Enantiospecific synthesis of ABC-ring system of A-nor and abeo 4(3→2) tetra and pentacyclic triterpenes

Article abstract of DOI:10.1016/j.tet.2009.11.114

Enantiospecific synthesis of ABC-ring systems of A-nor and abeo 4(3→2) tetra and pentacyclic triterpenes has been accomplished starting from the readily available monoterpene (R)-carvone. (R)-Carvone was used as the B-ring of the target molecules. A lithi

Full text of DOI:10.1016/j.tet.2009.11.114

Tetrahedron 66 (2010) 852–861
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantiospecific synthesis of ABC-ring system of A-nor and abeo 4(3/2) tetra and
pentacyclic triterpenes
*
A. Srikrishna , R. Ramesh Babu, B. Beeraiah
Department of Organic Chemistry, Indian Institute of Science, C.V. Raman Avenue, Bangalore 560012, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiospecific synthesis of ABC-ring systems of A-nor and abeo 4(3/2) tetra and pentacyclic tri-
terpenes has been accomplished starting from the readily available monoterpene (R)-carvone. (R)-Car-
vone was used as the B-ring of the target molecules. A lithium-liquid ammonia mediated cyclisation of
Received 9 November 2009
Received in revised form 27 November 2009
Accepted 27 November 2009
Available online 4 December 2009
d,3-unsaturated ester was employed for the cyclopentannulation at the C-5 and C-6 carbons of carvone
and an RCM reaction was employed for the cyclohexannulation to generate the ABC-ring system of A-nor
tetra and pentacyclic triterpenes. The strategy has been extended for the synthesis of the ABC-ring
system of abeo 4(3/2) tetra and pentacyclic triterpenes.
Keywords:
Triterpenes
A-nortriterpenes
Ó 2009 Elsevier Ltd. All rights reserved.
Abeo triterpenes
Cyclopentannulation
Ring-closing olefin metathesis
Cyclohexannulation
Enatiospecific synthesis
Reductive allylation
1. Introduction
HO
H
O
H
H
HO
O
Triterpenes comprising six isoprene units contain a number of
arrangements ranging from acyclic to heptacyclic systems. How-
ever, majority of triterpenes isolated so far from a variety of natural
sources contain either tetra or pentacyclic carbon frameworks, e.g.
dammarane, lanostane, betulin, oleane, ursane, lupane, hopane.1
Among these tetra and pentacyclic triterpene groups, except for
lanostanes all share a common ABC-ring system. In addition to
these groups, a number of A-ring modified siblings were also iso-
lated from natural sources. For example, a number of A-nor tetra
and pentacyclic triterpenoids were reported during the last seven
decades.2 Similarly, a number of abeo 4(3/2) and abeo 3(2/1)
tetra and pentacyclic triterpenes have also been isolated from
a number of natural sources.2 Some representative examples are
depicted in Chart 1.
O
COOH
O
H
H
H
COOH
COOH
H
H
H
Ceanothenic acid
Jingullic acid
Viburnol E
(A-nor tetra and pentacyclic triterpenes)
HO
H
HO
R1
H
HO
HO1
2
O
H
CO2R
3
RO2C
MeO2C
H
H
HO
R2
4
HO
H
H
R=R2=H, R1=OH, Musancropic acid, A
R=R1=H, R2=OH, Musancropic acid, B
Viburnol F
(abeo 4(3 2) tetra and pentacyclic triterpenes)
A number of triterpenes are known to exhibit important biol-
ogical properties and have been used in folk medicines.3 In addi-
tion, there have been a number of studies reported in the literature
on the multifarious pharmacological activities of A-ring modified
triterpene derivatives obtained by ring contraction and trans-
formation of A-ring of naturally available pentacyclic triterpenes.4
HO
HO
H
2
HOH2C
CO2H
HOH2C
CO2H
OHC
H
H
CO2H
H
1
3
H
H
HO
H
4
H
H
H
Sculponeatic acid
Zizyberanalic acid
Coleonolic acid
(abeo 3(2 1) tetra and pentacyclic triterpenes)
* Corresponding author. Tel.: þ91 80 22932215; fax: þ91 80 23600529.
E-mail address: ask@orgchem.iisc.ernet.in (A. Srikrishna).
Chart 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.114

A. Srikrishna et al. / Tetrahedron 66 (2010) 852–861
853
Some of the A-ring modified derivatives were proved to exhibit
significant inhibitory activity against HIV virus, produce nitric oxide
(NO) induced by interferin-g (IFN-g) in mouse macrophages, cel-
(for 2 steps). The stereochemistry of the acetate side chain in the
keto ester 4 was assigned in analogy to the well established al-
kylation of (R)-carvone, i.e., approach of the electrophile from the
opposite side of the isopropenyl group.8 To overcome the practical
problems at later stages, the ketone group in the keto ester 4 was
masked. Chemo- and stereoselective reduction of the keto ester 4
with sodium borohydride in methanol at ꢀ20 ꢁC furnished exclu-
sively the hydroxy ester 5 in 77% yield. The stereochemistry of the
hydroxy group in the ester 5 was assigned as trans to the acetate
side chain, in analogy with the reduction of 5-alkylcyclohex-
enones.9 The hydroxy group in the hydroxy ester 5 was protected as
its methoxymethyl (MOM) ether by treatment with ethyl-
diisopropylamine (DIPEA), methoxymethyl chloride and a catalytic
amount of DMAP in anhydrous methylene chloride at RT for six
hours to furnish the MOM ether 6 in 89% yield, whose structure was
established from its spectral data.
lular proliferation of human leukaemia and breast cancer cell lines,
etc. Presence of electron withdrawing substituents on the A-ring
proven to be more biological active against monocytic differentia-
tion of human myeloid leukaemia cells and adipogenic differenti-
ation of mouse. Recently, the research group of Subba Rao reported5
the A-ring modified oleananes, 2-cyano-3,12-dioxooleanane-
1,19(11)-dien-28-oic acid (CDDO) analogues, which were found to
exhibit cytotoxic activities against human leukaemia and breast
cancer cell lines.
In all the A-nor and abeo-tetra and pentacyclic triterpenes
known so far, ABC-ring system is common, including the location of
the carbon substituents and stereochemistry at the ring junction
carbons, cf. Chart 1. In continuation of our interest6 in the synthesis
of a variety of bi- and tricyclic carbon frameworks, enroute to
natural products, starting from the readily available monoterpene
carvone 1, herein we report an enantiospecific approach for the
construction of ABC-ring system of A-nor and abeo-tetra and
pentacyclic triterpenes.
O
O
O
LDA, THF
LDA, THF
MeI, 88%
MeO2C
BrCH2CO2Me
82%
3
1
4
NaBH4
MeOH
77%
2. Results and discussion
OMOM
OH
OMOM
Li-liq. NH3
DIPEA, MOMCl
MeO2C
MeO2C
-33 °C
84%
Initially, synthesis of the ABC-ring system 2 of A-nor tetra and
pentacyclic triterpenes has been investigated. It was readily
visualised that (R)-carvone 1 can serve as the B-ring of 2, as the
absolute configuration at the C-5 position of the target correlates to
the stereo centre of carvone 1, and the isopropenyl group can serve
as the C-4 carbon of the target along with the gem dimethyl groups.
Stereocontrolled cyclopentannulation at the C-5 and C-6 carbons,
and cyclohexannulation at the C-1 and C-2 carbons of carvone 1
would lead to the ABC-ring system 2 of A-nor tetra and pentacyclic
triterpenes.
DMAP (cat.)
89%
HO
6
7a,b (1:4)
5
PCC
92%
silica gel
OMOM
OMOM
OMOM
NaBH4
MeOH
83%
HO
HO
O
+
(
4 : 1 )
7a
7b
8
Scheme 1.
Next, construction of the five membered ring by employing
lithium in liquid ammonia mediated cyclisation of the -un-
O
1
d,3
1
6
5
2
saturated ester in the ester 6 was explored. Thus, reaction of the
ester 6 in THF with lithium in freshly distilled liquid ammonia
furnished a 1:4 epimeric mixture of the bicyclic alcohols 7a and 7b
in 84% yield. The stereochemistry of the secondary hydroxy group
was assigned on the basis of thermodynamic considerations.
Mechanistically the alcohol 7 was formed by the reduction of the
initially formed cyclic ketone 8 under the reaction conditions
(lithium in liquid ammonia), which is expected to generate ther-
modynamic product. For further confirmation, the 1:4 epimeric
mixture of the alcohols 7a and 7b was oxidised to the ketone 8 and
carried out the reduction to generate the epimeric alcohols under
kinetic conditions. Thus, oxidation of the epimeric mixture of the
alcohol 7 with PCC and silica gel in anhydrous methylene chloride
at RT for two hours furnished the ketone 8 in 92% yield. Reduction
of the ketone 8 with sodium borohydride in methanol at room
temperature for 30 min furnished, as expected, a 4:1 mixture of the
epimeric alcohols 7a and 7b, in 83% yield, which was separated by
column chromatography on silver nitrate impregnated silica gel.
The minor alcohol 7b obtained in the reduction was identified (IR,
1H and 13C NMR) as the major isomer that was obtained during the
lithium-liquid ammonia mediated cyclisation of the ester 6. Based
on the approach of the hydride from the less hindered face in the
hydrindanone (i.e. opposite to the tertiary methyl group at the ring
junction), the major alcohol 7a was assigned as the 8S isomer. For
proceeding further, the hydroxy group in 7a was protected by
treating with sodium hydride, benzyl chloride and a catalytic
amount of TBAI in refluxing THF to furnish the benzyl ether 9 in 86%
yield. For the construction of the C-ring, the C-2 ketone was
regenerated. Hydrolysis of the MOM ether 9 using a catalytic
H
4
H
H
2
1
Li, liq. NH3
ð1Þ
(eqn. 1)
OH
CO2R
For the cyclopentannulation at the C-5 and C-6 carbons of car-
vone 1, lithium-liquid ammonia mediated cyclisation of -un-
d,3
saturated esters (Eq. 1), a methodology7 developed earlier in our
laboratory, was investigated involving the isopropenyl group of
carvone. Since the AB-ring system of 2 required trans ring junction,
first methyl group followed by an acetate group were introduced at
the C-6 position of the carvone 1 exploiting the well established
preference of kinetic alkylation on carvone derivatives.8 Thus,
generation of the kinetic dienolate of carvone 1 employing LDA in
dry THF and alkylation with methyl iodide generated a 2:3 di-
astereomeric mixture of 6-methylcarvone8 3, Scheme 1. Repeating
the alkylation one more time on 6-methylcarvone 3 using LDA and
methyl bromoacetate furnished the trans-keto ester 4 in 72% yield

854
A. Srikrishna et al. / Tetrahedron 66 (2010) 852–861
amount of PTSA in refluxing methanol furnished the alcohol 10 in
84% yield, which on oxidation with PCC and silica gel in anhydrous
methylene chloride at RT furnished the enone 11 in 86% yield. For
the construction of the C-ring, introduction of two allyl units at C-2
and C-3 carbons of the hydrindane 11, followed by an RCM reaction
was conceived, Scheme 2.
yield, which was separated by column chromatography on silica
gel. The stereochemistry at the two newly created chiral centers in
bisallyl ketone 20 was assigned on the basis of the thermodynamic
considerations, which was supported by literature precedent.6k,11
Finally, RCM reaction of the bisallyl ketone 20 with 10 mol % of
Grubbs’ first generation catalyst in methylene chloride at room
temperature furnished the tricyclic ketone 24 in 91% yield, whose
structure was deduced from its spectral data.
