Enantiospecific total synthesis of (-)-4-thiocyanatoneopupukeanane

Article abstract of DOI:10.1021/jo0102765

Enantiospecific synthesis of the natural enantiomer of the marine sesquiterpene (-)-4-thiocyanatoneopupukeanane (6) is described. The bicyclo[2.2.2]octanecarboxylate 14, obtained from (R)-carvone via Michael-Michael reaction, was transformed into neopupuk

Full text of DOI:10.1021/jo0102765

J . Org. Chem. 2001, 66, 4379-4385
4379
En a n tiosp ecific Tota l Syn th esis of
(-)-4-Th iocya n a ton eop u p u k ea n a n e†
A. Srikrishna* and Santosh J . Gharpure
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
ask@orgchem.iisc.ernet.in
Received March 12, 2001
Enantiospecific synthesis of the natural enantiomer of the marine sesquiterpene (-)-4-thiocyana-
toneopupukeanane (6) is described. The bicyclo[2.2.2]octanecarboxylate 14, obtained from (R)-
carvone via Michael-Michael reaction, was transformed into neopupukeananedione 12 by employing
rhodium acetate catalyzed intramolecular C-H insertion of the diazo ketones 16 or 19 as the key
reaction. Regioselective deoxygenation of the C-2 ketone transformed the dione 12 into neopupukean-
4-one 10. Alternately, the keto ester 18 was also transformed into neopupukean-4-one 10 via
regioselective deoxygenation of the ketone in 18 followed by intramolecular rhodium carbenoid
C-H insertion of the diazo ketone 31. Finally, neopupukean-4-one 10 was transformed into (-)-
4-thiocyanatoneopupukeanane 6 via the alcohol 32 and the mesylate 33.
Among the natural products, terpenoids occupy a
special position on account of their widespread occurrence
and the bewildering array of carbocyclic skeleta that they
embody.1 Because of the phenomenal structural diversity,
this class of natural products holds special appeal to
synthetic chemists and provides a fertile ground for
developing and testing new synthetic strategies.2 In a
variety of marine organisms, chemical defense via secre-
tion of toxic and/or strong smelling organic compounds
from their skin glands is a common phenomenon as part
of the self-defense mechanism to protect themselves from
higher animals. On the basis of the observation that the
nudibranch Phyllidia varicosa Lamarck secretes a toxic
substance lethal to fish and crustaceans, Scheuer and co-
workers investigated on the chemical constituents of the
skin extracts of P. varicosa and also from its prey, a
sponge Ciocalypta sp. These investigations led to the
isolation3 of two isotwistane (1) based sesquiterpenes, 9-
and 2-isocyanopupukeananes 2 and 3. Subsequently,
during their biosynthetic experiments directed toward
discovering the origin of the isocyano group in marine
sponges, Scheuer and co-workers4 isolated a new ses-
quiterpene 4 from the sponge Ciocalypta sp. containing
a new carbon framework neopupukeanane. Later the
research groups of Scheuer, Higa, and Faulkner reported5
the isolation of two thiocyanate containing sesquiterpe-
nes, 2- and 4-thiocyanatoneopupukeananes 5 and 6, from
the sponge Phycopsis terpnis (from Okinawa), Axinyssa
aplysinoides from Palau, and an unidentified species from
Pohnpei. Biosynthetically, origin of pupukeananes and
neopupukeananes can be explained by a common path-
way via cyclization and rearrangement of cadinanes.4 It
is interesting to note that very few (<10) natural products
have been reported to contain a thiocyanate group. Even
though significant amount of synthetic activity6,7 was
reported on the synthesis of pupukeananes, there was
no report on the synthesis of neopupukeananes prior to
1998.8,9 In continuation of our interest in the enantiospe-
cific synthesis of sesquiterpenes,10 we embarked on the
enantiospecific total synthesis of 4-thiocyanatoneo-
(5) (a) Pham, A. T.; Ichiba, T.; Yoshida, W. Y.; Scheuer, P. J .; Uchida,
T.; Tanaka, J .-i.; Higa, T. Tetrahedron Lett., 1991, 32, 4843. (b) He,
H.-y.; Salva, J .; Catalos, R. F.; Faulkner, D. J . J . Org. Chem., 1992,
57, 3191.
(6) Synthesis of 2-isocyanopupukeanane and pupukean-2-ones: (a)
Corey, E. J .; Ishiguro, M. Tetrahedron Lett., 1979, 2745. (b) Frater,
G.; Wenger, J . Helv. Chim. Acta 1984, 67, 1702. (c) Chang, N.-C.;
Chang, C.-K. J . Org. Chem. 1996, 61, 4967. (d) Kaliappan, K.; Subba
Rao, G. S. R. Tetrahedron Lett. 1997, 38, 2185. (e) Kaliappan, K.; Subba
Rao, G. S. R. J . Chem. Soc., Perkin Trans. 1 1997, 3387. (f) Kaliappan,
K.; Subba Rao, G. S. R. J . Chem. Soc., Perkin Trans. 1 1997, 3393. (g)
Srikrishna, A.; Vijaykumar, D.; Sharma, G. V. R. Tetrahedron Lett.
1997, 38, 2003. (h) Srikrishna, A.; Vijaykumar, D.; Sharma, G. V. R.
Indian J . Chem. 1999, 38B, 766. (i) Biju, P. J .; Subba Rao, G. S. R.
Tetrahedron Lett. 1999, 40, 181. (j) Biju, P. J .; Kaliappan, K.; Laxmisha,
M. S.; Subba Rao, G. S. R. J . Chem. Soc., Perkin Trans. 1 2000, 3714.
For enantiospecific synthesis of pupukean-2-one, see: (k) Srikrishna,
A.; Reddy, T. J . J . Chem. Soc., Perkin Trans. 1 1997, 3293. (l)
Srikrishna, A.; Reddy, T. J . J . Chem. Soc., Perkin Trans. 1 1998, 2137.
(m) Srikrishna, A.; Kumar, P. R.; Gharpure, S. J . Tetrahedron Lett.
2001, 42, 3929.
(7) Synthesis of 9-isocyanopupukeanane and pupukean-9-ones: (a)
Corey, E. J .; Behforouz, M.; Ishiguro, M. J . Am. Chem. Soc. 1979, 101,
1608. (b) Yamamoto, H.; Sham, H. L. J . Am. Chem. Soc. 1979, 101,
1609. (c) Schiehser, G. A.; White, J . D. J . Org. Chem. 1980, 45, 1864.
