The substrate dependent competitive formation of cyclobutanones and cyclopentanones in an intramolecular rhodium carbenoid CH insertion reaction: Enantiospecific total synthesis of silphiperfol-6-ene

Article abstract of DOI:10.1016/j.tetasy.2012.01.016

The enantiospecific total synthesis of silphiperfol-6-ene has been accomplished starting from the readily available monoterpene (R)-limonene, employing a rhodium carbenoid insertion into the CH bond of a tertiary methyl group. A substrate dependent competitive insertion of the rhodium carbenoid in the γ- and β-CH bonds to form cyclopentanone and cyclobutanones, respectively, has been described.

Full text of DOI:10.1016/j.tetasy.2012.01.016

Tetrahedron: Asymmetry 23 (2012) 170–175
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The substrate dependent competitive formation of cyclobutanones and
cyclopentanones in an intramolecular rhodium carbenoid CH insertion
reaction: enantiospecific total synthesis of silphiperfol-6-ene
⇑
Adusumilli Srikrishna , Gopalasetty Nagaraju
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 silphiperfol-6-ene has been accomplished starting from the readily
available monoterpene (R)-limonene, employing a rhodium carbenoid insertion into the CH bond of a ter-
tiary methyl group. A substrate dependent competitive insertion of the rhodium carbenoid in the c- and
b-CH bonds to form cyclopentanone and cyclobutanones, respectively, has been described.
Received 22 December 2011
Accepted 25 January 2012
Available online 16 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
as a chiral pool starting material,6 we have explored the synthesis
of silphiperfol-6-ene 3 by employing an intramolecular rhodium
carbenoid insertion into a tertiary methyl group as the key step,
where we observed the competitive formation of cyclobutanones
and cyclopentanones.
The majority of triquinane sesquiterpene natural products con-
tain either a cis,anti,cis-linear triquinane 1 or an angular triquinane
2 framework.1 Sesquiterpenes containing an angular triquinane 2
moiety fall into five different skeletal types (isocomane, pentalen-
ane, silphinane, silphiperfolane and cameroonane) on the basis of
the arrangement of the four one carbon substituents on the tricy-
clo[6.3.0.01,5]undecane 2 system. Among the natural angular triqu-
inane sesquiterpenes, silphiperfolanes have been found to be
abundant. The first member silphiperfol-6-ene 3 was isolated in
1980 by Bohlmann et al. from the root extract of Silphium perfolia-
tum.2 Since then, a number of silphiperfolanes with varying func-
tionalities have been isolated from a variety of natural sources,
both terrestrial and marine. Several of the siliphiperfolanes, in par-
ticular those containing an acid functionality, have been found to ex-
hibit interesting biological properties, such as cardiotoxic activity.3
2. Results and discussion
Recently,6l we have reported a highly regioselective intramolec-
ular rhodium carbenoid insertion7 into the CH bond of a tertiary
methyl group at the ring junction of a diquinane, for the conversion
of diazoketone 4 into the angular triquinane 5 (Eq. 1). On the basis
of this, we thought that siliphiperfol-6-ene 3 (Scheme 1) could be
synthesized via an intramolecular rhodium carbenoid CH insertion
reaction of diazo ketone 6. The diazo ester 6 could be obtained
from diquinane 7 containing two methyl groups on the cyclopen-
tane in addition to two tertiary methyl groups at the ring junction
positions. It was conceived that diquinane 7 could be obtained
from acid 8 via ketone 9. The synthesis of acid 8 from limonene
10 via allyl alcohol 11 has already been developed.6c
H
5
3
H
H
1
9
8
H
H
O
O
H
H
O
O
Rh2(OAc)4
1
2
3
H
ð1Þ
87%
O
N2
O
COOEt
From a synthetic point of view, a variety of strategies have been
explored for the synthesis of silphiperfol-6-ene 3, both in racemic4
and enantiopure5 forms. In a continuation of our interest in the
enantiospecific synthesis of natural products using (R)-limonene
EtOOC
5
4
The synthetic sequence is depicted in Schemes 2 and 3. The
synthesis of acid 8 was carried out by employing a previously re-
ported method.6c,k The requisite allyl alcohol 11 was obtained from
(R)-limonene 10 in three steps, which entailed controlled ozonoly-
sis, intramolecular aldol condensation and Luche reduction.6a
⇑
Corresponding author. Fax: +91 80 23600529.
E-mail address: askiisc@gmail.com (A. Srikrishna).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.01.016

A. Srikrishna, G. Nagaraju / Tetrahedron: Asymmetry 23 (2012) 170–175
171
3
H
H
H
O
O
N2
7
9
ROOC
6
COOH
O
OH
H
10
11
8
Scheme 1.
O
ref. 6c
OH
OH
8
11
a
71%
10
O
O
O
b
c
N2
76%
86%
(2:1)
88%
9
13
12
d
OH
OH
f
e
85%
74%
O
O
14
15
16
g
90%
h
93%
O
O
N2
EtOOC
EtOOC
17
18
Scheme 2. Reagents and conditions: (a) (i) (COCl)2, C6H6, rt, 3 h, (ii) CH3CHN2, Et2O, 0 °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, THF, rt, 4 h; (e) O3/O2, CH2Cl2–MeOH (4:1), ꢀ70 °C; Me2S, rt, 4 h; (f) PTSA, CH2Cl2, rt, 4 h; (g) LiHMDS, THF, ꢀ70 °C; ClCO2Et, rt, 4 h; (h) TsN3, Et3N,
CH3CN, rt, 4 h.
