Synthesis and configuration of the phenolic nonadecanediol isolated from the resinous exudates of heliotropium sinuatum

Article abstract of DOI:10.1002/ejoc.201201184

The (3S,5R) and (3R,5R) isomers of the title compound were synthesized from enantiopure epoxide chiral building blocks readily accessible from D-gluconolactone. The former (a syn-1,3-diol) gave ¹H and ¹³C NMR spectroscopic data and optical rotation in good agreement with those reported for the natural product, whereas distinct differences were found with the data for the latter (an anti-1,3-diol). These results unambiguously showed that the absolute configuration of the natural product must be (3S,5R).

Full text of DOI:10.1002/ejoc.201201184

FULL PAPER
DOI: 10.1002/ejoc.201201184
Synthesis and Configuration of the Phenolic Nonadecanediol Isolated from the
Resinous Exudates of Heliotropium sinuatum
Chao-Yuan Chen,[a,b] Shao-Min Zhang,[b] Yikang Wu,*[b] and Po Gao*[a]
Keywords: Chiral pool / Metathesis / Configuration determination / Total synthesis / Natural products
The (3S,5R) and (3R,5R) isomers of the title compound were
synthesized from enantiopure epoxide chiral building blocks
readily accessible from D-gluconolactone. The former (a syn-
1,3-diol) gave 1H and 13C NMR spectroscopic data and op-
tical rotation in good agreement with those reported for the
natural product, whereas distinct differences were found
with the data for the latter (an anti-1,3-diol). These results
unambiguously showed that the absolute configuration of the
natural product must be (3S,5R).
rected toward synthesis of another natural product. Benzyl
protection of the hydroxy group gave 3,[6] which – on reac-
tion[5] with the carbanion derived from dithiane 4[7] – gave
alcohol 5.[8] The newly formed hydroxy group was masked
with a benzyl group, and the acetonide was removed by
hydrolysis with 50% aq. CF3CO2H/CH2Cl2[9] to deliver diol
7.
Introduction
Antioxidants are of great interest because of their in-
volvement in important biological and industrial processes.
They have been found to be active against cancer, cardio-
vascular disease, and inflammation, and to have many other
activities.[1] Phenols, such as vitamin E and gingerols,[2] are
among the most well-studied antioxidants. In their system-
atic investigation on Chilean desert plants, Torres[3] et al.
found a new phenolic diol 1 (Figure 1), which has a struc-
ture very similar to that of gingerol, and which showed anti-
oxidant activity. The planar structure of 1 was assigned by
spectroscopic means. However, the relative and absolute
configurations remain unknown to date. In this paper, we
wish to report the synthesis of 1 and the establishment of
its configuration.
Figure 1. The planar structure of 1.
Results and Discussion
Scheme 1. Reagents and conditions. (a) NaH, BnBr, DMF, 83%;
(b) (i) nBuLi, 4, THF, –78 °C, (ii) HMPA, –30 °C, 94% from 3;
(c) NaH, BnBr, DMF, 87%; (d) 50% aq. CF3CO2H, CH2Cl2, 71%
(along with 25% recovered 6). Bn = benzyl, DMF = N,NЈ-dimeth-
ylformamide.
Our synthesis was based on the transformation of
known[4] epoxide 2 (prepared from d-gluconolactone) into
diol 7 (Scheme 1) in a fashion similar to our study[5] di-
[a] School of Chemistry and Materials, Heilongjiang University,
Harbin 150080, China
[b] State Key Laboratory of Bioorganic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences,
To introduce the long linear alkyl chain, we opted for
a cross-metathesis-based approach (Scheme 2), because the
coupling conditions were mild, and saturation of the re-
sulting C=C double bonds could be achieved at the same
time as the removal of the benzyl protecting groups and
the thioketal. To this end, the primary hydroxy group was
345 Lingling Road, Shanghai 200032, China
E-mail: yikangwu@sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201184.
348
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 348–355

Synthesis and Configuration of a Phenolic NonadecanediolSynthesis and Configuration of a Phenolic Nonadecanediol
selectively tosylated by using pTsCl/Et3N/nBu2SnO/DMAP/
Alternatively, diol 7 could be transformed into (3S,5R)-1
MeCN.[10] The intermediate tosylate was then transformed following the route shown in Scheme 3, which avoided the
into epoxide 8 by treatment with K2CO3 in MeOH.
use of KSeCN (a highly toxic and expensive substance with
an unbearable stench), and gave a substantially better yield
in the metathesis reaction. In this alternative synthesis, the
hydroxy groups in 7 were mesylated with MsCl/Et3N, and
the thioketal in the product (i.e., 15) was reductively cleaved
[14]
by using NiCl2·6H2O/NaBH4
to deliver dimesylate 16.
The desired vinyl group was then installed by treatment
with Zn/NaI[15] in refluxing DMF.
Scheme 3. Reagents and conditions. (a) MsCl, Et3N, CH2Cl2, 0 °C,
1 h, 98%; (b) NiCl2·6H2O, MeOH/THF (3:1, v/v), NaBH4, 0 °C,
70%; (c) NaI, Zn dust, DMF, reflux, 4 h, 84%; (d) 10, 12
(Grubbs II cat., 10 mol-%), CH2Cl2, reflux, 4 h, 65%; (e) H2
(1 atm), Pd/C, EtOH, room temp., 2 d, 96%. Ms = methylsulfonyl.
In contrast to the sluggish coupling between 13 and 10
mentioned above, the cross-metathesis reaction of alkene 17
with 10 proceeded smoothly with 12 as the catalyst to give
pure trans-18 in 65% yield (together with traces of the cis
isomer), presumably because of the absence of the thioketal.
Saturation of the C=C double bond and removal of the
benzyl groups were then achieved by hydrogenation in the
presence of Pd/C (10%), which gave 14 in 96% yield.
Starting from known[5] 19 (the anti isomer of 7, also de-
rived from d-gluconolactone), and following the same se-
Scheme 2. Reagents and conditions. (a) pTsCl, nBu2SnO, Et3N,
DMAP, MeCN, r.t., 1 h; (b) K2CO3, MeOH, 0 °C, 1.5 h, 85% over
two steps (from 7); (c) KSeCN, tBuOH/H2O (3:1, v/v), reflux, 4 h,
96%; (d) Grubbs II cat. 12 (10 mol-%), CH2Cl2, reflux, 4 h, 51%;
(e) H2 (1 atm), Ra-Ni, EtOH, room temp., 2 d, 86%; (f) EtSH,
NaH, DMF, reflux, 10 h, 60%. pTs = p-tolylsulfonyl, DMAP = 4-
(dimethylamino)pyridine, Ra-Ni = Raney nickel.
Conversion of the epoxy function into a vinyl group was quence (Scheme 4), (3R,5R)-1 was also synthesized. Since 1
then effected with KSeCN[11] in tBuOH/H2O at reflux. The has only two stereogenic centers, the relative configuration
product (i.e., 9) was then coupled with commercially avail- of natural 1 must be either syn or anti. With both isomers
1
able 1-tetradecene (10) in the presence of the Hoveyda cata- in hand, a comparison of the H and 13C NMR spectro-
lyst (11). The reaction appeared to stop at an early stage, scopic data should allow a reliable assignment of the rela-
giving only little of desired product 13 (ca. 6%), apparently tive configuration.
