Synthesis and NMR spectroscopic elucidation of four diastereoisomers of oxygenated bisabolane side chain

Article abstract of DOI:10.1002/hlca.201400395

Four possible stereoisomers of a model compound of highly O-bearing bisabolane sesquiterpenes were synthesized and their NMR spectra were compared. Starting from isopulegol, allylic oxidation and Grignard reaction afforded a mixture of alcohols at C(8), which was separated. After metathesis reaction, both α- and β-epoxides were obtained via non-stereoselective epoxidation, while VO(OⁱPr)₃-catalyzed epoxidation afforded a single diastereoisomer selectively. NMR Spectra of twelve synthesized compounds, four stereoisomers of acetates, isobutyrates, and tiglates, were measured. A difference between C(8α)- and C(8β)-acyloxy isomers was observed in the δ-values of H-C(8) in CDCl₃. Within the 8β-acyloxy compounds, the α- and the β-epoxides were distinguished by either the J-value of H-C(8) or the chemical shift of CH₂(9). Within the 8α-acyloxy compounds, two epoxide isomers were distinguished by the J-value of H-C(10) in C₆D₆ or in CD₃OD.

Full text of DOI:10.1002/hlca.201400395

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Synthesis and NMR Spectroscopic Elucidation of Four Diastereoisomers of
Oxygenated Bisabolane Side Chain
by Misaki Hiraia), Rurina Miyazakia), Kana Mitsuia), Kota Kiuchib), Hiroyuki Onukib)c),
Hiroshi Hirotab)d), and Chiaki Kuroda*a)
a) Department of Chemistry, Rikkyo University, Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
(e-mail: chkkuroda@rikkyo.ac.jp)
b) Genomic Sciences Center, RIKEN, Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
c) Tokyo Chemical Industry Co., Ltd., Toshima, Kita-ku,Tokyo 114-0003, Japan
d) Antibiotics Laboratory, RIKEN, Hirosawa, Wako, Saitama 351-0198, Japan
Four possible stereoisomers of a model compound of highly O-bearing bisabolane sesquiterpenes
were synthesized and their NMR spectra were compared. Starting from isopulegol, allylic oxidation and
Grignard reaction afforded a mixture of alcohols at C(8), which was separated. After metathesis
reaction, both a- and b-epoxides were obtained via non-stereoselective epoxidation, while VO(OiPr)3-
catalyzed epoxidation afforded a single diastereoisomer selectively. NMR Spectra of twelve synthesized
compounds, four stereoisomers of acetates, isobutyrates, and tiglates, were measured. A difference
between C(8a)- and C(8b)-acyloxy isomers was observed in the d-values of HÀC(8) in CDCl3. Within
the 8b-acyloxy compounds, the a- and the b-epoxides were distinguished by either the J-value of HÀC(8)
or the chemical shift of CH2(9). Within the 8a-acyloxy compounds, two epoxide isomers were
distinguished by the J-value of HÀC(10) in C6D6 or in CD3OD.
Introduction. – Bisabolanes are a major class of sesquiterpenoids found in various
sources [1]. Highly oxidized bisabolane compounds with an OH or acyloxy group at
C(8) and an epoxy group at C(10)ÀC(11) positions were previously isolated from
various Ligularia species (Asteraceae), such as L. dentata [2 – 4], L. thyrsoidea [5], L.
songarica [6][7], and L. cymbulifera [8][9]. Although a number of compounds were
isolated, the configurations at C(8) and C(10) of the isolated compounds had not been
determined. Over the course of our continuous study on the diversity in chemical
composition of Ligularia species in the Hengduan Mountains area of P. R. China [10],
we isolated nine O-bearing bisabolane compounds 1 – 5 [11] and 6 – 9 [12] from L.
lankongensis, but the configurations at C(8) and C(10) could not be determined for any
of them. The configurations of related highly O-bearing bisabolanes had also not been
determined [2 – 9], except for diol 10, the structure and relative configuration of which
was determined by X-ray analysis [13].
Various J-values were recorded for HÀC(8) of these compounds. For example, the
corresponding signal in compounds 1 – 5 was observed as dd (doublet of doublets) with
J ¼ 5 – 5.5 and 8 – 8.5 Hz [11], while the signal in 11 was observed with J ¼ 2.2 and
11.6 Hz [6]. The HÀC(8) was observed as a triplet (J ¼ 7 – 7.5) for both compounds 12
[9] and 13 [5]. These data suggest the presence of various configurations in the side
chain. Because the use of X-ray analysis is limited, it would be useful to synthesize
model compounds of all four possible stereoisomers with respect to the stereogenic
ꢀ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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centers of the side chain, that is, C(8) and C(10). Based on this background, we planned
to synthesize model compounds starting from isopulegol. Twelve compounds, acetates
14a – 17a, isobutyrates 14b – 17b, and tiglates 14c – 17c were the target molecules as
models with various ester groups at the C(1) and C(8). These ester groups are often
found in nature.
Results and Discussion. – Synthesis. (À)-Isopulegol (18) was used after separation
from its epimer with respect to the OH-bearing C-atom. Protection of the OH group
with TBS followed by oxidation with SeO2 afforded aldehyde 19 [14]. In order to obtain
both 8a- and 8b-OH isomers, a non-stereoselective alkylation reaction was employed
using allylmagnesium chloride, giving a 1:1 mixture of 20 and 21, and the two isomers

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were separated by HPLC (Scheme 1). The configuration of the newly generated chiral
center was determined by advanced Mosherꢁs method [15]. Namely, compounds 20 and
21 were converted to both (R)-MTPA (obtained from (S)-(þ)-MTPACl) and (S)-
MTPA (obtained from (R)-(À)-MTPACl) esters 22a, 22b and 23a, 23b, respectively,
and the configuration at C(8) was determined to be (S) for 20 and (R) for 21 from the
1
difference in chemical shifts in the H-NMR spectra (Fig. 1).
Compounds 20 and 21 were then subjected to the metathesis reaction with 2-
methylbut-2-ene in the presence of Grubbs II catalyst [16] to afford 24 (89% yield) and
25 (83% yield), respectively (Scheme 2). Direct prenylation of aldehyde 19 or its
analog to 24/25 was also tried but was unsuccessful. To obtain each stereoisomer of the
epoxide selectively, Yamamotoꢁs enantioselective epoxidation for homoallylic alcohols
[17] was examined. However, the same isomer of the epoxide was obtained selec-
tively when 24 was treated with VO(OiPr)3 in the presence of either 26a (30% yield)
or 26b (45% yield), indicating that the chiral environment in the substrate was
more effective than in the chiral ligand. The product was determined to be b-epoxide 28
by Moscherꢁs method at a later stage (vide infra). Similarly, 25 afforded epoxide 29
in 61% (26a as the ligand) or 17% (26b) yield under the same reaction conditions.
The method was also examined without Yamamotoꢁs ligand to obtain the same
Scheme 1
t
a) TBSOTf, 2,6-lutidine, CH2Cl2, r.t. b) SeO2, BuOOH, CH2Cl2, 608; c) CH2¼CHCH2MgCl, Et2O,
À 508, then HPLC. d) (þ)- or (À)-MTPACl, Et3N, CH2Cl2, r.t.
Fig. 1. Dd (d(S)MTPA À d(R)MTPA) Value of MTPA esters 22 and 23

