Enantiospecific approach to the tricyclic core structure of tricycloillicinone, ialibinones, and takaneones via ring-closing metathesis reaction

Article abstract of DOI:10.1016/j.tet.2009.01.096

Enantiospecific synthesis of the tricyclic core structure present in the biologically active natural products tricycloillicinone, ialibinones, and takaneones, starting from the readily available campholenaldehyde employing a transannular RCM reaction as t

Full text of DOI:10.1016/j.tet.2009.01.096

Tetrahedron 65 (2009) 2649–2654
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Tetrahedron
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Enantiospecific approach to the tricyclic core structure of tricycloillicinone,
ialibinones, and takaneones via ring-closing metathesis reaction
*
A. Srikrishna , B. Beeraiah, V. Gowri
Department of Organic Chemistry, Indian Institute of Science, C. V. Raman Avenue, Bangalore 560012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 January 2009
Received in revised form 28 January 2009
Accepted 28 January 2009
Available online 4 February 2009
Enantiospecific synthesis of the tricyclic core structure present in the biologically active natural products
tricycloillicinone, ialibinones, and takaneones, starting from the readily available campholenaldehyde
employing a transannular RCM reaction as the key step, has been accomplished.
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated to Late Professor G. S. Krishna Rao
Keywords:
Tricyclo[5.3.1.01,5]undecane
(S)-Campholenaldehyde
Enantiospecific synthesis
RCM reaction
Diquinanes
Illicinones
1. Introduction
against KB cell line. Recent widespread interest in the antidepressant
activity of Hypericum species led Takaishi and co-workers to in-
During a search for potent neurotropic substances from Illicium
tashiroi collected from Ishigaki Island, Fukuyama and co-workers
isolated a novel C6–C3 prenylated compound and named as tricy-
cloillicinone1onthebasisofitsbiogeneticrelationshiptoillicinones.
The tetracyclic structure of 1, comprising of an interesting 3,4,4-tri-
methyltricyclo[5.3.1.01,5]-undecane 2, which is isomeric to that
present in cedranoid sesquiterpenes, was elucidated on the basis of
extensive spectral studies.1 It was found that 1 could significantly
increase choline acetyltransferase (ChAT) activity in culture of P10
rat septal neurons. The tricyclic structure 2 was also present in two
groups of acylphloroglucinoid natural products. In the traditional
medicine of Papua New Guinea, leaves of the plant Hypericum pap-
uanum Ridley are used for the treatment of sores, and its extract is
known to exhibit antibacterial activity. In their search for the bio-
logicallyactive compounds, in2001, Sticherandco-workers reported
the bioassay guided isolation of five tricyclic acylphloroglucinol
derivatives (along with several bicyclic derivatives) ialibinones A–E
3a–d and 4, and also their hydroxy derivatives 5a–c from the
petroleum ether extract of H. papuanum Ridley.2 Compounds 3 and 5
showed good antibacterial activity against Bacillus cereus, Staphy-
lococcus epidermidis, and Micrococcus luteus, and cytotoxic activity
vestigate on the bioactive natural products from H. sikokumontanum,
which resulted in the isolation of three tricyclic compounds taka-
neones A–C 6a–c.3 Takaneones 6b–c showed almost equal cytotox-
icities against both K562/Adr multi-drug resistant cancer cells as
well as sensitive cell lines (e.g., KB and K 562).
2. Results and discussion
Presence of an interesting tricyclic carbon framework 2, coupled
with potential neurotropic properties made tricycloillicinone 1
a challenging synthetic target. So far there are three approaches
reported in the literature.4–6 First total synthesis of tricycloillici-
none 1 in racemic form was reported by the research group of
Danishefsky in 1998.4 In 2003, Terashima and Furuya reported an
enantioselective synthesis of tricycloillicinone 1.5 Very recently,6
Danishefsky co-workers reported an improved biomimetic method
for the generation of racemic tricycloillicinone 1 via illicinone A. In
contrast, there is no report in the literature on either model studies
or total synthesis of ialibinones and takaneones either in racemic
or optically active forms. (S)-Campholenaldehyde 7 is a readily
available cyclopentane based chiral starting material. It has been
employed in the synthesis of a variety of industrially (fragrance)
important monocyclic compounds.7 However, it has been under
utilized in the synthesis of polycyclic compounds in organic
* Corresponding author. Tel.: þ91 80 22932215; fax: þ91 80 23600529.
E-mail address: ask@orgchem.iisc.ernet.in (A. Srikrishna).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.096

2650
A. Srikrishna et al. / Tetrahedron 65 (2009) 2649–2654
H
introduction of the allyl group at the C-3 position syn to the vinyl
H
5
O
group. Thus, sonochemically accelerated reaction of the ketone 15
with lithium and allyl bromide furnished the tertiary alcohol 16 in
91% yield in a stereoselective (w9:1) manner. The stereochemistry
of the major isomer 16 was assigned on the basis of the preferential
approach of the nucleophile from the exo face of the convex shaped
diquinane 15. The key RCM reaction13 for the generation of the
tricyclic ring system of tricycloillicinone containing an oxygen
functionality at the C-7 carbon was carried out employing Grubbs’
first generation catalyst [Cl2(PCy3)2Ru]CHPh]. Reaction of a 0.05 M
methylene chloride solution of the hydroxydiene 16 with 10 mol %
of Grubbs’ first generation catalyst at room temperature for 8 h
furnished the tricyclic compound 17 in 90% yield. Structure of 17
was established from its spectral data. To rule out the possibility of
di- and trimeric structures for the product (a serious competing side
reaction encountered during RCM mediated construction of bridged
compounds)14 formed in the RCM reaction of the hydroxydiene 16,
RCM was also carried out with the corresponding acetate 18. Acyl-
ation of the tertiary alcohol 16 with acetic anhydride and pyridine in
methylene chloride in the presence of a catalytic amount of 4-N,N-
dimethylaminopyridine (DMAP) generated the acetate 18.
The RCM reaction of the acetate 18 with 10 mol % of Grubbs’ first
generation catalyst in methylene chloride at room temperature
furnished the tricyclic acetate 19, whose structure was established
from its spectral data. The high-resolution mass spectrum
confirmed the monomeric nature of 19. Hydrolysis of the tricyclic
acetate 19 with potassium carbonate in methanol at room tem-
perature furnished the alcohol 17, which was found to be identical
with that generated via the RCM reaction of the hydroxydiene 16.