(d) Piers, E.; Winter, M. J ustus Liebigs Ann. Chem. 1982, 973. (e)
Hsieh, S.-L.; Chiu, C.-T.; Chang, N.-C. J . Org. Chem. 1989, 54, 3820.
For enantiospecific synthesis of analogues of pupukean-9-ones, see: (f)
Srikrishna, A.; Hemamalini, P.; Sharma, G. V. R. Tetrahedron Lett.
1991, 32, 6609. (g) Srikrishna, A.; Hemamalini, P.; Sharma, G. V. R.
J . Org. Chem. 1993, 58, 2509. (h) Srikrishna, A.; Danieldoss, S. J . Org.
Chem. 1997, 62, 7863.
* Fax: 91-80-3600683.
† Chiral Synthons from Carvone. Part 48. For Part 47, see ref 6m.
(1) (a) Fraga, B. M. Nat. Prod. Rep. 1985, 2, 147; 1986, 3, 273; 1987,
4, 473; 1988, 5, 497; 1990, 7, 61 and 515; 1992, 9, 217 and 557; 1993,
10, 397; 1994, 11, 533; 1995, 12, 303; 1996, 13, 307; 1997, 14, 145;
1998, 15, 73; 1999, 16, 21 and 711; 2000, 17, 483. (b) Gribble, G. W.
In Progress in the Chemistry of Organic Natural Products; Herz, W.,
Kirby, G. W., Moore, R. E., Steglich, W., Tamm, Ch., Eds.; Springer:
Wien, New York, 1996; Vol. 68, pp 1-87.
(2) Heathcock, C. H. In The Total Synthesis of Natural Products;
ApSimon, J ., Ed.; Wiley: New York, 1973; Vol. 2, pp 197-558.
Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.; White, C.
T. In The Total Synthesis of Natural Products; ApSimon, J ., Ed.;
Wiley: New York, 1983; Vol. 5.
(3) (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.
(4) Karuso, P.; Poiner, A.; Scheuer, P. J . J . Org. Chem. 1989, 54,
2095.
(8) Part of the work described here has been included in a prelimi-
nary communication: Srikrishna, A.; Gharpure, S. J . Chem. Commun.
1998, 1589.
10.1021/jo0102765 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/22/2001

4380 J . Org. Chem., Vol. 66, No. 12, 2001
Srikrishna and Gharpure
Sch em e 1
pupukeanane 6 starting from (R)-carvone employing an
approach based on a regiospecific rhodium carbenoid
C-H insertion reaction.8
Sch em e 2a
It was envisaged that the rhodium acetate catalyzed
reaction of the diazo ketone 7, derived from bicyclo[2.2.2]-
octanecarboxylic acid 8, would generate the isotwistanone
9 (eq 1) in a regioselective manner via preferential
a
Reagents: (a) LiHMDS, methyl methacrylate; (b) NaOH; (c)
formation of a five-membered ring by insertion of the
intermediate rhodium carbenoid into the only available
γ C-H bond,11 as the other four γ C-H bonds are not
approachable as a result of steric reasons. On the basis
of this concept, enantiospecific synthesis of 4-thiocyana-
toneopupukeanane (6) was conceived via neopupukean-
4-one 10, Scheme 1. It was anticipated that rhodium
carbenoid C-H insertion of the diazo ketone derived from
the acid 11 would generate neopupukeananedione 12,
which could be transformed into neopupukean-4-one 10
via regioselective deoxygenation. Michael-Michael reac-
tion12 of (R)-carvone (13) with methyl methacrylate could
(i) (COCl)2, (ii) CH2N2; (d) Rh2(OAc)4; (e) H2, 10% Pt/C.
be exploited for the generation of the bicyclo[2.2.2]-
octanecarboxylic acid 11.
Synthesis of the neopupukeananedione 12 is depicted
in Scheme 2. Thus, reaction of (R)-carvone 13 with
lithium hexamethyldisilazide (LiHMDS) in hexane at
-78 °C followed by reaction of the resultant kinetic
dienolate with 1 equiv of methyl methacrylate furnished
the bicyclic keto ester 14, mp 59-61 °C (lit.12a 60-61 °C)
via the Michael-Michael reaction in 60% yield in a highly
regio- and stereoselective manner. Refluxing a solution
of the keto ester 14 and sodium hydroxide in 1:1
methanol and water led to the hydrolysis of the ester
moiety to furnish the keto acid 15, mp 119-120 °C, in
92% yield. It is worth mentioning that in the keto ester
14 and the keto acid 15, the stereochemistry of the
secondary methyl group at the C-6 carbon (R to the keto
group) is anti with respect to the acid group, which was
ideally suited for the projected C-H insertion reaction
for the generation of the isotwistane system. Reaction of
the acid 15 with an excess of oxalyl chloride in benzene
at room temperature followed by treatment of the result-
ant acid chloride with an excess of ethereal diazomethane
at 0 °C furnished the diazo ketone 16 (2100, 1710, and
1620 cm-1). Treatment of the diazo ketone 16 with a
catalytic amount of rhodium acetate in refluxing dichlo-
romethane furnished, as anticipated, the isotwistane
dione 17, mp 111-113 °C, containing the complete carbon
framework of neopupukeananes, via regiospecific C-H
insertion of the intermediate rhodium carbenoid. The
structure of 9-epineopupukean-13-ene-2,5-dione (or neo-
pupukean-13-ene-4,10-dione) 17 was established from its
spectral data. Presence of the molecular ion at m/z 232
(C15H20O2) in the mass spectrum and the presence of
(9) To the best of our knowledge, there is no report on the synthesis
of neopupukeananes prior to the publication of our preliminary
communication.8 For the synthesis of (()-9-isocyanoneopupukeanane,
see: (a) Ho, T.-L.; J ana, G. H. J . Org. Chem. 1999, 64, 8965. For the
synthesis of (()-2-thiocyanatoneopupukeanane, see: (b) Uyehara, T.;
Onda, K.; Nozaki, N.; Karikomi, M.; Ueno, M.; Sato, T. Tetrahedron
Lett., 2001, 42, 699. For the enantiospecific synthesis of 2-thiocyana-
toneopupukeanane, see: (c) Srikrishna, A.; Gharpure, S. J . J . Chem.
