An enantiospecific approach to pinguisanes from (R)-carvone. Total synthesis of (+)-pinguisenol

Article abstract of DOI:10.1039/b004770h

Enantiospecific total synthesis of (+)-pinguisenol 1, a sesquiterpene containing a cis-1,2,6,7-tetramethylbicyclo[4.3.0]nonane carbon framework incorporating two vicinal quaternary carbon atoms and four cis-oriented methyl groups on four contiguous carbon atoms, isolated from a liverwort, is described. The orthoester Claisen rearrangement of the allyl alcohol 9, obtained from (R)-carvone, generates the ester 12. Intramolecular cyclopropanation of the diazo ketone 13, derived from the ester 12, furnishes the tricyclic ketone 7. Degradation of the isopropenyl group followed by regioselective reductive cyclopropane ring cleavage transforms compound 7 into the hydroxy ketone 21. Wblff-Kishner reduction of the hydroxy ketone 21 followed by oxidation and Grignard reaction furnishes pinguisenol (+)-1. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b004770h

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An enantiospecific approach to pinguisanes from (R)-carvone.
Total synthesis of (؉)-pinguisenol†
Adusumilli Srikrishna* and Dange Vijaykumar
1
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received (in Cambridge, UK) 14th June, Accepted 4th July 2000
Published on the Web 1st August 2000
Enantiospecific total synthesis of (ϩ)-pinguisenol 1, a sesquiterpene containing a cis-1,2,6,7-tetramethylbicyclo-
[4.3.0]nonane carbon framework incorporating two vicinal quaternary carbon atoms and four cis-oriented methyl
groups on four contiguous carbon atoms, isolated from a liverwort, is described. The orthoester Claisen rearrange-
ment of the allyl alcohol 9, obtained from (R)-carvone, generates the ester 12. Intramolecular cyclopropanation of
the diazo ketone 13, derived from the ester 12, furnishes the tricyclic ketone 7. Degradation of the isopropenyl group
followed by regioselective reductive cyclopropane ring cleavage transforms compound 7 into the hydroxy ketone 21.
Wolff–Kishner reduction of the hydroxy ketone 21 followed by oxidation and Grignard reaction furnishes
pinguisenol (ϩ)-1.
The creativity of Nature in devising varied molecular archi-
tecture is revealed through the isolation of a wide range of
natural products with remarkable skeletal complexity and
multifarious functionalities. Among the natural products,
terpenoids (isoprenoids) occupy a special position on account
of their widespread occurrence and the bewildering array of
carbocyclic skeleta that they embody. Sesquiterpenes, com-
posed of three isoprene units, biogenetically derived from
farnesyl pyrophosphate, are assembled in acyclic, monocyclic,
bicyclic, tricyclic and even tetracyclic structures containing
small, medium and large rings with a wide range of function-
alities.1 Liverworts are endowed with a rich and wide variety
of sesquiterpenoids, such as acorane, aristolane, azulene,
cedrane, chamigrane, caryophyllane, himachalane, longifolane,
thapsane, pinguisanes, etc.2 An important endogenous charac-
ter of the Hepaticae family is that most of the sesquiterpenoids
from liverworts are enantiomeric to those found in higher
plants. In 1976 Asakawa and co-workers,3a have reported the
isolation of the sesquiterpene pinguisenol 1 from the liverwort
Porella vernicosa. Pinguisenol 1 belongs to the pinguisane
group of sesquiterpenes, whose first member pinguisone 2 was
isolated in 1969 by Benesova and co-workers from the essential
oil obtained from the pentane extract of liverwort Aneura
pinguis (L.) Dum.3b Asakawa and co-workers on the basis of
spectral and chemical studies unambiguously determined the
structure of pinguisenol 1. Recently, the relative stereostructure
of pinguisenol 1 was established by the total synthesis of
the racemic compound.4 Since the isolation of pinguisone 2,
more than 25 pinguisanes have been isolated from various
liverworts such as the families Lejeuneaceae, Porellaceae,
co-workers,7 on the basis of labelling studies, postulated their
plausible biosynthetic pathway via trifareinyl cation. Recently,
we have accomplished8 a formal total synthesis of pinguisenol
( )-1 via the Schinzers ketone 4. Elated by the successful com-
pletion of the formal total synthesis of racemic pinguisenol 1,
we embarked on the enantiospecific synthesis of pinguisenol
and a few other pinguisanes starting from (R)-carvone 5, and
herein we describe the details of the first enantiospecific total
synthesis of (ϩ)-pinguisenol (ϩ)-1.9
Results and discussion
In the last two decades overwhelming emphasis on the use of
carbohydrates10 as chirons in natural product synthesis has
somewhat marginalised the importance of the abundantly avail-
able monoterpenes11 as chiral building blocks in asymmetric
synthesis. This has come despite the fact that many mono-
terpenes are cheap, readily accessible and are endowed with
only one or two chiral centres with modest functionality, which
means it does not require recourse to wasteful manoeuvres
to dispense with excessive chirality or functionality. We have
successfully employed the readily available monoterpene (R)-
carvone 5 as the chiral starting material in the synthesis of a
variety of natural products.12 For the enantiospecific synthesis
of pinguisanes, the isopropenyl group in carvone 5 was readily
identified as a masked hydroxy group. The retrosynthetic
Trichocoleaceae, Ptilidiaceae and Aneuraceae.
A notable
structural feature of these sesquiterpenes is that almost all
these compounds have a cis-fused 1,2,6,7-tetramethylbicyclo-
[4.3.0]nonane framework 3 incorporating two vicinal quater-
nary carbon atoms and four methyl groups attached to four
contiguous carbon atoms, in an all-cis orientation.3,5 Biosyn-
thetically these compounds are interesting. Earlier6 the bio-
synthesis of these compounds was explained from farnesyl
pyrophosphate via the formation of, first, bisabolane and
then acorane, followed by a series of 1,2-migrations eventually
leading to the pinguisane skeleton. Recently, Tazaki and
analysis of chiral pinguisenol 1 via the Schinzer’s ketone4
4
based on a combination of a Claisen rearrangement and intra-
molecular diazo ketone cyclopropanation reactions is depicted
† Chiral synthons from carvone, Part 44. For part 43, see ref. 21.
