Asymmetric syntheses of heliannuols B and D

Article abstract of DOI:10.1016/j.tet.2007.05.034

The synthesis of heliannuol D along with the first synthesis of heliannuol B has been achieved using Mitsunobu reaction and ring-closing metathesis as the key steps.

Full text of DOI:10.1016/j.tet.2007.05.034

Tetrahedron 63 (2007) 6990–6995
Asymmetric syntheses of heliannuols B and D
Jiyong Zhang,a Xiaolei Wang,a Wenkuan Wang,a Weiguo Quan,a
a,
Xuegong Shea,b, and Xinfu Pan
*
*
aDepartment of Chemistry, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
bState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000, PR China
Received 26 March 2007; revised 29 April 2007; accepted 10 May 2007
Available online 16 May 2007
Abstract—The synthesis of heliannuol D along with the first synthesis of heliannuol B has been achieved using Mitsunobu reaction and ring-
closing metathesis as the key steps.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
sesquiterpenes attractive targets for chemical synthesis.2
Heliannuols B (1) and D (2) contain the same basic skeleton
(Fig. 1). The absolute configuration of 2 as (7R,10R) has
been determined by two total syntheses of Shishido.2c,f To
the best of our knowledge, none preparations of 1 have
been reported. Herein we report the synthesis of heliannuol
D along with the first synthesis of heliannuol B with a com-
mon strategy.
Heliannuols (A–L), a new class of sesquiterpenes possessing
interesting allelopathic activity were isolated from Helian-
thus annuus by Macıas and co-workers. These compounds
feature novel structure of benzo-fused six-, seven-, and
eight-membered cyclic ethers. The confluence of structural
distinction and notable biological activity has made these
1
ꢀ
Our retrosynthetic analysis of 1 and 2 is depicted in Scheme
1. Heliannuol D (2) could be derived from 1 via a catalytic
hydrogenation reaction. Through a ring-closing metathesis
reaction, the construction of the benzo-fused seven-mem-
bered framework of 1 was envisioned available from 3,
which could be accomplished by Mitsunobu reaction of phe-
nol 4 and alcohol 5. The stereocenter at C-10 could be estab-
lished at this stage. The compound 4, in turn, would be
prepared from styrene 6.
14
7
7R
6
8
5
4
HO
15
HO
1
2
9
10
10R
O
O
3
13
11
OH
OH
12
(+)-Heliannuol D (2)
(+)-Heliannuol B (1)
Figure 1.
HO
HO
TBDPSO
10
O
O
O
OTBS
OH
OH
2
1
3
OH
TBDPSO
MeO
4
+
OH
OMe
OTBS
5
4
6
Scheme 1. Retrosynthetic analysis of 1 and 2.
* Corresponding authors. E-mail: shexg@lzu.edu.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.034

J. Zhang et al. / Tetrahedron 63 (2007) 6990–6995
6991
2. Results and discussion
TBAF in THF gave the desired (ꢀ)-heliannuol B (2). Fur-
thermore, catalytic hydrogenation of 2 was conducted with
Pd/C (5%) in EtOAc to afford (+)-heliannuol D (1).
The syntheses commenced from olefin 6.3 As shown in
Scheme 2, hydroboration of 6 gave the racemic alcohol 7,
which was then oxidized to aldehyde 8 with Dess–Martin
periodinane4 followed by a Wittig reaction to afford olefin
9. After an oxidation with CAN, compound 9 was converted
to quinone 10.5 Reduction of the quinone with Na2S2O4
gave hydroquinone 11. Selective protection of the sterically
less congested hydroxyl moiety (C-5) of 11 as the tert-butyl-
diphenylsilyl ether led to phenol 4.
