requires 265.1804.

Preparation of (1R*,2R*)-2-allyl-1-(1-((7R*,8R*)-8-(prop-1-en-2-yl)-1,4-dioxaspiro[4.5]decan-7- yl)vinyl)cyclopentanol (19a) and (1S*,2S*)-2-allyl-1-(1-((7R*,8R*)-8-(prop-1-en-2-yl)-1,4- dioxaspiro[4.5]decan-7-yl)vinyl)cyclopentanol (19b)
A solution of 13 (150 mg, 0.52 mmol) in Et2O (5 mL) was treated with tBuLi (in pentane, 1.59 M, 0.98 mL, 1.56 mmol) at -50 °C for 20 min. A solution of 2-allylcyclopentanone (96.7 mg, 0.78 mmol) in Et2O (2 mL) was added and the mixture was stirred for 8 h. Saturated aq. NaHCO3 soln. was added and the mixture was extracted with Et2O. The organic layer was washed with brine, dried (MgSO4), and then evaporated to afford a residue. The residue was purified by silica-gel column chromatography (hexane-EtOAc, 0-40%) to give 19a (42.2 mg, 25%) and 19b (21.3 mg, 12%).
19a: FTIR 3490, 1640 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.77 (1H, m), 5.24 (1H, s), 5.02 (1H, s), 5.01 (1H, d, J = 17.1 Hz), 4.95 (1H, d, J = 10.2 Hz), 4.77 (1H, s), 4.70 (1H, s), 3.96-3.91 (4H, m), 2.44 (1H, td, J = 12.0, 4.2 Hz), 2.24-2.02 (4H, m), 2.00-1.69 (7H, m), 1.69 (3H, s), 1.66-1.38 (6H, m); 13C NMR (75 MHz, CDCl3) δ 154.9 (C), 148.6 (C), 138.1 (CH), 114.8 (CH2), 112.3 (CH2), 109.8 (CH2), 108.6 (C), 84.8 (C), 64.4 (CH2), 64.2 (CH2), 50.0 (CH), 45.5 (CH), 44.2 (CH2), 40.1 (CH), 39.5 (CH2), 34.8 (CH2), 33.5 (CH2), 29.5 (CH2), 29.2 (CH2), 21.9 (CH3), 23.1 (CH2); MS (Cl) m/z 332 [M]+, 315 (base), 270, 253, 229, 213, 181, 99, 56; HRMS (CI) Found m/z 332.2343 [M]+, C21H33O3 requires 332.2352.
19b: FTIR 3480, 1640 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.75 (1H, m), 5.27 (1H, s), 5.02 (1H, s), 4.98 (1H, d, J = 17.0 Hz), 4.92 (1H, d, J = 9.9 Hz), 4.74 (1H, s), 4.69 (1H, s), 3.95 (4H, s), 2.36-2.09 (4H, m), 1.99-1.60 (11H, m), 1.67 (3H, s), 1.50-1.37 (3H, m); 13C NMR (75 MHz, CDCl3) δ 154.9 (C), 147.9 (C), 138.2 (CH), 114.8 (CH2), 112.2 (CH2), 110.0 (CH2), 108.7 (C), 85.1 (C), 64.4 (CH2), 64.2 (CH2), 49.1 (CH), 45.7 (CH), 45.2 (CH2), 41.0 (CH), 39.8 (CH2), 34.8 (CH2), 33.0 (CH2), 30.1 (CH2), 28.9 (CH2), 21.8 (CH3), 21.3 (CH2); MS (Cl) m/z 333, [M+H]+, 315 (base), 271, 253, 181, 99, 69, 51; HRMS (CI) Found m/z 333.2430 [M+H]+, C21H33O3 requires 333.2429.

