Enantiospecific first total synthesis and confirmation of the relative and absolute stereostructure of isocalamusenone

Article abstract of DOI:10.1016/j.tetasy.2010.09.008

The enantiospecific total synthesis of two epimers of the sesquiterpene isocalamusenone has been accomplished starting from the readily available monoterpene (R)-limonene, which of the natural product established the stereostructure and the absolute configuration.

Full text of DOI:10.1016/j.tetasy.2010.09.008

Tetrahedron: Asymmetry 21 (2010) 2512–2516
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantiospecific first total synthesis and confirmation of the relative
and absolute stereostructure of isocalamusenone
⇑
Adusumilli Srikrishna , Vijendra H. Pardeshi, Konda Mahesh
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantiospecific total synthesis of two epimers of the sesquiterpene isocalamusenone has been
accomplished starting from the readily available monoterpene (R)-limonene, which of the natural prod-
uct established the stereostructure and the absolute configuration.
Received 31 August 2010
Accepted 21 September 2010
Available online 26 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1
. Introduction
Of the various bicyclo[5.3.0]decane containing sesquiterpenes,
So far there are no reports in the literature on the synthesis of
isocalamusenone 2 and as a result the stereochemistry of the sec-
ondary methyl group is yet to be established. In continuation of our
4
guaianes constitute as a large group and are present in plants
and liverwort, as well as marine sources. Sweet flag oil (Acorus cal-
amus) is a rich source of oxygenated sesquiterpenes of great struc-
tural variety and a large number of sesquiterpenes have been
isolated from the plant Acorus calamus L that grows in Japan. In
interest in the synthesis of natural products starting from the
1
readily available monoterpene (R)-limonene 5, and in order to
establish the relative stereostructure as well as the absolute con-
figuration of the natural product, the enantiospecific first total syn-
thesis of both the C-6 epimers of isocalamusenone 2a and 2b has
been investigated.
1
979, Rohr et al. reported2 the isolation of two sesquiterpene
ketones 1 and 2, in addition to tropone 3 from the high boiling frac-
tions of sweet flag oil in 3.5% and 0.2% yield, respectively. The ma-
jor component of the essential oil was named as calamusenone 1
and the minor as isocalamusenone 2. The structure of calamuse-
none 1 was deduced on the basis of spectroscopic data (UV, IR,
2
. Results and discussion
Since there are no reports in the literature on either the synthe-
sis or the relative (stereochemistry at C-6 was not assigned) as well
as the absolute configuration of isocalamusenone 2, we decided to
develop a synthesis of isocalamusenones 2a and 2b with a defined
stereochemistry at the C-6 position in order to establish the rela-
tive as well as the absolute stereostructure of the natural product.
It was thought (Scheme 1) that the synthesis of isomeric isocal-
amusenones 2a and 2b could be achieved starting from the C-6
epimeric hydroxy ketones 6a and 6b, whose synthesis from (R)-
limonene 5 had been recently accomplished in our laboratory,
1
13
mass, H and C NMR) and confirmed by a single crystal X-ray
diffraction analysis of the p-bromophenylpyrazoline derivative 4.
Calamusenone 1 was found to exhibit antinociceptive and antimi-
3
crobial activities. The structure of isocalamusenone 2 was as-
1
13
signed on the basis of spectroscopic data (UV, IR, MS, H and
C
NMR) in combination with double resonance experiments and
europium reagent induced NMR shift analysis. However, the ste-
reochemistry of the secondary methyl group in isocalamusenone
2
was inconclusive.
H
6
7
O
O
O
N
N
Br
1
2
3
4
4
f
enroute to the aciphyllenes, employing a type II carbonyl ene
reaction of aldehyde 7 as the key step.
5
⇑
Corresponding author. Fax: +91 80 23600529.
E-mail address: ask@orgchem.iisc.ernet.in (A. Srikrishna).
0
957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.09.008

A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 2512–2516
2513
H
H
H
H
H
H
6
O
OH
O
CHO
O
2
2
a β-H
b α-H
6a β-H
6b α-H
O
7
5
Scheme 1.
H
H
H
a,b
c,d
e
CO Et
H
5
2
Br
CHO
CH3
8
9
1
0
O
f
H
H
H
4
3
OH
i
g,h
CHO
H
CO Et
2
H
O
O
O
12
O
7
O
1
1
j
H
H
H
H
OH
+
OH
O
O
6a
( 3 : 4 )
6b
Scheme 2. Reagents: (a) O
3
/O
2
, CH
2
Cl
2 2
–MeOH; Me S; (b) piperidine, AcOH, C
6
H
6
; (c) NaBH
4
3 2 2 2 3 2 2
, MeOH; (d) PBr , py, Et O; (e) MeCOCH COOEt, K CO , acetone; (f) (CH OH) , p-
TSA, C
6
H
6
; (g) LAH, Et
2
O; (h) IBX, DMSO; (i) BF
3
2
ꢀEt O, CH
Cl
2 2
; (j) H
2
, (Ph
3
P)
3
RhCl, EtOAc.
