Chiral and stereoselective total synthesis of (-)-mesembranol starting from D-glucose

Article abstract of DOI:10.1039/a604365h

A chiral synthesis of the Sceletium alkaloid (-)-mesembranol 1 is described. The cyclohexane ring in 1 is prepared in an optically active form from D-glucose using Ferrier's carbocyclisation, and the critical stereochemistry of the quaternary carbon in 1 is constructed stereoselectively via chirality transfer by way of Claisen rearrangement of the cyclohexenol derivative 14a. The perhydroindole skeleton in 1 is effectively generated by intramolecular aminomercuriation of the amino-olefin 18.

Full text of DOI:10.1039/a604365h

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Chiral and stereoselective total synthesis of (Ϫ)-mesembranol
starting from D-glucose
Noritaka Chida, Kohji Sugihara, Seiji Amano and Seiichiro Ogawa
Department of Applied Chemistry, Faculty of Science and Technology, Keio University,
Hiyoshi, Kohoku-ku, Yokohama 223, Japan
A chiral synthesis of the Sceletium alkaloid (Ϫ)-mesembranol 1 is described. The cyclohexane ring in 1
is prepared in an optically active form from D -glucose using Ferrier’s carbocyclisation, and the critical
stereochemistry of the quaternary carbon in 1 is constructed stereoselectively via chirality transfer by
way of Claisen rearrangement of the cyclohexenol derivative 14a. The perhydroindole skeleton in 1 is
effectively generated by intramolecular aminomercuriation of the amino-olefin 18.
Ferrier’s carbocyclisation (Ferrier rearrangement) is one of the
most efficient procedures for the construction of optically pure
cyclohexanone derivatives from aldohexoses1 and is frequently
used in the synthesis of cyclitols and aminocyclitols.2 Such
chiral and highly oxygenated cyclohexanes derived from aldoses
are potentially versatile chiral building blocks in natural prod-
uct synthesis, however, applications of this reaction to the prep-
aration of structurally more complex natural products are
limited.3 If one can transfer the carbon–oxygen chirality in
cyclohexanes derived from aldohexoses into stereogenic
carbon–carbon bond formation, the potential of Ferrier’s carbo-
cyclisation would be further amplified. In this article, as a
part of our continuous study to utilize Ferrier’s carbocyclis-
ation in the preparation of natural products containing a
OMe
OMe
Ar
4
3
3a
5
6
2
7a
7
N
NHMe
OH
OR
H
Me
i
(–)-Mesembranol 1
Ar
Ar
OHC
cyclohexane unit, we report
a total synthesis of (Ϫ)-
OR
mesembranol 1,4,5 a Sceletium alkaloid possessing an interest-
ing structure including a perhydroindole skeleton with a
quaternary carbon, from -glucose.6 Our retrosynthetic analy-
sis (Fig. 1) suggested that the perhydroindole skeleton in 1
would be constructed by intramolecular aminomercuriation–
demercuriation reaction of the amino-olefin i. Compound i was
envisioned to be derived from aldehyde ii, whose quaternary
carbon was planned to be generated from the cyclohexenol iii
via chirality transfer by way of a [3,3]-sigmatropic rearrange-
ment. The cyclohexenol iii, in turn, was planned to be prepared
from aryllithium and cyclohexanone iv, which would be effect-
ively synthesized in an optically pure form from -glucose by
catalytic Ferrier’s carbocyclisation.
OR
OH
ii
iii
OMe
OMe
Ar =
O
+
ArLi
D-glucose
R2O
OR
OR1
iv
Fig. 1
The synthesis of 1 commenced with the known methyl 4,6-O-
benzylidene-α--altropyranoside 2,7 prepared from -glucose
in five steps. The hydroxy groups in 2 was protected as a bis-
methoxymethyl ether to give 3, which was treated with N-
bromosuccinimide (NBS) in the presence of BaCO3 8 to afford 4
(90% from 2). Compound 4 was dehydrobrominated with 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) to give a 5-enopyrano-
side derivative 5 in 96% yield. Catalytic Ferrier’s carbocyclis-
ation of 5 using mercury() trifluoroacetate (0.5 mol%)9 in
acetone–water (2:1) at room temperature cleanly provided the
cyclohexanone 6, which, without purification, was transformed
into the enone 7 by the action of methanesulfonyl chloride
(MsCl) and triethylamine (88% yield from 5). Reaction of 7
with 3,4-dimethoxyphenyllithium 10 in diethyl ether at Ϫ78 ЊC,
followed by MeONa treatment gave the diol 8 as a single prod-
uct in 56% yield. Saturation of the double bond in 8 afforded
9, quantitatively. The newly formed stereocentre in compound 8
was assigned by a NOE measurement of the O-acetyl derivative
10; the observed NOE between 2-H and aromatic protons
(2Ј-H, 7.4%; 6Ј-H, 11.0% enhancement) suggested the stereo-
chemistry at C-1 should be S (Scheme 1). The diol 9 was then
transformed into the thiocarbonate derivative 11 in 95% yield.
The facile formation of the thiocarbonate ring from 9 also
supported the assigned stereochemistry at C-1. Treatment of
11 with trimethyl phosphite11 provided 12 in 74% yield.
With the optically active, protected allyl ether 12 to hand,
generation of a quaternary carbon by chirality transfer was
next explored (Scheme 2). To deprotect the O-MOM group in
12, a variety of aqueous or non-aqueous acidic reaction con-
ditions12 (aqueous HCl–THF, aqueous TFA, aqueous acetic
acid, pyridinium toluene-p-sulfonate–ButOH, HCl–MeOH, tri-
methylsilyl bromide–CH2Cl2, ZnBr2–CH2Cl2, TFA–CH2Cl2)
were examined; however, it was found that compound 12 was
quite labile to acidic conditions and quickly aromatized to give
v. The best results were obtained when compound 12 was
treated with aqueous formic acid at 30 ЊC for 6 h, and a mixture
consisting of the allyl alcohols 14a, 14b, the allyl formates 13a,
13b and starting material was obtained. This result clearly sug-
gested that the reaction involved the allyl cation intermediates
vi generated by elimination of allylic (methoxymethyl)oxy
group. Alkaline hydrolysis of this mixture and subsequent
J. Chem. Soc., Perkin Trans. 1, 1997
275

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Ph
O
OMe
OMe
OMe
OMe
O
5'
6'
O
2'
D-Glucose
RO
OMe
12
+
OR
2 R = H
3 R = MOM
2
3
4
RO
RO
OMOM
OMOM
13b R = CHO
14b R = H
15b R = Ac
13a R = CHO
14a R = H
15a R = Ac
CH2Br
BzO
BzO
O
O
MOMO
OMe
OMOM
MOMO
OMe
OMOM
+
OMe
OMe
OMe
OMe
OMe
OMe
5
4
O
O
+
BzO
BzO
OMOM
OMOM
v
MOMO
vi
H5
MOMO
OH
OMOM
OMOM
H5
7
6
H3
OAc
OMOM
OAc
H3
Ar
Ar
5'
2'
OMe
OMe
OMe
OMe
OMOM
6'
6'
H4
H4
HO
HO
HO
2
RO
2'
15a: J3,4 = 6.0 Hz
15b: J3,4 = 3.5 Hz
1
1
2
J4,5 = 7.0 Hz
J
4,5 = 10.0 Hz
MOMO
MOMO
Scheme 2
OMOM
OMOM
9 R = H
10 R = Ac
8
5'
OMe
OMe
6'
EtO2C
14a
2'
1
2
3
OMe
OMe
OMe
S
4
OMe
5'
6'
O
O
OMOM
2'
16
2
MOMO
OMe
3
OMOM
4
OMe
MOMO
OMe
11
OMOM
12
R
OMe
4
Scheme 1
3
2
5
6
7a
7
N
OMOM
OMOM
H
Me
chromatographic separation provided a mixture of 14a and 14b
(57%), and recovered 12 (23%). The mixture of compounds 14a
and 14b was acetylated, and the products were cleanly isolated
in pure form by silica gel chromatography to afford 15a (39%
from 12) and 15b (18% from 12), respectively. The coupling con-
stants observed in 1H NMR spectra of 15a and 15b (J3,4 6.0 Hz,
for 15a and 3.5 Hz for 15b) supported the assigned structures.
