Concise total syntheses of heliannuols B and D

Article abstract of DOI:10.1016/j.tet.2013.11.070

Concise and efficient enantioselective total syntheses of heliannuols B and D have been accomplished using chirality transfer through a Lewis acid-promoted Claisen rearrangement for the construction of the C7 tertiary stereogenic center and a relay ring-c

Full text of DOI:10.1016/j.tet.2013.11.070

Tetrahedron 70 (2014) 742e748
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Concise total syntheses of heliannuols B and D
*
*
Yuki Manabe, Makoto Kanematsu , Hiromasa Yokoe, Masahiro Yoshida, Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 October 2013
Received in revised form 16 November 2013
Accepted 20 November 2013
Available online 3 December 2013
Concise and efficient enantioselective total syntheses of heliannuols B and D have been accomplished
using chirality transfer through a Lewis acid-promoted Claisen rearrangement for the construction of the
C7 tertiary stereogenic center and a relay ring-closing metathesis for assembling the dihydrobenzo[b]
oxepine backbone of the natural products as the key steps.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Sesquiterpenoids
Relay ring-closing metathesis
Diastereoselectivity
Claisen rearrangement
1. Introduction
The helianane sesquiterpenoids heliannuols B (1) and D (2) were
isolated from the moderately polar active fractions of the aqueous
leaf extract of Helianthus annuus L. var. SH-222 and VYP.1 Their
structures were elucidated by extensive spectroscopic studies, X-
ray crystallographic analysis (for 2), and chemical correlations. The
absolute configurations were established by our first enantiose-
lective total synthesis of heliannuol D (2).2 These sesquiterpenoids
significantly inhibit the growth of both dicotyledon (Lactuca sativa
and Lepidium sativum) and monocotyledon species (Hordeum vul-
gare and Triticum aestivum). Consequently they are excellent can-
didates for natural herbicide models with certain specificity against
dicotyledon species.3 Because of their intriguing structural features,
biological profiles, and limited availability, these natural products
represent attractive targets for total synthesis. To date, several
successful total syntheses have been reported in racemic and op-
tically active forms.4,5 In this report, we describe the concise
enantioselective total syntheses of heliannuols B (1) and D (2) via
chirality transfer through a Lewis acid-mediated Claisen rear-
rangement for the construction of the benzylic tertiary stereogenic
center at C7 and relay ring-closing metathesis (RRCM) for assem-
bling the dihydrobenzo[b]oxepine skeleton, the core structure of
the natural products, as the key steps (Fig. 1).
Fig. 1. Structures of heliannuols B and D.
During the course of our synthetic studies on the related heli-
anane sesquiterpenoid heliannuol K (5), we developed a useful
technique for constructing the dihydrobenzo[b]oxocinone 4, which
was efficiently converted to 5, employing the ring-closing me-
tathesis (RCM) of the functionalized diene 3 (Scheme 1).6 It was
thought that this strategy could also be applied to the assembly of
the dihydrobenzo[b]oxepine backbone of heliannuol B (1).
* Corresponding authors. Tel.: þ81 88 633 7287; fax: þ81 88 633 9575; e-mail
addresses: makotokanematsu@yahoo.co.jp (M. Kanematsu), shishido@ph.tokush-
ima-u.ac.jp (K. Shishido).
Scheme 1. Synthesis of heliannuol K via RCM.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.070

Y. Manabe et al. / Tetrahedron 70 (2014) 742e748
743
2. Results and discussion
Our retrosynthetic analysis is shown in Scheme 2. We envi-
sioned a sequential RCM7 of the suitably functionalized dienyl al-
cohol 6, possessing the correct absolute configurations of the two
stereogenic centers at C7 and C10, and deprotection to give heli-
annuol B (1), which could be converted to heliannuol D (2) by
hydrogenation.4a The diene 6 would be derived from 7 by desily-
lation followed by dehydration of the resulting primary alcohol.
Compound 7, in turn, would be prepared by coupling of (S)-methyl
4-(tert-butyldiphenylsilyloxy)-2-hydroxybutanoate (8)8 with the
phenol 9,5d,6 which can be prepared by the substrate controlled
chirality transfer through the Lewis acid-promoted Claisen rear-
rangement of 10, with inversion of configuration at the future C10
(Scheme 2).
Scheme 2. Retrosynthetic analysis.
Scheme 3. Attempted RCM of 6 and 13. Reagents and Conditions: (a) Me3Al, hexane,
room temperature, 0.5 h, 88% for 9, 10% for 11; (b) Tf2O, 2,6-lutitine, CH2Cl2, ꢁ20 ꢀC,
20 min, quant.; (c) 9, K2CO3, MeCN, room temperature, 4 h, quant.; (d) MeMgBr, THF,
Treatment of 10 with trimethylaluminum in hexane at room
temperature for 0.5 h provided a chromatographically separable
mixture of 9 and 11 in 88% (>99% ee) and 10% yield, respective-
ly.5d,6 For the synthesis of 7, we initially examined the Mitsunobu
reaction of the phenol 9 with the optically pure alcohol 8, using
various Mitsunobu conditions;9 however, the reaction did not
work and only the unreacted starting materials were recovered.
Therefore, we turned our attention to an SN2 type coupling of the
triflate 12, derived from 8, and 9. Treatment of 12 with 9 in the
presence of K2CO3 in acetonitrile at room temperature provided 7
quantitatively.10 Grignard reaction of 7 with methylmagnesium
bromide followed by desilylation of the resulting tertiary carbinol
13 produced the diol 14. Selective dehydration of the primary al-
cohol using the NishizawaeGrieco protocol11 provided the requi-
site diene 6 for the key RCM. Treatment of 6 in refluxing CH2Cl2
with 5 mol % of Grubbs’ second-generation catalyst12 did not give
the expected cyclized product 15 and the unreacted 6 was re-
covered in 94% yield.13 When the reaction was conducted in tol-
uene at 80 ꢀC, 6 was also recovered in 92% yield. Under refluxing
toluene for two days, only the phenol 16, generated via the Claisen
rearrangement, was produced in 26% yield. Since this result can be
attributed to the steric bulkiness around the allyl ether moiety, we
therefore chose the ester 17 as the substrate for the RCM leading
to 19 because it was likely to be less sterically congested than the
tertiary carbinol functionality in 6. Sequential desilylation and
dehydration provided 18, which was exposed to the RCM condi-
tions under refluxing CH2Cl2 or toluene; however, only the
unreacted 18 was produced in 72% and 94% yield, respectively
(Scheme 3).
0
ꢀC, 0.5 h, 89%; (e) TBAF, THF, room temperature, 0.5 h, 87%; (f) o-NO2C6H4SeCN,
nBu3P, THF, room temperature, 0.5 h; (g) H2O2 (aqueous), THF, 60 ꢀC, 15 min, 50% (two
steps for 6), 47% (two steps for 18); (h) Grubbs’ second-generation cat. (5 mol %),
CH2Cl2 or toluene reflux; (i) HF$pyridine, THF, pyridine, room temperature, 1.5 h, 78%.
As seen in the previous paper, the ineffectiveness of standard
RCM protocols led us to use a RRCM, which worked well with
a substrate possessing a higher level of steric congestion around
the olefinic bonds.14 Consequently, we decided to use this meth-
odology for assembling the functionalized dihydrobenzo[b]oxe-
pine, the backbone of the heliannuols
B and D. Selective
debenzylation of 13 with LiDBB15 followed by allylation of the
resulting alcohol 20 provided the allyl ether 21 in 90% yield for the
two steps. This was subjected to sequential desilylation and de-
hydration to give 23 in 62% overall yield. Treatment of a solution of
23 in CH2Cl2 with Grubbs’ second-generation catalyst (5 mol %) at
room temperature for 3 h delivered the requisite 15 quantitatively
via the ruthenium alkylidene species 24. Thus, the problem was
overcome by the use of RRCM to affect the crucial cyclization.