1
due to deactivation of the catalyst. However, this problem
The H NMR spectroscopic data of (3S,5R)-1, the syn
was later circumvented by using the Grubbs II catalyst isomer, was in good agreement with that of natural 1 (cf.
(12),[12] and trans-alkene 13 was isolated in 51% isolated Tables 1 and 2), whereas the spectrum of (3R,5R)-1, the
yield (along with traces of the cis isomer).
anti-diol, had a two-proton multiplet at δ = 4.02–3.90 rather
Alkene 13 was then treated with hydrogen at atmospheric than at δ = 3.90–3.78 ppm. This revealed that natural 1
pressure in the presence of excess Ra-Ni. The benzyl groups must have a syn relative configuration. Critical differences
and the thioketal were both removed, and the C=C double were also observed in the signals for C-3 and C-5 (the two
bond was saturated. Finally, cleavage of the methoxy group carbon atoms bearing hydroxy groups) between the 13C
with NaH/EtSH[13] in DMF led to the end product [i.e., NMR spectroscopic data for anti 1 and natural 1; for the
(3S,5R)-1].
former compound, the two signals were at δ = 69.0 and
Eur. J. Org. Chem. 2013, 348–355
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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349

C.-Y. Chen, S.-M. Zhang, Y. Wu, P. Gao
FULL PAPER
Table 2. Comparison of the 13C NMR spectroscopic data for natu-
ral 1, (3S,5R)-1 (syn-1), and (3R,5R)-1 (anti-1).
Natural 1[a]
(3S,5R)-1[b]
(3S,5R)-1[b,c] (3R,5R)-1[b]
14.1 (C-19)
22.7 (C-18)
25.3 (C-17)
29.3 (C-16)
29.6 (C-8 to C-15)
30.7 (C-1)
14.1
22.7
25.3
29.3
14.0
22.6
25.3
29.2
14.1
22.7
25.7
29.3
29.59, 29.65, 29.69 29.6
30.8
29.60, 29.64, 29.68
31.2
30.6
31.9 (C-7)
31.9
31.8
31.9
38.0 (C-6)
38.3
38.6
37.5
39.9 (C-2)
39.9
39.9
39.1
42.6 (C-4)
42.9
42.5
42.3
72.2 (C-5)
72.4
72.2
69.0
72.9 (C-3)
73.3
72.9
69.6
115.3 (C-2Ј, C-6Ј)
129.3 (C-3Ј C-5Ј)
133.1 (C-1Ј)
154.6 (C-4Ј)
115.3
129.5
133.9
153.8
115.1
129.2
133.1
154.5
115.3
129.4
133.7
154.0
[a] Taken from ref.[3] with the assignments; measured at 75 MHz
in CDCl3 + CD3OD without specifying the ratio. [b] This work;
measured at 100 MHz in CDCl3. [c] This work; measured at
100 MHz in CDCl3 (0.6 mL) + CD3OD (0.01 mL).
trum of natural 1 was measured in a mixture of CDCl3
and CD3OD. Therefore, we next measured the 13C NMR
spectrum of our syn-1 in CDCl3 containing a small amount
of CD3OD. The results were rather pleasing; the phenolic
carbon signal did indeed shift to δ = 154.5 ppm in the pres-
ence of CD3OD.
Once the relative configuration had been assigned, the
remaining task was to compare the optical rotations to es-
tablish the absolute configuration of natural 1. The first
measurement we obtained for (3S,5R)-1 was [α]2D5 = –3.1 (c
= 0.31, MeOH), which seemed compatible with the rotation
Scheme 4. Reagents and conditions. (a) MsCl, Et3N, CH2Cl2, 0 °C,
1 h, 93%; (b) NiCl2·6H2O, MeOH/THF (3:1, v/v), NaBH4, 0 °C,
65%; (c) NaI, Zn dust, DMF, reflux, 4 h, 77%; (d) 10, 12
(Grubbs II cat., 10 mol-%), CH2Cl2, reflux, 4 h, 83%; (e) H2
(1 atm), Pd/C, EtOH, room temp., 2 d, 83%; (f) EtSH, NaH, DMF,
reflux, 10 h, 81%.
69.6 ppm, respectively, while for the latter, the signals were of natural 1 {[α]2D5 = –5.71 (c = 1.9, MeOH)}, albeit with
at δ = 72.2 and 72.9 ppm, respectively. These pieces of evi- some discrepancy. We suspected that the rotation might be
dence taken together unambiguously excluded the anti con- concentration-dependent, and so we next measured the ro-
figuration for natural 1.
tation at other concentrations.
Although in principle, the definite exclusion of the anti
The results indeed showed some concentration depen-
configuration already leaves the syn configuration as the dency: [α]2D6 = –1.7 (c = 0.14, MeOH), [α]D26 = –3.8 (c = 0.67,
only possibility, the 0.8 ppm difference between the chemi- MeOH), and [α]2D6 = –4.7 (c = 1.00, MeOH). However, be-
cal shifts for the phenolic carbon signals in the 13C NMR cause of the limited quantity of (3S,5R)-1 in hand, measure-
for syn-1 (δ = 153.8 ppm) and natural 1 (δ = 154.6 ppm) ments at higher concentrations were not accessible. Then,
seemed to raise some doubt (more than one would normally inspired by the observed effect of CD3OD on the chemical
1
expect). Then, we noticed that unlike the H NMR spec- shift of the phenolic carbon signal in the 13C NMR spec-
trum (which was recorded in CDCl3) the 13C NMR spec- trum mentioned above (presumably caused by deuteration
1
Table 1. Comparison of the H NMR spectroscopic data for natural 1, (3S,5R)-1 (syn-1), and (3R,5R)-1 (anti-1).
Natural 1[a]
(3S,5R)-1[b]
(3R,5R)-1[b]
0.87 (t, 3 H, H-19)
1.25 (m, 24 H, H-7 to H-18)
1.45 (m, 2 H, H-6)
1.59 (m, 2 H, H-4)
1.75 (m, 2 H, H-2)
0.88 (t, J = 6.3 Hz, 3 H)
1.31–1.22 (m, 24 H)
1.48–1.42 (m, 2 H)
1.63–1.58 (m, 2 H)
1.82–1.69 (m, 2 H)
2.76–2.56 (m, 2 H)
0.88 (t, J = 6.4 Hz, 3 H)
1.31–1.23 (m, 24 H)
1.52–1.41 (m, 2 H)
1.67–1.59 (m, 2 H)
1.90–1.69 (m, 2 H)
2.74–2.54 (m, 2 H)
2.64 (m, 2 H, H-1)
3.84 (m, 1 H, H-5)
3.87 (m, 1 H, H-3)
3.91–3.78 (m, 2 H)
4.02–3.90 (m, 2 H)
6.75 (d, J = 8.4 Hz, 2 H, H-3Ј, H-5Ј)
7.05 (d, J = 8.4 Hz, 2 H, H-2Ј, H-6Ј)
6.75 (d, J = 8.3 Hz, 2 H)
7.07 (d, J = 7.8 Hz, 2 H)
6.74 (d, J = 8.2 Hz, 2 H)
7.03 (d, J = 8.2 Hz, 2 H)
[a] Taken from ref.[3] with the assignments; measured at 300 MHz in CDCl3. [b] This work; measured at 400 MHz in CDCl3.