Soc., Perkin Trans. 1 2000, 3191. For the enantiospecific synthesis (-)-
4-thiocyanatoneopupukeanane, see: (d) Srikrishna, A.; Gharpure, S.
J . Tetrahedron Lett. 1999, 40, 1035.
(10) (a) Srikrishna, A.; Reddy, T. J . Indian J . Chem. 1995, 34B, 844.
(b) Srikrishna, A.; Vijaykumar, D.; Reddy, T. J . Tetrahedron 1997, 53,
1439. (c) Srikrishna, A.; Reddy, T. J .; Kumar, P. P. Chem. Commun.
1996, 1369. (d) Srikrishna, A.; Kumar, P. P.; Reddy, T. J . Tetrahedron
Lett. 1998, 39, 5815. (e) Srikrishna, A.; Reddy, T. J . Tetrahedron 1998,
54, 11517. (f) Srikrishna, A.; Viswajanani, R.; Dinesh, C. J . Chem. Soc.,
Perkin Trans. 1 2000, 4321. (g) Srikrishna, A.; Anebouselvy, K.; Reddy,
T. J . Tetrahedron Lett. 2000, 41, 6643. (h) Srikrishna, A.; Vijaykumar,
D. J . Chem. Soc., Perkin Trans. 1 2000, 2583.
(11) (a) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091. (b) Doyle,
M. P. In Comprehensive Organometallic Chemistry II; Hegedus, L. S.,
Ed.; Pergamon Press: New York, 1995; Vol. 12, Chapter 5.2. (c) Doyle,
M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds: from Cyclopropanes to Ylides; J ohn
Wiley and Sons: New York, 1998. (d) Doyle, M. P. Aldrichimica Acta
1996, 29, 3.
(12) (a) Zhao, R.-B.; Zhao, Y.-F.; Song, G.-Q.; Wu, Y.-L. Tetrahedron
Lett. 1990, 31, 3559. (b) Maiti, S.; Bhaduri, S.; Achari, B.; Banerjee,
A. K.; Nayak, N. P.; Mukherjee, A. K. Tetrahedron Lett. 1996, 37, 8061.

Synthesis of (-)-4-Thiocyanatoneopupukeanane
J . Org. Chem., Vol. 66, No. 12, 2001 4381
cided to use Barton’s protocol13 for deoxygenation of the
C-2 ketone. Thus, reduction of the ketone moiety in the
keto ketal 20 with LAH in THF at 0 °C followed by basic
workup furnished the alcohol 21 in 94% yield. Treatment
of the alcohol 21 with sodium hydride in the presence of
a catalytic amount of imidazole and reaction of the
resultant alkoxide with dry carbon disulfide followed by
methyl iodide furnished the xanthate 22 in 80% yield.
Reaction of a 0.027 M solution of the xanthate 22 in
benzene with tributyltin hydride and a catalytic amount
of AIBN at reflux temperature, followed by hydrolysis of
the product mixture with 3 N aqueous hydrochloric acid
in THF, furnished an ∼3:2 mixture of neopupukean-4-
one 10, mp 66-68 °C, and 10-methoxyneopupukean-4-
one 23, mp 127-128 °C, in 91% yield, which were
separated by silica gel column chromatography. The
structures of the ketones 10 and 23 were delineated from
their spectral data. The structure of the byproduct 23 was
confirmed by comparison with an authentic sample
obtained by methylation of the hydroxy group in the ketal
21 with sodium hydride and methyl iodide in a mixture
of THF and DMF in the presence of a catalytic amount
of tetrabutylammonium iodide (TBAI) followed by hy-
drolysis of the ketal moiety. Even though it is not
common to obtain the methoxy derivative as a byproduct
in Barton’s deoxygenation of xanthates using tributyltin
hydride and AIBN, in 1997 Cornforth and Hanson
reported14 formation of the methyl ether 25a as the
byproduct in the reaction of the xanthate 24 with an
excess of tributyltin hydride and AIBN (eq 2). To sup-
Sch em e 3a
a
Reagents: (a) (CH2OH)2; (b) LiAlH4; (c) NaH; CS2; MeI; (d) (i)
nBu3SnH, AIBN, (ii) H3O+.
carbonyl absorption bands at 1740 and 1720 cm-1 due to
two ketone groups (a cyclopentanone and a cyclohex-
anone, respectively) in the IR spectrum indicated the
1
formation of the dione 17. In the H NMR spectrum, the
presence of three singlets at δ 4.83 and 4.79 (olefinic) and
1.76 (methyl) due to the isopropenyl group, two singlets
at 1.25 and 1.24 due to two tertiary methyl groups, two
doublets at 2.52 and 2.10 (J ) 18.9 Hz) due to the H-4
methylene protons (CH2CdO), and a multiplet at 2.55-
2.50 ppm due to the two bridgehead protons H-1 and H-9
established the structure of the dione 17. The 15-lines
13C NMR spectrum with characteristic resonances at δ
218.6 and 217.6 due to two carbonyl carbons, a quater-
nary carbon at 146.8, and a methylene carbon at 110.4
due to the olefinic carbons of the isopropenyl group, two
quaternary carbons at 50.9 (C-3) and 48.5 (C-6), three
methine signals at 49.0 (C-1), 46.3 and 45.1 (C-7 and 9),
three methylene signals at 48.1 (C-4), 35.2 (C-10) and
20.7 (C-8), and three methyl signals at 22.0, 19.5 and 18.1
ppm confirmed the structure of the dione 17. Hydrogena-
tion of the dione 17 in ethanol with 10% platinum on
carbon as the catalyst at 1 atm pressure of hydrogen
furnished 9-epineopupukeanane-2,5-dione 12, mp 131-
133 °C, quantitatively. Alternatively, hydrogenation of
the keto ester 14 with 10% platinum on carbon as the
catalyst in ethanol furnished the keto ester 18, mp 71-
73 °C (lit.12a 71.5-73 °C), quantitatively, which on base-
catalyzed hydrolysis furnished the keto acid 11. Treat-
ment of the keto acid 11 with oxalyl chloride in benzene
at room temperature, followed by reaction of the resultant
acid chloride with an excess of ethereal diazomethane
solution, furnished the diazo ketone 19. Reaction of the
diazo ketone 19 in refluxing dichloromethane in the
presence of a catalytic amount of rhodium acetate for 4
h also furnished the dione 12 in 63% yield (from the acid
11).
press the formation of the methyl ether 23, a few
variations in experimental conditions were explored.