Exposure of 15 to 6 M aqueous hydrochloric acid in THF gave
(ꢁ)-heliannuol B (1) quantitatively. The only discrepancy con-
cerned the specific rotation: we observed in repeated measure-
ments under higher concentrations a value of ½a D25
ꢁ77.5 (c 1.10,
ꢂ
CHCl3) for synthetic heliannuol B (1), whereas significantly lower
values of ½a 2D5
ꢂ
ꢁ15.0 (c 0.10, CHCl3),1 and ½a D25
ꢂ
ꢁ22 (c 0.7, CHCl3)4a
were reported for the natural and synthetic 1, respectively. This
noticeable discrepancy remains unresolved at the present time.
Compound 1 was then hydrogenated over palladium on carbon to

744
Y. Manabe et al. / Tetrahedron 70 (2014) 742e748
provide (þ)-heliannuol D (2), {½a D25
ꢂ
þ18.2 (c 0.75, CHCl3); lit.1 ½a D25
ꢂ
performed on silica gel using the indicated solvent. Thin layer
þ16 (c 0.10, CHCl3); lit.5b
½
a 2D8
ꢂ
þ18.0 (c 1.01, CHCl3)}, in 94% yield.
chromatography was performed on precoated plates, and com-
pounds were visualized with UV light and p-anisaldehyde stains.
All melting points were reported as uncorrected.
The spectral properties of 1 and 2 were identical with those for the
natural heliannuols B and D (Scheme 4).
4.1.1. (2R,3E)-2-[5-(Benzyloxy)pent-3-en-2-yl]-4-(methoxymethoxy)-
5-methylphenol and (2S,3Z)-2-[5-(benzyloxy)pent-3-en-2-yl]-4-(me-
thoxymethoxy)-5-methylphenol (9 and 11). To a stirred solution of aryl
allyl ether 105d,6 (500 mg, 1.46 mmol) in hexane (10.0 mL) was added
Me3Al (1.08 M in hexane, 4.00 mL, 4.38 mmol) at 0 ꢀC. After being
stirred for 0.5 h at room temperature, the reaction mixture was di-
luted with Et2O. The resultant mixture was quenched with water, and
then filtered through a pad of Celite. The residue upon workup was
chromatographed on silica gel with hexane/AcOEt (9:1 v/v) as eluent
to afford phenol 9 (441 mg, 88%, >99% ee) as a colorless oil and the Z-
isomer 11 (48.5 mg, 10%) as a colorless oil; 9: ½a D25
ꢁ3.83 (c 1.20,
ꢂ
CHCl3); IR (neat) 3375, 2960, 2928, 1513, 1453, 1398, 1148, 1004, 740,
698 cmꢁ1; 1H NMR (400 MHz, CDCl3) 7.36 (5H, m), 6.82 (1H, s), 6.61
(1H, s), 5.94 (1H, dd, J¼6.0 and 15.6 Hz), 5.71 (1H, ddt, J¼1.2, 6.0, and
15.6 Hz), 5.09 (2H, s), 4.60 (1H, s, OH, D2O exchangeable), 4.50 (2H, s),
4.02 (2H, d, J¼6.0 Hz), 3.66 (1H, quint., J¼7.2 Hz), 3.49 (3H, s), 2.18 (3H,
s), 2.18 (3H, s), 1.38 (3H, d, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3) 149.5
(C), 148.1 (C), 138.2 (C), 138.0 (CH), 138.0 (CH), 128.8 (CH), 128.3 (CH),
127.8 (CH), 127.6 (CH), 126.8 (C), 126.8 (C), 125.7 (CH), 114.9 (CH), 118.3
(CH), 95.8 (CH2), 71.9 (CH2), 70.6 (CH2), 56.0 (CH3), 36.1 (CH), 19.3
(CH3), 15.8 (CH3); HRMS (ESI) m/z calcd for C21H27O4 [MþH]þ
343.1909, found 343.1902. Enantiomeric excess was determined by
HPLC analysis [Chiralcel AD column, 10% isopropanol/hexane, 1.0 mL/
Scheme 4. RRCM approach for the syntheses of 1 and 2. Reagents and conditions: (a)
LiDBB, THF, ꢁ78 ꢀC, 3 min, 91%; (b) NaH, allyl bromide, THF, room temperature, 6 h, 99%;
n
(c) TBAF, THF, room temperature, 3 min, quant.; (d) o-NO2C6H4SeCN, Bu3P, THF, 0 ꢀC,
5 min; (e) H2O2 (aqueous), THF, 60 ꢀC, 20 min, 62% (two steps); (f) Grubbs’ second-
generation cat. (5 mol %), CH2Cl2, room temperature, 3 h, quant.; (g) 6 M HCl (aqueous),
THF, 0 ꢀC, 0.5 h, quant.; (h) H2, 10% PdeC, AcOEt, room temperature, 2.5 h, 94%.
min,
l
¼254 nm, retention times 22.1 min (R) and 25.3 min (S)]; 11:
½
a 2D5
ꢂ
þ154.1 (c 2.59, CHCl3); IR (neat) 3365, 2960, 2927, 1513, 1454,
3. Conclusion
1398, 1190, 1149, 1007, 738, 699 cmꢁ1; 1H NMR (400 MHz, CDCl3) 7.37
(5H, m), 6.87 (1H, s), 6.64 (1H, s), 6.42 (1H, s, OH, D2O exchangeable),
5.60 (1H, dt, J¼6.4 and 10.8 Hz), 5.55 (1H, dd, J¼8.4 and 10.8 Hz), 5.10
(2H, s), 4.62 (1H, d, J¼12.0 Hz), 4.58 (1H, d, J¼12.0 Hz), 4.23 (1H, dd,
J¼4.4 and 11.2 Hz), 4.03 (1H, dq, J¼2.8 and 6.8 Hz), 3.93 (1H, dd, J¼6.0
and 11.2 Hz), 3.50 (3H, s), 2.18 (3H, s), 1.32 (3H, d, J¼7.2 Hz); 13C NMR
(100 MHz, CDCl3) 149.5 (C), 148.8 (C), 140.0 (CH), 140.0 (CH), 137.3 (C),
128.5 (CH), 128.2 (CH), 127.9 (CH), 127.9 (CH), 127.0 (C), 127.0 (C), 122.9
(CH), 118.9 (CH), 113.5 (CH), 95.9 (CH3), 72.8 (CH3), 65.1 (CH3), 56.0
(CH2), 31.5 (CH), 19.8 (CH2), 15.8 (CH3); HRMS (ESI) m/z calcd for
We have completed concise enantioselective total syntheses of
heliannuols B (1) and D (2) using the RRCM of 23 for assembling the
dihydrobenzo[b]oxepine backbone of the natural products as the
key step. The syntheses were efficiently achieved in a longest linear
sequence of eight steps in 50% yield and nine steps in 47% yield,
respectively, from the phenol 9, which was prepared by the use of
chirality transfer through a Lewis acid-promoted Claisen rear-
rangement for the construction of the tertiary stereogenic center at
C7 (natural product numbering).16 The synthetic route developed
here could be applied to the synthesis of not only other helianane
sesquiterpenoids but also new families of man-made compounds
for biological screening.
