Indian Journal of Chemistry
Vol. 51B, February 2012, pp. 345-355
Enantiospecific synthesis of pacifigorgianes
A Srikrishna* & Dattatraya H Dethe
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
E-mail: askiisc@gmail.com
Received 19 July 2011; accepted 21 October 2011
Enantiospecific synthesis of the sesquiterpenes pacifigorgianes has been described. (R)-Carvone has been employed as
the chiral starting material and an entropy assisted ring-closing metathesis reaction by Grubbs first generation catalyst was
employed as the key strategy.
Keywords: Pacifigorgianes, bicyclo[4.3.0]nonanes, carvone, entropy effect, ring-closing metathesis, enantiospecific
synthesis
Pacifigorgianes 1 are a small group of sesquiterpenes,
containing bicyclo[4.3.0]nonane moiety, found to be
present in both marine and terrestrial sources. The
first member of this group, ichthyotoxic (+)pacifigorgiol 2 was isolated in 1982 by the research
groups of Fenical and Clardy1 from the pacific
gorgonian coral Pacifigorgia cf. adamssi. Later in
1986, Simpa and coworkers2 reported the isolation of
(–)-pacifigorgiol 2 from the essential oil of Valeriana
officinalis, which was found to be optical antipode of
that isolated by Fenical and Clardy from the marine
sources. In 1984 Conolly and coworkers3 reported the
isolation of the second member of the family, (+)tamariscol 3 from the liverwort Frullania tamarisci.
The absolute configuration of (–)-tamariscol 3 was
assigned by Asakawa and coworkers4 via degradation
of tamariscol 3 in to the bicyclic ketone 4, which was
found to be enantiomeric to a synthetic sample
obtained from (R)-carvone. In 2001 Konig and
coworkers5 reported the isolation of five new pacifigorgianes, pacifigorgia-1(9),10-diene 5, pacifigorgia-1,10-diene 6, pacifigorgia-1(6),10-diene 6,
pacifigorgia-2(10),11-diene 7, pacifigorgia-2,10-diene
8, from the liverwort Frullania fragilifolia collected
at the Hinanger Wasserfall (Sonthofen, Allgau,
Germany). Subsequently, French and coworkers6 have
reported the isolation of pacifigorgia-7,10-diene 10
from the root extracts of Aristolochia salvadorensis
(Figure 1).
From the synthesis point of view, so far only one
report each on the synthesis of pacifigorgiol 2 and
tamariscol 3 (along with its C-2 epimer) have been
appeared in the literature prior to the initiation of the
research work described here7. In 1982, Clardy and
Martin8 reported the synthesis of (±)-pacifigorgiol 2
starting from commercially available 3-methoxyindanone using Birch reduction and cyclopropanation as
key steps. In 1990, Asakawa and coworkers9 reported
the synthesis of (±)-2-epitamariscol and tamariscol 3
starting from 3-methoxyindanone. So far there is no
report in the literature on the synthesis of any
pacifigorgiadienes either in racemic or enantiopure
form.
Last fifteen years had witnessed an exponential
growth in the application of the olefin metathesis10
reaction in organic synthesis. The catalytic nature of
the reaction in combination with its operational
simplicity, remarkable tolerance of some of the
catalysts to various functional groups and their
stability to various conditions are some of the key
factors responsible for the increased use of olefin
metathesis reaction in recent years, particularly the
intramolecular version, i.e. ring-closing metathesis
(RCM) reaction10. Of the three commonly employed
catalysts 11-13 developed by Schrock and Grubbs, the
first generation Grubbs catalyst 12 is more selective,
less reactive, generally provides a cleaner reaction
and is much less expensive than 11 and 13. In general,
the catalyst 12 is found to be highly selective towards
terminal monosubstituted olefins to form disubstituted
cyclic olefins, and is very reluctant to react with
sterically demanding geminally disubstituted olefins
to yield tri- and tetrasubstituted olefins. It is well
documented that a more reactive catalyst such as
Schrock’s molybdenum catalyst 11 or Grubbs' second
generation ruthenium catalyst 13 is required for
INDIAN J. CHEM., SEC B, FEBRUARY 2012
346
5
H
6
H
H
H
8
3
1
OH
10
H
HO
H
O
2 Pacifigorgiol
1 pacifigorgiane
3 Tamariscol
H
6
7
5
4
H
H
H
H
H
H
9
8
10
Figure 1
F3 C
F3 C
H3C
H3C
F3C CF
3
PCy3
Ru
Cl
PCy3 Ph
Cl
O
N
Mo
O
Ph
12
11
Schrock catalyst
O
Mes N
N Mes
Cl
Ru
Cl
PCy3 Ph
13
Grubbs' catalysts
O
Me
Me
12 (20 mol%)
10%
H
14
H
15
Me
Me
12 (10 mol%)
100%
O
H
16
generating tri- and tetrasubstituted cyclic olefins by
RCM reaction of dienes. In this context, we have
discovered7 a highly efficient RCM reaction, assisted
by the entropic effect, using Grubbs' first generation
catalyst 12 and involving a geminally disubstituted
olefin. For example, 6-methyl-6-allylcarvone 14 was
found to be inefficient (only 10%) to RCM reaction
with Grubbs’ first generation catalyst 12 to generate
the bicyclo[4.3.0]nonane 15. On the other hand,
introduction of steric crowding on the carbon next to
O
H
17
one of the reaction centers, e.g. 3-butyl-4-dimethyl-4allylcarvone 16, the reaction with Grubbs’ first
generation catalyst 12 to generate the bicycle[4.3.0]nonane 17 was found to be extremely facile
(quantitative). This efficient RCM reaction of 16 can
be attributed to the entropy effect, commonly referred
as Thorpe-Ingold (or reactive rotamer) effect11. Based
on this concept, in continuation of our interest in the
enantiospecific synthesis of natural products12 from
the readily available monoterpene (R)-carvone 18,
SRIKRISHNA et al.: ENANTIOSPECIFIC SYNTHESIS OF PACIFIGORGIANES
347
O
H
18
20
19
1
O
O
Scheme I
H
H
i
H
BuBr, Li
+
))))
R
H
O
18 R = H
20t R = allyl
90%
95%
H
HO
LDA
CH2=CHCH2Br
HO
22t
LDA
70%
AcOH
H
H
H
90%
H
HO
90%
H
19t
PCC
silica gel
23c
20c
19c
H
O
H
O
12 (10 mol%)
19t
21t
O
BuBr, Li
))))
O
(1 : 2)
H
H
H
i
H
PCC O
silica gel
19c
H
100%
12 (10 mol%)
100%
24t
H
24c
Scheme II
herein we present the details of our investigations7 on
the synthesis of pacifigorgianes.
Results and Discussion
Based on the entropy assisted efficient RCM
reaction, referred above, an enantiospecific approach
to pacifigorgianes 1 has been investigated. It was
readily identified that generation of 4-allyl-3isobutylcarvone 19 from 6-allylcarvones 20, followed
by RCM reaction would lead to pacifigorgianes 1
(Scheme I).