DOI: 10.1039/b004770h
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6-methylcarvone 10, which on low-temperature recrystallisation
in hexanes yielded stereochemically pure trans-6-methylcarvone
10. Next, attention was turned towards the transformation of
trans-6-methylcarvone 10 into the allyl alcohol 9. An alkylative
1,3-enone transposition strategy14 was chosen for the con-
version of trans-6-methylcarvone 10 into trans-3,4-dimethyl-
carvone 11. Consequently, regioselective 1,2-addition of methyl-
magnesium iodide to trans-6-methylcarvone 10, followed by
oxidation of the resulting allylic tertiary alcohol with pyr-
idinium chlorochromate (PCC) and silica gel generated trans-
3,4-dimethylcarvone 11 in 74% yield. Lithium aluminium
hydride reduction of the enone 11 in diethyl ether at Ϫ70 ЊC
furnished the allyl alcohol 9 in 83% yield, with excellent regio-
and stereoselectivity. The syn stereochemistry of the hydroxy
and isopropenyl groups in the allyl alcohol 9 was assigned
based on the preferential axial approach of the hydride as both
the C-4 and C-5 substituents direct the incoming hydride anti
to the C-5 isopropenyl group.15
For the creation of the first quaternary centre an orthoester
variant of the Claisen rearrangement16 was employed. Thus,
thermal activation of a solution of the allyl alcohol 9, triethyl
orthoacetate and a catalytic amount of propionic acid in a
sealed tube furnished the diene ester 12 in 65% yield, which on
base-catalysed hydrolysis furnished the acid 8 (see Scheme 3).
Scheme 1
in Scheme 1. It was conceived that degradation of the iso-
propenyl side-chain of 10-methylenepinguisane 6 would give
the Schinzer’s ketone 4. The 10-methylenepinguisane 6 could,
in turn be obtained from the tricyclic ketone 7 via regio-
selective reductive cyclopropane cleavage and deoxygenation of
the ketone. An intramolecular diazo ketone cyclopropanation
reaction would generate the tricyclic ketone 7 from the γ,δ-
unsaturated acid 8, which in turn could be obtained via Claisen
rearrangement of the allyl alcohol 9. The allyl alcohol 9 could
be obtained from carvone 5 via trans-6-methylcarvone 10.
The requisite starting material trans-6-methylcarvone 10 was
prepared by kinetic alkylation13 of (R)-carvone 5 which is less
expensive than (S)-carvone. Thus, regioselective alkylation of
(R)-carvone 5 employing lithium diisopropylamide (LDA) and
methyl iodide at Ϫ10 ЊC generated a 3:2 mixture of trans- and
cis-6-methylcarvone 10 in 98% yield (Scheme 2). Treatment
Scheme 3 Reagents and conditions: (a) i, CH3C(OEt)3, EtCO2H, reflux;
ii, NaOH; (b) i, (COCl)2; ii, CH3CHN2; (c) CuSO4; (d) Li, liq. NH3;
(e) Wolff–Kishner reduction.
The stereochemistry of the newly created quaternary centre
rests secured from the well established stereospecificity of the
Claisen rearrangement. An intramolecular diazo ketone cyclo-
propanation reaction17 was employed for the stereoselective
creation of the second quaternary carbon. It was contemplated
that cyclopropanation of the diazo ketone 13 followed by regio-
selective cyclopropane cleavage of the resulting tricyclic ketone
will also introduce the requisite fourth methyl group on the
fourth contiguous carbon atom in a stereoselective manner.
Consequently, treatment of the acid 8 with oxalyl dichloride in
benzene followed by reaction of the resulting acid chloride
with an excess of ethereal solution of diazoethane furnished
the diazo ketone 13. Anhydrous copper()-sulfate-catalysed
decomposition of the diazo ketone 13 in refluxing cyclohexane,
Scheme 2 Reagents and conditions: (a) i, LDA, MeI; ii, DBU;
iii, recrystallisation; (b) i, MeMgI; ii, PCC–silca gel; (c) LiAlH4.
of this 3:2 epimeric mixture of 6-methylcarvone 10 with one
mole equivalent of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
at room temperature furnished a 3:1 mixture of trans- and cis-
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using a tungsten lamp, led to the intramolecular insertion of
the intermediate keto carbenoid into the ring olefinic moiety in
a regio- and stereoselective manner, resulting in the formation
of the tricyclic ketone 7 in 52% yield (from the diene acid 8),
whose structure rests secured from its spectral data. The stereo-
selective formation of the tricyclic ketone 7 was due to the
approach of the intermediate carbenoid from the syn face of
the olefin.
with m-chloroperbenzoic acid (MCPBA) under a variety of
conditions failed to generate the acetate 15. In another
direction for the generation of Schinzer’s ketone 4, brief (and
unsuccessful) attempts were made to isomerise the isopropenyl
group to an isopropylidene group in 10-methylenepinguisane
6 and to generate the thermodynamic enol acetate of the
ketone 16.
The unexpected failure of the attempted Baeyer–Villiger
oxidation of pinguisan-10-one 16 forced us to modify our
synthetic sequence, and degradation of the isopropenyl moiety
was carried out at an earlier stage of the sequence. Thus,
ozonation of the tricyclic ketone 7 in methanol–methylene
dichloride followed by treatment of the resulting methoxy
hydroperoxide with acetic anhydride and triethylamine in the
presence of a catalytic amount of 4-(dimethylamino)pyridine
(DMAP) in refluxing benzene, furnished a 2:3 mixture of the
rearrangement product 17 and the tetracyclic keto alcohol
18 (Scheme 5), which were separated by employing silica gel
After successful synthesis of the tricyclic ketone 7, which
incorporates the cis fused-six–five bicyclic system with four
methyl groups on four contiguous carbon atoms in an all-
cis fashion, the stage was set for further elaboration into
pinguisanes. Accordingly, reductive cyclopropane ring cleavage,
deoxygenation of carbonyl moiety and degradation of the iso-
propenyl group were addressed, sequentially. For the reductive
cleavage of the cylopropane bond, standard Birch reduction
conditions were employed since it is well established that the
cyclopropane bond18 which has better overlap with the π-
orbital of the carbonyl bond will be cleaved under these con-
ditions. Thus, treatment of the tricyclic ketone 7 with lithium in
liquid ammonia furnished the bicyclic ketone 14 regioselectively
in 81% yield. It is worth noting that the bicyclic ketone 14
contains all the carbons of pinguisanes with the appropriate
stereochemistry i.e., the bicyclic ketone 14 is 10-methylene-
pinguisan-8-one or 10-methylpinguis-10-en-8-one. Huang-
Minlon-modified Wolff–Kishner reduction of the bicyclic
ketone 14 with hydrazine hydrate in diethylene glycol and
ethylene glycol furnished 10-methylenepinguisane 6 (or 10-
methylpinguis-10-ene) in 70% yield.