Since there are three and two carbon side chains present at the
C-3 carbon of the tricyclo[5.3.1.01,5]undecane system in ialibinones
3,5 and takaneones 6, after successfully developing enantiospecific
synthesis of the tricyclic core of tricycloillicinone 1, it was con-
ceived to elaborate the side chain at C-3 position in 17. The tertiary
hydroxy group in 17 was protected as its methyl ether by reacting
with sodium hydride and methyl iodide in the presence of tetra-
butylammonium iodide (TABI) in THF to furnish quantitatively the
ether 20. A selenium dioxide mediated allylic oxidation was opted
for functionalizing the methyl group at the C-3 carbon of the tri-
cyclic compound 20. Thus, refluxing an aqueous dioxane solution of
the ether 20 with selenium dioxide for 50 min furnished the al-
dehyde 21 in moderate yield. Grignard reaction of the aldehyde 21
with methylmagnesium bromide in THF generated predominantly
one isomer of the secondary alcohol 22 in 92% yield, which on
oxidation with pyridinium dichromate (PDC) in methylene chloride
at room temperature for 3 h furnished the ketone 23 in 83% yield.
Grignard reaction of the ketone 23 with methylmagnesium bro-
mide in THF at ice temperature for 2 h furnished the tertiary alcohol
24 in 80% yield. Structures of the ketone 23 and the tertiary alcohol
24 were established from their spectral data.
7
1
3
H
O
O
OH
9
O
O
1
R
O
2
3a. α-H; R = H
3b. β-H; R = H
3c. β-H; R = Me
3d. α-H; R = Me
H
H
H
O
R'
O
HO
O
H
H
O
OH
O
OH
O
O
O
R
O
R
O
5a. α-H; R = H
5b. β-H; R = H
6a. α-H; R = -COCHMe2; R' = Me
6b. βH; R = -COCHMe2; R' = Me
6c. β-H; R = Me; R' = -COCHMe2
4
5c. β-H; R = Me
synthesis.8 Recently, we have reported an efficient route for the
enantiospecific conversion of (S)-campholenaldehyde into
7
diquinanes, e.g., 8, employing an intramolecular rhodium carbe-
noid CH insertion reaction.9 In continuation of our interest in the
enantiospecific synthesis of polycyclic compounds starting from
(S)-campholenaldehyde 7, herein we report an enantiospecific
approach to the tricyclic core structure present in the natural
products tricycloillicinone, ialibinones, and takaneones employing
a ring-closing metathesis (RCM) reaction as the key step.
It was contemplated (Scheme 1) that an RCM reaction of the
hydroxydiene 9, containing syn oriented vinyl and allyl groups at
the C-1 and C-3 carbons of a diquinane, could lead to the tricyclic
system 10 containing an oxygen functionality at the C-7 carbon
atom as in tricycloillicinone 1. For the generation of the hydroxy-
diene 9, the diquinane 8 was chosen as a suitable precursor, whose
synthesis from campholenaldehyde 7 has already been developed.
The synthetic sequence starting from the b-ketoester 8, which
was prepared9 from campholenaldehyde 7 in three steps employing
an intramolecular rhodium carbenoid CH insertion10 of the
a
-diazo-b-ketoester 11, is depicted in Scheme 2. For the in-
troduction of a vinyl group at the C-1 carbon of the diquinane 8
a cuprate based methodology11 was conceived via the dienone 12.
For the introduction of the requisite olefin at C-1, a regioselective
selenation-deselenation sequence was employed. Thus, reaction of
the b-ketoester 8 with phenylselenyl chloride in the presence of
pyridine in methylene chloride furnished the selenide 13 in 88%
yield in a highly regio- and stereoselective manner, which on oxi-
dation with 30% hydrogen peroxide at ice temperature furnished
the requisite diene ester 12 in 90% yield. Reaction of the diene ester
12 with vinylmagnesium bromide in the presence of copper iodide
In summary, we have accomplished enantiospecific synthesis of
the tricyclic core structure present in the biologically active natural
products tricycloillicinone 1, ialibinones 3,5 and takaneones 6. A
transannular RCM reaction was employed as the key step for the
in THF at low temperature furnished the vinylated
b-ketoester 14 in
62% yield, which was found to exist predominantly in the enol form
14b. Krapcho’s decarboxylation12 of the
b-ketoester 14 with sodium
chloride and DMSO in the presence of water at 180 ꢀC furnished the
construction of the tricyclo[5.3.1.0
1,5]undecane system starting
diquinane 15 in 87% yield. A Barbier reaction was explored for the
from campholenaldehyde 7 via the diquinane 8.
H
H
H
OH
H
OH
3
O
1
CHO
H
COOMe
10
9
8
7
Scheme 1.

A. Srikrishna et al. / Tetrahedron 65 (2009) 2649–2654
2651
H
H
H
H
c
a,b
d
88%
O
O
7
O
SePh
COOMe
81%
89%
COOMe
N2
H
8
COOMe
11
13
90%
e
H
H
H
OH
f
O
O
62%
COOMe
COOMe
COOMe
14b
g
12
87%
14a
H
H
H
OH
(9:1)
j
OAc
h
91%
O
89%
15
18
16
90%
H
i
i
94%
H
H
OMe
OAc
OH
k
l
100%
100%
20
47%
m
17
19
H
H
H
OMe
HO
OMe
X
OMe
OHC
n
n
92%
80%
22. X = H,OH
23. X = O
21
24
o, 83%
Scheme 2. Reagents: (a) SnCl2$2H2O, N2CHCO2Me, CH2Cl2; (b) TsN3, NEt3, CH3CN; (c) Rh2(OAc)4, CH2Cl2; (d) PhSeCl, pyridine, CH2Cl2; (e) 30% aq H2O2, CH2Cl2; (f) CH2]CHMgBr,
CuI, THF; (g) DMSO, NaCl, H2O; (h) CH2]CHCH2Br, Li, THF,))); (i) Cl2(PCy3)2Ru]CHPh, CH2Cl2; (j) Ac2O, pyridine, DMAP, CH2Cl2; (k) K2CO3, MeOH; (l) NaH, MeI, TBAI; (m) SeO2,
dioxane, H2O; (n) MeMgBr, THF; (o) PDC, CH2Cl2.
