Enantiospecific first total synthesis of (6S,7R)-silphiperfolan-6-ol

Article abstract of DOI:10.1016/j.tet.2012.01.063

Enantiospecific first total synthesis of the angular triquinane sesquiterpene (6S,7R)-silphiperfolan-6-ol has been accomplished, starting from 2-(3-isopropenyl-2-methylene-1-methylcyclopent-1-yl)acetic acid (readily available from (R)-limonene) employing an efficient, regioselective intramolecular rhodium carbenoid insertion into the CH bond of a tertiary methyl group as the key step.

Full text of DOI:10.1016/j.tet.2012.01.063

Tetrahedron 68 (2012) 2650e2656
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Enantiospecific first total synthesis of (6S,7R)-silphiperfolan-6-ol
*
A. Srikrishna , Gopalasetty Nagaraju, Vishal M. Sheth
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:
Enantiospecific first total synthesis of the angular triquinane sesquiterpene (6S,7R)-silphiperfolan-6-ol
has been accomplished, starting from 2-(3-isopropenyl-2-methylene-1-methylcyclopent-1-yl)acetic
acid (readily available from (R)-limonene) employing an efficient, regioselective intramolecular rhodium
carbenoid insertion into the CH bond of a tertiary methyl group as the key step.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 7 December 2011
Received in revised form 19 January 2012
Accepted 23 January 2012
Available online 28 January 2012
Dedicated to Professor G. S. R. Subba Rao on
the occasion of his 75th birthday
Keywords:
Angular triquinanes
Silphiperfolane
Enantiospecific synthesis
Rhodium carbenoid CH insertion
Limonene
1. Introduction
6
OH
7
The sesquiterpene natural products containing an angular tri-
quinane moiety, isolated so far, fall into five different skeletal types
(isocomane, pentalenane, silphinane, silphiperfolane, and camer-
oonane) on the basis of the arrangement of the four carbon sub-
stituents on the tricyclo[6.3.0.01,5]undecane 1.1 Among the natural
angular triquinane sesquiterpenes, silphiperfolanes were found to
be abundant (more than a dozen), whose first member silphiperfol-
6-ene 2 was isolated in 1980 by Bohlmann and co-workers from the
root extract of Silphium sp.2,3 The essential oil of the rhizomes of
Echinops giganteus var. lelyi C. D. Adams, an endemic species of
Cameroon and Nigeria, has a strong patchouli-like odor. In 1997,
Weyerstahl and co-workers reported4 the isolation of all the four
possible diastereomers (at C-6 and C-7) of silphiperfolan-6-ol 3e6
from this essential oil, along with several triquinane and related
sesquiterpenes. Structures of silphiperfolan-6-ols 3e6 were
assigned by spectral studies, in particular the 1 and 2D NMR and
comparison of solvent (C6D6 and pyridine-d5) induced NMR shifts.
Of the four isomers 3e6, isolation of the compound 3 (wrongly
assigned4a as 4) from the red algae Laurencia majuscula along with
a chamigrene derivative was reported earlier in 1990 by Wright and
co-workers.5
H
H
H
3 (6S,7R)
OH
1
2
OH
OH
H
H
4 (6R,7S)
5 (6R,7R)
6 (6S,7S)
From the synthesis point of view so far there is no report on the
synthesis of any of silphiperfolan-6-ols 3e6 either in racemic or
enantiopure form, although synthesis of a variety of silphiperfo-
lanes was reported in the literature.6 As a part of our interest in the
chiral pool based enantiospecific synthesis of natural products
starting from the readily available monoterpene (R)-limonene,7
recently we have developed a rhodium carbenoid CeH insertion
based approach7l for the construction of angular triquinanes.
Extending its application, in continuation, herein we report the
enantiospecific first total synthesis of (6S,7R)-silphiperfolan-6-ol 3.
* Corresponding author. Fax: þ91 80 23600529; e-mail address: askiisc@
gmail.com (A. Srikrishna).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.063

A. Srikrishna et al. / Tetrahedron 68 (2012) 2650e2656
2651
2. Results and discussion
O
ref 7c
OH
It was contemplated (Scheme 1) that the angular triquinane 7
OH
could be generated via the insertion of the rhodium carbenoid8
10
derived from the diazo ketone 8 in to the g-CH bond of the ter-
13
tiary methyl group at the ring junction position, which could be
further transformed into silphiperfolanol 3. It was readily identified
that the diazo ketone 8 could be obtained by modification of the
isopropenyl group present in the diquinane 9, which contain the
requisite methyl groups and the tertiary hydroxy group in a masked
fashion. It was conceived that the diquinane 9 could be obtained
from the acid 10 via the ketone 11, which could be obtained from
the acid 10 by an intramolecular diazo ketone cyclopropanation
followed by a regioselective cyclopropane ring cleavage. Synthesis
of the acid 10 from limonene 12 via the allyl alcohol 13 has already
been developed by us7k enroute to the sesquiterpene cucumin-H.
71%
O
a
12
O
O
b
76%
c
N2
86%
(2:1)
11
15
14
88%
d
OMOM
+
OR
f
OMOM
83%
O
O
17a
17
( 1 : 2 )
16 R = H
9
e 87%
R = MOM
OR
H
H
Scheme 2. Reagents and conditions: (a) i. (COCl)2, C6H6, rt, 3 h; ii. CH3CHN2, Et2O, ꢀC,
4 h; (b) Cu, anhydrous CuSO4, W-lamp, c-C6H12, reflux, 4 h; (c) Li, liq. NH3, THF, ꢁ33 ꢀC,
0.25 h; (d) MeMgCl, Et2O, rt, 4 h; (e) MOMCl, DIPEA, DMAP, CH2Cl2, rt, 6 h; (f) O3/O2,
CH2Cl2/MeOH (4:1), ꢁ70 ꢀC; Me2S, rt, 4 h.
OH
OR
O
O
3
N2
8
7
O
OR
11
9
g
90%
i
17
OMOM
OMOM
H
COOH
84%
O
OH
COOEt
O
COOEt
X
20
18 X = H,H
19 X = N2
h 90%
13
j
10
12
70%
Scheme 1.
The synthetic sequence is depicted in Schemes 2e4. To begin with,
k
OMOM
synthesis of the acid 10 was carried out employing the methodology
reported earlier by us.7c,k The requisite allyl alcohol 13 was obtained
from (R)-limonene 12 in three steps viz. controlled ozonolysis, intra-
molecular aldol condensation, and Luche reduction.7a Johnson’s
orthoester Claisen rearrangement9 of the cyclopentenylmethanol 13
with triethyl orthoacetate in the presence of a catalytic amount of
propionic acid, followed by base catalyzed hydrolysis of the resultant
ester furnished the acid 10. It was readily identified that for the gen-
eration of the diquinane 11 with a secondary methyl group, it will be
more appropriate to employ an intramolecular cyclopropanation of
the diazo ketone 14 derived from diazoethane, followed by regiospe-
cific cyclopropane ring cleavage. Thus, treatment of the acid 10 with
oxalyl chloride followed by reaction of the resultant acid chloride with
an excess of ethereal diazoethane generated the diazo ketone 14 in 71%
yield. Anhydrous copper sulfateecopper catalyzed intramolecular
diazo ketone cyclopropanation10 of the diazo ketone 14 in refluxing
cyclohexane generated the tricyclic ketone 15 in a regio- and stereo-
specific manner in 76% yield. Regiospecific cyclopropane ring cleav-
age11 in the tricyclic ketone 15 with lithium in liquid ammonia
furnished a 2:1 epimeric mixture of the diquinane 11 in 86% yield.