Basic methanolysis of 15a generated 14a, and that of 15b gave
14b, both in high yields. The undesired diastereoisomer 14b was
effectively transformed into 14a by Mitsunobu inversion 13 fol-
lowed by alkaline hydrolysis in 62% yield.
The crucial step, generation of a quaternary carbon via chir-
ality transfer, was successfully achieved by Claisen rearrange-
ment 14 of 14a with triethyl orthoacetate in the presence of
powdered molecular sieves (3 Å) and a catalytic amount of
propionic acid to provide the rearranged product 16 in 56%
yield as the sole product (Scheme 3). Other variant reaction
19
17 R = CHO
18 R = CH2NHMe
(–)-Mesembranol 1
Scheme 3
conditions of Claisen rearrangement (Ireland ester enolate
rearrangement,15a Eshenmoser type rearrangement,14d vinyl
allyl ether rearrangement 15b) were found to be less effective
for this substrate. Reduction of the ester function in 16 with
diisobutylaluminium hydride (DIBAL) at Ϫ78 ЊC gave the
corresponding aldehyde 17 (82%), which was converted into
the secondary amine 18 by means of reductive amination
(dimethylamine and NaBH3CN, 65% yield). Another crucial
step, construction of the perhydroindole skeleton, was achieved
276
J. Chem. Soc., Perkin Trans. 1, 1997

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by intramolecular aminomercuriation–demercuriation 16 to
provide the protected mesembranol 19 in quantitative yield.
Treatment of 19 with aqueous HCl followed by basic extraction
graphed on a silica gel column (150 g), with EtOAc–toluene
(1:5, v/v) to give compound 4 (7.49 g, 90%) as a colourless syrup
(Found: C, 48.05; H, 5.9. C18H25O8Br requires C, 48.2; H,
5.6%); [α]D22 +64 (c 1.0, CHCl3); νmax(neat)/cmϪ1 1720 (C᎐O);
1
afforded (Ϫ)-mesembranol 1 as crystals in 68% yield. The H
᎐
(270 MHz) and 13C (67 MHz) NMR spectral data of 1 were
identical with those reported by Ishibashi and Ikeda,5d and the
physical properties of 1 [mp 146–147 ЊC, [α]D24 Ϫ28 (c 0.2,
CHCl3), lit.,5a mp 144–146 ЊC, [α]D30 Ϫ32 (CHCl3)] showed good
agreement with those reported in the literature.5a
δH (270 MHz) 3.28, 3.45 and 3.50 (each 3 H, 3 s, OCH3), 3.54
(1 H, dd, J 11.0 and 7.3, 6-H), 3.65 (1 H, dd, J 11.0 and 2.6,
6Ј-H), 3.91 (1 H, dd, J 3.7 and 1.5, 2-H), 4.26 (1 H, dd, J 3.7 and
3.7, 3-H), 4.48 (1 H, ddd, J 9.5, 7.3 and 2.6, 5-H), 4.62 and 4.73
(each 2 H, 2 d, J 7.0, CH3OCH2), 4.75 and 4.76 (each 2 H, 2 s,
CH3OCH2), 4.70–4.80 (1 H, m, 1-H), 5.30 (1 H, dd, J 9.5 and 3.7,
4-H) and 7.42–8.06 (5 H, m, phenyl); m/z 418 (M+, 7%), 416
(M+, 7), 388 (2), 386 (2), 342 (5), 311 (3), 309 (3) and 221 (100).
In summary, a chiral and stereoselective synthesis of (Ϫ)-
mesembranol 1 has been achieved. This work revealed that
Claisen rearrangement of cyclohexenols derived from aldo-
hexoses by Ferrier’s carbocyclisation should be a potent
method for the stereoselective construction of carbon–carbon
bonds, whose chirality could be effectively transferred from the
carbon–oxygen bond in sugars.
Methyl 4-O-benzoyl-2,3-bis-O-(methoxymethyl)-6-deoxy-á-D-
arabino-hex-5-enopyranoside 5
A solution of compound 4 (1.22 g, 2.71 mmol) and DBU (1.33
cm3, 8.14 mmol) in toluene (30 cm3) was stirred at 75 ЊC for
20 h. The reaction mixture was diluted with EtOAc, washed
successively with aq. HCl (1 mol dmϪ3), saturated aq. sodium
hydrogen carbonate and brine, dried and evaporated to leave a
residue. This was chromatographed on a column of silica gel
(45 g), with acetone–toluene (1:20, v/v) as eluent, to afford
compound 5 (690 mg, 96%) as a colourless syrup (Found: C,
58.3; H, 6.9. C18H24O8 requires C, 58.7; H, 6.6%); [α]D22 +57
(c 0.7, CHCl3); νmax(neat)/cmϪ1 1670 (C᎐C) and 1730 (C᎐O);
Experimental
Mps were determined on a Mitamura-riken micro-hot-stage
and are uncorrected. 1H NMR Spectra were measured with
JEOL JNM EX-90 (90 MHz) and JNM-GSX 270 (270 MHz)
spectrometers, with tetramethylsilane as the internal standard
for solutions in deuteriochloroform, unless otherwise noted; J
values are given in Hz. 13C NMR Spectra were taken on a JEOL
JNM-GSX 270 (67 MHz) spectrometer. Mass spectra were
measured using a JEOL JMS-DX 303 spectrometer with EI
mode (70 eV). Optical rotations were measured with a JASCO
DIP-370 instrument and values of [α]D are recorded in units of
10Ϫ1 deg cm2 gϪ1. IR Spectra were taken with a JASCO IR-810
spectrometer. Organic extracts were dried over anhydrous
Na2SO4 and concentrated <40 ЊC under reduced pressure.