H
H
H
H
H
H
H
H
a
OH
OH
H
+
+
OH
OH
O
6a
O
13a (67%)
14a (18%)
O + 2a
15a (8%)
H
H
H
H
H
b
c
d
13a
O
O
7
6%
9
1%
94%
OH
H
16a
2a
2 2 3 2 2 2 2
Scheme 3. Reagents and conditions: (a) MeMgCl, THF, rt, 4 h; (b) PCC, NaOAc, CH Cl , rt, 2 h; (c) MsCl, NEt , CH Cl , rt, 4 h; (d) DBU, CH Cl , rt, 7 h.
The synthetic sequence is depicted in Schemes 2 and 3. To begin
catalyst generated a mixture of the hydroxy ketones 6a and 6b.
The stereochemistry of the secondary methyl group as well as the
other stereogenic centers in 6a and 6b was confirmed by the single
with, the synthesis of the hydroxy ketones 6a and 6b was carried
4
f
out by employing the methodology developed in our laboratory.
Thus, a two step conversion of (R)-limonene 5 generated aldehyde
. Reduction of the aldehyde 8 followed by its conversion to bro-
4
f
crystal X-ray diffraction analysis of the minor isomer 6a.
8
First the conversion of hydroxy ketone 6a into enone 2a was
carried out, which required oxidation of the secondary alcohol,
the introduction of the fifteenth carbon atom, and the generation
of the second olefin (Scheme 3). To avoid the regiochemical prob-
lems, the fifteenth carbon atom was introduced by a Grignard reac-
tion. Thus, the reaction of the hydroxy ketone 6a with an excess of
methylmagnesium chloride in anhydrous THF furnished diol 13a in
67% yield, along with the by-products enone 14a (18%) and the ter-
mide 9 and its coupling with ethyl acetoacetate generated ketoes-
ter 10. Protection of the ketone as the corresponding ketal 11,
followed by a two step conversion of the ester transformed keto
ester 10 into aldehyde 7. A boron trifluoride diethyl etherate medi-
ated type II carbonyl ene reaction of aldehyde 7 gave the key precur-
sor hydroxy ketone 12 in a stereoselective manner. Stereoselective
hydrogenation of the exomethylene group in 12 using Wilkinson

2
514
A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 2512–2516
tiary alcohol 15a (8%), whose structures were deduced from their
spectroscopic data. Oxidation of the secondary alcohol in diol
D
Jasco DIP-370 and Jasco P-1020 polarimeters and [a] values are
ꢂ1
2
ꢂ1
given in units of 10 deg cm g . Analytical thin-layer chroma-
tography (TLC) were performed on glass plates (7.5 ꢃ 2.5 and
7.5 ꢃ 5.0 cm) coated with Acme’s silica gel G containing 13% cal-
cium sulfate as binder and various combinations of ethyl ace-
tate–hexane and methylene chloride–hexane were used as
eluent. Visualization of the spots was accomplished by exposure
to iodine vapor. Acme’s silica gel (100–200 mesh) was used for col-
umn chromatography.
1
3a using pyridinium chlorochromate (PCC) and sodium acetate in
methylene chloride gave hydroxy ketone 16a in 76% yield. Dehydra-
tion of the b-hydroxy ketone 16a with an excess of methanesulfonyl
chloride and triethylamine in methylene chloride furnished a mix-
ture of olefinic ketones, which upon isomerisation with 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) in methylene chloride at room
temperature gave enone 2a in 94% yield, whose structure was estab-
1
13
lished from its spectroscopic data. Comparison of the H and
C
NMR spectroscopic data and the specific rotation of 2a with those re-
ported for natural isocalamusenone differed, suggesting that it is
epi-isocalamusenone and the natural product might have an
opposite stereochemistry at one of the two stereocentres.
4.2. (3R,4S,6R,7S)-6,10-Dimethyl-3-(2-hydroxyprop-2-yl)bicyclo-
[5.3.0]dec-1(10)-en-4-ol 13a
To a cold (0 °C), magnetically stirred solution of the hydroxy ke-
4
f
tone 6a (60 mg, 0.27 mmol) in anhydrous THF (1 mL) was added,
drop wise, methylmagnesium chloride (3.0 M in THF, 0.36 mL,
H
H
H
H
1
.08 mmol) and stirred for 4 h at rt. The reaction was quenched with
aq NH
Cl (5 mL) and extracted with ether (3 ꢃ 5 mL). The combined
organic layer was washed with brine (8 mL) and dried (Na SO ).