350 Eur. J. Org. Chem. 2013, 348–355
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Synthesis and Configuration of a Phenolic NonadecanediolSynthesis and Configuration of a Phenolic Nonadecanediol
1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.38–7.27 (m, 5
of the phenolic OH group), we suspected that the optical
rotation for 1 might also change slightly after deuteration.
Therefore, we next measured the rotation of a sample reco-
vered from the CDCl3/CD3OD solution used for 13C NMR
spectroscopy, which turned out to be [α]2D6 = –5.8 (c = 1.00,
MeOH), fully consistent with the value reported previously
for natural 1. Finally, the melting points of (3S,5R)-1 and
(3R,5R)-1 (without exposure to CD3OD) were measured to
be 65–67 °C and 70–73 °C, respectively, giving further sup-
H), 4.67 (d, J = 11.4 Hz, 1 H), 4.61 (d, J = 11.4 Hz, 1 H), 4.17 (q,
J = 6.3 Hz, 1 H), 4.09 (dd, J = 8.4, 6.5 Hz, 1 H), 3.91 (dd, J = 8.4,
5.9 Hz, 1 H), 3.65 (q, J = 5.9 Hz, 1 H), 3.14–3.07 (m, 1 H), 2.75
(t, J = 4.9 Hz, 1 H), 2.49 (q, J = 2.8 Hz, 1 H), 1.90 (dt, J = 12.8,
4.9 Hz, 1 H), 1.81 (dt, J = 14.7, 6.2 Hz, 1 H), 1.42 (s, 3 H), 1.36 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.0, 128.4, 127.83,
127.77, 109.2, 77.64, 77.56, 72.3, 66.6, 49.3, 46.9, 34.5, 26.6,
25.2 ppm. IR (film): ν = 3027, 2987, 2932, 1495, 1450, 1380, 1371,
˜
1256, 1212, 1073, 856, 739, 699 cm–1. ESI-MS: m/z = 301.1 [M +
port to the assigned (3S,5R) configuration for natural 1 Na]+. ESI-HRMS: calcd. for C16H22O4Na [M + Na]+ 301.1410;
found 301.1403.
(m.p. 64–66 °C).
Ring-Opening of 3 with 4 To Afford 5: nBuLi (2.5 m in hexanes,
2 mL, 5.30 mmol) was added to a solution of 4 (1.20 g, 5.31 mmol)
and Ph3CH (6 mg, 0.024 mmol, as an indicator) in dry THF (6 mL)
stirred at –78 °C under N2 (balloon). Stirring was continued at –30
to –20 °C for 2 h. A wine-red color gradually developed. The bath
was then cooled to –78 °C before dry HMPA (1.0 mL, 5.31 mmol)
was added. A solution of 3 (1.15 g, 5.30 mmol) in dry THF (5 mL)
was then introduced. The stirring was continued while the bath was
warmed to –30 to –20 °C. When TLC showed completion of the
reaction (ca. 30 min), NH4Cl (satd. aq., 10 mL) was added (the
wine-red color faded quickly). The mixture was extracted with
EtOAc (3ϫ 30 mL). The combined organic extracts were washed
with brine and dried with anhydrous Na2SO4. Removal of the sol-
vent by rotary evaporation and column chromatography (initially
8:1 then 4:1 PE/EtOAc) on silica gel gave 5 (2.514 g, 4.98 mmol,
Conclusions
The phenolic nonadecandiol isolated from the resinous
exudates of Heliotropium sinuatum, a natural antioxidant,
has been synthesized in (3S,5R) and (3R,5R) forms with the
stereogenic centers deriving from the enantiomerically pure
epoxide chiral building blocks readily accessible from d-glu-
conolactone. Comparison of the 1H and 13C NMR spectro-
scopic data, optical rotations, and melting points of the nat-
ural product and the synthetic diastereomers revealed that
the absolute configuration of the natural product must be
(3S,5R). Interesting effects of deuteration on the 13C NMR
shift and the optical rotation were observed, which may be
useful in studies of similar compounds. The optical-rotation
value of the title compound free from any influence of deut-
eratation, which is presumably a better reference value than
that acquired after deuteration of the hydroxy group(s), was
also recorded.
94%) as a colorless oil. [α]2D0 = +16.7 (c = 2.00, CHCl3). H NMR
1
(400 MHz, CDCl3): δ = 7.82 (d, J = 8.9 Hz, 2 H), 7.34–7.22 (m, 5
H), 6.90 (d, J = 9.2 Hz, 2 H), 4.59 (d, J = 11.2 Hz, 1 H), 4.47 (d,
J = 11.4, 1 H), 4.07 (q, J = 6.5 Hz, 1 H), 4.03–3.94 (m, 2 H), 3.82
(d, J = 6.9 Hz, 1 H), 3.79 (s, 3 H), 3.61 (q, J = 5.6 Hz, 1 H), 2.77–
2.69 (m, 4 H), 2.34 (dd, J = 15.0, 8.3 Hz, 1 H), 2.16 (dd, J = 14.9,
2.5 Hz, 1 H), 1.99–1.89 (m, 2 H), 1.68 (dt, J = 14.8, 7.4 Hz, 1 H),
1.54 (dt, J = 9.8, 4.7 Hz, 1 H), 1.37 (s, 3 H), 1.31 (s, 3 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 158.6, 138.1, 133.4, 129.6, 128.3,
127.7, 127.5, 113.9, 109.0, 78.0, 72.4, 66.1, 66.0, 56.9, 55.1, 52.1,
Experimental Section
General Methods: NMR spectra were recorded with a Bruker Av-
ance NMR spectrometer operating at 400 MHz (1H) with TMS as
the internal standard. IR spectra were measured with a Nicolet
380 infrared spectrophotometer. ESI-MS data were acquired with
a Shimadzu LCMS-2010EV mass spectrometer. HRMS data were
obtained with a Bruker APEXIII 7.0 Tesla FT mass spectrometer.
Optical rotations were measured with a Jasco 1030 polarimeter.
Melting points were measured with a hot-stage melting-point appa-
ratus equipped with a microscope. CH2Cl2 was dried with activated
4 Å MS (molecular sieves). All chemicals were reagent grade and
used as purchased. Column chromatography was performed on sil-
ica gel (300–400 mesh) under slightly positive pressure. PE = petro-
leum ether (boiling range 60–90 °C).
39.1, 27.7, 27.3, 26.4, 25.1, 24.7 ppm. IR (film): ν = 3491, 2980,
˜
2931, 1605, 1504, 1453, 1364, 1250, 1071, 1035, 843, 736, 695 cm–1.
ESI-MS: m/z
= 527.4 [M +
Na]+. ESI-HRMS: calcd. for
C27H36O5S2Na [M + Na]+ 527.1896; found 527.1906.
Benzyl Protection of 5 To Afford 6: NaH (60% suspension in min-
eral oil, 48 mg, 1.98 mmol, washed with PE prior to use) was added
to a solution of 5 (663 mg, 1.31 mmol) in dry DMF (2 mL) stirred
in an ice/water bath. The mixture was stirred at the same tempera-
ture for 40 min. BnBr (0.18 mL, 1.45 mmol) was added dropwise.