C
21H27O4 [MþH]þ 343.1909, found 343. 1895.
4.1.2. (2S)-Methyl 2-(trifluoromethylsulfonyloxy)-4-(tert-butyldiphe
nylsilyloxy)butanoate (12). To a stirred solution of alcohol 88
(100 mg, 0.268 mmol) in CH2Cl2 (0.500 mL) were added 2,6-
4. Experimental
lutidine (40.0 mL, 0.295 mmol) and Tf2O (50.0 mL, 0.298 mmol) at
ꢁ20 ꢀC. After being stirred for 20 min at the same temperature, the
reaction mixture was quenched with silica gel (35.0 mg) and stirred
at room temperature for 10 min, then filtered off the silica gel and
concentrated. The residue was chromatographed on silica gel with
hexane/AcOEt (4:1 v/v) as eluent to afford triflate 12 (135 mg,
4.1. General experimental methods
All nonaqueous reactions were carried out under a positive at-
mosphere of argon in dried glassware unless otherwise indicated.
Materials were obtained from commercial suppliers and used
without further purification expect when otherwise noted. Sol-
vents were dried and distilled according to standard protocols. The
phrase ‘residue upon workup’ refers to the residue obtained when
the organic layer was separated and dried over anhydrous MgSO4
and the solvent was evaporated under reduced pressure. NMR
spectra were recorded on a 400 MHz or 500 MHz instrument. 1H
NMR were measured in CDCl3 solution and referenced to TMS
(0.00 ppm). 13C NMR were measured in CDCl3 solution and refer-
enced to CDCl3 (77.0 ppm). Chemical shifts are reported in parts per
million (from TMS). When peak multiplicities are reported, the
following abbreviations are used: s, singlet; d, doublet; t, triplet; q,
quartet; quint, quintet; m, multiplet; br, broadened. IR spectra were
measured on FT/IR spectrometer. Type of mass analyzer was time of
flight mass spectrometry (TOF-mass). Column chromatography was
quant.) as a colorless oil; ½a D30
ꢂ
ꢁ20.0 (c 1.15, CHCl3); IR (neat) 2932,
1769, 1419, 1212, 1145, 1112 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
7.66e7.64 (4H, m), 7.46e7.37 (6H, m), 5.48 (1H, dd, J¼2.8 and
7.6 Hz), 3.82 (3H, s), 3,77 (2H, t, J¼6.0 Hz), 2.26e2.13 (2H, m), 1.05
(9H, s); 13C NMR (100 MHz, CDCl3) 167.8 (C), 135.5 (CH), 135.5 (CH),
135.5 (CH), 135.5 (CH), 132.9 (C), 132.8 (C), 129.9 (CH), 129.9 (CH),
127.8 (CH), 127.8 (CH), 127.8 (CH), 127.8 (CH), 118.4 (C, q,
JCF¼318 Hz), 80.2 (CH), 58.0 (CH2), 53.2 (CH3), 34.8 (CH2), 26.6
(CH3), 26.6 (CH3), 26.6 (CH3), 19.1 (C); HRMS (ESI) m/z calcd for
C
22H28O6SiSF3 [MþH]þ 505.1328, found 505.1324.
4.1.3. (2R)-Methyl 2-{2-[(2R,3E)-5-(benzyloxy)pent-3-en-2-yl]-4-(me-
thoxymethoxy)-5-methylphenoxy}-4-(tert-butyldiphenylsilyloxy)buta-
noate (7). To a stirred solution of phenol 9 (100 mg, 0.292 mmol) and
K2CO3 (60.5 mg, 0.438 mmol) in MeCN (2.00 mL) was added

Y. Manabe et al. / Tetrahedron 70 (2014) 742e748
745
a solution of triflate 12 (221 mg, 0.438 mmol) in MeCN (1.00 mL) at
room temperature. After being stirred for 4 h, the reaction mixture
was filtered off, and then the filtrate was concentrated. The residue
was dissolved in AcOEt. The combined extracts were washed with
water, saturated aqueous NaHCO3 and brine, and the residue upon
workup was chromatographed on silica gel with hexane/AcOEt (3:2 v/
J¼6.0 Hz), 3.86 (1H, quint., J¼6.8 Hz), 3.77 (1H, dt, J¼10.8 and
5.6 Hz), 3.66e3.59 (1H, m), 3.48 (3H, s), 2.52 (1H, br s, OH, D2O
exchangeable), 2.40 (1H, br s, OH, D2O exchangeable), 2.20 (3H, s),
2.02e1.87 (2H, m), 1.33 (3H, d, J¼6.8 Hz), 1.30 (3H, s), 1.27 (3H, s);
13C NMR (100 MHz, CDCl3) 150.2 (C), 149.4 (C), 138.8 (CH), 138.2 (C),
131.8 (C), 128.3 (CH), 128.3 (CH), 127.8 (CH), 127.8 (CH), 127.5 (CH),
126.2 (C), 124.9 (CH), 114.9 (CH), 114.8 (CH), 95.6 (CH2), 81.2 (CH),
73.0 (C), 72.0 (CH2), 70.7 (CH2), 59.0 (CH2), 56.0 (CH3), 35.2 (CH),
32.8 (CH2), 26.2 (CH3), 25.7 (CH3),19.9 (CH3),16.3 (CH3); HRMS (ESI)
m/z calcd for C27H38O6Na [MþNa]þ 481.2566, found 481.2592.
v) as eluent to afford ether 7 (204 mg, quant.) as a colorless oil; ½a D31
ꢂ
þ33.0 (c 0.42, CHCl3); IR (neat) 3425, 2930, 2857, 1758, 1505, 1195,
1112 cmꢁ1; 1H NMR (400 MHz, CDCl3) 7.65 (2H, d, J¼7.2 Hz), 7.58 (2H,
d, J¼7.2 Hz), 7.43e7.25 (11H, m), 6.84 (1H, s), 6.58 (1H, s), 5.91 (1H, dd,
J¼5.6 and 15.6 Hz), 5.61 (1H, dt, J¼5.6 and 15.6 Hz), 5.10 (1H, d,
J¼10.4 Hz), 5.08 (1H, d, J¼10.4 Hz), 4.96 (1H, dd, J¼4.0 and 8.4 Hz),
4.48 (2H, s), 3.98 (2H, d, J¼6.0 Hz), 3.80e3.96 (3H, m), 3.69 (3H, s),
3.47 (3H, s), 2.24e2.09 (2H, m), 2.16 (3H, s), 1.23 (3H, d, J¼7.2 Hz), 1.04
(9H, s); 13C NMR (100 MHz, CDCl3) 172.5 (C), 150.1 (C), 149.7 (C), 138.6
(C), 138.5 (CH), 135.6 (CH), 135.6 (CH), 135.5 (CH), 135.5 (CH), 133.5 (C),
133.5 (C),132.9 (C),129.7 (CH),129.6 (CH),128.3 (CH),127.8 (CH),127.8
(CH), 127.7 (CH), 127.7 (CH), 127.7 (CH), 127.7 (CH), 127.5 (CH), 126.1
(C), 124.9 (CH),124.9 (CH), 115.0 (CH), 114.9 (CH), 95.7 (CH2), 73.7 (CH),
71.7 (CH2), 71.0 (CH2), 59.5 (CH2), 56.0 (CH3), 52.1 (CH3), 36.0 (CH2),
34.5 (CH), 26.9 (CH3), 26.9 (CH3), 26.9 (CH3), 19.8 (CH3), 19.2 (C), 16.2
(CH3); HRMS (ESI) m/z calcd for C42H53O7Si [MþH]þ 697.3561, found
697.3558.
