A formal total synthesis of (±)-9-isocyanoneopupukeanane

Article abstract of DOI:10.1016/j.tet.2005.07.016

A formal total synthesis of the marine sesquiterpene (±)-9- isocyanoneopupukeanane starting from the readily available monoterpene carvone has been accomplished employing a combination of intermolecular Michael addition-intramolecular Michael addition reaction and an intramolecular rhodium carbenoid C-H insertion reaction as key steps, and identifying the isopropenyl group as a masked hydroxy group.

Full text of DOI:10.1016/j.tet.2005.07.016

Tetrahedron 61 (2005) 8855–8859
A formal total synthesis of (G)-9-isocyanoneopupukeanane
*
A. Srikrishna and G. Satyanarayana
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India
Received 30 April 2005; revised 27 June 2005; accepted 7 July 2005
Available online 28 July 2005
Abstract—A formal total synthesis of the marine sesquiterpene (G)-9-isocyanoneopupukeanane starting from the readily available
monoterpene carvone has been accomplished employing a combination of intermolecular Michael addition–intramolecular Michael addition
reaction and an intramolecular rhodium carbenoid C–H insertion reaction as key steps, and identifying the isopropenyl group as a masked
hydroxy group.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In a variety of marine organisms, chemical defence via
secretion of toxic and/or strong smelling organic com-
pounds from skin glands is a common phenomenon as part
of the self-defence mechanism to protect themselves from
higher animals. Based on the observation that the
nudibranch Phyllidia varicosa Lamarck secretes a toxic
substance lethal to fish and crustaceans, investigations on
the chemical constituents of the skin extracts of P. varicosa
and also from its prey, a sponge, Hymeniacidon sp. by
the research group of Scheuer led to the isolation1 of two
novel sesquiterpenes, 9-isocyano- and 2-isocyano-
pupukeananes 1 and 2. The pupukeananes 1 and 2 contain
a tricyclo[4.3.1.03,7]decane (isotwistane 3) carbon frame-
work, which was observed for the first time among the
natural products. Subsequently, during their biosynthetic
experiments directed towards discovering the origin of the
isocyano group in marine sponges, Scheuer and co-workers2
isolated a new sesquiterpene 4 from the sponge Ciocalypta
sp. containing the isocyano functionality and a new carbon
framework named as neopupukeanane. Later, the research
groups of Scheuer, Higa and Faulkner reported3 the
isolation of two more sesquiterpenes belonging to this
group, 4- and 2-thiocyanatoneopupukeananes 5 and 6, from
the sponge Phycopsis terpnis (from Okinawa) and from an
unidentified species from Pohnpei.
The presence of the tricyclo[4.3.1.03,7]decane carbon
framework (isotwistane) incorporating two quaternary
carbon centres besides the thiocyanate and isonitrile
functionalities made neopupukeananes attractive and
challenging synthetic targets. In 1999, Ho and Jana
reported4,5 the first total synthesis of (G)-9-isocyanone-
opupukeanane 4 via the symmetric isotwistanone 7. Herein
we report a formal total synthesis of (G)-4 starting from
readily available monoterpene carvone 8.
2. Results and discussion
It was anticipated (Scheme 1) that the rhodium carbenoid
C–H insertion6 of the diazoketone 10, derived from
bicyclo[2.2.2]octanecarboxylate 11, would generate the
isotwistanedione 9 in a regioselective manner via prefer-
ential formation of a five-membered ring by the insertion of
the rhodium carbenoid into the only available g C–H bond,
Keywords: Marine sesquiterpenes; Neopupukeanane; Double Michael
reaction; Rhodium CH insertion reaction.