Johnson’s orthoester Claisen rearrangement8 of cyclopentenyl-
methanol 11 with triethyl orthoacetate in the presence of a cata-
lytic amount of propionic acid, followed by base catalyzed
hydrolysis of the resultant ester furnished the acid 8. It was readily
identified that for the generation of diquinane 9 with a secondary
methyl group, it would be more appropriate to employ an intramo-
lecular cyclopropanation of the diazo ketone 12 derived from dia-
zoethane, followed by regiospecific cyclopropane ring cleavage.
Thus, treatment of acid 8 with oxalyl chloride followed by reaction
of the resultant acid chloride with an excess of ethereal diazoe-
thane gave diazo ketone 12 in a 71% yield. The anhydrous copper
sulfate-copper catalyzed intramolecular diazo ketone cyclopropa-
nation9 of diazo ketone 12 in refluxing cyclohexane generated
the tricyclic ketone 13 in a regio- and stereospecific manner in a
76% yield. Regiospecific cyclopropane ring cleavage10 of tricyclic
ketone 13 with lithium in liquid ammonia furnished a 2:1 epimeric
mixture of diquinane 9 in an 86% yield. As the mixture was found
to be inseparable and since it had no consequence in this sequence,
it was progressed further. The reaction of diquinane 9 with excess
methylmagnesium chloride generated a 2:1 diastereomeric mix-
ture of alcohol 14. In order to avoid regiochemical problems in
the ozonolysis of the isopropenyl group in 7, we thought that the
dehydration of the tertiary alcohol could be carried out after the
oxidation of the isopropenyl group. Thus, ozonolytic cleavage of
the olefin of the isopropenyl group in 14 followed by reductive
work-up with dimethyl sulfide furnished a 2:1 mixture of hydroxy

172
A. Srikrishna, G. Nagaraju / Tetrahedron: Asymmetry 23 (2012) 170–175
H
EtOOC
a
H
+
86%
H
H
O
O
O
O
N2
18
COOEt
EtOOC
19
20
b
83%
H
+
H
( 5 : 3 )
O
21
22
d
c
H
H
H
>95%
H
88%
+
O
( 3 : 2 )
3
3a
21
23
Scheme 3. Reagents and conditions: (a) Rh2(OAc)4, CH2Cl2, reflux, 1.5 h; (b) LiCl, DMSO, H2O, 140 °C, 3 h; (c) tAmOK, Ph3P+CH3Brꢀ, C6H6, rt, 6 h; (d) H2 (1 atm), 10% Pd/C,
EtOAc, rt, 1.5 h.
ketones 15 in an 85% yield. Treatment of hydroxy ketone 15 with a
catalytic amount of 4-toluenesulfonic acid in methylene chloride at
room temperature led to dehydration to furnish olefin 16. For effi-
cient generation of the diazo ketone, the acetyl group in 16 was
transformed into a b-keto ester by reacting with lithium hexam-
ethyldisilazide (LHMDS) and ethyl chloroformate to furnish b-keto
ester 17 in a 90% yield. A diazo transfer reaction was carried out on
b-keto ester 17 with p-toluenesulfonyl azide and triethylamine to
in the diquinane, which reduced the flexibility of the ring system,
and the distance between the rhodium carbenoid and the tertiary
methyl group, which might have slightly increased, thus making
an alternate pathway competitive.
The angular triquinane 21 was further elaborated into siliphi-
perfol-6-ene 3. Wittig reaction of ketone 21 with excess methyltri-
phenylphosphonium bromide and potassium tert-amyloxide in dry
benzene furnished silphiperfol-6,9(15)-diene 23 in an 88% yield,
whose structure was established from its spectroscopic data. Reg-
ioselective hydrogenation of the exomethylene in 23 in ethyl ace-
tate employing 10% palladium over carbon as the catalyst
furnished a 3:2 mixture of silphiperfol-6-ene 3 and its C-9 epimer
3a in quantitative yield, whose structures were confirmed by com-
paring the 1H and 13C NMR spectra with those reported in the
literature.4,5
furnish the precursor for the key reaction, the a-diazo-b-keto ester
18 in a 93% yield.
Treatment of a-diazo-b-keto ester 18 with a catalytic amount of
rhodium acetate in refluxing methylene chloride for 1.5 h fur-
nished a mixture of regioisomeric tricyclic keto esters 19 and 20
via insertion of the intermediate rhodium carbenoid into the
c- and b-CH bonds (those of tertiary methyl group and the C-3
methylene of the diquinane), respectively. In order to resolve the
mixture of 19 and 20, Krapcho’s dealkoxycarbonylation reaction
was carried out with lithium chloride in aqueous dimethyl sulfox-
ide to furnish a 5:3 mixture of tricyclic ketones 21 and 22, which
were separated by column chromatography on silica gel. The struc-
tures of tricyclic ketones 21 and 22 were established from their
spectroscopic data, in particular IR, 1H and 13C NMR spectroscopy.