Evaporation of the solvent and purification of the residue on a silica
gel column using CH Cl –hexane (1:19) as eluent first furnished 1-
4
OH
O
2
4
2
2
O
[(6R,7S)-6,10-dimethylbicyclo[5.3.0]deca-1(10),3-dien-3-yl]etha-
6b
2
b
4f
27
D
none 14a (10 mg, 18%) as a colorless oil.
½
a
ꢁ
¼ þ17:5 (c 2.3,
ꢂ1
CHCl
3
); IR (neat):
mmax/cm 3048, 2952, 2928, 2871, 2841, 1667
The same set of reactions was carried out on the epimeric hy-
droxy ketone 6b. Accordingly, the reaction of the hydroxy ketone
b with an excess of methylmagnesium chloride in anhydrous
(
C@O), 1638, 1456, 1376, 1342, 1299, 1260, 1234, 1165, 956, 896;
1
0
H NMR (400 MHz): d 6.95 (1H, t, J 7.3 Hz, H-4 ), 3.82 and 2.49 (2H,
6
0
2
2
1
ꢃ d, J 14.6 Hz, H-2 ), 2.45–2.30 (2H, m), 2.28 (3H, s, CH
3
C@O),
), 1.45–1.20 (2H, m),
THF furnished diol 13b in 62% yield, as well as enone 14b (16%)
and the tertiary alcohol 15b (9%). Oxidation of diol 13b in methy-
lene chloride with PCC and sodium acetate at room temperature
furnished the hydroxy ketone 16b in 76% yield. Dehydration of
the b-hydroxy ketone 16b with an excess of methanesulfonyl chlo-
ride and triethylamine in methylene chloride, followed by isomeri-
sation with DBU furnished isocalamusenone 2b in 95% yield. The
synthetic sample 2b exhibited H and C spectral data identical
to those of the natural isocalamusenone, confirming its relative
configuration. However, the sign of the specific rotation of the syn-
.28–2.00 (5H, m), 1.65 (3H, s, olefinic-CH
.00 (3H, d, J 6.6 Hz, sec-CH
3
1
3
3
); C NMR (100 MHz): d 197.3 (C,
0
C@O), 143.6 (C), 143.0 (CH, C-4 ), 132.4 (C), 132.0 (C), 58.7 (CH, C-
0
0
7
), 38.4 (CH, C-6 ), 36.0 (CH
CH C@O), 23.6 (CH ), 22.4 (CH
20ONa (M+Na): 227.1412. Found: 227.1405.
Further elution of the column with CH Cl –hexane (1:9) gave
the tertiary alcohol 2-[(6R,7S)-6,10-dimethylbicyclo[5.3.0]deca-
2 2 2 3
), 35.5 (CH ), 29.1 (CH ), 24.9 (CH ,
3
2
3 3
), 14.0 (CH ); HRMS: m/z calcd for
14
C H
1
13
2
2
1
(10),3-dien-3-yl]propan-2-ol 15a (5 mg, 8%) as a colorless oil.
27
D
ꢂ1
2
4
½
a
3
ꢁ
¼ ꢂ67:5 (c 4.0, CHCl
3
); IR (neat):
m
max/cm
3378 (OH),
thetic isocalamusenone 2b, ½
aꢁ
¼ þ176:2 (c 0.5, CHCl
3
), was
D
052, 2969, 2951, 2926, 2870, 2837, 1457, 1374, 1335, 1165,
2
found to be opposite to that of natural isocalamusenone, {lit.
1
0
2
D
2
1138, 948, 890, 854; H NMR: d 5.79 (1H, t, J 7.2 Hz, H-4 ), 3.16
½
a
ꢁ
¼ ꢂ178 (c 1.02, CHCl
3
)}, thus establishing the absolute config-
0
and 2.66 (2H, 2 ꢃ d, J 14.6 Hz, H-2 ), 2.30–1.95 (6H, m), 1.66 (3H,
uration of natural isocalamusenone.
s, olefinic-CH
3
), 1.60–1.20 (2H, m), 1.33 (3H, s) and 1.31 (3H, s)
[
2 ꢃ tert-CH
3
], 1.30–1.25 (1H, m), 0.92 (3H, d, J 6.6 Hz, sec-CH
3
0
);
3
. Conclusion
13
0
C NMR: d 147.2 (C, C-3 ), 133.6 (C), 130.4 (C), 122.2 (CH, C-4 ),
0
0
7
(
(
2
3.2 (C, C-2), 58.8 (CH, C-7 ), 39.7 (CH, C-6 ), 36.1 (CH
2
), 34.4
) [C-1 and 3], 26.9
); HRMS: m/z calcd for C15
23 (MꢂOH):
The first enantioselective total synthesis of ent-isocalamuse-
CH
CH
2
), 29.3 (CH
2 3 3
), 28.7 (CH ) and 28.6 (CH
none 2b and epi-isocalamusenone 2a has been accomplished. The
present sequence establishes the configuration of natural isocal-
amusenone as (6S,7S)-3-isopropylidine-6,10-dimethylbicyclo[5.3.0]-
dec-1(10)-en-4-one 2b.