*
Corresponding author. Tel.: C91 80 22932215; fax: C91 80 23600683;
e-mail: ask@orgchem.iisc.ernet.in
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.016

8856
A. Srikrishna, G. Satyanarayana / Tetrahedron 61 (2005) 8855–8859
Scheme 1.
which could be further elaborated to symmetric isotwista-
none 7 via reductive deoxygenation of the two ketones and
degradation of the isopropenyl group. An intermolecular
Michael addition followed by an intramolecular Michael
reaction of carvone 8 with methyl methacrylate was
exploited for generating the bicyclo[2.2.2]octanone carb-
oxylate 11.7 Thus, reaction of carvone 8 with lithium
hexamethyldisilazide (LiHMDS) in hexane at K70 8C
followed by reaction of the resultant kinetic dienolate with
one equivalent of methyl methacrylate furnished the
bicyclic keto ester 11 via the Michael–Michael reaction in
70% yield in a highly regio- and stereoselective manner
(Scheme 2). Base catalysed hydrolysis of the keto ester 11
furnished the keto acid 12, which was converted into the
diazoketone 10 via the corresponding acid chloride.
Treatment of the diazoketone 10 with a catalytic amount
of rhodium acetate in dichloromethane at reflux furnished
the isotwistane dione 9 in 89% yield, containing the
complete carbon framework of neopupukeananes,8 via
regiospecific C–H insertion of the intermediate rhodium
carbenoid. As the olefin moiety in the isopropenyl group
was found to isomerise under acidic conditions, it was
contemplated to degrade the isopropenyl group prior to
the reductive deoxygenation of the ketones. Since the
ozonolysis followed by Baeyer–Villiger rearrangement
would lead to regiochemical problems, a one pot
ozonolysis-Criegee rearrangement9 was chosen for the
conversion of the isopropenyl moiety into an acetoxy
group. Thus, ozonolysis of the isotwistanedione 9 in
methanol–methylene chloride medium followed by treat-
ment of the resultant methoxyhydroperoxide with acetic
anhydride, triethylamine and a catalytic amount of 4-N,N-
dimethylaminopyridine (DMAP) in benzene at reflux
furnished the diketoacetate 13 in 81% yield along with
the normal ozonolysis product triketone 14 (11%). For the
reductive deoxygenation of the two ketones, a two step
protocol was employed via the corresponding bis-dithio-
ketal. Accordingly, treatment of the diketoacetate with
ethanedithiol in the presence of a catalytic amount of either
iodine10 or boron trifluoride diethyl etherate furnished a
mixture of bis and mono dithioketals 15 and 16 in 52 and
28% yields, respectively. Raney nickel mediated desulfuri-
sation of the bis-dithioketal 15 furnished the 9-isotwistanyl
acetate 17. Hydrolysis of the acetate group in 17 with
potassium carbonate in methanol followed by oxidation of
the resultant isotwistanol 18 with pyridinium chlorochro-
mate (PCC) and silica gel in methylene chloride furnished
the isotwistanone 7. Both the alcohol 18 and the ketone 7
exhibited spectral data, in particular 1H and 13C NMR,
identical to those reported by Ho and Jana. Since the
conversion of isotwistanone 7 into 9-isocyanoneopupu-
keanane (G)-4 has already been accomplished by Ho and
Jana,4 the present sequence constitute a formal total
synthesis of the marine sesquiterpene 4.
In summary, we have developed a convenient approach to
9-isocyanoneopupukeanane starting from readily available
monoterpene carvone. The isopropenyl group of carvone
has been identified as a masked hydroxy group. A combi-
nation of double Michael reaction and a regiospecific
intramolecular rhodium carbenoid CH insertion reaction
have been employed as key steps for the regio- and
stereospecific efficient construction of the isotwistane
skeleton.