OMOM
OMOM
OH
PTSA
NaH, BnCl, TBAI
THF, reflux
86%
HO
BnO
MeOH
BnO
PCC
reflux
O
H
OH
OEt
H
H
10
O
84%
OEt
Li, Liq. NH3
-33 °C
83%
9
7a
86%
MeO2C
O
MeO2C
O
OH
HO
Zn, )))), THF
Br
silica gel
CH2Cl2
PPTS (cat.)
90%
BnO
H
15
H
BnO
H
5
16
85%
H
PPTS, MeOH
OH
12
PCC
86%
11
71%
O
O
silica gel
CH2Cl2
MnO2
Li, liq NH3
X
CH2Cl2
HO
BnO
HO
HO
HO
+
Br
88%
O
O
H
H
H
13
14
18a 4 : 1
18b
17
DIPEA, MOMCl
DMAP
92%
Scheme 2.
OH
O
For the introduction of an allyl moiety at the C-2 carbon, an
PCC
Li, )))), THF
MOMO
MOMO
alkylative 1,3-enone transposition methodology10 was chosen.
Sonochemically accelerated Barbier reaction of the enone 11 with
zinc and allyl bromide in THF generated the tertiary alcohol 12 in
85% yield, which on oxidation with PCC and silica gel in anhydrous
methylene chloride furnished the transposed enone 13. A reductive
allylation reaction was explored for the introduction of the second
silica gel
H2C=CHCH2Br
MOMO
H
O
90%
H
H
21
88%
22
19
Li, Liq. NH3
H2C=CHCH2Br
83%
PCy3
Cl
Ru
PCy3
MOMO
Cl
Ph MOMO
MOMO
H
O
O
O
allyl group at the
a-position of the enone 13, which will also cleave
H
+
CH2Cl2
RT, 91%
H
H
the benzyl ether. However, reaction of the enone 13 with lithium in
liquid ammonia, both in the presence as well as in the absence of
a proton source, followed by quenching with allyl bromide did not
furnish the bisallyl product 14.
( 6 : 1 )
20
23
24
Scheme 3.
Since the reductive allylation reaction was unsuccessful with the
enone 13, partly may be due to the competing side reactions due to
the benzyl ether, change of the protecting group was considered. A
methoxymethyl group was chosen as it will be stable to standard
reductive allylation conditions. In order to avoid the regiochemical
complications in deprotecting MOM ether of the allyl alcohol (at
the C-2 position) in the presence of MOM ether at the C-8 position,
The tricyclic system 24 represents the ABC-ring system of A-nor
tetra and pentacyclic triterpenes. The oxygen functionality present
in the A-ring of 24, as it is a masked ketone, could be used for the
introduction of the requisite carbon in the A-ring to modify 24 into
ABC-ring system of both abeo 4(3/2) or abeo 3(2/1) tetra and
pentacyclic triterpenes. However, it was contemplated to introduce
the requisite carbon in the early part of the sequence to generate the
ABC-ring system of abeo 4(3/2) tetra and pentacyclic triterpenes,
starting from the hydroxy acetal 16, Scheme 4. Oxidation of the
bicyclic alcohol 16 with IBX12 in dimethyl sulfoxide for 1 h at room
temperature furnished a 1:1 diastereomeric mixture of the ketone
25 in 82% yield. Introduction of the C-3 carbon of abeo 4(3/2)
triterpenes via a Wittig olefination was then investigated. Since, the
conventional Wittig reaction with methylenetriphenylphosphor-
ane was unsuccessful, methylenation was carried out by employing
the conditions developed by Yan and co-workers,13 which also
resulted in the hydrolysis of the ethoxyethyl moiety. Treatment of
the ketone 25 with methylene chloride, magnesium and titanium
chloride in THF furnished the hydroxyolefin 26 in 79% yield, whose
structure was assigned from its spectral data. Oxidation of the allyl
alcohol 26 with PCC and silica gel in anhydrous methylene chloride
furnished the enone 27 in 92% yield. A sonochemically accelerated
Barbier reaction of the enone 27 with lithium and allyl bromide
generated the allylic tertiary alcohol 28 in 87% yield, which on ox-
idation with a mixture of PCC and silica gel in methylene chloride
furnished the transposed enone 29. Reaction of the enone 29 with
lithium in liquid ammonia followed by alkylation with allyl bromide
generated the bisallyl ketone 30 in 76% yield, in a highly regio- and
stereoselective manner. Finally, RCM reaction of the bisallyl ketone
30 with Grubbs’ first generation catalyst in 0.005 M anhydrous
methylene chloride solution at room temperature furnished the
tricyclic ketone 31 in 91% yield, whose structure was established
from its spectral data. The tricyclic ketone 31 represents the ABC-
a more labile a-ethoxyethyl group was opted for protecting the
allyl alcohol. With this reasoning, sequence was modified starting
from the hydroxy ester 5, Scheme 3. Treatment of the hydroxy ester
5 with ethyl vinyl ether and a catalytic amount of pyridinium
p-toluenesulfonate (PPTS) in methylene chloride at room temper-
ature furnished a 2:3 epimeric mixture (at the ethoxy group) of the
acetal 15 in 90% yield. Reaction of the ester 15 in THF with lithium in
freshly distilled liquid ammonia furnished a mixture of the bicyclic
alcohol 16 in 83% yield. Hydrolysis of the acetal 16 using a catalytic
amount of PPTS in methanol furnished a 4:1 epimeric mixture of
the diol 17 in 86% yield. Selective allylic oxidation of the diol 17 with
manganese dioxide in methylene chloride furnished a 4:1 epimeric
mixture of the hydroxy ketones 18a and 18b in 88% yield, which
was separated by column chromatography on silica gel. The se-
quence was then continued with the major hydroxy ketone 18a.
Treatment of the alcohol 18a with DIPEA, methoxymethyl chloride
and a catalytic amount of DMAP at room temperature gave the
MOM ether 19 in 92% yield. Attention was then focused on the
construction of the C-ring via the bisallyl ketone 20. Sonochemi-
cally accelerated Barbier reaction of the enone 19 with lithium and
allyl bromide in THF generated the tertiary allyl alcohol 21 in 88%
yield, which on oxidation with a mixture of PCC and silica gel in
methylene chloride furnished the enone 22 in 90% yield. Reaction
of the enone 22 with lithium in liquid ammonia followed by al-
kylation of the resultant enolate with allyl bromide furnished a 1:6
mixture of O-allyl and C-allyl ethers 23 and 20, respectively, in 83%

A. Srikrishna et al. / Tetrahedron 66 (2010) 852–861
855
ring system of abeo 4(3/2) tetra and pentacyclic triterpenes,
containing the requisite trans, anti, trans-ring fusion and function-
alities in all the rings for further elaboration.
accomplished by exposure to iodine vapour. Acme’s silica gel (100–
200 mesh) was used for column chromatography (approximately
15–20 g per 1 g of the crude product). All small-scale dry reactions
were carried out using standard syringe-septum technique. Low
temperature reactions were carried out using a bath made of so-
dium chloride and ice, or alcohol and liquid nitrogen.
OH
O
OEt
O
OEt
Mg / TiCl4
IBX
CH2Cl2 : THF
HO
O
4.1.1. Methyl 2-[(1S,6S)-6-isopropenyl-1,3-dimethyl-2-oxocyclohex-
3-enyl]acetate (4). To a cold (0 ꢁC), magnetically stirred solution of
diisopropylamine (1.2 mL, 8.54 mmol) in anhydrous THF (2 mL)
was added a solution of nBuLi (2.4 M in hexane, 3 mL, 7.20 mmol)
and stirred for 10 min. To LDA thus formed was added drop wise
a solution of 6-methylcarvone8 3 (700 mg, 4.27 mmol) in anhy-
drous THF (6 mL) over a period of 5 min and stirred for 45 min at
the same temperature. To the enolate thus formed was added
a solution of methyl bromoacetate (980 mg, 6.40 mmol) in THF
(1 mL) at the same temperature and stirred for 8 h at rt. The re-
action mixture was then diluted with water (4 mL) and extracted
with ether (3ꢂ5 mL). The combined organic 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
DMSO
82%
79%
26
16
25
PCC
silica gel
O
92%
OH
PCC
silica gel
84%
Li, )))), THF
H2C=CHCH2Br
87%
O
29
28
27
Li, Liq. NH3
H2C=CHCH2Br
76%
PCy3
Ru
PCy3
Cl
Cl
36
Ph
H
O
O
10 mol%
RT, 91%
30
31
Scheme 4.
acetate–hexane (1:9) as eluent furnished the keto ester 4 (831 mg,
26
82%) as oil. Rf (1:9 EtOAc:hexane) 0.5; [
a
]
þ22.4 (c 3.2, CHCl3); IR
D
3. Conclusions and summary
(neat): nmax/cmꢀ1 3077, 2973, 2925, 1740, 1670, 1641, 1436, 1406,
1377, 1356, 1198, 1170, 1078, 1019, 902, 842; 1H NMR (400 MHz):
Enantiospecific synthesis of ABC-ring systems of A-nor tetra and
pentacyclic triterpenes and abeo 4(3/2) tetra and pentacyclic
triterpenes has been accomplished starting from the readily avail-
able monoterpene (R)-carvone 1. It was readily visualised (R)-car-
vone 1 as the B-ring of the target molecules, as the absolute
configuration at the C-5 position of the target correlates to the
stereo centre of (R)-carvone 1, and the isopropenyl group can serve
as the C-4 carbon of the target molecules along with the gem di-
methyl groups. Cyclopentannulation at the C-5 and C-6 carbons of
carvone 1 was accomplished by employing a lithium-liquid am-
d
6.63 (1H, br s, H-40), 4.91 (1H, s) and 4.72 (1H, s) [C]CH2], 3.59
(3H, s, OCH3), 3.27 (1H, dd, J 11.1 and 4.8 Hz), 2.86 and 2.29 (2H,
2ꢂd, J 16.9 Hz, H-2), 2.54–2.42 (1H, m), 2.30–2.20 (1H, m), 1.76 (3H,
s) and 1.70 (3H, s) [2ꢂolefinic-CH3], 1.01 [3H, s, tert-CH3]; 13C NMR
(100 MHz):
d 201.8 (C, C]O), 171.7 (C, OC]O), 144.5 (C, C]CH2),
142.5 (CH, C-40), 133.9 (C, C-30), 115.2 (CH2, C]CH2), 51.1 (CH3,
OCH3), 47.0 (C, C-10), 46.1 (CH, C-60), 39.7 (CH2, C-2), 28.4 (CH2, C-
50), 23.3 (CH3), 19.0 (CH3), 16.5 (CH3); HRMS: m/z Calcd for
C14H20O3Na (MþNa): 259.1310; Found 259.1315.
monia mediated cyclisation of d,3-unsaturated ester, which was
4.1.2. Methyl 2-[(1S,2S,6S)-2-hydroxy-6-isopropenyl-1,3-dimethylcy-
clohex-3-enyl]acetate (5). To a cold (ꢀ20 ꢁC), magnetically stirred
solution of the keto ester 4 (610 mg, 2.58 mmol) in dry methanol
was added NaBH4 (150 mg, 3.87 mmol) in three portions over
a period of 15 min and stirred for 15 min at the same temperature.
Water (5 mL) was added to the reaction mixture and extracted with
ether (2ꢂ5 mL). The combined ether extract was washed with brine
(5 mL) and dried (Na2SO4). Evaporation of the solvent and purifi-
cation of the residue over a silica gel column using ethyl acetate–
obtained by sequential kinetic alkylations of carvone 1. Reductive
allylation of the bicyclic enone 22, followed by RCM reaction of the
bisallyl hydrindane 20 generated the ABC-ring system 24, which
also contained the BC-trans ring junction as in A-nor tetra and
pentacyclic triterpenes. The strategy has been further extended for
the synthesis of the ABC-ring system 31 of abeo 4(3/2) tetra and
pentacyclic triterpenes.