The sequence was initiated with (R)-carvone 18 as
depicted in Scheme II. Reaction of carvone 18 with
LDA and treatment of the resultant kinetic dienolate
with allyl bromide generated a 5:1 mixture of the
trans and cis isomers of 6-allylcarvone 20t and 20c,
which were carefully separated by column chromatography on silica gel13. An alkylative 1,3-enone
transposition strategy14 was exploited for converting
6-allylcarvones into the requisite RCM precursors.
Sonochemically accelerated Barbier reaction of trans6-allylcarvone 20t with lithium and isobutyl bromide
in anhydrous THF furnished a 2:1 diastereomeric
mixture of the tertiary allyl alcohols 21 and 22, in
95% yield, which were separated by column
chromatography on silica gel. Structures of the major
and minor alcohols 21 and 22 were established from
their spectral data. Stereochemistry of the major
alcohol 21 was assigned based on the preferred
approach of the nucleophile opposite to the more
bulkier isopropenyl side chain at C-5. Oxidation of
the alcohol 21 with PCC and silica gel in methylene
chloride at RT furnished the transposed enone 19t in
90% yield. In a similar manner, oxidation of the
minor alcohol 22 with PCC and silica gel in
methylene chloride also furnished the same enone
INDIAN J. CHEM., SEC B, FEBRUARY 2012
348
19t. For the generation of the pacifigorgiane
derivatives with cis ring junction, synthesis of cis-4allyl-3-isobutylcarvone 19c was also studied starting
from cis-6-allylcarvone 20c. Since cis-6-allylcarvone
20c was formed as a minor product in the allylation of
carvone 18, inversion of the stereochemistry at the C6 position of trans-6-allylcarvone 20t under kinetic
conditions was explored. Thus, generation of the
kinetic dienolate of 6-allylcarvone 20 with LDA at
–70°C, followed by quenching with acetic acid at the
same temperature generated cis-6-allylcarvone 20c.
Barbier reaction of cis-6-allylcarvone 20c with
lithium and isobutyl bromide in anhydrous THF gave
the alcohol 23 in a highly regio- and stereoselective
manner. Stereochemistry of the alcohol 23 was
assigned based on the preferred approach of the
nucleophile anti to both the substituents at the C-5
and C-6 carbons. Oxidation of the alcohol 23 using
PCC and silica gel in methylene chloride at room
temperature for 4 hr furnished the enone 19c, whose
structure was established from its spectral data (IR, 1H
and 13C NMR and mass) in comparison with that of
the enone 19t. In line with the earlier observations,
refluxing a 0.005 M methylene chloride solution of
the enone 19t with 10 mol% of the Grubbs' first
generation catalyst 12 for 3 hr furnished pacifigorgia2,7-dien-4-one 24t in quantitative yield. It is worth
noting that the RCM reaction is very facile even when
the isopropenyl and allyl groups are oriented trans to
each other. The structure of the bicyclic dienone 24t
was delineated from its spectral data. Presence of the
molecular ion at m/z 218 (C15H22O) in the mass
spectrum and presence of carbonyl absorption band at
1664 cm-1 due to the enone moiety and absence of
absorption bands due to terminal olefin in the IR
spectrum revealed the formation of the dienone 24t.
In the 1H NMR spectrum, presence of a singlet at δ
5.44 due to only one olefinic proton, two singlets at δ
1.74 and 1.71 due to two olefinic methyl groups and
two doublets at δ 1.01 and 0.88 due to two methyls of
the isobutyl group along with other signals established
the structure of the bicyclic dienone 24t. The 15 lines
13
C NMR spectrum with characteristic signals [three
quaternary carbon resonances at δ 198.9, 158.1 and
132.2 due to the ketone, β and α carbons,
respectively, of the enone moiety, a quaternary carbon
resonance at δ 142.8 and a methine at δ 124.6 due to
cyclopentene olefin carbons, three methines at δ 50.7,
50.2 and 28.2, three methylenes at δ 42.9, 41.8 and
33.8 and four methyls at δ 23.7, 22.4, 14.5 and 12.0
due to the remaining aliphatic carbons] further
confirmed the structure of pacifigorgia-2,7-dien-4-one
24t. In a similar manner, refluxing a 0.005 M
methylene chloride solution of the enone 19c with 10
mol % Grubbs' first generation catalyst 12 for 3 hr
generated cis-pacifigorgia-2,7-dien-4-one 24c in
quantitative yield, whose structure was also
established from spectral data (IR, 1H and 13C NMR
and mass) in comparison with that of the trans
dienone 24t.
Subsequently, RCM reaction of the alcohols 21-23
were also investigated (Scheme III). The alcohol 21t
contains the allyl and isobutyl side chains cis to each
other and hence expected to have the entropy effect in
the RCM reaction. As anticipated, reaction of the
H
H
12 (10 mol%)
OH
HO
H
>95%
H
HO
25
21
H
H
12 (15 mol%)
OH
HO
10%
H
H
HO
26
H
23
H
12 (10 mol%)
+ 22
100%
OH
HO
H
H
HO
27
22
Scheme III
(1:1)
SRIKRISHNA et al.: ENANTIOSPECIFIC SYNTHESIS OF PACIFIGORGIANES
alcohol 21t, with 10 mol% of the Grubbs' first
generation catalyst 12 in 0.005 M methylene chloride
solution under reflux conditions for 3 hr furnished the
RCM product, pacifigorgia-3,7-dien-2-ol 25 in near
quantitative yield. In contrast, the tertiary alcohol 23c
contains the allyl and isobutyl groups trans
pseudodiaxial to each other and hence it should not
have any entropy effect in the RCM reaction. As
expected, RCM reaction of the tertiary allyl alcohol
23c was found to be inefficient with 12, even though
the allyl and isopropenyl groups are cis to each other,
analogous to earlier result7. Thus, refluxing a 0.005 M
methylene chloride solution of the alcohol 23c with
15 mol% of the Grubbs' first generation catalyst 12
for 12 hr furnished the RCM product 26 in less than
10% yield along with substantial amount (85%) of
unreacted starting material 23c. On the other hand, in
contrast to the alcohol 23c, even though the minor
alcohol 22t contains the isobutyl and allyl groups
trans to each other, it is likely that they orient in
trans-diequatorial manner and hence there is a
possibility of marginal entropy effect because of the
reasonable steric repulsion between the gem-dimethyl
group of isobutyl and allyl (or intermediate rhodium
carbenoid) groups. It is gratifying to find that the allyl
alcohol 22t underwent RCM reaction to a significant
extent even though the allyl and isopropenyl groups
are trans to each other. Thus, refluxing a 0.005 M
H
H
Zn, KOH
70%
H
O
20t
O
i
BuBr, Li
H
28
))))
H
H
12 (10 mol%)
H
HO
>95%
H
HO
30
29
Scheme IV
90%
methylene chloride solution of the alcohol 22 with 10
mol% of the Grubbs' first generation catalyst 12 for 6
hr furnished a 1:1 mixture of pacifigorgia-3,7-dien-2ol 27 and the unreacted starting material in
quantitative yield, which were separated by silica gel
column chromatography. The structures of the
bicyclic alcohols 25-27 rests secured from their
spectral data.