Next, our attention was turned towards degradation of
the isopropenyl side-chain for conversion of 10-methylene-
pinguisane 6 in to the Schinzer’s ketone 4. It was anticipated
that the isopropenyl group could be converted into an acetoxy
group by employing a one-pot ozonation–Criegee rearrange-
ment sequence.19 Accordingly, ozonation, in methanol–
methylenedichloride, oftheisopropenylmoietyin10-methylene-
pinguisane 6, followed by treatment of the intermediate
methoxy hydroperoxide with pyridine or triethylamine and
p-nitrobenzoyl chloride in refluxing benzene, however, failed
to give the Criegee rearrangement product 15, and instead the
simple ozonolysis product pinguisan-10-one 16 was obtained
(Scheme 4). Quite expectedly, ozonolysis of 10-methylene-
Scheme 5
column chromatography. Formation of the keto alcohol 18
can be explained via the base-catalysed intramolecular aldol
condensation of the normal ozonolysis product as the two
carbonyl functions are spatially close to each other due to its
convex topology. The structure of keto alcohol 18 was con-
firmed by chemical transformation. Treatment of keto alcohol
18 with lithium in liquid ammonia furnished pinguisane-8,10-
dione 19 in 70% yield (Scheme 6). Ozonolysis of the bicyclic
Scheme 4
pinguisane 6 in methanol–methylene dichloride followed by
reductive work-up with dimethyl sulfide also furnished
pinguisan-10-one 16, whose structure was established on the
basis of its spectral data. Since the one-pot Criegee rearrange-
ment strategy was unsuccessful for the generation of the acetate
15, a stepwise sequence was attempted via Baeyer–Villiger
oxidation of 16. However, treatment of pinguisan-10-one 16
Scheme 6
ketone 14 in methanol–methylene dichloride followed by
reductive work-up with dimethyl sulfide furnished the dione 19
in 69% yield, confirming the structure of the keto alcohol 18.
J. Chem. Soc., Perkin Trans. 1, 2000, 2583–2589
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Next, our attention was turned towards the conversion of
the tricyclic acetoxy ketone 17 into Schinzer’s ketone 4. Treat-
ment of the acetoxy ketone 17 with lithium in liquid ammonia
furnished the keto alcohol 20 in 85% yield, via regioselective
cleavage of the cyclopropane ring and hydrolysis of the acetoxy
group (Scheme 7). Modified Wolff–Kishner reduction of the
(THF) (90 ml) was slowly added a hexane solution of n-BuLi
(1.6 M; 76 ml, 124.8 mmol) over a period of 20 min. To the
LDA thus formed was added dropwise a solution of (R)-
carvone 5 (14.4 g, 95.7 mmol) in anhydrous THF (135 ml)
and the mixture was stirred for 2 h at the same temperature.
The enolate was then treated with an excess of methyl iodide
(30 ml, 482 mmol) and the reaction mixture was stirred at room
temperature for 12 h. It was then diluted with water and
extracted with diethyl ether (3 × 30 ml). The combined organic
extract was washed successively with 3 M aq. HCl, saturated
aq. NaHCO3, and brine, and dried (Na2SO4). Evaporation of
the solvent and purification of the residue over a silica gel
column, using ethyl acetate–hexane (1:40 to 1:20) as eluent,
furnished a 3:2 epimeric mixture of 6-methylcarvone 10 (15.4
g, 98%) as an oil.
To a magnetically stirred solution of a 3:2 epimeric mixture
of 6-methylcarvone 10 (1 g, 6.09 mmol) in CH2Cl2 (10 ml) was
added DBU (0.9 ml, 6.09 mmol) and the reaction mixture was
stirred at room temperature for 24 h. It was then washed succes-
sively with 1 M aq. HCl, water and brine, and dried (Na2SO4).
Evaporation of the solvent and purification of the residue over
a silica gel column, using ethyl acetate–hexane (1:40) as eluent
furnished a 3:1 epimeric mixture of 6-methylcarvone 10 (950
mg, 95%). Repeated recrystallisation of the epimeric mixture at
Ϫ10 ЊC using hexanes as solvent furnished stereochemically
pure trans-6-methylcarvone 10 (450 mg, 45%), mp 38–40 ЊC
(lit.,13 36–38 ЊC); [α]D23 ϩ2.03 (c 4.3, CHCl3); νmax (neat) 1670,
890, 850 cmϪ1; δH (90 MHz; CDCl3) 6.70 (1 H, m, H-3), 4.80
(2 H, s, C᎐CH ), 2.20–2.50 (4 H, m), 1.76 (3 H, s) and 1.69 (3 H,
᎐
2
s) (together 2 × olefinic CH3), 1.05 (3 H, d, J 6.5 Hz, sec-CH3);
δC (22.5 MHz; CDCl3) 200.8 (s), 145.3 (s), 142.8 (d), 134.3 (s),
112.7 (t), 50.3 (d), 43.8 (d), 30.9 (t), 17.8 (q), 15.7 (q), 12.2 (q);
HRMS m/z for C11H16O (Calc.: M, 164.1202. Found: Mϩ,
164.1197).
Scheme 7 Reagents and conditions: (a) Li, liq. NH3; (b) Wolff–Kishner
reduction; (c) PCC, silica gel; (d) CH2᎐᎐CHMgBr.
(4S,5R)-(؊)-5-Isopropenyl-2,3,4-trimethylcyclohex-2-enone 11
keto alcohol 20 furnished the alcohol 21 in 69% yield, which on
oxidation with PCC and silica gel furnished the bicyclic ketone
(Ϫ)-4, which was identified by comparison of the TLC and
spectral data with those of the racemic Schinzer’s ketone 4.4,8
Finally, addition of vinylmagnesium bromide at Ϫ10 ЊC to the
bicyclic ketone (Ϫ)-4 furnished pinguisenol (ϩ)-1 in 80% yield.
To a cold (Ϫ5 ЊC), magnetically stirred solution of methyl-
magnesium iodide (12.5 mmol) [prepared from magnesium
(300 mg, 12.5 mmol) and methyl iodide (2.27 g, 16 mmol) and
a catalytic amount of iodine] in 30 ml of dry diethyl ether was
added a solution of trans-6-methylcarvone 10 (650 mg, 3.96
mmol) in dry diethyl ether over a period of 30 min. The reaction
mixture was slowly warmed to room temperature and stirred
for 3 h. It was then poured into saturated aq. NH4Cl and
extracted with diethyl ether (2 × 15 ml). The extract was washed
with brine and dried (Na2SO4). Evaporation of the solvent
furnished a tertiary alcohol.
To a magnetically stirred suspension of PCC (1.5 g, 7.0
mmol) and silica gel (1.5 g) in anhydrous CH2Cl2 (5 ml) was
added a solution of the tertiary alcohol obtained above in
dry CH2Cl2 (2 ml) in one portion. The reaction mixture was
stirred at room temperature for 3 h, filtered through a silica
gel column, and the column was eluted with more CH2Cl2.