Thus, increasing the dilution to 0.008 M for the deoxy-
genation of the xanthate 22 in refluxing benzene, followed
by hydrolysis, furnished an ∼4:1 mixture of ketones 10
and 23. Changing the solvent to toluene, thereby increas-
ing the temperature of the deoxygenation reaction, fol-
lowed by hydrolysis furnished exclusively neopupukean-
4-one 10 in 73% yield.
After successfully accomplishing the synthesis of neo-
pupukean-4-one 10, before proceeding further, an alter-
nate route was also considered for the synthesis of
neopupukean-4-one 10, Scheme 4. Regioselective reduc-
tion of the keto ester 18 with sodium borohydride in
methanol at 0 °C furnished the alcohol 26, mp 68-70
°C. Treatment of the alcohol 26 with sodium hydride in
the presence of a catalytic amount of imidazole and
reaction of the resultant alkoxide with dry carbon di-
sulfide followed by methyl iodide furnished the xanthate
27 in 80% yield. Treatment of the xanthate 27 with
tributyltin hydride and a catalytic amount of AIBN in
Next, attention was turned toward the conversion of
the dione 12 into neopupukean-4-one 10, Scheme 3. Since
the C-2 ketone is more hindered and less reactive than
the C-5 ketone in the dione 12, for the selective deoxy-
genation of the C-2 ketone, the C-5 ketone needs to be
masked. Thus, refluxing a benzene solution of the dione
12 and ethylene glycol in the presence of a catalytic
amount of p-toluenesulfonic acid (PTSA) using a Dean-
Stark water trap furnished the keto ketal 20, mp 107-
108 °C, in 84% yield, in a highly regioselective manner.
Since the Wolff-Kishner reduction as well as the Huang-
Minlon modified version were unsuccessful, it was de-
(13) (a) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin
Trans. 1 1975, 1574. (b) Barton, D. H. R.; Crich, D.; Lobberding, A.;
Zard, S. Z. Tetrahedron 1986, 42, 2329. (c) Barton, D. H. R.; Mother-
well, W. B. Pure Appl. Chem. 1981, 53, 15. (d) Hartwig, W. Tetrahedron
1983, 39, 2609.
(14) Bensasson, C. S.; Cornforth, J .; Du, M.-H.; Hanson, J . R. Chem.
Commun. 1997, 1509.

4382 J . Org. Chem., Vol. 66, No. 12, 2001
Srikrishna and Gharpure
Sch em e 4a
tion of a diazo ketone were exploited for the rapid
construction of the neopupukeanane carbon framework.
Exp er im en ta l Section
Melting points are not corrected. In the 13C NMR spectra,
the nature of the carbons (C, CH, CH2, or CH3) was determined
by either recording the off-resonance spectra or the DEPT-
135 experiment and are given in parentheses. Values for [R]D
are given in units of 10-1 deg cm2 g-1. Silica gel (100-200
mesh) was used for column chromatography. All solvent
extracts were washed with brine, dried over anhydrous Na2-
SO4, and concentrated on a rotavapor. All IR spectra were
recorded as thin films, and NMR spectra were recorded either
in CDCl3 or in a 1:1 mixture of CDCl3 and CCl4.
(-)-Meth yl (1R,2R,4S,6S,8R)-8-Isopr open yl-2,6-dim eth yl-
5-oxobicyclo[2.2.2]octa n e-2-ca r boxyla te (14). To a cold
(-78 °C), magnetically stirred solution of hexamethyldisila-
zane (4.22 mL, 20 mmol) in dry hexane (36 mL) was slowly
added n-BuLi (12.5 mL of a 1.6 M solution in hexane, 20
mmol), and the mixture was stirred for 15 min. To the
LiHMDS thus formed was added, dropwise, a solution of (R)-
carvone 13 (3.0 g, 20 mmol) in dry hexane (30 mL), and the
reaction mixture stirred for 45 min at the same temperature.
The enolate was treated with methyl methacrylate (2.14 mL,
20 mmol) and stirred for 3 h at room temperature. 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 14 (3.0 g, 60%) as a white solid,
which was recrystallized from hexanes. Mp: 59-61 °C (lit.12a
a
Reagents: (a) NaBH4; (b) NaH; CS2; MeI; (c) nBu3SnH, AIBN;
(d) KOH; (e) (i) (COCl)2, (ii) CH2N2; (f) Rh2 (OAc)4.
refluxing benzene furnished an ∼2:1 mixture of the
deoxygenated ester 28 and the methoxy ester 29, in 90%
yield, which was separated by column chromatography
on silica gel. As in the earlier case, formation of the
methoxy ester 29 could be suppressed by increasing the
temperature of the reaction. Refluxing the ester 28 in 2
M methanolic potassium hydroxide furnished the acid 30
in 91% yield. Treatment of the acid 30 with oxalyl
chloride followed by treatment of the resultant acid
chloride with an excess of ethereal diazomethane solution
furnished the diazo ketone 31 in 54% yield. Refluxing a
dichloromethane solution of the diazo ketone 31 and a
catalytic amount of rhodium acetate furnished neo-
pupukean-4-one 10 in 75% yield.
60-61.5 °C). [R]22D: -43.5 (c 3.77, MeOH) [lit.12a [R]25 -42.6
D
(c 1.00, MeOH)]. IR: νmax 1720, 1645, 895. 1H NMR (300
MHz): δ 4.75 (1 H, s), 4.72 (1 H, s), 3.71 (3 H, s), 2.70 (1 H,
dd, J ) 14.5 and 2.5 Hz), 2.60-2.40 (2 H, m), 2.25-2.00 (3 H,
m), 1.71 (3 H, s), 1.70-1.55 (2 H, m), 1.46 (3 H, s), 1.10 (3 H,
d, J ) 6.9 Hz). 13C NMR (22.5 MHz): δ 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 (2 C, q and t), 12.3 (q). HRMS:
m/z for C15H22O3 calcd 250.1569, found 250.1556. Anal. Calcd
for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.84; H, 9.00.
