Synthesis of α-Methylene-γ-lactone Structure by Cyclization of ω-Formylallylsilane in Water

Abstract

Surfactant-type protonic acid-promoted intramolecular cyclization of functionalized allylsilanes was studied in water for the synthesis of α-methylene-γ-lactone compounds. ω-Formyl-β-(acetoxymethyl)allylsilane afforded carbocyclic compounds in good yields, while the cyclization product was not obtained from the corresponding β-ethoxycarbonyl derivative. It was found that (Z)-β-(acetoxymethyl)allylsilane predominantly afforded the cis-product, while (E)-β-(acetoxymethyl)allylsilane afforded both cis- and trans-products at a ratio of almost 1 : 1. The stereoselectivity of the cyclization reaction was almost the same as a protonic acid-promoted reaction in CH₂Cl₂ and was explained by an interaction between the C(Si)–C(alkene) bond and the carbonyl moiety. The cyclization products were converted to α-methylene-γ-lactone compounds.

α-Methylene-γ-lactone (4,5-dihydro-3-methylene-2(3H)-furanone) structures fused to various carbocycles are often found in natural terpenoids, such as germacranolides, guaianolides, and eudesmanolides, and some of them have biological activities including anti-inflammatory, antibacterial, and cytotoxic properties.^1–3) The two rings, carbocycle and α-methylene-γ-lactone, can be synthesized at once by acid- or fluoride-promoted intramolecular cyclization of β-(ethoxycarbonyl)allylsilane with aldehyde^4,5) (Chart 1). During the 1990 s, we^6–9) and Nishitani’s group^10–14) independently synthesized various α-methylene-γ-lactone compounds by this method. A non-conjugated moiety, β-(acetoxymethyl)allylsilane, was also used to synthesize large-size ring compounds.¹⁵⁾ β-(Ethoxycarbonyl)allylsilane and its derivatives are carbon-1,3-dipole equivalents; that is, the γ-carbon of allylsilane acts as a nucleophile and the carbonyl carbon as an electrophile. A variety of carbon 1,3-dipole compounds are known to be versatile building blocks in organic synthesis.^16–18) We prepared some related compounds, such as bicyclo[4.3.0]nonanes,^19,20) spiro[4.5]decanes,^21,22) and cycloundecanes^23,24) by related reactions, such as carbobicyclization, Nazarov reaction, and homo-Cope reaction, respectively.

Chart 1. Intramolecular Cyclization of ω-Formyl-β-(ethoxycarbonyl)-allylsilane

Organic reactions in water, in which the use of harmful organic solvents can be avoided, have recently been extensively developed.^25–29) Among them, C–C bond formation in water is especially important because many common reactions, such as Grignard and Wittig reactions, utilize various carbanions or their equivalents, but carbanions are not stable in water. Allylsilanes are water-stable carbanion equivalents. Thus, it is useful to study the above carbocyclization reactions in water. In organic solvents, the cyclization reactions have largely been carried out under aprotic conditions using TiCl₄, BF₃·OEt₂, and other Lewis acid catalysts.^{8–15,19–22)} These common Lewis acids are not applicable for use in water. Instead, surfactant-type protonic acids such as dodecylbenzenesulfonic acid (DBSA) are useful.^26,28,30) Here, we report that the cyclization reaction proceeds in good yield using DBSA as a surfactant-type protonic acid catalyst.

Results and Discussion

We initially studied the cyclization of 1, which is known to cyclize by treatment with a Lewis acid in organic solvents in good yields.^10,11) Compound 1 was prepared as a mixture of Z- and E-isomers (ratio ca. 2 : 1) from 1,6-hexanediol according to previous reports^10,11,19) with a slight modification (Chart 2). Namely, monoprotection of 1,6-hexanediol with tetrahydropyranyl (THP) group followed by Swern oxidation produced 2. The β-(ethoxycarbonyl)allylsilane moiety was introduced by Horner–Wadsworth–Emmons reaction to afford 3, which was converted to 1 by deprotection and oxidation. When 1 was treated with DBSA in water, only a complex mixture was obtained. HBF₄/sodium dodecyl sulfate³¹⁾ was also employed instead of DBSA but the reaction proved unsuccessful. We previously obtained cyclization products from related compounds by protonic acid treatment in acetone.^6,7) Thus, p-toluenesulfonic acid (p-TsOH) was used as a protonic acid in tetrahydrofuran (THF)/H₂O (9 : 1) or acetone/H₂O (9 : 1) but again, no cyclization product was afforded. Scandium and ytterbium trifluoromethanesulfonate (Sc(OTf)₃ and Yb(OTf)₃) are often used as Lewis acid catalysts in aqueous organic reactions.^32,33) However, the expected cyclization reaction did not occur when 1 was treated with these Lewis acids.