Stereochemistry of the secondary methyl group in the major isomer of
11 was assigned as exo on the basis of the thermodynamic reasoning,
as the ratio of the isomers did not change on attempted equilibration
with 1,8-diazabicyclo[5.4.0]undec-8-ene (DBU). As the mixture was
found to be inseparable, it was taken further and separated at a later
stage. Reaction of the diquinane 11 with an excess methylmagnesium
chloride generated a 2:1 diastereomeric mixture of the alcohol 16.
Stereochemistry of the hydroxy group in 16 was assigned on the basis
OMOM
80%
H
H
O
21
22
98%
l
OH
m
+
H
X
H
94%
OMOM
X
H
(2:1)
3 X=Me; Y=H
3a X=H; Y=Me
Y
(1:2)
Y
2 X=Me; Y=H
2a X=H; Y=Me
(1:1)
23 & 23a
Scheme 3. Reagents and conditions: (g) LiHMDS, THF, ꢁ70 ꢀC; ClCO2Et, rt, 4 h; (h)
TsN3, Et3N, CH3CN, rt, 6 h; (i) Rh2(OAc)4, CH2Cl2, reflux, 2 h; (j) NaOH, MeOH/H2O,
reflux, 4 h; (k) tAmOK, Ph3PþCH3 Brꢁ, C6H6, rt, 6 h; (l) H2 (1 atm), 10% Pd/C, EtOAc, rt,
1 h; (m) 3 N HCl, THF, rt, 12 h.
H3O+
OH
OH
H
X
+
H
H
Y
2 X=Me; Y=H
2a X=H; Y=Me
3+3a
3
Scheme 4.

2652
A. Srikrishna et al. / Tetrahedron 68 (2012) 2650e2656
of the preferred approach of the nucleophile from less hindered face
(opposite to the neighboring methyl group). Reaction of the mixture of
the alcohols 16 with methoxymethyl (MOM) chloride, ethyl-
diisopropylamine (DIPEA), and a catalytic amount of 4-N,N-dimethy-
laminopyridine (DMAP) furnished a 2:1 diastereomeric mixture of the
MOM ethers 9 in 87% yield. Ozonolytic cleavage of the olefin of the
isopropenyl group in 9 followed by reductive workup with dimethyl
sulfide furnished a 2:1 mixture of the ketones 17 and 17a in 83% yield,
which were separated by column chromatography on silica gel. Pres-
ence of a carbonyl absorption band at 1711 cmꢁ1 in the IR spectrum
and presence of the sodiated molecular ion at 291.1936 (C16H28O3Na)
established the identity of the keto ether 17. In the 1H NMR spectrum
The key reaction is the highly regioselective efficient insertion of
a rhodium carbenoid into the CeH bond of a tertiary methyl group
at the ring junction position of a diquinane for the generation of the
angular triquinane system. In the present sequence (6S,7R)-silphi-
perfolan-6-ol 3 was obtained from the acid 10 in 13 steps with an
overall yield of w2.6%, and silphiperfol-6-ene 2 in w1.3% (corre-
sponding C-9 epimers 3a and 2a were obtained in w1.3 and 2.6%,
respectively). Extension of the strategy for the enantiospecific
synthesis of other silphiperfolan-6-ols and related cyclopentanoid
natural products is in progress.
3. Experimental section
3.1. General
appearance of an AB quartet at d 4.68 and 4.51, and a singlet at 3.31 due
to the MOM group, and a singlet at 2.11 due to the methyl of the acetyl
group in addition to the three singlets at 1.21, 1.00, and 0.88, and
a doublet at 0.95 ppm due to the four methyl groups established the
structure of the keto ether 17, which was confirmed by the sixteen
lines 13C NMR spectrum containing a diagnostic quaternary carbon
resonance at 211.6 due to the ketone, a methylene at 91.1 and a methyl
resonance at 55.1 due to the MOM group. Quite expectedly, the iso-
meric keto ether 17a also exhibited similar spectral data.
IR spectra were recorded on PerkineElmer Spectrum BX FTIR
spectrophotometer. 1H (400 MHz) and 13C (100 MHz) NMR spectra
were recorded on a Brucker Avance 400 spectrometer. The chemical
shifts (
standard fashion with reference to either internal tetramethylsilane
(for 1H) or the central line (77.0 ppm) of CDCl3 (for 13C). In the 13
d ppm) and coupling constants (Hz) are reported in the
C
The sequence was then carried out with the major isomer 17 as
it contains the requisite stereochemistry at the C-2 and C-3 carbons,
Scheme 3. For efficient generation of a diazo ketone, the acetyl
NMR, nature of the 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
micromass spectrometer using electron spray ionization mode.
Optical rotations were measured using a Jasco P-1020 digital po-
group in 17 was transformed into a
lithium hexamethyldisilazide (LHMDS) and ethyl chloroformate to
furnish the -keto ester 18 in 90% yield. A diazo transfer reaction
was carried out on the -keto ester 18 with p-toluenesulfonyl azide
and triethylamine to furnish the precursor for the key reaction, the
-diazo- -keto ester 19 in 90% yield. Treatment of the -diazo-
b-keto ester by reacting with
b
larimeter and ½a D
ꢂ
values are given in units of 10ꢁ1 deg cm2 gꢁ1
.
b
Thin-layer chromatographies (TLC) were performed on glass plates
(7.5ꢃ2.5 and 7.5ꢃ5.0 cm) coated with Acme’s silica gel G containing
13% calcium sulfate as binder and various combinations of ethyl
acetate 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
(100e200 mesh) was used for column chromatography (approxi-
mately 15e20 g per 1 g of the crude product).
a
b
a
b-
keto ester 19 with a catalytic amount of rhodium acetate in
refluxing methylene chloride for 2 h furnished the triquinane 20 in
84% yield in a highly regioselective manner.
Reactionof the b-keto ester20withsodiumhydroxideinrefluxing
aqueous methanol led to ester hydrolysis and decarboxylation, and
furnished the triquinane ketone 21 in 70% yield. Structure of the ke-
tone 21 was established fromits spectral data, inparticular the 1H and
13C NMR spectroscopy. The fifteenth carbon required for silphi-
perfolane system was introduced by Wittig reaction of the ketone 21
with excess methyltriphenylphosphonium bromide and potassium
tert-amyloxide in dry benzene to furnish silphiperfol-9(15)-ene 22, in
80% yield, whose structure was established from its spectral data.
Hydrogenation of the exomethylene in 22 in ethyl acetate employing
10% palladium over carbon as the catalyst furnished a 1:1 inseparable
mixture of the MOM ethers of (6S,7R)-silphiperfolan-6-ol 23 and its
C-9 epimer 23a in 98% yield. Finally, hydrolysis of the epimeric
mixture 23 and 23a with 3 N aqueous hydrochloric acid and THF,
which also led to partial dehydration, furnished a mixture of silphi-
perfol-6-enes 2 and 2a and silphiperfolan-6-ols 3 and 3a. Column
chromatography of the mixture on silica gel first furnished a w1:2
mixture ofsilphiperfol-6-ene 2 and its C-9 epimer 2ain 45% yield, and
subsequently a 2:1 mixture of silphiperforlan-6-ol 3 and its C-9 epi-
mer 3a in 49% yield.