Preparation of (1R*,2R*)-2-allyl-1-(1-((7R*,8R*)-8-(prop-1-en-2-yl)-1,4-dioxaspiro[4.5]decan-7- yl)vinyl)cyclopentanol triethylsilyl ether (21a)
A solution of 19a (20 mg, 0.06 mmol) in CH2Cl2 (1.0 mL) was treated with iPr2NEt (46.5 mg, 0.36 mmol) at 0 °C for 5 min followed by the addition of TESOTf (47.6 mg, 0.18 mmol). The temperature of the mixture was gradually raised to rt overnight. Saturated aq. NaHCO3 was added and the mixture was extracted with Et2O. The organic layer was washed with brine, dried (MgSO4), and then evaporated to afford a residue. The residue was purified by silica-gel column chromatography (hexane-toluene, 0-90%) to give 21a (25.6 mg, 97%). 1H NMR (300 MHz, CDCl3) δ 5.78 (1H, ddt, J = 17.0, 10.0, 6.9 Hz), 5.33 (1H, s), 5.04 (1H, d, J = 1.2 Hz), 4.95 (1H, dq, J = 17.0, 2.4 Hz), 4.88 (1H, dq, J = 10.0, 1.2 Hz), 4.74 (1H, s), 4.67 (1H, s), 3.90 (4H, m), 2.18-2.00 (4H, m), 1.90-1.68 (8H, m), 1.66 (3H, s), 1.64-4.36 (5H, m), 0.94 (9H, t, J = 8.1 Hz), 0.61 (6H, q, J = 8.1 Hz); 13C NMR (75 MHz, CDCl3) δ 154.0 (C), 147.0 (C), 139.2 (CH), 114.0 (CH2), 112.7 (CH2), 111.4 (CH2), 109.3 (C), 67.9 (C), 64.4 (CH2), 64.1 (CH2), 50.1 (CH), 48.4 (CH), 44.8 (CH2), 40.5 (CH), 36.7 (CH2), 35.0 (CH2), 32.9 (CH2), 29.8 (CH2), 29.4 (CH2), 22.2 (CH3), 21.9 (CH2), 7.36 (CH3 × 3), 6.73 (CH2 × 3); MS (Cl) m/z 446 [M]+, 417, 363, 315, 279, 154 (base); HRMS (CI) Found m/z 446.3208 [M]+, C27H46O3Si requires 446.3217.

Preparation of (1S*,2S*)-2-allyl-1-(1-((7R*,8R*)-8-(prop-1-en-2-yl)-1,4-dioxaspiro[4.5]decan-7- yl)vinyl)cyclopentanol triethylsilyl ether (21b)
A solution of 19b (9.2 mg, 0.028 mmol) in CH2Cl2 (1.0 mL) was similarly treated with iPr2NEt (10.7 mg, 0.083 mmol) and TESOTf (14.8 mg, 0.056 mmol) to afford (21b) (9.2 mg, 74%). 1H NMR (300 MHz, CDCl3) δ 5.70 (1H, ddt, J = 17.1, 11.1, 7.5 Hz), 5.31 (1H, s), 5.03 (1H, s), 4.89 (1H, d, J = 17.1 Hz), 4.83 (1H, d, J = 11.1 Hz), 4.73 (1H, s), 4.66 (1H, s), 3.95 (4H, s), 2.23 (1H, t, J = 11.1 Hz), 2.13-2.03 (3H, m), 1.93 (1H, dt, J = 13.8, 2.4 Hz), 1.82-1.71 (6H, m), 1.65 (3H, s), 1.63-1.56 (2H, m), 1.45-1.26 (4H, m), 0.94 (9H, t, J = 7.5 Hz), 0.58 (6H, q, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ 153.3 (C), 147.5 (C), 139.2 (CH), 114.1 (CH2), 112.2 (CH2), 111.5 (CH2), 108.7 (C), 87.7 (C), 64.4 (CH2), 64.3 (CH2), 48.6 (CH), 47.7 (CH), 45.1 (CH2), 41.1 (CH), 36.8 (CH2), 34.8 (CH2), 32.5 (CH2), 30.3 (CH2), 28.9 (CH2), 21.8 (CH2), 21.6 (CH2), 7.4 (CH3 × 3), 6.7 (CH2 × 3); MS (Cl) m/z 447 [M+H]+, 446, 417, 371, 315 (base), 253, 239, 207, 154, 99, 89, 53; HRMS (CI) Found m/z 447.3284 [M+H]+, C27H47O3Si requires 447.3294.