In order to find the effect of the ring olefin (i.e.
presence of sp2 carbons in cyclohexane as they
influence on the conformation) on the RCM reaction,
the reaction was carried out with the dihydro
derivative 28 (Scheme IV). Thus, reaction of trans-6allylcarvone 20t with zinc and potassium hydroxide in
refluxing ethanol for 10 hr furnished the allyldihydrocarvone 28 in 70% yield. The stereochemistry of the
secondary methyl group was assigned as trans to
isopropenyl group and cis to allyl group on the basis
of the thermodynamic considerations. Barbier
reaction of the ketone 28 with lithium and isobutyl
bromide in anhydrous THF furnished the tertiary
alcohol 29 in 90% yield in a highly stereoselective
manner. Stereochemistry of the isobutyl group was
assigned based on the approach of the nucleophile
from the less crowded equatorial side (opposite to C-2
and C-6 substituents). Similar to the alcohol 22, the
allyl and isobutyl side chains in the alcohol 29 are
arranged in trans-diequatorial manner, and hence
some entropic assistance is expected in the RCM
reaction. Thus, refluxing a 0.005 M methylene
chloride solution of the alcohol 29 with 10 mol% of
Grubbs' first generation catalyst 12 for 4 hr generated
pacifigorgia-7-en-2-ol 30 in near quantitative yield,
whose structure was delineated from its spectral data.
Finally, the strategy has been extended to a four
step short route for the enantiospecific synthesis of
the bicyclic ketone 4, a degradation product of
tamariscol 3 as well as known precursor for epitamariscol and tamariscols, was developed (Scheme V).
Refluxing a 0.005 M methylene chloride solution of
the allyldihydrocarvone 28 with 10 mol% Grubbs'
first generation catalyst 12 for 12 hr generated the
bicyclic enone 31 in low yield (10-15%) analogous to
H
H
O
28
H
5% Pd-C, H2
13 (5 mol%)
H
349
99%
>95%
O
H
31
Scheme V
O
H
4
350
INDIAN J. CHEM., SEC B, FEBRUARY 2012
allylmethylcarvone 14. Since the efficiency of the
RCM reaction is low with Grubbs' first generation
catalyst 12, the reaction was carried out with Grubbs'
second generation catalyst 13. Thus, reaction of a
0.005 M methylene chloride solution of allyldihydrocarvone 28 with 5 mol% Grubbs' second generation
catalyst 13 at room temperature for 2 hr generated the
bicyclic enone 31 in near quantitative yield, whose
structure was established from its spectral data.
Catalytic hydrogenation of the bicyclic enone 31 in
ethanol using 10% palladium on charcoal as the
catalyst furnished the saturated ketone 4 in quantitative yield in a highly stereoselective manner, whose
structure was established from its spectral data. It was
further confirmed by comparing the optical rotation
9
[α] 23
D : –16.4 (c 1.0, CHCl3) {lit. [α] D : –14.3 (c 0.25,
1
CHCl3)} and spectral data (IR, H and 13C NMR) with
that reported in the literature by Asakawa and
coworkers. Transformation of the bicyclic ketone 4
into tamariscol 3 and its C-2 epimer by addition of 2methylpropenyllithium has already been reported9 by
Asakawa and coworkers.
In conclusion, enantiospecific synthesis of a
number of pacifigorgianes have been accomplished,
employing the entropy assisted RCM reaction using
the first generation Grubbs' catalyst. Enantiospecific
synthesis of the degradation product 4 as well as
formal total synthesis of tamariscol and its C-2 epimer
has also been accomplished.
Experimental Section
IR spectra were recorded on Jasco FTIR 410
spectrophotometer. UV spectra were recorded on
Shimadzu UV-2100 spectrophotometer. 1H (300
MHz) and 13C (75 MHz) NMR spectra were recorded
on JEOL JNM λ-300 spectrometer. In the NMR
spectra, chemical shifts (δ, ppm) and coupling
constants (Hz) are reported in the standard fashion
with reference to either internal tetramethylsilane (for
1
H) 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 experiment, and is given in parentheses.
Low-resolution mass spectra were recorded using
Shimadzu QP-5050A GCMS instrument using direct
inlet mode. Relative intensities are given in
parentheses. High-resolution mass spectra were
recorded using micromass Q-TOF spectrometer using
electrospray ionisation. Optical rotations were
measured using a Jasco DIP-370 digital polarimeter
and [α]D values are given in units of 10-1 deg cm2 g-1.
Hydrogenation reaction at one atmospheric pressure
was carried out using a balloon. Analytical thin-layer
chromatographies (TLC) were performed on glass
plates (7.5 × 2.5 and 7.5 × 5.0 cm) coated with
Acme's silica gel G containing 13% calcium sulfate as
binder and various combinations of ethyl acetate,
methylene chloride and hexane were used as eluent.
Visualization of spots was accomplished by exposure
to iodine vapor. Acme's silica gel (100-200 mesh) was
used for column chromatography (approximately 1520 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
conducted in a bath made of sodium chloride and ice,
or alcohol and liquid nitrogen.
(1S,5R,6S)-and-(1R,5R,6S)-6-Allyl-5-isopropenyl-2-methyl-1-(2-methylpropyl)cyclohex-2-enols,
22t and 21t. To a suspension of lithium (28 mg, 4.0
mmol) in anhydrous THF (5 mL) in a round bottom
flask, placed in an ultrasonic cleaning bath, were
added trans-6-allylcarvone13 20t (145 mg, 0.76 mmol)
and isobutyl bromide (205 mg, 1.5 mmol). Then the
reaction mixture was sonochemically irradiated for 40
min. The reaction mixture was decanted from the
excess lithium, quenched with saturated aq. NH4Cl
and extracted with ether (3 × 5 mL). The ether extract
was washed with brine and dried (Na2SO4).