Stirring was continued at the same temperature until TLC showed
completion of the reaction (ca. 6 h). Water (10 mL) was carefully
added to destroy the excess hydride. The mixture was diluted with
water (50 mL) and extracted with Et2O (3ϫ 50 mL). The combined
organic layers were washed with brine (20 mL) and dried with an-
hydrous Na2SO4. Removal of the solvent by rotary evaporation and
column chromatography (10:1 PE/EtOAc) on silica gel gave 6
(680 mg, 1.14 mmol, 87%) as a colorless oil. [α]2D6 = +1.2 (c = 2.00,
Protection of 2 To Afford 3: NaH (60% suspension in mineral oil,
78 mg, 3.25 mmol, washed with PE prior to use) was added to a
solution of 2 (280 mg, 1.48 mmol) in dry DMF (2 mL) stirred in
an ice/water bath. The mixture was stirred at the same temperature
for 40 min. BnBr (0.25 mL, 2.22 mmol) was added dropwise. Stir-
ring was continued at the same temperature until TLC showed
completion of the reaction (ca. 2 h). Water (10 mL) was carefully
added to destroy the excess hydride. The mixture was diluted with
water (50 mL) and extracted with Et2O (3ϫ 50 mL). The combined
organic extracts were washed with brine (20 mL) and dried with
anhydrous Na2SO4. Removal of the solvent by rotary evaporation
and column chromatography (8:1 PE/EtOAc) on silica gel gave 3
(328 mg, 1.18 mmol, 83%) as a colorless oil. [α]2D6 = +37.9 (c =
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 9.1 Hz, 2
H), 7.34–7.22 (m, 10 H), 6.87 (d, J = 9.1 Hz, 2 H), 4.53 (d, J =
11.2 Hz, 1 H), 4.38 (d, J = 10.9 Hz, 1 H), 4.32 (d, J = 11.4 Hz, 1
H), 4.27 (d, J = 10.9 Hz, 1 H), 4.00–3.90 (m, 2 H), 3.79 (d, J =
7.2 Hz, 1 H), 3.74 (s, 3 H), 3.70–3.64 (m, 1 H), 3.53–3.47 (m, 1 H),
2.77–2.60 (m, 4 H), 2.49 (dd, J = 14.6, 5.6 Hz, 1 H), 2.23 (dd, J =
14.6, 3.4 Hz, 1 H), 1.97–1.89 (m, 2 H), 1.75 (ddd, J = 14.4, 6.8,
5.6 Hz, 1 H), 1.53 (ddd, J = 14.5, 6.8, 4.6 Hz, 1 H), 1.39 (s, 3 H),
1.34 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.4, 138.5,
Eur. J. Org. Chem. 2013, 348–355
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351

C.-Y. Chen, S.-M. Zhang, Y. Wu, P. Gao
Conversion of Epoxide 8
into Alkene 9: KSeCN[16] (14 mg,
FULL PAPER
138.4, 133.4, 130.2, 128.1, 128.0, 127.7, 127.6, 127.3, 127.2, 113.7,
108.9, 78.2, 76.0, 72.8, 72.7, 70.1, 65.7, 57.4, 55.1, 50.7, 37.6, 27.5, 0.10 mmol) was added to a solution of 8 (34 mg, 0.06 mmol) in
26.4, 25.3, 24.9 ppm. IR (film): ν = 3030, 2985, 2931, 1605, 1504, tBuOH (4.5 mL) and H2O (0.5 mL). The mixture was heated at
˜
1454, 1379, 1250, 1211, 1181, 1070, 858, 736, 698 cm–1. ESI-MS:
m/z = 617.5 [M + Na]+. ESI-HRMS: calcd. for C34H42O5S2Na [M
+ Na]+ 617.2366; found 617.2379.
reflux with stirring for 4 h, after which time TLC showed comple-
tion of the reaction. tBuOMe (2 mL) was added. The red solids
were filtered off. The filtrate was concentrated by rotary evapora-
tion. The residue was purified by chromatography (40:1 PE/EtOAc)
on silica gel to give 9 (30 mg, 0.06 mmol, 96%) as a colorless oil.
Hydrolysis of Acetonide in 6 To Afford Diol 7: Aqueous CF3CO2H
(50%, 0.9 mL) was added to a solution of 6 (283 mg, 0.48 mmol)
in CH2Cl2 (4 mL) stirred at ambient temperature. The mixture was
stirred at the same temperature until TLC showed completion of
the reaction (ca. 40 min). Water (2 mL) was added. The phases were
separated. The organic phase was washed with NaHCO3 (satd. aq.,
2 mL), water (2 mL), and brine (2 mL) before being dried with an-
hydrous Na2SO4. Removal of the solvent by rotary evaporation and
column chromatography (initially 4:1 then 2:1 PE/EtOAc) on silica
gel gave diol 7 (187 mg, 0.34 mmol, 71%) as a colorless oil along
with recovered 6 (73 mg, 0.12 mmol). Data for 7: [α]2D7 = +39.9 (c
= 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.86 (d, J =
9.3 Hz, 2 H), 7.38–7.19 (m, 10 H), 6.88 (d, J = 9.1 Hz, 2 H), 4.84
(d, J = 11.2 Hz, 1 H), 4.34 (d, J = 11.1 Hz, 2 H), 4.17 (d, J =
11.0 Hz, 1 H), 3.77 (s, 3 H), 3.75–3.70 (m, 1 H), 3.62 (dd, J = 11.2,
3.7 Hz, 1 H), 3.57 (d, J = 5.3 Hz, 1 H), 3.55–3.43 (m, 2 H), 2.78–
2.62 (m, 4 H), 2.45 (dd, J = 15.1, 3.8 Hz, 1 H), 2.27 (dd, J = 14.8,
5.8 Hz, 1 H),1.99–1.88 (m, 2 H), 1.88–1.73 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 158.5, 138.2, 137.7, 133.2, 130.2,
128.31, 128.27, 128.0, 127.8, 127.6, 113.9, 77.8, 72.5, 72.4, 71.8,
[α]2D0 = –15.2 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
7.85 (d, J = 8.9 Hz, 2 H), 7.37–7.16 (m, 10 H), 6.88 (d, J = 9.1 Hz,
2 H), 5.56 (ddd, J = 17.3, 9.8, 7.8 Hz, 1 H), 5.15 (dd, J = 11.4,
1.1 Hz, 1 H), 4.99 (d, J = 17.2 Hz, 1 H), 4.44 (d, J = 11.6 Hz, 1
H), 4.34 (d, J = 11.3 Hz, 1 H), 4.19 (t, J = 10.4 Hz, 2 H), 3.77 (s,
3 H), 3.71 (q, J = 6.9 Hz, 1 H), 3.58 (quint, J = 5.2 Hz, 1 H), 2.80–
2.60 (m, 4 H), 2.47 (dd, J = 14.7, 5.0 Hz, 1 H), 2.25 (dd, J = 14.7,
4.1 Hz, 1 H), 1.98–1.83 (m, 3 H), 1.49–1.40 (m, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 158.5, 138.64, 138.55, 133.4, 130.3,
128.2, 128.1, 127.9, 127.7, 127.3, 127.2, 117.3, 113.8, 77.8, 72.5,
70.1, 57.4, 55.2, 50.7, 41.6, 29.7, 27.63, 27.57, 25.0 ppm. IR (film):
ν = 2926, 2849, 1602, 1504, 1450, 1249, 1091, 927, 834, 733,
˜
697 cm–1. ESI-MS: m/z = 543.1 [M + Na]+. ESI-HRMS: calcd. for
C31H36O3S2Na [M + Na]+ 543.1998; found 543.1997.