For example, the presence of a carbonyl absorption band at
1775 cmꢀ1 revealed the presence of a cyclobutanone in the minor
tricyclic ketone 22. The presence of two singlets at d 1.07 and
0.97 ppm due to the two tertiary methyl groups in the 1H NMR
and the presence of two methines and three methylenes in the
13C NMR spectrum in addition to other relevant signals confirmed
the structure of the minor ketone 22. In a similar manner, the pres-
ence of a typical cyclopentanone carbonyl absorption band at
1736 cmꢀ1 in the IR spectrum, the presence of a singlet at
1.07 ppm due to one tertiary methyl group, and the presence of
one methine and five methylenes in the 13C NMR spectrum con-
firmed the structure of norsiliphiperfolenone 21. Although the for-
mation of cyclobutanones via intramolecular rhodium carbenoid
CH insertion is not that uncommon,11 it is surprising to note the
formation of cyclobutanone via competitive intramolecular inser-
tion of the rhodium carbenoid in the CH bond of the b-carbon,
which is in contrast to the exclusive insertion in the CH bond of
tertiary methyl group in the diazo ketone 4 (Eq. 1), indicating that
slight perturbations can alter the course of the reaction. This might
be due to the presence of an olefin in one of the cyclopentane rings
3. Conclusions
In conclusion, we have accomplished an enantiospecific total
synthesis of silphiperfol-6-ene 3 starting from acid 8 [readily avail-
able from the monoterpene (R)-limonene 10]. The key reaction is
the insertion of a rhodium carbenoid into the C–H bond of a ter-
tiary methyl group at the ring junction position of the diquinane
for the generation of the angular triquinane system. Herein, silph-
iperfol-6-ene 3 and its C-9 epimer 3a were obtained from the acid
8 in 12 steps and with an overall yield of ꢁ2.6. We also observed
the substrate dependent intramolecular insertion of the rhodium
carbenoid in the
and cyclobutanones in a competitive manner.
c- and b-CH bonds to generate cyclopentanone
4. Experimental
4.1. General
IR spectra were recorded on a Jasco FTIR 410 and Perkin Elmer
FTIR spectrum BX and GX spectrophotometers. 1H (400 MHz) and
13C (100 MHz) NMR spectra were recorded on a Brucker Avance
400 spectrometer. The chemical shifts (d ppm) and coupling con-
stants (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 spectra, the nature

A. Srikrishna, G. Nagaraju / Tetrahedron: Asymmetry 23 (2012) 170–175
173
of the carbons (C, CH, CH2, or CH3) was determined by recording
the DEPT-135 spectra, and is given in parentheses. High resolution
mass spectra were recorded on a Micromass Q-TOF micro mass
spectrometer using electron spray ionization mode. Optical rota-
tions were measured using a Jasco DIP-370 and Jasco P-1020 pola-
(3 ꢂ 5 mL). The combined ether extract was washed with brine
(8 mL) and dried (Na2SO4). Evaporation of the solvent and purifica-
tion of the residue on a silica gel column using ethyl acetate–hex-
ane (1:19) as eluent furnished a 2:1 epimeric mixture of bicyclic
ketone 9 (401 mg, 75%) as oil. ½a D24
¼ þ29:0 (c 8.7, CHCl3); IR
ꢃ
rimeters and [
a]
values are given in units of 10ꢀ1 deg cm2 gꢀ1
.
(neat): m
max/cmꢀ1 3077, 2969, 2875, 1740 (C@O), 1641, 1452,
D
Analytical thin-layer chromatography (TLC) was performed on
glass plates (7.5 ꢂ 2.5 and 7.5 ꢂ 5.0 cm) coated with Acme’s silica
gel G containing 13% calcium sulfate as binder and various combi-
nations of ethyl acetate–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 column chromatography.
1411, 1380, 1182, 890 (C@CH2); 1H NMR (400 MHz, CDCl3 + CCl4):
(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), 2.02–1.66 (5 H, 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 peaks due to the minor isomer): 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, CDCl3 + CCl4): (peaks due to the major isomer) d 220.0
(C, C@O), 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): 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 (M+Na): 229.1568; Found: 229.1568. Fur-
ther elution of the column with ethyl acetate–hexane (1:19) fur-
nished the unreacted tricyclic ketone 13 (56 mg, 10%).
4.2. (1S,3R,6S,9S)-9-Isopropenyl-3,6-dimethyltricyclo[4.3.0.01,3]-
nonan-4-one 13
To a magnetically stirred solution of acid6c 8 (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 ether solu-
tion of diazoethane [excess prepared from N-nitroso-N-ethylurea
(8 g, 68.6 mmol), 60% KOH solution (50 mL) and ether (20 mL)].