3. Experimental
3.1. General
Scheme 2. (a) LiN(TMS)2, CH2]C(Me)COOMe, hexane; (b) NaOH,
MeOH–H2O, reflux; (c) (i) (COCl)2, C6H6; (ii) CH2N2, Et2O;
(d) Rh2(OAc)4, CH2Cl2; (e) O3/O2, MeOH–CH2Cl2, K70 8C; Ac2O, NEt3,
DMAP, C6H6, reflux; (f) (CH2SH)2, I2, CHCl3; (g) Raney Ni, EtOH, reflux;
(h) K2CO3, MeOH; (i) PCC, silica gel, CH2Cl2; (j) Ref. 4.
Melting points are recorded using Tempo and Mettler FP1
melting point apparatus in capillary tubes and are
uncorrected. IR spectra were recorded on a Jasco FTIR

A. Srikrishna, G. Satyanarayana / Tetrahedron 61 (2005) 8855–8859
8857
410 spectrophotometer. 1H (300 MHz) and 13C (75,
22.5 MHz) spectra were recorded on JNM l-300 or JEOL
FX-90Q spectrometers. The chemical shifts (d ppm) and
coupling constants (Hz) are reported in the standard fashion
furnish the acid 12 (870 mg, 92%) as a sticky solid, which
was recrystallized from a mixture of hexane and CH2Cl2,8
mp 119–120 8C. [a]D26K47.7 (c 1.30, CHCl3). nmax (neat)
1720, 1700, 890 cmK1. dH (300 MHz, 1:1 CDCl3CCCl4)
4.74 (1H, s), 4.72 (1H, s), 2.68 (1H, dd, JZ14.7, 2.4 Hz),
2.55–2.45 (2H, m), 2.30–2.10 (3H, m), 1.71 (3H, s), 1.75–
1.50 (2H, m), 1.59 (1H, dd, JZ14.7, 3.3 Hz), 1.52 (3H, s),
1.12 (3H, d, JZ6.9 Hz). dC (22.5 MHz, CDCl3) 217.7 (s),
183.4 (s), 146.7 (s), 110.0 (t), 47.3 (d), 44.7 (d), 44.1 (s),
42.1 (d), 41.5 (d), 33.7 (t), 26.5 (q), 21.7 (2C, q and t),
12.5 (q).
1
with reference to either internal tetramethylsilane (for H)
or the central line (77.1 ppm) of CDCl3 (for 13C). In the 13
C
NMR spectra, the nature of the carbons (C, CH, CH2 or
CH3) were determined either by recording the DEPT-135 or
off-resonance decoupling, and are given in parentheses.
Low-resolution mass spectra were recorded using a
Shimadzu QP-5050A GCMS instrument using direct inlet
(EI) mode. Relative intensities are given in parentheses.
High resolution mass spectra were recorded on a Micromass
Q-TOF micro mass spectrometer using electron spray
ionization mode. Optical rotations were measured using a
Jasco DIP-370 digital polarimeter and [a]D values are given
in units of 10K1 deg cm2 gK1. Ozonolysis experiments were
carried out using Fischer 502 ozone generator by passing
pre-cooled (K70 8C) oxygen (for generating dry ozone).
Acme’s silica gel (100–200 mesh) was used for column
chromatography (approximately 15–20 g per 1 g of the
crude product). Dry THF was obtained by distillation over
sodium-benzophenone ketyl. Dry ether was obtained by
distillation over sodium and stored over sodium wire. Dry
dichloromethane was prepared by distilling over calcium
hydride. All the commercial reagents were used as such
without further purification.
3.1.3. (1S,3R,6R,7S,9R)-9-Isopropenyl-3,6-dimethyltri-
cyclo[4.3.1.03,7]decane-2,5-dione (9). To a magnetically
stirred solution of the acid 12 (500 mg, 2.12 mmol) in dry
benzene (3 ml) was added oxalyl chloride (0.93 ml,
10.6 mmol) and the reaction mixture was stirred for 2 h at
rt. Evaporation of benzene and the excess oxalyl chloride in
vacuo furnished the acid chloride, which was taken in dry
ether (5 ml) and added to a cold (0 8C) magnetically stirred
solution of diazomethane (25 ml, prepared from 3 g of
N-nitroso-N-methylurea and 30 ml of 60% aq KOH
solution). The reaction mixture was slowly warmed up to
rt, stirred for 2 h and the excess diazomethane and ether
were carefully evaporated on a water bath. Rapid
purification by filtration of the crude product through a
neutral alumina column using CH2Cl2 as eluent furnished
the diazoketone 10 (495 mg, 90%) as yellow oil. IR (neat).
