Synthesis of α-methylene-γ-lactone structure by cyclization of ω-formylallylsilane in water

Article abstract of DOI:10.1248/cpb.c18-00077

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)allylsi-lane 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.

Full text of DOI:10.1248/cpb.c18-00077

568
Chem. Pharm. Bull. 66, 568–574 (2018)
Vol. 66, No. 5
Regular Article
Synthesis of α-Methylene-γ-lactone Structure by Cyclization of
ω-Formylallylsilane in Water
,a
Hiroki Fukushima,a Daisuke Ikegami,a Chiaki Kuroda,* and Kenichi Kobayashib
a Department of Chemistry, Rikkyo University; Nishi-Ikebukuro, Toshima-ku, Tokyo 171–8501, Japan: and b Graduate
School of Pharmaceutical Sciences, Meiji Pharmaceutical University; 2–522–1 Noshio, Kiyose, Tokyo 204–8588,
Japan.
Received January 31, 2018; accepted February 27, 2018
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)allylsi-
lane 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.
Key words aqueous organic reaction; allylsilane; α-methylene-γ-lactone; stereochemistry
α-Methylene-γ-lactone
(4,5-dihydro-3-methylene-2(3H)- useful to study the above carbocyclization reactions in water.
furanone) structures fused to various carbocycles are often In organic solvents, the cyclization reactions have largely been
found in natural terpenoids, such as germacranolides, carried out under aprotic conditions using TiCl4, BF3·OEt2,
guaianolides, and eudesmanolides, and some of them have and other Lewis acid catalysts.8–15,19–22) These common Lewis
biological activities including anti-inflammatory, anti- acids are not applicable for use in water. Instead, surfactant-
bacterial, and cytotoxic properties.1–3) The two rings, carbo- type protonic acids such as dodecylbenzenesulfonic acid
cycle and α-methylene-γ-lactone, can be synthesized at once (DBSA) are useful.26,28,30) Here, we report that the cyclization
by acid- or fluoride-promoted intramolecular cyclization of reaction proceeds in good yield using DBSA as a surfactant-
β-(ethoxycarbonyl)allylsilane with aldehyde4,5) (Chart 1). Dur- type protonic acid catalyst.
ing the 1990s, we6–9) and Nishitani’s group10–14) independently
synthesized various α-methylene-γ-lactone compounds by
this method. A non-conjugated moiety, β-(acetoxymethyl)-
Results and Discussion
We initially studied the cyclization of 1, which is known to
allylsilane, was also used to synthesize large-size ring com- cyclize by treatment with a Lewis acid in organic solvents in
pounds.15) β-(Ethoxycarbonyl)allylsilane and its derivatives are good yields.10,11) Compound 1 was prepared as a mixture of
carbon-1,3-dipole equivalents; that is, the γ-carbon of allylsi- Z- and E-isomers (ratio ca. 2:1) from 1,6-hexanediol accord-
lane acts as a nucleophile and the carbonyl carbon as an elec- ing to previous reports10,11,19) with a slight modification (Chart
trophile. A variety of carbon 1,3-dipole compounds are known 2). Namely, monoprotection of 1,6-hexanediol with tetrahydro-
to be versatile building blocks in organic synthesis.16–18) We pyranyl (THP) group followed by Swern oxidation produced
prepared some related compounds, such as bicyclo[4.3.0]- 2. The β-(ethoxycarbonyl)allylsilane moiety was introduced
nonanes,19,20) spiro[4.5]decanes,21,22) and cycloundecanes23,24) by Horner–Wadsworth–Emmons reaction to afford 3, which
by related reactions, such as carbobicyclization, Nazarov reac- was converted to 1 by deprotection and oxidation. When 1
tion, and homo-Cope reaction, respectively.