(-)-(1R ,2R ,4S ,6S ,8R )-8-Isop r op e n yl-2,6-d im e t h yl-5-
oxobicyclo[2.2.2]octa n e-2-ca r boxylic Acid (15). To a solu-
tion of the keto ester 14 (1.0 g, 4 mmol) in 5 mL of methanol
was added 10% aqueous NaOH solution (5 mL). The reaction
mixture was refluxed for 8 h. It was then cooled to room
temperature and washed with CH2Cl2 (10 mL). The aqueous
layer was acidified with 3 N aqueous HCl and extracted with
CH2Cl2. Evaporation of the solvent furnished the acid 15 (870
mg, 92%) as a sticky solid, which was recrystallized from a
mixture of hexane and CH2Cl2. Mp: 119-120 °C. [R]26D: -47.7
(c 1.30, CHCl3). IR: νmax 3140, 3080, 1720, 1700, 1645, 890.
1H NMR (300 MHz): δ 4.74 (1 H, s), 4.72 (1 H, s), 2.68 (1 H,
dd, J ) 14.7 and 2.4 Hz), 2.55-2.45 (2 H, m), 2.30-2.10 (3 H,
m), 1.71 (3 H, s), 1.75-1.50 (2 H, m), 1.59 (1 H, dd, J ) 14.7
and 3.3 Hz), 1.52 (3 H, s), 1.12 (3 H, d, J ) 6.9 Hz). 13C NMR
(22.5 MHz): δ 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 (2 C,
q and t), 12.5 (q). HRMS: m/z for C14H20O3 calcd 236.1412,
found 236.1402. Anal. Calcd for C14H20O3: C, 71.16; H, 8.53.
Found: C, 71.17; H, 8.83.
Stereoselective reduction of the ketone group in 10 with
sodium borohydride in methanol at ice temperature
furnished the alcohol 32, which on treatment with
methanesulfonyl chloride in pyridine in the presence of
a catalytic amount of DMAP cleanly furnished the
methanesulfonate 33, mp 52-54 °C, in 84% yield. Fi-
nally, reaction of the methanesulfonate 33 with potas-
sium thiocyanate in acetone (sealed tube) at 80 °C for 5
days furnished 4-thiocyanatoneopupukeanane 6 in 68%
yield (40% conversion), [R]28 -117.6 (c 1.08, CHCl3),
D
which exhibited optical rotation and 1H and 13C NMR
spectral data identical5a to that of the natural product
establishing its absolute configuration as 1S,3R,4R,6R,-
7R,9S.
(-)-(1S,3R,6R,7S,9R)-9-Isop r op en yl-3,6-d im et h ylt r i-
cyclo[4.3.1.03,7]d eca n e-2,5-d ion e (17). To a magnetically
stirred solution of the acid 15 (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 room
temperature. Evaporation of benzene and the excess oxalyl
chloride under reduced pressure furnished the acid chloride,
which was taken in dry ether (5 mL) and added dropwise to a
cold (0 °C), magnetically stirred solution of diazomethane (25
mL, prepared from 3 g of N-nitroso-N-methylurea and 30 mL
of 60% aqueous KOH solution). The reaction mixture was
slowly warmed to room temperature and stirred for 2 h, and
the excess diazomethane and ether were carefully evaporated
In conclusion, a short and efficient synthesis of the
natural enantiomer of the marine sesquiterpene 4-thio-
cyanatoneopupukeanane (6) has been accomplished start-
ing from the readily available monoterpene (R)-carvone.
A stereoselective Michael-Michael reaction and a re-
giospecific intramolecular rhodium carbenoid C-H inser-

Synthesis of (-)-4-Thiocyanatoneopupukeanane
J . Org. Chem., Vol. 66, No. 12, 2001 4383
on a water bath. Rapid purification by filtration of the crude
product through a neutral alumina column using CH2Cl2 as
eluent furnished the diazo ketone 16 (495 mg, 90%) as yellow
oil. IR: νmax/cm-1 2100, 1710, 1620, 890. To a magnetically
stirred, refluxing solution of rhodium acetate (4 mg) in dry
CH2Cl2 (30 mL) was added, dropwise, a solution of the diazo
ketone 16 (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 17 (392 mg, 89%) as a white solid, which was recrystal-
lized from a mixture of ethyl acetate and hexane. Mp: 111-
113 °C. [R]26D: -45.5 (c 1.32, CHCl3). IR: νmax/cm-1 1740, 1710,
2.45 (1 H, br s), 2.20-2.00 (3 H, m), 1.55-1.30 (3 H, m), 1.47
(3 H, s), 1.20-1.05 (1 H, m), 1.11 (3 H, d, J ) 6.9 Hz), 0.97 (1
H, dd, J ) 6.6 and 2.1 Hz), 0.89 (6 H, d, J ) 6.6 Hz). 13C NMR
(75 MHz): δ 217.3 (C), 184.2 (C), 46.3 (CH), 45.1 (CH), 44.4
(C), 44.1 (CH), 42.1 (CH), 33.7 (CH), 33.5 (CH2), 26.8 (CH3),
23.1 (CH2), 20.72 (CH3), 20.68 (CH3), 12.4 (CH3). Mass: m/z
239 (M + 1, 4%), 135 (8), 123 (8), 109 (100), 108 (15). Reaction
of the acid 11 (1.0 g, 4.2 mmol) with oxalyl chloride (1.83 mL,
21 mmol) in dry benzene (3 mL) followed by treatment of the
resultant acid chloride with an ice-cold solution of an excess
of ethereal diazomethane (50 mL, prepared from 5 g of
N-nitroso-N-methylurea and 60 mL of 60% aqueous KOH
solution) furnished the diazo ketone 19 (1.0 g, 90%) as yellow
oil. IR: νmax/cm-1 2100, 1710, 1620. Decomposition of the diazo
ketone 19 (1.0 g, 3.82 mmol) in the presence of rhodium acetate
(8 mg) in refluxing CH2Cl2 (70 mL) and purification of the
product on a silica gel column using ethyl acetate-hexane
(1:10) as eluent furnished the tricyclic dione 12 (625 mg, 70%),
which was identified by comparison of TLC and spectral data
(IR and 1H and 13C NMR) with those of the sample obtained
by hydrogenation of the dione 17.