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Scheme 2
t
a) 2-Methylbut-2-ene, Grubbs II catalyst, r.t. b) VO(OiPr)3, BuOOH, 26a or 26b, toluene, 08. c) m-
CPBA, CH2Cl2, r.t. d) TBAF, THF, r.t. e) for 14a – 17a, Ac2O, pyridine, r.t., then HPLC; for 14b – 17b,
(Me2CHCO)2O, pyridine, r.t., then HPLC; for 14c – 17c, tiglic anhydride, DMAP, CH2Cl2, r.t., then
HPLC.
Scheme 3. Stereoselective Formation of Epoxides
epoxides (from 24 to 28: 39%; from 25 to 29: 46%), confirming that the selectivity
was determined by the chirality of the substrates. The stereoselective formation of
the epoxides can be explained by the attack of the vanadium reagent coordinated with
the OH group at C(8) (Scheme 3; see below for the conformation). Then, to obtain all
four possible stereoisomers, a non-stereoselective method was carried out. When 24
was treated with m-CPBA, a 1:1 mixture of 27 and 28 was obtained; however,

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Scheme 4
a) AcOH, H2O, THF, r.t. b) (þ)- or (À)-MTPACl, Et3N, CH2Cl2, r.t.
Fig. 2. Dd (d(S)MTPA À d(R)MTPA) Value of MTPA esters 37 and 38
separation of the isomers was unsuccessful at this stage. Similarly, 25 afforded a mixture
of 29 and 30.
A mixture of 27 and 28 was converted to the acetates via deprotection followed by
acetylation reaction, and the resulting diacetates 14a and 15a were separated by
repeated HPLC (SiO2, hexane/AcOEt; Scheme 2). Similarly, 16a and 17a were
obtained from a mixture of epoxides 29 and 30. Compounds 28 and 29, respectively,
prepared by VO(OiPr)3 epoxidation, were also converted to 15a and 16a, respectively,
in the same way. Isobutyrates 14b – 17b were prepared by the related procedures. In the
synthesis of tiglates 14c – 17c, DMAP was used as the base, because the esterification
reaction of HOÀC(1) was very slow.
The absolute configuration of the epoxides was determined at this stage.
Compounds 15a and 16a were hydrolyzed to diols 35 and 36, respectively, by treatment
with aqueous AcOH [18] (Scheme 4). Then, the configuration at C(10) was determined
to be (R) for 35 and (S) for 36 by Mosherꢁs method after conversion to (R)- and (S)-
MTPA esters 37a, 37b and 38a, 38b, respectively (Fig. 2).
In the above epoxide-opening reaction, an acetate-assisted mechanism is possible
(Scheme 5). If the reaction proceeds by this mechanism, 40 is also a possible product
from 15a. This type of reaction product has been reported as an artifact of natural
bisabolane sesquiterpenes [3]. To confirm the configuration, diol 32 was treated under
the same epoxide-opening reaction conditions. As a result, tetraol 39 was obtained, and
the same compound was obtained by hydrolysis of 35 (Scheme 6). These results
indicate that the epoxide-opening reaction did not occur in the acetate-assisted mode
but in ꢂnormalꢁ mode. Thus, the configuration of C(10) was established.

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Scheme 5. Proposal of an Acetate-Assisted Mechanism of Epoxide Opening
Scheme 6
a) AcOH, H2O, THF, r.t. b) K2CO3, MeOH, r.t.
Comparison of NMR Spectra of Four Stereoisomers. NMR Spectra were first
1
measured in CDCl3 for all twelve compounds 14 – 17. All H- and 13C-signals of each
compound were assigned using COSY, HSQC, and HMBC spectra, and the results are
listed in Tables 1 and 2. A variety of J-values was observed for HÀC(8), as in natural
products. However, compounds 15b and 16b showed the same J-values (dd, J ¼ 4.5,
8.0), indicating that the estimation of the configuration of the natural products from
only the J-value of HÀC(8) is difficult (Table 1). The 13C-NMR data were too similar to
distinguish isomers (Table 2).
Distinct differences in chemical shifts were observed between compounds having an
8b-acyloxy group (14 and 15) and an 8a-acyloxy group (16 and 17). The chemical shift
of HÀC(8) of 8b-acyloxy compounds was observed at about 0.2 ppm higher field than
that of 8a-acyloxy compounds (Table 1). The H-atoms of 14a – 14c and 15a – 15c were
observed at 5.18 – 5.33, while those of 16a – 16c and 17a – 17c at 5.41 – 5.51 ppm. The
chemical shift of HeqÀC(5) was also different between 8b-acyloxy (2.00 – 2.12 ppm) and
8a-acyloxy compounds (1.78 – 1.87 ppm). These data indicate that 8b-acyloxy and 8a-
acyloxy derivatives are distinguishable. For the 8b-acyloxy compounds, differences
between 14 (a-epoxide) and 15 (b-epoxide) were recorded both in the J-value of
HÀC(8) and in the d-value of CH2(9). The difference between two J-values in HÀC(8)
was large in 14 (j J(8,9a) – J(8,9b) j¼ 6.0 Hz for 14a, 6.2 Hz for 14b, 6.3 Hz for 14c) and
small in 15 (2.3 Hz for 15a, 3.5 Hz for 15b, 2.3 Hz for 15c). Two H-atoms (CH2(9)) of
14a – 14c resonated separately (Dd > 0.1 ppm) while those of 15a – 15c did not.
Some of these observations can be explained by conformer A with respect to the
orientation of the exo-methylene group (Fig. 3). Predominance of conformer A over B
was confirmed by NOE observation between HEÀC(14) and HaxÀC(5), and between
HÀC(6) and HÀC(8), for all twelve compounds. The lower shift of HeqÀC(5) in
compounds 14 and 15 (2.00 – 2.12 ppm) can be explained by conformer A, in which the

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Fig. 3. Conformation of cyclohexane and exo-methylene moieties
H-atom and the C(8)-acyloxy group were on the same side. Although HÀC(6) and
HÀC(8) do not appear on the plane of the C(7)¼C(14) bond, hereafter conformer A is
used as the dominant conformation.
The J-value of HÀC(8) depends on the contribution of two conformers C and D (or
C’ and D’) with respect to the C(8)ÀC(9) bond (Fig. 4). The third possible conformer
can be ruled out because of steric hindrance. Conformer C (14 and 15) is unfavorable
because of the presence of steric interaction between C(10) and C(1)-acyloxy group
(Fig. 5), while such interaction is absent in conformer D. The large difference between
J(8,9a) and J(8,9b) in 14 indicates that the disadvantage of conformer C is larger in 14
than in 15, suggesting that 14 exists mainly in one conformer D. This was supported by
the difference in the chemical shifts between two H-atoms (CH2(9)) in 14.
In contrast to the 8b-acyloxy derivatives (14 and 15), it was difficult to distinguish
the two 8a-acyloxy derivatives, 16 (a-epoxide) and 17 (b-epoxide), from the data
obtained in CDCl3. Then, the NMR spectra were taken in C6D6, which is often used in
natural product chemistry (Tables 3 and 4). As a result, HÀC(10) of 16a – 16c was
observed as dd (j J(9a,10) – J(9b,10) j> 1.5 Hz), while that of 17 as a triplet (17a and
17b) or a triplet-like dd (17c, j J(9a,10) – J(9b,10) j¼ 0.7 Hz). The results suggest that 16
and 17 can be distinguished on the basis of the NMR data. A difference in chemical
shifts of HÀC(8) between 8b-acyloxy compounds (14 and 15) and 8a-acyloxy
compounds (16 and 17) was observed as in CDCl3, however, the difference was not
distinct enough to be useful for the structure determination. A large difference between
Fig. 4. Newman projection with respect to C(8)
(circle) and C(9) (dot). Conformers C and D for
compounds 14 and 15; conformers C’ and D’ for
compounds 16 and 17.
Fig. 5. Conformer C of compounds 14 and 15