was treated with DBSA in water, only a complex mixture
Organic reactions in water, in which the use of harmful or- was obtained. HBF4/sodium dodecyl sulfate31) was also em-
ganic solvents can be avoided, have recently been extensively ployed instead of DBSA but the reaction proved unsuccess-
developed.25–29) Among them, C–C bond formation in water is ful. We previously obtained cyclization products from related
especially important because many common reactions, such compounds by protonic acid treatment in acetone.6,7) Thus,
as Grignard and Wittig reactions, utilize various carbanions p-toluenesulfonic acid (p-TsOH) was used as a protonic acid
or their equivalents, but carbanions are not stable in water. in tetrahydrofuran (THF)/H2O (9:1) or acetone/H2O (9:1)
Allylsilanes are water-stable carbanion equivalents. Thus, it is 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.
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.
Chart 1. Intramolecular Cyclization of ω-Formyl-β-(ethoxycarbonyl)-
Thus, the aldehyde group in 1 was oxidized to carboxylic
allylsilane
*To whom correspondence should be addressed. e-mail: chkkuroda@rikkyo.ac.jp
© 2018 The Pharmaceutical Society of Japan

Vol. 66, No. 5 (2018)
Chem. Pharm. Bull.
569
Chart 2. Synthesis of ω-Formyl-β-(ethoxycarbonyl)allylsilane 1
Chart 3. Synthesis of Thioester Derivative 5
Chart 4. Synthesis and Cyclization Reaction of Allylsilane 8
Chart 5. Synthesis of ω-Formyl-β-(acetoxymethyl)allylsilane 14
acid 4 (79% yield) followed by thioesterification34) to afford in 0.07 and 0.03M solutions to obtain 10 in almost the same
5 (65%) (Chart 3). However, aqueous cyclization of 5 was un- yield (73 to 74%).
successful; namely, when 5 was treated with DBSA in water,
only a hydrolysis product (4) was afforded.
After the success of the cyclization of the non-conjugated
allylsilane compound, β-(acetoxymethyl)allylsilane 14 was
From these results, we thought that the nucleophilicity of designed to synthesize the α-methylene-γ-lactone compound.
the allylsilane moiety in both 1 and 5 was lower than H2O We previously reported that cyclization of ω-formyl-β-
due to the presence of a conjugated ethoxycarbonyl group. As (acetoxymethyl)allylsilane proceeded in better yields than
a model study, we prepared a simple allylsilane 8 and studied that of the β-ethoxycarbonyl derivative in the synthesis of
its cyclization reaction. Compound 8 was prepared from 2 by large rings.15) Compound 14 was synthesized from 3 via a
analogous methods, namely, Wittig reaction (6, 93%), hydro- diisobutylalminium hydride (DIBAL-H) reduction (11, 88%),
lysis (7, 91%), and oxidation (8, 93%) (Chart 4). When 8 was acetylation (12, 91%), removal of the THP group (13, 93%),
treated with 1eq of DBSA in water (0.3M), the expected cy- and Dess–Martin oxidation (14, 84%) (Chart 5).
clization reaction occurred. However, the cyclization product
DBSA-promoted intramolecular cyclization reactions of
9 was too volatile to isolate. Then, the product was obtained 14 were examined (Table 1 and Chart 6). The expected
as benzoate 10 in 74% yield by treatment of 9 with benzoyl cyclization products (15a and 15b) were obtained together
chloride (BzCl). The cyclization reaction was also carried out with acetyl-migrated products (16a and 16b) and hydrolyzed

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Chem. Pharm. Bull.
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Chart 6. Cyclization Reaction of 14
Table 1. DBSA Promoted Cyclization of 14 in Water under Various
Conditionsa)
Yield (%)c)
Conc. of DBSA
(M)b)
Time
(h)
Entry
15a, b
16a, b
17a, b
1
2
3
4
5
6
0.01
0.01
0.01
0.02
0.1
1
1.5
24
24
95
20
49
51
18
15
20
25
20
6
0
3
56
13
d)
d)
d)
—
d)
—
—
d)
d)
0.25
—
—
—
a) 14z:14e=ca. 2:1. b) 1eq of DBSA was used. c) The ratio was determined from
Fig. 1. Conformation of the Cyclization Reaction
1
the H-NMR data of the reaction mixture. d) Only a complex mixture was afforded.