3. Experimental section
3.1. General
3.2. Methyl (1R,2S,5R)-6,6,7-trimethyl-3-oxo-2-
phenylselenobicyclo[3.3.0]oct-7-ene-2-carboxylate 13
To a magnetically stirred ice cold solution of PhSeCl (218 mg,
1.14 mmol) and pyridine (0.15 mL, 1.90 mmol) in dry CH2Cl2
(1.5 mL) was added dropwise a solution of the keto ester 8 (211 mg,
0.95 mmol) in dry CH2Cl2 (2 mL) and stirred for 1 h at the same
temperature. The reaction was then quenched with 3 N HCl (4 mL)
and extracted with CH2Cl2 (3ꢂ8 mL). The CH2Cl2 extract was
washed with brine (10 mL) and dried (Na2SO4). Evaporation of the
solvent and purification of the residue on a silica gel column using
Melting points are recorded using Mettler FP1 melting point
apparatus in capillary tubes and are uncorrected. IR spectra were
recorded on Jasco FTIR spectrum BX spectrophotometer. 1H (300
and 400 MHz) and 13C (75 and 100 MHz) NMR spectra were
recorded on JNM
1:1 mixture of CDCl3 and CCl4 was used as solvent for recording
NMR spectra. The chemical shifts ( ppm) and coupling constants
l-300 and Brucker Avance 400 spectrometers. A
d
(Hz) are reported in the standard fashion with reference to either
internal tetramethylsilane (for 1H) or the central line (77.0 ppm) of
CDCl3 (for 13C). In the 13C NMR, the nature of carbons (C, CH, CH2,
CH3) was determined by recording the DEPT-135 spectra, and is
given in parentheses. High-resolution mass spectra were recorded
using Micromass Q-TOF micro mass spectrometer using electron
spray ionization mode. Elemental analyses were carried out using
Carlo Erba 1106 CHN analyzer, at the Department of Organic
Chemistry, Indian Institute of Science. Optical rotations were
ethyl acetate–hexane (1:20) as eluent furnished the selenide 13
23
(315 mg, 88%) as colorless oil. Rf (1:19 EtOAc–hexane) 0.5; [a] :
D
ꢁ10.8 (c 3.5, CHCl3); IR (neat): nmax/cmꢁ1 3056, 2957, 2867, 1752,
1730, 1579, 1475, 1438, 1300, 1274, 1238, 1155, 1073, 1021, 999, 742,
691; 1H NMR (300 MHz):
d 7.55 (2H, d, J 6.9 Hz) and 7.45–7.25 (3H,
m) [Ar–H], 5.03 (1H, s, olefinic H), 3.71 (3H, s, OCH3), 3.40 (1H, br s,
H-1), 2.65–2.56 (2H, m, H-4), 2.40–2.25 (1H, m), 1.58 (3H, s, olefinic
CH3), 1.02 (3H, s) and 1.01 (3H, s) [2ꢂtert-CH3]; 13C NMR (75 MHz):
d
204.0 (C, C]O), 168.9 (C, OC]O), 150.2 (C, C-7), 137.5 (2C, CH),
measured using a Jasco P-1020 digital polarimeter and [
a
]
values
130.1 (C, CH), 129.0 (2C, CH), 126.7 (C), 121.1 (CH, C-8), 60.0 (C, C-2),
53.8 (CH3, OCH3), 52.2 (CH), 47.8 (C, C-6), 47.1 (CH), 38.1 (CH2, C-4),
26.2 (CH3), 21.5 (CH3), 12.8 (CH3); HRMS: m/z calcd for
C19H22O3SeNa (MþNa): 401.0632. Found: 401.0627.
D
are given in units of 10ꢁ1 deg cm2 gꢁ1. Thin-layer chromatographies
(TLC) were performed on glass plates (7.5ꢂ2.5 and 7.5ꢂ5.0 cm)
coated with Acme’s silica gel G containing 13% calcium sulfate as
binder and various combinations of ethyl acetate, methylene
chloride, and hexane were used as eluent. Visualization of spots
was accomplished by exposure to iodine vapor or anisaldehyde–
H2SO4 or MeOH–H2SO4 spray followed by heating. Acme’s silica gel
(100–200 mesh) was used for column chromatography (approxi-
mately 15–20 g per 1 g of the crude product).
3.3. Methyl (5R)-6,6,7-trimethyl-3-oxobicyclo[3.3.0]octa-
1,7-diene-2-carboxylate 12
To a magnetically stirred, ice cold solution of the selenide 13
(315 mg, 0.83 mmol) in CH2Cl2 (4 mL) was added 30% aq H2O2

2652
A. Srikrishna et al. / Tetrahedron 65 (2009) 2649–2654
(4 mL) and stirred for 1 h at the same temperature. It was then
diluted with water (5 mL) and extracted with CH2Cl2 (3ꢂ10 mL).
The combined organic extract was washed with brine (10 mL) and
dried (Na2SO4). Evaporation of the solvent and purification of the
residue over a silica gel column using ethyl acetate–hexane (1:2) as
48.3 (C), 40.2 (CH2, C-4), 28.4 (CH3), 23.3 (CH3), 12.5 (CH3); HRMS:
m/z calcd for C13H18ONa (MþNa): 213.1255. Found: 213.1263.