2
), 22.2 (CH ), 14.3 (CH
3
3
H
03.1800. Found: 203.1795.
Further elution of the column with ethyl acetate–hexane (1:9)
27
D
yielded the diol 13a (43 mg, 67%) as a colorless oil. ½
aꢁ
¼ þ62:8
ꢂ1
(
1
c 1.0, CHCl
3
); IR (neat):
m
max/cm 3268 (OH), 2952, 2920, 2873,
4
4
. Experimental
.1. General
461, 1439, 1410, 1372, 1308, 1216, 1147, 1020, 945, 918, 823;
1
H NMR: d 4.45–4.30 (1H, m, H-4), 3.30 (1H, br s, H-7), 2.68 (1H,
br s), 2.52 (1H, d, J 14.5 Hz), 2.30–1.95 (5H, m), 1.89 (1H, dd, J
1
1
0
7
3.7 and 7.4 Hz), 1.80–1.60 (1H, m), 1.65 (3H, s, olefinic-CH
], 1.40–1.15 (3H, m),
); C NMR: d 139.2 (C), 130.1 (C),
3
),
IR spectra were recorded on Jasco FTIR 410 and Perkin Elmer
FTIR spectrum BX and GX spectrophotometers. H (400 MHz) and
.38 (3H, s) and 1.31 (3H, s) [2 ꢃ tert-CH
3
1
1
3
.92 (3H, d, J 6.7 Hz, sec-CH
3
1
3
C (100 MHz) NMR spectra were recorded on a Brucker Avance
00 spectrometer, using a 1:1 mixture of CDCl and CCl as solvent.
0
3.7 (C, C-2 ), 71.5 (CH, C-4), 58.7 (CH, C-7), 49.7 (CH, C-3), 43.8
4
3
4
(
(
CH
CH
2
), 36.6 (CH
2
), 34.8 (CH, C-6), 29.9 (CH
2
), 29.0 (CH
); HRMS: m/z
Na (M+Na): 261.1830. Found: 261.1824.
3
) and 28.7
The chemical shifts (d ppm) and coupling constants (Hz) are re-
0
0
3
) [C-1 and 3 ], 22.3 (CH
3
2
), 21.0 (CH ), 13.9 (CH
3
ported in the standard fashion with reference to either internal tet-
calcd for C15
H
26
O
2
1
ramethylsilane (for H) or the central line (77.0 ppm) of CDCl
3
(for
2
,
1
3
13
C). In the C NMR spectra, the nature of the carbons (C, CH, CH
4
.3. (3S,6R,7S)-6,10-Dimethyl-3-(2-hydroxyprop-2-
or CH ) was determined by recording the DEPT-135 spectra and is
3
yl)bicyclo[5.3.0]dec-1(10)-en-4-one 16a
given in parentheses. High resolution mass spectra were recorded
on a Micromass Q-TOF micro mass spectrometer using electron
spray ionization mode. Optical rotations were measured using a
To a suspension of PCC (215 mg, 1 mmol) and NaOAc (123 mg,
.5 mmol) in dry CH Cl (0.5 mL) was added a solution of diol
2 2
1

A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 2512–2516
2515
1
3a (42 mg, 0.18 mmol) in CH
for 2 h at rt. The reaction mixture was then filtered through a short
silica gel column using CH Cl . Evaporation of the solvent and puri-
2
Cl
2
(0.5 mL) and stirred vigorously
dropwise methylmagnesium chloride (0.33 mL, 1.0 mmol, 3.0 M
in THF) and stirred for 3 h at rt. The reaction was quenched with
2
2
aq NH
organic layer was washed with brine (8 mL) and dried (Na
Evaporation of the solvent and purification of the residue on a silica
gel column using CH Cl –hexane (1:19) as eluent first furnished 1-
4
Cl (5 mL) and extracted with ether (3 ꢃ 5 mL). The combined
fication of the residue on a silica gel column using ethyl acetate–
hexane (1:19) as eluent furnished the hydroxy ketone 16a
2
SO ).
4
2
D
6
(
(
(
32 mg, 76%) as a colorless oil. ½
aꢁ
¼ ꢂ81:1 (c 1.6, CHCl
3
); IR
2
2
ꢂ1
neat):
m
max/cm
3453 (OH), 2962, 2931, 2871, 2845, 1689
[(6S,7S)-6,10-dimethylbicyclo[5.3.0]deca-1(10),3-dien-3-yl]etha-
1
4f
26
D
C@O), 1461, 1439, 1376, 1328, 1268, 1164, 1138, 943; H NMR:
none 14b (8 mg, 16%) as a colorless oil.