᎐
᎐
δH (270 MHz) 3.35, 3.45 and 3.59 (each 3 H, 3 s, OCH3), 3.37
(1 H, dd, J 8.1 and 3.3, 3-H), 4.02 (1 H, dd, J 8.1 and 5.5, 2-H),
4.59 (1 H, d, J 5.5, 1-H), 4.73 and 4.76 (each 1 H, 2 d, J 7.0,
CH3OCH2), 4.78 (1 H, d, J 1.1, 6-H), 4.81 and 4.85 (each 1 H,
2 d, J 6.6, CH3OCH2), 4.85 (1 H, d, J 1.1, 6Ј-H), 5.91 (1 H, d, J
3.3, 4-H) and 7.41–8.06 (5 H, m, phenyl); m/z 337 [(M Ϫ OMe)+,
3%], 306 (18), 294 (14), 275 (8) and 105 (100).
2L-(2,3/4)-2-O-Benzoyl-3,4-bis-O-(methoxymethyl)-2,3,4-
trihydroxy-5-cyclohexen-1-one 7
Methyl 4,6-O-benzylidene-2,3-bis-O-(methoxymethyl)-á-D-
altropyranoside 3
A mixture of compound 5 (4.27 g, 11.6 mmol) and mercuric
trifluoroacetate (25 mg, 0.059 mmol) in acetone–water (2:1,
100 cm3) was stirred at room temperature for 72 h. The mixture
was partially concentrated to remove acetone and extracted
with EtOAc. The extract was washed successively with 10% aq.
KI, 20% aq. Na2S2O3 and saturated aq. sodium hydrogen car-
bonate and brine, dried and evaporated to give crude 6 (4.40 g)
as a syrup. This was used in the next reaction without purifi-
cation. To a solution of crude 6 (4.40 g) in CH2Cl2 (100 cm3) at
0 ЊC was added triethylamine (9.26 cm3, 69.6 mmol) and meth-
anesulfonyl chloride (2.69 cm3, 37.8 mmol), and the resulting
mixture was stirred at room temp. for 30 min. After the mixture
had been diluted with CH2Cl2 it was washed successively with
aq. HCl (1 mol dmϪ3), saturated aq. sodium hydrogen carbon-
ate and brine, dried and evaporated to leave a residue. This was
chromatographed on a column of silica gel (150 g), with
acetone–toluene (1:10, v/v) as eluent, to afford compound 7
(3.42 g, 88%) as a colourless syrup (Found: C, 60.5; H, 6.2.
C17H20O7 requires C, 60.7; H, 6.0%); [α]D22 Ϫ96 (c 0.9, CHCl3);
νmax(neat)/cmϪ1 1710 (ketone) and 1730 (ester); δH (270 MHz)
3.37 and 3.45 (each 3 H, 2 s, OCH3), 4.44–4.49 (2 H, m, 3-H and
4-H), 4.75, 4.80, 4.84 and 4.85 (each 1 H, 4 d, J 7.0, 2 ×
CH3OCH2), 6.08 (1 H, d, J 2.6, 2-H), 6.19 (1 H, d, J 9.9, 6-H),
6.88 (1 H, ddd, J 9.9, 4.8 and 2.2, 5-H) and 7.43–8.14 (5 H, m,
phenyl); m/z 336 (M+, 12%), 305 (2), 275 (2), 253 (5), 208 (4),
128 (77) and 105 (100).
A
mixture of methyl 2,3-anhydro-4,6-O-benzylidene-α--
allopyranoside (5.11 g, 19.3 mmol) and sodium hydroxide (6.64
g, 118 mmol) in water (170 cm3) was heated under reflux for 48
h. After cooling of the reaction mixture, the products were
extracted with CH2Cl2. The extract was washed with water,
dried and evaporated to afford crude methyl 4,6-O-benzylidene-
α--altropyranoside7 as an oil, which was dissolved in CH2Cl2
(100 cm3). To this solution at 0 ЊC were added N,N-
diisopropylethylamine (11.6 cm3, 67.7 mmol) and chloromethyl
methyl ether (5.10 cm3, 67.7 mmol) and the resulting mixture
was heated under reflux for 18 h. After cooling, the reaction
mixture was diluted with CH2Cl2, washed successively with aq.
HCl (1 mol dmϪ3), saturated aq. sodium hydrogen carbonate
and brine, dried and evaporated to leave a syrup. This was
chromatographed on a column of silica gel (100 g), with
EtOAc–toluene (1:3, v/v) as eluent, to afford compound 3 (6.09
g, 85%) as a colourless syrup (Found: C, 58.0; H, 6.7. C18H26O8
requires C, 58.4; H, 7.1%); [α]D22 +45 (c 0.96, CHCl3); νmax(neat)/
cmϪ1 2940 and 2900 (CH); δH (270 MHz) 3.40, 3.42 and 3.42
(each 3 H, 3 s, OCH3), 3.77 (1 H, dd, J 11.0 and 9.5, 6-H), 3.90
(1 H, dd, J 2.9 and 0.7, 2-H), 3.96 (1 H, dd, J 9.5 and 2.9, 4-H),
4.14 (1 H, dd, J 2.9 and 2.9, 3-H), 4.25–4.35 (2 H, m, 5-H and
6Ј-H), 4.65 (1 H, d, J 0.7, 1-H), 4.70, 4.75, 4.75 and 4.84 (each
1 H, 4 d, J 7.0, 2 × CH3OCH2), 5.58 (1 H, s, PhCH) and
7.33–7.48 (5 H, m, phenyl); m/z 371 [(M + 1)+, 2%], 370 (2), 341
(3), 340 (13), 161 (52) and 83 (100).
Methyl 4-O-benzoyl-6-bromo-6-deoxy-2,3-bis-O-(methoxy-
methyl)-á-D-altropyranoside 4
1L-[1(OH),2,3/4]-3,4-Bis-O-(methoxymethyl)-1-(3,4-dimethoxy-
phenyl)cyclohex-5-ene-1,2,3,4-tetrol 8
The mixture of compound 3 (7.53 g, 20.3 mmol), N-
bromosuccinimide (3.98 g, 22.4 mmol) and barium carbonate
(2.09 g, 10.6 mmol) in carbon tetrachloride (150 cm3) and
1,1,2,2-tetrachloroethane (15 cm3) was heated under reflux for
20 h. After cooling, the reaction mixture was washed with brine,
dried and evaporated to afford a residue. This was chromato-
To a solution of 4-bromo-1,2-dimethoxybenzene (1.81 cm3,
12.6 mmol) in diethyl ether (50 cm3) under Ar at Ϫ78 ЊC was
added dropwise butyllithium in hexane (1.6 mol dmϪ3; 7.89 cm3,
12.6 mmol) and the resulting mixture was stirred at Ϫ78 ЊC for
1 h. To this mixture was added dropwise a solution of com-
pound 7 (2.12 g, 6.31 mmol) in diethyl ether (60 cm3) at Ϫ78 ЊC.