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two J-values for HÀC(8) of 14 was also observed (j J(8,9a) – J(8,9b) j¼ 5.4 to 5.9 Hz).
The 13C-NMR data were too similar to distinguish isomers, as in CDCl3 (Table 4).
The NMR spectra were also measured in CD3OD (Tables 5 and 6). The difference
of the J-value of HÀC(10) between 16 and 17 was more distinct than in C6D6. Namely,
HÀC(10) was observed as dd (j J(9a,10) – J(9b,10) jꢁ 2 Hz) in 16 and as a triplet in 17.
HÀC(10) of 14 and 15 was observed as triplet (14a, 14c and 15b, 15c) or triplet-like
signal (14b and 15a; j J(9a,10) – J(9b,10) jꢂ 1 Hz), indicating that the 8a-acyloxy-10a-
epoxide structure (i.e., 16) can be distinguished from the other stereoisomers (14, 15,
and 17) only from NMR data in CD3OD. However, other data such as the difference in
d- and J-values of HÀC(8) were not distinct in CD3OD. These data indicate that
measurements of NMR spectra in various solvents are essential to determine the
relative configuration.
As described, we isolated several bisabolane compounds from Ligularia lankon-
gensis. Among them, compound 9 has trans-substituents at C(1) and C(6) with respect
to the cyclohexane ring, as in the present model compounds (the absolute configuration
of natural product has not been determined [12]). The d value of HÀC(8) of compound
9 (5.27 (dd, J ¼ 5.0, 9.0)) was very similar to that observed for 14 and 15, suggesting that
9 has the C(8) configuration related to 14 or 15. Two CH2(9) H-atoms were not
separated (1.82 – 1.92 (m, 2 H)), suggesting that the compound has the same configura-
tion as 15. Thus, compound 9 is likely to have the structure either 9a or its antipode.
Conclusions. – Twelve model compounds of highly O-bearing bisabolane sesqui-
terpenes 14a – 14c, 15a – 15c, 16a – 16c, and 17a – 17c were synthesized from isopulegol,
using two non-stereoselective reactions to obtain all four possible stereoisomers. The
NMR spectra of the compounds were compared. A distinct difference in chemical shifts
in CDCl3 was observed between 8b- and 8a-acyloxy isomers. Within the 8b-acyloxy
compounds, the a-epoxides 14a – 14c and the b-epoxides 15a – 15c could be distin-
guished by either the J-value of HÀC(8) or the chemical shift of CH2(9). Within the 8a-
acyloxy compounds, the a-epoxides 16a – 16c and the b-epoxides 17a – 17c could be
distinguished by the J-value of HÀC(10) in C6D6 or in CD3OD. Accordingly, the four
stereoisomers can be distinguished by the NMR data. The present data will provide a
guide regarding structural determination of natural products.
Experimental Part
General. Anal. TLC: Merck Kieselgel 60 F254 (0.2 mm thickness), using p-anisaldehyde/AcOH/
H2SO4 as a visualizing agent. Column chromatography (CC): silica gel (Wakogel C-200 or C-300).
HPLC: Kanto Mightysil Si60 (10 Â 250 mm) column with a solvent system of hexane/AcOEt, Shimadzu
LC-20AT pump, SPD-20A Prominence UV/VIS detector. Optical rotations: JASCO DIP-370 digital
1
polarimeter. IR Spectra: JASCO FT/IR-230 spectrometer; n˜ in cmÀ1. H- and 13C-NMR spectra: JEOL
ECX-400 (400 MHz for 1H and 100 MHz for 13C) or JEOL ECA-500 (500 MHz for 1H and 125 MHz for
13C) spectrometer using CDCl3 as the solvent unless otherwise noted; d in ppm rel. to Me4Si (0.00 ppm)
or CHCl3 (7.26 for 1H and 77.0 ppm for 13C) as internal standard, J in Hz. MS: JEOL JMS-700V (GC/MS
(double focused), EI mode), Agilent/Varian QFT-7 (hybrid of quadrupole and ICR/FT, ESI mode), or
Waters Synapt G2 (hybrid of quadrupole of TOF, ESI mode); in m/z.
(3S)-2-[(1S,2R,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-methylcyclohexyl]hexa-1,5-dien-3-ol (20)
and (3R)-2-[(1S,2R,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-methylcyclohexyl]hexa-1,5-dien-3-ol (21).