3. Conclusion
In summary, asymmetric syntheses of the sesquiterpenes
heliannuols B and D have been accomplished with a common
strategy, in which heliannuol B was synthesized for the first
time. The stereocenter at C-10 was introduced from allylic
alcohol (S)-5 via Mitsunobu reaction. Two diastereoisomers
(7R,10R)-12 and (7S,10R)-13 were separated after a ring-
closing metathesis reaction.
With phenol 4 in hand, we turned to construct the framework
of the final products (Scheme 3). The (S)-allylic alcohol 5
was obtained from mannitol through literature procedures.6
Mitsunobu reaction7 between 4 and (S)-5 furnished diene 3
with inversion of the C-10 configuration. Treatment of 3
with the second-generation Grubbs catalyst 128 produced
the separable benzoxepenes (7R,10R)-13 and (7S,10R)-14,
via ring-closing metathesis reaction.
4. Experimental
4.1. General
Oxygen- and moisture-sensitive reactions were carried out
an under argon atmosphere. Solvents were purified and dried
by standard methods prior to use. All commercially avail-
able reagents were used without further purification unless
otherwise noted. Column chromatography was performed
on silica gel (200–300 mesh). Melting points were measured
on a Kofler apparatus and are uncorrected. Optical rotations
were measured on a Perkin Elmer model 341 polarimeter. In-
frared spectra were recorded on a Nicolet NEXUS 670 FT-IR
spectrometer. 1H NMR and 13C NMR spectra were recorded
To achieve heliannuol B (2) from 13, several functional
group transformations were required (Scheme 4). Selective
cleavage of the TBS ether of 13 under acidic conditions, fol-
lowed by oxidation with IBX9 of the resulting primary alco-
hol 15, gave the corresponding aldehyde 16. This crude
aldehyde was not purified and was directly attacked by
MeMgI to obtain secondary alcohol 17. A second oxida-
tion/MeMgI attack operation of 18, the tertiary alcohol 19
was gained. Finally, deprotection of the TBDPS of 19 with
MeO
MeO
OH
MeO
O
MeO
HO
c
f
b
e
a
CHO
OMe
OMe
OMe
OMe
6
7
8
5
d
OH
O
9
10
11
TBDPSO
OH
4
Scheme 2. Reagents and conditions: (a) BH3$THF, THF, 0 ꢁC, then NaOH, H2O2, rt, 87%; (b) Dess–Martin periodinane, CH2Cl2, rt, 93%; (c) Ph3P+CH2Iꢀ,
n-BuLi, THF, 0 ꢁC–rt, 87%; (d) CAN, 1:1 CH3CN/H2O, rt, 98%; (e) Na2S2O4, Et2O, H2O, rt, 97%; and (f) TBDPSCl, imidazole, DMAP (cat), 0 ꢁC, 73%.
OH
7
10
TBDPSO
TBDPSO
TBDPSO
b
a
+
OTBS
OH
O
3
OTBS
5
4
7
7
MesN
NMes
Ru
TBDPSO
+
Cl
Cl
10
10
O
O
Ph
PCy3
12
OTBS
OTBS
13
14
Scheme 3. Reagents and conditions: (a) DIAD, PPh3, THF, rt, 71% and (b) second-generation Grubbs catalyst 12, CH2Cl2, rt, 47% for 13 and 45% for 14.

6992
J. Zhang et al. / Tetrahedron 63 (2007) 6990–6995
TBDPSO
TBDPSO
TBDPSO
TBDPSO
b
a
c
13
O
O
O
OH
OH
CHO
15
16
17
HO
TBDPSO
c
b
d
O
O
O
O
OH
OH
1
18
19
HO
HO
e
O
O
OH
OH
1
2
Scheme 4. Reagents and conditions: (a) TsOH, 10:1 THF/H2O, rt, 91%; (b) IBX, 9:1 THF/DMSO, rt; (c) MeMgI, Et2O, rt, 84% for 17 and 81% for 19 over 2
steps; (d) TBAF, THF, rt, 96%; and (e) Pd/C, H2, EtOAc, rt, 98%.
on Varian Mercury-300 (300 MHz) spectrometers. Chemical
shifts are reported as d values relative to internal chloroform
(d 7.26 for 1H and 77.0 for 13C).