The reaction mixture was stirred at 0 °C for 4 h. Careful evapora-
tion 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 diazo ketone 12
4.4. (1R,5S,8S)-8-Isopropenyl-1,2,3,5-tetramethylbicyclo[3.3.0]-
octan-3-ol 14
To a magnetically stirred solution of methylmagnesium chlo-
ride (2.22 mL, 5.55 mmol, 2.5 M in THF) in anhydrous THF was
(1.13 g, 71%) as a greenish yellow oil. [IR (neat): m
max/cmꢀ1 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
copper 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 diazo ketone 12 (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, after
which copper and copper sulfate were filtered off on a small Celite
pad using CH2Cl2 (20 mL). Evaporation of the solvent and purifica-
tion of the residue on a silica gel column using ethyl acetate–hex-
ane (1:19) as eluent furnished the tricyclic ketone 13 (754 mg,
added dropwise a solution of bicyclic ketone 9 (382 mg,
1.85 mmol) in THF over a period of 15 min and stirred for 4 h at
room temperature. The reaction was then quenched with a satu-
rated aq NH4Cl solution (6 mL) and extracted with ether
(3 ꢂ 5 mL). The combined ether extract was washed with brine
(8 mL) and dried (Na2SO4). Evaporation of the solvent and purifica-
tion of the residue on a silica gel column using ethyl acetate–hex-
ane (1:19) as eluent furnished a 2:1 mixture of the diastereomeric
alcohols 14 (364 mg, 88%) as an oil. ½a D23
¼ þ6:6 (c 1.6, CHCl3); IR
ꢃ
(neat):
m
max/cmꢀ1 3474 (OH), 3071, 2956, 2874, 1639, 1459,
1376, 1174, 1069, 919, 888 (@CH2); 1H NMR (400 MHz,
CDCl3 + CCl4): (peaks due to the major isomer) d 4.76 (1H, s) and
4.65 (1H, s) [C@CH2], 2.32 (1H, t, J 7.0 Hz), 1.88–1.40 (8H, m),
1.70 (3H, s olefinic CH3), 1.19 (3H, s) and 1.06 (3H, s) [2 ꢂ tert-
CH3], 0.86 (3H, d, J 7.2 Hz, sec-CH3), 0.78 (3H, s, tert-CH3); (impor-
tant peaks due to the minor isomer): 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) [2 ꢂ tert-CH3]; 13C NMR (100 MHz, CDCl3 + CCl4): (peaks due to
the major isomer) d 147.3 (C, C@CH2), 112.4 (CH2, C@CH2), 81.6
(C, C–OH), 59.9 (CH), 57.1 (CH2), 56.7 (C), 56.3 (CH), 51.1 (C),
43.2 (CH2), 29.5 (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, C-OH), 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).
76%) as an oil. ½a D24
ꢃ
¼ ꢀ53:4 (c 6.4, CHCl3); IR (neat):
m
max/cmꢀ1
3073, 2956, 2873, 1717 (C@O), 1645, 1454, 1412, 1377, 1334,
1145, 1121, 1073, 1028, 890 (@CH2); 1H NMR (400 MHz,
CDCl3 + CCl4): 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), 2.08–1.94 (1H, m), 1.92 (1H, d, J 18.4 Hz,
H-5B), 1.86–1.62 (2H, m), 1.72 (3H, s, olefinic CH3), 1.48–1.26
(2H, m), 1.08 (3H, s) and 1.05 (3H, s) [2 ꢂ tert-CH3], 0.93 (1H, d, J
5.0 Hz, H-2B); 13C NMR (100 MHz, CDCl3 + CCl4): 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 (M+Na): 227.1412; Found: 227.1412.
4.3. (1R,5S,8S)-8-Isopropenyl-1,2,5-trimethylbicyclo[3.3.0]-
octan-3-one 9
4.5. (1S,5S,8R)-8-Acetyl-1,2,3,5-tetramethylbicyclo[3.3.0]octan-
To magnetically stirred, freshly distilled (over sodium and ferric
chloride) ammonia (30 mL) in a two necked flask, equipped with a
Dewar condenser, was added freshly cut lithium (92 mg,
13.2 mmol) followed by a solution of tricyclic ketone 13 (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
3-ol 15
Dry ozone in oxygen was passed through a cold (ꢀ70 °C) solu-
tion of alcohol 14 (401 mg, 1.81 mmol) and a catalytic amount of
NaHCO3 in a 1:4 solution of MeOH and CH2Cl2 (15 mL) until a blue
color appeared (ca. 4 min). The excess ozone was flushed off with
oxygen. Dimethyl sulfide (0.53 mL, 7.24 mmol) was added to the
reaction mixture and stirred for 4 h at rt. Excess Me2S was

174
A. Srikrishna, G. Nagaraju / Tetrahedron: Asymmetry 23 (2012) 170–175
evaporated on a hot water bath. Water (4 mL) was added to the
reaction mixture and extracted with CH2Cl2 (3 ꢂ 5 mL). The com-
bined 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 (1:9) as an elu-
ent furnished a diastereomeric mixture of the hydroxyketones 15
olefinic CH3], 1.28 (3H, t, J 7.0 Hz, OCH2CH3), 1.00 (3H, s) and
0.86 (3H, s) [2 ꢂ tert-CH3]; (important peaks due to the enol form)
12.23 (1H, s, OH), 4.98 (1H, s, olefinic), 2.49 (1H, t, J 7.8 Hz, H-20);
13C NMR (100 MHz, CDCl3 + CCl4): (peaks due to the keto form) d
206.0 (C, C@O), 167.4 (C, OC@O), 136.4 (C, C-80) and 129.5 (C, C-
70), 63.7 (C, C-10), 61.4 (CH2, OCH2CH3), 58.2 (CH), 52.4 (CH2),
51.4 (CH2), 50.0 (C, C-50), 41.6 (CH2), 28.2 (CH2), 23.4 (CH3), 17.6
(CH3), 14.6 (CH3), 14.2 (CH3), 10.8 (CH3); (peaks due to the enol
form) 181.5 (C, C-3), 173.0 (C, OC@O), 137.9 (C, C-80) and 128.0
(C, C-70), 90.0 (CH, C-2), 63.3 (C, C-10), 60.0 (CH2, OCH2CH3), 53.1
(CH), 52.0 (CH2), 41.5 (CH2), 28.1 (CH2), 23.3 (CH3), 17.0 (CH3),
14.4 (CH3), 14.2 (CH3), 10.7 (CH3); HRMS: m/z Calcd for C17H26O3Na
(M+Na): 301.1780; Found: 301.1779.