½
aꢁ
¼ þ297 (c 3.0, CHCl
3
);
ꢂ1
d 3.13 (1H, br s, H-7), 2.77 (1H, t, J 12.0 Hz, H-3), 2.69 (1H, dd, J
IR (neat):
m
max/cm 2955, 2928, 2877, 2841, 1666 (C@O), 1635,
1440, 1379, 1349, 1258, 1232, 1174, 1019; H NMR (400 MHz): d
1
1
1
1
3.7 and 3.9 Hz), 2.40–2.00 (7H, m), 1.63 (3H, s, olefinic-CH
3
0
),
0
0
0
.60–1.40 (2H, m), 1.28 (3H, s) and 1.22 (3H, s) [H-1 and 3 ],
6.77 (1H, br s, H-4 ), 3.75 and 2.45 (2H, 2 ꢃ d, J 16.0 Hz, H-2 ), 2.86
13
0
.04 (3H, d, J 6.6 Hz, sec-CH
3
); C NMR: d 216.8 (C, C@O), 135.0
(1H, br s, H-7 ), 2.40–2.10 (6H, m), 2.28 (3H, s, CH
3
C@O), 1.90–1.80
0
(
C, C-1), 134.9 (C, C-10), 72.0 (C, C-2 ), 61.1 (CH, C-3), 57.5 (CH,
3
(1H, m), 1.59 (3H, s, olefinic-CH ), 1.60–1.40 (2H, m), 0.82 (3H, d, J
1
3
C-7), 50.8 (CH
and 26.4 (CH ) [C-1 and 3 ], 28.2 (CH
3.7 (CH ); HRMS: m/z calcd for C15
Found: 259.1670.
2
, C-5), 38.5 (CH, C-6), 36.5 (CH
2
, C-2), 28.7 (CH
), 25.2 (CH ), 22.2 (CH
Na (M+Na): 259.1674.
3
)
),
6.9 Hz, sec-CH
3
); C NMR (100 MHz): d 198.2 (C, C@O), 142.7 (CH,
0
0
0
0
3
2
2
3
C-4 ), 142.2 (C), 133.4 (C), 132.8 (C), 54.5 (CH, C-7 ), 36.9 (CH
2
),
0
1
3
H
24
O
2
33.7 (CH, C-6 ), 32.8 (CH
2
), 25.3 (CH
), 13.8 (CH ); HRMS: m/z calcd for C14
M+Na): 227.1412. Found: 227.1422.
Further elution of the column with CH
tertiary alcohol 2-[(6S,7S)-6,10-dimethylbicyclo[5.3.0]deca-1(10),
3
, CH
3
C@O), 24.9 (CH
2
), 24.3
2
(CH ), 16.5 (CH
3
3
H20ONa
(
2 2
Cl –hexane (1:9) gave
4
1
.4. (6R,7S)-3-Isopropylidine-6,10-dimethylbicyclo[5.3.0]dec-
(10)-en-4-one 2a
2
D
8
3
-dien-3-yl]propan-2-ol 15b (5 mg, 9%) as a colorless oil. ½
a
ꢁ
¼
ꢂ1
þ28:6 (c 0.8, CHCl
3
); IR (neat):
m
max/cm 3394 (OH), 2969, 2951,
To a cold (0 °C), magnetically stirred solution of the hydroxy ke-
1
2
5
2
1
1
926, 2870, 2837, 1458, 1374, 1135, 947, 890, 853; H NMR: d
tone 16a (24 mg, 0.1 mmol) in anhydrous CH
added Et N (0.14 mL, 1 mmol) and MsCl (0.08 mL, 1 mmol) and
stirred for 4 h at rt. 3 M HCl (8 mL) was added to the reaction mix-
ture and extracted with CH Cl
(3 ꢃ 6 mL). The combined organic
layer was washed with brine (8 mL) and dried (Na SO ). Evapora-
tion of the solvent and purification of the residue on a silica gel col-
umn using ethyl acetate–hexane (1:19) as eluent furnished a 2:1:1
mixture of three isomeric olefinic ketones (20 mg, 91%) as a color-
2 2
Cl (2 mL) were
0
.61 (1H, t, J 7.1 Hz, H-4 ), 3.14 and 2.60 (2H, 2 ꢃ d, J 14.6 Hz, H-
3
0
0
), 3.01 (1H, br s, H-7 ), 2.35–2.05 (5H, m), 2.00–1.65 (2H, m),
.64 (3H, s, olefinic-CH ), 1.45–1.25 (3H, m), 1.35 (3H, s) and
.34 (3H, s) [H-1 and 3], 0.78 (3H, d, J 6.3 Hz, sec-CH
3
2
2
13
3
); C NMR:
2
4
0
0
0
0
d 146.0 (C, C-3 ), 134.1 (C, C-1 ), 131.7 (C, C-10 ), 120.9 (CH, C-4 ),
0
0
7
3.6 (C, C-2), 55.0 (CH, C-7 ), 37.1 (CH
CH ), 29.1 (CH ) and 28.9 (CH ) [C-1 and 3], 27.2 (CH
(CH ), 16.3 (CH ), 14.1 (CH ); HRMS: m/z calcd for C15H (MꢂOH):
2
), 34.0 (CH, C-6 ), 31.9
(
2
3
3
2
), 24.9
ꢂ1
less oil. IR (neat):