Coupling of 9 with 10 by Cross-Metathesis To Afford 13: A mixture
of 9 (29 mg, 0.06 mmol), 1-tetradecene 10 (0.2 mL, 0.6 mmol), and
Grubbs II catalyst 12 (6 mg, 0.006 mmol) in CH2Cl2 (1 mL) was
heated under N2 (balloon) for 4 h, after which time TLC showed
that 9 was no longer consumed. The mixture was concentrated by
rotary evaporation. The residue was purified by chromatography
(60:1 PE/EtOAc) on silica gel to give 13 (21 mg, 0.03 mmol, 51%
from 9) as a colorless oil. [α]2D7 = –10.6 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.84 (d, J = 9.2 Hz, 2 H), 7.35–7.13 (m, 10
H), 6.87 (d, J = 8.6 Hz, 2 H), 5.35 (dt, J = 15.5, 6.7 Hz, 1 H), 5.12
(dd, J = 11.5, 8.6 Hz, 1 H), 4.43 (d, J = 11.8 Hz, 1 H), 4.33 (d, J
= 11.3 Hz, 1 H), 4.18 (d, J = 11.6 Hz, 1 H), 4.16 (d, J = 11.6 Hz,
1 H), 3.77 (s, 3 H), 3.66 (q, J = 6.6 Hz, 1 H), 3.53 (quint, J =
5.5 Hz, 1 H), 2.79–2.59 (m, 4 H), 2.45 (dd, J = 14.8, 4.6 Hz, 1 H),
2.25 (dd, J = 14.9, 4.8 Hz, 1 H), 2.01 (q, J = 6.5 Hz, 2 H), 1.97–
1.90 (m, 2 H), 1.87 (dt, J = 14.0, 7.3 Hz, 1 H), 1.32–1.18 (m, 21
H), 0.87 (t, J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 158.5, 139.0, 138.7, 134.7, 133.4, 130.4, 130.3, 128.2, 128.1,
127.9, 127.7, 127.2, 113.8, 77.4, 77.3, 72.7, 70.1, 69.7, 57.4, 55.2,
50.7, 42.1, 32.3, 31.9, 29.70, 29.66, 29.5, 29.3, 29.2, 27.7, 27.6, 25.1,
70.4, 63.5, 57.1, 55.2, 50.5, 36.7, 27.6, 27.5, 24.8 ppm. IR (film): ν
˜
= 3441, 2930, 2904, 1605, 1504, 1453, 1249, 1089, 1029, 837, 736,
698 cm–1. ESI-MS: m/z = 577.4 [M + Na]+. ESI-HRMS: calcd. for
C31H38O5S2Na [M + Na]+ 577.2053; found 577.2075.
Conversion of Diol 7 into Epoxide 8: nBu2SnO (3 mg, 0.013 mmol),
DMAP (2 mg, 0.013 mmol), and Et3N (20 μL, 0.14 mmol) were
added subsequently to a solution of diol 7 (72 mg, 0.13 mmol) in
dry MeCN (0.5 mL). The mixture was stirred at ambient tempera-
ture for 30 min before pTsCl (27 mg, 0.14 mmol) was introduced.
Stirring was continued at ambient temperature until TLC showed
completion of the reaction (ca. 1 h). Et2O (5 mL) was added. The
white solids were filtered off. The filtrate was concentrated by ro-
tary evaporation to give a yellowish oil (the crude intermediate tos-
ylate), which was dissolved in MeOH (4 mL). With cooling (ice/
water bath) and stirring, powdered K2CO3 (35 mg) was added. Stir-
ring was continued at the same temperature for 1.5 h, after which
time TLC showed completion of the reaction. Et2O (5 mL) was
added. The white solids were filtered off. The filtrate was neutral-
ized with HCl (1 n) and extracted with EtOAc (3ϫ 30 mL). The
combined organic extracts were washed with brine (20 mL) and
dried with anhydrous Na2SO4. Concentration by rotary evapora-
tion and column chromatography (8:1 PE/EtOAc) on silica gel gave
epoxide 8 (59 mg, 0.11 mmol, 85% from 7) as a colorless oil. [α]2D0
22.7, 14.1 ppm. IR (film): ν = 3030, 2924, 2852, 1606, 1504, 1455,
˜
1250, 1091, 971, 809, 733, 697 cm–1. ESI-MS: m/z = 711.5 [M +
Na]+. ESI-HRMS: calcd. for C43H60O3S2Na [M + Na]+ 711.3876;
found 711.3861.
Conversion of 13 into 14: A mixture of 13 (111 mg, 0.27 mmol) and
Ra-Ni (ca. 1 g, with solvent) in EtOH (5 mL) was stirred under H2
for 2 d, after which time TLC showed that the reaction was com-
plete. The solids were removed by filtration, and the filtrate was
concentrated by rotary evaporation. The residue was purified by
chromatography (4:1 PE/EtOAc) on silica gel to give 14 (95 mg,
0.23 mmol, 86%) as a white solid. M.p. 56–59 °C. [α]2D9 = –27.5 (c
= 0.20, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.12 (d, J =
8.6 Hz, 2 H), 6.83 (d, J = 8.7 Hz, 2 H), 3.91–3.80 (m, 2 H), 3.79
(s, 3 H), 2.77–2.59 (m, 2 H), 2.33 (br. s, 2 H), 1.84–1.66 (m, 2 H),
1.65–1.57 (m, 1 H), 1.56–1.49 (m, 1 H), 1.49–1.42 (m, 2 H), 1.35–
1.21 (m, 24 H), 0.88 (t, J = 6.5 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 157.9, 134.0, 129.3, 113.9, 73.2, 72.3, 55.3, 43.1, 40.0,
38.4, 31.9, 30.8, 29.7, 29.64, 29.59, 29.3, 25.3, 22.7, 14.1 ppm. IR
1
= –11.6 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.88
(d, J = 8.8 Hz, 2 H), 7.41–7.20 (m, 10 H), 6.87 (d, J = 8.5 Hz, 2
H), 4.49 (d, J = 11.3 Hz, 1 H), 4.36 (d, J = 11.0 Hz, 1 H), 4.29 (d,
J = 14.1 Hz, 2 H), 3.76 (s, 3 H), 3.75–3.70 (m, 1 H), 3.26–3.20 (m,
1 H), 2.83–2.78 (m, 1 H), 2.77–2.65 (m, 4 H), 2.64–2.60 (m, 2 H),
2.50 (dd, J = 15.1, 6.0 Hz, 1 H), 2.24 (dd, J = 14.7, 2.7 Hz, 1 H),
1.98–1.89 (m, 2 H), 1.88–1.79 (m, 1 H), 1.70–1.61 (m, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 158.4, 138.49, 138.46, 133.5,
130.3, 128.2, 128.1, 127.8, 127.6, 127.5, 127.2, 113.8, 77.3, 75.3,
72.6, 72.3, 70.3, 57.5, 55.2, 53.4, 50.8, 45.5, 38.5, 27.6, 25.0 ppm.
IR (film): ν = 3033, 2904, 1605, 1503, 1453, 1249, 1091, 1029, 834,
(film): ν = 3348, 2956, 2915, 2849, 1515, 1464, 1254, 1115, 1089,
˜
˜
736, 698 cm–1. ESI-MS: m/z = 559.3 [M + Na]+. ESI-HRMS: calcd.