4.1.6. (3R)-3-{2-[(2R,3E)-5-(Benzyloxy)pent-3-en-2-yl]-4-(methox-
ymethoxy)-5-methylphenoxy}-2-methylpent-4-en-2-ol (6). To a stir-
red solution of diol 14 (14.0 mg, 30.5
added o-nitrophenylselenocyanide (20.8 mg, 91.5
(18.9 L, 91.5 mol) at room temperature. After being stirred for
m
mol) in THF (2.00 mL) was
m
mol) and nBu3P
m
m
0.5 h, the reaction mixture was concentrated. The residue was fil-
tered through silica gel column chromatography (hexane/EtOAc,
4:1 v/v) to give the corresponding selenide (21.2 mg), as a yellow
oil, which was used to the next reaction without further purifica-
tion. To a stirred solution of selenide in THF (2.00 mL) was added
30% aqueous H2O2 (0.300 mL) at room temperature. After being
stirred for 15 min at 60 ꢀC, the reaction mixture was treated with
saturated aqueous NaHCO3 and extracted with Et2O. The combined
extracts were washed with brine, and the residue upon workup was
chromatographed on silica gel with hexane/AcOEt (3:2 v/v) as el-
uent to afford diene 6 (6.70 mg, 50% for two steps) as a yellow oil;
4.1.4. (3R)-3-[2-(2R,3E)-5-Benzyloxypent-3-en-2-yl-4-methoxy-
methoxy-5-methylphenoxy]-5-(tert-butyldiphenylsilyloxy)-2-
methylpentan-2-ol (13). To a stirred solution of ester 7 (542 mg,
0.777 mmol) in THF (3.10 mL) was added MeMgBr (1.11 M in THF,
2.80 mL, 3.11 mmol) at ꢁ78 ꢀC. After being stirred for 0.5 h at 0 ꢀC, the
reaction mixture was quenched with saturated aqueous NH4Cl and
extracted with Et2O. The combined extracts were washed with brine,
and the residue upon workup was chromatographed on silica gel
hexane/AcOEt (4:1 v/v) as eluent to afford alcohol 13 (454 mg, 84%) as
½
a 3D3
ꢂ
ꢁ4.77 (c 0.57, CHCl3); IR (neat) 3500, 2972, 1501, 1393, 1191,
1150, 1010 cmꢁ1; 1H NMR (400 MHz, CDCl3) 7.36e7.21 (5H, m), 6.86
(1H, s), 6.63 (1H, s), 5.90 (1H, ddd, J¼14.4, 6.4, and 1.2 Hz), 5.82 (1H,
ddd, J¼17.6, 10.8, and 6.8 Hz), 5.59 (1H, dtd, J¼15.2, 6.4, and 1.6 Hz),
5.32 (1H, dt, J¼9.6 and 1.2 Hz), 5.28 (1H, dt, J¼17.6 and 1.2 Hz), 5.09
(2H, s), 4.49 (2H, s), 4.37 (1H, d, J¼6.8 Hz), 4.03e3.96 (2H, m), 3.92
(1H, quint., J¼7.2 Hz), 3.47 (3H, s), 2.48 (1H, br s, OH, D2O ex-
changeable), 2.19 (3H, s),1.34 (3H, d, J¼7.2 Hz), 1.29 (3H, s), 1.27 (3H,
s); 13C NMR (100 MHz, CDCl3) 149.6 (C), 149.4 (C), 138.8 (CH), 138.3
(C), 134.2 (CH), 132.0 (C), 128.3 (CH), 128.3 (CH), 127.7 (CH), 127.7
(CH), 127.5 (CH), 125.9 (CH), 125.1 (C), 119.7 (CH), 116.2 (CH), 114.4
(CH), 95.6 (CH2), 86.2 (CH), 72.4 (C), 71.9 (CH2), 70.7 (CH2), 56.0
(CH3), 34.8 (CH2), 25.6 (CH3), 24.6 (CH3), 19.9 (CH3), 16.2 (CH3);
HRMS (ESI) m/z calcd for C27H36O5Na [MþNa]þ 463.2460, found
463.2490.
a colorless oil; ½a D25
ꢂ
þ7.60 (c 1.04, CHCl3); IR (neat) 3476, 2960, 2930,
1499, 1190, 1150, 1111, 1075, 1011 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
7.63 (2H, dd, J¼1.2 and 8.0 Hz), 7.48 (2H, dd, J¼1.2 and 8.0 Hz), 6.94
(1H, s), 7.27e7.44 (11H, m), 6.87 (1H, s), 5.85 (1H, dd, J¼6.4 and
15.6 Hz), 5.57 (1H, dt, J¼6.0 and 15.6 Hz), 5.12 (1H, d, J¼10.4 Hz), 5.09
(1H, d, J¼10.4 Hz), 4.55 (1H, dd, J¼3.2 and 8.4 Hz), 4.48 (2H, s), 3.96
(2H, d, J¼6.4 Hz), 3.88 (1H, m), 3.69 (2H, dd, J¼3.6 and 7.6 Hz), 3.49
(3H, s), 2.55 (1H, br s, OH, D2O exchangeable), 1.55 (3H, s), 1.94e1.86
(1H, m),1.78e1.71 (1H, m), 1.27 (3H, s), 1.27 (3H, d, J¼6.4 Hz),1.26 (3H,
s), 1.03 (9H, s); 13C NMR (100 MHz, CDCl3) 151.1 (C), 149.4 (C), 138.8
(CH), 138.3 (C), 135.4 (CH), 135.4 (CH), 135.3 (CH), 135.3 (CH), 133.3 (C),
133.3 (C), 131.5 (C), 129.6 (CH), 129.5 (CH), 128.2 (CH), 127.7 (CH), 127.7
(CH), 127.6 (CH), 127.6 (CH), 127.6 (CH), 127.6 (CH), 127.4 (CH), 126.2
(C), 124.9 (CH), 124.9 (CH), 115.4 (CH), 114.5 (CH), 95.6 (CH2), 81.1 (CH),
72.9 (C), 71.9 (CH2), 70.7 (CH2), 60.2 (CH2), 55.9 (CH3), 34.7 (CH), 34.0
(CH2), 26.7 (CH3), 26.7 (CH3), 26.7 (CH3), 26.0 (CH3), 25.0 (CH3), 19.8
(CH3), 19.0 (C), 16.1 (CH3); HRMS (ESI) m/z calcd for C43H57O6Si
[MþH]þ 697.3924, found 697.3931.