1
1640, 890. H NMR (300 MHz): δ 4.83 (1 H, s) and 4.79 (1 H,
s) [CdCH2], 2.55-2.50 (2 H, m, H-1 and 9), 2.52 (1 H, d, J )
18.9 Hz, H-4a), 2.21 (1 H, ddd, J ) 14.4, 10.5 and 3.3 Hz),
2.10 (1 H, d, J ) 18.9 Hz, H-4b), 1.94 (1 H, ddd, J ) 14.7, 6.3
and 2.7 Hz), 1.90 (1 H, br s), 1.80 (1 H, dd, J ) 14.7 and 4.2
Hz), 1.76 (3 H, s, olefinic CH3), 1.59 (1 H, d, J ) 14.7 Hz), 1.25
(3 H, s) and 1.24 (3 H, s) [2 x tert.CH3]. 13C NMR (75 MHz):
δ 218.6 (C) and 217.6 (C) [C-2 and 5], 146.8 (C, C)CH2), 110.4
(CH2, C)CH2), 50.9 (C, C-3), 49.0 (CH, C-1), 48.5 (C, C-6), 48.1
(CH2, C-4), 46.3 (CH) and 45.1 (CH) [C-7 and 9], 35.2 (CH2,
C-10), 22.0 (CH3), 20.7 (CH2, C-8), 19.5 (CH3), 18.1 (CH3).
HRMS: m/z for C15H20O2 calcd 232.1463, found 232.1465. Anal.
Calcd for C15H20O2: C, 77.55; H, 8.68. Found: C, 77.51; H,
8.79.
(-)-(1S,3R,6R,7S,9S)-5,5-E t h ylen ed ioxy-9-isop r op yl-
3,6-d im eth yltr icyclo[4.3.1.03,7]d eca n -2-on e (20). To a mag-
netically stirred refluxing solution of the dione 12 (300 mg,
1.28 mmol) and ethylene glycol (0.1 mL, 1.79 mmol) in benzene
(20 mL) was added a catalytic amount of PTSA, and the
reaction mixture was refluxed for 10 h with a Dean-Stark
water trap. Excess benzene was distilled off, and the residue
was diluted with 5 mL of saturated aqueous NaHCO3 and
extracted with ether. Purification of the residue on a silica gel
column using ethyl acetate-hexane (1:10) as eluent furnished
the ketal 20 (300 mg, 84%) as a white solid, which was
recrystallized from a mixture of hexane and CH2Cl2. Mp: 107-
(-)-(1S,3R,6R,7S,9S)-9-Isop r op yl-3,6-d im eth yltr icyclo-
[4.3.1.03,7]d eca n e-2,5-d ion e (12). To 10% Pt-C (25 mg) was
added a solution of the tricyclic dione 17 (500 mg, 2.16 mmol)
in dry ethanol (5 mL). The reaction mixture was stirred for 4
h at room temperature in an atmosphere of hydrogen created
by evacuative displacement of air by hydrogen (balloon), and
then the catalyst was filtered off. Evaporation of the solvent
furnished the tricyclic dione 12 (484 mg, 96%) as a white solid,
which was recrystallized from a mixture of ethyl acetate and
1
108 °C. [R]23D: -111.0 (c 0.93, CHCl3). IR: νmax/cm-1 1717. H
NMR (300 MHz): δ 3.95-3.80 (4 H, m), 2.32 (1 H, br s), 2.26
(1 H, dd, J ) 14.7 and 3.8 Hz), 2.00-1.90 (1 H, m), 1.95 (1 H,
d, J ) 14.7 Hz), 1.90-1.80 (1 H, m), 1.77 (1 H, d, J ) 14.4
Hz), 1.40-1.00 (3 H, m), 1.23 (1 H, d, J ) 14.7 Hz), 1.09 (3 H,
s), 1.06 (3 H, s), 0.90 (3 H, d, J ) 6.0 Hz), 0.88 (3 H, d, J ) 6.3
Hz). 13C NMR (75 MHz): δ 219.9 (C), 117.3 (C), 65.1 (CH2),
64.7 (CH2), 51.6 (C), 49.0 (CH), 47.9 (CH2), 47.2 (CH), 45.3 (C),
44.9 (CH), 34.2 (CH), 33.5 (CH2), 22.6 (CH2), 20.8 (CH3), 20.5
(CH3), 19.5 (CH3), 18.3 (CH3). HRMS: m/z for C17H26O3 calcd
278.1882, found 278.1869. Anal. Calcd for C17H26O3: C, 73.35;
H, 9.41. Found: C, 73.42; H, 9.57.
hexane. Mp: 131-133 °C. [R]26D: -48.9 (c 1.48, CHCl3). IR:
1
ν
max/cm-1 1740, 1720. H NMR (300 MHz): δ 2.48 (1 H, br s),
2.47 (1 H, d, J ) 19.0 Hz), 2.20-2.05 (1 H, m), 2.09 (1 H, d, J
) 19.0 Hz), 1.86 (1 H, t, J ) 3.0 Hz), 1.78 (1 H, dd, J ) 14.7
and 4.5 Hz), 1.75-1.60 (1 H, m), 1.55-1.45 (1 H, m), 1.47 (1
H, d, J ) 15.0 Hz), 1.26 (3 H, s), 1.20 (3 H, s), 1.20-1.15 (1 H,
m), 0.94 (3 H, d, J ) 6.3 Hz), 0.91 (3 H, d, J ) 6.6 Hz). 13C
NMR (75 MHz): δ 217.8 (C), 216.9 (C), 50.7 (C), 49.5 (CH),
48.3 (C), 47.7 (CH2), 47.0 (CH), 45.1 (CH), 34.7 (CH2), 34.2
(CH), 21.6 (CH2), 20.8 (CH3), 20.0 (CH3), 19.6 (CH3), 18.2 (CH3).
HRMS: m/z for C15H22O2 calcd 234.1620, found 234.1615. Anal.
Calcd for C15H22O2: C, 76.88; H, 9.46. Found: C, 76.98; H,
9.64.