4. Experimental section
4.1. General
hexane (1:9) as eluent furnished the hydroxy ester 5 (475 mg, 77%)
25
as colourless oil. Rf (1:9 EtOAc:hexane) 0.4; [
a
]
þ68.5 (c 1.5,
D
CHCl3); IR (neat): nmax/cmꢀ1 3489, 3074, 2951, 2918, 1736, 1640,
1439, 1378, 1215, 1165, 1064, 1043, 1015, 896; 1H NMR (400 MHz):
d
5.42 (1H, br s, H-40), 4.87 (1H, s) and 4.80 (1H, s) [C]CH2], 4.22
IR spectra were recorded on Jasco FTIR 410 and Perkin Elmer FTIR
spectrophotometer. 1H (300 and 400 MHz) and 13C (75 and
100 MHz) NMR spectra were recorded on JNM
AMX 400 spectrometers using a 1:1 mixture of CDCl3 and CCl4 as
solvent. The chemical shifts ( ppm) and coupling constants (Hz) are
(1H, br s, H-20), 3.66 (3H, s, OCH3), 2.79 (1H, br s, OH), 2.48 and 2.18
(2H, 2ꢂd, J 14.5 Hz, H-2), 2.37 (1H, dd, J 11.5 and 4.9 Hz), 2.30–2.10
(1H, m), 2.00–1.80 (1H, m), 1.77 (3H, s) and 1.71 (3H, s) [2ꢂolefinic-
l-300 and Brucker
d
CH3], 1.00 (3H, s, tert-CH3). 13C NMR (100 MHz):
d 174.3 (C, OC]O),
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 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 ionisation mode. Optical rotations were measured using
a Jasco DIP-370 digital polarimeter and Jasco P-1020 polarimeter
146.1 (C, C]CH2), 135.4 (C, C-30), 122.2 (CH, C-40), 114.7 (CH2,
C]CH2), 76.8 (CH, C-2), 51.5 (CH3, OCH3), 48.8 (CH, C-60), 43.4 (CH2,
C-2), 40.9 (C, C-10), 28.9 (CH2, C-50), 23.2 (CH3), 19.6 (CH3), 12.7
(CH3); HRMS: m/z Calcd for C14H22O3Na (MþNa): 261.1467; Found
261.1465.
4.1.3. Methyl [(1S,2S,6S)-2-(2-methoxymethoxy)-1,3-dimethyl-6-iso-
propenylcyclohex-3-enyl]acetate (6). To an ice cold solution of the
alcohol 5 (386 mg, 1.62 mmol) in dry CH2Cl2 (1 mL) were added
DIPEA (0.6 mL, 3.24 mmol), DMAP (20 mg, 10 mol %), and MOMCl
(0.2 mL, 3.24 mmol) and stirred for 30 min at the same tempera-
ture. The reaction mixture was stirred at RT for 6 h and then poured
into water (4 mL) and extracted with CH2Cl2 (2ꢂ5 mL). Combined
and [a]
values are given in units of 10ꢀ1 deg cm2 gꢀ1. Analytical
D
thin-layer chromatography (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 and hexane were used as eluent. Visualisation of spots was

856
A. Srikrishna et al. / Tetrahedron 66 (2010) 852–861
CH2Cl2 extract was washed with brine (4 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
d
5.42 (1H, br s, H-4), 4.65 and 4.60 (2H, 2ꢂd, J 6.8 Hz, OCH2O), 3.83
(1H, dd, J 7.9 and 1.9 Hz, H-8), 3.69 (1H, br s, H-2), 3.34 (3H, s, OCH3),
1.96 (1H, dd, J 13.8 and 7.9 Hz) and 1.66 (1H, dd, J 13.8 and 2.4 Hz) [H-
9], 1.95–1.50 (2H, m), 1.61 (3H, s, olefinic-CH3), 1.45 (1H, br s, OH),
1.29 (1H, dd, J 12.0 and 4.8 Hz), 0.96 (3H, s), 0.92 (3H, s) and 0.89 (3H,
furnished the MOM ether 6 (410 mg, 89%) as colourless oil. Rf (1:19
27
EtOAc:hexane) 0.55; [
a]
þ98.7 (c 9.1, CHCl3); IR (neat): nmax/cmꢀ1
D
3077, 2950, 2919, 2848, 1738, 1637, 1437, 1366, 1216, 1190, 1162,
s) [3ꢂtert-CH3]; 13C NMR (100 MHz):
d 136.0 (C, C-3), 124.4 (CH, C-
1093, 1032, 966, 920, 898; 1H NMR (400 MHz):
d
5.40 (1H, br s, H-
4), 97.0 (CH2, OCH2O), 87.5 (CH, C-2), 82.2 (CH, C-8), 55.8 (CH3,
OCH3), 54.3 (CH, C-6), 47.5 (CH2, C-9), 44.5 (C), 42.5 (C), 31.0 (CH3),
23.2 (CH2, C-5), 20.0 (CH3), 19.4 (CH3), 15.1 (CH3); HRMS: m/z Calcd
for C15H26O3Na (MþNa): 277.1780; Found277.1781.
40), 4.79 (1H, s) and 4.72 (1H, s) [C]CH2], 4.65 (2H, s, OCH2O), 4.56
(1H, s, H-20), 3.58 (3H, s, COOCH3), 3.36 (3H, s, OCH2OCH3), 2.88 (1H,
dd, J 11.6 and 5.1 Hz), 2.53 and 2.20 (2H, 2ꢂd, J 17.5 Hz, H-2), 2.30–
2.10 (1H, m), 1.86 (1H, d, J 17.8 Hz), 1.71 (3H, s) and 1.68 (3H, s)
Further elution of the column with ethyl acetate–hexane (1:9) as
eluent furnished the (1S,2S,6S,8R) isomer 7b (53 mg, 17%) as col-
[2ꢂolefinic-CH3], 0.91 (3H, s, tert-CH3); 13C NMR (100 MHz):
d 172.3
(C, OC]O), 146.0 (C, C]CH2), 135.0 (C, C-30), 122.7 (CH, C-40), 114.5
(CH2, C]CH2), 99.1 (CH2, OCH2O), 83.0 (CH, C-20), 56.0 (CH3) and
50.6 (CH3) [2ꢂOCH3], 45.7 (CH, C-60), 39.6 (C, C-10), 38.9 (CH2, C-2),
28.8 (CH2, C-50), 22.5 (CH3), 20.3 (CH3), 15.6 (CH3); HRMS: m/z Calcd
for C16H26O4Na (MþNa): 305.1729; Found: 305.1726.
ourless oil. Rf (1:4 EtOAc:hexane) 0.45 on silver nitrate (15%) im-
pregnated silica gel; [
24
a]
ꢀ38.8 (c 3.6, CHCl3); IR (neat): nmax/cmꢀ1
D
3437, 2948, 2894, 2858, 1465, 1439, 1381, 1213, 1151, 1098, 1045,
1032,1004, 918, 902; 1H NMR (400 MHz):
d 5.39 (1H, br s, H-4), 4.63
and 4.58 (2H, 2ꢂd, J 6.8 Hz, OCH2O), 3.96 (1H, dd, J 9.9 and 6.8 Hz, H-
8), 3.74 (1H, br s, H-2), 3.33 (3H, s, OCH3), 2.13 (1H, dd, J 11.6 and
6.8 Hz, H-9A), 2.00–1.60 (3H, m), 1.60 (3H, s, olefinic-CH3), 1.49 (1H,
dd, J 11.6 and 5.6 Hz, H-9B), 1.30 (1H, t, J 10.7 Hz), 0.91 (3H, s), 0.81
4.1.4. (1S,2S,6R)-2-(Methoxymethoxy)-1,3,7,7-tetramethylbicy-
clo[4.3.0]non-3-en-8-one (8). To
a magnetically stirred, freshly
distilled (over sodium and ferric chloride) ammonia (20 mL) in a two-
necked round bottom flask equipped with Dewar condenser was
added a solution of the ester 6 (428 mg, 1.51 mmol) in dry THF (4 mL)
followed by freshly cut lithium (52 mg, 7.55 mmol). The resulting
blue coloured solution was stirred at ꢀ33 ꢁC for 45 min and then the
reaction was carefully quenched with solid NH4Cl. After evaporation
of ammonia, the residue was taken in water (6 mL) and extracted
with ether (2ꢂ5 mL). The combined organic extract was washed with
brine (4 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 1:4 epimeric mixture of the
bicyclic alcohols 7a and 7b (320 mg, 84%) as oil.
(3H, s) and 0.79 (3H, s) [3ꢂtert-CH3]; 13C NMR (100 MHz):
d 135.5 (C,
C-3), 123.9 (CH, C-4), 97.2 (CH2, OCH2O), 87.1 (CH, C-2), 81.3 (CH, C-
8), 55.9 (CH3, OCH3), 53.9 (CH, C-6), 47.9 (CH2, C-9), 41.9 (C), 39.8 (C),
26.2 (CH3), 25.4 (CH3), 23.6 (CH2, C-5), 20.0 (CH3),14.1 (CH3); HRMS:
m/z Calcd for C15H26O3Na (MþNa): 277.1780; Found: 277.1779.
4.1.6. (1S,2S,6S,8S)-8-Benzyloxy-2-(methoxymethoxy)-1,3,7,7-tetra-
methylbicyclo[4.3.0]non-3-ene (9). To a magnetically stirred sus-
pension of NaH (36 mg, 0.9 mmol) and a catalytic amount of TBAI
(4 mg) in THF (2 mL) was added a solution of the alcohol 7a (92 mg,
0.36 mmol) in THF (1 mL) and benzyl chloride (0.1 mL, 1.08 mmol)
and refluxed for 16 h. It was then quenched with water (3 mL) and
extracted with ether (2ꢂ5 mL). The combined ether extract was
washed with brine (3 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 benzyl ether 9
To a magnetically stirred solution of the alcohols 7a and 7b
(320 mg, 1.26 mmol) in anhydrous CH2Cl2 (2 mL) was added a ho-
mogeneous mixture of PCC (670 mg, 3.12 mmol) and silica gel
(670 mg), and stirred at RT for 2 h. The reaction mixture was filtered
through a small pad of silica gel using CH2Cl2 (10 mL) as eluent.