RCM reaction of (1R*,2R*)-2-allyl-1-(1-((7R*,8R*)-8-(prop-1-en-2-yl)-1,4-dioxaspiro[4.5]decan-7- yl)vinyl)cyclopentanol triethylsilyl ether (21a)
A solution of 21a (7.3 mg, 0.016 mmol) in CH2Cl2 (16 mL) was heated under reflux with Grubbs II (5.4 mg, 0.0048 mmol) for 25 h. The solvent was evaporated and the residue was separated by silica-gel column chromatography (hexane-AcOEt, 5%) to give a mixture of 22a and 24 (3.5 mg), which was further purified by HPLC (hexane-AcOEt, 2%) to give 22a and 24.
22a: 1H NMR (300 MHz, CDCl3) δ 5.37 (1H, br t, J = 7.8 Hz), 5.00 (1H, s), 4.74 (1H, s), 4.00-3.89 (4H, m), 2.51 (1H, br s), 2.18 (1H, br s), 1.96 (1H, br d, J = 11.1 Hz), 1.85-1.79 (2H, m), 1.56 (3H, s), 0.97 (9H, t, J = 7.8 Hz), 0.68 (6H, q, J = 7.8 Hz) [protons could not be assigned due to slow rotation]; MS (Cl) m/z 419 [M+H]+ (base), 418, 389, 287, 249, 89; HRMS (CI) Found m/z 419.2985 [M+H]+, C25H43O3Si requires 419.2982.
24: 1H NMR (600 MHz, CDCl3) δ 5.43 (1H, ddd, J = 15.6, 7.4, 1.1 Hz), 5.28 (1H, dqd, J = 15.6, 6.6, 0.8 Hz), 5.27 (1H, s), 4.96 (1H, s), 4.72 (1H, s), 4.66 (1H, s), 3.95-3.92 (4H, m), 2.22 (1H, m), 2.16 (1H, m), 2.14 (1H, m), 2.07 (1H, m), 1.94 (1H, dt, J = 13.2, 3.0 Hz), 1.78 (1H, m), 1.76 (2H, m), 1.70 (2H, m), 1.66 (3H, m), 1.65 (3H, s), 1.62 (3H, d, J = 6.6 Hz), 1.52 (1H, m), 1.37 (1H, m), 0.94 (9H, q, J = 7.5 Hz), 0.61 (6H, t, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ 154.1 (C), 147.1 (C), 130.9 (CH), 125.0 (CH), 112.6 (CH2), 111.0 (CH2), 108.8 (CH2), 88.4 (C), 64.4 (CH2), 64.2 (CH2), 52.1 (CH), 50.1 (CH), 44.6 (CH2), 40.4 (CH), 36.9 (CH2), 34.8 (CH2), 30.3 (CH2), 29.8 (CH2), 22.1 (CH3), 22.0 (CH2), 18.3 (CH3), 7.3 (CH3 × 3), 6.7 (CH2 × 3); MS (Cl) m/z 447 [M+H]+, 446, 417, 363, 315 (base), 253, 154, 99, 86; HRMS (CI) Found m/z 447.3271 [M+H]+, C27H47O3Si requires 447.3295.