Since it was observed that dehydration of the C-9 epimer 3a was
relatively faster than 3, a kinetic purification of 3 was adopted,
Scheme 4. Thus, treatment of a mixture of 3 and 3a with 3 N
aqueous hydrochloric acid and THF for 10 h furnished cleanly
a mixture of silphiperfol-6-enes 2 and 2a, and pure silphiperfolan-
3-ol 3. Structures of silphiperfol-6-ene 2 and its C-9 epimer 2a were
established by comparing the 13C NMR spectra with those reported
in the literature.6a,h Synthetic silphiperfolan-6-ol 3 exhibited
spectral data (1H and 13C NMR in C6D6) identical to those reported4
for the natural product.
3.1.1. (1S,3R,6S,9S)-9-Isopropenyl-3,6-dimethyltricyclo[4.3.0.01,3
]
nonan-4-one (15). To a magnetically stirred solution of the acid7k
10 (1.33 g, 6.86 mmol) in dry benzene (5 mL) was added oxalyl
chloride (1.74 mL, 20.6 mmol) and stirred at room temperature for
4 h. Evaporation of the excess oxalyl chloride and solvent under
reduced pressure furnished the acid chloride, which was taken in
dry ether (10 mL) and added to a cold (0 ꢀC), magnetically stirred
ethereal solution of diazoethane [excess prepared from N-nitroso-
N-ethylurea (8 g, 68.6 mmol), 60% KOH solution (50 mL), and ether
(20 mL)], and the reaction mixture was stirred at 0 ꢀC for 4 h.
Careful evaporation of the excess diazoethane and solvent on a hot
water bath and purification of the residue on a silica gel column
using ethyl acetate/hexane (1:19) as eluent furnished the diazo
ketone 14 (1.13 g, 71%) as greenish yellow oil. [IR (neat): nmax/cmꢁ1
3074, 2960, 2872, 2066 (N]N), 1635 (C]O), 1455, 1354, 1271, 1109,
1052, 1020, 891]. To a magnetically stirred refluxing (by placing two
100 W tungsten lamps near the reaction flask) suspension of cop-
per powder (928 mg, 14.6 mmol) and anhydrous copper sulfate
(2.33 g, 14.6 mmol) in anhydrous cyclohexane (50 mL) was added
dropwise, a solution of the diazo ketone 14 (1.13 g, 4.87 mmol) in
anhydrous cyclohexane (30 mL) over a period of 30 min and the
reaction mixture was refluxed for 4 h. It was then cooled, copper
and copper sulfate were filtered off on a small Celite pad using
CH2Cl2 (20 ml). Evaporation of the solvent and purification of the
residue on a silica gel column using ethyl acetate/hexane (1:19) as
eluent furnished the tricyclic ketone 15 (754 mg, 76%) as oil. ½a D24
ꢂ
ꢁ53.4 (c 6.4, CHCl3); IR (neat): nmax/cmꢁ1 3073, 2956, 2873, 1717
(C]O), 1645, 1454, 1412, 1377, 1334, 1145, 1121, 1073, 1028, 890 (]
In conclusion, we have accomplished the enantiospecific first
total synthesis of (6S,7R)-silphiperfolan-6-ol 3 starting from the
acid 10 (readily available from the monoterpene (R)-limonene 12).
CH2); 1H NMR (400 MHz, CDCl3þCCl4):
d 4.70 (2H, s, C]CH2), 2.59
(1H, t, J 8.8 Hz), 2.12 (1H, d, J 18.4 Hz, H-5A), 2.08e1.94 (1H, m), 1.92

A. Srikrishna et al. / Tetrahedron 68 (2012) 2650e2656
2653
(1H, d, J 18.4 Hz, H-5B), 1.86e1.62 (2H, m), 1.72 (3H, s, olefinic CH3),
1.48e1.26 (2H, m), 1.08 (3H, s) and 1.05 (3H, s) [2ꢃ tert-CH3], 0.93
(CH2), 28.2 (CH3), 25.9 (CH3), 23.6 (CH3), 15.3 (CH3), 8.4 (CH3);
(peaks due to the minor isomer): 147.8 (C, C]CH2),113.7 (CH2, C]
CH2), 79.7 (C, CeOH), 56.7 (C), 56.3 (C), 55.9 (CH2), 51.0 (CH), 50.9
(C), 40.4 (CH2), 30.1 (CH2), 28.2 (CH3), 25.8 (CH3), 23.5 (CH3), 20.9
(CH3), 9.1 (CH3).
d
(1H, d, J 5.0 Hz, H-2B); 13C NMR (100 MHz, CDCl3þCCl4):
d
214.0 (C,
C]O), 147.0 (C, C]CH2), 111.8 (CH2, C]CH2), 50.7 (C), 47.2 (CH2,
CH2C]O), 45.6 (CH), 44.2 (C), 39.4 (C), 39.3 (CH2) 30.0 (CH2), 22.8
(CH2), 22.4 (CH3), 20.1 (CH3), 12.0 (CH3); HRMS: m/z calcd for
C14H20ONa (MþNa): 227.1412; found: 227.1412.