Evaporation of the solvent and purification of the residue over a silica
gel column using ethyl acetate–hexane (1:19) as eluent furnished the
ketone 8 (291 mg, 92%) as colourless oil. Rf (1:9 EtOAc:hexane) 0.6;
(106 mg, 86%) as oil. Rf (1:19 EtOAc:hexane) 0.6; IR (neat): nmax
/
cmꢀ1 3063, 3028, 2947, 2894, 2858, 1496, 1454, 1381, 1351, 1212,
1151, 1122, 1097, 1068, 1045, 1031, 964, 918, 735, 698; 1H NMR
(300 MHz): d 7.50–6.75 (5H, m, Ar-H), 5.58 (1H, br s, H-4), 4.81 and
[a]
27 64.3 (c 20, CHCl3); IR (neat): nmax/cmꢀ1 3023, 2971, 2951, 2897,
4.75 (2H, 2ꢂd, J 6.6 Hz, OCH2O), 4.66 and 4.52 (2H, 2ꢂd, J 12.0 Hz,
OCH2Ph), 3.84 (1H, br s, H-2), 3.67 (1H, dd, J 8.1 and 2.4 Hz, H-8), 3.49
(3H, s, OCH3), 2.25–1.50 (4H, m), 1.77 (3H, s, olefinic-CH3), 1.42 (1H,
D
2850, 2824, 1739, 1467, 1454, 1411, 1383, 1246, 1214,1193,1152, 1099,
1044, 1032, 980, 919; 1H NMR (400 MHz):
d
5.51 (1H, s, H-4), 4.64
(2H, s, OCH2O), 3.92 (1H, s, H-2), 3.36 (3H, s, OCH3), 2.30 (2H, s, H-9),
2.15–1.80 (3H, m),1.69 (3H, s, olefinic-CH3),1.00 (6H, s) and 0.90 (3H,
dd, J 11.7 and 4.8 Hz), 1.11 (6H, s) and 1.09 (3H, s) [3ꢂtert-CH3]; 13
C
NMR (75 MHz):
d 139.4, 135.9, 130.9, 128.4 (2C), 127.0 (2C), 124.5,
s) [3ꢂtert-CH3]; 13C NMR (100 MHz):
d
222.1 (C, C]O),136.0 (C, C-3),
97.0 (OCH2O), 89.3 (C-2), 87.4 (C-8), 72.0 (OCH2Ph), 55.8 (OCH3),
54.3, 44.7, 44.1, 42.7, 31.8, 23.2, 20.0, 14.5; HRMS: m/z Calcd for
C22H32O3Na (MþNa): 367.2249; Found: 277.1781.
123.4 (CH, C-4), 97.2 (CH2, OCH2O), 86.1 (CH, C-2), 55.8 (CH3, OCH3),
52.1 (CH2, C-9), 51.5 (CH, C-6), 44.9 (C, C-7), 40.8 (C, C-1), 27.7 (CH3),
22.9 (CH2), 21.5 (CH3), 20.0 (CH3), 14.1 (CH3); HRMS: m/z Calcd for
C15H24O3Na (MþNa): 275.1623; Found: 275.1615.
4.1.7. (1S,2S,6R,8S)-8-Benzyloxy-1,3,7,7-tetramethylbicyclo[4.3.0]-
non-3-en-2-ol (10). To a magnetically stirred solution of the MOM
ether 9 (30 mg, 0.09 mmol) in methanol (2 mL) was added a cata-
lytic amount of PTSA (3 mg, 20 mol %) and the reaction mixture was
refluxed for 3 h. The solvent was evaporated under reduced pres-
sure, NaHCO3 solution (3 mL) was added to the reaction mixture
and extracted with ether (2ꢂ5 mL). The combined ether layer was
washed with brine (3 mL) and dried (Na2SO4). Evaporation of the
solvent and purification of the residue over a silica gel column using
4.1.5. (1S,2S,6S,8S) and (1S,2S,6S,8R)-2-(Methoxymethoxy)-1,3,7,7-
tetramethylbicyclo[4.3.0]non-3-en-8-ols (7a and 7b). To a magneti-
cally stirred solution of the ketone 8 (291 mg, 1.15 mmol) in dry
methanol (2 mL) was added NaBH4 (65 mg, 1.73 mmol) in two
portions and stirred at RT for a period of 30 min. The solvent was
evaporated under reduced pressure, water (3 mL) was added to the
reaction mixture and extracted with ether (2ꢂ5 mL). The combined
ether layer was washed with brine (3 mL) and dried (Na2SO4).
Evaporation of the solvent and purification of the residue over
a silver nitrate (15%) impregnated silica gel column using ethyl ac-
etate–hexane (1:9) as eluent first furnished the (1S,2S,6S,8S) isomer
ethyl acetate–hexane (1:19) as eluent furnished the allyl alcohol 10
26
(23 mg, 84%) as colourless oil. Rf (1:19 EtOAc:hexane) 0.4; [a]
D
þ12.8 (c 2.0, CHCl3); IR (neat): nmax/cmꢀ1 3448, 3088, 3064, 3027,
2947, 2896, 2860, 1497, 1454, 1438, 1380, 1364, 1350, 1169, 1120,
7a (212 mg, 66%) as colourless oil. Rf (1:4 EtOAc:hexane) 0.5 on silver
1087,1067,1037, 992, 880, 734, 697; 1H NMR (400 MHz):
d 7.40–7.10
23
nitrate (15%) impregnated silica gel; [
a
]
ꢀ14.6 (c 3.5, CHCl3); IR
(5H, m, Ar-H), 5.43 (1H, br s, H-4), 4.53 and 4.37 (2H, 2ꢂd, J 12.0 Hz,
OCH2Ph), 3.77 (1H, s, H-2), 3.53 (1H, dd, J 7.6 and 2.6 Hz), 2.00–1.20
(4H, m), 1.65 (3H, s, olefinic-CH3), 1.28 (1H, dd, J 12.0 and 3.2 Hz),
D
(neat): nmax/cmꢀ1 3437, 2948, 2894, 2858, 1465, 1439, 1381, 1214,
1151, 1098, 1045, 1032, 1004, 982, 918, 902; 1H NMR (400 MHz):

A. Srikrishna et al. / Tetrahedron 66 (2010) 852–861
857
0.98 (3H, s), 0.96 (3H, s) and 0.95 (3H, s) [3ꢂtert-CH3]; 13C NMR
m, Ar-H), 5.71 (1H, ddt, J 17.0,10.6 and 6.0 Hz, CH]CH2), 5.01 (1H, dd,
J 10.6 and 1.5 Hz) and 4.96 (1H, dd, J 17.1 and 1.6 Hz) [CH]CH2], 4.52
and 4.40 (2H, 2ꢂd, J 12.2 Hz, OCH2Ph), 3.60 (1H, dd, J 5.9 and 2.2 Hz),
3.02 (1H, dd, J 15.0 and 5.7 Hz), 2.90 (1H, dd, J 15.0 and 5.7 Hz), 2.50–
2.25 (2H, m), 2.00–1.50 (3H, m),1.64 (3H, s, olefinic-CH3),1.17 (3H, s),
1.01 (3H, s) and 0.99 (3H, s) [3ꢂtert-CH3]; 13C NMR (100 MHz):
(100 MHz): d 139.3 (C),136.4 (C),128.2 (2C, CH),127.2 (2C, CH),127.1
(CH), 124.3 (CH), 89.1 (CH, C-8), 81.7 (CH, C-2), 71.8 (CH2, OCH2Ph),
54.1 (CH, C-6), 44.7 (C), 43.2 (C), 43.1 (CH2, C-9), 31.5 (CH3), 23.3
(CH2, C-5), 20.0 (CH3), 19.2 (CH3), 13.7 (CH3); HRMS: m/z Calcd for
C20H28O2Na (MþNa): 323.1987; Found: 323.1980.
d
200.3 (C, C]O), 163.3 (C, C-5), 139.0 (C, C-4), 134.0 (CH, CH]CH2),
4.1.8. (1S,6S,8S)-8-Benzyloxy-1,3,7,7-tetramethylbicyclo[4.3.0]non-
3-en-2-one (11). To a magnetically stirred solution of the alcohol 10
(20 mg, 0.07 mmol) in anhydrous CH2Cl2 (0.5 mL) was added a ho-
mogeneous mixture of PCC (45 mg, 0.21 mmol) and silica gel
(45 mg), and stirred at RT for 2.5 h. The reaction mixture was fil-
tered through a small pad of silica gel using CH2Cl2 (10 mL) as el-
uent. Evaporation of the solvent and purification of the residue over
a silica gel column using ethyl acetate–hexane (1:19) as eluent
131.3 (C), 128.3 (2C, CH), 127.3 (CH), 127.0 (2C, CH), 116.5 (CH2,
CH]CH2), 87.9 (CH, C-8), 72.3 (CH2, OCH2Ph), 55.0 (CH, C-1), 47.8 (C),
43.2 (C), 41.2 (CH2), 35.3 (CH2), 35.2 (CH2), 32.1 (CH3), 20.5 (CH3),19.9
(CH3), 11.5 (CH3); HRMS: m/z Calcd for C23H30O2Na (MþNa):
361.2144; Found: 361.2141.
4.1.11. Methyl 2-[(1S,2R,6S)-2-(1-ethoxyethoxy)-6-isopropenyl-1,3-
dimethylcyclohex-3-enyl]acetate (15). To a magnetically stirred so-
lution of the alcohol 5 (480 mg, 2.01 mmol) in dry CH2Cl2 (2 mL)
was added ethyl vinyl ether (0.3 mL, 6.03 mmol) and PPTS (25 mg,
5 mol %) and stirred the reaction mixture at RT for 6 h. Solid
NaHCO3 (15 mg) was added to the reaction mixture and the solvent
was removed under reduced pressure at rt. The residue was puri-
fied on a silica gel column using ethyl acetate–hexane (1:19) as
furnished the enone 11 (19 mg, 86%) as colourless oil. Rf (1:19
26
EtOAc:hexane) 0.55; [
a
]
ꢀ28.1 (c 2.7, CHCl3); IR (neat): nmax/cmꢀ1
D
3065, 2951, 2926, 2868,1681,1454,1375,1355,1199,1157,1142,1112,
1088, 1067, 1050, 1028, 1010, 841, 735, 697; 1H NMR (400 MHz):
d
7.40–7.10 (5H, m, Ar-H), 6.57 (1H, br s, H-4), 4.55 and 4.36 (2H,
2ꢂd, J 12.4 Hz, OCH2Ph), 3.51 (1H, dd, J 7.8 and 2.4 Hz, H-8), 2.40–
2.00 (3H, m), 1.78 (1H, dd, J 14.0 and 2.4 Hz), 1.71 (3H, s, olefinic-
CH3),1.65 (1H, dd, J 11.5 and 4.2 Hz),1.14 (3H, s),1.04 (3H, s) and 0.98
eluent to furnish a 2:3 epimeric mixture of the acetal 15 (562 mg,
21
92%) as oil. Rf (1:19 EtOAc:hexane) 0.6; [
a
]
D
þ49.4 (c 10.8, CHCl3);
(3H, s) [3ꢂtert-CH3]; 13C NMR (100 MHz):
d
204.6 (C, C]O), 143.1
IR (neat): nmax/cmꢀ1 3076, 2981, 2951, 2922, 1738, 1636, 1436, 1378,
(CH, C-4), 139.1 (C), 134.4 (C), 128.3 (2C, CH), 127.3 (CH), 127.1 (2C,
CH), 87.9 (CH, C-8), 71.9 (CH2, OCH2Ph), 54.7 (CH, C-6), 51.4 (C, C-1),
43.6 (C, C-7), 37.7 (CH2, C-9), 31.0 (CH3), 24.7 (CH2, C-5), 20.3 (CH3),
18.3 (CH3), 16.4 (CH3); HRMS: m/z Calcd for C20H26O2Na (MþNa):
321.1830; Found: 321.1817.