3.6. (1S,3S,5R)-3-Allyl-6,6,7-trimethyl-1-vinylbicyclo-
[3.3.0]oct-7-en-3-ol 16
eluent furnished the a,b-unsaturated keto ester 12 (165 mg, 90%) as
oil. Rf (1:2 EtOAc–hexane) 0.4; [
a
]
23: ꢁ40.3 (c 3.0, CHCl3); IR (neat):
To a suspension of lithium (12 mg, 1.74 mmol) in anhydrous THF
(1 mL) in a round bottom flask, placed in an ultrasonic cleaning
bath, was added a solution of the ketone 15 (33 mg, 0.17 mmol) and
allyl bromide (0.2 mL, 1.74 mmol) in THF (2 mL) and the reaction
mixture was sonicated for 1 h. Then the reaction mixture was
decanted from the excess lithium, quenched with satd aq NH4Cl
(5 mL) and extracted with ether (3ꢂ3 mL). The ether extract was
washed with brine (5 mL) and dried (Na2SO4). Evaporation of the
solvent and purification of the residue on a silica gel column using
ethyl acetate–hexane (1:9) as eluent furnished a 1:9 diastereomeric
mixture of the alcohol 16 (37 mg, 91%) as oil. Rf (1:9 EtOAc–hexane)
D
nmax/cmꢁ1 2958, 2928, 2869, 1741, 1705, 1614, 1577, 1464, 1435,
1378, 1361, 1275, 1222, 1191, 1125, 1066, 1028, 861; 1H NMR
(300 MHz): d 6.72 (1H, s, olefinic H), 3.74 (3H, s, OCH3), 2.97 (1H, t, J
6.7 Hz, H-5), 2.47 (1H, dd, J 17.2 and 7.1 Hz) and 2.27 (1H, dd, J 17.2
and 5.6 Hz) [H-4], 2.01 (3H, s, olefinic CH3), 1.20 (3H, s) and 0.89
(3H, s) [2ꢂtert-CH3]; 13C NMR (75 MHz):
d 202.1 (C, C]O), 193.0 (C,
C-1), 177.7 (C, C-7), 162.5 (C, OC]O), 124.2 (CH, C-8), 119.3 (C, C-2),
55.6 (CH3, OCH3), 51.2 (CH, C-5), 48.0 (C, C-6), 38.1 (CH2, C-4), 24.9
(CH3), 23.5 (CH3), 15.0 (CH3); HRMS: m/z calcd for C13H16O3Na
(MþNa): 243.0995. Found: 243.0996.
0.5; [
a]
22: ꢁ21.4 (c 2.1, CHCl3); IR (neat): nmax/cmꢁ1 3406, 3080,
D
3.4. Methyl (1R,5R)-6,6,7-trimethyl-3-oxo-1-vinyl-
2928, 2862, 1638, 1513, 1435, 1370, 1304, 1220, 995, 910, 840; 1H
bicyclo[3.3.0]oct-7-ene-2-carboxylate 14
NMR (400 MHz, signals due to the major isomer): d 5.95 (1H, dd, J
17.2 and 10.4 Hz, vinylic HC]CH2), 6.01–5.84 (1H, m, HC]CH2),
5.25 (1H, s, H-8), 5.20–5.10 (2H, m), 4.91 (1H, d, J 17.2 Hz), 4.86 (1H,
d, J 10.4 Hz), 2.55–2.21 (4H, m), 2.00–1.75 (4H, m), 1.66 (3H, s,
olefinic CH3), 1.05 (3H, s) and 1.03 (3H, s) [2ꢂtert-CH3]; 13C NMR
(100 MHz, signals due to the major isomer): 148.1 (C, C-7), 146.6
(CH), 134.7 (CH), 130.0 (CH), 117.6 (CH2), 110.7 (CH2), 81.7 (C, C-3),
60.1 (C), 58.3 (CH, C-5), 50.1 (CH2), 48.4 (C), 44.6 (CH2), 41.9 (CH2),
30.2 (CH3), 23.6 (CH3), 12.6 (CH3); HRMS: m/z calcd for C16H24ONa
(MþNa): 255.1725. Found: 255.1715.
To a cold (ꢁ30 ꢀC), magnetically stirred suspension of CuI
(22 mg, 0.11 mmol) in dry THF (2 mL) was added a solution of
vinylmagnesium bromide (2.5 mL, 1 M solution in THF, 2.5 mmol)
over a period of 20 min. After stirring the reaction mixture for
30 min at ꢁ30 ꢀC, a solution of the keto ester 12 (250 mg,
1.14 mmol) in dry THF (3 mL) was added and stirred for 1 h at the
same temperature. It was then quenched with saturated aq NH4Cl
(10 mL) and extracted with ether (3ꢂ10 mL). The ether extract was
washed with brine (10 mL) and dried (Na2SO4). Evaporation of the
solvent and purification of the residue on a silica gel column using
ethyl acetate–hexane (1:20) as eluent furnished the keto ester 14
(174 mg, 62%) as colorless oil, which was found to exist in the enol
3.7. (1S,5R,7S)-3,4,4-Trimethyltricyclo[5.3.1.01,5]undec-
2,9-dien-7-ol 17
form 14b. Rf (1:19 EtOAc–hexane) 0.4; [
a
]
25: 2.0 (c 8.1, CHCl3); IR
To a magnetically stirred solution of the alcohol 16 (20 mg,
0.08 mmol) in dry CH2Cl2 (2 mL) was added Grubbs’ first genera-
tion catalyst (6 mg, 10 mol %) and the reaction mixture was stirred
at rt for 8 h. Evaporation of the solvent under reduced pressure and
purification of the residue over a silica gel column using ethyl ac-
etate–hexane (1:9) as eluent furnished the tricyclic compound 17
(16 mg, 90%) as solid. Mp: 91–92 ꢀC; Rf (1:9 EtOAc–hexane) 0.5;
D
(neat): nmax/cmꢁ1 3261, 3081, 3046, 2956, 2866, 1760, 1732, 1651,
1615, 1446, 1354, 1281, 1218, 1167, 1042, 993, 912, 845, 804; 1H NMR
(300 MHz, for the enol form 14b): d 10.55 (1H, s, OH), 5.87 (1H, dd, J
18.0 and 9.9 Hz, HC]CH2), 5.41 (1H, s, H-8), 4.88 (1H, d, J 9.9 Hz)
and 4.87 (1H, d, J 18.0 Hz) [HC]CH2], 3.72 (3H, s, OCH3), 2.64 (1H,
dd, J 18.3 and 8.7 Hz), 2.51–2.42 (1H, m), 2.21 (1H, dd, J 9.3 and
3.0 Hz), 1.64 (3H, s, olefinic CH3), 1.05 (3H, s, tert-CH3), 0.93 (3H, s,
[a
]
2D1: þ43.0 (c 0.7, CHCl3); IR (neat): nmax/cmꢁ1 3363, 3025, 2955,
tert-CH3); 13C NMR (75 MHz, signals due to enol form 14b):
d
176.1
2861, 1640, 1462, 1359, 1333, 1158, 1067, 1007, 950, 831, 712; 1H
(C, CO2CH3), 170.0 (C, C-3), 147.6 (C, C-7), 144.7 (CH, HC]CH2), 126.6
(CH, C-8), 111.3 (CH2, HC]CH2), 104.6 (C, C-2), 62.5 (C), 55.2 (CH3,
OCH3), 50.8 (CH, C-5), 47.8 (C), 32.2 (CH2, C-4), 29.2 (CH3), 22.8
(CH3), 12.7 (CH3); HRMS: m/z calcd for C15H20O3Na (MþNa):