3.1.4. (1R,5S,8S)-8-Isopropenyl-1,2,3,5-tetramethylbicyclo[3.3.0]oct-
3-yl methoxymethyl ether (9). To a cold (0 ꢀC), magnetically stirred
solution of the tertiary alcohol 16 (382 mg, 1.85 mmol) in anhy-
drous CH2Cl2 (2 mL) was added DIPEA (1.1 mL, 6.32 mmol) and
stirred for 10 min. MOMCl (0.48 mL, 6.32 mmol) was added drop-
wise to the reaction mixture, slowly warmed up to rt and stirred for
6 h. It was then diluted with water (4 mL) and extracted with
CH2Cl2 (3ꢃ5 mL). The combined organic extract was washed with
brine (8 mL) and dried (Na2SO4). Evaporation of the solvent and
purification of the residue on a silica gel column using CH2Cl2/
hexane (1:9) as eluent furnished a 1:2 diastereomeric mixture of
3.1.2. (1R,5S,8S)-8-Isopropenyl-1,2,5-trimethylbicyclo[3.3.0]octan-3-
one (11). To a magnetically stirred, freshly distilled (over sodium
and ferric chloride) ammonia (30 mL) in two necked flask, equip-
ped with Dewar condenser, was added freshly cut lithium (92 mg,
13.2 mmol) followed by a solution of the tricyclic ketone 15
(536 mg, 2.63 mmol) in anhydrous THF (4 mL). The resulting blue
colored solution was stirred for 15 min at ꢁ33 ꢀC and then the
reaction was quenched with solid NH4Cl. After evaporation of
ammonia, water (4 mL) was added to the residue and extracted
with ether (3ꢃ5 mL). The combined ether extract was washed with
brine (8 mL) and dried (Na2SO4). Evaporation of the solvent and
purification of the residue on a silica gel column using ethyl acetate/
hexane (1:19) as eluent furnished a 2:1 epimeric mixture of the
the MOM ether 9 (366 mg, 87%) as oil. ½a D25
þ27.9 (c 6.8, CHCl3); IR
ꢂ
(neat): nmax/cmꢁ1 3073, 2954, 2876, 1634, 1455, 1378, 1208, 1148,
1093, 1065, 1040, 921, 889; 1H NMR (400 MHz, CDCl3þCCl4): (peaks
due to the major isomer)
d 4.76 (1H, s) and 4.66 (1H, s) [C]CH2],
a 24
bicyclic ketone 11 (401 mg, 75%) as oil. ½ ꢂD þ29.0 (c 8.7, CHCl3); IR
4.71 and 4.52 (2H, 2ꢃ d, J 6.9 Hz, OCH2O), 3.32 (3H, s, OCH3), 2.31
(1H, t, J 6.7 Hz), 1.94 (1H, d, J 14.1 Hz), 1.84e1.32 (5H, m), 1.71 (3H, s,
olefinic CH3), 1.50 (1H, d, J 14.1 Hz), 1.21 (3H, s) and 1.01 (3H, s) [2ꢃ
tert-CH3], 0.90 (3H, d, J 7.2 Hz, sec-CH3), 0.79 (3H, s, tert-CH3);
(neat): nmax/cmꢁ1 3077, 2969, 2875, 1740 (C]O), 1641, 1452, 1411,
1380, 1182, 890 (C]CH2); 1H NMR (400 MHz, CDCl3þCCl4): (peaks
due to the major isomer)
d 4.87 (1H, s) and 4.74 (1H, s) [C]CH2],
2.55 (1H, t, J 9.4 Hz), 2.43 (1H, d, J 18.9 Hz), 2.06 (1H, d, J 18.9 Hz),
2.02e1.66 (5H, m), 1.75 (3H, s olefinic CH3), 1.05 (3H, s, tert-CH3),
0.99 (3H, d, J 7.4 Hz, sec-CH3), 0.71 (3H, s, tert-CH3); (important
(selected peaks due to the minor isomer): d 4.82 (1H, s) and 4.76
(1H, s) [C]CH2], 4.74 and 4.58 (2H, 2ꢃ d, J 6.9 Hz, OCH2O), 3.35 (3H,
s, OCH3), 3.16 (1H, t, J 8.8 Hz), 2.05 (1H, d, J 14.4 Hz), 1.31 (1H, d, J
14.0 Hz), 1.73 (3H, s, olefinic CH3), 1.21 (3H, s, tert-CH3), 1.03 (3H, d, J
7.3 Hz, sec-CH3), 0.93 (3H, s) and 0.81 (3H, s) [2ꢃ tert-CH3]; 13C NMR
peaks due to the minor isomer): d 4.80 (1H, s) and 4.74 (1H, s) [C]
CH2], 1.73 (3H, s, olefinic CH3), 1.08 (3H, s, tert-CH3), 1.04 (3H, d, J
6.9 Hz, sec-CH3), 1.00 (3H, s, tert-CH3); 13C NMR (100 MHz,
(100 MHz, CDCl3þCCl4): (peaks due to the major isomer):
d 147.5 (C,
CDCl3þCCl4): (peaks due to the major isomer)
d
220.0 (C, C]O),
C]CH2), 112.4 (CH2, C]CH2), 91.1 (CH2, OCH2O), 86.6 (C,
CeOMOM), 59.9 (CH), 58.4 (CH), 56.6 (C), 55.0 (CH3, OCH3), 52.9
(CH2), 50.8 (C), 43.5 (CH2), 29.3 (CH2), 25.9 (CH3), 23.7 (CH3), 23.5
(CH3), 15.2 (CH3), 8.5 (CH3); (peaks due to the minor isomer):
145.8 (C, C]CH2),113.0 (CH2, C]CH2), 56.6 (CH), 55.4 (CH), 53.6 (C),
51.0 (CH2), 47.9 (C), 38.5 (CH2), 28.5 (CH2), 24.1 (CH3), 23.7 (CH3),
13.3 (CH3), 10.1 (CH3); (peaks due to the minor isomer):
d 219.3 (C,
C]O), 146.5 (C, C]CH2), 114.7 (CH2, C]CH2), 55.6 (CH), 54.5 (CH),
51.0 (C), 50.3 (CH2), 48.1 (C), 37.1 (CH2), 28.7 (CH2), 22.3 (CH3), 18.2
(CH3), 13.3 (CH3), 9.3 (CH3); HRMS: m/z calcd for C14H22ONa
(MþNa): 229.1568; found: 229.1568. Further elution of the column
with ethyl acetate/hexane (1:19) furnished the unreacted tricyclic
ketone (56 mg, 10%) as oil.
d 148.0 (C, C]CH2), 113.6 (CH2, C]CH2), 91.2 (CH2, OCH2O), 84.8 (C,
CeOMOM), 57.4 (CH), 56.2 (C), 55.0 (CH3, OCH3), 51.8 (CH2), 51.2 (C),
50.8 (CH), 40.4 (CH2), 30.1 (CH2), 25.9 (CH3), 25.2 (CH3), 20.9 (CH3),
15.2 (CH3), 9.3 (CH3); HRMS: m/z calcd for C17H30O2Na (MþNa):
289.2144; found: 289.2144.