(341 mg, 85%) as a colorless oil. ½a D24
¼ ꢀ50:0 (c 7.2, CHCl3); IR
ꢃ
(neat):
m
max/cmꢀ1 3503 (OH), 2959, 2875, 1705 (C@O), 1456,
1374, 1360, 1237, 1172, 1071, 949, 922, 866; 1H NMR (400 MHz,
CDCl3 + CCl4): d (peaks due to the major isomer) 2.74 (1H, dd, J
6.9 and 5.1 Hz), 2.10 (3H, s, CH3CO),1.90–1.35 (8H, m), 1.19 (3H,
s) and 1.04 (3H, s) [2 ꢂ tert-CH3], 0.92 (3H, d, J 7.2 Hz, sec-CH3),
0.88 (3H, s, tert-CH3); 13C NMR (100 MHz, CDCl3 + CCl4): d (peaks
due to the major isomer) 212.1 (C, C@O), 80.9 (C, C-OH), 62.7
(CH, C-8), 57.9 (C), 56.7 (CH2, C-1), 55.2 (CH), 51.1 (C, C-5), 42.6
(CH2), 32.7 (CH3, CH3CO), 28.7 (CH3), 27.0 (CH2), 25.3 (CH3), 15.3
(CH3), 8.4 (CH3); HRMS: m/z Calcd for C14H24O2Na (M+Na):
247.1674; Found: 247.1674.
4.8. Ethyl 2-diazo-3-[(1R,2R,5S)-1,5,7,8-tetramethylbicyclo-
[3.3.0]oct-7-en-2-yl]-3-oxopropanoate 18
To a magnetically stirred solution of the b-keto ester 17 (40 mg,
0.14 mmol) in acetonitrile (1.5 mL) were added tosyl azide (34 mg,
0.17 mmol) and triethylamine (0.1 mL, 0.7 mmol) and stirred at rt
for 4 h. The solvent was evaporated under reduced pressure and
the residue was purified on a silica gel column using CH2Cl2–hex-
4.6. 2-[(1R,2R,5S)-1,5,7,8-Tetramethylbicyclo[3.3.0]oct-7-en-2-
yl]ethanone 16
To a magnetically stirred solution of a diastereomeric mixture
of the hydroxy ketones 15 (200 mg, 0.97 mmol) in CH2Cl2
(1.5 mL) was added a catalytic amount of PTSA and stirred at rt
for 4 h. The reaction was then quenched with a saturated aq. NaH-
CO3 (6 mL) solution and extracted with CH2Cl2 (3 ꢂ 5 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 CH2Cl2–hexane (1:4) as an eluent fur-
ane (1:4) as an eluent to furnish the
a
-diazo-b-keto ester 18
(40 mg, 93%) as a colorless oil. ½a D24
ꢃ
¼ ꢀ65:4 (c 1.8, CHCl3); IR
(neat): m
max/cmꢀ1 2938, 2873, 2834, 2134 (N@N), 1719 (OC@O),
1654 (C@O), 1648, 1458, 1376, 1297, 1199, 1131, 1081, 1043,
1018, 753; 1H NMR (400 MHz, CDCl3 + CCl4): d 4.28 (2H, q, J
7.1 Hz, OCH2CH3), 4.10–4.00 (1H, dd, J 7.0 and 4.0 Hz, H-20), 2.17
(2H, s), 2.05–1.80 (1H, m), 1.80–1.50 (3H, m), 1.57 (3H, s) and
1.55 (3H, s) [2 ꢂ olefinic CH3], 1.33 (3H, t, J 7.1 Hz, OCH2CH3),
1.04 (3H, s) and 0.88 (3H, s) [2 ꢂ tert-CH3]; 13C NMR (100 MHz,
CDCl3 + CCl4): d 196.6 (C, C@O), 161.6 (C, OC@O), 136.7 (C, C-80),
129.6 (C, C-70), 77.0 (C, C-2), 65.0 (C, C-10), 61.4 (CH2, OCH2CH3),
54.2 (CH2), 53.2 (CH, C-20), 49.3 (C, C-50), 43.4 (CH2), 29.1 (CH2),
24.4 (CH3), 17.6 (CH3), 14.7 (CH3), 14.5 (CH3), 10.7 (CH3); HRMS:
m/z Calcd for C17H24N2O3Na (M+Na): 327.1685; Found: 327.1684.
nished bicyclic ketone 16 (135 mg, 74%) as
a colorless oil.
