An enantiospecific synthesis of (-)-2-pupukeanone via a rhodium carbenoid C-H insertion reaction

Article abstract of DOI:10.1016/S0040-4039(01)00585-8

An enantiospecific synthesis of (-)-2-pupukeanone, starting from (R)-carvone employing a Michael-Michael reaction and an intramolecular rhodium carbenoid C-H insertion reaction as the key steps for the generation of the isotwistane framework, is described

Full text of DOI:10.1016/S0040-4039(01)00585-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3929–3931
An enantiospecific synthesis of (−)-2-pupukeanone via a rhodium
carbenoid CꢀH insertion reaction†
A. Srikrishna,* P. Ravi Kumar and Santosh J. Gharpure
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 13 March 2001; accepted 6 April 2001
Abstract—An enantiospecific synthesis of (−)-2-pupukeanone, starting from (R)-carvone employing a Michael–Michael reaction
and an intramolecular rhodium carbenoid CꢀH insertion reaction as the key steps for the generation of the isotwistane framework,
is described. © 2001 Elsevier Science Ltd. All rights reserved.
The nudibranch Phyllidia varicosa Lamarck, 1801
secretes, as part of its defence mechanism, two volatile
substances that are lethal to fish and crustaceans.
Scheuer and co-workers reported the isolation of these
two isotwistane (1) based sesquiterpenes 9- and 2-iso-
cyanopupukeananes 2 and 3 from the skin extracts of P.
varicosa and also from its prey, a sponge Ciocalypta sp.,
and the structures were elucidated based on degradative
and single-crystal X-ray diffraction studies.1 The pres-
ence of an interesting isotwistane carbon framework
made these pupukeananes 2 and 3, and the correspond-
ing ketones 4 and 5 interesting and challenging synthetic
targets. Since the first report on the synthesis of ( )-2-
isocyanopupukeanane 3 by Corey et al., several reports
have appeared on the synthesis of racemic 2-
pupukeanone ( )-5.2 In contrast, there is only one
approach reported in the literature for the synthesis of
(+)-2-pupukeanone 5 which employs a radical cyclisa-
tion reaction as the key step.3 In continuation of our
interest in the enantiospecific synthesis of sesquiterpenes
starting from the readily available monoterpene (R)-car-
vone 6,3,4 herein, we report an enantiospecific synthesis
of (−)-2-pupukeanone 5 employing an intramolecular
rhodium carbenoid CꢀH insertion as the key reaction.
It was anticipated that intramolecular rhodium car-
benoid CꢀH insertion of the diazo ketone 7, derived
from the carboxylic acid 8, could generate the
isotwistanedione 9.5 A Michael–Michael reaction of a
cyclohexenone with acrylate could be exploited for the
generation of the carboxylic acid 8, and a suitable
derivative of (R)-carvone 6 could be used as a chiral
starting material for the enantiospecific generation of a
chiral analogue of the carboxylic acid 8.
The synthetic sequence starting from (R)-carvone 6 is
depicted in Schemes 1 and 2. Thus, (R)-carvone 6 was
transformed into 6-methylcarvone 10, which on
O
NC
9
NC
1
O
10
2
7
3
5
1
2
3
5
4
O
O
O
O
COOH
N2
O
O
9
7
8
6
* Corresponding author. Fax: 91-80-3600683; e-mail: ask@orgchem.iisc.ernet.in
†
Chiral synthons from carvone Part 47. For Part 46, see: Ref. 4a.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00585-8

3930
A. Srikrishna et al. / Tetrahedron Letters 42 (2001) 3929–3931
O
O
O
a
c,d
b
O
COOR
11 R=Me
12 R=H
N2
O
6
10
13
e
OAc
O
O
O
g
h
f
O
O
O
O
O
15
17
16
14
Scheme 1. Reagents, conditions and yields: (a) LDA, MeI, THF, 0°C“rt, 10 h, 98%; (b) LiHMDS, hexane, CH2ꢁCHCOOMe,
0°C“rt, 3 h, 70%; (c) 5% NaOH in MeOH–H2O (1:1), reflux, 8 h, 93%; (d) i. (COCl)2, C6H6, rt, 2 h; ii. CH2N2, Et2O, 0°C, 2
h, 95%; (e) Rh2(tfa)4, CH2Cl2, reflux, 4 h, 56%; (f) i. O3/O2, CH2Cl2–MeOH (5:1), −78°C; ii. Ac2O, Et3N, DMAP, C6H6, reflux,
5 h, 48%; (g) FVP, 500°C/0.05 mm; (h) H2, 1 atm, 10% Pd–C, EtOH, 8 h, 15% (two steps).