Chart 2. Synthesis of ω-Formyl-β-(ethoxycarbonyl)allylsilane 1

The reaction was also studied using thioester, which is a good electrophile in aqueous organic reactions. Thioesters are often found in biological compounds such as acetyl CoA. Thus, the aldehyde group in 1 was oxidized to carboxylic acid 4 (79% yield) followed by thioesterification³⁴⁾ to afford 5 (65%) (Chart 3). However, aqueous cyclization of 5 was unsuccessful; namely, when 5 was treated with DBSA in water, only a hydrolysis product (4) was afforded.

Chart 3. Synthesis of Thioester Derivative 5

From these results, we thought that the nucleophilicity of the allylsilane moiety in both 1 and 5 was lower than H₂O due to the presence of a conjugated ethoxycarbonyl group. As a model study, we prepared a simple allylsilane 8 and studied its cyclization reaction. Compound 8 was prepared from 2 by analogous methods, namely, Wittig reaction (6, 93%), hydrolysis (7, 91%), and oxidation (8, 93%) (Chart 4). When 8 was treated with 1 eq of DBSA in water (0.3 M), the expected cyclization reaction occurred. However, the cyclization product 9 was too volatile to isolate. Then, the product was obtained as benzoate 10 in 74% yield by treatment of 9 with benzoyl chloride (BzCl). The cyclization reaction was also carried out in 0.07 and 0.03 M solutions to obtain 10 in almost the same yield (73 to 74%).

Chart 4. Synthesis and Cyclization Reaction of Allylsilane 8

After the success of the cyclization of the non-conjugated allylsilane compound, β-(acetoxymethyl)allylsilane 14 was designed to synthesize the α-methylene-γ-lactone compound. We previously reported that cyclization of ω-formyl-β-(acetoxymethyl)allylsilane proceeded in better yields than that of the β-ethoxycarbonyl derivative in the synthesis of large rings.¹⁵⁾ Compound 14 was synthesized from 3 via a diisobutylalminium hydride (DIBAL-H) reduction (11, 88%), acetylation (12, 91%), removal of the THP group (13, 93%), and Dess–Martin oxidation (14, 84%) (Chart 5).

Chart 5. Synthesis of ω-Formyl-β-(acetoxymethyl)allylsilane 14

DBSA-promoted intramolecular cyclization reactions of 14 were examined (Table 1 and Chart 6). The expected cyclization products (15a and 15b) were obtained together with acetyl-migrated products (16a and 16b) and hydrolyzed products (17a and 17b). When the reaction was carried out in 0.01 M DBSA solution for 24 h, the products were obtained in 94% total yield (entry 3). The hydrolyzed products (17a and 17b) were not obtained with shorter reaction times (entries 1 and 2), indicating that hydrolysis occurred after cyclization. In 0.02 M solution, the products were obtained in lower yield with some by-products (entry 4), and only complex mixtures were afforded in 0.1 and 0.25 M solutions (entries 5 and 6). The stereoselectivity of the reaction was then studied. Although it was difficult to isolate each 14z and 14e in pure form, mixtures at various ratios were obtained and their cyclization reactions were examined (Table 2). From the data, it was determined that 14z and 14e afforded the cis-products (15a, 16a, and 17a) and trans-products (15b, 16b, and 17b) at ratios of 86 : 14 and 46 : 54, respectively; that is, the cyclization of 14z was cis-selective, while that of 14e was non-stereoselective.

Chart 6. Cyclization Reaction of 14

Table 1. DBSA Promoted Cyclization of 14 in Water under Various Conditions^a)

Entry	Conc. of DBSA (M)b)	Time (h)	Yield (%)c)
			15a, b	16a, b	17a, b
1	0.01	1	49	20	0
2	0.01	1.5	51	25	3
3	0.01	24	18	20	56
4	0.02	24	15	6	13
5	0.1	95	—d)	—d)	—d)
6	0.25	20	—d)	—d)	—d)

a) 14z : 14e=ca. 2 : 1. b) 1 eq of DBSA was used. c) The ratio was determined from the ¹H-NMR data of the reaction mixture. d) Only a complex mixture was afforded.

Table 2. Cyclization of 14 with Various Z/E Ratios^a)

Entry	Substrate ratio (14z : 14e)	Product ratio (cis : trans)b),c)
1	95 : 5	83 : 17
2	75 : 25	80 : 20
3	69 : 31	72 : 28
4	57 : 43	67 : 33
5	34 : 66	60 : 40

a) Conditions: 0.01 M DBSA in water, r.t., 24 h. b) cis-products=15a, 16a, and 17a; trans-products=15b, 16b, and 17b. c) The ratio was determined from the ¹H-NMR data of the reaction mixture. Total yields were 87–93%.