Evaporation of the solvent and purification of the
residue on a silica gel column using CH2Cl2-hexane
(1:5) as eluent furnished the tertiary alcohol 22t (60
mg, 31.5%). [α] 24
D : –12.9º (c 2.4, CHCl3); IR (neat):
3546 (OH), 3073, 1638, 1377, 1139, 997, 911
(CH=CH2), 892 (C=CH2) cm-1; 1H NMR (300 MHz,
CDCl3+CCl4): δ 5.90 (1 H, ddt, J = 17.1, 9.9 and 6.9
Hz, CH=CH2), 5.37 (1 H, br s, H-3), 5.05 (1 H, d, J =
17.1 Hz) and 4.99 (1 H, d, J = 9.9 Hz) [CH=CH2],
4.81 (1 H, s) and 4.77 (1 H, s) [C=CH2], 2.37 (1 H, q,
J = 6.9 Hz), 2.30-1.80 (7 H, m), 1.74 (3 H, s) and 1.72
(3 H, s) [2 × olefinic-CH3], 1.50 (1 H, dd, J = 14.4
and 6.6 Hz), 1.39 (1 H, dd, J = 14.4 and 5.4 Hz), 0.99
(3 H, d, J = 6.6 Hz) and 0.96 (3 H, d, J = 6.6 Hz)
[(CH3)2CH]; 13C NMR (75 MHz, CDCl3+CCl4): δ
149.4 (C, C=CH2), 139.7 (CH, CH=CH2), 139.3 (C,
C-2), 122.1 (CH, C-3), 115.7 (CH2, CH=CH2), 112.2
(CH2, C=CH2), 76.4 (C, C-OH), 46.4 (CH), 45.3
(CH2), 43.1 (CH), 34.2 (CH2), 28.2 (CH2), 25.2 (CH3),
24.9 (CH3), 24.3 (CH), 20.0 (CH3), 19.0 (CH3); MS:
m/z (%) 249 (M + 1, 5), 191 (M – C4H9, 70), 149 (15),
125 (20), 121 (25), 109 (40), 107 (20), 105 (20), 91
SRIKRISHNA et al.: ENANTIOSPECIFIC SYNTHESIS OF PACIFIGORGIANES
(30); HRMS: m/z for C17H28ONa (M + Na), Calcd.:
271.2038. Found: 271.2045.
Further elution of the column with CH2Cl2-hexane
(1:5) furnished the tertiary alcohol 21t (120 mg, 63%)
as oil. [α] 24
D : +10.4º (c 2.4, CHCl3); IR (neat): 3446
(OH), 3073, 1639, 1375, 1286, 1024, 997, 950, 906
(CH=CH2), 891 (C=CH2) cm-1; 1H NMR (300 MHz,
CDCl3+CCl4): δ 5.93 (1 H, ddt, J = 17.1, 9.9 and 7.3
Hz, CH=CH2), 5.54 (1 H, d, J = 6.0 Hz, H-3), 5.00 (1
H, d, J = 17.1 Hz) and 4.90 (1 H, d, J = 9.9 Hz)
[CH=CH2], 4.83 (1 H, s) and 4.79 (1 H, s) [C=CH2],
2.42-2.25 (2 H, m), 2.20-1.85 (3 H, m), 1.78 (1 H, dt,
J = 12.0 and 4.6 Hz), 1.82-1.65 (2 H, m), 1.56 (1 H,
septet, J = 6.3 Hz), 1.72 (3 H, s) and 1.68 (3 H, s) [2 ×
olefinic-CH3], 1.35 (1 H, s), 0.93 (3 H, d, J = 6.3 Hz)
and 0.89 (3 H, d, J = 6.6 Hz) [(CH3)2CH]; 13C NMR
(75 MHz, CDCl3+CCl4): δ 147.1 (C, C=CH2), 139.7
(CH, CH=CH2), 137.8 (C, C-2), 125.5 (CH, C-3),
115.2 (CH2, CH=CH2), 113.5 (CH2, C=CH2), 75.8 (C,
C-OH), 44.7 (CH2), 44.1 (CH), 42.7 (CH), 32.8
(CH2), 31.6 (CH2), 25.0 (CH), 24.9 (CH3), 22.3 (2 C,
CH3), 19.2 (CH3); MS: m/z (%) 249 (M + 1, 1), 192
(15), 191 (M – C4H9, 100), 173 (10), 149 (15), 140
(10), 131 (12), 125 (18), 121 (23), 109 (40), 107 (25);
HRMS: m/z for C17H28ONa (M + Na), Calcd.:
271.2038. Found: 271.2040.
(4S,5R)-4-Allyl-5-isopropenyl-2-methyl-3-(2-methylpropyl)cyclohex-2-enone, 19t. To a magnetically
stirred solution of a mixture of the tertiary alcohols 21
and 22 (124 mg, 0.5 mmol) in anhydrous CH2Cl2 (3
mL) was added a homogenous mixture of PCC (215
mg, 1.0 mmol) and silica gel (215 mg) and stirred
vigorously for 4 hr at RT. The reaction mixture was
then filtered through a small silica gel column and the
column eluted with excess CH2Cl2. Evaporation of the
solvent and purification of the residue on a silica gel
column using CH2Cl2-hexane (1:5) as eluent furnished
the enone 19t (110 mg, 90%) as oil. [α] 24
D : +77.1º
(c 2.8, CHCl3); UV (CH3CN): λmax 245 (ε = 11989);
IR (neat): 3077, 1666 (C=O), 1381, 1357, 1311, 1162,
996, 913 (CH=CH2), 894 (C=CH2) cm-1; 1H NMR
(300 MHz, CDCl3+CCl4): δ 5.85-5.65 (1 H, m,
CH=CH2), 5.20-5.05 (2 H, m, CH=CH2), 4.80 (1 H, s)
and 4.58 (1 H, s) [C=CH2], 2.62 (1 H, br s), 2.55 (1 H,
d, J = 6.0 Hz), 2.50-2.20 (5 H, m), 1.98 (1 H, dd, J =
12.6 and 5.4 Hz), 1.90-1.73 (1 H, m), 1.74 (3 H, s)
and 1.71 (3 H, s) [2 × olefinic-CH3], 0.99 (3 H, d, J =
6.6 Hz) and 0.83 (3 H, d, J = 6.6 Hz) [(CH3)2CH]; 13C
NMR (75 MHz, CDCl3+CCl4): δ 196.8 (C, C=O),
156.6 (C, C-3), 145.8 (C, C=CH2), 135.9 (CH,
351
CH=CH2), 131.9 (C, C-2), 117.5 (CH2, CH=CH2),
112.5 (CH2, C=CH2), 41.8 (2 C, CH and CH2), 41.4
(CH), 37.5 (CH2), 36.7 (CH2), 28.0 (CH), 23.6 (CH3),
22.0 (CH3), 21.6 (CH3), 11.5 (CH3); MS: m/z (%) 247
(M + 1, 3), 246 (M+, 3), 205 (M – C3H5, 22), 190 (15),
163 (60), 149 (40), 135 (15), 121 (57), 107 (57), 105
(22), 93 (25), 91 (20); HRMS: m/z for C17H26ONa (M
+ Na), Calcd.: 269.1881. Found: 269.1896.