4.1.7. 6-[(2R,3E)-5-(Benzyloxy)pent-3-en-2-yl]-2-[(2E)-4-hydroxy-
4-methylpent-2-enyl]-4-(methoxymethoxy)-3-methylphenol (16). To
a stirred solution of diene 6 (3.90 mg, 8.85
mmol) in degassed tol-
uene (10.0 mL) was added Grubbs’ second-generation catalyst
(1.30 mg, 0.443 mmol) at room temperature. After being stirred for
53 h at 110 ꢀC, the resultant mixture was concentrated and the
residue was chromatographed on silica gel with hexane/AcOEt (4:1
v/v) as eluent to afford the phenol (16) (1.00 mg, 26%) as a yellow
oil; ½a 2D9
ꢂ
ꢁ9.00 (c 0.02, CHCl3); IR (neat) 3446, 2922, 2357,1152, 972,
4.1.5. (3R)-3-{2-[(2R,3E)-5-(Benzyloxy)pent-3-en-2-yl]-4-(methox-
743 cmꢁ1 1H NMR (400 MHz, CDCl3) 7.34e7.23 (5H, m), 6.78 (1H,
;
ymethoxy)-5-methylphenoxy}-4-methylpentane-1,4-diol
a stirred solution of alcohol 13 (15.0 mg, 21.5 mol) in THF
(0.500 mL) was added TBAF (1.00 M in THF, 20.0 L, 23.7 mol) at
(14). To
s), 5.93 (1H, dd, J¼5.6 and 15.6 Hz), 5.75e5.68 (3H, m), 5.63 (1H, d,
J¼15.6 Hz), 5.10 (2H, s), 4.81 (1H, s), 4.50 (2H, s), 4.01 (2H, d,
J¼5.6 Hz), 3.68 (1H, m), 3.49 (3H, s), 3.40 (2H, d, J¼5.6 Hz), 2.17 (3H,
s), 1.39 (3H, d, J¼7.2 Hz), 1.27 (6H, s); 13C NMR (125 MHz, CDCl3)
149.6 (C), 147.0 (C), 139.0 (CH), 138.3 (C), 137.6 (CH), 131.2 (C), 128.4
(CH), 128.4 (CH), 128.3 (C), 127.8 (CH), 127.8 (CH), 127.6 (CH), 126.3
(CH), 125.7 (C), 124.1 (CH), 113.1 (CH), 96.0 (CH2), 72.1 (CH2), 70.7
(C), 70.5 (CH2), 56.1 (CH3), 36.8 (CH), 29.8 (CH3), 29.8 (CH3), 26.5
(CH2), 19.2 (CH3) 11.9 (CH3),; HRMS (ESI) m/z calcd for C27H36O5Na
[MþNa]þ 463.2460, found 463.2474.
m
m
m
room temperature. After being stirred for 0.5 h, the reaction mix-
ture was quenched with water and extracted with CH2Cl2. The
combined extracts were washed with brine, and the residue upon
workup was chromatographed on silica gel hexane/AcOEt (7:3 v/v)
as eluent to afford alcohol 14 (8.6 mg, 87%) as a colorless oil; ½a D32
ꢂ
þ6.06 (c 0.78, CHCl3); IR (neat) 3380, 2930, 1500, 1393, 1190, 1150,
1102 cmꢁ1; 1H NMR (400 MHz, CDCl3) 7.37e7.25 (5H, m), 6.87 (1H,
s), 6.77 (1H, s), 5.88 (1H, dd, J¼15.6 and 6.4 Hz), 5.60 (1H, dtd,
J¼15.6, 6.4, and 1.2 Hz), 5.10 (2H, s), 4.51 (1H, d, J¼12.0 Hz), 4.48
(1H, d, J¼12.0 Hz), 4.33 (1H, dd, J¼6.4 and 4.8 Hz), 3.98 (2H, d,
4.1.8. (3R)-Methyl
2-{2-[(2R,3E)-5-(benzyloxy)pent-3-en-2-yl]-4-
(methoxymethoxy)-5-methylphenoxy}-4-hydroxybutanoate (17). To

746
Y. Manabe et al. / Tetrahedron 70 (2014) 742e748
a stirred solution of ester 7 (20.0 mg, 28.7
mmol) in THF/pyridine
and 6.4 Hz), 7.44e7.29 (6H, m), 6.97 (1H, s), 6.89 (1H, s), 5.82 (1H,
(0.500 mL, 3/1 v/v) was added a drop of HF$pyridine at 0 ꢀC. After
being stirred at room temperature for 1.5 h, the reaction mixture
was quenched with saturated aqueous NaHCO3 and extracted with
AcOEt. The combined extracts were washed with brine, and the
residue upon workup was chromatographed on silica gel hexane/
AcOEt (7:3 v/v) as eluent to afford alcohol 17 (10.2 mg, 78%) as
dd, J¼6.4 and 15.6 Hz), 5.60 (1H, dt, J¼6.0 and 15.6 Hz), 5.12 (2H, t,
J¼1.2 Hz), 4.55 (1H, dd, J¼3.2 and 8.4 Hz), 4.06 (2H, br m), 3.87 (1H,
m), 3.71 (2H, m), 3.51 (3H, s), 2.13 (3H, s), 1.78e1.70 (1H, m), 2.63
(1H, br s, OH, D2O exchangeable), 1.92e1.84 (1H, m), 1.79e1.70 (1H,
m), 1.28 (3H, d, J¼7.2 Hz), 1.26 (6H, s), 1.04 (9H, s); 13C NMR
(100 MHz, CDCl3) 151.2 (C), 149.4 (C), 137.7 (CH), 135.5 (CH), 135.5
(CH), 135.4 (CH), 135.4 (CH), 133.4 (C), 133.3 (C), 131.3 (C), 129.7
(CH), 129.5 (CH), 128.1 (CH), 127.7 (CH), 127.7 (CH), 127.6 (CH), 127.6
(CH), 126.4 (C), 115.3 (CH), 114.5 (CH), 95.6 (CH2), 81.1 (CH), 73.2 (C),
63.5 (CH2), 60.2 (CH2), 56.0 (CH3), 34.7 (CH), 34.1 (CH2), 26.8 (CH3),
26.8 (CH3), 26.8 (CH3), 26.1 (CH3), 24.8 (CH3), 19.8 (CH3), 19.1 (C),
16.1 (CH3); HRMS (ESI) m/z calcd for C36H51O6Si [MþH]þ 607.3455,
found 607.3450.
a colorless oil; ½a D32
ꢂ
þ37.0 (c 0.47, CHCl3); IR (neat) 3468, 2957, 1753,
1502, 1192, 1150, 1011 cmꢁ1
;
1H NMR (400 MHz, CDCl3) 7.34e7.25
(5H, m), 6.85 (1H, s), 6.52 (1H, s), 5.95 (1H, ddt, J¼15.6, 5.6, and
1.2 Hz), 5.65 (1H, dtd, J¼15.6, 6.4, and 1.6 Hz), 5.10 (1H, d, J¼6.8 Hz),
5.07 (1H, d, J¼6.8 Hz), 4.83 (1H, t, J¼6.0 Hz), 4.50 (2H, s), 4.02 (1H,
dd, J¼6.4 and 0.8 Hz), 3.92 (1H, quint., J¼6.8 Hz), 3.85 (1H, q,
J¼5.2 Hz), 3.72 (3H, s), 3.46 (3H, s), 2.18 (3H, s), 2.22e2.17 (2H, m),
1.88 (1H, br s, OH, D2O exchangeable), 1.34 (3H, d, J¼6.8 Hz); 13C
NMR (100 MHz, CDCl3) 172.5 (C), 150.1 (C), 149.5 (C), 138.4 (C), 138.3
(CH), 132.6 (C), 128.3 (CH), 128.3 (CH), 127.8 (CH), 127.8 (CH), 127.5
(CH), 126.3 (CH), 126.1 (C), 125.0 (CH), 115.2 (CH), 114.8 (CH), 95.6
(CH2), 74.4 (CH), 71.9 (CH2), 71.0 (CH2), 56.0 (CH3), 55.2 (CH3), 35.5
(CH), 35.3 (CH3), 19.7 (CH3), 16.2 (CH3); HRMS (ESI) m/z calcd for
4.1.11. (3R)-3-{2-[(2R,3E)-5-(Allyloxy)pent-3-en-2-yl-4-(methox-
ymethoxy)-5-methylphenoxy]-5-tert-butyldiphenylsilyloxy}-2-
methylpentan-2-ol (21). To a stirred solution of allyl alcohol 20
(349 mg, 0.575 mmol) in THF (2.50 mL) was added NaH (69.0 mg,
1.73 mmol) at 0 ꢀC. After being stirred for 0.5 h, the resultant
mixture was added allyl bromide (0.150 mL, 1.73 mmol) at 0 ꢀC. The
mixture was allowed to warm to room temperature, and then
stirring was continued for 6 h at the same temperature. The re-
sultant mixture was treated with H2O and extracted with AcOEt.