In the previous study, Lewis acid- or protonic acid-promoted cyclization reactions of both (Z)- and (E)-β-(ethoxycarbonyl)allylsilanes in organic solvent were stereoselective, affording cis- and trans-products, respectively.^6,7,10,11) Nishitani et al. explained the stereoselectivity of the cyclization of (Z)- and (E)-1 in terms of “secondary orbital overlapping” between the trimethylsilyl-bearing carbon and the carbonyl oxygen in the conformers ZA and EB (Fig. 1, R=COOEt).¹¹⁾ In their case and in our previous case,⁷⁾ the conformers ZC, ZD, EC, and ED were not considered because the bulky β-(ethoxycarbonyl)allylsilane moiety takes an axial orientation with respect to the newly forming cyclohexane ring. Later, Schlosser et al. explained the phenomenon in terms of “antiparallel electron flow” between the C(Si)–C(alkene) bond and the acid-activated C=O bond.³⁵⁾ In their case, the conformers ZC, ZD, EC, and ED were considered because of the absence of bulky substituents (Fig. 1, R=H, Me). As reported by Schlosser et al., only ZA has the benefit of “antiparallel electron flow” in the Z-precursor (the C(Si)–C(alkene) and C=O bonds are parallel only in ZA), while both EB and EC are favorable conformers in the E-precursor (Fig. 1). The stereoselectivity of the cyclization of 14 can also be explained by the contribution of ZA to 14z, and EB and EC to 14e (Fig. 1, R=CH₂OAc).³⁶⁾ Although DBSA may have formed micelles under the present reaction conditions (critical micelle concentration of DBSA=ca. 5×10⁻⁴ M³⁷⁾), it is not clear whether the reaction occurred in the micelles or in the bulk water solution.

Fig. 1. Conformation of the Cyclization Reaction

Dotted lines indicate interaction¹¹⁾ and arrows indicate antiparallel electron flow³⁵⁾ (14: R=CH₂OAc).

Reactivity of organic compounds in water is sometimes different from that in organic solvents due to the hydrophobic effect.^38,39) Thus, as a reference, we also studied the acid-promoted cyclization of 14 in organic solvent. The reactions were carried out in CH₂Cl₂ at room temperature (r.t.) using camphorsulfonic acid (CSA) or BF₃·OEt₂ as a protonic acid or Lewis acid catalyst, respectively; the results are shown in Table 3. From these data, stereoselectivity of each 14z and 14e was calculated. The CSA-promoted reaction of 14z was cis-selective (cis : trans=93 : 7) and that of 14e was non-stereoselective (cis : trans=43 : 57) (entries 1 and 2), as in the case of water solvent, but the yields were lower than in water. In contrast, both 14z and 14e afforded cis- and trans-products in almost the same ratio in BF₃·OEt₂-promoted cyclization (cis : trans=ca. 3 : 7 for both 14z and 14e, respectively) (entries 3 and 4).⁴⁰⁾ These results indicated that the stereochemistry of cyclization depends on the catalyst, protonic acid, or Lewis acid.

Table 3. Acid Promoted Cyclization of 14 in CH₂Cl₂^a)

Entry	Substrate ratio (14z : 14e)	Acidb)	Product ratio (cis : trans)c)	Yield (%)
1	95 : 5	CSA	90 : 10	68
2	69 : 31	CSA	77 : 23	51
3	95 : 5	BF3·OEt2	28 : 72	74
4	69 : 31	BF3·OEt2	29 : 71	80

a) Conditions: the reactions were carried out at r.t. b) About 1.2 eq of acid was used. c) cis-products=15a, 16a, and 17a; trans-products=15b, 16b, and 17b.

Finally, lactonization reactions were performed. A mixture of 15a, 15b, 16a, and 16b was hydrolyzed to obtain 17a and 17b, which were then separated. When 17a was treated with MnO₂, the desired lactone 18 was obtained in 55% yield (Chart 7). However, 17b did not afford the corresponding lactone 20 and yielded only aldehyde 19. The lactone 20 was finally obtained by a Nishiyama’s method using MnO₂ and NaCN.⁴¹⁾

Chart 7. Lactonization Reaction

Conclusion

Intramolecular cyclization of ω-formyl-β-(acetoxymethyl)allylsilane 14 successfully proceeded in aqueous media to afford the corresponding carbocyclic compounds in good yield. The stereoselectivity of the cyclization reaction was almost the same as the CSA-promoted reaction in CH₂Cl₂. Thus, it was proved that aprotic organic solvents could be effectively replaced by water in cyclization reactions of allylsilanes.