(5R,6R)-6-Allyl-5-isopropenyl-2-methylcyclohex2-enone 20c. To a cold (–70°C), magnetically stirred
solution of diisopropylamine (0.5 mL, 3.5 mmol) in
anhydrous THF (10 mL) was slowly added a solution
of n-BuLi (2.5 M in hexane, 1.2 mL, 3.0 mmol) and
stirred for 10 min. To the LDA thus formed was
added drop wise a solution of a mixture of trans- and
cis-6-allylcarvone 20 (500 mg, 2.63 mmol) in
anhydrous THF (10 mL) over a period of 10 min and
stirred for 40 min at the same temperature. The
enolate was then treated with acetic acid (0.5 mL,
excess) in THF (1 mL) and stirred for 1 hr at RT. The
reaction mixture was then diluted with water (15 mL)
and extracted with ether (2 × 15 mL). The combined
organic extract was washed with brine and dried
(Na2SO4). Evaporation of the solvent followed by
purification of the residue over a silica gel column
using CH2Cl2-hexane (1:5) as eluent furnished cis-6allylcarvone 20c (350 mg, 70%), whose spectral data
was identical with the sample obtained earlier.13
[α] 21
D : +8.2 (c 3.4, CHCl3); IR (neat): 3077, 1671
(C=O), 1641, 1376, 995, 895 (CH=CH2), 889
(C=CH2) cm-1; 1H NMR (300 MHz, CDCl3+CCl4): δ
6.62 (1 H, br s, H-3), 5.80-5.60 (1 H, m, CH=CH2),
4.96 (1 H, s), 4.95-4.90 (2 H, m), 4.72 (1 H, s), 2.852.75 (1 H, m), 2.65-2.05 (5 H, m), 1.77 (3 H, s) and
1.71 (3 H, s) [2 × olefinic-CH3]; 13C NMR (75 MHz,
CDCl3+CCl4): δ 201.0 (C, C=O), 144.6 (C, C=CH2),
142.4 (CH, C-3), 136.1 (CH, CH=CH2), 134.3 (C, C2), 116.4 (CH2, CH=CH2), 112.4 (CH2, C=CH2), 48.7
(CH), 44.6 (CH), 30.0 (CH2), 27.7 (CH2), 22.2 (CH3),
16.1 (CH3); MS: m/z (%) 190 (M+, 5%), 189 (10), 175
(M – CH3, 12), 161 (15), 149 (M – C3H5, 15), 135
(22), 121 (25), 109 (30), 107 (32), 95 (32), 93 (35), 91
(40). Further elution of the column using CH2Cl2hexane (1:5) furnished trans-6-allylcarvone 20t (145
mg, 29%) as oil.
(1R,5R,6R)-6-Allyl-5-isopropenyl-2-methyl-1-[2methylpropyl]cyclohex-2-enol, 23c. Barbier reaction
of cis-6-allylcarvone 20c (95 mg, 0.5 mmol) with
isobutyl bromide (137 mg, 1.0 mmol) and lithium (21
mg, 3 mmol) in THF (5 mL) and work up as
352
INDIAN J. CHEM., SEC B, FEBRUARY 2012
described for the alcohol 21, and purification on a
silica gel column using CH2Cl2-hexane (1:5) as eluent
furnished the tertiary alcohol 23c (112 mg, 90%) as
oil. [α] 21
D : –90.5º (c 2.0, CHCl3); IR (neat): 3587
(OH), 3084, 1638, 1368, 1303, 1150, 1130, 1034,
998, 908 (CH=CH2), 890 (C=CH2) cm-1; 1H NMR
(300 MHz, CDCl3+CCl4): δ 6.05-5.90 (1 H, m,
CH=CH2), 5.32 (1 H, s, H-3), 5.03 (1 H, dd, J = 17.1
and 1.8 Hz) and 4.95 (1 H, d, J = 9.6 Hz) [CH=CH2],
4.88 (1 H, d, J = 1.2 Hz) and 4.70 (1 H, s) [C=CH2],
2.45-2.25 (2 H, m), 2.15-1.80 (5 H, m), 1.80 (3 H, s)
and 1.72 (3 H, s) [2 × olefinic-CH3], 1.63 (1 H, s),
1.58 (2 H, d, J = 6.0 Hz), 1.04 (3 H, d, J = 6.6 Hz) and
0.96 (3 H, d, J = 6.6 Hz) [(CH3)2CH]; 13C NMR (75
MHz, CDCl3+CCl4): δ 146.7 (C, C=CH2), 141.7 (CH,
CH=CH2), 139.1 (C, C-2), 121.0 (CH, C-3), 114.9
(CH2, CH=CH2), 111.1 (CH2, C=CH2), 78.9 (C, COH), 47.6 (CH2), 41.8 (CH), 41.4 (CH), 29.3 (CH2),
26.0 (CH2), 25.5 (CH3), 24.4 (CH), 24.1 (CH3), 22.8
(CH3), 17.9 (CH3); MS: m/z (%) 248 (M+, 5), 247 (M
– 1, 20), 191 (M – C4H9, 100), 173 (13), 163 (18), 149
(30), 135 (25), 121 (65), 109 (60), 107 (50), 91 (60);
HRMS: m/z for C17H27 (M – OH), Calcd.: 231.2113.
Found: 231.2101
(4R,5R)-4-Allyl-5-isopropenyl-2-methyl-3-(2-methylpropyl)cyclohex-2-enone, 19c. Oxidation of the
tertiary alcohol 23 (60 mg, 0.24 mmol) in anhydrous
CH2Cl2 (2 mL) using PCC (112 mg, 0.5 mmol) and
silica gel (100 mg) for 4 hr as described for the enone
19t, followed by purification on a silica gel column
using CH2Cl2-hexane (1:4) as eluent furnished the
enone 19c (55 mg, 90%) as oil. [α] 21
D : +214.1º (c 1.7,
CHCl3); UV (CH3CN): λmax 245 (ε = 10622); IR
(neat): 3081, 1666 (C=O), 1624, 1383, 1347, 1311,
1275, 1163, 1083, 996, 912 (CH=CH2), 892 (C=CH2)
cm-1; 1H NMR (300 MHz, CDCl3+CCl4): δ 5.81-5.65
(1 H, m, CH=CH2), 5.05-4.85 (2 H, m, CH=CH2),
4.96 (1 H, s) and 4.72 (1 H, s) [C=CH2], 2.70-2.25 (6
H, m), 2.05-1.85 (3 H, m), 1.78 (3 H, s) and 1.76 (3
H, s) [2 × olefinic-CH3], 1.00 (3 H, d, J = 6.6 Hz) and
0.93 (3 H, d, J = 6.6 Hz) [(CH3)2CH]; 13C NMR (75
MHz, CDCl3+CCl4): δ 198.4 (C, C=O), 162.1 (C, C3), 144.7 (C, C=CH2), 137.3 (CH, CH=CH2), 131.5
(C, C-2), 116.5 (CH2, CH=CH2) 112.1 (CH2, C=CH2),
44.4 (CH), 43.9 (CH2), 41.7 (CH), 37.2 (CH2), 33.7
(CH2), 28.3 (CH), 23.3 (CH3), 22.9 (CH3), 22.2 (CH3),
11.4 (CH3); MS: m/z (%) 246 (M+, 10), 205 (M –
C3H5, 40), 190 (25), 177 (20), 163 (100), 149 (70),
135 (30), 121 (100), 107 (95), 105 (40); HRMS: m/z
for C17H27O (M + 1), Calcd.: 247.2062. Found:
247.2066.