Dotted lines indicate interaction11) and arrows indicate antiparallel electron
flow35) (14: R=CH2OAc).
Table 2. Cyclization of 14 with Various Z/E Ratiosa)
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 orienta-
tion 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 “anti-
parallel electron flow” in the Z-precursor (the C(Si)–C(alkene)
Entry
Substrate ratio (14z:14e) Product ratio (cis:trans)b),c)
1
2
3
4
5
95:5
83:17
80:20
72:28
67:33
60:40
75:25
69:31
57:43
34:66
a) Conditions: 0.01M DBSA in water, r.t., 24h. 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%.
products (17a and 17b). When the reaction was carried out in and C=O bonds are parallel only in ZA), while both EB and
0.01M DBSA solution for 24h, the products were obtained in EC are favorable conformers in the E-precursor (Fig. 1). The
94% total yield (entry 3). The hydrolyzed products (17a and stereoselectivity of the cyclization of 14 can also be explained
17b) were not obtained with shorter reaction times (entries 1 by the contribution of ZA to 14z, and EB and EC to 14e (Fig.
and 2), indicating that hydrolysis occurred after cyclization. In 1, R=CH2OAc).36) Although DBSA may have formed micelles
0.02M solution, the products were obtained in lower yield with under the present reaction conditions (critical micelle concen-
some by-products (entry 4), and only complex mixtures were tration of DBSA=ca. 5×10−4
afforded in 0.1 and 0.25M solutions (entries 5 and 6). The reaction occurred in the micelles or in the bulk water solution.
stereoselectivity of the reaction was then studied. Although Reactivity of organic compounds in water is sometimes
M
37)), it is not clear whether the
it was difficult to isolate each 14z and 14e in pure form, different from that in organic solvents due to the hydrophobic
mixtures at various ratios were obtained and their cyclization effect.38,39) Thus, as a reference, we also studied the acid-
reactions were examined (Table 2). From the data, it was de- promoted cyclization of 14 in organic solvent. The reactions
termined that 14z and 14e afforded the cis-products (15a, 16a, were carried out in CH2Cl2 at room temperature (r.t.) using
and 17a) and trans-products (15b, 16b, and 17b) at ratios of camphorsulfonic acid (CSA) or BF3·OEt2 as a protonic acid
86:14 and 46:54, respectively; that is, the cyclization of 14z or Lewis acid catalyst, respectively; the results are shown
was cis-selective, while that of 14e was non-stereoselective.
in Table 3. From these data, stereoselectivity of each 14z
In the previous study, Lewis acid- or protonic acid-promoted and 14e was calculated. The CSA-promoted reaction of 14z
cyclization reactions of both (Z)- and (E)-β-(ethoxycarbonyl)- was cis-selective (cis:trans=93:7) and that of 14e was non-
allylsilanes in organic solvent were stereoselective, affording stereoselective (cis:trans=43:57) (entries 1 and 2), as in the
cis- and trans-products, respectively.6,7,10,11) Nishitani et al. case of water solvent, but the yields were lower than in water.
explained the stereoselectivity of the cyclization of (Z)- and In contrast, both 14z and 14e afforded cis- and trans-products
(E)-1 in terms of “secondary orbital overlapping” between in almost the same ratio in BF3·OEt2-promoted cyclization
the trimethylsilyl-bearing carbon and the carbonyl oxygen (cis:trans=ca. 3:7 for both 14z and 14e, respectively) (entries
in the conformers ZA and EB (Fig. 1, R=COOEt).11) In 3 and 4).40) These results indicated that the stereochemistry of

Vol. 66, No. 5 (2018)
Chem. Pharm. Bull.