1326, 1217, 1162, 1127, 1096, 1058, 1039, 953, 898; 1H NMR
(400 MHz, 2:3 mixture of diastereomers):
d
5.39 (1H, br s, H-40),
4.77 (1H, s), 4.69 (2H, s), 4.59 (1H, q, J 5.0 Hz, OCH(CH3)O), 3.60 and
3.57 (3H, s, OCH3), 3.52 and 3.40 (2H, q, J 7.0 Hz, OCH2CH3), 2.92
(1H, d, J 17.8 Hz), 2.81 (1H, dd, J 10.9 and 4.9 Hz), 2.50–2.00 (2H, m),
1.84 (1H, t, J 18.4 Hz), 1.75 and 1.72 (3H, s, olefinic-CH3), 1.71 and
1.67 (3H, s, olefinic-CH3), 1.29 (3H, d, J 5.0 Hz, OCH(CH3)O), 1.19 and
4.1.9. (1S,2S,6S,8S)-2-Allyl-8-benzyloxy-1,3,7,7-tetramethylbicy-
clo[4.3.0]non-3-en-2-ol (12). To a sonochemically irradiated sus-
pension of zinc (52 mg, 0.8 mmol) in dry THF (2 mL) in a round
bottom flask placed in an ultrasonic clean bath, was added a mixture
of the enone 11 (30 mg, 0.1 mmol) and allyl bromide (0.1 mL,
1.0 mmol) in THF (1 mL) at 15–20 ꢁC over a period of 1 min. The re-
action mixture was sonochemically irradiated for 1 h. The reaction
mixture was then decanted from excess lithium, quenched with
saturated aqueous NH4Cl solution (2 mL) and extracted with ether
(2ꢂ5 mL). The combined ether extract was washed with brine (3 mL)
and dried (Na2SO4). Evaporation of the solvent and purificationof the
residue on a silica gel column using ethyl acetate–hexane (1:19) as
1.10 (3H, t, J 7.0 Hz, OCH2CH3), 0.92 and 0.89 (3H, s) [tert-CH3]; 13
NMR (100 MHz): 172.4 and 172.8 (C, OC]O), 146.2 and 146.1 (C,
C
d
C]CH2), 135.8 and 135.3 (C, C-30), 122.0 and 123.0 (CH, C-40), 114.5
(CH2, C]CH2), 102.0 and 102.1 (CH, OCH(CH3)O), 79.1 and 80.2 (CH,
C-20), 62.5 and 61.8 (CH2, OCH2CH3), 50.8 and 50.4 (CH3, OCH3), 46.2
and 45.5 (CH, C-60), 40.4 and 39.4 (C, C-10), 39.3 and 38.6 (CH2, C-2),
28.9 and 28.7 (CH2, C-50), 22.1 and 22.3 (CH3), 21.1 and 20.4 (CH3),
20.7 and 20.2 (CH3), 15.9 and 15.6 (CH3), 15.5 and 15.1 (CH3); HRMS:
m/z Calcd for C18H30O4Na (MþNa): 333.2042; Found: 333.2036.
4.1.12. (1S,2R,6S)-2-(1-Ethoxyethoxy)-1,3,7,7-tetramethylbicy-
eluent, furnished the tertiary alcohol 12 (29 mg, 85%) as oil. Rf (1:14
clo[4.3.0]non-3-en-8-ol (16). To a magnetically stirred, freshly
26
EtOAc:hexane) 0.5; [
a
]
ꢀ26.4 (c 2.0, CHCl3); IR (neat): nmax/cmꢀ1
distilled (over sodium and ferric chloride) ammonia (20 mL) in
a two-necked round bottom flask equipped with Dewar condenser
was added a solution of the ester 15 (400 mg,1.29 mmol) in dry THF
(1 mL) followed by freshly cut lithium (45 mg, 6.45 mmol). The
resulting blue coloured solution was stirred at ꢀ33 ꢁC for 45 min
and then the reaction was carefully quenched with solid NH4Cl.
After evaporation of ammonia, the residue was taken in water
(5 mL) and extracted with ether (3ꢂ5 mL). The combined organic
extract was washed with brine (10 mL) and dried (Na2SO4). Evap-
oration of the solvent and purification of the residue on a silica gel
column using ethyl acetate–hexane (1:9) as eluent furnished a di-
D
3490, 3068, 2948, 2863, 1637, 1497, 1453, 1378, 1364, 1352, 1159,
1088, 1068, 1028, 1002, 908, 811, 734, 697; 1H NMR (400 MHz):
d
7.30–7.10 (5H, m, Ar-H), 5.81 (1H, ddt, J 16.9, 9.8 and 6.7 Hz,
CH]CH2), 5.47 (1H, br s, H-4), 4.98 (1H, d, J 16.9) and 4.96 (1H, d, J
9.8 Hz) [CH]CH2], 4.53 and 4.36 (2H, 2ꢂd, J 12.2 Hz, OCH2Ph), 3.47
(1H, dd, J 7.4 and 3.6 Hz, H-8), 2.55–2.25 (2H, m), 2.06 (1H, dd, J 13.8
and 7.4 Hz), 2.00–1.25 (5H, m), 1.65 (3H, s, olefinic-CH3), 1.05 (3H, s),
0.97 (3H, s) and 0.93 (3H, s) [3ꢂtert-CH3]; HRMS: m/z Calcd for
C23H32O2Na (MþNa): 363.2292; Found: 363.2274.
4.1.10. (1R,6S,8S)-5-Allyl-8-benzyloxy-4,6,9,9-tetramethylbicy-
clo[4.3.0]non-4-en-3-one (13). To a magnetically stirred solution of
the alcohol 12 (23 mg, 0.07 mmol) in anhydrous CH2Cl2 (0.5 mL) was
added a homogeneous mixture of PCC (60 mg, 0.27 mmol) and silica
gel (60 mg), and stirred at RT for 8 h. The reaction mixture was then
filtered through a small pad of silica gel using CH2Cl2 (10 mL) as el-
uent. Evaporation of the solvent and purification of the residue over
a silica gel column using ethyl acetate–hexane (1:19) as eluent fur-
astereomeric mixture of the bicyclic alcohol 16 (302 mg, 83%) as oil.
21
Rf (1:9 EtOAc:hexane) 0.5; [
a
]
ꢀ28.9 (c 19.0, CHCl3); IR (neat):
D
nmax/cmꢀ1 3402, 2973, 2895, 1448, 1378, 1342, 1328, 1147, 1125,
1095, 1035, 998, 935, 892, 807; 1H NMR (400 MHz, mixture
of isomers):
d 5.42 (1H, br s, H-4), 4.90–4.60 (1H, m, J 5.3 Hz,
OCH(CH3)O), 4.20–3.30 (4H, m), 2.30–1.50 (5H, m), 1.68 and 1.63
(3H, s, olefinic-CH3), 1.30 (3H, d, J 5.2 Hz), 1.25–1.00 (4H, m), 0.96
(3H, s), 0.88 (3H, s), 0.87 and 0.81 (3H, s); 13C NMR (100 MHz,
nished the enone 13 (18 mg, 71%) as colourless oil. Rf (1:19 EtOA-
signals due to two major isomers): d 136.1 and 135.9 (C, C-3), 123.6
25
c:hexane) 0.5; [
a
]
þ49.0 (c 2.0, CHCl3); IR (neat): nmax/cmꢀ1 3065,
and 123.4 (CH, C-4), 101.2 and 99.2 (CH, OCH(CH3)O), 85.7 and 85.1
(CH, C-2), 81.4 and 81.2 (CH, C-8), 59.9 and 59.5 (CH2, OCH2CH3),
54.0 (CH, C-6), 48.3 and 48.0 (CH), 42.2 (C), 40.0 and 39.4 (C), 26.3
D
3030, 2948, 2866,1663,1607,1454,1376,1352,1322,1280,1158,1096,
1066, 1028, 993, 913, 735, 697; 1H NMR (400 MHz):
d 7.35–7.10 (5H,

858
A. Srikrishna et al. / Tetrahedron 66 (2010) 852–861
and 26.2 (CH3), 25.5 (CH3), 23.6 and 23.5 (CH2), 20.3 and 20.2 (CH3),
20.1 and 19.9 (CH3), 15.5 and 15.4 (CH3), 14.2 and 14.1 (CH3); HRMS:
m/z Calcd for C17H30O3Na (MþNa): 305.2085; Found: 305.2085.
Evaporation of the solvent and purification of the residue over
a silica gel column using ethyl acetate–hexane (1:19) as eluent
furnished the MOM ether 19 (161 mg, 92%) as colourless oil. Rf (1:19
26
EtOAc:hexane) 0.5; [
a]
ꢀ98.0 (c 2.4, CHCl3); IR (neat): nmax/cmꢀ1
D
4.1.13. (1S,2S,6S)-1,3,7,7-Tetramethylbicyclo[4.3.0]non-3-ene-2,8-
diol (17). To a magnetically stirred solution of the alcohol 16
(372 mg, 1.33 mmol) in methanol (2 mL) was added PPTS (35 mg,
10 mol %) and the reaction mixture was stirred at RT for 6 h. Solid
NaHCO3 (20 mg) was added to the reaction mixture. Solvent was
then removed under reduced pressure at RT and the residue was
purified on a silica gel column using ethyl acetate–hexane (1:3) as
2961, 2929, 2889, 1682, 1466, 1450, 1375, 1147, 1103, 1047, 999, 917,
843; 1H NMR (400 MHz):
d 6.54 (1H, br s, H-4), 4.56 and 4.52 (2H,
2ꢂd, J 6.7 Hz, OCH2O), 3.86 (1H, dd, J 9.5 and 6.8 Hz, H-8), 3.28 (3H,
s, OCH3), 2.30–2.00 (3H, m), 1.90 (1H, dd, J 10.3 and 5.6 Hz), 1.69
(3H, s, olefinic-CH3), 1.60 (1H, dd, J 12.3 and 10.0 Hz), 1.01 (3H, s),
0.99 (3H, s) and 0.88 (3H, s) [3ꢂtert-CH3]; 13C NMR (100 MHz):
d
203.7 (C, C]O), 142.6 (CH, C-4), 134.3 (C, C-3), 95.9 (CH2, OCH2O),
eluent to furnish a 1:4 epimeric mixture of the alcohol 17 (239 mg,
84.9 (CH, C-8), 55.1 (CH3, OCH3), 54.6 (CH, C-6), 49.1 (C, C-1), 40.8
(C, C-7), 39.3 (CH2), 27.2 (CH3), 25.8 (CH3), 24.8 (CH2), 17.5 (CH3) and
16.3 (CH3); HRMS: m/z Calcd for C15H24O3Na (MþNa): 275.1617;
Found: 275.1608.
25
86%) as oil. Rf (1:3 EtOAc:hexane) 0.4; [
a]
ꢀ45.5 (c 7.2, CHCl3); IR
D
(neat): nmax/cmꢀ1 3376, 2955, 2925, 2893, 2864, 1450, 1381, 1346,
1256, 1149, 1121, 1048, 1036, 995, 877; 1H NMR (400 MHz, 1:4
epimeric mixture):
d 5.45 (1H, br s, H-4), 4.04 (1H, dd, J 9.6 and
7.0 Hz, H-8), 3.89 and 3.82 (1H, br s, H-2), 2.22 (1H, dd, J 11.9 and
4.1.16. (1S,2S,6S,8R)-2-Allyl-8-(methoxymethoxy)-1,3,7,7-tetrame-
thylbicyclo[4.3.0]non-3-en-2-ol (21). To a sonochemically irradiated
suspension of lithium (44 mg, 6.34 mmol) in dry THF (2 mL) in
a round bottom flask placed in an ultrasonic cleaning bath, was
added a solution of the enone 19 (160 mg, 0.63 mmol) and allyl
bromide (0.4 mL, 5.07 mmol) in THF (1 mL) at 15–20 ꢁC over a pe-
riod of 2 min. The reaction mixture was sonochemically irradiated
for 1 h. The reaction mixture was then decanted from the excess
lithium, quenched with saturated aqueous NH4Cl solution (4 mL)
and extracted with ether (2ꢂ5 mL). The combined ether extract
was washed with brine (4 mL) and dried (Na2SO4). Evaporation of
the solvent and purification of the residue on a silica gel column
6.6 Hz), 2.00–1.20 (8H, m), 1.70 (3H, s, olefinic-CH3), 1.00 (3H, s),
0.96 and 0.90 (3H, s), 0.85 (3H, s); 13C NMR (100 MHz):
d 136.5 and
136.0 (C, C-3), 124.1 and 123.5 (CH, C-4), 82.2 and 81.4 (CH, C-2),
81.5 and 81.0 (CH, C-8), 54.1 and 53.7 (CH, C-6), 46.6 and 47.1 (CH2,
C-9), 42.9 and 42.2 (C, C-1), 40.4 (C, C-7), 26.2 (CH3), 30.6 and 25.5
(CH3), 23.3 and 23.7 (CH2), 19.2 (CH3), 14.3 and 13.4 (CH3); HRMS:
m/z Calcd for C13H21O (MꢀOH): 193.1587; Found: 193.1592.