(1R,6S)-4,9-Dimethyl-5-(2-methylpropyl)bicyclo[4.3.0]nona-4,8-dien-3-one
(trans-pacifigorgia2,7-dien-4-one), 24t. To a magnetically stirred
solution of the enone 19t (25 mg, 0.1 mmol) in
anhydrous CH2Cl2 (20 mL, 0.005 M) was added
Grubbs’ first generation catalyst 12 (8 mg, 10 mol%).
The reaction mixture was refluxed for 3 hr and the
catalyst was filtered off through a short silica gel
column. Evaporation of the solvent and purification of
the residue on a silica gel column using CH2Cl2hexane (1:4) as eluent furnished the bicyclic dienone
24t (22 mg, 100%). [α] 24
D : +20.0º (c 3.5, CHCl3); UV
(CH3CN): λmax 240 (ε = 8021); IR (neat): 3038, 1664
(C=O), 1604, 1378, 1346, 1315, 792 cm-1; 1H NMR
(300 MHz, CDCl3+CCl4): δ 5.44 (1 H, s, H-8), 2.82 (1
H, dd, J = 16.0 and 3.6 Hz), 2.60-2.30 (4 H, m), 2.352.00 (3 H, m), 2.00-1.75 (1 H, m), 1.74 (3 H, s) and
1.71 (3 H, s) [2 × olefinic-CH3], 1.01 (3 H, d, J = 6.6
Hz) and 0.88 (3 H, d, J = 6.6 Hz) [(CH3)2CH]; 13C
NMR (75 MHz, CDCl3+CCl4): δ 198.9 (C, C=O),
158.1 (C, C-5), 142.8 (C, C-9), 132.2 (C, C-4), 124.6
(CH, C-8), 50.7 (CH), 50.2 (CH), 42.9 (CH2), 41.8
(CH2), 33.8 (CH2), 28.2 (CH), 23.7 (CH3), 22.4 (CH3),
14.5 (CH3), 12.0 (CH3); MS: m/z (%) 218 (M+, 10%),
175 (10), 161 (M – C4H9, 25), 147 (15), 133 (30), 125
(40), 117 (25), 105 (25), 91 (40); HRMS: m/z for
C15H22ONa (M + Na), Calcd.: 241.1568. Found:
241.1564.
(1R,6R)-4,9-Dimethyl-5-(2-methylpropyl)bicycle[4.3.0]nona-4,8-dien-3-one
(cis-pacifigorgia-2,7dien-4-one), 24c. RCM reaction of the enone 19c (10
mg, 0.04 mmol) in anhydrous CH2Cl2 (8 mL, 0.005
M) using Grubbs’ first generation catalyst 12 (3.5 mg,
10 mol%) for 3 hr at reflux temperature and work up
as described for the compound 19t, followed by
purification on a silica gel column using CH2Cl2hexane (1:4) as eluent furnished the bicyclic dienone
24c (8.5 mg, 100%) as oil. [α] 22
D : -137.3º (c 1.1,
CHCl3); IR (neat): 3039, 2956, 1669 (C=O), 1622,
1379, 1359, 1308, 1162, 1016 cm-1; 1H NMR (300
MHz, CDCl3+CCl4): δ 5.31 (1 H, s, H-8), 3.05-2.90 (1
H, m), 2.90-2.75 (1 H, m), 2.70-2.45 (2 H, m), 2.402.10 (3 H, m), 2.05-1.85 (2 H, m), 1.77 (3 H, s) and
1.71 (3 H, s) [2 × olefinic-CH3], 0.99 (3 H, d, J = 5.1
Hz) and 0.89 (3 H, d, J = 5.4 Hz) [(CH3)2CH];
13
C NMR (75 MHz, CDCl3+CCl4): δ 198.6 (C, C=O),
156.3 (C, C-5), 144.4 (C, C-9), 131.0 (C, C-4), 123.2
(CH, C-8), 45.5 (CH), 43.1 (CH), 42.2 (CH2), 38.7
SRIKRISHNA et al.: ENANTIOSPECIFIC SYNTHESIS OF PACIFIGORGIANES
(CH2), 36.2 (CH2), 27.7 (CH), 23.6 (CH3), 22.5 (CH3),
15.1 (CH3), 11.8 (CH3); MS: m/z (%) 218 (M+, 15%),
161 (M – C4H9, 10), 147 (6), 133 (10), 125 (15), 105
(10); HRMS: m/z for C15H22ONa (M + Na), Calcd.:
241.1568. Found: 241.1557.
(1S,2R,6R)-3,7-Dimethyl-2-(2-methylpropyl)bicyclo[4.3.0]nona-3,7-dien-2-ol (trans-pacifigorgia3,7-dien-2-ol), 25. RCM reaction of the trienol 21 (25
mg, 0.1 mmol) in anhydrous CH2Cl2 (20 mL, 0.005
M) using Grubbs’ first generation catalyst 12 (8 mg,
10 mol%) for 3 hr at reflux temperature and work up
as described for the compound 24t, followed by
purification on a silica gel column using CH2Cl2hexane (1:5) as eluent furnished the bicyclic dienol 25
(22 mg, 97%) as oil. [α] 24
D : –103.3º (c 1.8, CHCl3);
IR (neat): 3429 (OH), 3034, 1438, 1377, 1286, 1143,
1044, 1022, 948, 930, 795 cm-1; 1H NMR (300 MHz,
CDCl3+CCl4): δ 5.56 (1 H, d, J = 5.4 Hz, H-4), 5.34
(1 H, s, H-8), 2.35-2.00 (4 H, m), 1.91 (1 H, td, J =
11.4 and 6.9 Hz), 1.80-1.60 (3 H, m), 1.75 (3 H, s)
and 1.68 (3 H, s) [2 × olefinic-CH3], 1.60-1.40 (2 H,
m), 0.94 (3 H, d, J = 6.3 Hz) and 0.90 (3 H, d, J = 6.6
Hz) [(CH3)2CH]; 13C NMR (75 MHz, CDCl3+CCl4): δ
142.1 (C), 140.5 (C), 126.6 (CH), 124.5 (CH), 73.9
(C, C-OH), 52.7 (CH), 44.9 (CH2), 43.9 (CH), 30.3
(CH2), 30.0 (CH2), 25.1 (CH3), 24.9 (CH), 23.5 (CH3),
18.7 (CH3), 14.7 (CH3); MS: m/z (%) 202 (M – H2O,
1%), 163 (M – C4H9, 12), 161 (12), 159 (10), 145 (M
– C4H9 – H2O, 100), 105 (15); HRMS: m/z for
C15H24ONa (M + Na), Calcd.: 243.1725. Found:
243.1725.