The combined extracts were washed with brine, and the residue
upon workup was chromatographed on silica gel with hexane/
AcOEt (4:1 v/v) as eluent to afford diene 21 (360 mg, 99%) as
C
26H34O7Na [MþNa]þ 481.2202, found 481.2214.
4.1.9. (3R)-Methyl
(methoxymethoxy)-5-methylphenoxy}but-3-enoate (18). To a stirred
solution of alcohol 17 (10.2 mg, 22.2 mol) in THF (1.00 mL) was
added o-nitrophenylselenocyanide (15.1 mg, 66.7
mol) and nBu3P
(13.8 L, 66.7 mol) at room temperature. After being stirred for
2-{2-[(2R,3E)-5-(benzyloxy)pent-3-en-2-yl]-4-
m
m
m
m
0.5 h, the reaction mixture was concentrated. The residue was fil-
tered through silica gel column chromatography (hexane/EtOAc,
4:1 v/v) to give the corresponding selenide (21.0 mg), as a yellow
oil, which was used to the next reaction without further purifica-
tion. To a stirred solution of selenide in THF (2.00 mL) was added
30% aqueous H2O2 (0.300 mL) at room temperature. After being
stirred for 15 min at 60 ꢀC, the reaction mixture was treated with
saturated aqueous NaHCO3 and extracted with Et2O. The combined
extracts were washed with brine, and the residue upon workup was
chromatographed on silica gel with hexane/AcOEt (4:1 v/v) as el-
uent to afford diene 18 (4.60 mg, 47% for two steps) as a yellow oil;
a colorless oil; ½a D25
ꢂ
þ3.21 (c 1.00, CHCl3); IR (neat) 3463, 2960,
1500, 1190, 1111, 1011, 703 cmꢁ1
;
1H NMR (400 MHz, CDCl3) 7.62
(2H, d, J¼6.4 Hz), 7.47 (2H, d, J¼6.4 Hz), 7.44e7.28 (6H, m), 6.94 (1H,
s), 6.87 (1H, s), 5.94e5.81 (2H, m), 5.54 (1H, dt, J¼6.0 and 15.6 Hz),
5.25 (1H, dd, J¼1.6 and 17.2 Hz), 5.16 (1H, dd, J¼1.6 and 10.8 Hz),
5.12 (1H, d, J¼10.8 Hz), 5.10 (1H, d, J¼10.8 Hz), 4.55 (1H, dd, J¼3.2
and 8.4 Hz), 3.94 (2H, d, J¼8.8 Hz), 3.92 (2H, d, J¼8.8 Hz), 3.87 (1H,
m), 3.69 (2H, d, J¼3.6 and 7.6 Hz), 3.50 (3H, s), 2.55 (1H, br s, OH,
D2O exchangeable), 2.13 (3H, s), 1.95e1.86 (1H, m), 1.79e1.72 (1H,
m), 1.28e1.25 (9H, m), 1.02 (9H, s); 13C NMR (100 MHz, CDCl3) 151.1
(C), 149.4 (C), 138.8 (CH), 135.5 (CH), 135.5 (CH), 135.4 (CH), 135.4
(CH), 134.8 (CH), 133.4 (C), 133.4 (C), 131.6 (C), 129.7 (CH), 129.5
(CH), 127.7 (CH), 127.7 (CH), 127.6 (CH), 127.6 (CH), 126.3 (C), 124.9
(CH), 116.9 (CH2), 115.4 (CH), 114.6 (CH), 95.7 (CH2), 81.2 (CH), 73.0
(C), 70.9 (CH2), 70.7 (CH2), 60.3 (CH2), 56.0 (CH3), 34.7 (CH), 34.0
(CH2), 26.8 (CH3), 26.8 (CH3), 26.8 (CH3), 26.1 (CH3), 25.0 (CH3), 19.8
(CH3), 19.1 (C), 16.2 (CH3); HRMS (ESI) m/z calcd for C39H55O6Si
[MþH]þ 647.3768, found 647.3771.
½
a 3D2
ꢂ
þ22.28 (c 0.78, CHCl3); IR (neat) 2955, 1761, 1503, 1394, 1193,
1151, 1015 cmꢁ1; 1H NMR (400 MHz, CDCl3) 7.35e7.24 (5H, m), 6.91
(1H, s), 6.55 (1H, s), 6.06 (1H, ddd, J¼5.6, 10.4, and 16.0 Hz), 5.96
(1H, ddt, J¼6.0, 15.6, and 1.2 Hz), 5.68 (1H, ddt, J¼1.6, 15.6, and
6.0 Hz), 5.60 (1H, dq, J¼17.2 and 1.2 Hz), 5.40 (1H, dq, J¼10.8 and
1.2 Hz), 5.11 (1H, d, J¼6.4 Hz), 5.07 (1H, d, J¼6.4 Hz), 5.06 (1H, dt,
J¼5.6 and 1.6 Hz), 4.04e4.01 (3H, m), 4.50 (2H, s), 3.75 (3H, s), 3.47
(3H, s), 2.19 (3H, s), 1.35 (3H, d, J¼6.8 Hz); 13C NMR (100 MHz,
CDCl3) 170.3 (C), 150.3 (C), 149.1 (C), 138.4 (CH), 138.4 (C), 133.3 (C),
132.2 (CH), 128.2 (CH), 128.2 (CH), 127.7 (CH), 127.7 (CH), 127.4 (CH),
126.0 (C), 125.0 (CH), 118.9 (CH2), 115.9 (CH), 114.7 (CH), 95.4 (CH2),
78.7 (CH), 71.6 (CH3), 70.9 (CH2), 56.0 (CH3), 52.4 (CH3), 34.7 (CH),
19.8 (CH3), 16.2 (CH3); HRMS (ESI) m/z calcd for C26H32O6Na
[MþNa]þ 463.2097, found 463.2103.
4.1.12. (3R)-3-{2-[(2R,3E)-5-(Allyloxy)pent-3-en-2-yl]-4-(methox-
ymethoxy)-5-methylphenoxy}4-methyl-pentane-1,4-diol
a stirred solution of TBDPS ether 21 (33.5 mg, 53.1
(3.00 mL) was added TBAF (1.00 M in THF, 60.0
(22). To
mol) in THF
L, 58.4 mmol) at
m
m
room temperature. After being stirred for 3 min at room temper-
ature, the reaction mixture was treated with water and extracted
with CH2Cl2. The combined extracts were washed with brine, and
the residue upon workup was chromatographed on silica gel with
hexane/AcOEt (3:2 v/v) as eluent to afford diol 22 (25.9 mg, quant.)