(s, 3H), 3.81–3.88 (m, 1H), 6.58 (s, 1H), 6.75 (s, 1H), 9.67
(s, 1H); 13C NMR (75 MHz, CDCl3) d 13.5, 16.2, 47.2,
56.0, 111.5, 114.1, 124.4, 126.6, 150.7, 151.9, 202.0;
HRMS (m/z) calcd for C12H16O3Na, 231.0997 [M+Na]+;
found, 231.1001.
4.1.1. 2-(2,5-Dimethoxy-4-methylphenyl)propan-1-ol (7).
To a solution of BH3$THF in THF (1.0 M, 22.0 mL,
22.0 mmol) at 0 ꢁC was added a solution of olefin 6
(3.84 g, 20.0 mmol) in 60 mL THF. After 1 h, 8 mL of
30% H2O2 and 16 mL of 10% NaOH were added. The result-
ing mixture was warmed to rt and stirred for an additional
2 h. The reaction mixture was then diluted with EtOAc
and the layers were separated. The aqueous phase was ex-
tracted with EtOAc (3ꢂ50 mL). The combined organic
phases were washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by column chroma-
tography (hexanes/EtOAc, 6:1) to give alcohol 7 (3.652 g,
87%) as white crystals. Mp 74–75 ꢁC; IR (KBr) 3375,
4.1.3. 1-(But-3-en-2-yl)-2,5-dimethoxy-4-methylbenzene
(9). To a suspension of methyltriphenylphosphonium iodide
(8.02 g, 19.85 mmol) in dry THF (50 mL) at 0 ꢁC was added
n-BuLi (10.5 mL, 1.8 M in hexanes, 18.91 mmol). The reac-
tion mixture was stirred for 15 min at 0 ꢁC and was then
warmed to rt while stirring was continued for 45 min. The
solution was then recooled to 0 ꢁC, and a solution of alde-
hyde 8 (3.276 g, 15.75 mmol) in dry THF (20 mL) was
added slowly via syringe. The reaction mixture was then
warmed to rt and stirred for an additional 2 h. The reaction
was quenched with saturated NH4Cl and extracted with
Et2O (3ꢂ50 mL). The combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated in
vacuo. The residue was purified by column chromatography
(hexanes/EtOAc, 50:1) to give alkene 9 (2.828 g, 87%) as
a colorless oil. IR (KBr) 3388, 2970, 1505, 1208,
1506, 1208, 1046 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d 1.26 (d, J¼7.2 Hz, 3H), 2.21 (s, 3H), 3.36–3.45 (m, 1H),
3.70 (dd, J¼7.5, 1.2 Hz), 3.79 (s, 3H), 3.80 (s, 3H), 6.70
(s, 1H), 6.71 (s, 1H); 13C NMR (75 MHz, CDCl3) d 16.0,
16.4, 35.4, 56.1, 56.2, 67.9, 110.2, 114.3, 125.2, 129.6,
151.0, 151.9; HRMS (m/z) calcd for C12H18O3Na,
233.1154 [M+Na]+; found, 233.1158.
1047 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 1.33 (d,
J¼7.2 Hz, 3H), 2.23 (s, 3H), 3.80 (s, 3H), 3.80 (s, 3H),
3.92 (dq, J¼7.2, 6.0 Hz, 1H), 5.05–5.11 (m, 2H), 6.07
(ddd, J¼16.1, 10.3, 6.0 Hz, 1H), 6.67 (s, 1H), 6.72 (s, 1H);
13C NMR (75 MHz, CDCl3) d 16.1, 19.5, 35.5, 56.0, 56.3,
110.2, 112.8, 114.3, 124.7, 131.9, 142.9, 150.4, 151.7;
HRMS (m/z) calcd for C13H19O2, 207.1386 [M+H]+; found,
207.1384.