3.1.1. Methyl (1R,2R,4S,6S,8R)-8-isopropenyl-2,6-
dimethyl-5-oxobicyclo[2.2.2]octane-2-carboxylate (11).
To a cold (K78 8C), magnetically stirred solution of
hexamethyldisilazane (2.02 ml, 9.33 mmol) in dry hexane
(20 ml) was slowly added by a syringe a solution of n-BuLi
(4.56 ml, 1.9 M in hexane, 20 mmol) and the mixture stirred
for 15 min. To the LiHMDS thus, formed was added drop
wise a solution of (R)-carvone 8 (1 g, 6.66 mmol) in dry
hexane (5 ml) and continued stirring for 45 min at the same
temperature. The enolate was treated with methyl meth-
acrylate (0.78 ml, 7.33 mmol) and stirred for 3 h at rt. The
reaction mixture was then filtered through a small silica gel
column. Evaporation of the solvent and purification of the
residue on a silica gel column using ethyl acetate/hexane
(1:20) as eluent furnished the bicyclic adduct 11 (1.16 g,
70%) as a white solid,7 which was recrystallized from
hexanes, mp 59–61 8C (lit.7 60–61.5 8C). [a]D22K43.5
(c 3.77, MeOH) [lit.7 [a]D25K42.6 (c 1.00, MeOH)]. nmax
(neat) 1720, 1645, 895 cmK1. dH (300 MHz, CDCl3) 4.75
(1H, s), 4.72 (1H, s), 3.71 (3H, s), 2.70 (1H, dd, JZ14.5,
2.5 Hz), 2.60–2.40 (2H, m), 2.25–2.00 (3H, m), 1.71 (3H, s),
1.70–1.55 (2H, m), 1.46 (3H, s), 1.10 (3H, d, JZ6.9 Hz). dC
(22.5 MHz, CDCl3) 216.7 (s), 177.5 (s), 146.7 (s), 109.7 (t),
52.0 (q), 47.2 (d), 44.5 (d), 44.2 (s), 42.1 (d), 41.5 (d), 33.9
(t), 26.4 (q), 21.7 (2C, q and t), 12.3 (q).
nmax/cmK1 2100, 1710, 1620, 890 cmK1
.
To a magnetically stirred, refluxing solution of rhodium
acetate (4 mg) in dry CH2Cl2 (30 ml) was added drop wise a
solution of the diazoketone 71 (495 mg, 1.91 mmol) in
CH2Cl2 (10 ml) and the reaction mixture was refluxed for
4 h. Evaporation of the solvent and purification of the
residue on a silica gel column using ethyl acetate/hexane
(1:10) as eluent furnished the dione 9 (392 mg, 89%) as a
white solid, which was recrystallized from a mixture of
ethyl acetate/hexane,8 mp 111–113 8C. [a]2D6K45.5 (c 1.32,
CHCl3). nmax (neat) 1740, 1710, 890 cmK1. dH (300 MHz,
CDCl3) 4.83 (1H, s), 4.79 (1H, s), 2.55–2.50 (2H, m), 2.52
(1H, d, JZ18.9 Hz), 2.21 (1H, ddd, JZ14.4, 10.5, 3.3 Hz),
2.10 (1H, d, JZ18.9 Hz), 1.94 (1H, ddd, JZ14.7, 6.3,
2.7 Hz), 1.90 (1H, br s), 1.80 (1H, dd, JZ14.7, 4.2 Hz), 1.76
(3H, s), 1.59 (1H, d, JZ14.7 Hz), 1.25 (3H, s), 1.24 (3H, s).
dC (75 MHz, 1:1 CDCl3CCCl4) 218.6 (C), 217.6 (C), 146.8
(C), 110.4 (CH2), 50.9 (C), 49.0 (CH), 48.5 (C), 48.1 (CH2),
46.3 (CH), 45.1 (CH), 35.2 (CH2), 22.0 (CH3), 20.7 (CH2),
19.5 (CH3), 18.1 (CH3).