Michael–Michael reaction with LiHMDS and methyl
acrylate furnished the keto ester 11 in a highly regio-
and stereoselective manner.6 Hydrolysis of the ester 11
generated the acid 12 (102–103°C), which was con-
verted into the diazo ketone 13 via the corresponding
acid chloride. Reaction of the diazo ketone 13 with
rhodium acetate in refluxing methylene chloride fur-
nished the isotwistanedione 14 in only 11% yield. How-
ever, changing the catalyst5 to the more reactive
rhodium trifluoroacetate generated the dione 14‡ in
53% yield (from the acid 12). Next, attention was
turned towards the degradation of the isopropenyl
group, via ozonolysis and Criegee rearrangement,7 for
the generation of the dione 15, an intermediate in
Chang’s synthesis of 2-pupukeanone. Accordingly,
ozonolysis of the dione 14 in a 1:5 mixture of
methanol–methylene chloride followed by treatment of
the resultant methoxyhydroperoxide with acetic anhy-
dride, triethylamine and DMAP in refluxing benzene
furnished the acetate 16 in 48% yield along with varying
amounts of the normal ozonolysis product. Flash vac-
uum pyrolysis of the acetate 16 at 500°C (0.05 mm)
followed by hydrogenation of the resultant olefin 17‡
using 10% Pd/C as the catalyst generated the dione 15
in 15% yield (from 16). Since the yield of the dione 15
is low, the strategy was altered, and the degradation of
the isopropenyl group was carried out prior to the
construction of the isotwistane framework (Scheme 2).
Consequently, ozonolysis followed by Criegee rear-
rangement of the keto ester 11 generated the acetate 18‡
in 55% yield along with 20% of the normal ozonolysis
product. Hydrolysis of the acetate with potassium car-
bonate in methanol followed by oxidation of the resul-
tant alcohol 19 with a mixture of PCC and silica gel in
methylene chloride transformed the acetate 18 into the
diketo ester 20. Thioketalisation of the diketo ester 20
with ethanedithiol and a catalytic amount of BF3·Et2O
in benzene regioselectively furnished the thioketal 21 in
82% yield, which on desulfurisation with Raney nickel
in refluxing ethanol generated the keto ester 22‡ in 79%
yield. Hydrolysis of the ester moiety in 22 generated the
acid 23, which was transformed into the diazo ketone
24. Rhodium trifluoroacetate catalysed intramolecular
CꢀH insertion reaction of the diazo ketone 24 furnished
‡ All the compounds exhibited spectral data consistent with their
structures. Selected spectral data for the dione 14: mp 89–90°C. [h]D24
−63.5 (c 1.15, CHCl3). IR (neat): wmax/cm−1 1745, 1719, 1637, 908.
1H NMR (300 MHz, CDCl3+CCl4): l 4.75 (1H, s), 4.65 (1H, s), 2.67
(1H, d, J=11.0 Hz), 2.55–2.40 (1H, m), 2.44 (1H, d, J=19.2 Hz),
2.25–2.15 (2H, m), 2.10 (1H, d, J=19.2 Hz), 2.02 (1H, dd, J=14.7
and 11.0 Hz), 1.95–1.80 (1H, m), 1.58 (3H, s), 1.35–1.20 (1H, m), 1.34
(3H, s), 0.94 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4, DEPT): l
219.4 (C), 215.0 (C), 146.0 (C), 113.9 (CH2), 53.3 (CH), 52.5 (C), 48.9
(CH2), 47.9 (CH), 45.3 (C), 42.5 (CH), 35.9 (CH2), 23.4 (CH2), 20.3
(CH3), 19.0 (CH3), 18.2 (CH3). For the diketoacetate 16: mp
185–186°C. [h]D25 −31.6 (c 0.95, CHCl3). IR (neat): wmax/cm−1 1745,
1726. 1H NMR (300 MHz, CDCl3+CCl4): l 4.92 (1H, d, J=9.3 Hz),
2.59 (1H, dd, J=10.5 and 5.1 Hz), 2.50–2.30 (2H, m), 2.38 (1H, d,
J=18.7 Hz), 2.12 (1H, d, J=18.7 Hz), 2.10–1.95 (1H, m), 2.03 (3H,
s), 1.87 (1H, d with fine splitting, J=15.9 Hz), 1.41 (1H, d, J=14.7
Hz), 1.32 (3H, s), 0.98 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4):
l 215.4 (C), 215.1 (C), 169.8 (C), 76.0 (CH), 52.4 (C), 49.3 (CH2),
47.9 (CH), 46.5 (C), 42.6 (CH), 30.7 (CH2), 26.6 (CH2), 20.9 (CH3),
18.2 (CH3), 16.8 (CH3). For the diketoolefin 17: [h]2D3 −147.1 (c 0.7,
CHCl3). IR (neat): wmax/cm−1 1748, 1720. 1H NMR (300 MHz,
CDCl3+CCl4): l 6.34 (1H, dd, J=8.1 and 6.6 Hz), 6.05 (1H, d, J=8.1
Hz), 3.05 (1H, t, J=4.8 Hz), 2.57 (1H, dd, J=11.1 and 4.8 Hz), 2.37
(1H, d, J=19.2 Hz), 2.09 (1H, d, J=19.2 Hz), 1.77 (1H, dd, J=12.6
and 10.8 Hz), 1.49 (1H, d, J=13.8 Hz), 1.24 (3H, s), 1.22 (3H, s).