½
a 2D5
ꢃ
¼ ꢀ110:8 (c 4.3, CHCl3); IR (neat):
m
max/cmꢀ1 2958, 2934,
2875, 1709 (C@O), 1445, 1378, 1356, 1260, 1165; 1H NMR
(400 MHz, CDCl3 + CCl4): d 2.90 (1H, t, J 7.0 Hz, H-20), 2.16 (3H, s,
CH3C@O), 2.18–2.00 (2H, m), 1.92–1.80 (1H, m), 1.80–1.60 (1H,
m), 1.59 (3H, s) and 1.53 (3H, s) [2 ꢂ olefinic], 1.60–1.40 (2H, m),
0.98 (3H, s) and 0.81 (3H, s) [2 ꢂ tert-CH3]; 13C NMR (100 MHz,
CDCl3 + CCl4): d 212.0 (C, C@O), 137.0 (C, C-80), 128.9 (C, C-70),
63.1 (C, C-10), 58.7 (CH, C-20), 52.0 (CH2), 50.1 (C, C-50), 41.4
(CH2), 32.4 (CH3, CH3C@O), 27.9 (CH2), 23.2 (CH3), 17.5 (CH3),
14.6 (CH3), 10.8 (CH3); HRMS: m/z Calcd for C14H22ONa (M+Na):
229.1568; Found: 229.1572.
4.9. (1R,2R,5S,7R)-1,7,9,10-Tetramethyltricyclo[5.3.0.02,5]dec-9-
en-3-one 22 and (1R,5R,8S)-8,10,11-trimethyltricyclo[6.3.0.01,5]-
undec-10-en-4-one 21
To a magnetically stirred refluxing suspension of Rh2(OAc)4
(3 mg) in dry CH2Cl2 (3 mL) was added a solution of a-diazo-b-keto
4.7. Ethyl 3-[(1R,2R,5S)-1,5,7,8-tetramethylbicyclo[3.3.0]oct-7-
en-2-yl]-3-oxopropanoate 17
ester (40 mg, 0.13 mmol) in dry CH2Cl2 (10 mL) over a period of
30 min and refluxed for 1.5 h. Evaporation of the solvent and puri-
fication of the residue on a silica gel column using CH2Cl2–hexane
(3:7) as eluent furnished a mixture of the tricyclic b-keto esters 19
To a cold (ꢀ70 °C) magnetically stirred solution of hexamethyl-
disilazane (0.36 mL, 1.7 mmol) in anhydrous THF (2 mL) was added
a solution of n-butyllithium in hexane (2.5 M, 0.5 mL, 1.26 mmol)
dropwise over a period of 5 min after which the reaction mixture
was stirred for 15 min at ꢀ70 °C. To the LHMDS thus formed was
added dropwise a solution of the ketone 16 (70 mg, 0.34 mmol)
in dry THF (1 mL) and stirred at the same temperature for
40 min. Ethyl chloroformate (0.04 mL, 0.41 mmol) was added in
one portion and the reaction mixture was stirred for 4 h at rt.
Water (4 mL) was added to the reaction mixture and extracted
with ether (3 ꢂ 5 mL). The ether extract was washed with brine
(6 mL) and dried (Na2SO4). Evaporation of the solvent and purifica-
tion of the residue on a silica gel column using CH2Cl2–hexane
(1:4) as eluent furnished keto ester 17 (85 mg, 90%) as a colorless
and 20 (31 mg, 86%) as an oil. ½a D23
¼ ꢀ25:1 (c 1.1, CHCl3); IR
ꢃ
(neat):
m
max/cmꢀ1 2961, 2933, 2874, 2837, 1782, 1752, 1728,
1661, 1621, 1447, 1371, 1340, 1311, 1253, 1172, 1097, 1028,
793; HRMS: m/z Calcd for C17H24O3Na (M+Na): 299.1623; Found:
299.1623.
A solution of a mixture of keto esters 19 and 20 (64 mg,
0.23 mmol) and LiCl (49 mg, 1.15 mmol), DMSO (0.5 mL) and water
(0.01 mL) was placed in a Carius tube and heated to 140 °C for 3 h.
The reaction mixture was cooled to rt, diluted with ether (5 mL),
washed with water (4 mL) and brine (10 mL), and dried (Na2SO4).
Evaporation of the solvent and purification of the residue on a silica
gel column using CH2Cl2–hexane (1:9) as an eluent first furnished
the minor tricyclic ketone 22 (15 mg, 32%) as an oil. ½a D24
¼ þ214:9
ꢃ
oil. ½a 2D3
ꢃ
¼ ꢀ103:8 (c 2.35, CHCl3); IR (neat):
m
max/cmꢀ1 2960, 2875,
(c 0.7, CHCl3); IR (neat): m
max/cmꢀ1 2964, 2921, 2876, 2836, 1774
2835, 1748 (OC@O), 1714 (C@O), 1645, 1622, 1464, 1446, 1424,
1306, 1237, 1150, 1039, 843, 802; 1H NMR (400 MHz,
CDCl3 + CCl4): (peaks due to the keto form) d 4.18 (2H, q, J 7.1 Hz,
OCH2CH3), 3.47 (2H, s, H-2), 2.99 (1H, t, J 6.6 Hz, H-20), 2.20–2.00
(2H, m), 1.90–1.50 (4 H, m), 1.58 (3H, s) and 1.55 (3H, s) [2 ꢂ
(C@O), 1446, 1387, 1226, 1099 1085; 1H NMR (400 MHz,
CDCl3 + CCl4): d 3.60–3.50 (1H, m), 3.20–3.05 (1H, m), 2.75–2.60
(2H, m), 2.25–2.00 (3H, m), 1.74 (1H, d, J 13.7 Hz), 1.54 (3H, s)
and 1.48 (3H, s) [2 ꢂ olefinic CH3], 1.07 (3H, s) and 0.97 (3H, s)
[2 ꢂ tert-CH3]; 13C NMR (100 MHz, CDCl3 + CCl4): d 214.6 (C,

A. Srikrishna, G. Nagaraju / Tetrahedron: Asymmetry 23 (2012) 170–175
175
C@O), 136.7 (C, C-5), 129.1 (C, C-4), 72.3 (CH, C-7), 65.2 (C), 53.4
(CH2), 51.8 (CH2), 51.6 (C), 48.4 (CH2), 28.8 (CH, C-1), 24.1(CH3),
16.4 (CH3), 14.9 (CH3), 10.4 (CH3); HRMS: m/z Calcd for C14H20ONa
(M+Na): 227.1412; Found: 227.1417.