Evaporation of the solvent and purification of the residue over
a silica gel column, using ethyl acetate–hexane (1:40 to 1:10)
as eluent, furnished the enone 11 (522 mg, 74% yield) as an oil,
[α]D24 Ϫ7.7 (c 6.0, CHCl3); νmax (neat) 1660, 890 cmϪ1; δH (90
1
The spectral data (IR, H and 13C NMR) of the pinguisenol
obtained in this study were found to be identical with those
of the racemic sample reported by Schinzer and Ringe.4 The
synthetic (ϩ)-pinguisenol (ϩ)-1 was found to be the optical
antipode of the natural product,3a thus establishing the
absolute configuration of the natural pinguisenol (Ϫ)-1 as
1S,2S,3S,6S,7R.
In conclusion, we have developed an enantiospecific approach
to pinguisanes starting from (R)-carvone by employing a
Claisen rearrangement, an intramolecular diazo ketone
cyclopropanation and a regioselective reductive cyclopropane
ring-cleavage sesquence. Synthesis of (ϩ)-pinguisenol was
accomplished in thirteen steps starting from trans-6-methyl-
carvone in an overall yield of 2.5%, which established the
absolute stereochemistry of the natural pinguisenol.
MHz; CDCl ) 4.83 (1 H, s) and 4.73 (1 H, s) (together C᎐CH ),
Experimental20
᎐
3
2
2.30–2.60 (4 H, m), 1.93 (3 H, s, 3-CH3), 1.77 (3 H, s), 1.7 (3 H,
s, 2-CH3), 1.19 (3 H, d, J 7.5 Hz, sec-CH3); δC (100 MHz;
CDCl3) 198.3, 157.3, 146.1, 130.5, 112.5, 48.4, 40.4, 40.0, 20.1,
16.7, 17.9, 11.2; HRMS m/z for C12H18O (Calc.: M, 178.1358.
Found: Mϩ, 178.1346).
Ozonolysis experiments were carried out using a Fischer 502
ozone generator. In the liquid ammonia reactions, the coolant
used in the Dewar condenser is a combination of ethanol and
liquid nitrogen. Optical rotations were measured using a Jasco
DIP-370 digital polarimeter and [α]D values are given in the
units of 10Ϫ1 deg cm2 gϪ1
.
(1S,4S,5R)-(Ϫ)-5-Isopropenyl-2,3,4-trimethylcyclohex-2-enol 9
To a magnetically stirred, cold (Ϫ78 ЊC) solution of the enone
11 (520 mg, 2.93 mmol) in diethyl ether (16 ml) was added
LiAlH4 (80 mg, 2.1 mmol). The reaction mixture was stirred at
Ϫ70 ЊC for 2 h, and then allowed to attain room temperature
(5R,6S)-(؉)-5-Isopropenyl-2,6-dimethylcyclohex-2-enone 1013
To a cold (Ϫ10 ЊC), magnetically stirred solution of diisopro-
pylamine (17.6 ml, 124.8 mmol) in anhydrous tetrahydrofuran
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over a period of 30 min. The reaction was quenched first with
wet diethyl ether and then with dil. aq. HCl. It was then
extracted with ether (3 × 10 ml) and the combined ether extract
was washed successively with saturated aq. NaHCO3 and brine,
and dried (Na2SO4). Evaporation of the solvent and purifica-
tion of the product on a silica gel column using ethyl acetate–
hexane (1:10 to 1:5) as eluent furnished the alcohol 9 (437 mg,
83%) as an oil, [α]D26 Ϫ13.0 (c 3.2, CHCl3); νmax (neat) 3330, 1635,
885 cmϪ1; δH (90 MHz; CDCl3) 4.79 (1 H, s) and 4.74 (1 H, s)
mixture was refluxed for 4 h. It was then cooled and copper()
sulfate was filtered off. Evaporation of the solvent and purifi-
cation of the residue on a silica gel column, using ethyl acetate–
hexane (1:20) as eluent, furnished the tricyclic ketone 7 (470
mg, 52% from the acid 8) as a pale yellow oil, [α]D24 ϩ28.0 (c 3.8,
CHCl3); νmax (neat) 1710, 1640, 1620, 890 cmϪ1; δH (200 MHz;
CDCl ) 4.75 (2 H, s, C᎐CH ), 2.15 (1 H, d, J 20 Hz) and 1.98
᎐
3
2
(1 H, d, J 20 Hz) (together CH C᎐O), 1.15–2.00 (5 H, m), 1.65
᎐
2
(3 H, t, J 1.1 Hz, olefinic CH3), 1.24 (3 H, s), 1.20 (3 H, s) and
1.16 (3 H, s) (together 3 × tert-CH3), 0.99 (3 H, d, J 6.9 Hz,
sec-CH3); δC (22.5 MHz; CDCl3) 214.7 (s), 147.7 (s), 111.4 (t),
56.0 (t), 52.0 (d), 43.7 (s), 39.0 (d), 38.3 (s), 37.2 (s), 35.0 (d),
26.0 (q), 24.4 (t), 19.4 (q), 18.6 (q), 16.2 (q), 11.8 (q); HRMS
m/z for C16H24O (Calc.: M, 232.1827. Found: Mϩ, 232.1828).
(together C᎐CH ), 4.03 (1 H, m, CHOH), 1.50–2.30 (5 H, m),
᎐
2
1.73 (6 H, s) and 1.67 (3 H, s) (together 3 × olefinic CH3), 0.95
(3 H, d, J 7.0 Hz, sec-CH3); δC (100 MHz; CDCl3) 149.2, 133.1,
128.6, 111.2, 71.1, 47.3, 38.1, 36.0, 20.2, 18.2, 17.4, 15.3; HRMS
m/z for C12H20O (Calc.: M, 180.1514. Found: Mϩ, 180.1521).