(1R,2R,6R)-3,7-Dimethyl-2-(2-methylpropyl)bicyclo[4.3.0]nona-3,7-dien-2-ol (cis-pacifigorgia-3,7dien-2-ol), 26. RCM reaction of the trienol 23c (20
mg, 0.08 mmol) in anhydrous CH2Cl2 (15 mL, 0.005
M) using Grubbs’ first generation catalyst 12 (10 mg,
15 mol%) for 12 hr at reflux temperature and work up
as described for the compound 24t, followed by
purification on a silica gel column using CH2Cl2hexane (1:5) as eluent first furnished the unreacted
starting material 23 (17 mg, 85%). Further elution of
the column with the same solvent furnished the
bicyclic dienol 26 (1.8 mg, 10%) as oil. [α] 22
D :
–202.5º (c 0.4, CHCl3); IR (neat): 3500 (OH), 3036,
1378, 1365, 1310, 1261, 1147, 1018, 798 cm-1;
1
H NMR (300 MHz, CDCl3+CCl4): δ 5.39 (1 H, br s,
H-4), 5.11 (1 H, s, H-8), 2.72 (1 H, q, J = 8.5 Hz),
2.55 (1 H, br t, J = 7.2 Hz), 2.25-1.90 (2 H, m), 1.901.55 (3 H, m), 1.69 (3 H, s) and 1.59 (3 H, s) [2 ×
353
olefinic-CH3], 1.40-1.10 (3 H, m), 0.94 (3 H, d, J =
6.3 Hz) and 0.88 (3 H, d, J = 6.6 Hz) [(CH3)2CH].
(1S,2S,6R)-3,7-Dimethyl-2-(2-methylpropyl)bicyclo[4.3.0]nona-3,7-dien-2-ol (trans-pacifigorgia3,7-dien-2-ol), 27. RCM reaction of the trienol 22 (22
mg, 0.09 mmol) in anhydrous CH2Cl2 (18 mL, 0.005
M) using Grubbs’ first generation catalyst 12 (7.5 mg,
10 mol%) for 6 hr at reflux temperature and work up
as described for the compound 24t, followed by
purification on a silica gel column using CH2Cl2hexane (1:5) as eluent first furnished the unreacted
starting material 22 (11 mg, 50%). Further elution of
the column with the same solvent furnished the
bicyclic dienol 27 (10 mg, 50%) as oil. [α] 24
D : –94.2º
(c 1.2, CHCl3); IR (neat): 3426 (OH), 3036, 1377,
1165, 1142, 1055, 989, 804 cm-1; 1H NMR (300 MHz,
CDCl3+CCl4): δ 5.46 (1 H, d, J = 5.1 Hz, H-4), 5.38
(1 H, s, H-8), 2.50-2.10 (4 H, m), 1.95-1.65 (4 H, m),
1.77 (3 H, s) and 1.66 (3 H, s) [2 × olefinic-CH3], 1.56
(2 H, dd, J = 6.0 and 0.9 Hz), 0.94 (6 H, d, J = 6.6 Hz,
(CH3)2CH); 13C NMR (75 MHz, CDCl3+CCl4): δ
142.2 (C), 141.5 (C), 124.6 (CH), 124.4 (CH), 75.9
(C, C-OH), 58.3 (CH), 46.4 (CH), 44.8 (CH2), 30.7
(CH2), 30.4 (CH2), 25.6 (CH), 24.8 (CH3), 23.7 (CH3),
17.8 (CH3), 14.6 (CH3); MS: m/z (%) 220 (M+, 1%),
191 (10), 177 (15), 163 (M – C4H9, 100), 145 (M
– C4H9 –H2O, 60), 135 (20), 121(15), 107 (20), 93
(20), 91 (17); HRMS: m/z for C15H24ONa (M + Na),
Calcd.: 243.1725. Found: 243.1724.
(2S,3R,6R)-2-Allyl-3-isopropenyl-6-methylcyclohexanone, 28. To a magnetically stirred refluxing
suspension of zinc powder (425 mg, 6.5 mmol),
potassium hydroxide (95 mg, 1.7 mmol), 95% ethanol
(2.5 mL) and water (1 mL) was added dropwise a
solution of 6-allylcarvone 20t (250 mg, 1.3 mmol) in
95% ethanol (1 mL) over a period of 2 hr and the
suspension was refluxed for 10 hr. The reaction
mixture was then cooled and solvent evaporated under
reduced pressure. The residue was extracted with
ether (3 × 5 mL) and the combined organic 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 the allyldihydrocarvone 28 (175 mg, 70%)
as oil. [α] 23
D : +10.0º (c 6.0, CHCl3); IR (neat): 3074,
1712 (C=O), 1643, 1377, 998, 897 (C=CH2) cm-1;
1
H NMR (300 MHz, CDCl3+CCl4): δ 5.90-5.70 (1 H,
m, CH=CH2), 4.93 (1 H, d, J = 15.0 Hz) and 4.89 (1
H, d, J = 8.1 Hz) [CH=CH2], 4.79 (1 H, s) and 4.74 (1
354
INDIAN J. CHEM., SEC B, FEBRUARY 2012
H, s) [C=CH2], 2.50-2.15 (4 H, m), 2.10-1.95 (2 H,
m), 1.90-1.65 (2 H, m), 1.71 (3 H, s, olefinic-CH3),
1.36 (1 H, qd, J = 12.9 and 4.5 Hz), 1.01 (3 H, d, J =
6.6 Hz, sec-CH3); 13C NMR (75 MHz, CDCl3+CCl4):
δ 211.4 (C, C=O), 145.6 (C, C=CH2), 137.2 (CH,
CH=CH2), 115.6 (CH2, CH=CH2), 112.7 (CH2,
C=CH2), 53.5 (CH), 53.0 (CH), 45.4 (CH), 35.5
(CH2), 31.6 (CH2), 30.8 (CH2), 18.2 (CH3), 14.6
(CH3); MS: m/z (%) 192 (M+, 6%), 149 (25), 147
(20), 133 (15), 121 (15), 119 (15), 110 (30), 107 (30),
105 (35), 95 (55); HRMS: m/z for C13H20ONa (M +
Na), Calcd.: 215.1412. Found: 215.1424.
(1R,2S,3R,6R)-2-Allyl-3-isopropenyl-6-methyl-1(2-methylpropyl)cyclohexanol, 29. Barbier reaction
of allyldihydrocarvone 28 (60 mg, 0.31 mmol) with
isobutyl bromide (70 mg, 0.5 mmol) and lithium (10
mg, 1.5 mmoles) in THF (4 mL) and work up as
described for compound 21, and purification of the
residue on a silica gel column using hexane as eluent
furnished the tertiary alcohol 29 (70 mg, 90%) as oil.