3.1.4. (1S,3R,6R,7S,9R)-9-Acetoxy-3,6-dimethyltri-
cyclo[4.3.1.03,7]decane-2,5-dione (13). Dry ozone in
oxygen gas was passed through a cold (K70 8C) solution
of the diketone 9 (215 mg, 0.92 mmol) and NaHCO3
(100 mg) in 1:9 MeOH/CH2Cl2 (10 ml) until (ca. 4.5 min)
pale blue colour appeared. Excess ozone was flushed off
with oxygen. The solvent was evaporated in vacuo and the
residue was dissolved in dry benzene (30 ml). Acetic
anhydride (0.61 ml, 6.49 mmol), triethylamine (1.29 ml,
9.26 mmol) and a catalytic amount of DMAP (10 mg) were
added to the reaction mixture and heated at reflux for 10 h. It
was then cooled, diluted with water (10 ml) and extracted
with ether (3!5 ml). The ether extract was washed with
3.1.2. (1R,2R,4S,6S,8R)-8-Isopropenyl-2,6-dimethyl-5-
oxobicyclo[2.2.2]octane-2-carboxylic acid (12). To a
solution of the keto ester 11 (1.0 g, 4 mmol) in 5 ml
methanol was added 10% aq NaOH solution (5 ml), and the
reaction heated at reflux for 8 h. It was then cooled to rt and
washed with CH2Cl2 (10 ml). The aqueous layer was
acidified with 3 M aq HCl and extracted with CH2Cl2
(3!15 ml). The CH2Cl2 extract was washed with brine,
dried (Na2SO4) and the solvent evaporated in vacuo to

8858
A. Srikrishna, G. Satyanarayana / Tetrahedron 61 (2005) 8855–8859
3 M aqueous 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 (1:5) as
eluent furnished the diketoacetate 13 (187 mg, 81%) as
colourless solid, which was recrystallised from a mixture of
CH2Cl2/hexane, mp 73–75 8C. [a]2D4K5.8 (c 5.5, CHCl3).
nmax (neat) 1740, 1729 cmK1. dH (300 MHz, 1:1 CDCl3C
CCl4) 5.09 (1H, ddd, JZ9.0, 4.2, 2.1 Hz, CHOAc), 2.56
(1H, t, JZ4.2 Hz), 2.44 (1H, d, JZ18.9 Hz), 2.37 (1H, ddd,
JZ16.5, 9.3, 3.0 Hz), 2.10 (1H, d, JZ18.9 Hz), 2.08 (1H, d,
JZ4.8 Hz), 2.03 (3H, s), 2.00–1.85 (1H, m), 1.76 (1H, dd,
JZ14.4, 4.8 Hz), 1.46 (1H, d, JZ14.4 Hz), 1.33 (3H, s),
1.16 (3H, s). dC (75 MHz, 1:1 CDCl3CCCl4) 216.6 (C),
214.5 (C), 169.4 (C), 71.6 (CH), 50.9 (C), 48.8 (CH), 48.0
(CH2), 47.7 (C), 46.4 (CH), 30.5 (CH2), 24.0 (CH2), 20.9
(CH3), 19.6 (CH3), 17.9 (CH3). m/z 250 (MC, 22), 234 (12),
208 (14), 191 (20), 190 (100), 175 (14), 162 (32), 147 (68),
134 (32), 121 (43), 119 (43), 105 (22), 93 (82%). HRMS:
MCCNa, found 273.1095. C14H18O4Na requires 273.1103.