(1R,2S,3R,6R,7R)-(؊)-3-Isopropenyl-1,2,6,7-tetramethyl-
bicyclo[4.3.0]nonan-8-one (10-methylenepinguisan-8-one) 14
(3R,2S,5R)-(؉)-5-Isopropenyl-2,3,4-trimethylcyclohexene-3-
acetic acid 8
To magnetically stirred, freshly distilled (over sodium) liquid
ammonia (50 ml) in a three-necked flask equipped with a Dewar
condenser was added a solution of the tricyclic ketone 7 (100
mg, 0.43 mmol) in dry THF (3 ml) followed by freshly cut
lithium (15 mg, 2.15 mmol) in small pieces. The resulting blue
coloured solution was stirred for 30 min and then the reaction
was quenched with solid NH4Cl. After evaporation of ammonia,
the residue was taken in water (10 ml) and extracted with diethyl
ether (2 × 10 ml). The extract was washed with brine and dried
(Na2SO4). Evaporation of the solvent and purification of the
product on a silica gel column, using ethyl acetate–hexane (1:20)
as eluent, furnished the bicyclic ketone 14 (82 mg, 81%) as a
colourless oil, [α]D27 Ϫ20 (c 1.2, CHCl3); νmax (neat) 1740, 1640,
880 cmϪ1; δ (200 MHz; CDCl ) 4.7 (2 H, br s, C᎐CH ), 2.78 (1
H, q, J 6.9 Hz), 2.35 (1 H, d, J 19.2 Hz) and 2.00 (1 H, d, J 19.2
Hz) (together H2-9), 1.62 (3 H, t, J 1.0 Hz, olefinic CH3), 1.40–
1.70 (6 H, m), 0.98 (3 H, s, tert-CH3), 0.92 (3 H, d, J 7.0 Hz, sec-
CH3), 0.76 (3 H, s, tert-CH3), 0.72 (3 H, d, J 6.6 Hz, sec-CH3);
δC (100 MHz; CDCl3,) 220.9, 148.6, 111.2, 49.0, 48.7, 47.3, 44.2,
42.6, 36.7, 30.3, 27.4, 20.4, 18.4, 14.9, 14.7, 7.9; HRMS m/z for
C16H26O (Calc.: M, 234.1984. Found: Mϩ, 234.1991).
A solution of the allyl alcohol 9 (2 g, 11.17 mmol), triethyl
orthoacetate (10.2 ml, 55.87 mmol) and a catalytic amount
(≈5 µl) of propionic acid was placed in two sealed tubes and
heated to 175 ЊC for 5 days in an oil-bath. The reaction mixture
was cooled, diluted with diethyl ether (2 × 25 ml), washed
successively with 0.5 M aq. HCl, saturated aq. NaHCO3 and
brine, and dried (Na2SO4). Evaporation of the solvent and
purification of the product on a silica gel column, using ethyl
acetate–hexane (1:40) as eluent, furnished the ester 12 (1.8 g,
65%) as an oil.
To a magnetically stirred solution of the ester 12 (1.5 g, 6.02
mmol) in methanol (12 ml) was added 10% aq. NaOH (12 ml)
and the reaction mixture was refluxed for 6 h. The solvent
was evaporated under reduced pressure, the residue was taken
in water (25 ml) and washed with CH2Cl2 (2 × 15 ml). The
aq. phase was acidified with 3 M aq. HCl and extracted with
CH2Cl2 (2 × 15 ml). The organic extract was then washed suc-
cessively with water (15 ml) and brine, and dried (Na2SO4).
Evaporation of the solvent furnished the acid 8 (1.2 g, 90%),
which was recrystallised from a mixture of CH2Cl2–hexane, mp
62–65 ЊC; [α]D24 ϩ10.2 (c 3.4, CHCl3); νmax (neat) 2900, 1695, 1635,
885 cmϪ1; δH (90 MHz; CDCl3) 5.35–5.55 (1 H, m, H-1), 4.69
᎐
H
3
2
(1R,2S,3R,6R,7S)-(؉)-3-Isopropenyl-1,2,6,7-tetramethyl-
bicyclo[4.3.0]nonane (10-methylenepinguisane) 6
(2 H, s, C᎐CH ), 2.52 (2 H, close ABq, J 15 Hz, CH C=O),
᎐
2
2
1.70–2.50 (4 H, m), 1.73 (3 H, s) and 1.65 (3 H, s) (together
2 × olefinic CH3), 0.96 (3 H, s, tert-CH3), 0.83 (3 H, d, J 6.4 Hz,
sec-CH3); δC (22.5 MHz; CDCl3) 178.3 (s), 148.0 (s), 137.7 (s),
123.1 (d), 112.0 (t), 44.8 (d), 41.3 (2 C, s and t), 36.1 (d), 30.9 (t),
21.3 (q), 19.5 (q), 17.9 (q), 13.1(q); HRMS m/z for C14H22O2
(Calc.: M, 222.1619. Found: Mϩ, 222.1621).
A solution of the bicyclic ketone 14 (73.5 mg, 0.314 mmol) and
hydrazine hydrate (0.2 ml, 4.2 mmol) in a mixture of diethylene
glycol (2 ml) and ethylene glycol (0.5 ml) was placed in a sealed
tube and heated to 180 ЊC for 2 h. The sealed tube was cooled to
70 ЊC and treated with a solution of sodium (82 mg, 3.6 mmol)
in diethylene glycol (3 ml). The reaction mixture was further
heated to 180 ЊC for 4 h. It was then cooled to room tem-
perature, poured into ice-cold water (5 ml) and extracted with
hexane (2 × 10 ml). The extract was washed with brine and
dried (Na2SO4). Evaporation of the solvent and purification
of the residue on a silica gel column, using hexane as eluent,
furnished 10-methylenepinguisane 6 (48 mg, 70%) as an oil,
[α]D28 ϩ30.7 (c 2.05, CHCl3); νmax (neat) 1640, 890 cmϪ1; δH (300
(1S,2S,4R,5S,6R,9S)-(؉)-4-Isopropenyl-1,5,6,9-tetramethyl-
tricyclo[4.3.0.02,9]nonan-8-one 7
A solution of the acid 8 (870 mg, 3.9 mmol) and oxalyl
dichloride (1.2 ml, 13.8 mmol) in dry benzene (5 ml) was mag-
netically stirred for 2 h at room temperature. Evaporation of
the excess of oxalyl dichloride and benzene under reduced pres-
sure afforded the corresponding acid chloride, which was taken
up in dry diethyl ether (4 ml) and added dropwise to a cold,
magnetically stirred ethereal solution of diazoethane (excess,
prepared from 5 g of N-ethyl-N-nitrosourea, 50 ml of 60% aq.
KOH and 50 ml of diethyl ether). The reaction mixture
was stirred for 2 h at room temperature and the excess of
diazoethane and ether were carefully evaporated on a water-
bath. Rapid purification of the product by filtration through a
silica gel column, using ethyl acetate–hexane (1:10) as eluent,
furnished the diazo ketone 13 as a yellow oil, νmax (neat) 2220,
MHz; CDCl ) 4.66 (1 H, s) and 4.64 (1 H, s) (together C᎐CH ),
᎐
3
2
2.40 (1 H, q, J 6.9 Hz), 1.75–1.90 (5 H, m), 1.62 (3 H, s, olefinic
CH3), 0.70–0.95 (5 H, m), 0.81 (3 H, d, J 6.6 Hz, sec-CH3), 0.78
(3 H, s, tert-CH3), 0.67 (3 H, d, J 6.6 Hz, sec-CH3), 0.62 (3 H, s,
tert-CH3); δC (75 MHz; CDCl3) 149.9, 110.3, 49.3, 47.3, 45.2,
35.8, 35.0, 34.4, 30.5, 29.1, 27.2, 19.4, 18.3, 15.1, 14.7, 14.6; m/z,
220 (Mϩ, 5%), 207 (15), 137 (99), 123 (55), 109 (100), 95 (88).