571
a)
Table 3. Acid Promoted Cyclization of 14 in CH2Cl2
Compound 1 (627mg, 2.32mmol) was dissolved in THF
(90mL), and t-BuOH (90mL), 2-methyl-2-butene (9.9mL), and
a solution of NaClO2 (845.2mg) and NaH2PO4·2H2O (1.45g)
in water (30mL) were added successively at r.t. with stirring.
After further stirring for 1d, 6M HCl aq. was added, and the
mixture was extracted with CH2Cl2 and dried. Evaporation of
the solvent followed by silica gel (20g) column chromatogra-
phy using hexane/EtOAc (96:4) as the eluent afforded a crude
product. To remove by-products, the crude product was dis-
solved in EtOAc, and extracted with Na2CO3 aq. The aqueous
layer was acidified by the addition of 2M HCl aq. and extract-
ed with CH2Cl2. After drying and removal of the solvent, the
residue was chromatographed on silica gel (20g), as above, to
Substrate ratio
(14z:14e)
Product ratio
Entry
Acidb)
Yield (%)
(cis:trans)c)
1
2
3
4
95:5
CSA
CSA
90:10
77:23
28:72
29:71
68
51
74
80
69:31
95:5
BF3·OEt2
BF3·OEt2
69:31
a) Conditions: the reactions were carried out at r.t. b) About 1.2eq of acid was
used. c) cis-products=15a, 16a, and 17a; trans-products=15b, 16b, and 17b.
1
yield 4 (526.5mg, 79%) as an oil; H-NMR (CDCl3) δ: −0.02
(9H×1/3, s), −0.01 (9H×2/3, s), 1.29 (3H×2/3, t, J=7.1Hz),
1.30 (3H×1/3, t, J=7.1Hz), 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=7.3Hz), 2.37 (2H, t, J=6.9Hz), 2.42 (2H×1/3, q, J=7.4Hz),
4.17 (2H×2/3, q, J=7.1Hz), 4.17 (2H×1/3, q, J=7.1Hz), 5.64
(1H×1/3, t, J=7.4Hz), 6.57 (1H×2/3, t, J=7.3Hz); 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:
Chart 7. Lactonization Reaction
cyclization depends on the catalyst, protonic acid, or Lewis 286.1594 (M+) (Calcd for C14H26O4Si: 286.1600).
acid. 2-[7-Ethoxycarbonyl-1-oxo-8-(trimethylsilyl)oct-6-en-
Finally, lactonization reactions were performed. A mixture 1-ylthio]propanoic Acid (5) To a stirred solution of 4
of 15a, 15b, 16a, and 16b was hydrolyzed to obtain 17a and (217.9mg, 0.762mmol) in dry CH2Cl2 (2.8mL), (COCl)2
17b, which were then separated. When 17a was treated with (190 µL) was added at once, and the mixture was stirred at
MnO2, the desired lactone 18 was obtained in 55% yield 50°C for 3h. The mixture was evaporated to dryness and dry
(Chart 7). However, 17b did not afford the corresponding CH2Cl2 (1.5mL) was added. A solution of HS(CH2)2COOH
lactone 20 and yielded only aldehyde 19. The lactone 20 was (70µL) and Et3N (0.22mL) in CH2Cl2 (1.6mL) was added at
finally obtained by a Nishiyama’s method using MnO2 and once at 0°C, and the mixture was stirred at r.t. for 1.5h. An
NaCN.41)
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
Conclusion
Intramolecular cyclization of ω-formyl-β-(acetoxymethyl)- the solvent followed by silica gel (5.4g) column chromatogra-
allylsilane 14 successfully proceeded in aqueous media to af- phy using hexane/EtOAc (8:2) afforded 5 (185.8mg, 65%) as
1
ford the corresponding carbocyclic compounds in good yield. an oil; H-NMR (CDCl3) δ: −0.01 (9H×1/3, s), 0.00 (9H×2/3,
The stereoselectivity of the cyclization reaction was almost s), 1.30 (3H×2/3, t, J=7.0Hz), 1.31 (3H×1/3, t, J=7.0Hz),
the same as the CSA-promoted reaction in CH2Cl2. Thus, it 1.40–1.52 (2H, m), 1.65–1.75 (2H, m), 1.74 (2H×1/3, s), 1.81
was proved that aprotic organic solvents could be effectively (2H×2/3, s), 2.11 (2H×2/3, q, J=7.2Hz), 2.42 (2H×1/3, q,
replaced by water in cyclization reactions of allylsilanes.