271.1310. Found: 271.1302.
NMR (400 MHz): d 5.86 (1H, d, J 9.2 Hz, H-10), 5.42 (1H, dt, J 9.2 and
3.4 Hz, H-9), 5.31 (1H, s, H-2), 2.45 (1H, dq, J 17.4 and 2.4 Hz), 2.37
(1H, d, J 17.4 Hz), 2.27 (1H, dd, J 7.8 and 7.5 Hz), 2.00–1.90 (2H, m),
1.73 and 1.68 (2H, 2ꢂd, J 10.0 Hz), 1.64 (3H, s, olefinic CH3), 1.74–
1.63 (1H, m, OH), 1.00 (6H, s, 2ꢂtert-CH3); 13C NMR (100 MHz):
d
149.3 (C, C-3), 139.8 (CH, C-10), 127.0 (CH, C-2), 123.1 (CH, C-9),
3.5. (1S,5R)-6,6,7-Trimethyl-1-vinylbicyclo[3.3.0]oct-
7-en-3-one 15
81.3 (C, C-7), 62.7 (CH, C-5), 56.9 (C, C-1), 48.3 (CH2), 47.2 (C, C-4),
44.2 (CH2), 40.4 (CH2), 29.4 (CH3), 24.2 (CH3), 13.0 (CH3). Anal.
Calcd: for C14H20O: C, 82.30; H, 9.87. Found: C, 82.00; H, 9.90.
A solution of the keto ester 14 (180 mg, 0.73 mmol), NaCl
(126 mg, 2.18 mmol), DMSO (2 mL), and water (0.01 mL) was placed
in a Carius tube and heated to 180 ꢀC for 2 h. The reaction mixture
was cooled to rt, diluted with ether (10 mL), washed with water
(5 mL) and brine (5 mL), and dried (Na2SO4). Evaporation of the
solvent and purification of the residue on a silica gel column using
3.8. (1S,3S,5R)-3-Allyl-6,6,7-trimethyl-1-vinylbicyclo-
[3.3.0]oct-7-en-3-yl acetate 18
To a magnetically stirred ice cold solution of the alcohol 16
(25 mg, 0.11 mmol) in CH2Cl2 (1 mL) were added DMAP (5 mg),
pyridine (0.2 mL, 3.90 mmol), and Ac2O (0.4 mL, 3.9 mmol) and
stirred for 2 h at rt; 3 N HCl (4 mL) was added to the reaction
mixture and extracted with CH2Cl2 (2ꢂ5 mL). The combined or-
ganic extract was washed with brine (5 mL) and dried (Na2SO4).
Evaporation of the solvent and purification of the residue on a silica
ethyl acetate–hexane (1:19) as eluent furnished the diquinane
23
ketone 15 (120 mg, 87%) as oil. Rf (1:19 EtOAc–hexane) 0.5; [a] :
D
ꢁ46.1 (c 4.4, CHCl3); IR (neat): nmax/cmꢁ1 3080, 2960. 1743, 1632,
1442, 1400, 1175, 1000, 911, 837; 1H NMR (400 MHz):
d 5.98 (1H, dd,
J 17.3 and 10.4 Hz, HC]CH2), 5.24 (1H, s, H-8), 4.97 (1H, d, J 17.3 Hz),
4.95 (1H, d, J 10.4 Hz), 2.45–2.20 (5H, m), 1.66 (3H, s, olefinic CH3),
1.08 (3H, s) and 0.91 (3H, s) [2ꢂtert-CH3]; 13C NMR (100 MHz):
gel column using ethyl acetate–hexane (1:19) as eluent furnished
21
the acetate 18 (26 mg, 89%) as oil. Rf (1:19 EtOAc–hexane) 0.5; [a] :
D
d
218.0 (C, C]O), 148.0 (C, C-7), 145.8 (CH, CH]CH2), 128.1 (CH,
þ15.0 (c 0.8, CHCl3); IR (neat): nmax/cmꢁ1 3081, 2961, 2930, 2867,
C-8), 111.7 (CH2, HC]CH2), 56.3 (C), 56.0 (CH, C-1), 48.6 (CH2, C-2),
1738, 1436, 1367, 1238, 1210, 1116, 1020, 994, 913, 843; 1H NMR

A. Srikrishna et al. / Tetrahedron 65 (2009) 2649–2654
2653
(400 MHz):
d
5.94 (1H, dd, J 17.6 and 10.4 Hz, vinylic HC]CH2),
1.83 (1H, dd, J 12.8 and 9.8 Hz), 1.64 (2H, s), 1.60 (3H, s, olefinic CH3),
5.85–5.70 (1H, m), 5.15–4.80 (5H, m), 2.77 (1H, dd, J 14.6 and
7.3 Hz), 2.55 (1H, dd, J 14.6 and 7.2 Hz), 2.40–1.80 (5H, m), 1.92 (3H,
s, CH3C]O), 1.62 (3H, s, olefinic CH3), 1.04 (3H, s) and 0.98 (3H, s)
0.96 (6H, s, 2ꢂtert-CH3); 13C NMR (100 MHz):
d 149.1 (C, C-3), 139.7
(CH, C-10), 127.2 (CH), 123.2 (CH), 85.6 (C, C-7), 62.5 (CH, C-5), 56.2
(C, C-1), 50.7 (CH3, OCH3), 47.4 (C, C-4), 44.4 (CH2), 39.9 (CH2), 36.2
(CH2), 29.4 (CH3), 24.1 (CH3), 13.0 (CH3); HRMS: m/z calcd for C14H19
(MꢁOMe): 187.1468. Found: 187.1461.