(1R,2S,3R,6R,7S)-(؉)-3-Acetyl-1,2,6,7-tetramethylbicyclo-
[4.3.0]nonane (pinguisan-10-one) 16
1640, 1620, 890 cmϪ1
.
To a magnetically stirred, refluxing (using two 100W tungsten
lamps placed near the reaction flask) suspension of anhydrous
copper() sulfate (870 mg, 5.45 mmol) in dry cyclohexane (60
ml) was added, dropwise, a solution of the diazo ketone 13 in
cyclohexane (10 ml) over a period of 30 min and the reaction
Dry ozone in oxygen gas was passed through a cold (Ϫ70 ЊC)
suspension of the alkene 6 (50 mg, 0.227 mmol) and NaHCO3
(5 mg) in 1:50 methanol–CH2Cl2 (5 ml) until the reaction
mixture turned blue in colour. Excess of ozone was flushed off
with oxygen. Dimethyl sulfide (0.008 ml, 1.135 mmol)
J. Chem. Soc., Perkin Trans. 1, 2000, 2583–2589
2587

View Article Online
was added to the reaction mixture at Ϫ70 ЊC, which was then
allowed to attain room temperature and was magnetically
stirred for 4 h. Evaporation of the solvent and purification of
the residue on a silica gel column, using ethyl acetate–hexane
(1:20), furnished pinguisan-10-one 16 (34 mg, 68%) as an oil,
[α]D29 ϩ14.0 (c 3.3, CHCl3); νmax (neat) 1705 cmϪ1; δH (300 MHz;
CDCl3) 2.50–2.20 (1 H, m), 2.13 (3 H, s), 2.1–1.2 (10 H, m), 0.87
(3 H, d, J 6.3 Hz, sec-CH3), 0.83 (3 H, s), 0.71 (3 H, d, J 5.5 Hz,
sec-CH3), 0.68 (3 H, s, tert-CH3); δC (75 MHz; CDCl3) 213.8,
55.0, 46.9, 45.0, 35.5, 34.9, 33.7, 29.7, 29.3, 28.9, 24.6, 19.2,
15.0, 14.6, 14.4; HRMS m/z for C15H26O (Calc.: M, 222.1984.
Found: Mϩ, 222.1970).
1.75–1.40 (4 H, m), 0.98 (3 H, s, tert-CH3), 0.92 (3 H, d, J 6.9
Hz, sec-CH3), 0.80 (3 H, d, J 6.6 Hz, sec-CH3), 0.76 (3 H, s, tert-
CH3); δC (22.5 MHz; CDCl3) 219.1 (s), 212.2 (s), 53.8 (d),
48.0 (t), 47.1 (d), 43.8 (s), 42.0 (s), 36.0 (d), 29.6 (t), 29.3 (q),
24.8 (t), 20.0 (q), 14.5 (2 C, q), 7.7 (q); m/z 236 (Mϩ, 16%), 221
(M Ϫ Me, 100), 205 (26), 177 (38), 137 (35), 135 (40), 134 (50),
124 (55), 123 (40), 121 (78), 109 (56), 95 (37).
(1R,2R,3R,6R,7R)-(؊)-3-Hydroxy-1,2,6,7-tetramethylbicyclo-
[4.3.0]nonan-8-one 20
To magnetically stirred, freshly distilled (over sodium) liquid
ammonia (50 ml) in a three-necked flask equipped with a Dewar
condenser, was added a solution of the keto acetate 17 (70 mg,
0.28 mmol) in dry THF (3 ml) followed by freshly cut lithium
(15 mg, 2.14 mmol) in small pieces. The resulting blue coloured
solution was stirred for 20 min and the reaction was quenched
with solid NH4Cl. After evaporation of ammonia, the residue
was taken up in water (10 ml) and extracted with diethyl ether
(2 × 10 ml). The extract was washed with brine and dried
(Na2SO4). Evaporation of the solvent and purification of the
product on a silica gel column, using ethyl acetate–hexane
(1:10) as eluent, furnished the keto alcohol 20 (50 mg, 85%) as
a colourless oil, [α]D24 Ϫ26.3 (c 1.8, CHCl3); νmax (neat) 3420, 1730
cmϪ1; δH (400 MHz; CDCl3) 3.45 (1 H, d of t, J 11.3 and 4.4 Hz,
CHOH), 2.76 (1 H, q, J 6.9 Hz, H-7), 2.35 (1 H, d, J 19.2 Hz)
and 1.96 (1 H, d, J 19.2 Hz) (together H2-9). 1.80–1.90 (1 H, m),
1.40–1.65 (5 H, m), 1.0 (3 H, d, J 6.5 Hz, sec-CH3), 0.97 (3 H, s,
tert-CH3), 0.92 (3 H, d, J 6.9 Hz, sec-CH3), 0.74 (3 H, s, tert-
CH3); δC (75 MHz; CDCl3) 220.2, 72.5, 48.8, 47.2, 43.9, 43.5,
42.4, 30.8, 29.0, 19.9, 15.1, 13.0, 7.8; HRMS m/z for C13H22O2
(Calc.: M, 210.1619. Found: Mϩ, 210.1605).
(1S,2S,4R,5R,6R,9S)-(؉)-4-Acetoxy-1,5,6,9-tetramethyl-
tricyclo[4.3.0.02,9]nonane-8-one 17 and (؉)-5-hydroxy-2,5,7,8,9-
pentamethyltetracyclo[4.3.1.02,9.04,8]decan-3-one 18
Pre-cooled, dry ozone in oxygen gas was passed through a cold
(Ϫ70 ЊC) suspension of the tricyclic ketone 7 (60 mg, 0.26
mmol) and NaHCO3 (5 mg) in 1:100 methanol–CH2Cl2 (1 ml)
until the reaction mixture turned blue in colour. Excess of
ozone was flushed off with oxygen. The solvent was evaporated
in vacuo and the residue was dissolved in dry benzene (5 ml).