m
max/cm 2956, 2929, 2872, 1703 (C@O), 1682,
2
3
3
23
1
203.1800. Found: 203.1806.
Further elution of the column with ethyl acetate–hexane (1:9)
1
642, 1457, 1440, 1376, 1332, 1270, 1122, 1028, 893 (C@CH
NMR: d 4.91 (s) and 4.84 (s) [C@CH
m), 2.45–1.95 (m), 1.95 (s), 1.86 (s), 1.76 (s), 1.65 (s), 1.61 (s),
2
); H
2
], 3.42 (d, J 15.2 Hz), 3.00–2.50
2
D
0
furnished diol 13b (37 mg, 62%) as a colorless oil. ½
aꢁ
¼ þ15:8 (c
(
ꢂ1
1
3
2.2, CHCl ); IR (neat):
m
/cm 3438 (OH), 2962, 2894, 2850,
1
.70–1.20 (m), 1.04 and 1.00 (d, J 6.6 Hz, sec-CH
3
); C NMR (peaks
), 135.5 (C),
), 59.2 (CH, C-3), 57.9 (CH, C-7), 47.6
), 28.3 (CH ), 27.8 (CH ), 22.5 (CH ),
3
max
1
1
464, 1379, 1139, 1112, 1054, 1012, 990, 875; H NMR d 4.71
due to major isomer): 212.0 (C, C@O), 143.2 (C, C@CH
1
2
(
(
1H, d, J 8.4 Hz, H-4), 3.18 (1H, br s), 2.65 (1H, d, J 15.5 Hz), 2.42
2
34.8 (C), 111.9 (CH , C@CH
2
1H, td, J 11.8 and 8.4 Hz), 2.30–1.85 (7H, m), 1.66 (3H, s, ole-
(
CH
2
), 39.8 (CH), 36.7 (CH
2
2
2
3
0
finic-CH
3
), 1.35–1.15 (3H, m), 1.30 (3H, s) and 1.21 (3H, s) [H-1
2
2.1 (CH
3
), 13.8 (CH
3
).
0
13
and 3 ], 0.87 (3H, d, J 7.0 Hz, sec-CH
1
3
); C NMR: d 132.9 (C, C-1),
31.7 (C, C-10 ), 75.5 (CH, C-4), 73.2 (C, C-2 ), 47.8 (CH), 40.7
To a magnetically stirred solution of the mixture of the olefins
obtained above (18 mg, 0.08 mmol) in anhydrous CH Cl (0.5 mL)
was added DBU (5 mg, 0.03 mmol) and stirred for 7 h at rt. Next,
M HCl was added to the reaction mixture and extracted with
CH Cl Cl extract was washed with
(3 ꢃ 5 mL). The combined CH
brine (5 mL) and dried (Na SO ). Evaporation of the solvent and
purification of the residue on a silica gel column using CH Cl –hex-
0
0
2
2
(
(
CH), 37.5 (CH
2
), 34.9 (CH
2
), 30.8 (CH
), 13.6 (CH ), 13.5 (CH
Na (M+Na): 261.1830. Found: 261.1831.