For the acetate 18: mp 102–103°C. [h]2D4 −32.7 (c 3.0, CHCl3). IR
(neat): wmax/cm−1 1731. 1H NMR (300 MHz, CDCl3+CCl4): l 4.89
(1H, dd, J=9.6 and 3.9 Hz), 3.68 (3H, s), 2.74 (1H, ddd, J=11.1,
6.0 and 2.1 Hz), 2.40–2.15 (2H, m), 2.13 (1H, dd, J=14.7 and 6.0
Hz), 1.98 (3H, s), 1.80 (1H, dd, J=14.7 and 11.1 Hz), 1.71 (1H, t of
d, J=14.7 and 2.7 Hz), 1.12 (3H, d, J=7.5 Hz), 0.94 (3H, s). 13C
NMR (75 MHz, CDCl3+CCl4): l 213.3 (C), 173.8 (C), 169.8 (C), 75.1
(CH), 52.1 (CH3), 46.4 (C), 42.4 (CH), 41.6 (CH), 36.8 (CH), 31.1
(CH2), 30.3 (CH2), 20.8 (CH3), 16.3 (CH3), 13.1 (CH3). For the
ketoester 22: [h]D24 −48.2 (c 5.0, CHCl3). IR (neat): wmax/cm−1 1730,
1723. 1H NMR (300 MHz, CDCl3+CCl4): l 3.66 (3H, s), 2.78 (1H,
ddd, J=11.0, 7.0 and 1.8 Hz), 2.32 (1H, q, J=7.3 Hz), 2.20 (1H, br
s), 2.04 (1H, ddd, J=14.3, 7.3 and 2.9 Hz), 1.90–1.45 (5H, m), 1.07
(3H, d, J=7.5 Hz), 0.92 (3H, s). 13C NMR (75 MHz, CDCl3+CCl4):
l 217.3 (C), 174.7 (C), 51.9 (CH3), 42.6 (CH), 42.5 (C), 41.9 (CH),
37.5 (CH), 32.7 (CH2), 31.5 (CH2), 21.6 (CH2), 20.1 (CH3), 13.0
(CH3).

A. Srikrishna et al. / Tetrahedron Letters 42 (2001) 3929–3931
3931
Scheme 2. Reagents, conditions and yields: (a) i. O3/O2, CH2Cl2–MeOH (5:1), −78°C; ii. Ac2O, Et3N, DMAP, C6H6, reflux, 5 h,
55%; (b) K2CO3, MeOH, rt, 3 h, 88%; (c) PCC, silica gel, CH2Cl2, 3 h, 90%; (d) (CH2SH)2, BF3·Et2O (catalytic), C6H6, 0°C“rt,
4 h, 82%; (e) Raney Ni, EtOH, reflux, 5 h, 79%; (f) 5% NaOH in MeOH–H2O (1:1), reflux, 8 h, 96%; (g) i. (COCl)2, C6H6, rt,
2 h; ii. CH2N2, Et2O, 0°C, 2 h; (h) Rh2(tfa)4, CH2Cl2, reflux, 4 h, 47% (from 23); (i) CH2ꢁC(Me)MgBr, anhyd. CeCl3, THF,
0°C“rt, 10 h; (j) i. PPTS, (CH2Cl)2, reflux, 6 h; ii. H2, 1 atm, 10% Pd–C, EtOH, 8 h; (k) i. H2, 1 atm 10% Pd–C, EtOH, 3 h,
90%; ii. p-TSA, C6H6, reflux, 5 h, 83%. (l) Reference 3.