J=7.4Hz), 2.58 (2H, t-like, J=7.3Hz), 2.67–2.72 (2H, m),
3.09–3.16 (2H, m), 4.18 (2H×2/3, q, J=7.0Hz), 4.18 (2H×1/3,
q, J=7.0Hz), 5.64 (1H×1/3, t, J=7.4Hz), 6.57 (1H×2/3, t,
Experimental
General Procedures 1H-NMR spectra were measured on J=7.1Hz); 13C-NMR (CDCl3) assigned for the Z-isomer δ:
a JEOL ECX-400 (400MHz) spectrometer in CDCl3 as the −1.1 (3C), 14.3, 23.5, 24.1, 25.3, 28.0, 28.7, 34.1, 43.8, 60.5,
solvent. The chemical shifts are expressed in ppm downfield 130.5, 137.5, 168.4, 177.0, 198.9; IR (neat/NaCl) cm−1: 3000
from either tetramethylsilane (δ=0.00) added as an internal (broad), 1726, 1711, 1636, 853; MS (EI) m/z: 359 (M+−Me,
standard, or CHCl3 (δ=7.26). 13C-NMR spectra were measured 27%), 223 (36), 185 (52), 151 (100), 73 (81); HR-EI-MS m/z:
at 100MHz. The chemical shifts are reported in ppm, relative 374.1582 (M+) (Calcd for C17H30O5SSi: 374.1583).
to tetramethylsilane (δ=0.0) or the central line of a triplet at
1-(Tetrahydro-2H-pyran-2-yl)oxy-8-(trimethylsilyl)oct-
77.0ppm for CDCl3. IR spectra were measured on a JASCO 6-ene (6) n-BuLi (2.6mL, 1.41M solution in hexane) was
FT/IR-230 spectrometer. High-resolution (HR) MS were ob- added to a stirred solution of Ph3P+CH2CH2SiMe3 I− (1.802g)
tained using a JEOL JMS 700 instrument with a direct inlet in dry THF (30mL) at −78°C, and the mixture was stirred
system. Column chromatography was carried out on silica gel at 0°C for 1.5h. The flask was cooled to −78°C, a solution
(Wakogel C-200 or C-300). Analytical TLC was performed of 2 (363.2mg, 1.816mmol) in THF (15mL) was added, and
on precoated TLC plates (Kieselgel 60 F254, layer thickness stirring was continued at 0°C for 18h. An aqueous solution
0.2mm). Anhydrous Na2SO4 or MgSO4 was used as the dry- of NH4Cl was added, and the mixture was extracted with
ing agents for the extracted organic layers.