J. Chem. Soc., Perkin Trans. 1, 1997
277

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After being stirred at Ϫ78 ЊC for 1 h, the reaction mixture was
quenched by the addition of saturated aq. NH4Cl, and
extracted with EtOAc. The extract was washed with brine, dried
and evaporated to leave a residue which was dissolved in
methanol (50 cm3). To this solution was added MeONa in
methanol (1 mol dmϪ3; 3.2 cm3) at 0 ЊC. The mixture was stirred
at room temp. for 1 h after which it was neutralized by adding
resin (IR-120B, H+ form) and then filtered to remove the insol-
uble materials. The filtrate was concentrated to give a residue,
which was chromatographed on a column of silica gel (150 g),
with EtOAc–toluene (1:1, v/v) as eluent, to afford compound 8
(1.32 g, 56%) as a colourless syrup (Found: C, 58.1; H, 7.3.
C18H26O8 requires C, 58.4; H, 7.1%); [α]D25 +21 (c 1.1, CHCl3);
νmax(neat)/cmϪ1 3435 (OH), 1610, 1595 and 1510 (C᎐C); δ (270
thiocarbonyldiimidazole (86 mg, 0.48 mmol) in acetone (5 cm3)
was heated under reflux for 48 h after which it was concentrated
to give a residue. This was chromatographed on a column of
silica gel (5 g), with EtOAc–toluene (1:4, v/v) as eluent, to
afford compound 11 (167 mg, 95%) as a colourless syrup
(Found: C, 54.9; H, 6.6. C19H26O8S requires C, 55.1; H, 6.3%);
[α]D25 Ϫ40 (c 1.1, CHCl3); νmax(neat)/cmϪ1 2940, 2900 (CH),
1610, 1590 and 1520 (C᎐C); δ (270 MHz) 1.72–1.81 (1 H, m,
᎐
H
3-H), 2.10–2.29 (3 H, m, 3Ј-H and 2-H2), 3.42 and 3.43 (each
3 H, 2 s, 2 × CH2OCH3), 3.89 and 3.90 (each 3 H, 2 s,
2 × ArOCH3), 4.06–4.16 (2 H, m, 4-H and 5-H), 4.75–4.78
(4 H, m, 2 × CH3OCH2), 5.11 (1 H, d, J 4.0, 6-H) and 6.88–6.93
(3 H, m, aryl); m/z 415 [(M + 1)+, 19%], 414 (60), 370 (18), 354
(11), 322 (27), 310 (11), 260 (44) and 219 (100).
᎐
H
MHz) 2.90 (1 H, br d, J 6.3, 2-OH), 3.38 and 3.43 (each 3 H, 2 s,
OCH3), 3.53 (1 H, s, OH), 3.87 and 3.90 (each 3 H, 2 s,
2 × ArOCH3), 3.99 (1 H, dd, J 4.9 and 2.4, 3-H), 4.08 (1 H, dd,
J 6.3 and 2.4, 2-H), 4.36 (1 H, dd, J 4.9 and 3.9, 4-H), 4.69, 4.75,
4.76 and 4.80 (each 1 H, 4 d, J 6.8, 2 × CH3OCH2), 5.86 (1 H, d,
J 9.8, 6-H), 5.99 (1 H, dd, J 9.8 and 3.9, 5-H), 6.84 (1 H, d, J 8.8,
6Ј-H), 6.96 (1 H, dd, J 8.8 and 1.7, 5Ј-H) and 7.09 (1 H, d, J 1.7,
2Ј-H); m/z 370 (M+, 21%), 353 (6), 308 (6), 279 (17), 263 (34)
and 221 (100).
(3R,4R)-3,4-Bis(methoxymethoxy)-1-(3,4-dimethoxyphenyl)-
cyclohexene 12
A mixture of compound 11 (959 mg, 2.31 mmol) and trimethyl
phosphite (5 cm3) was heated at 130 ЊC in a sealed tube for 72 h.
The reaction mixture was then concentrated to give a residue,
which was chromatographed on a column of silica gel (20 g),
with EtOAc–toluene (1:3, v/v) as eluent, to afford compound
12 (626 mg, 80%) as a colourless syrup (Found: C, 63.8; H, 8.0.
C18H26O6 requires C, 63.9; H, 7.7%); [α]D25 Ϫ34 (c 1.3, CHCl3);
νmax(neat)/cmϪ1 2940, 2900 (CH), 1600, 1580 and 1515 (C᎐C);
1L-[1(OH),2,3/4]-3,4-Bis-O-(methoxymethyl)-1-(3,4-dimethoxy-
phenyl)cyclohexane-1,2,3,4-tetrol 9
᎐
δH (270 MHz) 1.90 and 2.12 (2 H, m, 5-H2), 2.49–2.56 (2 H, m,
6-H2), 3.42 and 3.45 (each 3 H, 2 s, 2 × CH2OCH3), 3.86 (1 H,
ddd, J 8.8, 5.9 and 3.3, 4-H), 3.88 and 3.90 (each 3 H, 2 s,
2 × ArOCH3), 4.24 (1 H, m, 3-H), 4.78 (2 H, s, CH3OCH2), 4.80
and 4.86 (each 1 H, 2 d, J 6.6, CH3OCH2), 5.94 (1 H, ddd, J 3.3,
1.8 and 1.5, 2-H), 6.82 (1 H, d, J 8.4, 6Ј-H), 6.95 (1 H, dd, J 8.4
and 2.2, 5Ј-H) and 6.97 (1 H, d, J 2.2, 2Ј-H); m/z 339 [(M + 1)+,
28%], 338 (11), 276 (100) and 265 (25).
A mixture of 8 (2.04 g, 5.51 mmol) and 20% Pd(OH)2 on car-
bon (355 mg) in EtOAc (50 cm3) was hydrogenolysed under 1
atm of H2 at room temp. for 21 h. The catalyst was filtered off
and the filtrate was concentrated to give a residue, which was
chromatographed on a column of silica gel (40 g), with
acetone–toluene (1:5, v/v) as eluent, to afford compound 9
(2.05 g, 100%) as a colourless syrup (Found: C, 57.8; H, 7.7.
C18H28O8 requires C, 58.05; H, 7.6%); [α]D25 Ϫ13 (c 1.0, CHCl3);
νmax(neat)/cmϪ1 3450 (OH), 1600, 1585 and 1510 (C᎐C);
᎐
(3R,4R)-3-Acetoxy-1-(3,4-dimethoxyphenyl)-4-(methoxy-
δH (270 MHz) 1.69–1.80 (2 H, m, 5-H2), 1.99–2.36 (2 H, m, 6-
H2), 2.36 (1 H, br d, J 7.0, 2-OH), 3.42 and 3.45 (each 3 H, 2 s,
2 × CH2OCH3), 3.87 and 3.91 (each 3 H, 2 s, 2 × ArOCH3),
4.05–4.08 (3 H, m, 3-H, 4-H and 1-OH), 4.14 (1 H, dd, J 7.0 and
2.6, 2-H), 4.75 (2 H, s, CH3OCH2), 4.76 and 4.84 (each 1 H, 2 d,
J 6.6, CH3OCH2), 6.87 (1 H, d, J 8.4, 6Ј-H), 7.03 (1 H, dd, J 8.4
and 2.2, 5Ј-H) and 7.15 (1 H, d, J 2.2, 2Ј-H); m/z 373 [(M + 1)+,
5%], 372 (11), 323 (3), 310 (4), 291 (4), 266 (28), 265 (73) and
180 (100).
methoxy)cyclohexene 15a and its 3S-isomer 15b
A solution of compound 12 (515 mg, 1.52 mmol) in formic
acid–water (3:7, v/v; 9 cm3) was stirred at 30 ЊC for 6 h and then
poured into ice-cooled saturated aq. sodium hydrogen carbon-
ate. The products were extracted with CH2Cl2 and the extract
was dried and then concentrated to give a residue. This was
dissolved in MeOH (10 cm3) containing K2CO3 (100 mg). After
being stirred at room temp. for 1 h, the mixture was filtered to
remove the insoluble material and the filtrate was concentrated
to afford a syrup. This was diluted with CH2Cl2 and then
washed with brine, dried and evaporated to leave a residue.