3.1.5. 1-[(1S,2R,5S,7S,8R)-7-Methoxymethoxy-1,5,7,8-
tetramethylbicyclo[3.3.0]oct-2-yl]ethanone (17). Dry ozone gas in
oxygen was passed through a cold (ꢁ70 ꢀC) solution of a 1:2 di-
astereomeric mixture of the MOM ether 9 (366 mg, 1.37 mmol) and
a catalytic amount of NaHCO3 in 1:4 MeOH and CH2Cl2 (15 mL) for
4 min (until blue color appeared). Excess ozone was flushed off
with oxygen. Dimethyl sulphide (0.30 mL, 4.11 mmol) was added to
the reaction mixture and stirred for 4 h at rt. Excess Me2S was
evaporated on hot water bath. Water (4 mL) was added to the re-
action mixture and extracted with CH2Cl2 (3ꢃ5 mL). The combined
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 ethyl acetate/hexane (1:19) as an eluent first
3.1.3. (1R,5S,8S)-8-Isopropenyl-1,2,3,5-tetramethylbicyclo[3.3.0]oc-
tan-3-ol (16). To
a magnetically stirred solution of methyl-
magnesium chloride (2.22 mL, 5.55 mmol, 2.5 M in THF) in
anhydrous THF was added a solution of the bicyclic ketone 11
(382 mg, 1.85 mmol) in THF dropwise over a period of 15 min and
stirred for 4 h at room temperature. The reaction was then
quenched with saturated aq NH4Cl solution (6 mL) and extracted
with ether (3ꢃ5 mL). The combined ether extract was washed with
brine (8 mL) and dried (Na2SO4). Evaporation of the solvent and
purification of the residue on a silica gel column using ethyl acetate/
hexane (1:19) as eluent furnished a 2:1 mixture of the di-
astereomeric alcohols 16 (364 mg, 88%) as oil. ½a D23
þ6.6 (c 1.6,
ꢂ
CHCl3); IR (neat): nmax/cmꢁ1 3474 (OH), 3071, 2956, 2874, 1639,
1459, 1376, 1174, 1069, 919, 888 (]CH2); 1H NMR (400 MHz,
furnished the major isomer 17 (198 mg, 54%) as colorless oil. ½a D23
ꢂ
ꢁ9.0 (c 9.3, CHCl3); IR (neat): nmax/cmꢁ1 2933, 2877, 2821, 1711 (C]
CDCl3þCCl4): (peaks due to the major isomer)
d
4.76 (1H, s) and
O), 1463, 1455, 1378, 1360, 1300, 1269, 1211, 1166, 1148, 1095, 1078,
4.65 (1H, s) [C]CH2], 2.32 (1H, t, J 7.0 Hz), 1.88e1.40 (8H, m), 1.70
(3H, s olefinic CH3), 1.19 (3H, s) and 1.06 (3H, s) [2ꢃ tert-CH3], 0.86
(3H, d, J 7.2 Hz, sec-CH3), 0.78 (3H, s, tert-CH3); (important peaks
1038, 920; 1H NMR (400 MHz, CDCl3þCCl4):
4.68 and 4.51 (2H, 2ꢃ
d
d, J 7.0 Hz, OCH2O), 3.31 (3H, s, OCH3), 2.72 (1H, dd, J 6.9 Hz, 3.3 Hz),
2.11 (3H, s, CH3C]O), 1.91 (1H, d, J 14.2 Hz), 1.88e1.42 (5H, m), 1.48
(1H, d, J 14.2 Hz), 1.21 (3H, s) and 1.00 (3H, s) [2ꢃ tert-CH3], 0.95
(3H, d, J 7.1 Hz, sec-CH3), 0.88 (3H, s, tert-CH3); 13C NMR (100 MHz,
due to the minor isomer):
d 4.80 (1H, s) and 4.74 (1H, s) [C]CH2],
3.08 (1H, t, J 8.2 Hz), 1.74 (3H, s, olefinic CH3), 1.18 (3H, s, tert-CH3),
0.98 (3H, d, J 7.2 Hz, sec-CH3), 0.92 (3H, s) and 0.81 (3H, s) [2ꢃ tert-
CH3]; 13C NMR (100 MHz, CDCl3þCCl4): (peaks due to the major
CDCl3þCCl4):
d 211.6 (C, C]O), 91.1 (CH2, OCH2O), 85.7 (C,
CeOMOM), 62.4 (CH), 57.5 (C), 56.9 (CH), 55.1 (CH3, OCH3), 52.4
(CH2), 50.8 (C), 42.6 (CH2), 32.5 (CH3), 26.7 (CH2), 25.2 (CH3), 23.9
(CH3), 15.0 (CH3), 8.3 (CH3); HRMS: m/z calcd for C16H28O3Na
isomer)
d 147.3 (C, C]CH2), 112.4 (CH2, C]CH2), 81.6 (C, CeOH),
59.9 (CH), 57.1 (CH2), 56.7 (C), 56.3 (CH), 51.1 (C), 43.2 (CH2), 29.5

2654
A. Srikrishna et al. / Tetrahedron 68 (2012) 2650e2656
(MþNa): 291.1936; found: 291.1938. Further elution of the silica gel
14.4 (CH3), 8.0 (CH3); HRMS: m/z calcd for C19H30N2O5Na
(MþNa): 389.2052; found: 389.2052.
column with ethyl acetate/hexane (1:19) furnished the minor iso-
mer 17a (107 mg, 29%) as oil. ½a D23
ꢁ107.1 (c 6.3, CHCl3); IR (neat):
ꢂ
nmax/cmꢁ1 2957, 2875, 1705 (C]O), 1451, 1376, 1355, 1205, 1162,
3.1.8. Ethyl [(1S,5R,8S,10S,11R)-10-(methoxymethoxy)-4-oxo-8,10,11-
trimethyltricyclo[6.3.0.01,5]undecane-3-carboxylate (20). To a mag-
netically stirred refluxing suspension of Rh2(OAc)4 (4 mg) in dry
1146, 1092, 1068, 1036, 920; 1H NMR (400 MHz, CDCl3þCCl4):
d 4.70
and 4.54 (2H, 2ꢃ d, J 6.9 Hz, OCH2O), 3.47 (1H, t, J 7.8 Hz), 3.32 (3H,
s, OCH3), 2.11 (3H, s, CH3C]O), 2.01 (1H, d, J 14.5 Hz),1.80e1.38 (5H,
m), 1.34 (1H, d, J 14.5 Hz), 1.20 (3H, s, tert-CH3), 1.06 (3H, d, J 6.9 Hz,
sec-CH3), 0.90 (3H, s) and 0.79 (3H, s) [2ꢃ tert-CH3]; 13C NMR
CH2Cl2 (10 mL) was added a solution of the a-diazo-b-keto ester 19
(280 mg, 0.11 mmol) in dry CH2Cl2 (60 mL) over a period of 30 min
and refluxed for 1.5 h. Evaporation of the solvent and purification of
the residue on a silica gel column using ethyl acetate/hexane (1:19)
as eluent furnished an epimeric mixture of the triquinane ester 20
(218 mg, 84%) as an oil, which was found to exist as a mixture of
(100 MHz, CDCl3þCCl4):
d 212.1 (C, C]O), 91.2 (CH2, OCH2O), 84.8
(C, CeOMOM), 57.5 (C), 56.1 (CH), 56.0 (CH), 55.1 (CH3, OCH3), 51.9
(C), 51.8 (CH2), 40.3 (CH2), 32.0 (CH3, CH3C]O), 27.9 (CH2), 25.4
(CH3), 25.3 (CH3), 19.8 (CH3), 9.7 (CH3); HRMS: m/z calcd for
C16H28O3Na (MþNa): 291.1936; found: 291.1934.
keto and enol forms. ½a D24
ꢂ
ꢁ2.4 (c 4.9, CHCl3); IR (neat): nmax/cmꢁ1
2936, 2876, 1782, 1751, 1728, 1660, 1622, 1465, 1455, 1409, 1372,
1339, 1305, 1253, 1229, 1148, 1090, 1041, 920; 1H NMR (400 MHz,
3.1.6. Ethyl 3-[(1S,2R,5S,7S,8R)-7-(methoxymethoxy)-1,5,7,8-
tetramethylbicyclo[3.3.0]oct-2-yl]-3-oxopropanoate (18). To a cold
(ꢁ70 ꢀC) magnetically stirred solution of hexamethyldisilazane
(0.46 mL, 2.2 mmol) in anhydrous THF (2 mL) was added a solution
of n-butyllithium in hexane (2.4 M, 0.69 mL, 1.65 mmol) dropwise
over a period of 5 min and the reaction mixture stirred for 15 min at
ꢁ70 ꢀC. To the LHMDS thus formed was added a solution of the
ketone 17 (147 mg, 0.55 mmol) in dry THF (2 mL) dropwise and
stirred at the same temperature for 40 min. Ethyl chloroformate
(0.06 mL, 0.66 mmol) was added in one portion and the reaction
mixture was stirred for 4 h at rt. Water (4 mL) was then added to
the reaction mixture and extracted with ether (3ꢃ5 mL). The ether
extract was washed with brine (6 mL) and dried (Na2SO4). Evapo-
ration of the solvent and purification of the residue on a silica gel
column using ethyl acetate/hexane (1:19) as eluent furnished the
CDCl3þCCl4): (peaks due to the major isomer)
d 4.72 and 4.50 (2H,
2ꢃ d, J 6.9 Hz, OCH2O), 4.24e4.05 (2H, m), 3.31 (3H, s, OCH3), 3.08
(1H, dd, J 11.7 and 8.8 Hz), 2.50e2.10 (3H, m), 2.10e1.40 (6H, m),
1.37 (1H, d, J 14.0 Hz), 1.27 (3H, t, J 7.5 Hz, OCH2CH3), 1.21 (3H, s) and
1.09 (3H, s) [2ꢃ tert-CH3], 1.00 (3H, d, J 6.4 Hz, sec-CH3); 13C NMR
(100 MHz, CDCl3þCCl4): (peaks due to the major isomer)
d 214.8 (C,
C]O), 169.5 (C, OC]O), 91.1 (CH2, OCH2O), 85.2 (C, CeOMOM), 61.1
(CH2, OCH2), 60.3 (CH), 56.3 (CH), 55.1 (CH3, OCH3), 54.4 (CH), 51.6
(CH2), 50.4 (C), 42.7 (CH2), 29.0 (CH2), 26.6 (CH3), 26.0 (CH2), 21.9
(CH3), 14.2 (CH3), 9.2 (CH3); HRMS: m/z calcd for C19H30O5Na
(MþNa): 361.1991; found: 361.1991.