(1:20) as eluent furnished monodithioketal 16 (18 mg, 28%)
as a colourless solid, which was recrystallized from a
mixture of CH2Cl2/hexane, mp 123–125 8C. [a]2D7K103.2
(c 5.8, CHCl3). nmax (neat) 1736, 1716 cmK1. dH (300 MHz,
1:1 CDCl3CCCl4) 5.00–4.90 (1H, m), 3.40–3.10 (4H, m),
2.64 and 2.47 (2H, 2!d, JZ15.6 Hz), 2.42–2.30 (2H, m),
2.13–2.00 (1H, m), 2.10–1.95 (1H, m), 2.02 (3H, s), 1.70–
1.50 (2H, m), 1.32 (3H, s), 1.19 (3H, s). dC (75 MHz, 1:1
CDCl3CCCl4) 214.9 (C), 169.8 (C), 79.1 (C), 72.4 (CH),
56.0 (CH2), 52.2 (C), 50.7 (CH), 48.8 (C), 46.6 (CH), 40.7
(CH2), 39.7 (CH2), 34.1 (CH2), 25.0 (CH2), 22.2 (CH3), 21.1
(CH3), 17.8 (CH3). m/z 328 (MCC2, 9), 326 (82), 298 (34),
270 (46), 239 (27), 238 (31), 237 (30), 210 (37), 199 (45),
145 (100), 105 (41), 91 (26%). HRMS: MCNa, found
349.0912. C16H22O3S2Na requires 349.0908.
3.1.6. (R)-3,6-Dimethyltricyclo[4.3.1.03,7]decan-9-yl
acetate (17). To a magnetically stirred solution of the bis-
dithioketal 15 (34 mg, 0.08 mmol) in dry ethanol (3 ml) was
added Raney nickel (150 mg, excess) and the reaction
heated at reflux for 5 h. The reaction mixture was then
cooled and filtered through a short silica gel column to
remove the catalyst. Evaporation of the solvent and
purification of the residue over a silica gel column using
ethyl acetate/hexane (1:30) as eluent furnished the acetate
17 (12 mg, 64%) as oil. [a]2D7K13.0 (c 3.0, CHCl3). nmax
(neat) 1737 cmK1. dH (300 MHz, 1:1 CDCl3CCCl4) 4.70–
4.55 (1H, m), 2.14–1.90 (2H, m), 2.03 (3H, s), 1.75–1.22
(10H, m), 1.05 (3H, s), 1.01 (3H, s). dC (75 MHz, 1:1
CDCl3CCCl4) 170.4 (C), 71.9 (CH), 48.3 (CH), 41.7
(CH2), 40.9 (CH2), 40.4 (CH2), 39.8 (C), 39.4 (C), 36.4
(CH2), 30.4 (CH), 27.1 (CH3), 26.6 (CH3), 24.2 (CH2), 21.4
(CH3). m/z 162 (MCKAcOH, 91), 147 (21), 106 (80), 95
(100), 93 (47%). HRMS: MCNa found 245.1515.
C14H22O2Na requires 245.1517.