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To a stirred soln. of 19 [14] (421.2 mg, 1.49 mmol) in dry Et2O (16 ml), a soln. of allyl magnesium chloride
(2m in THF, 1.50 ml, 2.98 mmol) was added at À 508 under Ar. After stirring for 1 h, an aq. soln. of NH4Cl
was added, and the mixture was extracted with Et2O and dried (Na2SO4). Evaporation of the solvent
followed by CC (SiO2, 10 g) using hexane/AcOEt 99 :1 as eluent afforded a mixture of 20 and 21
(374.3 mg, 77%), which was separated by HPLC to yield 20 (137.0 mg) and 21 (149.5 mg).
Data of 20: Oil. [a]2D3:3 ¼ À73.0 (c ¼ 0.1, MeOH). IR (neat): 3455, 1643, 1254, 1054, 834. 1H-NMR:
0.03 (s, 3 H); 0.07 (s, 3 H); 0.87 (s, 9 H); 0.93 (d, J ¼ 6.5, Me); 1.08 (dt, J ¼ 10.9, 12.2, 1 H); 1.33 – 1.71 (m,
5 H); 1.89 (ddt, J ¼ 1.5, 12.4, 3.6, 1 H); 2.13 – 2.21 (m, 2 H); 2.35 (dt, J ¼ 14.0, 6.9, 1 H); 3.41 (dt, J ¼ 3.9,
10.2, HÀC(1)); 3.98 (br., OH); 4.13 (t, J ¼ 6.9, HÀC(8)); 4.91 (s, ¼CH2, 1 H); 4.98 (s, ¼CH2, 1 H); 5.01 –
5.09 (m, CH2(11)); 5.77 (ddt, J ¼ 10.0, 17.2, 7.1, HÀC(10)). 13C-NMR: À 4.5 (Me); À 4.4 (Me); 18.0 (C);
22.2 (Me); 25.8 (t-Bu); 31.7 (CH); 32.1 (CH2); 34.5 (CH2); 41.3 (CH2); 43.8 (CH); 44.7 (CH2); 76.0
(CH); 78.6 (CH); 110.6 (CH2); 116.7 (CH2); 135.2 (CH); 153.5 (C). EI-MS: 306 (0.4, [M À H2O]þ), 283
(23), 267 (12), 225 (25), 175 (53), 133 (59), 81 (91), 75 (100). HR-MS: 306.2366 ([M À H2O]þ,
C19H34OSiþ; calc. 306.2380).
Data of 21: Oil. [a]2D3:5 ¼ À47.2 (c ¼ 0.1, MeOH). IR (neat): 3448, 1643, 1254, 1063, 835. 1H-NMR:
À 0.01 (s, 3 H); 0.04 (s, 3 H); 0.85 (s, 9 H); 0.92 (d, J ¼ 6.5, Me); 1.03 (dt, J ¼ 10.9, 12.2, 1 H); 1.33 (dq, J ¼
3.3, 13.1, 1 H); 1.42 – 1.74 (m, 4 H); 1.81 – 1.91 (m, 2 H); 2.24 (dt, J ¼ 14.4, 7.2, 1 H); 2.40 – 2.48 (m, 1 H);
3.47 (dt, J ¼ 4.1, 10.2, HÀC(1)); 3.55 (br., OH); 4.07 (dd, J ¼ 4.3, 7.5, HÀC(8)); 4.92 (s, ¼CH2, 1 H); 5.14 (s,
¼CH2, 1 H); 5.08 – 5.16 (m, CH2(11)); 5.88 (ddt, J ¼ 10.0, 17.1, 6.9, HÀC(10)). 13C-NMR: À 4.4 (2 Me);
17.9 (C); 22.2 (Me); 25.8 (t-Bu); 31.6 (CH); 32.5 (CH2); 34.6 (CH2); 39.4 (CH2); 45.2 (CH2); 48.3 (CH);
73.9 (CH); 77.3 (CH); 107.7 (CH2); 117.3 (CH2); 135.4 (CH); 155.0 (C). EI-MS: 306 (0.3, [M À H2O]þ),
283 (7), 267 (13), 225 (18), 175 (55), 133 (49), 81 (93), 75 (100). HR-MS: 306.2375 ([M À H2O]þ,
C19H34OSiþ; calc. 306.2380).
Mosherꢁs Esters (22a, 22b, 23a, 23b). To a stirred soln. of 21 (13.5 mg, 0.043 mmol) in CH2Cl2 (1 ml),
Et3N (0.035 ml, 0.35 mmol) and (þ)-MTPACl (0.015 ml, 0.059 mmol) were added at r.t. under Ar. After
stirring for 2 h, H2O was added, and the mixture was extracted with Et2O. The org. layer was washed
successively with 1m HCl and aq. NaHCO3 and dried (Na2SO4). Evaporation of the solvent followed by
CC (SiO2, 9 g) afforded 23a (19.3 mg, 83%). In the same way, compounds 22a, 22b, and 23b were
prepared.
(3S)-2-[(1S,2R,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-methylcyclohexyl]hexa-1,5-dien-3-yl (2R)-
1
3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (22a). H-NMR: À 0.07 (s, 3 H); 0.02 (s, 3 H); 0.72 –
1.97 (m, 7 H); 0.83 (s, 9 H); 0.90 (d, J ¼ 6.3, MeÀC(3)); 1.64 (ddd, J ¼ 3.3, 10.0, 12.1, HÀC(6)); 2.33
(br. dt, J ¼ 15, 9, HÀC(9)); 2.71 (dddt, J ¼ 2.8, 6.0, 15.3, 1.5, HÀC(9)); 3.52 – 3.60 (m, HÀC(1)); 3.57 (s,
MeO); 4.81 (br. s, ¼CH2, 1 H); 4.86 (br. s, ¼CH2, 1 H); 5.05 – 5.15 (m, CH2(11)); 5.30 (dd, J ¼ 2.4, 9.4,
HÀC(8)); 5.81 (ddt, J ¼ 10.1, 16.9, 6.9, HÀC(10)); 7.34 – 7.56 (m, 5 arom. H).
(3S)-2-[(1S,2R,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-methylcyclohexyl]hexa-1,5-dien-3-yl (2S)-
1
3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (22b). H-NMR: À 0.04 (s, 3 H); 0.04 (s, 3 H); 0.78 –
1.97 (m, 7 H); 0.83 (s, 9 H); 0.91 (d, J ¼ 6.6, MeÀC(3)); 1.72 (ddd, J ¼ 3.3, 10.0, 12.1, HÀC(6)); 2.30
(br. dt, J ¼ 15, 8, HÀC(9)); 2.64 (dddt, J ¼ 3.0, 6.4, 15.2, 1.6, HÀC(9)); 3.61 (dt, J ¼ 4.2, 10.1, HÀC(1)); 3.52
(s, MeO); 4.94 (br. s, ¼CH2, 1 H); 4.93 – 5.13 (m, CH2(11)); 5.13 (br. s, ¼CH2, 1 H); 5.35 (dd, J ¼ 2.6, 9.2,
HÀC(8)); 5.67 (ddt, J ¼ 10.1, 16.9, 6.8, HÀC(10)); 7.34 – 7.55 (m, 5 arom. H).
(3R)-2-[(1S,2R,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-methylcyclohexyl]hexa-1,5-dien-3-yl (2R)-
3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (23a). 1H-NMR: À 0.06 (s, 3 H); 0.03 (s, 3 H); 0.71 – 1.68
(m, 6 H); 0.84 (s, 9 H); 0.91 (d, J ¼ 6.9, MeÀC(3)); 1.83 (ddd, J ¼ 3.0, 9.4, 12.6, HÀC(6)); 1.87 (br. q, J ¼
12, HÀC(2)); 2.42 – 2.56 (m, CH2(9)); 3.52 (br. s, MeO); 3.52 (dt, J ¼ 4.0, 10.5, HÀC(1)); 4.93 – 4.99 (m,
CH2(11)); 4.98 (br. s, ¼CH2, 1 H); 5.21 (br. s, ¼CH2, 1 H); 5.64 (ddt, J ¼ 9.8, 16.9, 7.2, HÀC(10)); 5.61 –
5.66 (m, HÀC(8)); 7.32 – 7.59 (m, 5 arom. H).
(3R)-2-[(1S,2R,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-methylcyclohexyl]hexa-1,5-dien-3-yl (2S)-
1
3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (23b). H-NMR: À 0.07 (s, 3 H); 0.01 (s, 3 H); 0.71 –
1.68 (m, 6 H); 0.84 (s, 9 H); 0.89 (d, J ¼ 6.6, MeÀC(3)); 1.79 (ddd, J ¼ 3.0, 9.4, 12.6, HÀC(6)); 1.87 (br.
q, J ¼ 12, HÀC(2)); 2.55 (t-like, J ¼ 6.8, CH2(9)); 3.56 (br. s, MeO); 3.48 (dt, J ¼ 4.0, 10.2, HÀC(1)); 4.93
(br. s, ¼CH2, 1 H); 5.03 – 5.11 (m, CH2(11)); 5.12 (br. s, ¼CH2, 1 H); 5.62 (t-like, J ¼ 5.6, HÀC(8)); 5.76
(ddt, J ¼ 10.1, 17.2, 6.9, HÀC(10)); 7.32 – 7.59 (m, 5 arom. H).