Et2O and dried. After removal of the solvent, the residue was
7-Ethoxycarbonyl-8-(trimethylsilyl)oct-6-enoic Acid (4) subjected to silica gel (20g) column chromatography using

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hexane/EtOAc (97:3) to afford 6 (477.9mg, 93%) as an oil; a solution of dimethylaminopyridine (DMAP) (48.4mg) in
1H-NMR (CDCl3) δ: −0.01 (9H, s), 1.32–1.41 (4H, m), 1.45 Et3N (8.7mL), and Ac2O (430µL) were mixed together at
(2H, brd, J=8.4Hz), 1.48–1.88 (8H, m), 1.95–2.02 (2H, m), r.t. After stirring for 1h, the mixture was extracted with
3.39 (1H, dt, J=9.5, 6.7Hz), 3.46–3.54 (1H, m), 3.73 (1H, dt, AcOEt/1 M HCl aq. The organic layer was washed with
J=9.5, 6.9Hz), 3.83–3.90 (1H, m), 4.57 (1H, dd, J=4.3, 2.7Hz), 1M HCl aq. and dried. Evaporation of the solvent followed
5.21–5.29 (1H, m), 5.33–5.42 (1H, m); 13C-NMR (CDCl3) δ: by silica gel (25g) column chromatography using hexane/
−1.8 (3C), 18.4, 19.7, 25.5, 26.0, 27.0, 29.6, 29.7, 30.8, 62.3, EtOAc (95:5) as the eluent afforded 12 (1225.2mg, 91%) as
1
67.6, 98.8, 125.4, 127.5; IR (neat/NaCl) cm−1: 1248, 858; MS an oil; H-NMR (CDCl3) δ: 0.00 (9H×1/3, s), 0.03 (9H×2/3,
(EI) m/z: 284 (M+, 5%), 85 (100), 73 (63); HR-EI-MS m/z: s), 1.33–1.87 (12H, m), 1.53 (2H×1/3, s), 1.54 (2H×2/3, s),
284.2173 (M+) (Calcd for C16H32O2Si: 284.2172).
1.93–2.11 (2H, m), 2.06 (3H×1/3, s), 2.07 (3H×2/3, s), 3.37
8-(Trimethylsilyl)oct-6-en-1-ol (7) H2O (3.8mL) and (1H×1/3, dt, J=9.4, 6.5Hz), 3.38 (1H×2/3, dt, J=9.4, 6.5Hz),
p-TsOH monohydrate (26.1mg) were added successively to a 3.46–3.53 (1H, m), 3.72 (1H×1/3, dt, J=9.4, 6.5Hz), 3.73
stirred solution of 6 (292.7mg, 1.03mmol) in MeOH (7.6mL), (1H×2/3, dt, J=9.4, 6.5Hz), 3.83–3.90 (1H, m), 4.40 (2H×2/3,
and the mixture was refluxed for 4h. After cooling to r.t., s), 4.51 (2H×1/3, s), 4.55–4.59 (1H, m), 5.24 (1H×1/3, t,
NaHCO3 aq. was added, and the mixture was extracted with J=7.4Hz), 5.32 (1H×2/3, t, J=6.9Hz); 13C-NMR (CDCl3) as-
EtOAc and dried. Evaporation of the solvent followed by silica signed for the Z-isomer δ: −0.7 (3C), 19.2, 19.7, 21.1, 25.5,
gel (5g) column chromatography using hexane/EtOAc (95:5) 26.1, 28.2, 29.3, 29.7, 30.8, 62.4, 63.4, 67.6, 98.9, 127.0, 131.8,
as the eluent afforded 735,42) (186.7mg, 91%).
171.0; assigned for the E-isomer δ: −1.3 (3C), 19.2, 19.7, 21.0,
8-(Trimethylsilyl)oct-6-enal (8) A solution of (COCl)2 25.0, 25.9, 27.8, 29.6, 30.0, 30.8, 62.3, 63.4, 67.5, 98.8, 129.0,
(260 µL) in CH2Cl2 (27mL) was cooled to −78°C, and a so- 131.2, 171.2; IR (neat/NaCl) cm−1: 1738, 1248, 851; MS (FAB)
lution of dimethylsulfoxide (0.3mL) in CH2Cl2 (1mL) was m/z: 357 ([M+H]+, 4%), 307 (15), 154 (62), 136 (49), 85 (100);
added. After stirring for 15min, a solution of 7 (272.4mg, HR-(FAB)-MS m/z: 357.2453 ([M+H]+) (Calcd for C19H37O4Si:
1.36mmol) in CH2Cl2 (4mL) was added, and stirring was 357.2461).
continued for an additional 30min. Et3N (1.2mL) was added,
8-Hydroxy-2-(trimethylsilylmethyl)oct-2-en-1-yl Acetate
and the mixture was stirred at r.t. for 2h. After the addition of (13) Pyridinium p-toluenesulfonate (86.9mg) was added
NH4Cl aq., the mixture was extracted with CH2Cl2 and dried. to a stirred solution of 12 (1225.3mg, 3.44mmol) in EtOH
Evaporation of the solvent afforded an oily residue, which (3.5mL), and the mixture was stirred at 55°C for 11h. An
was chromatographed on neutral alumina (30g, containing aqueous solution of NaHCO3 was added, and the aqueous
10% water) using hexane as the eluent to afford 835) (251.0mg, mixture was extracted with EtOAc, dried, and the solvent
93%).