4.1.2. 2-(2,5-Dimethoxy-4-methylphenyl)propanal (8). To
a stirred solution of alcohol 7 (3.61 g, 17.2 mmol) in dry
CH2Cl2 (100 mL) was added Dess–Martin periodinane
(10.20 g, 24.07 mmol) in one portion. The mixture was
stirred for 1 h at rt and quenched with a 1:1 mixture of satu-
rated Na2S2O3 (40 mL) and saturated NaHCO3 (40 mL).
The resulting mixture was diluted with CH2Cl2 (50 mL)
and the layers were separated. The aqueous phase was ex-
tracted with CH2Cl2 (3ꢂ50 mL). The combined organic
phases were washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by column chroma-
tography (hexanes/EtOAc, 15:1) to give aldehyde 8
(3.318 mg, 93%) as colorless oil. IR (KBr) 2935, 1733,
4.1.4. 2-(But-3-en-2-yl)-5-methylcyclohexa-2,5-diene-
1,4-dione (10). To a solution of 9 (2.794 g, 13.56 mmol) in
CH3CN (34 mL) at rt was added a solution of CAN
(18.58 g, 33.91 mmol) in H2O (34 mL) in one portion with
stirring. After 5 min, H2O (120 mL) and CH2Cl2 (120 mL)
were added, and the layers were separated. The aqueous
phase was extracted with CH2Cl2 (3ꢂ80 mL). The com-
bined organic phases were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was
1411, 1258, 861 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d 1.39 (d, J¼7.2 Hz, 3H), 2.23 (s, 3H), 3.78 (s, 3H), 3.78

J. Zhang et al. / Tetrahedron 63 (2007) 6990–6995
6993
purified by column chromatography (hexanes/EtOAc, 50:1)
to give 10 (2.339 g, 98%) as a yellow oil. IR (KBr) 3073,
2850, 1660, 1244, 1112; 1H NMR (300 MHz, CDCl3)
d 1.17 (d, J¼7.2 Hz, 3H), 1.99 (s, 3H), 3.55–3.60 (m, 1H),
5.03–5.11 (m, 2H), 5.79 (ddd, J¼16.5, 10.5, 7.2 Hz, 1H),
6.46 (s, 1H), 6.55 (s, 1H); 13C NMR (75 MHz, CDCl3)
d 15.3, 18.3, 35.0, 115.4, 131.5, 133.6, 139.2, 145.2,
152.0, 186.8, 188.2; HRMS (m/z) calcd for C11H12O2,
176.0837 [M]+; found, 176.0833.
15:1) to give both (7R,10R)-13 (609 mg, 47%) and
(7S,10R)-14 (553 mg, 43%) as colorless oils. Compound
13: [a]2D5: ꢀ10 (c 0.7, CHCl3); IR (KBr) 2930, 1500, 1201,
1
1112, 839, 704 cmꢀ1; H NMR (300 MHz, CDCl3) d 0.09
(s, 3H), 0.10 (s, 3H), 0.92 (s, 9H), 1.04 (d, J¼7.8 Hz, 3H),
1.10 (s, 9H), 2.30 (s, 3H), 2.85 (dq, J¼7.6, 6.5 Hz, 1H),
3.60 (dd, J¼10.2, 5.7 Hz, 1H), 3.78 (dd, J¼10.5, 7.4 Hz,
1H), 4.31–4.33 (m, 1H), 5.34 (dd, J¼12.0, 5.6 Hz, 1H),
5.67 (ddd, J¼11.7, 6.3, 2.4 Hz, 1H), 6.08 (s, 1H), 6.83 (s,
1H), 7.32–7.43 (m, 6H), 7.67–7.73 (m, 4H); 13C NMR