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Helvetica Chimica Acta – Vol. 98 (2015)
(3S)-2-[(1S,2R,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-methylcyclohexyl]-6-methylhepta-1,5-dien-
3-ol (24) and (3R)-2-[(1S,2R,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-methylcyclohexyl]-6-methylhep-
ta-1,5-dien-3-ol (25). In a 30 ml two-necked flask, Grubbs II catalyst (1.4 mg, 0.0017 mmol) and 20
(23.6 mg, 0.07 mmol) were dissolved in 2-methylbut-2-ene (2.5 ml) under Ar. After stirring at r.t. for 1 h,
the solvent was evaporated, and the residue was chromatographed (SiO2, 6 g) using hexane/AcOEt
(gradient) to afford 24 (22.7 mg, 89%). By the same procedure, 21 (82.5 mg, 0.25 mmol) yielded 25
(74.3 mg, 83%).
Data of 24: Oil. [a]2D3 ¼ À61.2 (c ¼ 0.1, MeOH). IR (neat): 3460, 1645, 1450, 1254, 1055. 1H-NMR:
0.03 (s, Me); 0.07 (s, Me); 0.87 (s, t-Bu, 9 H); 0.93 (d, J ¼ 6.5, Me); 1.08 (dt, J ¼ 11.0, 12.2, 1 H); 1.33 – 1.69
(m, 5 H); 1.61 (br. s, Me); 1.69 (q, J ¼ 1.0, Me); 1.86 – 1.92 (m, 1 H); 2.05 – 2.35 (m, 3 H); 3.41 (dt, J ¼ 4.0,
10.3, HÀC(1)); 3.91 (d, J ¼ 1.3, OH); 4.07 (br. t, J ¼ 6.9, HÀC(8)); 4.89 (s, ¼CH2, 1 H); 4.97 (s, ¼CH2,
1 H); 5.06 – 5.12 (m, HÀC(10)). 13C-NMR: À 4.5; À 4.4; 18.0 (2 C); 22.2; 25.8 (4 C); 31.7; 32.3; 34.6;
35.2; 43.9; 44.8; 76.3; 78.5; 110.4; 120.5; 133.0; 153.9. EI-MS: 352 (0.2, Mþ), 295 (11), 283 (67), 203 (32),
151 (100), 133 (80), 75 (72). HR-MS: 295.2089 ([M À t-Bu]þ, C17H31O2Siþ; calc. 295.2094).
Data of 25: Oil. [a]2D3 ¼ À43.0 (c ¼ 0.1, MeOH). IR (neat): 3354, 1651, 1452, 1261, 1053. 1H-NMR:
À 0.01 (s, Me); 0.04 (s, Me); 0.85 (s, t-Bu, 9 H); 0.92 (d, J ¼ 6.5, Me); 1.02 (dt, J ¼ 10.9, 12.2, 1 H); 1.32
(dq, J ¼ 3.4, 13.0, 1 H); 1.42 – 1.73 (m, 4 H); 1.64 (br. s, Me); 1.72 (q, J ¼ 1.0, Me); 1.80 – 1.91 (m, 2 H);
2.16 – 2.39 (m, 2 H); 2.47 (d, J ¼ 3.7, OH); 3.47 (dt, J ¼ 4.3, 10.2, HÀC(1)); 4.02 (dt-like, J ¼ 7.0, 4.0,
HÀC(8)); 4.90 (s, ¼CH2, 1 H); 5.12 (s, ¼CH2, 1 H); 5.16 – 5.22 (m, HÀC(10)). 13C-NMR: À 4.4 (2 C);
18.0 (2 C); 22.2; 25.9 (4 C); 31.6; 32.6; 33.8; 34.7; 45.3; 48.4; 74.7; 77.2; 107.5; 120.7; 134.1; 155.2. EI-MS:
352 (0.4, Mþ), 295 (11), 283 (41), 225 (55), 203 (39), 151 (100), 133 (97), 75 (96). HR-MS: 295.2086
([M À t-Bu]þ, C17H31O2Siþ; calc. 295.2094).
(2S)-3-[(1S,2R,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-methylcyclohexyl]-1-(3,3-dimethyloxiran-
2-yl)but-3-en-2-ol (27 and 28) and (2R)-3-[(1S,2R,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-methylcyclo-
hexyl]-1-(3,3-dimethyloxiran-2-yl)but-3-en-2-ol (29 and 30). By m-CPBA: To a stirred soln. of 24
(8.5 mg, 0.024 mmol) in CH2Cl2 (2 ml), m-CPBA (4.7 mg, 0.07 mmol) was added at À 308. After stirring
for 3.5 h, a sat. aq. soln. of NaHCO3 was added, and the mixture was extracted with CH2Cl2 and dried
(Na2SO4). Evaporation of the solvent followed by CC (SiO2, 6 g) using Et2O/AcOEt (gradient) as eluent
afforded an inseparable mixture of 27 and 28 (7.1 mg, 80%). Similarly, 25 (10.0 mg, 0.028 mmol) was
treated with m-CPBA (6.8 mg, 0.04 mmol) to afford a mixture of 29 and 30 (11.7 mg, 89%), which was
used in the next step without purification.
By Yamamotoꢁs method: To a stirred soln. of 26a (40.9 mg, 0.12 mmol) in toluene (1 ml), VO(OiPr)3
(3 ml, 0.013 mmol) was added, and the mixture was stirred for 1 h at r.t. After being cooled to 08, a soln. of
24 (8.8 mg, 0.012 mmol) in toluene (1 ml) was added, and the stirring was continued for an additional
4.5 h. A sat. aq. soln. of Na2SO3 was added, and the mixture was extracted with Et2O and dried (Na2SO4).
Evaporation of the solvent followed by CC (SiO2, 5 g) using hexane/AcOEt (gradient) afforded 28
(13.1 mg, 30%). Similarly, 25 (13.8 mg, 0.039 mmol) was treated with 26a (5.9 mg, 0.008 mmol) and
VO(OiPr)3 (3 ml, 0.013 mmol) at 08 for 3.5 h to afford 29 (8.8 mg, 61%).
Data of 28: Oil. [a]2D1 ¼ À42.0 (c ¼ 0.05, MeOH). IR (neat): 3444, 1450, 1255, 1049. 1H-NMR: 0.03 (s,
Me); 0.07 (s, Me); 0.87 (s, t-Bu, 9 H); 0.94 (d, J ¼ 6.5, Me); 1.01 – 1.93 (m, 9 H); 1.27 (s, Me); 1.30 (s, Me);
2.19 (ddd, J ¼ 3.2, 9.9, 12.7, 1 H); 2.78 (dd, J ¼ 5.0, 7.4, HÀC(10)); 3.42 (dt, J ¼ 4.0, 10.4, HÀC(1)); 4.04 (d,
J ¼ 0.7, OH); 4.29 (t, J ¼ 7.2, HÀC(8)); 4.96 (s, ¼CH2, 1 H); 5.08 (s, ¼CH2, 1 H). 13C-NMR: À 4.5; À 4.4;
18.0; 19.0; 22.2; 24.8; 25.8 (3 C); 31.7; 32.4; 34.5; 35.8; 43.9; 44.8; 57.9; 61.5; 74.1; 78.6; 110.8; 153.6. EI-
MS: 368 (1, Mþ); 311 (30), 225 (58), 149 (46), 75 (100), 71 (96). HR-MS: 311.2047 ([M À t-Bu]þ,
C17H31O3Siþ; calc. 311.2043).
Data of 29: Oil. [a]2D1 ¼ À36.6 (c ¼ 0.1, MeOH). IR (neat): 3456, 1452, 1257, 1082. 1H-NMR: À 0.01
(s, Me); 0.05 (s, Me); 0.84 (s, t-Bu, 9 H); 0.92 (d, J ¼ 6.5, Me); 1.07 – 1.95 (m, 11 H); 1.29 (s, Me); 1.33 (s,
Me); 2.99 (dd, J ¼ 5.5, 6.5, HÀC(10)); 3.48 (dt, J ¼ 4.0, 10.1, HÀC(1)); 4.24 (dd, J ¼ 3.6, 8.0, HÀC(8)); 4.99
(s, ¼CH2, 1 H); 5.17 (s, ¼CH2, 1 H). 13C-NMR: À 4.4; À 4.3; 18.0; 19.0; 22.2; 24.8; 25.9 (3 C); 31.6; 32.6;
34.1; 34.6; 45.2; 48.2; 57.9; 62.2; 73.6; 107.9; 154.8 (one C-atom signal overlapped with the signal of
CDCl3). EI-MS: 368 (3, Mþ), 311 (55), 225 (52), 149 (52), 75 (100), 71 (99). HR-MS: 368.2733 (Mþ,
C21H40O3Siþ; calc. 368.2748).