2-Vinylcyclohexan-1-yl Benzoate (10)
was evaporated. The residual oil was subjected to silica gel
solution of (26g) column chromatography using hexane/EtOAc (78:22)
A
DBSA (54.8mg, 0.17mmol) in water (0.6mL) was prepared to afford 13 (748.4mg, 80%) as an oil; 1H-NMR (CDCl3)
at r.t. with stirring, and 8 (31.4mg, 0.16mmol) was dissolved δ: 0.00 (9H×1/3, s), 0.03 (9H×2/3, s), 1.33–1.61 (7H, m),
in this solution. After stirring at r.t. for 1d, NaHCO3 aq. 1.54 (2H×1/3, s), 1.55 (2H×2/3, s), 1.96–2.10 (2H, m), 2.07
was added, and the mixture was extracted with CH2Cl2 and (3H×1/3, s), 2.07 (3H×2/3, s), 3.63 (2H×1/3, t, J=6.6Hz),
dried. The solvent was evaporated off carefully, and the crude 3.64 (2H×2/3, t, J=6.6Hz), 4.40 (2H×2/3, s), 4.52 (2H×1/3,
product 9 was dissolved in CH2Cl2 (25mL). Pyridine (640µL) s), 5.23 (1H×1/3, t, J=7.5Hz), 5.32 (1H×2/3, t, J=6.9Hz);
and benzoyl chloride (925µL) were added successively with 13C-NMR (CDCl3) assigned for the Z-isomer δ: −0.7 (3C),
stirring, and stirring was continued for 2d. NH4Cl aq. was 19.2, 21.1, 25.5, 28.2, 29.2, 32.7, 62.9, 70.1, 126.8, 131.9, 171.0.
added, and the mixture was extracted with CH2Cl2 and dried. assigned for the E-isomer δ: −1.3 (3C), 19.2, 21.0, 25.2, 27.8,
Evaporation of the solvent followed by silica gel (55g) column 29.9, 32.6, 63.4, 70.1, 128.9, 131.4, 171.2; IR (neat/NaCl) cm−1:
chromatography using hexane/EtOAc (98:2) as the eluent af- 1738, 1248, 845; MS (EI) m/z: 272 (M+, 0.2%), 212 (27), 133
forded 1043) (27.0mg, 74%).
(59), 117 (100); HR-EI-MS m/z: 272.1801 (M+) (Calcd for
8-(Tetrahydro-2H-pyran-2-yl)oxy-2-(trimethylsilylmethyl)- C14H28O3Si: 272.1808).