(75 MHz, CDCl3) d ꢀ5.3, 16.7, 18.3, 19.6, 22.3, 25.9,
26.6, 38.2, 65.9, 80.5, 117.8, 124.3, 126.5, 126.7, 127.6,
127.7, 129.8, 133.5, 135.4, 135.5, 137.4, 150.0; HRMS
(m/z) calcd for C35H48O3Si2, 572.3142 [M]+; found,
572.3151. Compound 14: [a]2D5: +31 (c 1.1, CHCl3); IR
4.1.5. 2-(But-3-en-2-yl)-4-[(tert-butyldiphenyl)oxyl]-
5-methylphenol (4). To the quinone 10 (2.328 g,
13.23 mmol) in Et2O (50 mL) at rt was added an aqueous so-
lution of Na2S2O4 (9.22 g, 52.91 mmol, in 50 mL H2O) in
one portion with rapid stirring. After 20 min more
Na2S2O4 solution (50 mL) was added. Fifteen minutes later
the layers were separated, and the aqueous phase was
extracted with Et2O (3ꢂ50 mL). The combined organic
phases were washed with brine, dried (Na2SO4 containing
Na2S2O4), and concentrated in vacuo. The residue was puri-
fied by flash column chromatography (hexanes/EtOAc, 6:1)
to give accordingly 1,4-dihydroquinone 11 (2.284 g, 97%)
as a colorless oil. This dihydroquinone was used for the
next step immediately.
1
(KBr) 2930, 1499, 1199, 1111, 839, 704 cmꢀ1; H NMR
(300 MHz, CDCl3) d 0.09 (s, 3H), 0.10 (s, 3H), 0.80 (d,
J¼7.2 Hz, 3H), 0.94 (s, 9H), 1.12 (s, 9H), 2.32 (s, 3H),
3.59 (dq, J¼7.4, 3.2 Hz, 1H), 3.63 (dd, J¼10.4, 4.8 Hz,
1H), 3.78 (dd, J¼10.4, 7.2 Hz, 1H), 4.37 (dd, J¼4.4,
2.4 Hz, 1H), 5.25 (dd, J¼12.4, 2.4 Hz, 1H), 5.47 (ddd,
J¼12.6, 8.0, 4.0 Hz), 6.16 (s, 1H), 6.87 (s, 1H), 7.34–7.44
(m, 6H), 7.69–7.74 (m, 4H); 13C NMR (75 MHz, CDCl3)
d ꢀ5.1, 16.6, 18.4, 18.7, 19.6, 25.9, 26.7, 32.7, 40.1, 65.3,
81.1, 115.4, 124.0, 126.2, 126.6, 127.7, 129.8, 133.4,
134.8, 135.5, 138.2, 149.7; HRMS (m/z) calcd for
C35H48O3Si2, 572.3142 [M]+; found, 572.3149.
Under Ar, to a stirred solution of compound 11 (2.273 g,
12.77 mmol) in dry CH2Cl2 (50 mL) at 0 ꢁC were added
imidazole (1.04 g, 15.23 mmol) followed by TBDPSCl
(3.69 g, 13.41 mmol) and DMAP (78 mg, 0.64 mmol). After
stirring overnight at 0 ꢁC, the reaction mixture was quenched
with H2O and the layers were separated. The aqueous phase
was extracted with CH2Cl2 (3ꢂ30 mL). The combined or-
ganic phases were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by column
chromatography (hexanes/CH2Cl2, 2:1) to give 4 (3.875 g,
73%) as a colorless oil. IR (KBr) 3398, 2931, 1507, 1410,
4.1.8. {(7R,10R)-7,10-Dihydro-5-[(tert-butyldiphenyl)-
oxyl]-4,7-dimethylbenzo[b]oxepin-2-yl}methanol (15).