[2ꢂtert-CH3]; 13C NMR (100 MHz):
d 169.8 (C, OC]O), 146.9 (CH),
145.0 (C), 133.4 (CH), 129.0 (CH), 117.9 (CH2), 110.6 (CH2), 89.6 (C),
58.0 (C), 57.1 (CH), 47.8 (C, C-4), 47.4 (CH2), 40.1 (CH2), 39.5 (CH2),
29.5 (CH3), 22.5 (CH3), 21.8 (CH3), 12.5 (CH3); HRMS: m/z calcd for
C18H26O2Na (MþNa): 297.1830. Found: 297.1833.
3.12. (1S,5R,7S)-7-Methoxy-4,4-dimethyltricyclo-
[5.3.1.01,5]undeca-2,9-dien-3-carboxaldehyde 21
3.9. (1S,5R,7S)-3,4,4-Trimethyltricyclo[5.3.1.01,5]undeca-
2,9-dien-7-yl acetate 19
To a solution of the methyl ether 20 (16 mg, 0.07 mmol) in di-
oxane (0.5 mL) and water (two drops) was added SeO2 (25 mg,
0.22 mmol) and refluxed for 50 min. The reaction mixture was
cooled, diluted with ether (2 mL), and quenched with satd aq NH4Cl
(1 mL). The organic layer was separated and the aqueous phase was
extracted with ether (3ꢂ3 mL). The combined organic phase was
washed with brine (5 mL) and dried (Na2SO4). Evaporation of the
solvent and purification of the residue over a silica gel column using
ethyl acetate–hexane (1:19) as eluent furnished the aldehyde 21
To a magnetically stirred solution of the acetate 18 (13 mg,
0.05 mmol) in dry CH2Cl2 (2 mL) was added Grubbs’ first genera-
tion catalyst (4 mg, 10 mol %) and the reaction mixture was stirred
at rt for 9 h. Evaporation of the solvent under reduced pressure and
purification of the residue over a silica gel column using ethyl ac-
etate–hexane (1:19) as eluent furnished the tricyclic acetate 19
(11 mg, 94%) as oil. Rf (1:19 EtOAc–hexane) 0.4; [
a
]
23: þ21.0 (c 1.2,
(8 mg, 47%) as oil. Rf (1:19 EtOAc–hexane) 0.5; [
a]
22: ꢁ22.0 (c 0.9,
D
D
CHCl3); IR (neat): nmax/cmꢁ1 3028, 2958, 2866, 1736, 1438, 1367,
CHCl3); IR (neat): nmax/cmꢁ1 3031, 2957, 2928, 2712, 1682, 1610,
1261, 1245, 1047, 1016, 913, 830; 1H NMR (400 MHz):
d
5.85 (1H, d, J
1514, 1463, 1361, 1342, 1324, 1251, 1214, 1162, 1118, 1080, 1022, 996,
9.2 Hz, H-10), 5.41 (1H, dt, J 9.2 and 3.4 Hz, H-9), 5.31 (1H, s, H-2),
2.85 (1H, d, J 17.3 Hz), 2.55 (1H, dq, J 17.3 and 2.8 Hz), 2.55–2.40 (1H,
m), 2.32 (1H, dd, J 9.4 and 6.0 Hz), 2.10–2.00 (2H, m), 2.03 (3H, s,
COCH3), 1.78 (1H, d, J 10.0 Hz), 1.64 (3H, s, olefinic CH3), 1.00 (3H, s)
830; 1H NMR (400 MHz):
d 9.64 (1H, s, HC]O), 6.63 (1H, s, H-2),
5.87 (1H, d, J 9.2 Hz, H-10), 5.51 (1H, dt, J 9.2 and 3.4 Hz, H-9), 3.23
(3H, s, OCH3), 2.47 (1H, dq, J 17.5 and 3.0 Hz), 2.38 (1H, dd, J 9.6 and
5.6 Hz), 2.30 (1H, d, J 17.5 Hz), 2.03 (1H, ddd, J 13.0, 5.5 and 3.0 Hz),
1.82 (1H, dd, J 13.0 and 10.1 Hz), 1.72 (2H, s), 1.17 (3H, s) and 1.13
and 0.98 (3H, s) [2ꢂtert-CH3]; 13C NMR (100 MHz):
d 169.9 (C,
OC]O), 149.4 (C, C-3), 139.1 (CH, C-10), 126.7 (CH), 123.1 (CH), 88.4
(C, C-7), 62.4 (CH, C-5), 55.2 (C, C-1), 47.2 (C, C-4), 45.8 (CH2), 40.2
(CH2), 37.7 (CH2), 29.4 (CH3), 24.1 (CH3), 21.9 (CH3), 12.9 (CH3);
HRMS: m/z calcd for C16H22O2Na (MþNa): 269.1517. Found:
269.1508.
(3H, s) [2ꢂtert-CH3]; 13C NMR (100 MHz):
d 190.3 (CH, CH]O),
154.4 (CH, C-2), 154.3 (C, C-3), 136.0 (CH, C-10), 125.1 (CH, C-9), 85.1
(C, C-7), 63.7 (CH, C-5), 57.5 (C, C-1), 50.9 (CH3, OCH3), 45.9 (C, C-4),
44.0 (CH2), 40.0 (CH2), 35.4 (CH2), 29.5 (CH3), 24.1 (CH3); HRMS:
m/z calcd for C15H20O2Na (MþNa): 255.1725. Found: 255.1738.
3.10. Hydrolysis of the tricyclic acetate 19
3.13. 1-[(1S,5R,7S)-7-Methoxy-4,4-dimethyltricyclo-
[5.3.1.01,5]undeca-2,9-dien-3-yl]ethanol 22
To a magnetically stirred solution of the tricyclic acetate 19
(12 mg, 0.05 mmol) in MeOH (0.5 mL) was added K2CO3 (138 mg,
1.0 mmol) and stirred for 6 h at rt. Water (2 mL) was added to the
reaction mixture and extracted with ether (2ꢂ5 mL). The combined
organic extract was washed with brine (5 mL) and dried (Na2SO4).
Evaporation of the solvent and purification of the residue on a silica
gel column using ethyl acetate–hexane (1: 9) as eluent furnished
the alcohol 17 (10 mg, 100%), which exhibited TLC and spectral
data (IR and 1H NMR) identical to the sample obtained by RCM
reaction of 16.