2
), 29.7 (CH
3
) and 28.9
0
0
3
CH ) [C-1 and 3 ], 20.2 (CH
2
3
3
); HRMS: m/z
3
calcd for C15
H
26
O
2
2
2
2
2
2
4
2
2
4.6. (3S,6S,7S)-6,10-Dimethyl-3-(2-hydroxyprop-2-yl)bicyclo-
ane (1:9) as eluent furnished the enone, (ꢂ)-epi-isocalamusenone
[5.3.0]dec-1(10)-en-4-one 16b
2
D
8
2
a (17 mg, 94%) as a colorless oil. ½
a
ꢁ
3
¼ ꢂ6:7 (c 0.7, CHCl ); IR
ꢂ1
(
1
neat):
m
max/cm
2954, 2923, 2871, 1680 (C@O), 1619, 1456,
To a suspension of PCC (215 mg, 1 mmol) and NaOAc (123 mg,
1
439, 1374, 1295, 1271, 1218, 1181, 1128, 1022; H NMR (CDCl
3
):
1.5 mmol) in dry CH
(36 mg, 0.15 mmol) in CH
3 h at rt. The reaction mixture was then filtered through a short sil-
ica gel column using CH Cl . Evaporation of the solvent and purifi-
2
Cl
2
(1 mL) was added a solution of diol 13b
d 3.44 and 2.70 (2H, 2 ꢃ d, J 15.1 Hz, H-2), 2.74 (1H, dd, J 13.4 and
1.1 Hz) and 2.29 (1H, dd, J 13.4 and 1.6 Hz) [H-5], 2.30–2.15 (3H,
m), 2.04 (1H, ddd, J 12.8, 8.4 and 4.8 Hz), 1.95 (3H, s) and 1.86 (3H,
s) [C@C(CH ], 1.63 (3H, s, C10–CH ), 1.60–1.30 (2H, m), 1.00 (3H,
d, J 6.7 Hz, sec-CH ): d 206.5 (C, C@O), 140.4 (C),
35.1 (C), 133.6 (C), 133.5 (C), 57.9 (CH, C-7), 51.3 (CH , C-2), 38.2
CH, C-6), 36.5 (CH , C-5), 28.7 (CH ), 28.4 (CH ), 22.8 (CH ), 22.2
CH ), 22.0 (CH ), 14.1 (CH , C –CH ); HRMS: m/z calcd for
22ONa (M+Na): 241.1568. Found: 241.1569.
2
Cl (1 mL) and stirred vigorously for
2
1
2
2
3
)
2
3
cation of the residue on a silica gel column using ethyl acetate–
1
3
3
); C NMR (CDCl
3
hexane (1:19) as eluent furnished hydroxyketone 16b (27 mg,
2
D
0
1
2
76%) as a colorless oil. ½
aꢁ
¼ ꢂ79:5 (c 0.9, CHCl
3
); IR (neat):
ꢂ1
(
(
2
2
2
3
m
max/cm 3462 (OH), 2965, 2930, 2884, 2848, 1685 (C@O), 1460,
1
3
3
3
6
3
1439, 1381, 1251, 1222, 1166, 1140, 1099; H NMR: d 3.97 (1H,
s), 2.85 (1H, br s), 2.68 (1H, dd, J 13.7 and 4.0 Hz, H-3), 2.56
C H
15
(
[
1H, dd, J 12.1 and 2.2 Hz) and 2.43 (1H, dd, J 12.1 and 8.0 Hz)
H-5], 2.40–2.10 (3H, m), 2.10–1.80 (2H, m), 1.67 (3H, s, ole-
4
.5. (3R,4S,6S,7S)-6,10-Dimethyl-3-(2-hydroxyprop-2-yl)bicyclo-
0
finic-CH
3
), 1.70–1.50 (2H, m), 1.28 (3H, s) and 1.19 (3H, s) [H-1
[
5.3.0]dec-1(10)-en-4-ol 13b
0
13
and 3 ], 0.82 (3H, d, J 7.1 Hz, sec-CH
C@O), 135.6 (C), 133.8 (C), 72.4 (C, C-2 ), 62.1 (CH, C-3), 54.2
(CH, C-7), 49.5 (CH , C-5), 37.4 (CH , C-2), 33.3 (CH, C-6), 28.8
3
); C NMR: d 217.8 (C,
0
To a cold (0 °C), magnetically stirred solution of hydroxy keto-
ne4f 6b (56 mg, 0.25 mmol) in anhydrous THF (1 mL) was added
2
2

2
516
A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 2512–2516
(
(
CH
CH
3
), 26.0 (CH
, C –CH ).