Helvetica Chimica Acta – Vol. 98 (2015)
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(1R,2S,5R)-2-[(3S)-4-(3,3-Dimethyloxiran-2-yl)-3-hydroxybut-1-en-2-yl]-5-methylcyclohexanol (31
and 32) and (1R,2S,5R)-2-[(3R)-4-(3,3-Dimethyloxiran-2-yl)-3-hydroxybut-1-en-2-yl]-5-methylcyclo-
hexanol (33 and 34). A mixture of 27 and 28 (7.1 mg, 0.02 mmol) was dissolved in THF (2 ml). TBAF
(0.02 ml, 0.02 mmol) was added, and the mixture was stirred at r.t. for 30 min. A sat. aq. soln. of NH4Cl
was added, and the mixture was extracted with AcOEt. After drying (Na2SO4), the solvent was
evaporated, and the resultant residue was chromatographed (SiO2, 6 g) using hexane/AcOEt (gradient)
to give a mixture of 31 and 32 (4.9 mg, 100%). By the same procedure, a mixture of 29 and 30 (29.4 mg,
0.080 mmol) afforded a mixture of 33 and 34 (19.6 mg, 96%); 28 (10.5 mg, 0.028 mmol), obtained by
Yamamotoꢁs epoxidation, afforded 32 (6.9 mg, 97%); 29 (23.1 mg, 0.063 mmol) afforded 33 (11.9 mg,
74%).
Data of 32: Oil. [a]2D4 ¼ À16.0 (c ¼ 0.025, MeOH). IR (neat): 3200 – 3400, 1647, 1444, 1039.
1H-NMR: 0.95 (d, J ¼ 6.5, Me); 0.97 – 2.05 (m, 12 H); 1.30 (s, Me); 1.32 (s, Me); 2.94 (dd, J ¼ 3.7, 8.5,
HÀC(10)); 3.53 (dt, J ¼ 4.1, 10.5, HÀC(1)); 4.38 (dd, J ¼ 5,8, 6.6, HÀC(8)); 5.08 (s, ¼CH2, 1 H); 5.26 (s,
¼CH2, 1 H). 13C-NMR: 18.9; 22.1; 24.7; 31.4; 32.7; 34.2; 34.6; 43.7; 46.5; 57.9; 61.7; 73.7; 74.6; 111.5; 153.5.
EI-MS: 254 (19, Mþ), 236 (17), 182 (15), 81 (59), 71 (100). HR-MS: 254.1880 (Mþ, C15H26Oþ3 ; calc.
254.1883).
Data of 33: Oil. [a]2D4 ¼ À22.8 (c ¼ 0.05, MeOH). IR (neat): 3402, 1646, 1454, 1051. 1H-NMR: 0.94
(d, J ¼ 6.5, Me); 0.97 – 2.07 (m, 12 H); 1.31 (s, Me); 1.33 (s, Me); 2.98 (dd, J ¼ 4.2, 8.2, HÀC(10)); 3.52 (dt,
J ¼ 4.0, 10.4, HÀC(1)); 4.35 (dd, J ¼ 4.0, 8.0, HÀC(8)); 5.08 (s, ¼CH2, 1 H); 5.28 (s, ¼CH2, 1 H).
13C-NMR: 19.0; 22.2; 24.7; 31.5; 32.3; 34.1; 34.6; 43.7; 49.4; 58.1; 62.3; 73.5; 74.5; 110.4; 153.7. EI-MS: 254
(6, Mþ), 236 (14), 190 (17), 71 (82), 43 (100). HR-MS: 254.1879 (Mþ, C15H26Oþ3 ; calc. 254.1883).
(1R,2S,5R)-2-{(3S)-3-(Acetyloxy)-4-[(2S)-3,3-dimethyloxiran-2-yl]but-1-en-2-yl}-5-methylcyclohex-
yl Acetate (14a), (1R,2S,5R)-2-{(3S)-3-(Acetyloxy)-4-[(2R)-3,3-dimethyloxiran-2-yl]but-1-en-2-yl}-5-
methylcyclohexyl Acetate (15a), (1R,2S,5R)-2-{(3R)-3-(Acetyloxy)-4-[(2S)-3,3-dimethyloxiran-2-yl]-
but-1-en-2-yl}-5-methylcyclohexyl Acetate (16a), and (1R,2S,5R)-2-{(3R)-3-(Acetyloxy)-4-[(2R)-3,3-
dimethyloxiran-2-yl]but-1-en-2-yl}-5-methylcyclohexyl Acetate (17a). To a stirred soln. of a mixture of 31
and 32 (4.9 mg, 0.02 mmol) in pyridine (2 ml), Ac2O (10 ml) was added, and the mixture was stirred at r.t.
for 1 d. H2O was added, the mixture was extracted with Et2O, and the org. layer was dried (Na2SO4).
Evaporation of the solvent followed by CC (SiO2, 6 g) using hexane/AcOEt (gradient) afforded a
mixture of 14a and 15a (5.4 mg, 83%), which was further separated by HPLC. By the same procedure, a
mixture of 33 and 34 (19.6 mg, 0.077 mmol) was acetylated to yield a mixture of 16a and 17a (22.0 mg,
84%), which was separated by HPLC. Compound 32 (15.3 mg, 0.06 mmol) afforded 15a (20.9 mg, 99%);
33 (37.0 mg, 0.15 mmol) afforded 16a (47.3 mg, 93%).
Data of 14a: Oil. [a]2D6 ¼ À40.5 (c ¼ 0.2, MeOH). IR (neat): 1738, 1664, 1242, 1034. 1H-NMR:
Tables 1, 3, and 5. 13C-NMR: Tables 2, 4, and 6. EI-MS: 278 (3, [M À AcOH]þ), 218 (36), 81 (28), 43
(100). HR-MS: 278.1881 ([M À AcOH]þ, C17H26O3þ ; calc. 278.1883).
Data of 15a: Oil. [a]2D6 ¼ À27.2 (c ¼ 0.42, MeOH). IR (neat): 1737, 1651, 1241, 1027. 1H-NMR:
Tables 1, 3, and 5. 13C-NMR: Tables 2, 4, and 6. EI-MS: 278 (2, [M – AcOH]þ), 218 (27), 85 (48), 43
(100). HR-MS: 278.1886 ([M À AcOH]þ, C17H26O3þ ; calc. 278.1883).
Dat of 16a: Oil. [a]2D6 ¼ À22.9 (c ¼ 0.37, MeOH). IR (neat): 1738, 1648, 1243, 1027. 1H-NMR:
Tables 1, 3, and 5. 13C-NMR: Tables 2, 4, and 6. EI-MS: 278 (2, [M À AcOH]þ), 218 (26), 85 (41), 43
(100). HR-MS: 278.1882 ([M – AcOH]þ, C17H26O3þ ; calc. 278.1883).
Data of 17a: Oil. [a]2D6 ¼ À23.9 (c ¼ 0.24, MeOH). IR (neat): 1738, 1664, 1242, 1036. 1H-NMR:
Tables 1, 3, and 5. 13C-NMR: Tables 2, 4, and 6. EI-MS: 278 (2, [M À AcOH]þ), 218 (17), 85 (22), 43
(100). HR-MS: 278.1888 ([M À AcOH]þ, C17H26O3þ ; calc. 278.1883).
(2S)-1-[(2S)-3,3-Dimethyloxiran-2-yl]-3-{(1S,2R,4R)-4-methyl-2-[(2-methylpropanoyl)oxy]cyclo-
hexyl}but-3-en-2-yl 2-Methylpropanoate (14b), (2S)-1-[(2R)-3,3-Dimethyloxiran-2-yl]-3-{(1S,2R,4R)-4-
methyl-2-[(2-methylpropanoyl)oxy]cyclohexyl}but-3-en-2-yl 2-Methylpropanoate (15b), (2R)-1-[(2S)-
3,3-Dimethyloxiran-2-yl]-3-{(1S,2R,4R)-4-methyl-2-[(2-methylpropanoyl)oxy]cyclohexyl}but-3-en-2-yl
2-Methylpropanoate (16b), and (2R)-1-[(2R)-3,3-Dimethyloxiran-2-yl]-3-{(1S,2R,4R)-4-methyl-2-[(2-
methylpropanoyl)oxy]cyclohexyl}but-3-en-2-yl 2-Methylpropanoate (17b). By the same procedure, a
mixture of 31 and 32 (60.8 mg, 0.24 mmol) was treated with isobutyric anhydride (160 ml) to afford a