(-)-(1S,2R,3R,6R,7R,9S)-5,5-Eth ylen edioxy-9-isopr opyl-
3,6-d im eth yltr icyclo[4.3.1.03,7]d eca n -2-ol (21). To a cold (0
°C) magnetically stirred solution of the keto ketal 20 (200 mg,
0.72 mmol) in 2 mL of THF was added LAH (40 mg, 1.05 mmol)
in one portion. The reaction mixture was then stirred for 2 h
at the same temperature. It was then diluted with ether and
quenched carefully with a few drops of water. The ether layer
was separated, and the aqueous phase was extracted with
ether. Purification of the residue on a silica gel column using
ethyl acetate-hexane (1:10) as eluent furnished the alcohol
21 (190 mg, 94%) as an oil. [R]23D: -101.0 (c 3.04, CHCl3). IR:
(-)-Meth yl (1R,2R,4S,6S,8S)-8-Isop r op yl-2,6-d im eth yl-
5-oxobicyclo[2.2.2]octan e-2-car boxylate (18). To 10% Pt-C
(50 mg) was added a solution of the keto ester 14 (1.0 g, 4
mmol) in dry ethanol (5 mL). The reaction mixture was stirred
for 4 h at room temperature in an atmosphere of hydrogen
(balloon), and then the catalyst was filtered off. Evaporation
of the solvent furnished the keto ester 18 (986 mg, 96%) as a
white solid, which was recrystallized from hexane. Mp: 71-
73 °C (lit.12a 71.5-73 °C). [R]23D: -46.9 (c 1.94, MeOH) [lit.12a
[R]25D: -41.1 (c 1.10, MeOH)]. IR: νmax/cm-1 1720. 1H NMR
(300 MHz): δ 3.67 (3 H, s), 2.64 (1 H, dd, J ) 14.7 and 2.7
Hz), 2.41 (1 H, br s), 2.14 (1 H, br s), 2.10-1.95 (2 H, m), 1.55-
1.30 (3 H, m), 1.37 (3 H, s), 1.30-1.00 (1 H, m), 1.05 (3 H, d,
J ) 7.5 Hz), 0.86 (3 H, d, J ) 6.6 Hz), 0.85 (3 H, d, J ) 6.3
Hz). 13C NMR (75 MHz): δ 218.1 (C), 178.2 (C), 52.2 (CH3),
46.3 (CH), 44.9 (CH), 44.4 (C), 43.9 (CH), 42.1 (CH), 33.7 (CH2),
33.6 (CH), 26.7 (CH3), 22.9 (CH2), 20.5 (2 C, CH3) 12.2 (CH3).
HRMS: m/z for C15H24O3 calcd 252.1725, found 252.1735. Anal.
Calcd for C15H24O3: C, 71.39; H, 9.59. Found: C, 71.35; H,
9.82.
ν
max/cm-1 3520. 1H NMR (300 MHz): δ 3.90-3.75 (4 H, m),
3.57 (1 H, d, J ) 4.4 Hz), 2.05 (1 H, m), 1.90-1.75 (3 H, m),
1.80 (1 H, d, J ) 14.3 Hz), 1.66 (1 H, d, J ) 14.3 Hz), 1.50-
1.30 (3 H, m), 1.05-0.80 (2 H, m), 1.03 (3 H, s), 0.94 (3 H, s),
0.90 (3 H, d, J ) 6.3 Hz), 0.84 (3 H, d, J ) 6.3 Hz). 13C NMR
(75 MHz): δ 118.2 (C), 82.1 (CH), 64.9 (CH2), 64.6 (CH2), 54.1
(CH2), 45.8 (CH), 45.1 (C), 43.6 (CH), 41.2 (C), 36.8 (CH2), 34.0
(CH), 33.7 (CH), 22.8 (CH2), 22.1 (CH3), 21.3 (CH3), 20.0 (CH3),
19.5 (CH3). Mass: m/z 280 (M+, C17H28O3).
(-)-(1S,3R,6R,7R,9S)-9-Isop r op yl-3,6-d im eth yltr icyclo-
[4.3.1.03,7]d eca n -4-on e (10). To a magnetically stirred sus-
pension of NaH (34 mg, 55% dispersion in oil, 0.71 mmol,
washed with dry hexane) in THF (1 mL) was added a solution
of the alcohol 21 (50 mg, 0.18 mmol) in 1 mL of THF followed
by a catalytic amount of imidazole (∼10 mg). The reaction
mixture was heated to 60 °C for 1 h. It was then cooled to
room temperature, dry CS2 (0.11 mL, 1.8 mmol) was added,
and the mixture was heated to 60 °C for 15 min. It was
recooled to room temperature, and MeI (0.11 mL, 1.8 mmol)
(-)-(1S,3R,6R,7S,9S)-9-Isop r op yl-3,6-d im eth yltr icyclo-
[4.3.1.03,7]d eca n e-2,5-d ion e (12). Hydrolysis of the keto ester
18 (1.0 g, 3.96 mmol) with 5% NaOH in 1:1 MeOH-water (10
mL) furnished the keto acid 11 (878 mg, 93%) as a viscous oil.
[R]21D: -49.9 (c 4.10, CHCl3). IR: νmax/cm-1 3000, 1720, 1700.
1H NMR (300 MHz): δ 2.66 (1 H, dd, J ) 14.4 and 2.4 Hz),

4384 J . Org. Chem., Vol. 66, No. 12, 2001
Srikrishna and Gharpure
was added. The reaction mixture was then refluxed for 3 h. It
was then cooled to room temperature, diluted with 5 mL of
water, and extracted with ether. Evaporation of the solvent
and rapid purification of the product on a silica gel column
using ethyl acetate-hexane (1:20) furnished the xanthate 22
(53 mg, 80%). IR: νmax/cm-1 1224. 1H NMR (300 MHz): δ 5.58
(1 H, d, J ) 4.8 Hz), 3.95-3.80 (4 H, m), 2.56 (3 H, s), 2.35-
2.25 (1 H, m), 2.05-1.90 (2 H, m), 1.97 (1 H, d, J ) 14.7 Hz),
1.86 (1 H, d, J ) 14.7 Hz), 1.70-1.45 (3 H, m), 1.42 (1 H, ddd,
J ) 14.2, 9.4 and 1.5 Hz), 1.11 (1 H, dd, J ) 14.7 and 3.3 Hz),
1.02 (3 H, s), 0.98 (3 H, s), 0.88 (3 H, d, J ) 6.6 Hz), 0.80 (3 H,
d, J ) 6.3 Hz). 13C NMR (75 MHz): δ 215.9 (C), 117.8 (C),
92.0 (CH), 65.0 (CH2), 64.7 (CH2), 53.8 (CH2), 45.9 (CH), 45.2
(C), 43.3 (CH), 41.8 (C), 36.1 (CH2), 34.0 (CH), 31.3 (CH), 23.1
(CH2), 22.2 (CH3), 21.2 (CH3), 20.2 (CH3), 19.5 (CH3), 19.2