To a solution of 12 (561 mg, 0.98 mmol) in 10:1 THF/H2O
(11 mL) was added TsOH$2H2O (19 mg, 0.10 mmol). The
resulting solution was stirred at rt for 24 h. Saturated
NaHCO3 was added, and the mixture was extracted with
EtOAc (4ꢂ15 mL). The combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated in va-
cuo. The residue was purified by column chromatography
(hexanes/EtOAc, 10:1) to give 15 (409 mg, 91%) as a white
foam. [a]2D5: ꢀ8 (c 0.5, CHCl3); IR (KBr) 2959, 1500, 1200,
1110, 923, 705 cmꢀ1; 1H NMR (300 MHz, CDCl3) d 1.08 (d,
J¼7.2 Hz, 3H), 1.12 (s, 9H), 2.33 (s, 3H), 2.37 (br s, 1H),
2.80 (dq, J¼7.2, 6.9 Hz, 1H), 3.67–3.71 (m, 2H), 4.38–
4.42 (m, 1H), 5,22 (dd, J¼11.7, 1.1 Hz, 1H), 5.75 (ddd,
J¼11.7, 6.9, 2.4 Hz, 1H), 6.10 (s, 1H), 6.85 (s, 1H), 7.33–
7.45 (m, 6H), 7.68–7.75 (m, 4H); 13C NMR (75 MHz,
CDCl3) d 16.7, 19.6, 22.7, 26.6, 38.7, 65.6, 80.9, 118.3,
123.9, 125.2, 127.1, 127.6, 129.8, 132.8, 133.1, 134.4,
135.4, 137.1, 149.9; HRMS (m/z) calcd for C29H34O3SiNa,
481.2175 [M+Na]+; found, 481.2178.
1
1197, 1111, 910, 702 cmꢀ1; H NMR (300 MHz, CDCl3)
d 0.92 (d, J¼7.2 Hz, 3H), 1.18 (s, 9H), 2.35 (s, 3H), 3.33–
3.42 (m, 1H), 4.67 (s, 1H), 4.88–4.94 (m, 2H), 5.68 (ddd,
J¼16.4, 10.6, 6.8 Hz, 1H), 6.24 (s, 1H), 6.64 (s, 1H),
7.37–7.48 (m, 6H), 7.74–7.77 (m, 4H); 13C NMR
(75 MHz, CDCl3) d 16.6, 18.5, 19.6, 26.7, 36.8, 113.7,
117.8, 118.2, 126.9, 127.6, 127.7, 129.7, 133.3, 135.5,
142.2, 146.9, 147.7; HRMS (m/z) calcd for C27H32O2Si,
416.2172 [M]+; found, 416.2177.
4.1.6. Dialkene 3. Under Ar, to a solution of PPh3 (2.405 g,
9.16 mmol), phenol 4 (3.812 g, 9.16 mmol) and (S)-1-[(tert-
butyldimethyl)oxyl] but-3-en-2-ol 5 (1.680 g, 8.33 mmol) in
dry THF (40 mL) at 0 ꢁC was added dropwise DIAD
(1.853 g, 9.06 mmol). The reaction mixture was warmed to
rt and stirred overnight. The solvent was then evaporated
and the residue was purified by column chromatography
(hexanes/EtOAc, 100:1) to give 3 (3.546 g, 71%) as a color-
less oil. This product is a mixture of two diastereoisomers at
C-7.
4.1.9. (7R,10R)-7,10-Dihydro-5-[(tert-butyldiphenyl)-
oxyl]-4,7-dimethylbenzo[b]oxepin-carbaldehyde (16). A
mixture of alcohol 15 (376 mg, 0.82 mmol) and IBX
(1.152 g, 4.11 mmol) in THF/DMSO (9:1, 24 mL) was
stirred for 4 h at rt, diluted with hexanes, filtered through
Celite, and rinsed with hexanes/EtOAc (3:1). The filtrate
was transferred to a separated funnel and washed with brine,
dried (Na2SO4), and concentrated in vacuo to give the crude
aldehyde 16. This crude aldehyde was used directly in the
following step without further purification.