1034, 812 cm–1. ESI-MS: m/z = 429.5 [M + Na]+. ESI-HRMS:
for C31H36O4S2Na [M + Na]+ 559.1947; found 559.1953.
calcd. for C26H46O3Na [M + Na]+ 429.3339; found 429.3341.
352
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 348–355

Synthesis and Configuration of a Phenolic NonadecanediolSynthesis and Configuration of a Phenolic Nonadecanediol
1
Conversion of 14 into (3S,5R)-1: EtSH (50 μL, 0.6 mmol) was added
to a mixture of NaH (60% suspension in mineral oil, 30 mg,
0.6 mmol, washed with PE) in deaerated DMF (0.1 mL) stirred in
an ice/water bath under N2 (balloon). A solution of 14 (24 mg,
0.06 mmol) in DMF (0.1 mL) was then added. The mixture was
heated at reflux with stirring for 10 h. The heating bath was re-
[α]2D6 = +1.0 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ =
7.38–7.23 (m, 10 H), 7.03 (d, J = 8.4 Hz, 2 H), 6.81 (d, J = 8.3 Hz,
2 H), 5.02 (q, J = 1.4 Hz, 1 H), 4.60 (d, J = 11.3 Hz, 1 H), 4.54–
4.40 (m, 5 H), 3.90–3.84 (m, 1 H), 3.77 (s, 3 H), 3.56 (quint, J =
5.3 Hz, 1 H), 3.00 (s, 3 H), 2.99 (s, 3 H), 2.69–2.50 (m, 2 H), 2.00–
1.69 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.8, 138.2,
moved. Water was added, followed by aq. HCl until pH = 1–2 was 137.2, 133.7, 129.2, 128.45, 128.41, 128.2, 128.0, 127.7, 113.8, 81.1,
reached. The mixture was extracted with CH2Cl2 (3ϫ 10 mL). The
combined organic extracts were washed with water and brine (5 mL
each) before being dried with anhydrous Na2SO4. Removal of the
solvent by rotary evaporation and column chromatography (3:1 PE/
EtOAc) on silica gel gave (3S,5R)-1 (12 mg, 0.03 mmol, 60%) as a
yellowish solid along with recovered 14 (7 mg, 0.02 mmol). Data
for (3S,5R)-1: M.p. 65–67 °C. [α]2D5 = –4.7 (c = 1.00, MeOH), [α]2D6
75.3, 74.7, 72.7, 70.9, 67.3, 55.2, 38.6, 37.6, 35.4, 34.9, 30.3 ppm.
IR (film): ν = 3030, 2935, 1611, 1512, 1360, 1246, 1176, 1028, 919,
˜
740, 699, 527 cm–1. ESI-MS: m/z = 629.3 [M + Na]+. ESI-HRMS:
calcd. for C30H38O9S2Na [M + Na]+ 629.1850; found 629.1843.
Conversion of Dimesylate 16 into Alkene 17: Zn dust (195 mg,
0.025 mmol) was added to a solution of 16 (30 mg, 0.05 mmol) in
DMF (5 mL), followed by NaI (375 mg, 0.025 mol). The mixture
was heated at reflux with stirring under N2 (balloon) for 4 h. Et2O
(20 mL) was added, and the solids were filtered off. The filtrate was
washed with water and brine (5 mL each) and dried with anhydrous
Na2SO4. Removal of the solvent by rotary evaporation and column
chromatography (30:1 PE/EtOAc) on silica gel gave 17 (18 mg,
0.04 mmol, 84%) as a colorless oil. [α]2D2 = –31.1 (c = 0.80, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.32–7.17 (m, 10 H), 6.98 (d, J
= 8.3 Hz, 2 H), 6.76 (d, J = 8.4 Hz, 2 H), 5.64 (ddd, J = 17.3, 9.5,
8.1 Hz, 1 H), 5.14 (d, J = 10.1 Hz, 1 H), 5.06 (d, J = 17.2 Hz, 1
H), 4.51 (d, J = 11.8 Hz, 1 H), 4.41 (d, J = 12.0 Hz, 1 H), 4.36 (d,
J = 12.0 Hz, 1 H), 4.24 (d, J = 11.6 Hz, 1 H), 3.85 (q, J = 7.0 Hz,
1 H), 3.72 (s, 3 H), 3.47 (quint, J = 5.8 Hz, 1 H), 2.68–2.47 (m, 2
H), 2.12–1.99 (m, 1 H), 1.77 (q, J = 7.0 Hz, 2 H), 1.67–1.56 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.7, 138.8, 138.7,
138.5, 134.3, 129.2, 128.3, 127.89, 127.86, 127.5, 117.6, 113.7, 77.8,
77.3, 75.0, 70.5, 70.1, 55.23, 55.17, 40.0, 36.0, 30.5 ppm. IR (film):
= –3.8 (c = 0.67, MeOH), [α]2D6 = –3.1 (c = 0.31, MeOH), [α]2D6
=
–1.7 (c = 0.14, MeOH), and after exposure to CD3OD: [α]2D6 = –5.8
1
(c = 1.00, MeOH). H NMR (400 MHz, CDCl3): δ = 7.07 (d, J =
7.8 Hz, 2 H), 6.75 (d, J = 8.3 Hz, 2 H), 3.91–3.78 (m, 2 H), 2.76–
2.56 (m, 2 H), 1.82–1.69 (m, 2 H), 1.63–1.58 (m, 2 H), 1.48–1.42
(m, 2 H), 1.31–1.22 (m, 24 H), 0.88 (t, J = 6.3 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 153.8, 133.9, 129.5, 115.3, 73.3, 72.4,
42.9, 39.9, 38.3, 31.9, 30.8, 29.69, 29.65, 29.59, 29.3, 25.3, 22.7,
14.1 ppm. 13C NMR [100 MHz, CDCl3 (0.6 mL) + CD3OD
(0.01 mL)]: δ = 154.5, 133.1, 129.2, 115.1, 72.9, 72.2, 42.5, 39.9,
38.6, 31.8, 30.6, 29.6, 29.2, 25.3, 22.6, 14.0 ppm. IR (film of solu-
tion in CH Cl ): ν = 3361, 2923, 2852, 1614, 1515, 1456, 1084,
˜
2
2
829 cm–1. ESI-MS: m/z = 415.4 [M + Na]+. ESI-HRMS: calcd. for
C25H44O3Na [M + Na]+ 415.3183; found 415.3165.
Mesylation of Diol 7 To Afford 15: Et3N (0.3 mL, 1.63 mmol) and
MsCl (0.2 mL, 1.63 mmol) were added sequentially to a solution
of diol 7 (300 mg, 0.54 mmol) in dry CH2Cl2 (4 mL) stirred in an
ice/water bath. The mixture was stirred at the same temperature for
1 h, after which time TLC showed completion of the reaction.
Water was added, and the mixture was extracted with CH2Cl2 (3ϫ
30 mL). The combined organic extracts were washed with NaHCO3
(satd. aq., 10 mL), water (10 mL), and brine (10 mL) before being
dried with anhydrous Na2SO4. Removal of the solvent by rotary
evaporation and column chromatography (1:1 PE/EtOAc) on silica
ν = 3030, 2936, 2861, 1611, 1512, 1497, 1454, 1246, 1178, 1070,
˜
925, 819, 735 cm–1. ESI-MS: m/z = 439.3 [M + Na]+. ESI-HRMS:
calcd. for C28H32O3Na [M + Na]+ 439.2244; found 439.2244.