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Helvetica Chimica Acta – Vol. 98 (2015)
mixture of 14b and 15b (88.7 mg, 94%), and the two compounds were separated. Similarly, a mixture of
33 and 34 afforded 15b and 16b (81%); 32 afforded 15b (45%); 33 afforded 16b (42%).
Data of 14b: Oil. [a]2D1 ¼ À78.4 (c ¼ 0.40, MeOH). IR (neat): 1734, 1653, 1157. 1H-NMR: Tables 1, 3,
and 5. 13C-NMR: Tables 2, 4, and 6. ESI-MS: 417 ([M þ Na]þ). HR-MS: 417.2610 ([M þ Na]þ,
C23H38NaOþ5 ; calc. 417.2617).
Data of 15b: Oil. [a]2D3 ¼ À28.2 (c ¼ 0.44, MeOH). IR (neat): 1735, 1651, 1158. 1H-NMR: Tables 1, 3,
and 5. 13C-NMR: Tables 2, 4, and 6. ESI-MS: 417 ([M þ Na]þ). HR-MS: 417.2614 ([M þ Na]þ,
C23H38NaOþ5 ; calc. 417.2617).
Data of 16b: Oil. [a]2D3 ¼ À19.0 (c ¼ 0.56, MeOH). IR (neat): 1733, 1652, 1159. 1H-NMR: Tables 1, 3,
and 5. 13C-NMR: Tables 2, 4, and 6. ESI-MS: 417 ([M þ Na]þ. HR-MS: 417.2614 ([M þ Na]þ,
C23H38NaOþ5 ; calc. 417.2617).
Data of 17b: Oil. [a]2D1 ¼ À8.8 (c ¼ 0.24, MeOH). IR (neat): 1734, 1651, 1157. 1H-NMR: Tables 1, 3,
and 5. 13C-NMR: Tables 2, 4, and 6. ESI-MS: 417 ([M þ Na]þ). HR-MS: 417.2611 ([M þ Na]þ,
C23H38NaOþ5 ; calc. 417.2617).
(1R,2S,5R)-2-[(3S)-4-[(2S)-3,3-Dimethyloxiran-2-yl]-3-{[(2E)-2-methylbut-2-enoyl]oxy}but-1-en-
2-yl]-5-methylcyclohexyl (2E)-2-Methylbut-2-enoate (14c), (1R,2S,5R)-2-[(3S)-4-[(2R)-3,3-Dimethy-
loxiran-2-yl]-3-{[(2E)-2-methylbut-2-enoyl]oxy}but-1-en-2-yl]-5-methylcyclohexyl (2E)-2-Methylbut-2-
enoate (15c), (1R,2S,5R)-2-[(3R)-4-[(2S)-3,3-Dimethyloxiran-2-yl]-3-{[(2E)-2-methylbut-2-enoyl]oxy}-
but-1-en-2-yl]-5-methylcyclohexyl (2E)-2-Methylbut-2-enoate (16c), and (1R,2S,5R)-2-[(3R)-4-[(2R)-
3,3-Dimethyloxiran-2-yl]-3-{[(2E)-2-methylbut-2-enoyl]oxy}but-1-en-2-yl]-5-methylcyclohexyl (2E)-2-
Methylbut-2-enoate (17c). A mixture of 31 and 32 (67.4 mg, 0.26 mmol) in dry CH2Cl2 (15 ml) was
treated with tiglic anhydride (235 ml) and DMAP (211.1 mg) to afford a mixture of 14c and 15c (103.0 mg,
95%), and the two compounds were separated by HPLC. Similarly, a mixture of 33 and 34 afforded 15c
and 16c (83%); 32 afforded 15c (71%); 33 afforded 16c (84%).
Data of 14c: Oil. [a]2D5 ¼ À45.7 (c ¼ 0.39, MeOH). IR (neat): 1710, 1652, 1256. 1H-NMR: Tables 1, 3,
and 5. 13C-NMR: Tables 2, 4, and 6. ESI-MS: 441 ([M þ Na]þ). HR-MS: 441.2615 ([M þ Na]þ,
C25H38NaOþ5 ; calc. 441.2617).
Data of 15c: Oil. [a]2D5 ¼ À55.8 (c ¼ 0.29, MeOH). IR (neat): 1713, 1705, 1652, 1256. 1H-NMR:
Tables 1, 3, and 5. 13C-NMR: Tables 2, 4, and 6. ESI-MS: 441 ([M þ Na]þ). HR-MS: 441.2619 ([M þ
Na]þ, C25H38NaOþ5 ; calc. 441.2617).
Data of 16c: Oil. [a]2D6 ¼ À42.4 (c ¼ 0.22, MeOH). IR (neat): 1706; 1652; 1255. 1H-NMR: Tables 1, 3,
and 5. 13C-NMR: Tables 2, 4, and 6. ESI-MS: 441 ([M þ Na]þ). HR-MS: 441.2619 ([M þ Na]þ,
C25H38NaOþ5 ; calc. 441.2617).
Data of 17c: Oil. [a]2D5 ¼ À27.0 (c ¼ 0.25, MeOH). IR (neat): 1713, 1705, 1652, 1255. 1H-NMR:
Tables 1, 3, and 5. 13C-NMR: Tables 2, 4, and 6. ESI-MS: 441 ([M þ Na]þ). HR-MS: 441.2614 ([M þ Na]þ
, C25H38NaOþ5 ; calc. 441.2617).
(1R,2S,5R)-2-[(3S,5R)-3-(Acetyloxy)-5,6-dihydroxy-6-methylhept-1-en-2-yl]-5-methylcyclohexyl
Acetate (35) and (1R,2S,5R)-2-[(3R,5S)-3-(Acetyloxy)-5,6-dihydroxy-6-methylhept-1-en-2-yl]-5-methyl-
cyclohexyl Acetate (36). To a stirred soln. of 15 (20.2 mg, 0.059 mmol) in THF (2 ml), AcOH/H2O (2 ml,
ratio 1:1) was added at r.t., and the stirring was continued for 1 d. An aq. soln. of Na2SO3 was added, and
the mixture was extracted with Et2O, washed with NaHCO3 aq., and dried (Na2SO4). Evaporation of the
solvent followed by CC (SiO2, 4 g) using hexane/AcOEt (85 :15) afforded 35 (16.1 mg, 77%). By the
same procedure, 16 (65.8 mg, 0.19 mmol) was treated with AcOH/H2O (6 ml) to yield 36 (52.8 mg, 78%).
Data of 35: Oil. [a]2D8 ¼ À28.4 (c ¼ 0.37, MeOH). IR (neat): 3438, 1726, 1645, 1254, 1038. 1H-NMR:
0.93 (d, J ¼ 6.5, Me); 0.96 – 2.14 (m, 11 H); 1.17 (s, Me); 1.20 (s, Me); 1.97 (s, Ac); 2.09 (s, Ac); 2.51 (br. d,
J ¼ 2.6, OH); 3.50 (br. d, J ¼ 9.8, HÀC(10)); 4.86 (dt, J ¼ 4.2, 11.0, HÀC(1)); 5.02 (s, ¼CH2, 1 H); 5.17 (s,
¼CH2, 1 H); 5.32 (t, J ¼ 6.3, HÀC(8)). 13C-NMR: 21.1; 21.4; 21.9; 23.8; 25.9; 31.2; 33.5; 34.4; 35.7; 40.5;
44.7; 72.6; 74.9; 75.3; 75.7; 111.1; 148.8; 169.9; 170.5. ESI-MS: 379 ([M þ Na]þ). HR-MS: 379.2091 ([M þ
Na]þ, C19H32NaOþ6 ; calc. 379.2091).
Data of 36: Oil. [a]2D8 ¼ À23.2 (c ¼ 0.48, MeOH). IR (neat): 3465, 1726, 1250, 1039. 1H-NMR: 0.93
(d, J ¼ 6.5, Me); 0.96 – 2.21 (m, 11 H); 1.17 (s, Me); 1.20 (s, Me); 2.00 (s, Ac); 2.07 (s, Ac); 2.59 (br. s,
OH); 3.46 (br. d, J ¼ 9.8, HÀC(10)); 4.82 (dt, J ¼ 4.2, 10.9, HÀC(1)); 5.06 (s, ¼CH2, 1 H); 5.18 (s, ¼CH2,
1 H); 5.49 (t, J ¼ 6.5, HÀC(8)). 13C-NMR: 21.3; 21.4; 21.9; 23.9; 25.9; 31.2; 32.7; 34.3; 35.1; 40.6; 44.9;