Preparation of (1R*,3R*,8R*,12R*)-5-ethylenedioxy-2-exomethylene-9-methyltricyclo[10.3.0.03,8]-9- pentadecen-1-ol (25a) and (1R*,3R*,8R*,11R*)-5-ethylenedioxy-2-exomethylene-9-methyltricyclo- [9.3.0.03,8]-9-tetradecen-1-ol (26)
A partially separated fraction (22.1 mg, 0.05 mmol) of the RCM reaction products from 21a was dissolved in THF (1 mL) and TBAF (in THF, 1 M, 0.1 mL, 0.1 mmol) was added at 0 °C. The mixture was stirred overnight. Water was added and the mixture was extracted with Et2O. The organic layer was washed with brine, dried (MgSO4), and was then evaporated to afford a residue. The residue was separated by silica-gel column chromatography (hexane-EtOAc, 0-50%) to give 25a (2.1 mg, 14%) and 26 (1.0 mg, 7%).
25a: FTIR 3480, 1640 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.42-5.23 (2H, m), 4.86 (1H, s), 3.96 (4H, s), 2.74-1.62 (15H, m), 1.57 (3H, s), 1.25-0.94 (4H, m); MS (Cl) m/z 305 [M+H]+, 287 (base), 242, 205, 161, 99, 89; HRMS (CI) Found m/z 305.2116 [M+H]+, C19H29O3 requires 305.2116.
26: FTIR 3380 cm-1; 1H NMR (600 MHz, CDCl3) δ 5.40 (1H, s), 5.07 (1H, s), 4.81 (1H, d, J = 1.6 Hz), 4.01-3.88 (4H, m), 2.54 (1H, ddd, J = 14.6, 10.2, 3.8 Hz), 2.48 (1H, br t, J = 10.0 Hz), 2.16 (1H, m), 2.13 (1H, m), 2.08 (1H, m), 1.92 (1H, m), 1.89 (3H, s), 1.86 (1H, m), 1.85 (1H, m), 1.84 (1H, m), 1.80 (2H, m), 1.70 (1H, m), 1.69 (1H, m), 1.68 (1H, m), 1.64 (1H, m); 13C NMR (150 MHz, CDCl3) δ 157.6 (C), 143.6 (C), 128.4 (C), 109.3 (C), 106.8 (CH2), 81.9 (C), 64.3 (CH2), 64.1 (CH2), 49.5 (CH), 43.1 (CH), 38.9 (CH2), 37.8 (CH2), 36.9 (CH), 33.8 (CH2), 31.8 (CH2), 26.5 (CH2), 23.4 (CH3), 22.0 (CH2); MS (Cl) m/z 291 [M+H]+, 273, 89 (base); HRMS (CI) Found m/z 291.1966 [M+H]+, C18H27O3 requires 291.1961.

RCM reaction of (1S*,2S*)-2-allyl-1-(1-((7R*,8R*)-8-(prop-1-en-2-yl)-1,4-dioxaspiro[4.5]decan-7- yl)vinyl)cyclopentanol triethylsilyl ether (21b)
A solution of 21b (16.2 mg, 0.036 mmol) in CH2Cl2 (72 mL) was treated with Grubbs II (9.7 mg, 0.011 mmol) under reflux for 6 h. The solvent was evaporated and the residue was separated by silica-gel column chromatography (hexane-AcOEt, 2%) to give 22b (6.2mg, 61%). FTIR 1610, 1000 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.39 (1H, t, J = 8.0 Hz), 4.72 (1H, s), 4.70 (1H, s), 3.95 (4H, s), 3.17 (1H, td, J = 11.4, 3.6 Hz), 2.56 (1H, td, J = 10.2, 3.0 Hz), 2.47 (1H, td, J = 13.2, 1.8 Hz), 2.40 (1H, t, J = 13.2 Hz), 2.30 (1H, m), 1.93 (1H, m), 1.76 (1H, m), 1.69-1.60 (8H, m), 1.56 (3H, s), 1.49-1.38 (1H, m), 1.42 (1H, m), 1.02 (9H, t, J = 7.8 Hz), 0.73 (6H, q, J = 7.8 Hz); 13C NMR (75 MHz, CDCl3) δ 158.2 (C), 139.3 (C), 125.6 (C), 111.1 (C), 109.0 (C), 89.4 (C), 64.2 (CH2), 64.0 (CH2), 59.0 (CH), 50.9 (CH), 42.4 (CH2), 41.1 (CH2), 38.3 (CH), 34.1 (CH2), 32.2 (CH2), 26.9 (CH2), 25.0 (CH2), 21.3 (CH2), 19.3 (CH3), 7.6 (CH3 × 3), 6.9 (CH2 × 3); MS (Cl) m/z 418 [M]+, 389, 375, 343, 329, 287 (base), 243; HRMS (CI) Found m/z 418.2910 [M]+, C25H42O3 Si requires 418.2903.

ACKNOWLEDGEMENTS
We thank Dr. Masami Tanaka and Miss Yasuko Okamoto, of Tokushima Bunri University, for measurement of 600 MHz NMR and MS spectra, respectively. This study was financially supported in part by a MEXT.HAITEKU, 2003-2007.

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