Further elution of the column with ethyl acetate/hexane
(1:3) furnished the triketone 14 (21 mg, 10%) as a colourless
solid, which was recrystallized from a mixture of CH2Cl2/
hexane, mp 68–70 8C. [a]2D7K70.0 (c 2.8, CHCl3). nmax
(neat) 1742, 1713 cmK1. dH (300 MHz, 1:1 CDCl3CCCl4)
3.40–3.25 (1H, m), 3.00–2.88 (1H, m), 2.70–2.52 (2H, m),
2.42 (1H, d, JZ19.2 Hz), 2.18 (3H, s), 2.07 (1H, d, JZ
19.2 Hz), 1.95–1.75 (2H, m), 1.59 (1H, d, JZ14.7 Hz), 1.27
(3H, s), 1.20 (3H, s). dC (75 MHz, 1:1 CDCl3CCCl4) 216.6
(C), 215.4 (C), 206.1 (C), 51.6 (CH), 51.2 (C), 48.8 (CH),
48.3 (C), 47.9 (CH2), 44.9 (CH), 34.0 (CH2), 28.0 (CH3),
19.6 (CH3), 18.0 (CH3), 15.5 (CH2). m/z 234 (MC, 46), 219
(16), 206 (36), 191 (29), 164 (14), 163 (13), 149 (26), 135
(20), 123 (62), 121 (44), 110 (72), 109 (100), 93 (73%).
HRMS: MCNa, found 257.1148. C14H18O3Na requires
257.1154.
3.1.7. (R)-3,7-Dimethyltricyclo[4.3.1.03,7]decan-9-ol (18).
To a magnetically stirred solution of the acetate 17 (12 mg,
0.05 mmol) in methanol (1 ml) was added K2CO3 (50 mg)
and the reaction stirred for 10 h at rt. The reaction mixture
was then filtered through a short silica gel column using
ethyl acetate/hexane (1:5). Evaporation of the solvent and
purification of the residue over a silica gel column using
ethyl acetate/hexane (1:10) as eluent furnished the alcohol
18 (8 mg, 82%) as oil.4 [a]D23K15.8 (c 1.2, CHCl3). nmax
(neat) 3276 cmK1. dH (300 MHz, 1:1 CDCl3CCCl4) 3.75–
3.65 (1H, m), 1.98 (1H, ddd, JZ14.7, 9.6, 3.3 Hz), 1.76
(1H, d, JZ13.5 Hz), 1.60–1.10 (11H, m), 1.06 (3H, s), 0.98
(3H, s). dC (75 MHz, 1:1 CDCl3CCCl4) 68.7 (CH, CHOH),
48.6 (CH), 42.0 (CH2), 40.8 (CH2), 40.4 (CH2), 39.9 (C),
39.2 (C), 35.6 (CH2), 33.9 (CH), 27.0 (CH3), 26.9 (CH2),
26.6 (CH3). m/z 162 (MCKH2O, 62), 149 (8), 107 (100),
106 (68), 105 (37), 95 (52), 93 (50), 91 (40%).
3.1.5. (1S,3R,6R,7S,9R)-9-Acetoxy-3,6-dimethyltri-
cyclo[4.3.1.03,7]decane-2,5-dione bis-dithioketal (15).
To a cold (0 8C) magnetically stirred solution of the
diketone 13 (50 mg, 0.20 mmol) and ethanedithiol
(0.33 ml, 4.0 mmol) in dry CHCl3 (5 ml) was added a
catalytic amount of iodine (10 mg) and stirring continued
for 16 h at rt. It was then diluted with ether (10 ml), washed
with 5% aqueous NaOH solution 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 first furnished the bis-thioketal 15 (42 mg,
52%) as oil. [a]D23K45.0 (c 5.8, CHCl3). nmax (neat)
1731 cmK1. dH (300 MHz, 1:1 CDCl3CCCl4) 4.76 (1H, t,
JZ9.3 Hz), 3.43 (1H, d, JZ16.5 Hz), 3.35–3.10 (6H, m),
3.12–2.90 (2H, m), 2.40 (1H, d, JZ16.5 Hz), 2.28 (1H, s),
2.20–1.80 (2H, m), 2.04 (3H, s), 1.89 (1H, ddd, JZ14.4, 9.0,
1.2 Hz), 1.75–1.50 (2H, m), 1.31 (3H, s), 1.21 (3H, s). dC
(75 MHz, 1:1 CDCl3CCCl4) 170.2 (C), 79.1 (C), 78.0 (C),
72.4 (CH), 60.8 (CH2), 50.6 (CH), 49.3 (C), 48.3 (CH), 47.7
(C), 40.6 (CH2), 40.5 (CH2), 40.4 (CH2), 39.4 (CH2), 37.0
(CH2), 24.5 (CH3), 22.9 (CH2), 21.7 (2C, CH3). m/z 402
(MC, 34), 374 (29), 158 (13), 145 (36), 119 (100), 105
(22%). HRMS: MCNa, found 425.0694. C18H26O2S4Na
requires 425.0713.