oct-2-en-1-ol (11) DIBAL-H (12.0mL, 1.0M in toluene) was
8-Oxo-2-(trimethylsilylmethyl)oct-2-en-1-yl Acetate (14)
added to a stirred solution of 3 (1129.6mg, 3.17mmol) in dry Pyridine (0.39mL) and Dess–Martin periodinane (1047.2mg)
CH2Cl2 (60mL), and the solution was stirred at −50°C for 3d. were added successively to a stirred solution of 13 (312.1mg,
The reaction was quenched by the addition of MeOH, and a 1.147mmol) in CH2Cl2 (18mL) at r.t. After further stirring
saturated solution of Rochelle salt was added. The mixture for 15min, Na2SO3 aq. and NaHCO3 aq. were added, and the
was extracted with CH2Cl2, dried, and the solvent was evapo- mixture was extracted with CH2Cl2 and dried. Evaporation
rated off. The resultant residue was chromatographed on silica of the solvent followed by silica gel (27g) column chroma-
gel (27g) using hexane/EtOAc (83:17) as the eluent to afford tography using hexane/EtOAc (9:1) as the eluent afforded 14
1
crude product 11 (879.5mg, 88%), which was used in the next (269.9mg, 87%) as an oil; H-NMR (CDCl3) δ: 0.00 (9H×1/3,
1
step without further purification. An oil; H-NMR (CDCl3) δ: s), 0.03 (9H×2/3, s), 1.33–1.44 (2H, m), 1.54 (2H, s), 1.57–1.71
0.00 (9H×1/3, s), 0.02 (9H×2/3, s), 1.31–1.88 (13H, m), 1.57 (2H, m), 1.95–2.13 (2H, m), 2.06 (3H×1/3, s), 2.07 (3H×2/3,
(2H×2/3, s), 1.59 (2H×1/3, s), 1.92–2.11 (2H, m), 3.34–3.42 s), 2.42 (2H×1/3, td, J=7.2, 1.8Hz), 2.43 (2H×2/3, td, J=7.3,
(1H, m), 3.46–3.53 (1H, m), 3.68–3.90 (2H, m), 3.95 (2H×2/3, 1.8Hz), 4.40 (2H×2/3, brs), 4.51 (2H×1/3, s), 5.21 (1H×1/3,
s), 4.06 (2H×1/3, s), 4.55–4.59 (1H, m), 5.11 (1H×1/3, t, t, J=7.5Hz), 5.30 (1H×2/3, t, J=6.9Hz), 9.75 (1H×1/3, t,
J=7.5Hz), 5.29 (1H×2/3, t, J=6.8Hz).
J=1.8Hz), 9.76 (1H×2/3, t, J=1.8Hz); 13C-NMR assigned for
8-(Tetrahydro-2H-pyran-2-yl)oxy-2-(trimethylsilylmethyl)- the Z-isomer δ: −0.7 (3C), 19.3, 21.1, 21.8, 27.9, 29.0, 43.8,
oct-2-en-1-yl Acetate (12) Compound 11 (1190.3mg, 3.79mmol), 69.9, 126.0, 132.4, 170.9, 202.6. assigned for the E-isomer δ:

Vol. 66, No. 5 (2018)
Chem. Pharm. Bull.
573
−1.3 (3C), 19.3, 21.0, 21.6, 27.6, 29.6, 43.7, 63.3, 128.2, 131.9, off through Celite®, and the filtrate was dried. Evaporation of
171.1, 202.5; IR (neat/NaCl) cm−1: 1732, 1258, 758; MS (EI) the solvent followed by silica gel (7g) column chromatography
m/z: 270 (M+, 0.6%), 210 (9), 133 (40), 117 (95), 73 (100); HR- using hexane/EtOAc (9:1) as the eluent afforded 2011) (7.2mg,
EI-MS m/z: 270.1652 (M+) (Calcd for C14H26O3Si: 270.1651).
Cyclization Reaction Compound 14 (32.1mg, 0.119mmol,
Z:E=57:43) was dissolved in a solution of DBSA in water
29%).
Acknowledgment This work was supported by the Stra-
(11.1mL, 0.11mmol; 0.01M), and the mixture was stirred at r.t. tegic Research Foundation Grant-aided Projects for Private
for 24h. An aqueous solution of NaHCO3 was added, and the Universities from the Ministry of Education, Culture, Sports,
mixture was extracted with EtOAc, and dried. After evapora- Science and Technology of Japan.
tion of the solvent, the residue was subjected to silica gel (7g)
column chromatography using hexane/EtOAc (gradient) to
Conflict of Interest The authors declare no conflict of
obtain 15a (3.1mg, 13%), an inseparable mixture of 15b, 16a, interest.
and 16b (7.5mg, 32%, ratio 28:56:16), and a mixture of 17a
and 17b (7.6mg, 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).
References and Notes
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574
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Vol. 66, No. 5 (2018)
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