Further elution of the column with CH2Cl2–hexane (1:4) fur-
nished norsilphiperfol-6-en-9-one 21 (24 mg, 51%) as an oil.
(peaks due to silphiperfol-6-ene 3): d 2.21 and 1.95 (2H, 2ꢂd, J
15.9 Hz, H-9), 1.71 (1H, td, J 10.6 and 5.9 Hz), 1.75–1.04 (9 H, m),
1.55 (3H, s) and 1.52 (3H, s) [2 ꢂ olefinic CH3], 1.00 (3H, s, tert-
CH3), 0.96 (3H, d, J 6.7 Hz, sec-CH3); (important peaks due to 9-
episilphiperfol-6-ene 3a): 2.07 (2H, br s, H-9), 1.54 (3H, s) and
1.50 (3H, s) [2 ꢂ olefinic CH3], 0.99 (3H, s, tert-CH3), 0.94 (3H, d, J
7.2 Hz, sec-CH3); 13C NMR (100 MHz, CDCl3): (peaks due to silphi-
perfol-6-ene 3) d 136.3 (C, C-2), 127.6 (C, C-3), 72.0 (C, C-1), 59.2
(CH), 52.5 (CH2), 49.8 (C, C-5), 41.5 (CH), 40.3 (CH2), 36.9 (CH2),
30.2 (CH2), 29.2 (CH2), 25.0 (CH3), 19.8 (CH3), 14.4 (CH3), 11.1
(CH3); (peaks due to 9-episilphiperfol-6-ene 3a): 136.7 (C, C-2),
126.6 (C, C-3), 71.8 (C, C-1), 53.4 (CH), 52.2 (CH2), 49.8 (C, C-5),
42.5 (CH2), 37.9 (CH), 34.9 (CH2), 30.7 (CH2), 26.1 (CH2), 22.7
(CH3), 15.4 (CH3), 14.6 (CH3), 10.3 (CH3).
½
a 2D4
ꢃ
¼ ꢀ142:2 (c 1.6, CHCl3); IR (neat):
m
max/cmꢀ1 2956, 2931,
2872, 2837, 1736 (C@O), 1446, 1264, 1197, 1149, 1120, 1010; 1H
NMR (400 MHz, CDCl3 + CCl4): d 2.35 (1H, dd, J 18.0 Hz, 7.8 Hz),
2.28 (1H, d, J 8.2 Hz), 2.22–2.05 (3H, m), 2.00–1.80 (3H, m), 1.80–
1.55 (2H, m), 1.58 (3H, s) and 1.53 (3H, s) [2 ꢂ olefinic CH3], 1.29
(1H, ddd, J 12.1, 10.8 and 7.0 Hz), 1.07 (3H, s, tert-CH3); 13C NMR
(100 MHz, CDCl3 + CCl4): d 223.6 (C, C@O), 133.0 (C, C-11), 131.0
(C, C-10), 68.9 (C, C-1), 57.2 (CH, C-5), 53.6 (CH2), 49.8 (C, C-8),
42.5 (CH2), 39.7 (CH2), 27.9 (CH2), 25.1 (CH2), 24.9 (CH3), 14.6
(CH3), 11.2 (CH3); HRMS: m/z Calcd for C14H20ONa (M+Na):
227.1412; Found: 227.1410.
Acknowledgement
We thank the Department of Science and Technology, New
Delhi for financial support and the Council of Scientific and Indus-
trial Research, New Delhi for the award of a research fellowship to
G.N.R.
4.10. (1R,5S,8S)-9-Methylene-2,3,5-trimethyltricyclo[6.3.0.01,5]-
undec-2-ene 23 (silphiperfol-6,9(15)-diene)
To freshly prepared tAmOK [from potassium (94 mg, 2.4 mmol)
t
t
and AmOH (5 mL) followed by evaporation of the AmOH under
vacuum] in dry benzene (5 mL) was added methyltriphenylphos-
phonium bromide (897 mg, 2.52 mmol) and the resulting yellow
solution was stirred for 1 h at rt. The solution was then allowed
to settle for 30 min. The dark yellow solution of methylenetriphen-
ylphosphorane was added to a magnetically stirred solution of ke-
tone 21 (24 mg, 0.12 mmol) in dry benzene (1 mL) at rt and stirred
for 3 h. Water (4 mL) was added to the reaction mixture and ex-
tracted with ether (3 ꢂ 5 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
hexane as an eluent furnished silphiperfol-6,9(15)-diene 23
References
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.
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Nat. Prod. 1986, 41, 845; (b) Groweiss, A.; Fenical, W.; Cun-heng, H.; Clardy, J.;
Zhongde, W.; Zhongnian, Y.; Kanghou, L. Tetrahedron Lett. 1985, 26, 2379.