4.1.14. (1S,6S,8S) and (1S,6S,8R)-8-Hydroxy-1,3,7,7-tetramethylbicy-
clo[4.3.0]non-3-en-2-ones (18a and 18b). To a magnetically stirred
solution of the diol 28 (208 mg, 0.99 mmol) in dry CH2Cl2 (2 mL)
was added MnO2 (258 mg, 2.97 mmol) and stirred at RT for 8 h.
The reaction mixture was filtered through a small pad of silica gel
column using CH2Cl2 (15 mL) as eluent. Evaporation of the solvent
and purification of the residue on a silica gel column using ethyl
using ethyl acetate–hexane (1:19) as eluent furnished the tertiary
26
alcohol 21 (165 mg, 88%) as oil. Rf (1:19 EtOAc:hexane) 0.45; [a]
D
ꢀ99.1 (c 1.1, CHCl3); IR (neat): nmax/cmꢀ1 3502, 3076, 2956, 2891,
2845, 1637, 1465, 1448, 1376, 1215, 1147, 1121, 1104, 1047, 998, 908,
acetate–hexane (1:19) as eluent first furnished the 1S,6S,8S-iso-
816; 1H NMR (400 MHz):
d 5.85 (1H, ddt, J 17.1, 10.0 and 6.1 Hz,
26
mer 18b (36 mg, 17%) as oil. Rf (1:4 EtOAc:hexane) 0.45; [
a
]
CH]CH2), 5.50 (1H, br s, H-4), 5.11 (1H, d, J 17.1 Hz) and 5.06 (1H, d,
J 10.1 Hz) [CH]CH2], 4.65 and 4.62 (2H, 2ꢂd, J 6.6 Hz, OCH2O), 3.89
(1H, dd, J 10.2 and 6.4 Hz, Hd8), 3.36 (3H, s, OCH3), 2.51 (1H, dd, J
14.4 and 6.0 Hz), 2.44 (1H, dd, J 14.4 and 8.8 Hz), 2.00–1.60 (5H, m),
1.69 (3H, s, olefinic-CH3), 1.55 (1H, br s, OH), 1.01 (3H, s), 0.93 (3H, s)
D
ꢀ56.1 (c 0.7, CHCl3); IR (neat): nmax/cmꢀ1 3466, 2954, 2926, 2899,
1672, 1450, 1433, 1375, 1195, 1158, 1107, 1089, 1046, 1023, 842,
830; 1H NMR (300 MHz):
d 6.63 (1H, br s, H-4), 3.91 (1H, dd, J 7.8
and 3.0 Hz, H-8), 2.36 (1H, dd, J 14.4 and 8.1 Hz), 2.40–2.10 (2H,
m), 1.77 (3H, s, olefinic-CH3), 1.73 (1H, dd, J 11.4 and 4.5 Hz), 1.62
(1H, dd, J 14.4 and 2.4 Hz), 1.55 (1H, br s, OH), 1.21 (3H, s) and 1.03
and 0.88 (3H, s) [3ꢂtert-CH3]; 13C NMR (100 MHz):
d 137.7 (C, C-3),
135.6 (CH, CH]CH2), 124.7 (CH, C-4), 117.6 (CH2, CH]CH2), 96.2
(CH2, OCH2O), 85.9 (CH, C-8), 78.2 (C, C-2), 55.1 (CH3, OCH3), 50.1
(CH, C-6), 45.6 (C), 41.2 (CH2), 39.6 (C), 39.3 (CH2), 26.8 (CH3), 26.5
(CH3), 23.8 (CH2), 18.4 (CH3), 16.8 (CH3); HRMS: m/z Calcd for
C18H30O3Na (MþNa): 317.2093; Found: 317.2101.
(6H, s) [3ꢂtert-CH3]; 13C NMR (75 MHz):
d 204.1 (C]O), 142.6 (C-
4), 134.5 (C-3), 81.3 (C-8), 54.9 (C-1), 51.2 (C-7), 43.5, 41.4, 30.3,
24.8, 19.6, 18.7, 16.4.
Further elution of the column with ethyl acetate–hexane (1:9)
as eluent furnished the 1S,6S,8R-isomer 18a (146 mg, 71%) as oil.
21
Rf (1:4 EtOAc:hexane) 0.4; [
a]
ꢀ130.7 (c 1.3, CHCl3); IR (neat):
4.1.17. (1R,6S,8R)-5-Allyl-8-(methoxymethoxy)-4,6,9,9-tetrame-
thylbicyclo[4.3.0]non-4-en-3-one (22). To a magnetically stirred
solution of the tertiary alcohol 21 (165 mg, 0.56 mmol) in anhy-
drous CH2Cl2 (1 mL) was added a homogeneous mixture of PCC
(240 mg, 1.12 mmol) and silica gel (240 mg) and stirred at RT for
8 h. The reaction mixture was filtered through a small pad of silica
gel column using CH2Cl2 (10 mL) as eluent. Evaporation of the
solvent and purification of the residue over a silica gel column using
D
nmax/cmꢀ1 3250, 2962, 2949, 2889, 2859, 1671, 1466, 1449, 1376,
1259, 1196, 1182, 1122, 1066, 1046, 1034, 1000, 962, 851, 742; 1H
NMR (400 MHz):
d 6.62 (1H, br s, H-4), 4.07 (1H, dd, J 8.9 and
7.2 Hz, H-8), 2.30–2.10 (3H, m), 1.98 (1H, dd, J 10.8 and 4.9 Hz),
1.75 (3H, s, olefinic-CH3), 1.90–1.50 (1H, m), 1.64 (1H, dd, J 12.7
and 9.4 Hz), 1.06 (3H, s), 1.05 (3H, s) and 0.94 (3H, s) [3ꢂtert-CH3];
13C NMR (100 MHz):
d 204.2 (C, C]O), 143.1 (CH, C-4), 134.2 (C, C-
3), 80.5 (CH, C-8), 54.6 (CH, C-6), 49.0 (C, C-1), 41.9 (CH2, C-9), 41.0
(C, C-7), 26.4 (CH3), 25.0 (CH3), 24.9 (CH2, C-5), 17.7 (CH3), 16.3
(CH3); HRMS: m/z Calcd for C13H20O2Na (MþNa): 231.1361; Found:
231.1358.
ethyl acetate–hexane (1:19) as eluent furnished the enone 22
25
(148 mg, 90%) as oil. Rf (1:19 EtOAc:hexane) 0.5; [
a
]
D
ꢀ8.3 (c 4.0,
CHCl3); IR (neat): nmax/cmꢀ1 3080, 2958, 2935, 2889, 2822, 1666,
1607, 1465, 1377, 1324, 1276, 1215, 1200, 1146, 1105, 1080, 1046, 995,
916; 1H NMR (400 MHz):
d 5.75 (1H, ddt, J 16.9, 10.7 and 6.1 Hz,
4.1.15. (1S,6S,8R)-8-Methoxymethoxy-1,3,7,7-tetramethylbicy-
clo[4.3.0]non-3-en-2-one (19). To an ice cold solution of the alcohol
18a (144 mg, 0.69 mmol) in dry CH2Cl2 (1.5 mL) were added DIPEA
(0.3 mL, 1.72 mmol), DMAP (8 mg, 10 mol %) and MOMCl (0.2 mL,
2.41 mmol), and stirred for 30 min at the same temperature. The
reaction mixture was stirred at RT for 5 h and then poured into
water (3 mL) and extracted with CH2Cl2 (2ꢂ5 mL). Combined
CH2Cl2 extract was washed with brine (4 mL) and dried (Na2SO4).
CH]CH2), 5.06 (1H, dd, J 10.7 and 1.5 Hz) and 5.03 (1H, dd, J 16.9
and 1.6 Hz) [CH]CH2], 4.63 and 4.61 (2H, 2ꢂd, J 6.7 Hz, OCH2O),
3.96 (1H, dd, J 9.7 and 6.9 Hz), 3.34 (3H, s, OCH2OCH3), 3.05 (1H, dd,
J 14.8 and 6.0 Hz), 2.97 (1H, dd, J 14.8 and 6.1 Hz), 2.50–2.20 (2H, m),
2.17 (1H, dd, J 11.6 and 6.6 Hz), 2.06 (1H, dd, J 13.2 and 5.9 Hz), 1.69
(3H, s, olefinic-CH3), 1.64 (1H, t, J 10.6 Hz), 1.05 (3H, s), 1.03 (3H, s)
and 0.93 (3H, s) [3ꢂtert-CH3]; 13C NMR (100 MHz):
d 199.9 (C,
C]O), 162.6 (C, C-5), 133.7 (CH, CH]CH2), 131.4 (C, C-4), 116.7 (CH2,

A. Srikrishna et al. / Tetrahedron 66 (2010) 852–861
859
CH]CH2), 96.3 (CH2, OCH2O), 84.7 (CH, C-8), 55.2 (CH, C-1), 54.5
(CH3, OCH3), 44.8 (C, C-6), 42.2 (CH2, C-2), 40.0 (C, C-9), 35.4 (CH2),
35.1 (CH2), 26.2 (CH3), 25.7 (CH3), 20.8 (CH3), 11.4 (CH3); HRMS: m/z
Calcd for C18H28O3Na (MþNa): 315.1936; Found: 315.1935.
917, 694, 662, 609; 1H NMR (400 MHz, CDCl3):
d
5.80–5.40 (2H, m,
olefinic H), 4.63 and 4.60 (2H, 2ꢂd, J 6.6 Hz, OCH2O), 4.02 (1H, dd, J
9.8 and 7.0 Hz, H-4), 3.35 (3H, s, OCH3), 2.56 (1H, t, J 14.8 Hz), 2.40–
1.80 (6H, m),1.75–1.50 (2H, m),1.08 (1H, t, J 6.8 Hz),1.06 (6H, s),1.00
(3H, s) and 0.91 (3H, s) [4ꢂtert-CH3]; 13C NMR (100 MHz, CDCl3):
4.1.18. (1R,6R,8R)-5-Allyl-8-(methoxymethoxy)-4,6,9,9-tetrame-
thylbicyclo[4.3.0]non-3-en-3-yl allyl ether (23) and (1R,4S,5R,6S,8R)-4,
5-bisallyl-8-methoxymethoxy-4,6,9,9-tetramethylbicyclo[4.3.0]-
nonan-3-one (20). To a magnetically stirred, freshly distilled (over
sodium and ferric chloride) ammonia (15 mL) in a two-necked
round bottom flask equipped with Dewar condenser was added
a solution of the enone 22 (150 mg, 0.51 mmol) and tBuOH (0.1 mL)
in dry THF (3 mL) followed by freshly cut lithium (22 mg,
3.05 mmol). The resulting blue coloured solution was stirred at
ꢀ33 ꢁC for 10 min and it was then carefully treated with allyl bro-
mide (0.4 mL, 5.13 mmol) and stirred the reaction mixture for
40 min. After evaporation of ammonia, NH4Cl solution (5 mL) was
added to the residue and extracted with ether (2ꢂ5 mL). The
combined organic extract was washed with brine (4 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
d 215.2 (C, C]O),125.5 (CH),125.1 (CH), 96.2 (CH2, OCH2O), 85.9 (CH,
C-4), 58.8 (CH), 55.2 (CH3, OCH3), 52.1 (CH, C-1), 46.9 (C, C-9), 46.7
(CH2), 41.1 (C), 40.5 (C), 38.0 (CH2), 36.7 (CH2), 25.9 (CH3), 25.7 (CH3),
24.7 (CH2), 19.3 (CH3) and 15.8 (CH3); HRMS: m/z Calcd for
C19H30O3Na (MþNa): 329.2093; Found: 329.2079.