3.1.9. (1S,5R,8S,10S,11R)-10-(Methoxymethoxy)-8,10,11-
trimethyltricyclo[6.3.0.01,5]undecan-4-one (21). To
a magnetically
stirred solution of the keto ester 20 (215 mg, 0.64 mmol) in methanol
(2 mL) was added 10% aqueous NaOH (2 mL) and refluxed for 4 h. The
reaction mixture was cooled to rt, water (3 mL) was added and
extracted with ether (3ꢃ5 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 (1:19) as eluent furnished the ketone 21 (118 mg, 70%) as
keto ester 18 (168 mg, 90%) as colorless oil. ½a D23
ꢁ18.6 (c 2.8,
ꢂ
CHCl3); IR (neat): nmax/cmꢁ1 2955, 2966, 2877, 1747 (OC]O), 1713
(C]O), 1642, 1624, 1465, 1426, 1378, 1303, 1244, 1149, 1095, 1079,
1038, 920; 1H NMR (400 MHz, CDCl3þCCl4): (peaks due to the
ketoform)
d
4.69 and 4.52 (2H, 2ꢃ d, J 6.6 Hz, OCH2O), 4.18 (2H, q, J
7.1 Hz, OCH2CH3), 3.39 (2H, s), 3.32 (3H, s, OCH3), 2.86e2.75 (1H,
m), 2.00e1.40 (7H, m),1.28 (3H, t, J 6.9 Hz),1.21 (3H, s) and 1.03 (3H,
s) [2ꢃ tert-CH3], 0.96 (3H, d, J 7.0 Hz, sec-CH3), 0.92 (3H, s, tert-CH3);
13C NMR (100 MHz, CDCl3þCCl4): (peaks due to the ketoform)
colorless oil. ½a D23
ꢂ
ꢁ54.6 (c 2.4, CHCl3); IR (neat): nmax/cmꢁ1 2955,
2877, 1739 (C]O),1464,1455,1409,1373,1273,1166,1149,1097,1079,
1041, 920; 1H NMR (400 MHz, CDCl3þCCl4):
4.74 and 4.52 (2H, 2ꢃ d,
d
d
205.4 (C, C]O), 167.0 (C, OC]O), 91.1 (CH2, OCH2O), 85.6 (C,
J 6.9 Hz, OCH2O), 3.33 (3H, s, OCH3), 2.40e2.25 (1H, m), 2.15e1.90
(5H, m), 1.88 (1H, d, J 14.0 Hz), 1.76e1.50 (3H, m), 1.38 (1H, d, J
14.0 Hz),1.22 (3H, s, tert-CH3),1.26e1.06 (1H, m),1.10 (3H, s, tert-CH3),
0.96 (3H, d, J 7.1 Hz, sec-CH3); 13C NMR (100 MHz, CDCl3þCCl4):
CeOMOM), 61.7 (CH), 61.1 (CH2, OCH2), 57.9 (C), 56.6 (CH), 55.1
(CH3, OCH3), 52.4 (CH2), 51.4 (CH2), 50.6 (C), 42.5 (CH2), 26.8 (CH2),
25.2 (CH3), 23.7 (CH3), 15.1 (CH3), 14.2 (CH3), 8.4 (CH3); HRMS: m/z
calcd for C19H32O5Na (MþNa): 363.2147; found: 363.2145.
d
222.9 (C, C]O), 91.2 (CH2, OCH2O), 85.4 (C, CeOMOM), 62.0 (C),
60.3 (CH), 55.1 (CH3, OCH3), 54.5 (CH), 51.5 (CH2), 50.5 (C), 42.9 (CH2),
39.6 (CH2), 26.5 (CH3), 25.8 (CH2), 24.1 (CH2), 22.2 (CH3), 9.3 (CH3);
HRMS: m/z calcd for C16H26O3Na (MþNa): 289.1780; found: 289.1779.