4.1.10. (4R,2E)-4-{2-[(3R)-1-(tert-Butyldiphenylsilyloxy)-4-hydroxy-
4-methylpentan-3-yloxy]-5-(methoxymethoxy)-4-methylphenyl}
pent-2-en-1-ol (20). To a stirred solution of benzyl ether 13
as a colorless oil; ½a D31
þ5.72 (c 0.48, CHCl3); IR (neat) 3398, 2966,
ꢂ
(50.0 mg, 71.7
mmol) in THF (5.00 mL) was added solution of lithium
1500, 1190, 1150, 1011 cmꢁ1; 1H NMR (400 MHz, CDCl3) 6.86 (1H, s),
6.77 (1H, s), 5.95e5.84 (2H, m), 5.57 (1H, dt, J¼6.4 and 15.6 Hz),
5.26 (1H, d, J¼17.2 Hz), 5.17 (1H, d, J¼10.4 Hz), 5.10 (2H, s), 4.33 (1H,
t, J¼5.6 Hz), 3.96e3.93 (4H, m), 3.85 (1H, dq, J¼6.8 and 7.2 Hz),
3.80e3.75 (1H, m), 3.63e3.57 (1H, m), 3.49 (3H, s), 2.50 (2H, br s,
OH, D2O exchangeable), 2.21 (3H, s), 2.04e1.87 (2H, m), 1.33 (3H, d,
J¼7.2 Hz), 1.31 (3H, s), 1.29 (3H, s); 13C NMR (100 MHz, CDCl3) 150.2
(C), 149.4 (C), 138.7 (CH), 134.7 (CH), 131.8 (C), 126.2 (C), 124.9 (CH),
117.0 (CH2), 115.0 (CH), 114.8 (CH), 95.6 (CH2), 81.2 (CH), 72.9 (C),
71.0 (CH2), 70.7 (CH2), 59.1 (CH2), 56.0 (CH3), 35.2 (CH), 32.9 (CH2),
di-tert-buthylbiphenilide (LiDBB) (1.45
M
in THF, 0.500 mL,
0.717 mmol) at ꢁ78 ꢀC. After being stirred for 3 min at ꢁ78 ꢀC, the
reaction mixture was treated with saturated aqueous NH4Cl and
extracted with AcOEt. The combined extracts were washed with
brine, and the residue upon workup was chromatographed on silica
gel hexane/AcOEt (2:1 v/v) as eluent to afford allyl alcohol 20
(39.6 mg, 91%) as a colorless oil; ½a D25
ꢂ
ꢁ8.22 (c 1.06, CHCl3); IR (neat)
3408, 2961, 1500, 1391, 1190, 1150, 1111, 1010 cmꢁ1
;
1H NMR
(400 MHz, CDCl3) 7.63 (2H, dd, J¼1.2 and 6.4 Hz), 7.50 (2H, dd, J¼1.2

Y. Manabe et al. / Tetrahedron 70 (2014) 742e748
747
26.2 (CH3), 25.8 (CH3), 19.9 (CH3), 16.3 (CH3); HRMS (ESI) m/z calcd
for C23H37O6 [MþH]þ 409.2590, found 409.2580.
25.3 (CH3), 24.7 (CH3), 23.2 (CH3), 15.4 (CH3); HRMS (ESI) m/z calcd
for C15H21O3 [MþH]þ 249.1491, found 249.1506.
4.1.13. (3R)-3-{2-[(2R,3E)-5-(Allyloxy)pent-3-en-2-yl]-4-(methox-
4.1.16. (þ)-Heliannuol D (2). A suspension of heliannuol B (1)
ymethoxy)-5-methylphenoxy}-2-methyl-pent-4-en-2-ol
a stirred solution of diol 22 (20.0 mg, 49.0 mol) in THF (2.00 mL)
was added o-nitrophenylselenocyanide (22.2 mg, 97.9 mol) and
nBu3P (20.2 mol) at 0 ꢀC. After being stirred for 5 min at
L, 97.9
ꢀC, the reaction mixture was concentrated to give the corre-
(23). To
(4.00 mg, 1.61 mmol) and PdeC (0.400 mg, 10% w/w) in AcOEt
m
(2.00 mL) was stirred under 1 atm of hydrogen gas. After being
stirred for 2.5 h at room temperature, the reaction mixture was
filtered through a pad of Celite and concentrated. The residue was
chromatographed on silica gel with hexane/AcOEt (3:2 v/v) as el-
uent to afford alcohol 16 (3.80 mg, 94%) as a colorless oil; mp
m
m
m
0
sponding selenide (28.7 mg), as a yellow oil, which was used to the
next reaction without further purification. To a stirred solution of
157e158 ꢀC (lit.5f,h 161e162 ꢀC); ½a 2D5
þ18.2 (c 0.75, CHCl3); IR
ꢂ
selenide in THF (2.00 mL) was added 30% aqueous H2O2 (80.0
mL) at
(neat) 3365, 2931, 1508, 1417, 1192, 1020 cmꢁ1; 1H NMR (400 MHz,
CDCl3) 6.73 (1H, s), 6.54 (1H, s), 4.55 (1H, br s, OH, D2O ex-
changeable), 3.30 (1H, d, J¼10.8 Hz), 2.90 (1H, br s), 2.70 (1H, br s,
OH, D2O exchangeable), 2.16 (3H, s), 2.09e1.99 (1H, m), 1.92e1.88
(1H, m), 1.79e1.70 (2H, m), 1.28 (3H, d, J¼7.2 Hz), 1.28 (6H, s); 13C
NMR (125 MHz, CDCl3) 151.7 (C), 149.6 (C), 138.1 (C), 123.5 (CH),
122.1 (C), 115.8 (CH), 90.5 (CH), 72.7 (C), 38.5 (CH), 31.8 (CH2), 26.1
(CH2), 25.5 (CH3), 24.4 (CH3), 18.6 (CH3), 15.3 (CH3); HRMS (ESI) m/z
calcd for C15H23O3 [MþH]þ 251.1647, found: 251.1643.
room temperature. After being stirred for 20 min at 60 ꢀC, the re-
action mixture was treated with saturated aqueous NaHCO3 and
extracted with Et2O. The combined extracts were washed with
brine, and the residue upon workup was chromatographed on silica
gel with hexane/AcOEt (4:1 v/v) as eluent to afford triene 23
(11.8 mg, 62% for two steps) as a yellow oil; ½a D25
ꢂ
ꢁ8.35 (c 1.11,
CHCl3); IR (neat) 3467, 2973, 1501, 1392, 1191, 1150 cmꢁ1
;
1H NMR
(400 MHz, CDCl3) 6.86 (1H, s), 6.63 (1H, s), 5.95e5.78 (3H, m), 5.56
(1H, dt, J¼6.0 and 15.6 Hz), 5.33e5.23 (3H, m), 5.16 (1H, dd, J¼1.2
and 10.4 Hz), 5.10 (2H, s), 4.37 (1H, d, J¼7.2 Hz), 3.96e3.87 (5H, m),
3.48 (3H, s), 2.48 (1H, br s, OH, D2O exchangeable), 2.19 (3H, s), 1.34
(3H, d, J¼6.8 Hz), 1.30 (3H, s), 1.27 (3H, s); 13C NMR (100 MHz,
CDCl3) 149.7 (C), 149.5 (C), 138.7 (CH), 134.9 (CH), 134.3 (CH), 132.1
(C), 126.0 (C), 125.1 (CH), 119.7 (CH2), 116.9 (CH2), 116.2 (CH), 114.5
(CH), 95.7 (CH2), 86.3 (CH), 72.5 (C), 71.0 (CH2), 70.7 (CH2), 56.0
(CH3), 34.8 (CH), 25.7 (CH3), 24.6 (CH3), 19.9 (CH3), 16.2 (CH3);
HRMS (ESI) m/z calcd for C23H35O5 [MþH]þ 391.2484, found
391.2478.
Acknowledgements
This work was financially supported by a Grant-in-Aid from the
Ministry of Education, Science, Sports, Culture and Technology, Ja-
pan and from the Program for the Promotion of Basic and Applied
Research for Innovation in the Bio-oriented Industry (BRAIN).