Experimental

General Procedures

¹H-NMR spectra were measured on a JEOL ECX-400 (400 MHz) spectrometer in CDCl₃ as the solvent. The chemical shifts are expressed in ppm downfield from either tetramethylsilane (δ=0.00) added as an internal standard, or CHCl₃ (δ=7.26). ¹³C-NMR spectra were measured at 100 MHz. The chemical shifts are reported in ppm, relative to tetramethylsilane (δ=0.0) or the central line of a triplet at 77.0 ppm for CDCl₃. IR spectra were measured on a JASCO FT/IR-230 spectrometer. High-resolution (HR) MS were obtained using a JEOL JMS 700 instrument with a direct inlet system. Column chromatography was carried out on silica gel (Wakogel C-200 or C-300). Analytical TLC was performed on precoated TLC plates (Kieselgel 60 F254, layer thickness 0.2 mm). Anhydrous Na₂SO₄ or MgSO₄ was used as the drying agents for the extracted organic layers.

7-Ethoxycarbonyl-8-(trimethylsilyl)oct-6-enoic Acid (4)

Compound 1 (627 mg, 2.32 mmol) was dissolved in THF (90 mL), and t-BuOH (90 mL), 2-methyl-2-butene (9.9 mL), and a solution of NaClO₂ (845.2 mg) and NaH₂PO₄·2H₂O (1.45 g) in water (30 mL) were added successively at r.t. with stirring. After further stirring for 1 d, 6 M HCl aq. was added, and the mixture was extracted with CH₂Cl₂ and dried. Evaporation of the solvent followed by silica gel (20 g) column chromatography using hexane/EtOAc (96 : 4) as the eluent afforded a crude product. To remove by-products, the crude product was dissolved in EtOAc, and extracted with Na₂CO₃ aq. The aqueous layer was acidified by the addition of 2 M HCl aq. and extracted with CH₂Cl₂. After drying and removal of the solvent, the residue was chromatographed on silica gel (20 g), as above, to yield 4 (526.5 mg, 79%) as an oil; ¹H-NMR (CDCl₃) δ: −0.02 (9H×1/3, s), −0.01 (9H×2/3, s), 1.29 (3H×2/3, t, J=7.1 Hz), 1.30 (3H×1/3, t, J=7.1 Hz), 1.41–1.54 (2H, m), 1.62–1.73 (2H, m), 1.73 (2H×1/3, s), 1.80 (2H×2/3, s), 2.12 (2H×2/3, q, J=7.3 Hz), 2.37 (2H, t, J=6.9 Hz), 2.42 (2H×1/3, q, J=7.4 Hz), 4.17 (2H×2/3, q, J=7.1 Hz), 4.17 (2H×1/3, q, J=7.1 Hz), 5.64 (1H×1/3, t, J=7.4 Hz), 6.57 (1H×2/3, t, J=7.3 Hz); ¹³C-NMR (CDCl₃) assigned for the Z-isomer δ: −1.1 (3C), 14.3, 24.3, 24.4, 28.2, 28.7, 33.6, 60.5, 129.9, 137.5, 168.3, 178.5; IR (neat/NaCl) cm⁻¹: 1713, 1636, 853; MS electron ionization (EI) m/z: 286 (M⁺, 14%), 271 (21), 185 (100), 73 (72); HR-EI-MS m/z: 286.1594 (M⁺) (Calcd for C₁₄H₂₆O₄Si: 286.1600).

2-[7-Ethoxycarbonyl-1-oxo-8-(trimethylsilyl)oct-6-en-1-ylthio]propanoic Acid (5)

To a stirred solution of 4 (217.9 mg, 0.762 mmol) in dry CH₂Cl₂ (2.8 mL), (COCl)₂ (190 µL) was added at once, and the mixture was stirred at 50°C for 3 h. The mixture was evaporated to dryness and dry CH₂Cl₂ (1.5 mL) was added. A solution of HS(CH₂)₂COOH (70 µL) and Et₃N (0.22 mL) in CH₂Cl₂ (1.6 mL) was added at once at 0°C, and the mixture was stirred at r.t. for 1.5 h. An aqueous solution of NH₄Cl was added, and the mixture was extracted with CH₂Cl₂ (5 M HCl aq. and NaCl aq. were also added during the extraction process) and dried. Evaporation of the solvent followed by silica gel (5.4 g) column chromatography using hexane/EtOAc (8 : 2) afforded 5 (185.8 mg, 65%) as an oil; ¹H-NMR (CDCl₃) δ: −0.01 (9H×1/3, s), 0.00 (9H×2/3, s), 1.30 (3H×2/3, t, J=7.0 Hz), 1.31 (3H×1/3, t, J=7.0 Hz), 1.40–1.52 (2H, m), 1.65–1.75 (2H, m), 1.74 (2H×1/3, s), 1.81 (2H×2/3, s), 2.11 (2H×2/3, q, J=7.2 Hz), 2.42 (2H×1/3, q, J=7.4 Hz), 2.58 (2H, t-like, J=7.3 Hz), 2.67–2.72 (2H, m), 3.09–3.16 (2H, m), 4.18 (2H×2/3, q, J=7.0 Hz), 4.18 (2H×1/3, q, J=7.0 Hz), 5.64 (1H×1/3, t, J=7.4 Hz), 6.57 (1H×2/3, t, J=7.1 Hz); ¹³C-NMR (CDCl₃) assigned for the Z-isomer δ: −1.1 (3C), 14.3, 23.5, 24.1, 25.3, 28.0, 28.7, 34.1, 43.8, 60.5, 130.5, 137.5, 168.4, 177.0, 198.9; IR (neat/NaCl) cm⁻¹: 3000 (broad), 1726, 1711, 1636, 853; MS (EI) m/z: 359 (M⁺−Me, 27%), 223 (36), 185 (52), 151 (100), 73 (81); HR-EI-MS m/z: 374.1582 (M⁺) (Calcd for C₁₇H₃₀O₅SSi: 374.1583).