4.1.7. Compounds 13 and 14. To a solution of 3 (1.356 g,
2.26 mmol) in degassed CH2Cl2 (230 mL) at rt was added
the second-generation Grubbs catalyst 12 (192 mg,
0.226 mmol). The reaction mixture was stirred at rt for
15 h. The solvent was then evaporated and the residue was
purified by column chromatography (hexanes/CH2Cl2,
4.1.10. Compound 17. To a solution of MeMgI in Et2O
(0.5 M, 3.96 mL, 1.98 mmol) at 0 ꢁC was added a solution

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J. Zhang et al. / Tetrahedron 63 (2007) 6990–6995
of the above crude aldehyde 16 (374 mg, 0.82 mmol) in dry
Et2O (5 mL). The reaction mixture was warmed to rt and
stirred for 30 min. The reaction was quenched with saturated
NH4Cl and the layers were separated. The aqueous phase
was extracted with Et2O (3ꢂ10 mL). The combined organic
phases were washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by column chroma-
tography (hexanes/EtOAc, 10:1) to give 17 (324 mg, 84%
over 2 steps) as a colorless oil. This product is a mixture
of two diastereoisomers at C-11.
149.5, 151.7; HRMS (m/z) calcd for C15H22O3, 250.1569
[M]+; found, 250.1573.
Acknowledgements
We are grateful for the generous financial support by the
Special Doctorial Program Funds of the Ministry of Edu-
cation of China (20040730008), NSFC (QT program,
No.20572037), NCET-05-0879, the key grant project of Chi-
nese ministry of Education (No.105169), and Gansu Science
Foundation (3ZS051-A25-004).
4.1.11. 2-{(7R,10R)-7,10-Dihydro-5-[(tert-butyldiphenyl)-
oxyl]-4,7-dimethylbenzo[b]oxepin-2-yl}propan-2-ol (19).
Alcohol 17 (289 mg, 0.61 mmol) was subjected to the
same oxidation/MeMgI attack operation as described above
for alcohol 15. Workup as above and column chromato-
graphy (hexanes/EtOAc, 30:1) afforded alcohol 19 (242 mg,
81% over 2 steps) as a colorless oil. [a]2D5: ꢀ5 (c 0.5, CHCl3);
References and notes
ꢀ
1. (a) Macıas, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G.;
Fronczek, F. R. Tetrahedron Lett. 1993, 34, 1999–2002; (b)
IR (KBr) 2961, 1489, 1197, 923, 704 cmꢀ1
;
1H NMR
Macıas, F. A.; Molinillo, J. M. G.; Varela, R. M.; Torres, A.;
ꢀ
Fronczek, F. R. J. Org. Chem. 1994, 59, 8261–8266; (c)
(300 MHz, CDCl3) d 1.04 (s, 9H), 1.11 (d, J¼6.6 Hz, 3H),
1.27 (s, 6H), 2.32 (s, 3H), 2.62–2.72 (m, 1H), 2.77 (br s,
1H), 4.05 (d, J¼1.1 Hz, 1H), 5.41 (dd, J¼11.7, 1.1 Hz,
1H), 5.77 (ddd, J¼11.7, 7.5, 2.4 Hz, 1H), 6.08 (s, 1H),
6.83 (s, 1H), 7.32–7.47 (m, 6H), 7.66–7.74 (m, 4H); 13C
NMR (75 MHz, CDCl3) d 16.7, 19.6, 24.5, 25.2, 26.6,
26.7, 39.4, 72.3, 86.9, 118.4, 123.6, 125.2, 127.2, 127.6,
127.8, 129.8, 132.8, 133.9, 135.4, 137.0, 149.8; HRMS
(m/z) calcd for C31H38O3SiNa, 509.2488 [M+Na]+; found,
509.2483.
ꢀ
Macıas, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G.