Coupling of 17 with 10 by Cross-Metathesis To Afford 18: A mixture
of 10 (0.16 mL, 0.4 mmol), 17 (17 mg, 0.04 mmol), and Grubbs II
catalyst 12 (4 mg, 0.004 mmol) in dry CH2Cl2 (1 mL) was heated
at reflux with stirring under N2 (balloon) for 4 h. The mixture was
concentrated by rotary evaporation. The residue was purified by
chromatography (60:1 PE/EtOAc) on silica gel to give 18 (11 mg,
0.03 mmol, 65%) as a colorless oil. [α]2D2 = –28.2 (c = 0.80, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.34–7.22 (m, 10 H), 7.02 (d, J
= 8.5 Hz, 2 H), 6.78 (d, J = 8.7 Hz, 2 H), 5.51 (dt, J = 15.8, 6.9 Hz,
1 H), 5.31 (dd, J = 15.5, 8.4 Hz, 1 H), 4.52 (d, J = 11.7 Hz, 1 H),
4.47 (d, J = 11.3 Hz, 1 H), 4.42 (d, J = 11.4 Hz, 1 H), 4.25 (d, J =
11.7 Hz, 1 H), 3.82 (q, J = 6.9 Hz, 1 H), 3.76 (s, 3 H), 3.50 (quint,
J = 6.5 Hz, 1 H), 2.67–2.50 (m, 2 H), 2.13–1.97 (m, 3 H), 1.79 (q,
J = 7.8 Hz, 2 H), 1.67–1.56 (m, 1 H), 1.32–1.16 (m, 20 H), 0.86 (t,
J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.7,
138.9, 138.8, 135.0, 134.4, 130.4, 129.3, 128.30, 128.27, 127.90,
127.85, 127.4, 127.3, 113.8, 77.4, 75.3, 70.5, 69.7, 55.2, 40.4, 36.1,
32.2, 31.9, 30.5, 29.7, 29.6, 29.5, 29.3, 29.22, 29.20, 22.7, 14.1 ppm.
gel gave 15 (375 mg, 0.53 mmol, 98%) as a colorless oil. [α]2D8
=
+23.1 (c = 4.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.85
(d, J = 8.9 Hz, 2 H), 7.35–7.19 (m, 10 H), 6.91 (d, J = 8.8 Hz, 2
H), 4.90–4.86 (m, 1 H), 4.48 (d, J = 12.2 Hz, 1 H), 4.43–4.29 (m,
3 H), 4.26–4.17 (m, 2 H), 3.76 (s, 3 H), 3.74–3.69 (m, 1 H), 3.61–
3.58 (m, 1 H), 2.95 (s, 3 H), 2.89 (s, 3 H), 2.78–2.60 (m, 4 H), 2.50
(dd, J = 14.9, 4.3 Hz, 1 H), 2.22 (dd, J = 14.9, 5.0 Hz, 1 H), 1.97–
1.85 (m, 2 H), 1.76–1.66 (m, 1 H), 1.64–1.53 (m, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 158.4, 137.8, 137.2, 133.0, 129.9,
128.1, 128.0, 127.8, 127.6, 127.3, 113.8, 80.6, 75.2, 72.2, 72.1, 70.4,
66.9, 56.7, 55.0, 49.9, 38.3, 37.2, 36.4, 27.34, 27.29, 24.6 ppm. IR
(film): ν = 3030, 2935, 2906, 1605, 1504, 1455, 1361, 1250, 1176,
˜
1028, 751, 699 cm–1. ESI-MS: m/z = 733.2 [M + Na]+. ESI-HRMS:
calcd. for C33H42O9S4Na [M + Na]+ 733.1604; found 733.1587.
IR (film): ν = 2925, 2854, 1512, 1455, 1246, 1071, 733, 697 cm–1.
˜
Cleavage of the Thioketal in 15 To Afford 16: NiCl2·6H2O (390 mg,
1.60 mmol) was added to a solution of 15 (70 mg, 0.10 mmol) in
MeOH/THF (3:1 v/v, 8 mL) stirred in an open flask cooled in an
ice/water bath. NaBH4 (200 mg, 4.80 mmol) was added in small
portions to the resulting transparent green solution. Black precipi-
tates formed, and gas and heat were evolved. The mixture was
stirred in the cooling bath for 30 min, after which time TLC showed
the disappearance of 15. Et2O (10 mL) was added, and the solids
were filtered off. The filtrate was concentrated by rotary evapora-
tion. The residue was purified by chromatography (1:1 PE/EtOAc)
on silica gel to give 16 (42 mg, 0.07 mmol, 70%) as a colorless oil.
ESI-MS: m/z
= 607.6 [M +
Na]+. ESI-HRMS: calcd. for
C40H56O3Na [M + Na]+ 607.4122; found 607.4107.
Conversion of 18 into 14: A mixture of 18 (15 mg, 0.02 mmol) and
Pd/C (10%, 4 mg) in EtOH (5 mL) was stirred at ambient tempera-
ture under H2 for 2 d, after which time TLC showed completion
of the reaction. The solids were filtered off, and the filtrate was
concentrated by rotary evaporation. The residue was purified by
chromatography (4:1 PE/EtOAc) on silica gel to give 14 (10 mg,
0.02 mmol, 96%) as a white solid. Data are given above under con-
version of 13 into 14.
Eur. J. Org. Chem. 2013, 348–355
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
353

C.-Y. Chen, S.-M. Zhang, Y. Wu, P. Gao
FULL PAPER
Mesylation of Diol 19 To Afford 20: The same procedure for the
conversion of diol 7 into 15 above was used by starting from diol
19 (100 mg, 0.18 mmol). Chromatography with 1:1 PE/EtOAc gave
20 (118 mg, 93%) as a colorless oil. [α]2D8 = –18.1 (c = 7.87, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 9.1 Hz, 2 H), 7.38–
7.17 (m, 10 H), 6.80 (d, J = 8.7 Hz, 2 H), 4.99–4.91 (m, 1 H), 4.42
(t, J = 10.8 Hz, 2 H), 4.25 (dd, J = 11.5, 8.0 Hz, 1 H), 4.15 (dd, J
= 11.6, 3.1 Hz, 1 H), 3.98 (dd, J = 11.1, 7.3 Hz, 2 H), 3.74 (s, 3
H), 3.68–3.59 (m, 2 H), 2.91 (s, 3 H), 2.90 (s, 3 H), 2.81–2.58 (m,
4 H), 2.49 (d, J = 14.5 Hz, 1 H), 2.15 (dd, J = 14.9, 7.9 Hz, 1 H),
2.00–1.89 (m, 2 H), 1.44–1.32 (m, 1 H), 1.32–1.23 (m, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 158.4, 137.9, 137.4, 132.4, 130.3,
128.3, 128.21, 128.15, 127.9, 127.7, 127.6, 113.8, 80.8, 75.8, 72.3,
71.2, 69.9, 67.1, 56.6, 55.1, 49.8, 38.6, 38.5, 37.4, 31.4, 27.5, 27.4,
1.32–1.19 (m, 20 H), 0.87 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 157.7, 138.9, 134.5, 134.3, 130.5, 129.3,
128.28, 128.26, 127.9, 127.44, 127.37, 113.7, 75.0, 71.2, 69.7, 55.2,
41.4, 36.4, 32.2, 31.9, 30.4, 29.65, 29.63, 29.5, 29.3, 29.19, 29.15,
22.7, 14.1 ppm. IR (film): ν = 2925, 2853, 1511, 1454, 1245, 1069,
˜
733, 697 cm–1. ESI-MS: m/z = 607.8 [M + Na]+. ESI-HRMS: calcd.
for C40H56O3Na [M + Na]+ 607.4122; found 607.4133.