4.1.20. (1S,2R,6S)-2-(1-Ethoxyethoxy)-1,3,7,7-tetramethylbicy-
clo[4.3.0]non-3-en-8-one (25). To a magnetically stirred solution of
the diastereomeric mixture of the alcohol 16 (150 mg, 0.53 mmol)
in DMSO (2 mL) was added IBX (300 mg, 1.06 mmol), and the re-
action mixture was stirred at RT for 1 h. Water (5 mL) and saturated
NaHCO3 solution (4 mL) were added to the reaction mixture and
extracted with ether (2ꢂ5 mL). The combined ether layer was
washed with brine (4 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 1:1 di-
furnished an epimeric mixture of the O-allylated compound 23
astereomeric mixture of the ketone 25 (122 mg, 82%) as oil. Rf (1:19
EtOAc:hexane) 0.5; [a]
D
þ63.1 (c 5.0, CHCl3); IR (neat): nmax/cmꢀ1
25
21
(21 mg, 12%) as oil. Rf (1:19 EtOAc:hexane) 0.5; [
a
]
ꢀ25.6 (c 1.6,
D
CHCl3). IR (neat): nmax/cmꢀ1 3077, 2958, 2928, 1667, 1639, 1465,
2975, 2934, 2898, 1740, 1455, 1384, 1246, 1127, 1095, 1055, 1038,
1376,1330,1298,1214,1148,1101,1048, 996, 917; 1H NMR (400 MHz,
935, 892; 1H NMR (400 MHz, mixture of isomers):
d 5.52 and 5.50
mixture of diastereomers):
d
6.10–5.70 (2H, m, 2ꢂCH]CH2), 5.31
(1H, br s, H-4), 4.72 and 4.70 (1H, q, J 5.2 Hz), 4.12 and 3.90 (1H, s, H-
2), 3.75–3.25 (2H, m), 2.50–2.20 (2H, m), 2.10–1.75 (3H, m),1.73 and
1.68 (3H, s, olefinic-CH3), 1.32 and 1.31 (3H, d, J 5.4 Hz, OCH(CH3)O),
(1H, d, J 17.1 Hz), 5.18 (1H, d, J 10.4 Hz), 5.07–4.90 (2H, m), 4.75–4.50
(2H, m, OCH2O), 4.30–4.15 (2H, m, OCH2), 3.90–3.75 (1H, m), 3.37
and 3.36 (3H, s, OCH3), 2.50–1.20 (7H, m), 1.67 and 1.62 (3H, s), 1.02
(3H, s), 0.92 (3H, s), 0.87 and 0.75 (3H, s); 13C NMR (100 MHz,
1.18 (3H, t, J 6.5 Hz, OCH2CH3), 1.00 (3H, s), 0.91 and 0.87 (3H, s); 13
C
NMR (100 MHz, mixture of isomers):
d 223.1 and 222.4 (C, C]O),
mixture of diastereomers):
d
147.6 and 147.0 (C, C-3), 140.0 and
136.5 and 136.2 (C, C-3), 123.4 and 123.3 (CH, C-4), 101.4 and 98.8
(CH, OCH(CH3)O), 85.6 and 83.3 (CH, C-2), 59.5 and 59.4 (CH2,
OCH2CH3), 52.5 and 52.4 (CH2, C-9), 51.6 and 51.5 (CH, C-6), 45.3
and 44.4 (C, C-7), 41.0 (C, C-1), 27.8 (CH3), 23.0 and 22.9 (CH2), 21.6
(CH3), 20.3 and 20.2 (CH3), 20.0 and 19.7 (CH3), 15.5 and 15.4 (CH3),
14.2 and 14.1 (CH3); HRMS: m/z Calcd for C17H28O3Na (MþNa):
303.1936; Found: 303.1927.
139.2 (CH), 134.9 (CH), 117.3 and 117.1 (C, C-4), 116.6 (CH2), 114.7 and
114.6 (CH2), 96.2 and 96.1 (CH2, OCH2O), 86.3 and 86.2 (CH, C-8),
69.3 and 69.1 (CH2, OCH2), 55.6 and 55.1 (CH3, OCH3), 51.8 and 50.3
(CH, C-5), 48.3 (CH, C-1), 45.6 and 41.5 (CH2), 41.0 and 40.3 (C), 39.2
and 39.0 (C), 34.1 and 33.8 (CH2), 26.7 and 26.6 (CH3), 26.5 and 26.3
(CH3), 24.1 and 23.7 (CH2), 22.0 and 15.8 (CH3), 14.4 and 13.4 (CH3).
Further elution of the column with ethyl acetate–hexane (1:19)
furnished the Cdallylated ketone 20 (120 mg, 70%) as oil. Rf (1:9
4.1.21. (1S,2S,6S)-1,3,7,7-Tetramethyl-8-methylenebicyclo[4.3.0]non-
3-en-2-ol (26). To an ice cold suspension of Mg (820 mg,
34.24 mmol) and TiCl4 (0.9 mL, 8.56 mmol) in CH2Cl2 (5 mL) was
added drop wise a solution of the ketone 25 (300 mg, 1.07 mmol) in
CH2Cl2 (2 mL) and THF (2 mL), and stirred for 30 min at 0 ꢁC, and
then stirred at RT for 5 h. The reaction mixture was recooled to 0 ꢁC
and saturated K2CO3 solution (3 mL) was added followed by 3 N HCl
(10 mL) and stirred for 15 min and extracted with ether (2ꢂ10 mL).
The combined ether layer 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 (1:19) as eluent
26
EtOAc:hexane) 0.5; [
a]
ꢀ27.9 (c 4.0, CHCl3); IR (neat): nmax/cmꢀ1
D
3076, 2957, 2935, 2888, 2823, 1699, 1639, 1466, 1442, 1416, 1376,
1214, 1146, 1120, 1102, 1046, 995, 916; 1H NMR (400 MHz):
d 5.77
(1H, ddt, J 17.2,10.0 and 6.6 Hz), 5.60–5.40 (1H, m), 5.10–4.85 (4H, m,
2ꢂCH]CH2), 4.59 and 4.56 (2H, 2ꢂd, J 6.7 Hz, OCH2O), 3.88 (1H, dd,
J 9.9 and 6.8 Hz), 3.33 (3H, s, OCH3), 2.49 (1H, dd, J 13.7 and 5.5 Hz),
2.40–2.10 (5H, m), 2.05 (1H, dd, J 13.7 and 9.1 Hz), 1.81 (1H, t, J
6.7 Hz), 1.61 (1H, dd, J 14.6 and 5.4 Hz), 1.23 (1H, t, J 10.8 Hz), 1.07
(3H, s), 0.96 (3H, s), 0.92 (3H, s) and 0.90 (3H, s) [4ꢂtert-CH3]; 13C
NMR (100 MHz):
d 215.0 (C, C]O), 139.4 (CH) and 134.9 (CH)
[2ꢂCH]CH2], 118.5 (CH2) and 115.5 (CH2) [2ꢂCH]CH2], 96.1 (CH2,
OCH2O), 85.6 (CH, C-8), 55.1 (CH3, OCH3), 54.9 (CH, C-5), 52.2 (C, C-
4), 52.0 (CH, C-1), 47.3 (CH2), 44.9 (CH2), 42.6 (C), 39.9 (C), 37.0 (CH2),
32.7 (CH2), 26.2 (CH3), 26.1 (CH3), 23.1 (CH3), 15.9 (CH3); HRMS: m/z
Calcd for C21H34O3Na (MþNa): 357.2406; Found: 357.2392.
furnished the alcohol 26 (174 mg, 79%) as oil. Rf (1:19 EtOAc:hexane)
26
0.5; [
a
]
þ8.1 (c 1.8, CHCl3); IR (neat): nmax/cmꢀ1 3402, 3068, 3019,
D
2975, 2956, 2920, 2894, 2859, 1652, 1462, 1438, 1378, 1362, 1060,
1035, 995, 880; 1H NMR (400 MHz):
d 5.47 (1H, br s, H-4), 4.91 (1H, d,
J 2.4 Hz) and 4.82 (1H, d, J 2.4 Hz) [C]CH2], 3.94 (1H, br s, H-2), 2.42
and 2.22 (2H, 2ꢂd, J 14.7 Hz, H-9), 2.00–1.50 (2H, m), 1.72 (3H, s,
olefinic-CH3),1.62 (1H, t, J 8.6 Hz),1.36 (1H, br s, OH),1.06 (3H, s),1.04
4.1.19. (1R,2S,4R,6R,9S)-4-(Methoxymethoxy)-2,5,5,9-tetramethyl-
tricyclo[7.4.0.02,6]tridec-11-en-8-one (24). To a magnetically stirred
solution of the bisallyl ketone 20 (30 mg, 0.09 mmol) in anhydrous
CH2Cl2 (3 mL) was added a solution of Grubbs first generation cat-
alyst (6 mg, 10 mol %) in anhydrous CH2Cl2 (6 mL) and the reaction
mixture was stirred at RT for 4 h. Evaporation of the solvent and
purification of the residue on a silica gel column using ethyl acetate–
(3H, s) and 0.80 (3H, s) [3ꢂtert-CH3]; 13C NMR (100 MHz):
d 161.6 (C,
C-8),136.5 (C, C-3),123.7 (CH, Cd4),105.5 (CH2, C]CH2), 80.6 (CH, C-
2), 54.2 (CH, C-6), 46.9 (CH2, C-9), 43.9 (C), 41.3 (C), 32.5 (CH3), 26.3
(CH3), 23.7 (CH2, C-5), 19.2 (CH3), 12.0 (CH3); HRMS: m/z Calcd for
C14H21 (MꢀOH): 189.1643; Found: 189.1643.
hexane (1:19) as eluent furnished the tricyclic ketone 24 (25 mg,
4.1.22. (1S,6S)-1,3,7,7-Tetramethyl-8-methylenebicyclo[4.3.0]non-3-
en-2-one (27). To a magnetically stirred solution of the alcohol 26
(130 mg, 0.63 mmol) in anhydrous CH2Cl2 (1 mL) was added a ho-
mogeneous mixture of PCC (340 mg, 1.57 mmol) and silica gel
26
91%) as oil. Rf (1:19 EtOAc:hexane) 0.5; [
a]
ꢀ38.0 (c 2.0, CHCl3); IR
D
(neat): nmax/cmꢀ1 3023, 2951, 2897, 1704, 1651, 1467, 1450, 1376,
1305, 1258, 1216, 1186, 1158, 1144, 1120, 1104, 1086, 1072, 1049, 993,

860
A. Srikrishna et al. / Tetrahedron 66 (2010) 852–861
(340 mg), and stirred at RT for 2 h. The reaction mixture was fil-
tered through a small pad of silica gel using CH2Cl2 (10 mL) as el-
uent. Evaporation of the solvent and purification of the residue over
a silica gel column using ethyl acetate–hexane (1:19) as eluent
(C), 44.1 (CH2, C-2), 41.2 (C), 35.3 (CH2), 35.2 (CH2), 32.0 (CH3), 25.4
(CH3), 19.9 (CH3), 11.5 (CH3); HRMS: m/z Calcd for C17H25O (MþH):
245.1905; Found: 245.1911.