To this mixture were added triethylamine (0.3 ml, 2.16 mmol),
acetic anhydride (0.4 ml, 4.2 mmol) and a catalytic amount of
DMAP and the mixture was stirred at room temperature for
1 h. Then the reaction mixture was refluxed for 6 h. Upon
work-up followed by purification of the residue over a silica gel
column, using ethyl acetate–hexane (1:40) as eluent, the keto
acetate 17 (20 mg, 31%) was obtained as colourless oil, [α]D24 ϩ3.8
(c 1.3, CHCl3); νmax (neat) 1735, 1715 cmϪ1; δH (400 MHz;
CDCl3) 4.72 (1 H, ddd, J 12.0, 7.2 and 4.9 Hz, H-4), 2.43 (1 H,
ddd, J 15.6, 8.9 and 7.4 Hz), 2.26 and 2.17 (2 H, ABq, J 19.6
Hz, H2-7), 2.03 (3 H, s, OCOCH3), 1.60–1.70 (1 H, m), 1.25–
1.35 (1 H, m), 1.24 (3 H, s), 1.22 (3 H, s), 1.17 (3 H, s) (together
3 × tert-CH3), 1.15–1.20 (1 H, m), 1.09 (3 H, d, J 7.3 Hz,
sec-CH3); δC (75 MHz; CDCl3) 214.8, 170.7, 75.9, 55.5, 44.1,
41.8, 38.5, 37.1, 32.3, 25.5, 23.8, 21.4, 17.0, 16.2, 12.4; HRMS
m/z for C15H22O3 (Calc.: M, 250.1569. Found: Mϩ, 250.1555).
Further elution of the column with ethyl acetate–hexane
(1:10) as eluent furnished the by-product, keto alcohol 18
(28 mg, 46%) as an oil, [α]D26 ϩ7.2 (c 3.2, CHCl3); νmax (neat)
3400–3500, 1700 cmϪ1; δH (400 MHz; CDCl3) 2.42 (1 H, d,
J 15.0 Hz), 1.94 (1 H, t of d, J 15.0 and 6.2 Hz), 1.90 (1 H, s),
1.88 (1 H, s), 1.74 (1 H, d of q, J 6.9 and 4.1 Hz), 1.70–1.60
(2 H, m), 1.32 (3 H, s, HOCCH3), 1.19 (3 H, s, tert-CH3), 1.14
(3 H, d, J 6.8 Hz, sec-CH3), 1.14 (2 H, s), 1.10 (3 H, s, tert-CH3),
1.04 (1 H, d, J 6.2 Hz); δC (75 MHz; CDCl3) 215.8, 73.5, 68.9,
49.2, 46.3, 41.6, 40.8, 40.5, 32.0, 30.5, 22.0, 17.6, 15.9, 12.2,
10.8; HRMS m/z for C15H22O2 (Calc.: M, 234.1620. Found:
Mϩ, 234.1621).
(1R,2R,3R,6R,7S)-(؉)-1,2,6,7-Tetramethylbicyclo[4.3.0]nonan-
3-ol 21
Modified Wolff–Kishner reduction of the keto alcohol 20
(25 mg, 0.0765 mmol) with hydrazine monohydrate (0.08 ml,
1.585 mmol) in a mixture of diethylene glycol (0.8 ml) and
ethylene glycol (0.2 ml), and a solution of sodium (65.8 mg,
2.86 mmol) in diethylene glycol (1.32 ml), as described for 10-
methylenepinguisane 6, furnished the alcohol 21 (16 mg, 69%),
[α]D24 ϩ3.4 (c 1.2, CHCl3); νmax (neat) 3340 cmϪ1; δH (300 MHz;
CDCl3) 3.31 (1 H, d of t, J 10.8 and 4.5 Hz, CHOH), 2.4 (1 H,
q, J 6.9 Hz), 1.10–1.90 (10 H, m), 0.95 (3 H, d, J 6.6 Hz)
and 0.81 (3 H, d, J 6.9 Hz) (together 2 × sec-CH3), 0.77 (3 H, s)
and 0.62 (3 H, s) (together 2 × tert-CH3); δC (75 MHz; CDCl3)
73.6, 41.7, 35.0, 34.5, 30.7, 29.2, 28.9, 19.0, 15.5, 14.6, 12.8;
HRMS m/z for C13H24O (Calc.: M, 196.1828. Found: Mϩ,
196.1814).
(1R,2R,6R,7S)-(؊)-1,2,6,7-Tetramethylbicyclo[4.3.0]nonan-3-
one 4
(1R,2S,3R,6R,7R)-(؊)-3-Acetyl-1,2,6,7-tetramethylbicyclo-
[4.3.0]nonan-8-one (pinguisane-8,10-dione) 19
To a solution of the alcohol 21 (15 mg, 0.075 mmol) in methyl-
ene dichloride (0.5 ml) were added PCC (40 mg, 0.186 mmol)
and silica gel (40 mg) and the mixture was stirred for 2 h,
filtered through a silica gel column, and the column, was eluted
with more CH2Cl2. Evaporation of the solvent and purification
of the residue over a silica gel column, using ethyl acetate–
hexane (1:40) as eluent, furnished the Schinzer’s ketone (Ϫ)
4 (14 mg, 92%) as an oil, which was identified by comparison of
the spectral data with that of the racemic sample 4;4,8 [α]D23 Ϫ38
(c 1, CHCl3); νmax (neat) 1715 cmϪ1; δH (400 MHz; CDCl3) 2.59
(1 H, q, J 6.5 Hz, H-2), 2.35–2.55 (2 H, m, H2-4), 2.16 (1 H,
ddd, J 15.5, 5.1 and 3.8 Hz), 1.65–2.00 (2 H, m), 1.61 (1 H, ddd,
J 14.1, 12.6 and 5.1 Hz), 1.25–1.50 (3 H, m), 0.95 (3 H, d, J 6.6
Hz) and 0.945 (3 H, d, J 6.8 Hz) (together 2 × sec-CH3), 0.719
(3 H, s) and 0.717 (3 H, s) (together 2 × tert-CH3); δC (50 MHz;
CDCl3) 214.1, 53.3, 48.4, 45.6, 37.7, 37.4, 35.5, 32.4, 29.2, 18.4,
16.5, 14.8, 8.7; m/z 194 (Mϩ, 20%), 179 (25), 137 (15), 123 (45),
122 (25), 109 (100).