To a magnetically stirred, ice cold solution of the aldehyde 21
(12 mg, 0.05 mmol) in THF (1 mL) was added MeMgBr (0.3 mL,
0.9 mmol, 3 M in THF) and stirred for 1 h at rt. The reaction mixture
was poured into ice cold satd aq NH4Cl solution (3 mL) and
extracted with ether (3ꢂ3 mL). The ether extract was washed with
brine (5 mL) and dried (Na2SO4). Evaporation of the solvent and
purification of the residue over a silica gel column using ethyl ac-
etate–hexane (1:9) as eluent furnished the secondary alcohol 22
(11 mg, 92%) as oil. Rf (1:9 EtOAc–hexane) 0.5; [
a
]
23: ꢁ14.5 (c 1.1,
D
CHCl3); IR (neat): nmax/cmꢁ1 3370, 2927, 2856, 1514, 1465, 1376,
3.11. (1S,5R,7S)-7-Methoxy-3,4,4-trimethyltricyclo-
1240, 1215, 1117, 1052, 1024, 829; 1H NMR (400 MHz):
d 5.80 (1H, d,
[5.3.1.01,5]undeca-2,9-diene 20
J 9.2 Hz, H-100), 5.67 (1H, s, H-20), 5.40 (1H, dt, J 9.2 and 3.3 Hz, H-
90), 4.19 (1H, q, J 6.3 Hz, CHOH), 3.22 (3H, s, OCH3), 2.46 (1H, dq, J
17.3 and 2.7 Hz), 2.30–2.20 (2H, m), 1.96 (1H, ddd, J 13.0, 5.5 and
3.0 Hz), 1.80 (1H, dd, J 13.0 and 9.6 Hz), 1.70–1.55 (3H, m), 1.30 (3H,
d, J 6.3 Hz, sec-CH3), 1.05 (3H, s) and 0.96 (3H, s) [2ꢂtert-CH3]; 13C
To an ice cold, magnetically stirred suspension of NaH (60%
dispersion in oil, 59 mg, 1.50 mmol, washed with dry hexane) and
tetrabutylammonium iodide (10 mg, catalytic) in THF (1 mL) was
added a solution of the alcohol 17 (30 mg, 0.15 mmol) in THF (2 mL)
and stirred for 30 min at rt. To the alkoxide thus formed was added
methyl iodide (0.1 mL, 1.50 mmol) and the reaction mixture was
stirred for 15 h at rt. Water (2 mL) was added to the reaction mix-
ture and extracted with ether (3ꢂ5 mL). The combined ether ex-
tract was washed with brine (5 mL) and dried (Na2SO4).
Evaporation of the solvent and purification of the residue over
a silica gel column using CH2Cl2–hexane (1:9) as eluent furnished
the methyl ether 20 (32 mg, 100%) as oil. Rf (1:9 CH2Cl2–hexane)
NMR (100 MHz): d
157.3 (C, C-30), 138.9 (CH, C-100), 127.8 (CH, C-20),
123.7 (CH, C-90), 85.7 (C, C-70), 64.2 (CH), 63.0 (CH), 56.1 (C, C-10),
50.8 (CH3, OCH3), 47.4 (C, C-40), 44.3 (CH2), 39.9 (CH2), 36.0 (CH2),
30.3 (CH3), 25.3 (CH3), 24.3 (CH3); HRMS: m/z calcd for C16H24O2Na
(MþNa): 271.1674. Found: 271.1646.
3.14. (1S,5R,7S)-3-Acetyl-7-methoxy-4,4-dimethyltri-
cyclo[5.3.1.01,5]undeca-2,9-diene 23
0.5; [
a]
22: þ26.1 (c 3.1, CHCl3); IR (neat): nmax/cmꢁ1 3027, 2957,
To a magnetically stirred solution of the secondary alcohol 22
(11 mg, 0.044 mmol) in CH2Cl2 (1 mL) was added PDC (150 mg,
0.44 mmol) and stirred for 3 h at rt. The reaction mixture was then
filtered through a small silica gel column and eluted the column
with an excess of CH2Cl2 (10 mL). Evaporation of the solvent and
D
2863, 2826, 1463, 1440, 1360, 1335, 1197, 1160, 1082, 711; 1H NMR
(400 MHz):
d 5.82 (1H, d, J 9.2 Hz, H-10), 5.40 (1H, dt, J 9.2 and
3.4 Hz, H-9), 5.27 (1H, s, H-2), 3.26 (3H, s, OCH3), 2.48 (1H, dq, J 17.3
and 2.7 Hz), 2.30–2.20 (2H, m), 1.99 (1H, ddd, J 12.8, 5.6 and 3.1 Hz),

2654
A. Srikrishna et al. / Tetrahedron 65 (2009) 2649–2654
purification of the residue over a silica gel column using ethyl ac-
(CH3); HRMS: m/z calcd for C17H26O2Na (MþNa): 285.1830. Found:
etate–hexane (1:19) as eluent furnished the ketone 23 (9 mg, 83%)
285.1826.
as oil. Rf (1:19 EtOAc–hexane) 0.5; [
a
]
24: ꢁ12.9 (c 0.8, CHCl3); IR
D
(neat): nmax/cmꢁ1 3028, 2962, 2930, 2864, 1671, 1605, 1463, 1361,
Acknowledgements
1281, 1259, 1201, 1162, 1122, 1087, 1024, 954, 706; 1H NMR
(400 MHz): d 6.67 (1H, s, H-2), 5.93 (1H, d, J 9.3 Hz, H-10), 5.56 (1H,
We thank Department of Science and Technology, New Delhi for
the financial support, Council of Scientific and Industrial Research,
New Delhi for the award of research fellowships to B.B. and V.G. We
are grateful to M/s Organica Aromatics (Bangalore) Pvt. Ltd. for the
generous gift of campholenaldehyde.
td, J 9.3 and 3.5 Hz, H-9), 3.31 (3H, s, OCH3), 2.55 (1H, dq, J 17.4 and
2.8 Hz), 2.40–2.30 (2H, m), 2.30 (3H, s, CH3CO), 2.10 (1H, ddd, J 12.3,
5.0 and 3.0 Hz), 1.88 (1H, dd, J 12.3 and 10.0 Hz), 1.80 and 1.76 (2H,
2ꢂd, J 10.0 Hz), 1.20 (6H, s, 2ꢂtert-CH3); 13C NMR (100 MHz):
d
197.2 (C, C]O), 152.4 (C, C-3), 146.4 (CH, C-2), 136.6 (CH, C-10),
124.8 (CH, C-9), 85.2 (C, C-7), 62.9 (CH, C-5), 56.7 (C, C-1), 51.0 (CH3,
OCH3), 47.2 (C, C-4), 43.9 (CH2), 40.1 (CH2), 35.4 (CH2), 29.9 (CH3),
27.9 (CH3), 24.4 (CH3); HRMS: m/z calcd for C16H22O2Na (MþNa):
269.1517. Found: 269.1507.
References and notes
1. Fukuyama, Y.; Shida, N.; Kodama, M.; Chaki, H.; Yugami, T. Chem. Pharm. Bull.
1995, 43, 2270.