3.1.7. Ethyl 2-diazo-3-[(1S,2R,5S,7S,8R)-7-(methoxymethoxy)-1,5,7,8-
tetramethylbicyclo[3.3.0]oct-2-yl]-3-oxopropanoate (19). To a mag-
netically stirred solution of the
b-keto ester 18 (168 mg,
0.49 mmol) in acetonitrile (2 mL) were added tosyl azide
(106 mg, 0.54 mmol) and triethylamine (0.2 mL, 1.47 mmol) and
stirred at rt for 6 h. Solvent was evaporated under reduced
pressure and the residue was purified on a silica gel column using
3.1.10. (1R,2R,3S,5S,8S)-9-Methylene-2,3,5-trimethyltricyclo
[6.3.0.01,5]undec-3-yl methoxymethyl ether (22). To a freshly pre-
t
pared AmOK [from potassium (172 mg, 4.4 mmol) and tAmOH
t
(8 mL) followed by evaporation of AmOH under vacuum] in dry
ethyl acetate/hexane (1:19) as an eluent to furnish the
a
-diazo-
benzene (6 mL) was added methyltriphenylphosphonium bromide
(1.78 g, 5 mmol) and the resulting yellow solution was stirred for
1 h at rt. The solution was allowed to settle for 30 min. The dark
yellow solution of methylenetriphenylphosphorane was added to
b
-keto ester 19 (162 mg, 90%) as colorless oil. ½a D23
ꢁ22.7 (c 5.3,
ꢂ
CHCl3); IR (neat): nmax/cmꢁ1 2937, 2880, 2135 (N]N), 1716 (OC]
O), 1650 (C]O), 1458, 1378, 1299, 1203, 1148, 1081, 1039, 920, 898,
756; 1H NMR (400 MHz, CDCl3þCCl4):
d
4.68 and 4.49 (2H, 2ꢃ d, J
a magnetically stirred solution of the ketone 21 (118 mg,
6.9 Hz, OCH2O), 4.26 (2H, q, J 7.1 Hz, eOCH2CH3), 3.85 (1H, dd,
J 5.3 and 4.0 Hz), 3.30 (3H, s, OCH3), 2.02e1.86 (1H, m), 1.92 (1H,
d, J 14.1 Hz), 1.86e1.68 (2H, m), 1.60e1.50 (2H, m), 1.44 (1H, d, J
14.1 Hz), 1.31 (3H, t, J 7.1 Hz, OCH2CH3), 1.19 (3H, s) and 1.03 (3H,
s) [2ꢃ tert-CH3], 0.97 (3H, d, J 7.1 Hz, sec-CH3), 0.88 (3H, s, tert-
0.44 mmol) in dry benzene (1 mL) at rt and stirred for 6 h. Water
(3 mL) was added to the reaction mixture and extracted with ether
(3ꢃ5 mL). The combined ether extract was washed with brine
(8 mL) and dried (Na2SO4). Evaporation of the solvent and purifi-
cation of the residue on a silica gel column using CH2Cl2/hexane
CH3); 13C NMR (100 MHz, CDCl3þCCl4):
d
196.0 (C, C]O), 161.2 (C,
(1:9) as an eluent furnished the alkene 22 (94 mg, 80%) as oil. ½a D23
ꢂ
OC]O), 91.1 (CH2, OCH2O), 85.7 (C, CeOMOM), 76.6 (C), 61.1 (CH2,
OCH2), 58.8 (C), 56.7 (CH), 56.5 (CH), 55.0 (CH3, OCH3), 52.8 (CH2),
50.3 (C), 43.6 (CH2), 27.3 (CH2), 25.6 (CH3), 23.3 (CH3), 15.4 (CH3),
ꢁ25.8 (c 1.9, CHCl3); IR (neat): nmax/cmꢁ1 3068, 2980, 2934, 2876,
1654, 1459, 1452, 1370, 1150, 1123, 1098, 1085, 1044, 921, 876;
1H NMR (400 MHz, CDCl3þCCl4):
d 4.82 (1H, s) and 4.74 (1H, s)

A. Srikrishna et al. / Tetrahedron 68 (2012) 2650e2656
2655
[C]CH2], 4.73 and 4.50 (2H, 2ꢃ d, J 6.9 Hz, OCH2O), 3.33 (3H, s,
OCH3), 2.42e2.18 (3H, m), 1.85e1.33 (9H, m), 1.20 (3H, s) and 1.05
(3H, s) [2ꢃ tert-CH3], 0.89 (3H, d, J 7.2 Hz, sec-CH3); 13C NMR
and 1.10 (3H, s) [2ꢃ tert-CH3], 0.92 (3H, d, J 6.2 Hz), 0.88 (3H, d, J
7.2 Hz, sec-CH3); 13C NMR (100 MHz, CDCl3):
81.1 (C, CeOH),
d
65.9 (C), 63.1 (CH), 55.7 (CH2), 53.9 (CH), 50.2 (C), 42.7 (CH2),
38.4 (CH), 37.1 (CH2), 27.8 (CH3), 27.5 (CH2), 27.0 (CH2), 26.3
(CH3), 19.7 (CH3), 8.3 (CH3). Selected peaks due to 9-
(100 MHz, CDCl3þCCl4):
d 157.2 (C, C]CH2), 104.5 (CH2, C]CH2),
91.1 (CH2, OCH2O), 85.6 (C, CeOMOM), 65.2 (C), 57.2 (CH), 55.0
(CH3, OCH3), 54.8 (CH), 51.5 (CH2), 50.1 (C), 42.5 (CH2), 34.9 (CH2),
29.9 (CH2), 28.3 (CH2), 26.0 (CH3), 22.3 (CH3), 9.3 (CH3); HRMS: m/z
calcd for C17H28O2Na (MþNa): 287.1987; found: 287.1987.
episilphiperfolan-6-ol 3a: 1H NMR (400 MHz, CDCl3):
d 0.99
(1H, q, J 8.1 Hz), 1.15 (3H, s, tert-CH3), 1.07 (3H, s, tert-CH3), 0.89
(3H, d, J 6.8 Hz) and 0.85 (3H, d, J 7.1 Hz) [2ꢃ sec-CH3]; 13C NMR
(100 MHz, CDCl3):
d 82.5 (C, CeOH), 66.1 (C), 57.6 (CH), 56.8
3.1.11. (1R,2R,3S,5S,8S)-2,3,5,9-Tetramethyltricyclo[6.3.0.01,5]undec-
3-yl methoxymethyl ether (23,23a). To a solution of the tricyclic
alkene 22 (92 mg, 0.35 mmol) in dry ethyl acetate (1 mL) was added
activated 10% Pd/C (10 mg). The reaction mixture was stirred for 5 h
at room temperature in an atmosphere of hydrogen, created by
evacuative replacement of air (balloon) and then the catalyst was
filtered on a small silica gel column. Evaporation of the solvent
furnished a 1:1 epimeric mixture of the triquinane MOM ether 23
(CH2), 54.0 (CH), 51.2 (C), 44.5 (CH2), 36.4 (CH), 35.5 (CH2), 28.0
(CH2), 27.8 (CH3), 26.8 (CH2), 24.6 (CH3), 15.0 (CH3), 8.4 (CH3); 1H
NMR (400 MHz, C6D6):
CH3), 1.04 (3H, d, J 6.3 Hz), 0.87 (3H, d, J 7.1 Hz); 13C NMR
(100 MHz, C6D6): 81.8 (C, CeOH), 66.6 (C), 57.7 (CH), 57.2 (CH2),
d 1.21 (3H, s, tert-CH3), 1.07 (3H, s, tert-
d
54.3 (CH), 51.5 (C), 44.8 (CH2), 36.9 (CH), 35.9 (CH2), 28.6 (CH3),
27.8 (CH2), 26.6 (CH3), 24.9 (CH3), 15.3 (CH3), 8.7 (CH3).
and 23a (90 mg, 98%) as oil. ½a D24
ꢂ
þ34.7 (c 3.5, CHCl3); IR (neat):
3.2. Kinetic purification of silphiperfolan-6-ol 3
nmax/cmꢁ1 2952, 2934, 2873,1463,1456,1151,1094,1080,1043, 921;
1H NMR (400 MHz, CDCl3þCCl4): (selected peaks due to one iso-
To a magnetically stirred solution of an epimeric mixture of
silphiperfolan-6-ol 3 and 3a (11 mg, 0.05 mmol) in THF (0.5 mL)
was added 3 N HCl (0.5 mL) and stirred for 10 h. The reaction
mixture was diluted with water (2 mL) and extracted with ether
(3ꢃ2 mL). The combined organic extract was washed with aq
NaHCO3 (3 mL) and brine (6 mL), and dried (Na2SO4). Evaporation
of the solvent and purification of the residue on a silica gel column
mer)
d
4.70 and 4.49 (2H, 2ꢃ d, J 6.9 Hz, OCH2O), 3.33 (3H, s, OCH3),
1.17 (3H, s) and 1.02 (3H, s) [2ꢃ tert-CH3], 0.92 (3H, d, J 6.7 Hz) and
0.91 (3H, d, J 6.0 Hz) [2ꢃ sec-CH3]; (selected signals due to the
second isomer):
d
4.68 and 4.53 (2H, 2ꢃ d, J 6.9 Hz, OCH2O), 3.32
(3H, s, OCH3),1.19 (3H, s) and 1.03 (3H, s) [2ꢃ tert-CH3], 0.89 (3H, d, J
6.6 Hz) and 0.88 (3H, d, J 6.8 Hz) [2ꢃ sec-CH3]; 13C NMR (100 MHz,
CDCl3þCCl4): (1:1 mixture of epimers)
d
91.1 and 91.0 (CH2,
using hexane as eluent first furnished a mixture of 9-
OCH2O), 87.1 and 85.7 (C, CeOMOM), 66.4 and 66.0 (C), 63.0 and
57.5 (CH), 55.9 (CH), 55.1 and 54.9 (CH3, OCH3), 52.2 and 51.3 (CH2),
50.1 (C), 44.7 and 42.7 (CH2), 38.5 and 36.5 (CH), 37.1 and 35.5
(CH2), 28.1 and 27.6 (CH2), 27.7 and 24.5 (CH3), 26.9 and 26.7 (CH2),
22.8 and 22.6 (CH3), 19.8 and 15.2 (CH3), 8.5 and 8.4 (CH3); HRMS:
m/z calcd for C17H30O2Na (MþNa): 289.2144; found: 289.2147.