4. (a) Reddy, T. J.; Rawal, V. H. Org. Lett. 2000, 2, 2711; (b) Kakiuchi, K.; Ue, M.;
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.
5. (a) Sha, C. K.; Santhosh, K. C.; Lih, S.-H. J. Org. Chem. 1998, 63, 2699; (b) Vo, N.
H.; Snider, B. B. J. Org. Chem. 1994, 59, 5419; (c) Dickson, J. K., Jr.; Fraser-Reid, B.
J. Chem. Soc. Chem. Commun. 1990, 1440; (d) Meyers, A. I.; Lefker, B. A.
Tetrahedron 1987, 43, 5663; (e) Paquette, L. A.; Roberts, R. A.; Drtina, G. J. J. Am.
Chem. Soc. 1984, 106, 6690.
6. (a) Srikrishna, A.; Babu, N. C. Tetrahedron Lett. 2001, 42, 4913; (b) Srikrishna, A.;
Babu, N. C.; Dethe, D. H. Indian J. Chem. 2003, 42B, 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, 6810; (g) Srikrishna, A.; Pardeshi, V. H.; Mahesh, K.
Tetrahedron: Asymmetry 2010, 21, 2512; (h) Srikrishna, A.; Pardeshi, V. H.;
Mahesh, K. Tetrahedron: Asymmetry 2010, 21, 2830; (i) Srikrishna, A.; Nagaraju,
G.; Ravi, G. Synlett 2010, 3015; (j) Srikrishna, A.; Nagaraju, G. Indian J. Chem.
2011, 50B, 73; (k) Srikrishna, A.; Dethe, D. H. Indian J. Chem. 2011, 50B, 1092; (l)
Srikrishna, A.; Seth, V. M.; Nagaraju, G. Synlett 2011, 2343; (m) Srikrishna, A.;
Nagaraju, G. Synlett 2012, 123.
7. (a) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091; (b) Doyle, M. P. In
Comprehensive Organometallic Chemistry II; Hegedus, L. S., Ed.; Pergamon Press:
New York, 1995. Vol. 12, Chapter 5.2; (c) Doyle, M. P.; McKervey, M. A.; Ye, T. In
Modern Catalytic Methods for Organic Synthesis with Diazo Compounds: from
Cyclopropanes to Ylides; John Wiley and Sons: New York, 1998. Chapter 3.
8. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.-T.;
Faulkner, D. J.; Petersen, R. J. Am. Chem. Soc. 1970, 92, 741.
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A. Org. React. 1979, 26, 361; (c) Mander, L. N. Synlett 1991, 134; (d) Padwa, A.;
Krumpe, K. E. Tetrahedron 1992, 48, 5385.
(21 mg, 88%) as an oil. ½a D23
¼ ꢀ141:4 (c 1.0, CHCl3); IR (neat):
ꢃ
m
max/cmꢀ1 3070, 2932, 2871, 2835, 1654, 1450, 1375, 878; 1H
NMR (400 MHz, CDCl3 + CCl4): d 4.81 (1H, s) and 4.73 (1H, s)
[C@CH2], 2.57 (1H, d, J 5.6 Hz), 2.40–2.22 (2H, m), 2.17 and 2.06
(2H, 2ꢂd, J 16.2 Hz), 1.80–1.62 (1H, m), 1.70–1.55 (2H, m), 1.56
(3H, s) and 1.50 (3H, s) [2 ꢂ olefinic CH3], 1.62–1.35 (3H, m),
1.05 (3H, s, tert-CH3); 13C NMR (100 MHz, CDCl3 + CCl4): d 158.8
(C, C@CH2), 134.8 (C, C-2), 128.9 (C, C-3), 104.4 (CH2, C@CH2),
71.8 (C, C-1), 54.2 (CH, C-8), 53.6 (CH2, C-4), 49.5 (C, C-5), 42.1
(CH2), 35.3 (CH2), 32.3 (CH2), 30.0 (CH2), 24.5 (CH3), 14.5 (CH3),
11.2 (CH3).
4.11. (1R,5S,8S)-2,3,5,9-Tetramethyltricyclo[6.3.0.01,5]undec-2-
ene (silphiperfol-6-ene 3 and 9-episilphiperfolene 3a)
To a solution of silphiperfoladiene 23 (17 mg, 0.08 mmol) in dry
hexane (1 mL) was added activated 10% Pd/C (4 mg). The reaction
mixture was stirred for 1.5 h at room temperature under an atmo-
sphere of hydrogen, created by evacuative replacement of air (bal-
loon), and then the catalyst was filtered on a small silica gel
column. Evaporation of the solvent furnished a 3:2 mixture of sil-
phiperfol-6-ene 3 and 9-episilphiperfol-6-ene 3a (17 mg, >95%) as
10. (a) Norin, T. Acta Chem. Scand. 1963, 17, 738; (b) Dauben, W. G.; Deviny, E. J. J.
Org. Chem. 1966, 31, 3794; (c) Dauben, W. G.; Wolf, R. E. J. Org. Chem. 1970, 35,
374. and 2361; (d) Srikrishna, A.; Krishnan, K.; Yelamaggad, C. V. Tetrahedron
1992, 48, 9725.
11. Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Pisani, E.; Rosati, O. Tetrahedron
1997, 53, 8501.
an oil. ½a 2D4
ꢃ
¼ ꢀ62:5 (c 0.85, CHCl3); 1H NMR (400 MHz, CDCl3):