This was chromatographed on a column of silica gel (20 g),
with EtOAc–hexane (3:2, v/v) as eluent to give starting
material 12 (118 mg, 23%). Further elution afforded a mixture
of the allyl alcohols 14a and 14b (256 mg, 57%) as a colourless
syrup. This syrup (256 mg) was treated with acetic anhydride (3
cm3) and pyridine (3 cm3). After the resulting mixture had been
stirred at room temp. for 12 h it was then diluted with EtOAc,
washed successively with aq. HCl (1 mol dmϪ3), saturated aq.
sodium hydrogen carbonate and brine, dried and evaporated to
leave a residue. This was chromatographed on a column of sil-
ica gel (20 g), with EtOAc–toluene (1:9, v/v) as eluent, to afford
compound 15a (199 mg, 39%) as a crystalline residue, mp
70–73 ЊC (Found: C, 63.9; H, 7.5. C18H24O6 requires C, 64.3; H,
1L-[1(OH),2,3/4]-2-O-Acetyl-3,4-bis-O-(methoxymethyl)-1-(3,4-
dimethoxyphenyl)cyclohexane-1,2,3,4-tetrol 10
A mixture of 9 (13 mg, 0.034 mmol) in acetic anhydride (0.4
cm3) and pyridine (0.8 cm3) was stirred at room temperature for
15 h. The reaction mixture was then concentrated to give a
residue. This was dissolved in EtOAc and the solution was then
washed successively with aq. HCl (1 mol dmϪ3), saturated aq.
sodium hydrogen carbonate and brine, dried and evaporated to
leave a residue. This was chromatographed on a column of sil-
ica gel (1 g), with EtOAc–toluene (2:3, v/v) as eluent, to afford
compound 10 (13.8 mg, 97%) as a colourless syrup (Found: M+,
414.1873. C20H30O9 requires M, 414.1890); [α]D22 Ϫ17 (c 0.7,
CHCl3); νmax(neat)/cmϪ1 3440 (OH), 1730 (C᎐O), 1600, 1585
᎐
and 1510 (C᎐C); δ (270 MHz) 1.70–1.90 (2 H, m, 5-H ), 1.89
᎐
H
2
(3 H, s, COCH3), 2.05–2.35 (2 H, m, 6-H2), 3.44, 3.87 and
3.90 (each 3 H, 3 s, OCH3), 4.02 (1 H, m, 4-H), 4.15 (1 H, dd,
J 3.3 and 3.7, 3-H), 4.48 (1 H, s, OH), 4.69–4.78 (4 H, m,
2 × CH3OCH2), 5.53 (1 H, d, J 3.3, 2-H), 6.81 (1 H, d, J 8.4, 6Ј-
H), 6.97 (1 H, dd, J 2.2 and 8.4, 5Ј-H) and 7.13 (1 H, d, J 2.3,
2Ј-H); m/z 415 [(M + 1)+, 52%], 414 (100), 355 (16), 352 (19),
341 (17), 337 (18), 331 (17), 321 (22), 310 (33), 309 (53) and 307
(99).
7.2%); [α]D20 Ϫ120 (c 1.1, CHCl3); νmax(KBr)/cmϪ1 1730 (C᎐O),
᎐
1600, 1580 and 1515 (C᎐C); δ (270 MHz) 1.86–2.17 (2 H, m,
᎐
H
5-H2), 2.10 (3 H, s, COCH3), 2.54–2.59 (2 H, m, 6-H2), 3.88,
3.90 and 3.90 (each 3 H, 3 s, 3 × OCH3), 3.90 (1 H, ddd, J 3.7,
6.0 and 7.0, 4-H), 4.73 and 4.77 (each 1 H, 2 d, J 7.0,
CH3OCH2), 5.46 (1 H, dddd, J 1.5, 1.8, 3.7 and 6.0, 3-H), 5.86
(1 H, ddd, J 1.5, 1.8 and 3.7, 2-H), 6.82 (1 H, d, J 8.1, 6Ј-H),
6.94 (1 H, d, J 2.2, 2Ј-H) and 6.96 (1 H, dd, J 2.2 and 8.1, 5Ј-H);
m/z 337 [(M + 1)+, 10%], 336 (52), 305 (8), 294 (6), 274 (96) and
231 (100).
(1S,4R,5S,6S)-4,5-Bis(methoxymethoxy)-1-(3,4-dimethoxy-
phenyl)-7,9-dioxabicyclo[4.3.0]nonane-8-thione 11
A mixture of compound 9 (157 mg, 0.422 mmol) and 1,1Ј-
Further elution gave compound 15b (92 mg, 18%) as a crys-
278
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
talline residue, mp 71–74 ЊC [Found: (M + 1)+, 337.1638.
C18H26O6 requires (M + 1), 337.1651]; [α]D25 Ϫ170 (c 0.8,
(1:5, v/v) as eluent, to give compound 16 (28 mg, 58%) as a
colourless syrup (Found: M+, 364.1867. C20H28O6 requires M,
364.1886); [α]D22 Ϫ12 (c 1.4, CHCl3); νmax(neat)/cmϪ1 1730
CHCl3); νmax(KBr)/cmϪ1 1730 (C᎐O), 1600, 1580 and 1510
᎐
(C᎐C); δ (270 MHz) 1.95–2.14 (2 H, m, 5-H ), 2.13 (3 H, s,
(ester), 1600, 1585 and 1515 (C᎐C); δ (270 MHz) 1.10 (3 H, t, J
᎐
᎐
H
2
H
COCH3), 2.49–2.70 (2 H, m, 6-H2), 3.41, 3.88 and 3.90 (each 3
H, 3 s, 3 × OCH3), 4.00 (1 H, ddd, J 3.3, 3.5 and 10.0, 4-H), 4.70
and 4.76 (each 1 H, 2 d, J 7.0, CH3OCH2), 5.58 (1 H, ddd, J 1.1,
3.5 and 4.8, 3-H), 5.99 (1 H, ddd, J 1.5, 1.8 and 4.8, 2-H), 6.82
(1 H, d, J 8.1, 6Ј-H), 6.95 (1 H, d, J 2.2, 2Ј-H) and 6.97 (1 H, dd,
J 2.2 and 8.1, 5Ј-H); m/z 337 [(M + 1)+, 12%], 336 (56), 305 (7),
294 (5), 274 (94) and 231 (100).