episilphiperfol-6-ene 2a and silphiperfol-6-ene 2 (6 mg, 60%) as
a colorless oil. Further elution of the column using CH2Cl2/hexane
(1:9) as an eluent furnished the unreacted pure silphiperfolan-6-ol
3 (2 mg, 18%) as oil. ½a D24
ꢂ
ꢁ5.1 (c 0.18, CHCl3); 1H NMR (400 MHz,
C6D6):
d 1.92e1.79 (2H, m), 1.79e1.48 (7H, m), 1.48e1.32 (4H, m),
1.28 (3H, s, tert-CH3), 1.32e1.10 (1H, m), 1.05 (3H, s, tert-CH3), 1.03
(3H, d, J 6.0 Hz), 0.90 (3H, d, J 7.1 Hz); 13C NMR (100 MHz, C6D6):
3.1.12. (1R,2R,3S,5S,8S,9R)-2,3,5,9-Tetramethyltricyclo[6.3.0.01,5]un-
decan-3-ol (3,3a). To a magnetically stirred solution of the tri-
quinane MOM ether 23 and 23a (90 mg, 0.34 mmol) in THF
(1 mL) was added 3 N HCl (1 mL) and stirred for 12 h. The re-
action mixture was diluted with water (2 mL) and extracted with
ether (3ꢃ5 mL). The combined organic extract was washed with
aq NaHCO3 (3 mL) and brine (6 mL), and dried (Na2SO4). Evap-
oration of the solvent and purification of the residue on a silica
gel column using hexane as eluent first furnished a 3:1 mixture
of episilphiperfol-6-ene 2a and silphiperfol-6-ene 2 (30 mg, 45%)
d 80.2 (C, CeOH), 66.1 (C), 63.2 (CH), 55.9 (CH2), 54.1 (CH), 50.3 (C),
42.7 (CH2), 38.6 (CH), 37.3 (CH2), 27.8 (CH3), 27.2 (CH2), 27.0 (CH2),
26.3 (CH3), 19.8 (CH3), 8.4 (CH3).
Acknowledgements
We thank the Department of Science and Technology, New Delhi
for financial support, and the CSIR, New Delhi for the award of
a research fellowship to GN.
as a colorless oil. ½a D24
ꢂ
ꢁ75.0 (c 3.0, CHCl3); 1H NMR (400 MHz,
References and notes
CDCl3): (selected peaks due to episilphiperfol-6-ene 2a)
d 2.06
1. (a) Mehta, G.; Srikrishna, A. Chem. Rev. 1997, 97, 671; (b) Singh, V.; Thomas, B.
Tetrahedron 1998, 54, 3647.
2. Bohlmann, F.; Jakupovic, J. Phytochemistry 1980, 19, 259.
3. The atom numbering reported2 for silphiperfolanes, which is different from
IUPAC numbering and is being followed generally, is given below.
(2H, br s), 1.52 (3H, s, olefinic CH3), 1.49 (3H, s, olefinic CH3), 0.98
(3H, s, tert-CH3), 0.93 (3H, d, J 6.8 Hz, sec-CH3); (selected peaks
due to silphiperfol-6-ene 2):
d 2.19 (1H, d, J 16.2 Hz), 2.04e1.98
(1H, m), 1.76e1.66 (1H, m), 1.66e1.16 (8H, m), 1.52 (3H, s, olefinic
CH3), 1.49 (3H, s, olefinic CH3), 1.10e1.00 (1H, m), 0.99 (3H, s, tert-
CH3), 0.95 (3H, d, J 6.9 Hz, sec-CH3); 13C NMR (100 MHz, CDCl3):
12
5
3
5
3
7
4
8
6
2
13
(peaks due to 9-episilphiperfol-6-ene 2a):
d
136.5 (C) and 126.4
1
7
1
11
1,5
9
(C) [C]C], 71.6 (C), 53.2 (CH), 52.0 (CH2), 49.6 (C), 42.3 (CH2),
37.7 (CH), 34.7 (CH2), 30.5 (CH2), 25.9 (CH2), 22.5 (CH3), 15.2
(CH3), 14.3 (CH3), 10.1 (CH3); (peaks due to silphiperfol-6-ene 2):
11
10
14
9
15
1
Silphiperfolane
tricyclo[6.3.0.0 ]undecane
d
136.1 (C) and 127.4 (C) [C]C], 72.0 (C), 59.2 (CH), 52.3 (CH2),
49.6 (C), 41.3 (CH), 40.2 (CH2), 36.7 (CH2), 29.9 (CH2), 29.0 (CH2),
24.8 (CH3), 19.6 (CH3), 14.2 (CH3), 10.9 (CH3). Further elution of
the silica gel column using CH2Cl2/hexane (1:9) as an eluent
furnished the unreacted MOM ether 23 and 23a (10 mg) as oil.
Further elution of the column with the same solvent furnished
a 2:1 mixture of silphiperfolan-6-ol 3 and 3a (33 mg, 49%) as oil.
IR (neat): nmax/cmꢁ1 3488 (OH), 2951, 2871, 1605, 1457, 1374,
1286, 1167, 1119, 1020, 917, 859. Peaks due to silphiperfolan-6-ol
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Org. Lett. 2000, 2, 2711; (b) Kakiuchi, K.; Ue, U.; Tsukahara, H.; Shimizu, T.;
Miyao, T.; Tobe, Y.; Odaira, Y.; Yasuda, M.; Shima, K. J. Am. Chem. Soc. 1989, 111,
3707; (c) Curran, D. P.; Kuo, S. C. Tetrahedron 1987, 43, 5653; (d) Wender, P. A.;
Singh, S. K. Tetrahedron Lett. 1985, 26, 5987 In enantioselective manner: (e) Sha,
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B. B. J. Org. Chem. 1994, 59, 5419; (g) Dickson, J. K., Jr.; Fraser-Reid, B. J. Chem.
3: 1H NMR (400 MHz, CDCl3):
d 1.90e1.20 (14H, m), 1.16 (3H, s)

2656
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