1-(Tetrahydro-2H-pyran-2-yl)oxy-8-(trimethylsilyl)oct-6-ene (6)

n-BuLi (2.6 mL, 1.41 M solution in hexane) was added to a stirred solution of Ph₃P⁺CH₂CH₂SiMe₃ I⁻ (1.802 g) in dry THF (30 mL) at −78°C, and the mixture was stirred at 0°C for 1.5 h. The flask was cooled to −78°C, a solution of 2 (363.2 mg, 1.816 mmol) in THF (15 mL) was added, and stirring was continued at 0°C for 18 h. An aqueous solution of NH₄Cl was added, and the mixture was extracted with Et₂O and dried. After removal of the solvent, the residue was subjected to silica gel (20 g) column chromatography using hexane/EtOAc (97 : 3) to afford 6 (477.9 mg, 93%) as an oil; ¹H-NMR (CDCl₃) δ: −0.01 (9H, s), 1.32–1.41 (4H, m), 1.45 (2H, br d, J=8.4 Hz), 1.48–1.88 (8H, m), 1.95–2.02 (2H, m), 3.39 (1H, dt, J=9.5, 6.7 Hz), 3.46–3.54 (1H, m), 3.73 (1H, dt, J=9.5, 6.9 Hz), 3.83–3.90 (1H, m), 4.57 (1H, dd, J=4.3, 2.7 Hz), 5.21–5.29 (1H, m), 5.33–5.42 (1H, m); ¹³C-NMR (CDCl₃) δ: −1.8 (3C), 18.4, 19.7, 25.5, 26.0, 27.0, 29.6, 29.7, 30.8, 62.3, 67.6, 98.8, 125.4, 127.5; IR (neat/NaCl) cm⁻¹: 1248, 858; MS (EI) m/z: 284 (M⁺, 5%), 85 (100), 73 (63); HR-EI-MS m/z: 284.2173 (M⁺) (Calcd for C₁₆H₃₂O₂Si: 284.2172).

8-(Trimethylsilyl)oct-6-en-1-ol (7)

H₂O (3.8 mL) and p-TsOH monohydrate (26.1 mg) were added successively to a stirred solution of 6 (292.7 mg, 1.03 mmol) in MeOH (7.6 mL), and the mixture was refluxed for 4 h. After cooling to r.t., NaHCO₃ aq. was added, and the mixture was extracted with EtOAc and dried. Evaporation of the solvent followed by silica gel (5 g) column chromatography using hexane/EtOAc (95 : 5) as the eluent afforded 7^35,42) (186.7 mg, 91%).

8-(Trimethylsilyl)oct-6-enal (8)

A solution of (COCl)₂ (260 µL) in CH₂Cl₂ (27 mL) was cooled to −78°C, and a solution of dimethylsulfoxide (0.3 mL) in CH₂Cl₂ (1 mL) was added. After stirring for 15 min, a solution of 7 (272.4 mg, 1.36 mmol) in CH₂Cl₂ (4 mL) was added, and stirring was continued for an additional 30 min. Et₃N (1.2 mL) was added, and the mixture was stirred at r.t. for 2 h. After the addition of NH₄Cl aq., the mixture was extracted with CH₂Cl₂ and dried. Evaporation of the solvent afforded an oily residue, which was chromatographed on neutral alumina (30 g, containing 10% water) using hexane as the eluent to afford 8³⁵⁾ (251.0 mg, 93%).