7.1, OCH2CH3), 1.20–1.51 (2 H, m, 5-H2), 1.83–2.00 (2 H, m, 6-
H2), 2.65 and 2.77 (each 1 H, 2 d, J 14.3, CH2CO2Et), 3.36, 3.85
and 3.88 (each 3 H, 3 s, 3 × OCH3), 3.98 (2 H, q, J 7.1,
OCH2CH3), 4.18 (1 H, m, 4-H), 4.69 and 4.72 (each 1 H, 2 d, J
7.0, CH3OCH2), 5.96 (1 H, ddd, J 1.1, 2.6 and 10.3, 3-H), 6.29
(1 H, ddd, J 1.5, 1.8 and 10.3, 3-H), 6.79 (1 H, d, J 8.1, 5Ј-H),
6.88 (1 H, d, J 2.2, 2Ј-H) and 6.89 (1 H, dd, J 2.2 and 8.1, 6Ј-H);
m/z 365 [(M + 1)+, 9%], 364 (29), 302 (2), 277 (8), 245 (18) and
215 (100).
(3R,4R)-1-(3,4-Dimethoxyphenyl)-3-hydroxy-4-(methoxy-
methoxy)cyclohexene 14a
A mixture of compound 15a (170 mg, 0.505 mmol) and K2CO3
(50 mg) in MeOH (3 cm3) was stirred at room temp. for 1 h after
which insoluble material was filtered off. The filtrate was con-
centrated to afford a syrup, which was chromatographed on a
column of silica gel (20 g), with EtOAc–toluene (1:3, v/v) as
eluent, to give compound 14a (147 mg, 98%) as a colourless
syrup (Found: C, 65.0; H, 7.8. C16H22O3 requires C, 64.9; H,
7.5%); [α]D20 +6 (c 1.2, CHCl3); νmax(neat)/cmϪ1 3410 (OH),
1600, 1580 and 1515 (C᎐C); δ (270 MHz) 1.84–2.14 (2 H, m,
5-H2), 2.51–2.56 (2 H, m, 6-H2), 3.48 (3 H, s, OCH3), 3.54 (1 H,
m, 4-H), 3.82 (1 H, s, OH), 3.88 and 3.89 (each 3 H, 2 s,
2 × OCH3), 4.31 (1 H, m, 3-H), 4.79 and 4.84 (each 1 H, 2 d, J
7.0, CH3OCH2), 5.92 (1 H, m, 2-H), 6.82 (1 H, d, J 8.1, 6Ј-H),
6.95 (1 H, dd, J 1.8 and 8.1, 5Ј-H) and 6.96 (1 H, d, J 1.8, 2Ј-H);
m/z 295 [(M + 1)+, 7%], 294 (28), 262 (10), 249 (32) and 232
(100).
2-[(1R,4R)-1-(3,4-Dimethoxyphenyl)-4-(methoxymethoxy)-
cyclohex-2-enyl]ethanal 17
To a solution of compound 16 (57 mg, 0.16 mmol) in toluene
(2 cm3) at Ϫ78 ЊC under Ar was added diisobutylaluminium
hydride (1.02 mol dmϪ3 solution in toluene; 0.16 cm3, 0.16
mmol). After being stirred at Ϫ78 ЊC for 15 min, the reaction
mixture was quenched by the addition of saturated aq. NH4Cl,
and then extracted with EtOAc. The extract was then washed
successively with aq. HCl (1 mol dmϪ3), saturated aq. sodium
hydrogen carbonate and brine, dried and evaporated to leave a
residue. This was chromatographed on a column of silica gel
(3 g), with EtOAc–toluene (1:5, v/v) as eluent, to afford com-
pound 17 (41 mg, 82%) as a colourless syrup (Found: M+,
320.1629. C18H24O5 requires M, 320.1622); [α]D22 Ϫ22 (c 1.2,
᎐
H
CHCl3); νmax(neat)/cmϪ1 1720 (C᎐O), 1605, 1590 and 1515
᎐
(C᎐C); δ (270 MHz) 1.44–1.57, 1.76–1.81, 1.84–1.93 and 2.00–
᎐
H
2.07 (4 H, 4 m, 5-H2 and 6-H2), 2.67 (1 H, dd, J 3.4 and 15.1,
CHCHO), 2.85 (1 H, dd, J 2.4 and 15.1, CHCHO), 3.37, 3.86
and 3.88 (each 3 H, 3 s, 3 × OCH3), 4.17–4.21 (1 H, m, 4-H),
4.70 and 4.72 (each 1 H, 2 d, J 6.8, CH3OCH2), 5.90–6.13 (2 H,
m, 3-H and 4-H), 6.80–6.97 (3 H, m, 2Ј-H, 5Ј-H and 6Ј-H) and
9.58 (1 H, dd, J 2.4 and 3.4, CH2CHO); m/z 321 [(M + 1)+,
28%], 320 (100), 291 (3), 290 (7), 277 (28), 260 (31), 245 (42)
and 215 (100).
(3S,4R)-1-(3,4-Dimethoxyphenyl)-3-hydroxy-4-(methoxy-
methoxy)cyclohexene 14b
Similar treatment of compound 15b (43 mg, 0.13 mmol) as
described for the preparation of compound 14a gave com-
pound 14b (38 mg, 100%) as a colourless syrup (Found: C, 64.7;
H, 7.8. C16H22O3 requires C, 64.9; H, 7.5%); [α]D20 +9 (c 1.0,
CHCl3); νmax(neat)/cmϪ1 3440 (OH), 1605, 1585 and 1520
(C᎐C); δ (270 MHz) 1.84–2.14 (2 H, m, 5-H ), 2.50–2.67 (2 H,
᎐
H
2
m, 6-H2), 2.69 (1 H, d, J 6.6, OH), 3.44, 3.88 and 3.89 (each 3 H,
3 s, 3 × OCH3), 3.91 (1 H, m, 4-H), 4.37 (1 H, m, 3-H), 4.77 and
4.82 (each 1 H, 2 d, J 6.6, CH3OCH2), 6.03 (1 H, ddd, J 1.5, 1.8
and 4.0, 2-H), 6.82 (1 H, d, J 6.9, 6Ј-H), 6.96 (1 H, dd, J 2.2 and
6.9, 5Ј-H) and 6.98 (1 H, d, J 2.2, 2Ј-H); m/z 295 [(M + 1)+,
11%], 294 (32), 262 (9), 249 (40) and 232 (100).