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72.6; 75.4; 75.7; 75.9; 112.6; 148.6; 170.0; 170.7. ESI-MS: 379 ([M þ Na]þ). HR-MS: 379.2090 ([M þ
Na]þ, C19H32NaOþ6 ; calc. 379.2091).
Mosherꢁs Esters (37a, 37b, 38a, 38b). By the same procedure described for 23a, 37a, 37b and 38a, 38b
were prepared from 35 and 36, resp.
(3R,5S)-5-(Acetyloxy)-6-[(1S,2R,4R)-2-(acetyloxy)-4-methylcyclohexyl]-2-hydroxy-2-methylhept-6-
1
en-3-yl (2R)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (37a). H-NMR: 0.82 – 2.07 (m, 9 H); 0.93
(d, J ¼ 6.5, Me); 1.18 (s, Me); 1.20 (s, Me); 1.74 (ddd, J ¼ 7.0, 8.0, 15.0, CH2(9), 1 H); 1.93 (s, Ac); 2.04 (s,
Ac); 2.17 (ddd, J ¼ 3.7, 5.7, 15.0, CH2(9), 1 H); 3.53 (s, MeO); 4.81 (dt, J ¼ 4.2, 10.8, HÀC(1)); 4.98 (dd,
J ¼ 3.7, 6.9, HÀC(10)); 5.01 (s, ¼CH2, 1 H); 5.11 (s, ¼CH2, 1 H); 5.15 (dd, J ¼ 5.8, 8.0, HÀC(8)); 7.40 – 7.62
(m, 5 arom. H).
(3R,5S)-5-(Acetyloxy)-6-[(1S,2R,4R)-2-(acetyloxy)-4-methylcyclohexyl]-2-hydroxy-2-methylhept-6-
1
en-3-yl (2S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (37b). H-NMR: 0.82 – 2.07 (m, 9 H); 0.93
(d, J ¼ 6.5, Me); 1.14 (s, Me); 1.15 (s, Me); 1.81 (ddd, J ¼ 7.0, 8.5, 15.2, CH2(9), 1 H); 1.94 (s, Ac); 1.95 (s,
Ac); 2.28 (ddd, J ¼ 3.2, 5.6, 15.3, CH2(9), 1 H); 3.63 (s, MeO); 4.81 (dt, J ¼ 4.1, 10.8, HÀC(1)); 4.98 (dd,
J ¼ 3.1, 6.9, HÀC(10)); 5.02 (s, ¼CH2, 1 H); 5.11 (s, ¼CH2, 1 H); 5.20 (dd, J ¼ 5.7, 8.6, HÀC(8)); 7.40 – 7.66
(m, 5 arom. H).
(3S,5R)-5-(Acetyloxy)-6-[(1S,2R,4R)-2-(acetyloxy)-4-methylcyclohexyl]-2-hydroxy-2-methylhept-6-
1
en-3-yl (2R)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (38a). H-NMR: 0.80 – 2.08 (m, 9 H); 0.93
(d, J ¼ 6.5, Me); 1.14 (s, Me); 1.15 (s, Me); 1.94 (overlapped with other signals, d value was determined by
COSY spectrum, CH2(9), 1 H); 1.95 (s, Ac); 2.02 (s, Ac); 2.17 (ddd, J ¼ 3.2, 6.4, 14.8, CH2(9), 1 H); 3.63
(s, MeO); 4.82 (dt, J ¼ 4.0, 10.5, HÀC(1)); 4.98 (dd, J ¼ 3.2, 7.0, HÀC(10)); 5.04 (s, ¼CH2, 1 H); 5.08 (s,
¼CH2, 1 H); 5.38 (dd, J ¼ 6.5, 8.2, HÀC(8)); 7.36 – 7.66 (m, 5 arom. H).
(3S,5R)-5-(Acetyloxy)-6-[(1S,2R,4R)-2-(acetyloxy)-4-methylcyclohexyl]-2-hydroxy-2-methylhept-6-
1
en-3-yl (2S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (38b). H-NMR: 0.80 – 2.08 (m, 9 H); 0.93
(d, J ¼ 6.5, Me); 1.17 (s, Me); 1.20 (s, Me); 1.86 (overlapped with other signals, d value was determined by
COSY spectrum, CH2(9), 1 H); 2.01 (s, Ac); 2.03 (s, Ac); 2.08 (ddd, J ¼ 3.8, 6.5, 15.0, CH2(9), 1 H); 3.52
(s, MeO); 4.82 (dt, J ¼ 4.1, 10.8, HÀC(1)); 4.97 (dd, J ¼ 3.7, 7.0, HÀC(10)); 5.03 (s, ¼CH2, 1 H); 5.10 (s,
¼CH2, 1 H); 5.35 (dd, J ¼ 6.5, 7.8, HÀC(8)); 7.37 – 7.70 (m, 5 arom. H).
(3R,5S)-6-[(1S,2R,4R)-2-Hydroxy-4-methylcyclohexyl]-2-methylhept-6-ene-2,3,5-triol (39). From
32: As described for 35, compound 32 (39.0 mg, 0.15 mmol) was treated with AcOH/H2O to yield 39
(17.6 mg, 43%).
From 35: To a stirred soln. of 35 (17.9 mg, 0.05 mmol) in MeOH (3 ml), K2CO3 (40.7 mg) was added,
and the stirring was continued at r.t. for 2.5 h. 1m HCl aq. was added, and the mixture was extracted with
CH2Cl2 and dried (Na2SO4). Evaporation of the solvent followed by CC (SiO2, 5 g) using hexane/AcOEt
(2 :3) afforded 39 (6.3 mg, 46%).
1
Data of 39: Oil. [a]2D5 ¼ À16.9 (c ¼ 0.38, MeOH). IR (neat): 3335, 1645. H-NMR: 0.96 (d, J ¼ 6.5,
Me); 1.06 (q, J ¼ 11.6, 1 H); 1.17 (s, Me); 1.22 (s, Me); 1.35 – 2.10 (m, 13 H); 3.46 (dt, J ¼ 4.1, 11.5,
HÀC(1)); 3.68 (dd, J ¼ 1.5, 9.9, HÀC(10)); 4.40 (dd, J ¼ 3.1, 9.7, HÀC(8)); 5.02 (s, ¼CH2, 1 H); 5.18 (s,
¼CH2, 1 H). 13C-NMR: 22.4; 24.2; 26.7; 31.8; 32.6; 34.7; 36.9; 44.5; 45.4; 72.8; 76.0; 76.7; 78.7; 112.2;
154.1. ESI-MS: 295 ([M þ Na]þ). HR-MS: 295.1892 ([M þ Na]þ, C15H28NaOþ4 ; calc. 295.1885).
We are grateful to Dr. Hiroyuki Osada, RIKEN Antibiotics Laboratory, for his encouragement and
discussions. This work was partly supported by a Grant-in-Aid for Scientific Research from JSPS (No.
21404009 and 25303010) and by the Strategic Research Foundation Grant-aided Project for Private
Universities from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
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Received December 22, 2014