2-Vinylcyclohexan-1-yl Benzoate (10)

A solution of DBSA (54.8 mg, 0.17 mmol) in water (0.6 mL) was prepared at r.t. with stirring, and 8 (31.4 mg, 0.16 mmol) was dissolved in this solution. After stirring at r.t. for 1 d, NaHCO₃ aq. was added, and the mixture was extracted with CH₂Cl₂ and dried. The solvent was evaporated off carefully, and the crude product 9 was dissolved in CH₂Cl₂ (25 mL). Pyridine (640 µL) and benzoyl chloride (925 µL) were added successively with stirring, and stirring was continued for 2 d. NH₄Cl aq. was added, and the mixture was extracted with CH₂Cl₂ and dried. Evaporation of the solvent followed by silica gel (55 g) column chromatography using hexane/EtOAc (98 : 2) as the eluent afforded 10⁴³⁾ (27.0 mg, 74%).

8-(Tetrahydro-2H-pyran-2-yl)oxy-2-(trimethylsilylmethyl)oct-2-en-1-ol (11)

DIBAL-H (12.0 mL, 1.0 M in toluene) was added to a stirred solution of 3 (1129.6 mg, 3.17 mmol) in dry CH₂Cl₂ (60 mL), and the solution was stirred at −50°C for 3 d. The reaction was quenched by the addition of MeOH, and a saturated solution of Rochelle salt was added. The mixture was extracted with CH₂Cl₂, dried, and the solvent was evaporated off. The resultant residue was chromatographed on silica gel (27 g) using hexane/EtOAc (83 : 17) as the eluent to afford crude product 11 (879.5 mg, 88%), which was used in the next step without further purification. An oil; ¹H-NMR (CDCl₃) δ: 0.00 (9H×1/3, s), 0.02 (9H×2/3, s), 1.31–1.88 (13H, m), 1.57 (2H×2/3, s), 1.59 (2H×1/3, s), 1.92–2.11 (2H, m), 3.34–3.42 (1H, m), 3.46–3.53 (1H, m), 3.68–3.90 (2H, m), 3.95 (2H×2/3, s), 4.06 (2H×1/3, s), 4.55–4.59 (1H, m), 5.11 (1H×1/3, t, J=7.5 Hz), 5.29 (1H×2/3, t, J=6.8 Hz).

8-(Tetrahydro-2H-pyran-2-yl)oxy-2-(trimethylsilylmethyl)oct-2-en-1-yl Acetate (12)

Compound 11 (1190.3 mg, 3.79 mmol), a solution of dimethylaminopyridine (DMAP) (48.4 mg) in Et₃N (8.7 mL), and Ac₂O (430 µL) were mixed together at r.t. After stirring for 1 h, the mixture was extracted with AcOEt/1 M HCl aq. The organic layer was washed with 1 M HCl aq. and dried. Evaporation of the solvent followed by silica gel (25 g) column chromatography using hexane/EtOAc (95 : 5) as the eluent afforded 12 (1225.2 mg, 91%) as an oil; ¹H-NMR (CDCl₃) δ: 0.00 (9H×1/3, s), 0.03 (9H×2/3, s), 1.33–1.87 (12H, m), 1.53 (2H×1/3, s), 1.54 (2H×2/3, s), 1.93–2.11 (2H, m), 2.06 (3H×1/3, s), 2.07 (3H×2/3, s), 3.37 (1H×1/3, dt, J=9.4, 6.5 Hz), 3.38 (1H×2/3, dt, J=9.4, 6.5 Hz), 3.46–3.53 (1H, m), 3.72 (1H×1/3, dt, J=9.4, 6.5 Hz), 3.73 (1H×2/3, dt, J=9.4, 6.5 Hz), 3.83–3.90 (1H, m), 4.40 (2H×2/3, s), 4.51 (2H×1/3, s), 4.55–4.59 (1H, m), 5.24 (1H×1/3, t, J=7.4 Hz), 5.32 (1H×2/3, t, J=6.9 Hz); ¹³C-NMR (CDCl₃) assigned for the Z-isomer δ: −0.7 (3C), 19.2, 19.7, 21.1, 25.5, 26.1, 28.2, 29.3, 29.7, 30.8, 62.4, 63.4, 67.6, 98.9, 127.0, 131.8, 171.0; assigned for the E-isomer δ: −1.3 (3C), 19.2, 19.7, 21.0, 25.0, 25.9, 27.8, 29.6, 30.0, 30.8, 62.3, 63.4, 67.5, 98.8, 129.0, 131.2, 171.2; IR (neat/NaCl) cm⁻¹: 1738, 1248, 851; MS (FAB) m/z: 357 ([M+H]⁺, 4%), 307 (15), 154 (62), 136 (49), 85 (100); HR-(FAB)-MS m/z: 357.2453 ([M+H]⁺) (Calcd for C₁₉H₃₇O₄Si: 357.2461).