furnished the enone 27 (118 mg, 92%) as colourless oil. Rf (1:19
4.1.25. (1R,4S,5R,6S)-4,5-bisallyl-4,6,9,9-tetramethyl-8-methyl-
enebicyclo[4.3.0]nonan-3-one (30). To a magnetically stirred,
21
EtOAc:hexane) 0.55; [
a]
ꢀ49.3 (c 1.5, CHCl3); IR (neat): nmax/cmꢀ1
D
3070, 2959, 2924, 2863, 1682, 1655, 1462, 1448, 1434, 1371, 1354,
freshly distilled (over sodium and ferric chloride) ammonia (15 mL)
in a two-necked round bottom flask equipped with Dewar con-
denser was added a solution of the enone 29 (100 mg, 0.41 mmol)
and tBuOH (0.1 mL) in dry THF (2 mL) followed by freshly cut lith-
ium (14 mg, 2 mmol). The resulting blue coloured solution was
stirred at ꢀ33 ꢁC for 10 min and then the enolate was carefully
quenched with allyl bromide (0.4 mL, 4.10 mmol) and stirred the
reaction mixture at ꢀ33 ꢁC to RT for 40 min. After evaporation of
ammonia, NH4Cl solution (5 mL) was added to the residue and
extracted with ether (2ꢂ5 mL). The combined organic extract was
washed with brine (4 mL) and dried (Na2SO4). Evaporation of the
solvent and purification of the residue on a silica gel column using
1195, 1047, 1009, 883, 841; 1H NMR (400 MHz):
d 6.64 (1H, s, H-4),
4.99 (1H, d, J 2.3 Hz) and 4.88 (1H, d, J 2.3 Hz) [C]CH2], 2.56 and
2.33 (2H, 2ꢂd, J 15.5 Hz, H-9), 2.30–2.20 (2H, m), 2.00 (1H, dd, J 9.7
and 6.0 Hz), 1.77 (3H, s, olefinic-CH3), 1.10 (3H, s), 1.08 (3H, s) and
1.00 (3H, s) [3ꢂtert-CH3]; 13C NMR (100 MHz):
d 204.0 (C, C]O),
159.6 (C, C-8), 142.9 (CH, C-4), 134.9 (C, C-3), 106.9 (CH2, C]CH2),
55.0 (CH, C-6), 50.2 (C, C-1), 41.7 (C, C-7), 41.3 (CH2, C-9), 31.9 (CH3),
26.6 (CH3), 24.9 (CH2), 16.9 (CH3), 16.3 (CH3); HRMS: m/z Calcd for
C14H21O (MþH): 205.1592; Found: 205.1593.
4.1.23. (1S,2S,6S)-2-Allyl-1,3,7,7-tetramethyl-8-methylenebi-
cyclo[4.3.0]non-3-en-2-ol (28). To a sonochemically irradiated sus-
pension of lithium (32 mg, 4.62 mmol) in dry THF (2 mL) in a round
bottom flask placed in an ultrasonic cleaning bath, was added
a mixture of the enone 27 (118 mg, 0.58 mmol) and allyl bromide
(0.3 mL, 3.46 mmol) in THF (1 mL) at 15–20 ꢁC over a period of
2 min. The reaction mixture was sonochemically irradiated for 1 h.
The reaction mixture was then decanted from the excess lithium,
quenched with saturated aqueous NH4Cl solution (4 mL) and
extracted with ether (2ꢂ5 mL). The combined ether extract was
washed with brine (4 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 the bisallyl ketone 30
21
(89 mg, 76%) as oil. Rf (1:6 CH2Cl2:hexane) 0.6; [
a
]
þ20.7 (c 3.5,
D
CHCl3); IR (neat): nmax/cmꢀ1 3075, 2976, 2959, 2886, 1703, 1654,
1639, 1462, 1442, 1416, 1375, 998, 912, 882; 1H NMR (400 MHz):
d
5.95–5.70 (1H, m) and 5.70–5.50 (1H, m) [2ꢂCH]CH2], 5.15–4.89
(4H, m, 2ꢂCH]CH2), 4.90 (1H, s) and 4.85 (1H, s) [C]CH2], 2.75–
2.00 (8H, m), 1.87 (1H, t, J 6.4 Hz), 1.65 (1H, dd, J 15.0 and 4.7 Hz),
1.09 (3H, s), 1.04 (3H, s), 0.99 (3H, s) and 0.92 (3H, s) [4ꢂtert-CH3];
13C NMR (100 MHz):
d 214.9 (C, C]O), 160.7 (C, C-8), 138.9 (CH,
CH]CH2), 134.7 (CH, CH]CH2), 117.8 (CH2, CH]CH2), 115.0 (CH2,
CH]CH2), 105.8 (CH2, C]CH2), 55.5 (CH, C-1), 52.1 (C), 50.4 (CH, C-
5), 49.3 (CH2, C-2), 43.6 (C), 43.4 (CH2), 40.4 (C), 36.6 (CH2), 31.9
(CH2), 31.8 (CH3), 24.8 (CH3), 22.4 (CH3) and 14.4 (CH3); HRMS: m/z
Calcd for C20H30O (MþNa): 309.2194; Found: 309.2202.
ethyl acetate–hexane (1:19) as eluent furnished the tertiary alcohol
21
28 (124 mg, 87%) as oil. Rf (1:19 EtOAc:hexane) 0.5; [
a
]
D
ꢀ30.0 (c
2.1, CHCl3); IR (neat): nmax/cmꢀ1 3500, 3072, 2977, 2955, 2923,
2853,1653,1638,1446,1376,1362,1025, 987, 910, 879, 816; 1H NMR
(400 MHz):
d
5.87 (1H, ddt, J 18.4, 10.8 and 6.1 Hz, CH]CH2), 5.53
4.1.26. (1R,2S,6R,9S)-2,5,5,9-Tetramethyl-4-methylenetri-
cyclo[7.4.0.02,6]tridec-11-en-8-one (31). To a magnetically stirred
solution of the ketone 30 (23 mg, 0.08 mmol) in anhydrous CH2Cl2
(2 mL) was added a solution of Grubbs first generation catalyst
(6 mg, 10 mol %) in anhydrous CH2Cl2 (5 mL) and the reaction
mixture was stirred at RT for 4 h. Evaporation of the solvent under
reduced pressure and purification of the residue on a AgNO3 (15%)
impregnated on silica gel column using ethyl acetate–hexane (1:19)
(1H, br s, H-4), 5.10 (1H, d, J 18.3 Hz) and 5.07 (1H, d, J 10.8 Hz)
[CH]CH2], 4.89 (1H, d, J 2.1 Hz) and 4.79 (1H d J 2.4 Hz) [C]CH2],
2.62 (1H, d, J 14.2 Hz), 2.54 (1H, dd, J 14.4 and 6.1 Hz), 2.47 (1H, dd, J
14.4 and 8.6 Hz), 2.10 (1H, d, J 14.2 Hz), 2.03 (1H, dd, J 11.8 and
6.0 Hz), 1.90–1.60 (2H, m), 1.72 (3H, s, olefinic-CH3), 1.51 (1H, br s,
OH), 1.05 (3H, s), 1.03 (3H, s) and 0.86 (3H, s) [3ꢂtert-CH3]; 13C NMR
(100 MHz):
d 161.7 (C, C-8), 138.2 (C, C-3), 135.8 (CH, CH]CH2),
124.8 (CH, C-4), 117.3 (CH2, CH]CH2), 104.7 (CH2, C]CH2), 77.8 (C,
C-2), 50.4 (CH, C-6), 47.5 (C), 41.5 (CH2), 41.4 (CH2), 40.7 (C), 33.0
(CH3), 26.0 (CH3), 24.1 (CH2), 18.4 (CH3) and 15.5 (CH3); HRMS: m/z
Calcd for C17H25 (MꢀOH): 229.1950; Found: 229.1954.
as eluent furnished the tricyclic ketone 31 (19 mg, 91%) as oil. Rf
21
(1:19 EtOAc:hexane) 0.5; [
a
]
þ15.4 (c 1.0, CHCl3); IR (neat): nmax
/
D
cmꢀ1 3067, 3022, 2955, 2935, 2904, 2861, 1703 (C]O), 1652, 1452,
1436, 1373, 883, 648; 1H NMR (400 MHz, CDCl3):
d
5.70–5.50 (2H,
m, CH]CH), 4.98 (1H, d, J 2.5 Hz) and 4.91 (1H, d, J 2.5 Hz)
[C]CH2], 2.62 (1H, t, J 15.0 Hz), 2.40–1.85 (6H, m), 1.80–1.50 (3H,
m), 1.09 (3H, s), 1.05 (3H, s) and 1.03 (6H, s) [4ꢂtert-CH3]; 13C NMR
4.1.24. (1S,6S)-5-Allyl-4,6,9,9-tetramethyl-8-methylene-
bicyclo[4.3.0]non-4-en-3-one (29). To a magnetically stirred solu-
tion of the tertiary alcohol 28 (124 mg, 0.50 mmol) in anhydrous
CH2Cl2 (1 mL) was added a homogeneous mixture of PCC (270 mg,
1.25 mmol) and silica gel (270 mg), and stirred at RT for 8 h. The
reaction mixture was filtered through a small pad of silica gel using
CH2Cl2 (10 mL) as eluent. Evaporation of the solvent and purifica-
tion of the residue over a silica gel column using ethyl acetate–
(100 MHz, CDCl3): d 215.4 (C, C]O), 161.2 (C, C-4), 125.5 (CH), 125.1
(CH), 106.9 (CH2, C]CH2), 59.3 (CH, C-6), 51.2 (CH, C-1), 48.5 (CH2,
C-7), 47.0 (C, C-9), 42.3 (C), 41.4 (C), 37.7 (CH2), 36.5 (CH2), 31.8
(CH3), 25.0 (CH3), 24.5 (CH2), 18.9 (CH3), 14.9 (CH3); HRMS: m/z
Calcd for C18H26ONa (MþNa): 281.1881; Found: 281.1875.
hexane (1:19) as eluent furnished the enone 29 (102 mg, 84%) as
Acknowledgements
21
colourless oil. Rf (1:19 EtOAc:hexane) 0.6; [
a
]
þ64.1 (c 1.4, CHCl3);
D
IR (neat): nmax/cmꢀ1 3073, 2958, 2930, 2863, 1666, 1609, 1456, 1374,
We thank Indian Institute of Science and University Grants
Commission, New Delhi for the award of research fellowships to BB
and RRB.
1319, 1277, 1195, 1080, 1020, 912, 883, 744; 1H NMR (400 MHz):
d
5.78 (1H, ddt, J 16.8, 10.4 and 6.2 Hz, CH]CH2), 5.10 (1H, d, J
10.4 Hz) and 5.04 (1H, d, J 16.8 Hz) [CH]CH2], 5.01 (1H, d, J 2.5 Hz)
and 4.92 (1H, d, J 2.5 Hz) [C]CH2], 3.08 (1H, dd, J 14.9 and 5.9 Hz),
2.97 (1H, dd, J 14.8 and 6.0 Hz), 2.80–2.20 (4H, m), 2.12 (1H, dd, J
13.5 and 5.5 Hz), 1.73 (3H, s, olefinic-CH3), 1.08 (3H, s), 1.07 (3H, s)
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