N-{2-[(1R,4R)-1-(3,4-Dimethoxyphenyl)-4-(methoxymethoxy)-
cyclohex-2-enyl]}ethyl-N-methylamine 18
To a solution of compound 17 (24 mg, 0.075 mmol) in meth-
anol (1 cm3) and methylamine (2.0 mol dmϪ3 solution in meth-
anol; 1 cm3) was added methylammonium chloride (20 mg, 0.30
mmol) and sodium cyanoborohydride (10 mg, 0.094 mmol) at
room temperature. After being stirred at room temperature for
24 h, the reaction mixture was treated with aq. HCl (1 mol
dmϪ3) at 0 ЊC, and then adjusted to pH 1–2. The mixture was
then partially concentrated and washed with chloroform. The
aqueous phase was then made basic (pH 12) with aq. potassium
hydroxide (1 mol dmϪ3), saturated with sodium chloride and
extracted twice with chloroform. The combined chloroform
extracts were washed with brine, dried and evaporated to leave
compound 18 (15 mg, 61%) as a colourless syrup. This was used
in the next reaction without further purification (Found: M+,
335.2074. C19H29NO4 requires M, 335.2095); νmax(neat)/cmϪ1
3380 (NH); δH (270 MHz) 1.4–2.6 (9 H, m, 5-H2, 6-H2 and
CH2CH2NHCH3), 2.38 (3 H, s, NCH3), 3.36, 3.86 and 3.88
(each 3 H, 3 s, 3 × OCH3), 4.17 (1 H, m, 4-H), 4.68 and 4.71
(each 1 H, 2 d, J 7.0, CH3OCH2), 5.93 (2 H, m, 3-H and 4-H),
6.79 (1 H, d, J 8.8, 5Ј-H), 6.86 (1 H, d, J 2.2, 2Ј-H) and 6.87
(1 H, dd, J 2.2 and 8.8, 6Ј-H); m/z 335 (M+, 8%), 334 (35), 306
(5), 305 (15), 289 (11) and 273 (100).
Conversion of compound 14b into compound 14a
To a solution of compound 14b (77 mg, 0.26 mmol), triphenyl-
phosphine (137 mg, 0.261 mmol) and benzoic acid (64 mg, 0.261
mmol) in diethyl ether (2 cm3) at 0 ЊC was added diethyl azodi-
carboxylate (0.082 cm3, 0.261 mmol). After being stirred at
room temperature for 30 min, the reaction mixture was concen-
trated to give a residue, which was dissolved in MeOH (2 cm3).
To this solution was added K2CO3 (100 mg) and the resulting
mixture was stirred at room temperature for 2 h. The insoluble
material was filtered off and the filtrate was concentrated to
afford a residue, which was chromatographed on a column of
silica gel (3 g), with EtOAc–toluene (1:2, v/v) as eluent, to give
compound 14a (48 mg, 62%) as a colourless syrup. The physical
and spectral properties of compound 14a were fully identical
with the sample obtained from 15a (vide supra).
Ethyl [(1R,4R)-1-(3,4-dimethoxyphenyl)-4-(methoxymethoxy)-
cyclohex-2-enyl]acetate 16
A mixture of compound 14a (40 mg, 0.13 mmol), powdered
molecular sieves (3 Å, 115 mg), propionic acid (0.001 cm3) and
ethyl orthoacetate (3 cm3) was heated in a sealed tube at 130 ЊC
for 48 h. The insoluble material was filtered off and the filtrate
was concentrated to afford a residue, which was chromato-
graphed on a column of silica gel (3 g), with EtOAc–toluene
(3aR,6R,7aS)-3a-(3,4-Dimethoxyphenyl)-6-(methoxymethoxy)-
1-methyloctahydroindole (O-methoxymethyl mesembranol) 19
To a solution of compound 18 (15 mg, 0.045 mmol) in tetra-
hydrofuran (1 cm3) was added mercury() acetate (20 mg, 0.063
mmol) at room temperature. After being stirred at room tem-
perature for 1 h, the mixture was treated with a solution of
J. Chem. Soc., Perkin Trans. 1, 1997
279

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2 N. Chida, M. Ohtsuka, K. Nakazawa and S. Ogawa, J. Org. Chem.,
sodium borohydride (112 mg, 2.96 mmol) in aqueous sodium
hydroxide (3 mol dmϪ3; 6 cm3). The insoluble material was fil-
tered off and the filtrate was extracted with CH2Cl2. The extract
was washed with brine, dried and evaporated to leave a residue.
This was chromatographed on a column of alumina (1.5 g),
with MeOH–chloroform (1:20, v/v) as eluent, to afford com-
pound 19 (15 mg, 100% from compound 18, 61% from com-
pound 17) as a colourless syrup (Found: M+, 335.2110.
C19H29NO4 requires M, 335.2095); [α]D22 Ϫ16 (c 0.4, CHCl3);
1991, 56, 2976; D. H. R. Barton, S. Augy-Dorey, J. Camara,
P. Dalko, J. M. Delaumeny, S. D. Gero, B. Quiclet-Sire and P. Stütz,
Tetrahedron, 1990, 46, 215; R. J. Ferrier and A. E. Stütz, Carbohydr.
Res., 1990, 200, 237; M. Miyamoto, M. L. Baker and M. D. Lewis,
Tetrahedron Lett., 1992, 33, 3725; N. Sakairi, M. Hayashida,
A. Amano and H. Kuzuhara, J. Chem. Soc., Perkin Trans. 1, 1990,
1301; S. Takahashi, H. Terayama and H. Kuzuhara, Tetrahedron
Lett., 1991, 32, 5123; K. Sato, S. Sakuma, S. Muramatsu and
M. Bokura, Chem. Lett., 1991, 1473; V. A. Estevez and G. D.
Prestwich, J. Am. Chem. Soc., 1991, 113, 9885; S. L. Bender and
R. J. Budhu, J. Am. Chem. Soc., 1991, 113, 9883.
νmax(neat)/cmϪ1 2950, 2850 (CH), 1610, 1590 and 1520 (C᎐C);
᎐
δH (270 MHz) 1.16–1.32 (1 H, m, 5-H), 1.59 (1 H, ddd, J 14.3,
11.0 and 3.3, 7-H), 1.74–1.96 (3 H, m, 3-H2 and 7-HЈ), 2.00–2.08
(2 H, m, 4-H2), 2.14–2.35 (2 H, m, 2-H and 5-HЈ), 2.35 (3 H, s,
NCH3), 2.73 (1 H, dd, J 2.9 and 3.3, 7a-H), 3.20 (1 H, ddd,
J 4.7, 8.8 and 8.8, 2-HЈ), 3.33 (3 H, s, OCH3), 3.83–3.91 (1 H,
m, 6-H), 3.87 and 3.89 (each 3 H, 2 s, 2 × OCH3), 4.66 (2 H, s,
CH3OCH2), 6.81 (1 H, d, J 8.4, 5Ј-H), 6.87 (1 H, d, J 2.2, 2Ј-H)
and 6.92 (1 H, dd, J 2.2 and 8.4, 6Ј-H); m/z 335 (M+, 35), 334
(80), 320 (23), 289 (83) and 273 (100).