2. Winkelmann, K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O. J. Nat. Prod. 2000,
63, 104; Winkelmann, K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O. Helv. Chim.
Acta 2001, 84, 3380.
3.15. 2-[(1S,5R,7S)-7-Methoxy-4,4-dimethyltricyclo-
[5.3.1.01,5]undeca-2,9-dien-3-yl]propan-2-ol 24
3. Tanaka, N.; Kashiwada, Y.; Sekiya, M.; Ikeshiro, Y.; Takaishi, Y. Tetrahedron Lett.
2008, 49, 2799.
4. Pettus, T. R. R.; Chen, X.-T.; Danishefsky, S. J. J. Am. Chem. Soc. 1998, 120, 12684;
Pettus, T. R. R.; Inoue, M.; Chen, X.-T.; Danishefsky, S. J. J. Am. Chem. Soc. 2000,
122, 6160; Wilson, R. M.; Danishefsky, S. J. Acc. Chem. Res. 2006, 39, 539.
5. Furuya, S.; Terashima, S. Tetrahedron Lett. 2003, 44, 6875.
6. Lei, X.; Dai, M.; Hua, Z.; Danishefsky, S. J. Tetrahedron Lett. 2008, 49, 6383.
7. Bajgrowicz, J. A.; Frank, I.; Frater, G.; Hennig, M. Helv. Chim. Acta 1998, 81, 1349;
Castro, J. M.; Linares-Palomino, P. J.; Salido, S.; Altarejos, J.; Nogueras, M.;
Sanchez, A. Tetrahedron 2005, 61, 11192.
8. For a few examples: Mehta, G.; Nandakumar, J. Tetrahedron Lett. 2001, 42, 7667;
Mehta, G.; Bera, M. K. Tetrahedron Lett. 2004, 45, 1113; Liu, H. J.; Chan, W. H. Can.
J. Chem. 1979, 57, 708; Chan. Can. J. Chem. 1982, 60, 1081; Sakurai, K.; Kitahara,
T.; Mori, K. Tetrahedron 1988, 44, 6581.
To a magnetically stirred, ice cold solution of the ketone 23
(7 mg, 0.03 mmol) in THF (1 mL) was added MeMgBr (0.2 mL,
0.6 mmol, 3 M in THF) and stirred for 2 h at rt. The reaction mixture
was poured into ice cold satd aq NH4Cl solution (3 mL) and
extracted with ether (3ꢂ3 mL). The combined ether extract was
washed with brine (5 mL) and dried (Na2SO4). Evaporation of the
solvent and purification of the residue over a silica gel column using
ethyl acetate–hexane (1:9) as eluent furnished the alcohol 24
(6 mg, 80%) as oil. Rf (1:19 EtOAc–hexane) 0.4; [
a
]
23: ꢁ17.1 (c 0.7,
D
9. Srikrishna, A.; Beeraiah, B.; Satyanarayana, G. Tetrahedron: Asymmetry 2006, 17,
1544.
CHCl3); IR (neat): nmax/cmꢁ1 3364, 3029, 2964, 2928, 2857, 1514,
1464, 1375, 1243, 1213, 1122, 1088, 1072, 1020, 945, 830; 1H NMR
(400 MHz): d
5.84 (1H, d. J 9.1 Hz, H-100), 5.61 (1H, s, H-20), 5.46 (1H,
10. Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091; Doyle, M. P. In Comprehensive
Organometallic Chemistry II; Hegedus, L. S., Ed.; Pergamon: New York, NY, 1995;
Vol. 12, Chapter 5.2; Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: from Cyclopropanes to
Ylides; John Wiley and Sons: New York, NY, 1998; Chapter 3.
11. Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.
dt, J 9.1 and 3.4 Hz, H-90), 3.31 (3H, s, OCH3), 2.52 (1H, dq, J 17.2 and
2.7 Hz), 2.40–2.25 (2H, m), 2.07 (1H, ddd, J 13.1, 5.2 and 3.1 Hz), 1.82
(1H, dd, J 13.1 and 10.8 Hz), 1.74 and 1.67 (2H, 2ꢂd, J 10.0 Hz), 1.70–
1.55 (1H, m, OH), 1.45 (6H, s, 2ꢂtert-CH3), 1.22 (3H, s) and 1.21 (3H,
12. Krapcho, A. P. Synthesis 1982, 893.
13. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413; (b) Fu¨ rstner, A. Angew.
Chem., Int. Ed. 2000, 39, 3013; (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001,
34, 18; (d) Grubbs, R. H. Tetrahedron 2004, 60, 7117.
14. Paquette, L. A.; Fabris, F.; Tae, J.; Gallucci, J. C.; Hofferberth, J. E. J. Am. Chem. Soc.
2000, 122, 3391; Lee, C. W.; Grubbs, R. H. J. Org. Chem. 2001, 66, 7155; Srik-
rishna, A.; Dethe, D. H. Tetrahedron Lett. 2005, 46, 3381.
s) [2ꢂtert-CH3]; 13C NMR (100 MHz):
d
159.4 (C, C-30), 139.3 (CH, C-
100), 128.1 (CH, C-20), 123.4 (CH, C-90), 85.8 (C, C-70), 72.7 (C, C-2),
64.2 (CH, C-50), 55.0 (C, C-10), 50.9 (CH3, OCH3), 48.8 (C, C-40), 43.9
(CH2), 40.1 (CH2), 35.5 (CH2), 32.7 (CH3), 32.6 (CH3), 31.2 (CH3), 26.3