3.1.8. 3,7-Dimethyltricyclo[4.3.1.03,7]decan-9-one (7). To
a magnetically stirred solution of the alcohol 18 (6 mg,
0.03 mmol) in dry CH2Cl2 (1 ml) was added a homogeneous
mixture of PCC (71 mg, 0.33 mmol) and silica gel (71 mg)
and the reaction stirred for 90 min at rt. The reaction
mixture was then filtered through a short silica gel column
and eluted with excess CH2Cl2. Evaporation of the solvent
and purification of the residue over a silica gel column using
ethyl acetate/hexane (1:30) as eluent furnished the ketone 7
Further elution of the column using ethyl acetate/hexane

A. Srikrishna, G. Satyanarayana / Tetrahedron 61 (2005) 8855–8859
8859
(5 mg, 83%) as oil.4 nmax (neat) 1732 cmK1. dH (300 MHz,
1:1 CDCl3CCCl4) 2.26 (2H, d, JZ3.3 Hz), 2.20–2.14 (1H,
m), 1.73–1.55 (8H, m), 1.31 (1H, t, JZ3.3 Hz), 1.08 (6H, s).
dC (75 MHz, 1:1 CDCl3CCCl4) 217.0 (C), 50.8 (CH), 43.6
(CH), 40.5 (2C, CH2), 40.1 (2C, CH2), 39.8 (2C, C), 33.1
(CH2), 26.7 (2C, CH3). m/z 178 (MC, 18%), 149 (100), 135
(7), 121 (10), 107 (21), 105 (73). HRMS: MCNa, found
201.1263. C12H18ONa requires 201.1255.
Burreson, B. J.; Scheuer, P. J.; Finer, J. S.; Clardy, J. Helv.
Chim. Acta 1979, 62, 2484–2494.
2. Karuso, P.; Poiner, A.; Scheuer, P. J. J. Org. Chem. 1989, 54,
2095–2097.
3. (a) Pham, A. T.; Ichiba, T.; Yoshida, W. Y.; Scheuer, P. J.;
Uchida, T.; Tanaka, J.-I.; Higa, T. Tetrahedron Lett. 1991, 32,
4843–4846. (b) He, H.-Y.; Salva, J.; Catalos, R. F.; Faulkner,
D. J. J. Org. Chem. 1992, 57, 3191–3194.
4. Ho, T.-L.; Jana, G. H. J. Org. Chem. 1999, 64, 8965–8967.
5. To the best of knowledge, there is only one report in the
literature4 on the synthesis of 9-isocyanoneopupukeanane.
6. Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091–1160.
7. Zhao, R.-B.; Zhao, Y.-F.; Song, G.-Q.; Wu, Y.-L. Tetrahedron
Lett. 1990, 31, 3559–3562.
Acknowledgements
We thank the Council of Scientific and Industrial Research,
New Delhi for the award of a research fellowship to GS.
8. Srikrishna, A.; Gharpure, S. J. J. Org. Chem. 2001, 66,
4379–4385.
9. Schreiber, S. L.; Liew, W.-F. Tetrahedron Lett. 1983, 24,
2363–2366.
References and notes
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2001, 66, 7527–7529.
1. (a) Burreson, B. J.; Scheuer, P. J.; Finer, J.; Clardy, J. J. Am.
Chem. Soc. 1975, 97, 4763–4764. (b) Hagadone, M. R.;