Tetrahedron Lett. 1999, 40, 4725–4728; (d) Macıas, F. A.;
ꢀ
Varela, R. M.; Torres, A.; Molinillo, J. M. G. J. Nat. Prod.
ꢀ
1999, 62, 1636–1639; (e) Macıas, F. A.; Varela, R. M.; Torres,
A.; Molinillo, J. M. G. J. Chem. Ecol. 2000, 26, 2173–2186;
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(f) Macıas, F. A.; Torres, A.; Galindo, J. L. G.; Varela, R. M.;
Alvarez, J. A.; Molinillo, J. M. G. Phytochemistry 2002, 61,
687–692.
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4.1.12. Heliannuol B (1). Under Ar, to a solution of 19
(183 mg, 0.38 mmol) in THF at rt was added TBAF$3H2O
(356 mg, 1.13 mmol) in one portion. After stirring at rt for
12 h, the solvent was evaporated in vacuo and the residue
was purified by column chromatography (hexanes/EtOAc,
5:1) to give heliannuol B (1) (89 mg, 96%) as a colorless
oil. [a]2D5: ꢀ22 (c 0.7, CHCl3); IR (KBr) 3386, 1630,
1
1260 cmꢀ1; H NMR (300 MHz, CDCl3) d 1.30 (s, 3H),
1.32 (s, 3H), 1.43 (d, J¼7.2 Hz), 2.18 (s, 3H), 2.86 (br
s, 1H), 3.14 (dq, J¼7.5, 7.3 Hz, 1H), 4.11 (br s, 1H),
5.48 (dd, J¼12.0, 1.2 Hz, 1H), 5.97 (ddd, J¼12.0, 7.6,
2.4 Hz, 1H), 6.51 (s, 1H), 6.82 (s, 1H); 13C NMR
(75 MHz, CDCl3) d 12.5, 23.2, 24.5, 25.2, 39.6, 72.5,
87.2, 114.7, 122.6, 124.0, 125.5, 133.8, 138.2, 150.0;
HRMS (m/z) calcd for C15H20O3, 248.1412 [M]+; found,
248.1416.
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Nishiyama, S. Synlett 2003, 411–413; (i) Macıas, F. A.;
Chinchilla, D.; Molinillo, J. M. G.; Marın, D.; Varela, R. M.;
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(47 mg, 0.19 mmol) and Pd/C (5%) (10 mg, 2.5 mol %) in
EtOAc (5 mL) at rt was hydrogenated under a H2 atmo-
sphere. After stirring at rt for 2.5 h, the reaction mixture
was filtered through Celite and the filtrate was concentrated
in vacuo. The residue was purified by column chromato-
graphy (hexanes/EtOAc, 4:1) to give heliannuol D (2)
(46 mg, 98%) as colorless crystals. Mp 160–161 ꢁC; [a]D25:
+23 (c 0.7, CHCl3); IR (KBr) 3372, 2955, 2924, 1620,
ꢀ
2004, 45, 983–985; (o) Lecorune, F.; Ollivier, J. Synlett 2004,
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1
1266 cmꢀ1; H NMR (300 MHz, CDCl3) d 1.27 (s, 3H),
1.27 (s, 3H), 1.27 (s, 3H), 1.28 (d, J¼7.2 Hz, 3H), 1.69–
1.73 (m, 1H), 1.74–1.78 (m, 1H), 1.85–1.90 (m, 3H),
2.01–2.05 (m, 1H), 2.16 (s, 3H), 2.87–2.90 (m, 1H), 3.29
(dd, J¼11.1, 1.5 Hz), 4.54 (br s, 1H), 6.54 (s, 1H), 6.73 (s,
1H); 13C NMR (75 MHz, CDCl3) d 15.3, 18.6, 24.4, 25.5,
26.1, 31.7, 38.5, 72.6, 90.5, 115.7, 121.9, 123.5, 138.1,

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