[α] 22
D : –11.3º (c 7.0, CHCl3); IR (neat): 3578 (OH),
3072, 1640, 1375, 1164, 1137, 1008, 907 (CH=CH2),
890 (C=CH2) cm-1; 1H NMR (300 MHz,
CDCl3+CCl4): δ 6.11-5.96 (1 H, m, CH=CH2), 5.05 (1
H, d, J = 17.1 Hz) and 4.98 (1 H, d, J = 9.9 Hz)
[CH=CH2], 4.79 (1 H, s) and 4.73 (1 H, s) [C=CH2],
2.49 (1 H, td, J = 11.7 and 3.6 Hz), 2.30-2.20 (2 H,
m), 1.80-1.25 (10 H, m), 1.65 (3 H, s, olefinic-CH3),
0.99 (6 H, d, J = 6.6 Hz, (CH3)2CH), 0.87 (3 H, d, J =
6.0 Hz, sec-CH3); 13C NMR (75 MHz, CDCl3+CCl4):
δ 148.3 (C, C=CH2), 138.9 (CH, CH=CH2), 116.2
(CH2, CH=CH2), 112.2 (CH2, C=CH2), 77.1 (C, COH), 45.9 (CH2), 45.5 (CH), 44.4 (CH), 38.6 (CH),
32.9 (CH2), 32.5 (CH2), 30.3 (CH2), 25.2 (CH), 24.7
(CH3), 24.3 (CH3), 18.6 (CH3), 16.0 (CH3); MS: m/z
(%) 233 (M – OH, 5), 193 (M – C4H9, 60), 175 (20),
109 (40), 107 (32), 105 (22), 95 (55), 93 (35), 91 (30);
HRMS: m/z for C17H30ONa (M + Na), Calcd.:
273.2194. Found: 273.2198.
(1S,2R,3R,6R)-3,7-Dimethyl-2-(2-methylpropyl)bicycle[4.3.0]non-7-en-2-ol (pacifigorgia-7-en-2-ol),
30. RCM reaction of the dienol 29 (14 mg, 0.056
mmol) in anhydrous CH2Cl2 (12 mL, 0.005 M) using
Grubbs’ first generation catalyst 12 (5 mg, 10 mol%)
for 4 hr at reflux temperature and work up as
described for the compound 24t, followed by
purification on a silica gel column using CH2Cl2hexane (1:10) as eluent furnished the bicyclic enol 30
(12 mg, 96%) as oil. [α] 23
D : +28.6º (c 0.7, CHCl3); IR
(neat): 3502 (OH), 3036, 1376, 1143, 1020, 987, 952,
930, 790 cm-1; 1H NMR (300 MHz, CDCl3+CCl4): δ
5.27 (1 H, s, H-8), 2.33 (1 H, br t, J = 12.0 Hz), 2.102.00 (2 H, m), 1.88 (1 H, dq, J = 11.7 and 3.3 Hz),
1.80-1.50 (5 H, m), 1.66 (3 H, s, olefinic-CH3), 1.501.25 (3 H, m), 1.02 (1 H, qd, J = 12.3 and 3.6 Hz),
0.95 (6 H, d, J = 6.6 Hz, (CH3)2CH), 0.88 (3 H, d, J =
6.6 Hz, sec-CH3); 13C NMR (75 MHz, CDCl3+CCl4):
δ 143.8 (C, C-7), 123.1 (CH, C-8), 74.3 (C, C-OH),
56.6 (CH), 47.0 (CH2), 46.5 (CH), 37.7 (CH), 32.1
(CH2), 30.4 (CH2), 29.0 (CH2), 25.1 (CH), 25.0 (CH3),
24.2 (CH3), 15.1 (CH3), 14.7 (CH3); MS: m/z (%) 221
(M – 1, 4%), 193 (12), 179 (M – C3H7, 25), 165 (M –
C4H9, 10), 163 (17), 147 (15), 123 (45), 110 (55), 107
(35), 105 (20), 95 (40); HRMS: m/z for C15H26ONa
(M + Na), Calcd.: 245.1881. Found: 245.1890.
(1S,3R,6R)-3,7-Dimethylbicyclo[4.3.0]non-7-en2-one, 31. RCM reaction of the diene 28 (30 mg,
0.156 mmol) in anhydrous CH2Cl2 (15 mL, 0.01 M)
using Grubbs’ second generation catalyst 13 (5 mg, 5
mol%) for 1 hr at RT and work up as described for the
compound 24t, followed by purification on a silica gel
column using CH2Cl2-hexane (1:10) as eluent
furnished the bicyclic enone 31 (25 mg, 98%) as oil.
[α] 25
D : –64.4º (c 0.9, CHCl3); IR (neat): 1717 (C=O),
1642, 1517, 1376, 1240, 1081, 1024, 800, 701 cm-1;
1
H NMR (300 MHz, CDCl3+CCl4): δ 5.40-5.30 (1 H,
m, H-8), 2.70-2.55 (1 H, m), 2.50-2.20 (4 H, m), 2.152.00 (2 H, m), 1.70 (3 H, s, olefinic-CH3), 1.46 (2 H,
d of sextet, J = 12.9 and 3.3 Hz), 1.02 (3 H, d, J = 6.6
Hz, sec-CH3); 13C NMR (75 MHz, CDCl3+CCl4): δ
210.1 (C, C-2), 141.3 (C, C-7), 124.6 (CH, C-8), 60.4
(CH, C-1), 56.1 (CH, C-6), 44.5 (CH, C-3), 37.7
(CH2, C-9), 28.9 (CH2), 28.8 (CH2), 14.7 (CH3), 14.5
(CH3); MS: m/z (%) 164 (M+, 2%), 163 (M – 1, 5),
161 (6), 135 (4), 122 (17), 107 (12), 105 (12), 93 (15),
91 (15), 86 (40), 84 (75), 79 (15), 51 (35), 49 (100);
HRMS: m/z for C11H16ONa (M + Na), Calcd.:
187.1099. Found: 187.1107.
(1S,3R,6R,7R)-3,7-Dimethylbicyclo[4.3.0]nonan2-one, 4. To the activated 10% Pd-C (5 mg) was
added a solution of the enone 31 (25 mg, 0.154 mmol)
in ethanol (2 mL). The reaction mixture was stirred
for 1 hr at RT in an atmosphere of hydrogen, created
by evacuative replacement of air (balloon) and then
the catalyst was filtered off. Evaporation of the
solvent furnished the saturated ketone4 4 (25 mg,
99%) as oil. [α] 25
D : –16.4º (c 1.0, CHCl3); IR (neat):
1710 (C=O), 1642, 1517, 1376, 1240, 1081, 1024,
800, 701 cm-1; 1H NMR (300 MHz, C6D6): δ 2.06 (1
H, m), 1.88 (1 H, m), 1.80-1.10 (10 H, m), 1.07 (3 H,
SRIKRISHNA et al.: ENANTIOSPECIFIC SYNTHESIS OF PACIFIGORGIANES
d, J = 6.6 Hz) and 0.80 (3 H, d, J = 6.6 Hz) [2 × secCH3]; 13C NMR (75 MHz, C6D6): δ 209.6 (C, C-2),
58.0 (CH), 56.8 (CH, C-6), 44.7 (CH, C-3), 40.6
(CH), 37.3 (CH2, C-9), 32.0 (CH2), 29.4 (CH2), 21.5
(CH2), 18.2 (CH3), 14.8 (CH3); MS: m/z (%) 166 (M+,
5%), 151 (6), 148 (14), 138 (17), 137 (12), 124 (12),
111 (15), 109 (100), 95 (40).
Acknowledgements
Authors thank the Department of Science and
Technology, New Delhi, for the financial support.
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