To magnetically stirred, freshly distilled (over sodium)
ammonia (50 ml) in a three-necked flask equipped with a Dewar
condenser was added a solution of the keto alcohol 18 (70 mg,
0.3 mmol) in dry THF (3 ml) followed by freshly cut lithium
(15 mg, 2.14 mmol) in small pieces. The resulting blue coloured
solution was stirred for 30 min and the reaction was quenched
with solid NH4Cl. After evaporation of ammonia, the residue
was taken up in water (10 ml) and extracted with diethyl ether
(2 × 10 ml). The extract was washed with brine and dried
(Na2SO4). Evaporation of the solvent and purification of the
product on a silica gel column, using ethyl acetate–hexane
(1:10) as eluent furnished the dione 19 (49 mg, 70%) as a col-
ourless oil, [α]D29 Ϫ8.8 (c 2.0, CHCl3); νmax (neat) 1730, 1705 cmϪ1
;
δH (300 MHz; CDCl3) 2.80 (1 H, q, J 6.9 Hz, H-7), 2.43 (1 H, m,
H-3), 2.33 (1 H, d, J 19 Hz), 2.16 (3 H, s, CH3C=O), 1.98 (1 H,
d, J 19.5 Hz, Hb-9), 1.86 (1 H, q of d, J 12 and 6.6 Hz, H-2),
2588
J. Chem. Soc., Perkin Trans. 1, 2000, 2583–2589

View Article Online
5 For synthesis of other pinguisanes see: S. Bernasconi, P. Gariboldi,
(1R,2R,3R,6R,7S)-(؉)-Pinguisenol 1
G. Jommi, S. Montanari and M. Sisti, J. Chem. Soc., Perkin Trans. 1,
1981, 2394; T. Uyehara, Y. Kabasawa, T. Kato and T. Furuta,
Tetrahedron Lett., 1985, 26, 2343; T. Uyehara, Y. Kabasawa and
T. Kato, Bull. Chem. Soc. Jpn., 1986, 59, 2521; A. Gambacorta,
M. Botta and S. Turchetta, Tetrahedron Lett., 1988, 29, 4846;
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Lett., 1995, 36, 4051.
6 M. Tori, H. Arbiyanti, Z. Taira and Y. Asakawa, Phytochemistry,
1993, 32, 335.
7 H. Tazaki, H. Soutome, T. Iwasaki, K. Nabeta and D. Arigoni,
Chem. Commun., 1997, 1101.
8 A. Srikrishna and D. Vijaykumar, J. Chem. Soc., Perkin Trans. 1,
1999, 1265.
9 For a preliminary communication, see: A. Srikrishna and D.
Vijaykumar, Tetrahedron Lett., 1998, 39, 4901.
10 S. Hannessian, Total Synthesis of Natural Products: The Chiron
Approach, Pergamon Press, Oxford, 1983.
11 T. L. Ho, Enantioselective Synthesis. Natural Products from Chiral
Terpenes, John Wiley, Chichester, 1992; G. Mehta, N. Krish-
namurthy and S. R. Karra, J. Am. Chem. Soc., 1991, 113, 5765;
A. A. Verstegen-Haaksma, B. J. M. Jansen and A. D. Groot,
Tetrahedron, 1992, 48, 3121; V. N. Zhanbinskii, A. J. Minnaard,
J. B. P. A. Wijnberg and A. D. Groot, J. Org. Chem., 1996, 61, 4022;
P. M. F. M. Bastiaansen, J. B. P. A. Wijnberg and A. D. Groot,
J. Org. Chem., 1996, 61, 4955 and references cited therein.
12 A. Srikrishna, P. Hemamalini and G. V. R. Sharma, Tetrahedron
Lett., 1991, 32, 6609; J. Org. Chem., 1993, 58, 2509; A. Srikrishna
and T. J. Reddy, Indian J. Chem., Sect. B, 1995, 34, 844; A.
Srikrishna, S. Nagaraju, T. J. Reddy and S. Venkateswarlu, Pure
Appl. Chem., 1996, 68, 699; A. Srikrishna, T. J. Reddy and
S. Nagaraju, Tetrahedron Lett., 1996, 37, 1679; A. Srikrishna and
R. Viswajanani, Tetrahedron Lett., 1996, 37, 2863; A. Srikrishna,
T. J. Reddy and P. P. Kumar, Chem. Commun., 1996, 1369;
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1997, 62, 7863; A. Srikrishna and T. J. Reddy, J. Chem. Soc., Perkin
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Tetrahedron Lett., 1998, 39, 5815; A. Srikrishna and T. J. Reddy,
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A. Srikrishna and S. J. Gharpure, Tetrahedron Lett., 1999, 40, 1035;
A. Srikrishna and C. Dinesh, Indian J. Chem., Sect. B, 1999, 38,
1151; A. Srikrishna, S. J. Gharpure and P. P. Kumar, Tetrahedron
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13 J.-P. Gesson, J.-C. Jaquesy and B. Renoux, Tetrahedron Lett., 1986,
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14 G. Buchi and B. Egger, J. Org. Chem., 1971, 36, 2021; A. Srikrishna
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15 Y.-D. Wu, K. N. Houk, J. Florez and B. M. Trost, J. Org. Chem.,
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16 L. Claisen, Ber. Dtsch. Chem. Ges., 1912, 45, 3157; W. S. Johnson, L.
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17 G. Stork and J. Ficini, J. Am. Chem. Soc., 1961, 83, 4678; S. D. Burke
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18 T. Norin, Acta Chem. Scand., 1963, 17, 738; W. G. Dauben and
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To a cold (Ϫ10 ЊC) magnetically stirred solution of the ketone 4
(12 mg, 0.062 mmol) in THF (2 ml) was added vinylmagnesium
bromide [prepared from magnesium (4.4 mg, 0.185 mmol)
and vinyl bromide (0.026 ml, 0.37 mmol) in THF (0.5 ml)] and
the solution was stirred for 2 h at the same temperature.
The reaction was then quenched with aq. NH4Cl and extracted
with diethyl ether. The organic layer was washed successively
with water and brine, and dried (Na2SO4). Evaporation of
the solvent and purification of the residue over a silica gel
column, using ethyl acetate–hexane (1:20) as eluent furnished
pinguisenol (ϩ)-1 (11 mg, 80%) as a colourless oil, [α]D25 ϩ22.5
(c 2, CHCl3); νmax (neat) 3610, 3480, 1640, 920 cmϪ1; δH (400
MHz; CDCl3) 5.79 (1 H, dd, J 17.2 and 10.7 Hz), 5.17 (1 H,
dd, J 17.2 and 1.2 Hz), 5.0 (1 H, dd, J 10.7 and 1.2 Hz), 2.20–
2.40 (1 H, m), 1.80–1.55 (5 H, m), 1.53 (1 H, q, J 7.0 Hz), 1.30–
1.10 (3 H, m), 0.95 (3 H, s, tert-CH3), 0.83 (3 H, d, J 6.2 Hz)
and 0.81 (3 H, d, J 6.7 Hz) (together 2 × sec-CH3), 0.68 (3 H, s,
tert-CH3). δC (100 MHz; CDCl3) 147.8, 110.7, 76.6, 47.3, 45.2,
40.6, 36.4, 34.1, 33.8, 29.4, 26.2, 19.3, 17.9, 14.6, 10.1.
Acknowledgements
We thank Professor Y. Asakawa, Tokushima Bunri University,
for sending a sample of natural pinguisenol, and Professor
Schinzer, Universitat Braunschweig, for sending copies of the
spectra of bicyclic ketone ( )-4. We are grateful to the Council
of Scientific and Industrial Research, New Delhi, for providing
a research fellowship to D. V. K.
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