8-Hydroxy-2-(trimethylsilylmethyl)oct-2-en-1-yl Acetate (13)

Pyridinium p-toluenesulfonate (86.9 mg) was added to a stirred solution of 12 (1225.3 mg, 3.44 mmol) in EtOH (3.5 mL), and the mixture was stirred at 55°C for 11 h. An aqueous solution of NaHCO₃ was added, and the aqueous mixture was extracted with EtOAc, dried, and the solvent was evaporated. The residual oil was subjected to silica gel (26 g) column chromatography using hexane/EtOAc (78 : 22) to afford 13 (748.4 mg, 80%) as an oil; ¹H-NMR (CDCl₃) δ: 0.00 (9H×1/3, s), 0.03 (9H×2/3, s), 1.33–1.61 (7H, m), 1.54 (2H×1/3, s), 1.55 (2H×2/3, s), 1.96–2.10 (2H, m), 2.07 (3H×1/3, s), 2.07 (3H×2/3, s), 3.63 (2H×1/3, t, J=6.6 Hz), 3.64 (2H×2/3, t, J=6.6 Hz), 4.40 (2H×2/3, s), 4.52 (2H×1/3, s), 5.23 (1H×1/3, t, J=7.5 Hz), 5.32 (1H×2/3, t, J=6.9 Hz); ¹³C-NMR (CDCl₃) assigned for the Z-isomer δ: −0.7 (3C), 19.2, 21.1, 25.5, 28.2, 29.2, 32.7, 62.9, 70.1, 126.8, 131.9, 171.0. assigned for the E-isomer δ: −1.3 (3C), 19.2, 21.0, 25.2, 27.8, 29.9, 32.6, 63.4, 70.1, 128.9, 131.4, 171.2; IR (neat/NaCl) cm⁻¹: 1738, 1248, 845; MS (EI) m/z: 272 (M⁺, 0.2%), 212 (27), 133 (59), 117 (100); HR-EI-MS m/z: 272.1801 (M⁺) (Calcd for C₁₄H₂₈O₃Si: 272.1808).

8-Oxo-2-(trimethylsilylmethyl)oct-2-en-1-yl Acetate (14)

Pyridine (0.39 mL) and Dess–Martin periodinane (1047.2 mg) were added successively to a stirred solution of 13 (312.1 mg, 1.147 mmol) in CH₂Cl₂ (18 mL) at r.t. After further stirring for 15 min, Na₂SO₃ aq. and NaHCO₃ aq. were added, and the mixture was extracted with CH₂Cl₂ and dried. Evaporation of the solvent followed by silica gel (27 g) column chromatography using hexane/EtOAc (9 : 1) as the eluent afforded 14 (269.9 mg, 87%) as an oil; ¹H-NMR (CDCl₃) δ: 0.00 (9H×1/3, s), 0.03 (9H×2/3, s), 1.33–1.44 (2H, m), 1.54 (2H, s), 1.57–1.71 (2H, m), 1.95–2.13 (2H, m), 2.06 (3H×1/3, s), 2.07 (3H×2/3, s), 2.42 (2H×1/3, td, J=7.2, 1.8 Hz), 2.43 (2H×2/3, td, J=7.3, 1.8 Hz), 4.40 (2H×2/3, br s), 4.51 (2H×1/3, s), 5.21 (1H×1/3, t, J=7.5 Hz), 5.30 (1H×2/3, t, J=6.9 Hz), 9.75 (1H×1/3, t, J=1.8 Hz), 9.76 (1H×2/3, t, J=1.8 Hz); ¹³C-NMR assigned for the Z-isomer δ: −0.7 (3C), 19.3, 21.1, 21.8, 27.9, 29.0, 43.8, 69.9, 126.0, 132.4, 170.9, 202.6. assigned for the E-isomer δ: −1.3 (3C), 19.3, 21.0, 21.6, 27.6, 29.6, 43.7, 63.3, 128.2, 131.9, 171.1, 202.5; IR (neat/NaCl) cm⁻¹: 1732, 1258, 758; MS (EI) m/z: 270 (M⁺, 0.6%), 210 (9), 133 (40), 117 (95), 73 (100); HR-EI-MS m/z: 270.1652 (M⁺) (Calcd for C₁₄H₂₆O₃Si: 270.1651).

Cyclization Reaction

Compound 14 (32.1 mg, 0.119 mmol, Z : E=57 : 43) was dissolved in a solution of DBSA in water (11.1 mL, 0.11 mmol; 0.01 M), and the mixture was stirred at r.t. for 24 h. An aqueous solution of NaHCO₃ was added, and the mixture was extracted with EtOAc, and dried. After evaporation of the solvent, the residue was subjected to silica gel (7 g) column chromatography using hexane/EtOAc (gradient) to obtain 15a (3.1 mg, 13%), an inseparable mixture of 15b, 16a, and 16b (7.5 mg, 32%, ratio 28 : 56 : 16), and a mixture of 17a and 17b (7.6 mg, 41%, ratio 66 : 34). From these data, the ratio of the cis-products (15a, 16a, and 17a) to the trans-products (15b, 16b, and 17b) was determined to be 67 : 33 (Table 2, entry 4).