Conversion of 23 into 24: The same procedure for the conversion of
18 into 14 above was used by starting from 23 (35 mg, 0.06 mmol).
Chromatography with 3:1 PE/EtOAc gave 24 (20 mg, 83%) as a
white solid. M.p. 85–88 °C. [α]2D8 = +0.9 (c = 0.95, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.12 (d, J = 8.6 Hz, 2 H), 6.83 (d,
J = 8.6 Hz, 2 H), 4.01–3.90 (m, 2 H), 3.78 (s, 3 H), 2.80–2.68 (m,
1 H), 2.66–2.56 (m, 1 H), 2.32 (s, 2 H), 1.89–1.68 (m, 2 H), 1.66–
1.58 (m, 2 H), 1.52–1.41 (m, 2 H), 1.31–1.23 (m, 24 H), 0.88 (t, J
= 6.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.8,
134.0, 129.3, 113.9, 69.5, 68.9, 55.2, 42.4, 39.3, 37.5, 31.9, 31.3,
24.9 ppm. IR (film): ν = 3030, 2935, 2905, 1605, 1504, 1455, 1361,
˜
1250, 1176, 1094, 751, 699 cm–1. ESI-MS: m/z = 733.5 [M + Na]+.
ESI-HRMS: calcd. for C33H42O9S4Na [M + Na]+ 733.1604; found
733.1620.
29.7, 29.63, 29.59, 29.3, 25.7, 22.7, 14.1 ppm. IR (film): ν = 3286,
˜
2955, 2916, 2848, 1514, 1470, 1252, 1114, 1063, 1028, 823 cm–1.
Cleavage of the Thioketal in 20 To Afford 21: The same procedure
for the conversion of 15 into 16 above was used by starting from
thioketal 20 (118 mg, 0.17 mmol). Chromatography with 1:1 PE/
EtOAc gave 21 (65 mg, 65%) as a colorless oil. [α]2D8 = –29.3 (c =
ESI-MS: m/z
= 429.6 [M +
Na]+. ESI-HRMS: calcd. for
C26H46O3Na [M + Na]+ 429.3339; found 429.3353.
Conversion of 24 into (3R,5R)-1: The same procedure for the con-
version of 14 into (3S,5R)-1 above was used by starting from 24
(22 mg, 0.05 mmol). Chromatography with 3:1 PE/EtOAc gave
(3R,5R)-1 (17 mg, 81%) as a yellowish solid. M.p. 70–73 °C. [α]2D6
1
5.13, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.39–7.22 (m, 10
H), 7.08 (d, J = 8.5 Hz, 2 H), 6.83 (d, J = 8.8 Hz, 2 H), 5.13–5.04
(m, 1 H), 4.63 (d, J = 11.4 Hz, 1 H), 4.52 (d, J = 11.2 Hz, 1 H),
4.44–4.34 (m, 2 H), 4.28 (d, J = 11.5 Hz, 1 H), 4.19 (d, J = 11.6 Hz,
1 H), 3.96–3.89 (m, 1 H), 3.79 (s, 3 H), 3.64–3.56 (m, 1 H), 3.02 (s,
3 H), 2.97 (s, 3 H), 2.70–2.61 (m, 1 H), 2.61–2.48 (m, 1 H), 2.01–
1.90 (m, 1 H), 1.89–1.80 (m, 1 H), 1.79–1.72 (m, 1 H), 1.71–1.65
(m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.8, 138.2,
137.3, 133.7, 129.2, 128.4, 128.1, 127.99, 127.95, 127.7, 113.8, 80.9,
75.7, 74.2, 72.8, 70.4, 67.2, 55.2, 38.6, 37.6, 36.2, 35.2, 29.9 ppm.
1
= –0.3 (c = 0.12, MeOH). H NMR (400 MHz, CDCl3): δ = 7.03
(d, J = 8.2 Hz, 2 H), 6.74 (d, J = 8.2 Hz, 2 H), 5.68 (br. s, 1 H),
4.02–3.90 (m, 2 H), 2.74–2.54 (m, 2 H), 1.90–1.69 (m, 2 H), 1.67–
1.59 (m, 2 H), 1.52–1.41 (m, 2 H), 1.31–1.23 (m, 24 H), 0.88 (t, J
= 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.0,
133.7, 129.4, 115.3, 69.6, 69.0, 42.3, 39.1, 37.5, 31.9, 31.2, 29.7,
29.64, 29.60, 29.3, 25.7, 22.7, 14.1 ppm. IR (film of solution in
CH Cl ): ν = 3259, 2911, 2840, 1513, 1468, 1248, 1072, 822 cm–1.
IR (film): ν = 3030, 2935, 1610, 1511, 1357, 1244, 1173, 1027, 914,
˜
˜
2
2
740, 698 cm–1. ESI-MS: m/z = 629.5 [M + Na]+. ESI-HRMS: calcd.
ESI-MS: m/z
= 415.6 [M +
Na]+. ESI-HRMS: calcd. for
for C30H38O9S2Na [M + Na]+ 629.1850; found 629.1876.
C25H44O3Na [M + Na]+ 415.3183; found 415.3193.
Conversion of Dimesylate 21 into Alkene 22: The same procedure
for the conversion of 16 into 17 above was used by starting from
dimesylate 21 (80 mg, 0.13 mmol). Chromatography with 30:1 PE/
EtOAc gave 22 (41 mg, 77%) as a colorless oil. [α]2D8 = –46.9 (c =
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra, FTIR spectra for all new com-
pounds.
1
2.33, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.37–7.17 (m, 10
Acknowledgments
H), 7.04 (d, J = 8.5 Hz, 2 H), 6.78 (d, J = 8.5 Hz, 2 H), 5.76 (ddd,
J = 17.4, 10.3, 7.4 Hz, 1 H), 5.28–5.16 (m, 2 H), 4.52 (d, J =
11.9 Hz, 1 H), 4.45 (d, J = 11.6 Hz, 1 H), 4.29 (d, J = 11.5 Hz, 1
H), 4.18 (d, J = 11.6 Hz, 1 H), 4.01–3.92 (m, 1 H), 3.75 (s, 3 H),
3.72–3.64 (m, 1 H), 2.59 (t, J = 8.0 Hz, 2 H), 1.88–1.67 (m, 4 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 157.7, 139.0, 138.8, 138.6,
134.4, 129.2, 128.3, 127.9, 127.48, 127.46, 116.7, 113.7, 74.9, 71.2,
This work was supported by the National Basic Research Program
of China (the 973 Program, 2010CB833200), and the National Nat-
ural Science Foundation of China (21172247, 21032002, 20921091,
20621062).
70.2, 55.2, 41.2, 36.3, 30.3 ppm. IR (film): ν = 3030, 2931, 2861,
˜
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11.3 Hz, 1 H), 4.33 (d, J = 11.5 Hz, 1 H), 4.20 (d, J = 11.8 Hz, 1
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Received: September 4, 2012
Published Online: November 20, 2012
[12] For similar previously reported cases of cross-metathesis reac-
tions in the presence of a thioketal, see, for example: a) G.
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