3 I. Dyong, H.-W. Hagedorn and J. Thiem, Liebigs Ann. Chem.,
1986, 551; M. J. Fisher, C. D. Myers, J. Joglar, S.-H. Chen and
S. J. Danishefsky, J. Org. Chem., 1991, 56, 5826; F. Chrétien,
S. I. Ahmed, A. Masion and Y. Chapleur, Tetrahedron, 1993, 49,
7463; N. Chida, M. Ohtsuka and S. Ogawa, J. Org. Chem., 1993, 58,
4441; M. S. Ermolenko, A. Olesker and G. Lukacs, Tetrahedron
Lett., 1994, 35, 715; M. S. Ermolenko, G. Lukacs and P. Poiter,
Tetrahedron Lett., 1995, 36, 2465; T. K. Park and S. J. Danishefsky,
Tetrahedron Lett., 1995, 36, 195; N. Chida, M. Jitsuoka,
Y. Yamamoto, M. Ohtsuka and S. Ogawa, Heterocycles, 1996, 43,
1385.
4 For reviews of Sceletium alkaloids, see P. W. Jeffs, in The Alkaloids,
ed. R. Rodrigo, Academic Press, New York, 1981, vol. 19, p. 1;
S. F. Martin, in Studies in Natural Products Chemistry, ed. Atta-ur-
Rahman, Elsevier, Amsterdam, 1989, vol. 4, p. 3.
5 For the structure determination of (Ϫ)-mesembranol, see (a)
P. W. Jeffs, R. L. Hawks and D. S. Farrier, J. Am. Chem. Soc., 1969,
91, 3831. For syntheses of (±)-mesembranol, see (b) P. W. Jeffs,
N. A. Cortese and J. Wolfram, J. Org. Chem., 1982, 47, 3881; (c)
H. Ishibashi, T. S. So, T. Sato, K. Kuroda and M. Ikeda, J. Chem.
Soc., Chem. Commun., 1989, 762; (d) H. Ishibashi, T. S. So,
K. Okochi, T. Sato, N. Nakamura, H. Nakatani and M. Ikeda,
J. Org. Chem., 1991, 56, 95.
6 Preliminary communication of this work, see N. Chida, K. Sugihara
and S. Ogawa, J. Chem. Soc., Chem. Commun., 1994, 901.
7 G. J. Robertson and W. Whitehead, J. Chem. Soc., 1940, 319.
8 S. Hanessian and N. R. Plessas, J. Org. Chem., 1969, 34, 1035.
9 N. Chida, M. Ohtsuka, K. Ogura and S. Ogawa, Bull. Chem. Soc.
Jpn., 1991, 64, 2118.
10 G. E. Keck and R. R. Webb, II, J. Org. Chem., 1982, 47, 1302.
11 L. A. Paquette, J. C. Philips and R. E. Wingard, Jr., J. Am. Chem.
Soc., 1971, 93, 4516.
(Ϫ)-Mesembranol 1
A solution of compound 19 (15 mg, 0.045 mmol) in tetrahydro-
furan (1 cm3) and aq. HCl (6 mol dmϪ3; 0.5 cm3) was stirred at
room temperature for 5 h after which it was diluted with water
and washed with CH2Cl2. The aqueous phase was made basic
(pH 10) with aq. sodium hydroxide (1 mol dmϪ3) and extracted
twice with chloroform. The combined extracts were washed
with brine, dried and evaporated to leave a crystalline residue.
This was recrystallized from chloroform–hexanes to give com-
pound 1 (9.0 mg, 68%) as crystals, mp 146–147 ЊC (Found: C,
68.6; H, 8.9; N, 4.6. C17H25NO3ؒ1/3H2O requires C, 68.7; H, 8.7;
N, 4.7%) (Found: M+, 291.1824. C17H25NO3 requires M,
291.1835); [α]D25 Ϫ24 (c 0.2, CHCl3); νmax(CCl4)/cmϪ1 3625, 3542
(NH and OH) and 1520 (C᎐C); δ (270 MHz) 1.13–1.28 (1 H,
᎐
H
m, 5-H), 1.52 (1 H, ddd, J 13.5, 11.0 and 3.3, 7-H), 1.63 (1 H, br
s, OH), 1.71–1.96 (3 H, m, 7-HЈ and 3-H2), 2.02–2.08 (2 H, m,
4-H2), 2.18 (1 H, m, 5-HЈ), 2.28 (1 H, ddd, J 11.0, 9.5 and 6.6,
2-H), 2.36 (3 H, s, NCH3), 2.74 (1 H, dd, J 2.6 and 3.3, 7a-H),
3.21 (1 H, ddd, J 4.8, 9.2 and 9.5, 2-HЈ), 3.87 and 3.89 (each 3 H,
2 s, 2 × OCH3), 3.99 (1 H, dddd, J 4.4, 4.6, 11.0 and 11.3, 6-H),
6.81 (1 H, d, J 8.4, 5Ј-H), 6.88 (1 H, d, J 2.2, 2Ј-H) and 6.92
(1 H, dd, J 2.2 and 8.4, 6Ј-H); δC[67 MHz in CD3Cl; 13CD3Cl as
internal standard (δC 77.7)] 32.8, 33.1, 34.9, 40.2, 40.5, 47.0,
54.3, 55.8, 55.9, 66.8, 70.0, 110.5, 110.8, 118.7, 139.2, 147.0 and
148.7; m/z 292 [(M + 1)+, 23], 291 (48), 290 (100), 276 (32), 274
(38), 248 (15), 233 (31) and 219 (55).
12 T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 2nd edn., John Wiley & Sons, Inc., New York, 1991, p. 17.
13 D. L. Hughes, Org. React., 1993, 42, 335.
14 For utilisation of the Claisen rearrangement in the synthesis of
the related alkaloids, see ref. 9; (a) S. Kano, T. Yokoyama, Y. Yuasa
and S. Shibuya, Chem. Lett., 1982, 1915; (b) H. F. Strauss and
A. Wiechers, Tetrahedron Lett., 1979, 4495; (c) H. Fujioka,
H. Annoura, K. Murano, Y. Kita and Y. Tamura, Chem. Pharm.
Bull., 1989, 37, 2047; (d) S. Bauermeister, I. D. Gouws, H. F. Strauss
and E. M. M. Venter, J. Chem. Soc., Perkin Trans. 1, 1991, 561.
15 (a) R. E. Ireland, P. Wipf and J. D. Armstrong, III, J. Org. Chem.,
1991, 56, 650; (b) M. Miyashita, T. Suzuki and A. Yoshikoshi, J. Am.
Chem. Soc., 1989, 111, 3728.
Acknowledgements
16 Y. Saitoh, Y. Moriyama, H. Hirota, T. Takahashi and Q. Khuong-
Huu, Bull. Chem. Soc. Jpn., 1981, 54, 488.
We thank Professors Hiroyuki Ishibashi and Masazumi Ikeda
(Kyoto Pharmaceutical University, Kyoto, Japan) for providing
us with spectral data of mesembranol.
References
Paper 6/04365H
Received 24th June 1996
Accepted 7th October 1996
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2413.
280
J. Chem. Soc., Perkin Trans. 1, 1997