2
), 25.8 (CH
3
), 25.2 (CH
2
), 15.3 (CH
3
, C10–CH
3
), 13.7
1258, 1209, 1144, 1024; 1H NMR (CDCl
2 ꢃ d, J 16.2 Hz, H-2), 2.85–2.75 (1H, m), 2.50–2.40 (1H, m), 2.32
1H, dd, J 16.7 and 11.1 Hz), 2.25–2.10 (3H, m), 1.85–1.70 (1H, m),
1.74 (3H, s) and 1.73 (3H, s) [C@C(CH ], 1.58 (3H, s, C10–CH ),
1.45–1.35 (1H, 3), 0.87 (3H, d, J 6.8 Hz, sec-CH ):
d 210.0 (C, C@O), 135.8 (C), 135.7 (C), 134.0 (C), 132.8 (C), 53.7
(CH, C-7), 47.5 (CH , C-2), 37.1 (CH , C-5), 31.0 (CH, C-6), 27.5
(CH ), 23.4 (CH ), 22.0 (CH ), 20.6 (CH ), 16.8 (CH ), 14.1 (CH );
22ONa (M+Na): 241.1568. Found:
3
): d 3.18 and 2.77 (2H,
3
6
3
(
4
1
.7. (6S,7S)-3-Isopropylidine-6,10-dimethylbicyclo[5.3.0]dec-
(10)-en-4-one 2b (isocalamusenone)
3
)
2
3
1
3
3
); C NMR (CDCl
3
To a cold (0 °C), magnetically stirred solution of the hydroxy ke-
tone 16b (27 mg, 0.11 mmol) in dry CH Cl (2 mL) were added Et
0.15 mL, 1.1 mmol) and MsCl (0.09 mL, 1.1 mmol) and stirred for
2
2
2
2
3
N
2
2
3
3
3
3
(
HRMS: m/z calcd for C15H
4
h at rt. Next, 3 M HCl (7 mL) was added to the reaction mixture
Cl
(3 ꢃ 5 mL). The combined organic layer
was washed with brine (8 mL) and dried (Na SO ). Evaporation of
241.1564.
and extracted with CH
2
2
2
4
Acknowledgment
the solvent and purification of the residue on a silica gel column
using ethyl acetate–hexane (1:19) as eluent furnished a mixture
We thank the Council of Scientific and Industrial Research, New
Delhi for the award of a research fellowship to V.H.P.
of three olefins (22 mg, 90%) as a colorless oil. IR (neat):
max
m /
ꢂ1
cm
2957, 2929, 2882, 2850, 1699 (C@O), 1457, 1377, 1249,
1
1
137, 1097, 1020, 891; H NMR: d 4.87 (s) and 4.77 (s) [C@CH
2
],
References
3
.12 (br d, J 16.3 Hz), 3.00–2.00 (m), 2.05–1.25 (m), 1.75 (s), 1.73
1
2
3
.
.
.
Foley, D. A.; Maguire, A. R. Tetrahedron 2010, 66, 1131.
(
s), 1.72 (s), 1.65 (s), 1.63 (s), 1.58 (s), 1.70–1.20 (m), 0.87, 0.80
and 0.79 (d, J 6.8 Hz, sec-CH ).
To a magnetically stirred solution of the mixture of the olefins,
obtained above (20 mg, 0.08 mmol), in dry CH Cl (0.5 mL) was
added DBU (6 mg, 0.03 mmol) and stirred for 7 h at rt. Next, 3 M
HCl was added to the reaction mixture and extracted with CH Cl
extract was washed with brine
). Evaporation of the solvent and purifica-
Cl –hexane
1:9) as eluent furnished (+)-isocalamusenone 2b (19 mg, 95%) as
Rohr, M.; Naegeli, P.; Daly, J. J. Phytochemistry 1979, 18, 279.
Arrigoni-Blank, M. F.; Antoniolli, A. R.; Caetano, L. C.; Campos, D. A.; Blank, A. F.;
Alves, P. B. Phytomedicine 2008, 15, 334.
(a) Srikrishna, A.; Babu, N. C. Tetrahedron Lett. 2001, 42, 4913; (b) Srikrishna, A.;
Babu, N. C.; Dethe, D. H. Indian J. Chem., Sect B 2003, 42, 1688; (c) Srikrishna, A.;
Dethe, D. H. Org. Lett. 2003, 5, 2295; (d) Srikrishna, A.; Babu, N. C.; Rao, M. S.
Tetrahedron 2004, 60, 2125; (e) Srikrishna, A.; Pardeshi, V. H.; Satyanarayana, G.
Tetrahedron: Asymmetry 2010, 21, 746; (f) Srikrishna, A.; Pardeshi, V. H.
Tetrahedron 2010, 66, 8160.
(a) Alder, K.; Pascher, F.; Schmitz, A. Ber. Dtsch. Chem. 1943, 76, 27; (b) Oppolzer,
W. Pure Appl. Chem. 1981, 53, 1181; (c) Oppolzer, W.; Snieckus, V. Angew. Chem.,
Int. Ed. Engl. 1978, 17, 476; (d) Taber, D. F. In Intramolecular Diels–Alder and Alder
Ene Reactions; Springer: Berlin, 1984.
3
4
.
.
2
2
2
2
(
(
3 ꢃ 5 mL). The combined CH
2 2
Cl
5 mL) and dried (Na SO
2
4
5
tion of the residue on a silica gel column using CH
2
2
(
2
D
4
ꢂ1
a colorless oil. ½
a
ꢁ
3
¼ þ176:2 (c 1.02, CHCl )}; IR (neat): mmax/cm
2
955, 2927, 2876, 2842, 1678 (C@O), 1607, 1454, 1377, 1299,