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.11.070.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
4.1.14. 2-{(2R,5R)-7-(Methoxymethoxy)-5,8-dimethyl-2,5-
dihydrobenzo[b]oxepin}-2-ylpropan-2-ol (15). To a stirred solution
of triene 23 (11.8 mg, 30.2
added Grubbs’ second-generation catalyst (1.30 mg, 1.51
m
mol) in degassed CH2Cl2 (10.0 mL) was
mol) at
m
room temperature. After being stirred for 3 h at room temperature,
the reaction mixture was concentrated and the residue was chro-
matographed on silica gel with hexane/AcOEt (3:2 v/v) as eluent to
afford O-MOM heliannuol B (15) (9.40 mg, quant.) as a yellow oil;
References and notes
1. Macías, F. A.; Molinillo, J. M. G.; Varela, R. M.; Torres, A.; Fronczek, F. R. J. Org.
Chem. 1994, 59, 8261e8266.
2. Takabatake, K.; Nishi, I.; Shindo, M.; Shishido, K. J. Chem. Soc., Perkin Trans. 1
2000, 1807e1808.
3. Macías, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G. J. Chem. Ecol. 2000, 26,
2173e2186.
4. Heliannuol B: for an enantioselective synthesis, see: (a) Zhang, J.; Wang, X.;
Wang, W.; Quan, W.; She, X.; Pan, X. Tetrahedron 2007, 63, 6990e6995 for
a racemic synthesis, see: (b) Roy, A.; Biswas, B.; Sen, P. K.; Venkateswaran, R. V.
Tetrahedron Lett. 2007, 48, 6933e6936.
5. Heliannuol D: for enantioselective syntheses, see: (a) Kishuku, H.; Yoshimura,
T.; Kakehashi, T.; Shindo, M.; Shishido, K. Heterocycles 2003, 61, 125e131; (b)
Osaka, M.; Kanematsu, M.; Yoshida, M.; Shishido, K. Tetrahedron: Asymmetry
2010, 21, 2319e2320; (c) Li, J.-Q.; Quan, X.; Anderson, P. G. Chem.dEur. J. 2012,
18, 10609e10616; (d) Manabe, Y.; Kanematsu, M.; Osaka, M.; Yoshida, M.;
Shishido, K. Heterocycles 2014, 88, http://dx.doi.org/10.3987/COM-13-S(S)50 in
press; (e) See also Refs. 3 and 4a; for racemic syntheses, see: (f) Vyvyan, J. R.;
Looper, R. E. Tetrahedron Lett. 2000, 41, 1151e1154; (g) Tuhina, K.; Bhowmik, D.
R.; Venkateswaran, R. V. Chem. Commun. 2002, 634e635; (h) Macías, F. A.;
Chinchilla, D.; Molinillo, J. M. G.; Marín, D.; Varela, R. M.; Torres, A. Tetrahedron
2003, 59, 1679e1683; (i) Doi, F.; Ohta, T.; Ogamino, T.; Sugai, T.; Higashinakasu,
K.; Yamada, K.; Shigemori, H.; Hasegawa, K.; Nishiyama, S. Phytochemistry 2004,
65, 1405e1411; (j) Sabui, S. K.; Venkateswaran, R. V. Tetrahedron Lett. 2004, 45,
983e985; (k) Sabui, S. K.; Venkateswaran, R. V. Tetrahedron Lett. 2004, 45,
2047e2048; (l) Osaka, M.; Kanematsu, M.; Yoshida, M.; Shishido, K. Heterocy-
cles 2010, 80, 1003e1012.
½
a 3D1
ꢂ
ꢁ51.1 (c 0.35, CHCl3); IR (neat) 3446, 2972, 1502, 1150,
1009 cmꢁ1; 1H NMR (400 MHz, CDCl3) 6.84 (1H, s), 6.78 (1H, s), 5.99
(1H, ddd, J¼2.4, 7.6, and 12.0 Hz), 5.48 (1H, d, J¼12.0 Hz), 5.15 (1H,
d, J¼11.2 Hz), 5.13 (1H, d, J¼11.2 Hz), 4.07 (1H, br s, OH, D2O ex-
changeable), 3.49 (3H, s), 3.20 (1H, m), 2.76 (1H, br s, OH, D2O
exchangeable), 2.19 (3H, s), 1.44 (3H, d, J¼7.2 Hz), 1.32 (3H, s), 1.30
(3H, s); 13C NMR (100 MHz, CDCl3) 151.8 (C), 151.0 (C), 137.9 (C),
134.0 (CH), 126.7 (C), 125.5 (CH), 123.9 (CH), 114.4 (CH), 95.1 (CH2),
87.2 (CH), 72.3 (CH3), 56.0 (CH), 40.0 (CH), 25.3 (CH3), 24.7 (CH3),
23.2 (CH3), 15.8 (CH3); HRMS (ESI) m/z calcd for C17H24O4Na
[MþNa]þ 315.1572, found 315.1561.
4.1.15. (ꢁ)-Heliannuol B (1). To a stirred solution of O-MOM heli-
annuol B (15) (5.00 mg,1.71 mmol) in THF (0.400 mL) was added 6 M
aqueous HCl (1.60 mL) at 0 ꢀC. After being stirred for 0.5 h at 0 ꢀC,
the reaction mixture was extracted with Et2O. The combined ex-
tracts were washed with water and brine, and the residue upon
workup was chromatographed on silica gel with hexane/AcOEt (7:3
v/v) as eluent to afford heliannuol B (1) (4.24 mg, quant.) as a yel-
6. Kanematsu, M.; Soga, K.; Manabe, Y.; Morimoto, S.; Yoshida, M.; Shishido, K.
Tetrahedron 2011, 67, 4758e4766 and references cited therein.
low oil; ½a 2D5
ꢁ75.5 (c 1.10, CHCl3); IR (neat) 3364, 2975, 1508, 1417,
ꢂ
7. Pan et al.4a and Venkateswaran, et al.4b have demonstrated independently the
RCM strategy for the construction of the dihydrobenzo[b]oxepine skeleton of
heliannuol B using the substrate with two terminal alkenes (monosubstituted
alkenes).
1192, 844 cmꢁ1; 1H NMR (400 MHz, CDCl3) 6.81 (1H, s), 6.51 (1H, s),
5.97 (1H, ddd, J¼1.2, 8.0, and 12.0 Hz), 5.49 (1H, dd, J¼1.2 and
12.0 Hz), 4.81 (1H, br s, OH, D2O exchangeable), 4.06 (1H, br s), 3.15
(1H, dq, J¼7.5 and 7.5 Hz), 2.82 (1H, br s, OH, D2O exchangeable),
2.19 (3H, s), 1.43 (3H, d, J¼7.2 Hz), 1.32 (3H, s), 1.30 (3H, s); 13C NMR
(100 MHz, CDCl3) 150.2 (C), 150.0 (C), 138.3 (C), 133.9 (CH), 125.6
(CH), 124.0 (CH), 122.7 (C), 114.8 (CH), 87.3 (CH), 72.5 (C), 39.7 (CH),
8. Hayashi, Y.; Yamaguchi, J.; Shoji, M. Tetrahedron 2002, 58, 9839e9846.
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React. 1992, 42, 335e656; (c) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28,
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11. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485e1486.
^

748
Y. Manabe et al. / Tetrahedron 70 (2014) 742e748
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13. We also tried Grubbs’ first-generation catalyst, but the reaction did not proceed
at all.
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16. The phenol 9 was prepared from 3-methyl-4-(methoxymethoxy) phenol in 71%
yield for the two steps as described in Refs. 5d and 6.