Acknowledgements
the isotwistane dione 15 in 47% yield (from the acid
23), [h]2D3 −28.1 (c 3.6, CHCl3) {lit.3 for (+)-15 [h]2D5
+27 (c 2, CHCl3)}, which exhibited spectral data (IR,
1H and 13C NMR) identical to its optical antipode
reported earlier.3 Chang et al. had already reported
the conversion of the racemic dione 15 into ( )-2-
pupukeanone.8 Anhydrous cerium chloride catalysed
addition of isopropenylmagnesium bromide to the
dione 15 generated, regioselectively, the tertiary alco-
hol 25. PPTS catalysed dehydration of the alcohol
followed by hydrogenation of the resultant diene in
ethanol with 10% Pd/C as the catalyst; or alterna-
tively catalytic hydrogenation followed by p-TSA
catalysed dehydration, transformed the tertiary alco-
hol 25 into the enone (−)-26, [h]2D4 −108.7 (c 1.5,
CHCl3) {lit.3 for (+)-26 [h]D25 +102 (c 2.3, CHCl3)},
We thank the Council of Scientific and Industrial
Research for the award of research fellowship to
P.R.K. and S.J.G.
References
1. (a) Burreson, B. J.; Scheuer, P. J.; Finer, J.; Clardy, J. J.
Am. Chem. Soc. 1975, 97, 4763; (b) Hagadone, M. R.;
Burreson, B. J.; Scheuer, P. J.; Finer, J. S.; Clardy, J. Helv.
Chim. Acta 1979, 62, 2484.
2. Corey, E. J.; Ishiguro, M. Tetrahedron Lett. 1979, 2745.
For the synthesis of racemic 2-pupukeanone, see: Biju, P.
J.; Kaliappan, K.; Laxmisha, M. S.; Subba Rao, G. S. R.
J. Chem. Soc., Perkin Trans. 1 2000, 3714 and references
cited therein.
3. For enantiospecific synthesis of pupukean-2-one, see:
Srikrishna, A.; Reddy, T. J. J. Chem. Soc., Perkin Trans. 1
1997, 3293; J. Chem. Soc., Perkin Trans. 1 1998, 2137.
4. (a) Srikrishna, A.; Viswajanani, R.; Dinesh, C. J. Chem.
Soc., Perkin Trans. 1 2000, 4321; (b) Srikrishna, A.;
Gharpure, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3191;
(c) Srikrishna, A.; Vijaykumar, D. J. Chem. Soc., Perkin
Trans. 1 2000, 2583 and references cited therein.
5. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds:
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1
which exhibited spectral data (IR, H and 13C NMR)
identical to that of its optical antipode (+)-26.3 Since
the enone (+)-26 has already been converted into (+)-
2-pupukeanone 5,3 present synthesis of (−)-26 consti-
tutes a synthesis of (−)-2-pupukeanone 5.
In conclusion, we have achieved an enantiospecific
synthesis of (−)-2-pupukeanone 5 starting from the
readily available monoterpene (R)-carvone, employing
a Michael–Michael reaction and an intramolecular
rhodium carbenoid CꢀH insertion reaction as the key
steps for the construction of the isotwistane carbon
framework. It is worth noting that the present
methodology and the radical cyclisation based
methodology reported earlier3 are complementary to
each other, as they generated optical antipodes of 2-
pupukeanone starting from (R)-carvone. Currently,
we are investigating the extension of this strategy for
the enantiospecific synthesis of 9-pupukeanone.
6. Zhao, R.-B.; Zhao, Y.-F.; Song, G.-Q.; Wu, Y.-L. Tetra-
hedron Lett. 1990, 31, 3559.
7. (a) Schreiber, S. L.; Liew, W.-F. Tetrahedron Lett. 1983,
24, 2363; (b) Criegee, R. Ber. Bunsenges. Phys. Chem.
1944, 77, 722.
8. Chang, N.-C.; Chang, C.-K. J. Org. Chem. 1996, 61, 4967.
.