2-[(1SR,2SR)-2-hydroxycyclohex-1-yl]prop-2-en-1-yl Acetate (15a)

An oil; ¹H-NMR (CDCl₃) δ: 1.20–1.82 (8H, m), 1.91–1.98 (1H, m), 2.08 (3H, s), 2.13 (1H, br d, J=13 Hz), 3.97 (1H, br s), 4.52 (1H, d, J=13.4 Hz), 4.58 (1H, d, J=13.4 Hz), 5.04 (1H, s), 5.20 (1H, s); ¹³C-NMR (CDCl₃) δ: 19.5, 20.9, 23.8, 25.9, 32.4, 45.2, 66.2, 66.6, 113.7, 145.8, 170.8; IR (neat/NaCl) cm⁻¹: 3480 (OH), 1732, 1649, 1244, 972; MS (EI) m/z: 198 (M⁺, 0.4%), 180 (1), 138 (47), 109 (100), 94 (91), 79 (75); HR-EI-MS m/z: 198.1248 (M⁺) (Calcd for C₁₁H₁₈O₃: 198.1255).

2-[(1SR,2RS)-2-hydroxycyclohex-1-yl]prop-2-en-1-yl Acetate (15b), 2-[(1SR,2SR)-2-acetoxycyclohex-1-yl]prop-2-en-1-ol (16a), and 2-[(1SR,2RS)-2-acetoxycyclohex-1-yl]prop-2-en-1-ol (16b)

¹H-NMR (CDCl₃) assigned for 16a δ: 1.21–1.94 (9H, m), 2.01 (3H, s), 2.24 (1H, br d, J=12.4 Hz), 4.11 (2H, br s), 4.88 (1H, s), 5.09 (1H, q, J=1.2 Hz), 5.29 (1H, br s); assigned for 15b δ: 2.11 (3H, s), 4.57 (2H, br s), 5.11 (1H, s), 5.18 (1H, q, J=1.3 Hz); assigned for 16b δ: 2.00 (3H, s), 4.90 (1H, s), 5.04 (1H, q, J=1.4 Hz).

2-[(1SR,2SR)-2-Hydroxycyclohex-1-yl]prop-2-en-1-ol (17a) and 2-[(1SR,2RS)-2-Hydroxycyclohex-1-yl]prop-2-en-1-ol (17b)

A mixture of 15a, 15b, 16a, and 16b (10.6 mg, 0.054 mmol, ratio 29 : 20 : 40 : 11) was dissolved in MeOH (1 mL) to which an aqueous solution of K₂CO₃ (1 mL, 1 M) was added. After stirring at r.t. for 1 d, NH₄Cl aq. was added, and the mixture was extracted with EtOAc and dried. Evaporation of the solvent afforded a residue, which was chromatographed on silica gel (7 g). Elution with hexane/EtOAc (3 : 2) afforded 17a⁴⁴⁾ (4.6 mg, 55%) and with hexane/EtOAc (1 : 1) afforded 17b⁴⁴⁾ (3.2 mg, 38%) as colorless oils.

(3aSR,7aSR)-3-Methylenehexahydro-2(3H)-benzofuranone (18)

MnO₂ (291.0 mg) was added at once to a stirred solution of 17a (14.0 mg, 0.090 mmol) in CH₂Cl₂ (4.2 mL), and the mixture was stirred at r.t. for 19 h. The solid material was filtered off through Celite^®, and the filtrate was concentrated. The resultant residue was chromatographed on silica gel (7 g) using hexane/EtOAc (85 : 15) as the eluent to afford 18¹¹⁾ (7.5 mg, 55%).

(3aSR,7aRS)-3-Methylenehexahydro-2(3H)-benzofuranone (20)

Compound 17b (25.3 mg, 0.16 mmol) was treated with MnO₂ (225.9 mg) as above to yield a crude product of 19 (24.6 mg), which was not purified. This was dissolved in dry THF (7.5 mL), and NaCN (43.1 mg), MnO₂ (291.4 mg), and 18-crown-6 (22.2 mg) were added successively at r.t. After stirring the mixture for 20 h, the solid materials were filtered off through Celite^®, and the filtrate was dried. Evaporation of the solvent followed by silica gel (7 g) column chromatography using hexane/EtOAc (9 : 1) as the eluent afforded 20¹¹⁾ (7.2 mg, 29%).

Acknowledgment

This work was supported by the Strategic Research Foundation Grant-aided Projects for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Conflict of Interest

The authors declare no conflict of interest.

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