(CH3). A solution of the xanthate 22 (30 mg, 0.08 mmol),
nBu3SnH (0.05 mL, 0.19 mmol), and a catalytic amount of
AIBN (∼5 mg) in 3 mL of benzene was refluxed for 4 h. The
reaction mixture was cooled, diluted with ether, washed
successively with 1% aqueous NH4OH solution, water, and
brine, and dried (Na2SO4). Evaporation of the solvent gave a
mixture of ketals, which was taken in THF (2 mL), and 3 N
aqueous HCl was added and stirred for 4 h at room temper-
ature. It was then diluted with ether and washed with water
and brine. Evaporation of the solvent and purification of the
residue on a silica gel column using ethyl acetate-hexane
(1:20) as eluent furnished, first, 4-neopupukeanone 10 (10 mg,
56% from xanthate) as a white solid, which was recrystallized
H, d, J ) 14.1 Hz), 1.45-1.25 (2 H, m), 1.10-0.80 (1 H, m),
1.05 (1 H, dd, J ) 14.3 and 3.3 Hz), 0.99 (3 H, s), 0.94 (3 H, s),
0.89 (3 H, d, J ) 6.3 Hz), 0.81 (3 H, d, J ) 6.6 Hz). 13C NMR
(75 MHz): δ 118.3 (C), 91.8 (CH), 64.9 (CH2), 64.6 (CH2), 58.6
(CH3), 55.0 (CH2), 46.2 (CH), 45.3 (C), 44.0 (CH), 41.8 (C), 36.8
(CH2), 32.5 (CH), 30.4 (CH), 22.6 (CH2), 21.8 (2 C, CH3), 20.6
(CH3), 19.6 (CH3). Mass: m/z 294 (M+, C18H30O3). Further
elution of the column with ethyl acetate-hexane (1:10) gave
the unreacted starting alcohol 21 (25 mg, 50%). To a magneti-
cally stirred solution of methyl ether (20 mg, 0.07 mmol) was
added a drop of 3 N aqueous HCl, and the reaction mixture
was stirred at room temperature for 3 h. It was then diluted
with ether (10 mL) and washed with brine. Evaporation of the
solvent and purification of the residue on a silica gel column
using ethyl acetate-hexane (1:10) as eluent furnished the
methoxy ketone 23 (16 mg, 94%), which was found to be
identical (TLC, IR, and 1H NMR) to the sample obtained via
the nBu3SnH reaction of the xanthate 22.
(-)-Meth yl (1R,2R,4S,5S,6S,8S)-5-Hyd r oxy-8-isop r op yl-
2,6-d im eth ylbicyclo[2.2.2]octa n e-2-ca r boxyla te (26). To a
cold (0 °C) magnetically stirred solution of the keto ester 18
(1.0 g, 3.94 mmol) in 5 mL of MeOH was added NaBH4 (200
mg, 5.28 mmol) over a period of 5 min. The reaction mixture
was stirred for 15 min at the same temperature, and then the
solvent was evaporated under reduced pressure. It was then
diluted with water and extracted with ether. Evaporation of
the solvent and purification of the product over a silica gel
column using ethyl acetate-hexane as eluent furnished the
alcohol 26 (857 mg, 85%) as a white solid, which was recrystal-
lized from hexane. Mp: 68-70 °C. [R]26D: -79.1 (c 1.82, CHCl3).
IR: νmax/cm-1 3530, 1725. 1H NMR (300 MHz): δ 3.95 (1 H,
dd, J ) 11.6 and 3.5 Hz), 3.67 (3 H, s), 2.33 (1 H, dd, J ) 14.1
and 2.4 Hz), 2.09 (1 H, br s), 2.00-1.50 (5 H, m), 1.43 (1 H,
dd, J ) 14.1 and 8.7 Hz), 1.30 (3 H, s), 1.21 (1 H, dd, J ) 14.1
and 4.2 Hz), 1.05-0.90 (1 H, m), 1.01 (3 H, d, J ) 6.9 Hz),
0.92 (3 H, d, J ) 6.0 Hz). 0.86 (3 H, d, J ) 6.3 Hz). 13C NMR
(22.5 MHz): δ 179.5 (s), 71.1 (d), 51.8 (q), 45.2 (s), 42.2 (d),
39.9 (d), 36.1 (t), 34.4 (d), 33.6 (2 C, d), 26.2 (q), 22.6 (q), 21.8
(t), 21.1 (q), 12.5 (q). Mass: m/z 254 (M+). Anal. Calcd for
from a mixture of hexane and ether. Mp: 66-68 °C. [R]22
:
D
-56.6 (c 0.76, CHCl3). IR:
ν
max/cm-1 1740. 1H NMR (300
MHz): δ 2.22 (1 H, d, J ) 18.9 Hz), 1.97 (1 H, d, J ) 18.9 Hz),
1.90 (1 H, ddd, J ) 14.7, 11.1 and 4.2 Hz), 1.75 (1 H, br s),
1.64 (1 H, dd, J ) 14.1 and 4.2 Hz), 1.58 (1 H, d, J ) 13.2 Hz),
1.50-1.15 (5 H, m), 1.16 (3 H, s), 1.04 (3 H, s), 0.95-0.80 (1
H, m), 0.94 (3 H, d, J ) 6.6 Hz), 0.83 (3 H, d, J ) 6.6 Hz). 13C
NMR (75 MHz): δ 222.3 (C), 54.4 (CH2), 48.3 (C), 46.4 (CH),
43.3 (CH), 40.0 (CH2), 35.8 (CH2), 35.3 (C), 32.5 (CH), 28.3
(CH), 25.9 (CH3), 22.5 (CH2), 21.1 (CH3), 20.8 (CH3), 19.8 (CH3).
Mass: m/z 220 (M+). Anal. Calcd for C15H24O: C, 81.76; H,
10.98. Found: C, 81.78; H, 11.28. Further elution of the column
with ethyl acetate-hexane (1:20 to 1:10) furnished the meth-
oxy ketone 23 (7 mg, 35%) as a white solid, which was
recrystallized from a mixture of hexane and ether. Mp: 127-
C
15H26O3: C, 70.83; H, 10.30. Found: C, 71.20; H, 10.68.
(-)-Met h yl (1R,2R,4S,5S,7R)-5-Isop r op yl-2,7-d im et h -
ylbicyclo[2.2.2]octa n e-2-ca r boxyla te (28). To a magneti-
cally stirred suspension of NaH (66 mg, 55% dispersion in oil,
1.38 mmol, washed with dry hexane) in THF (2 mL) was added
a solution of the alcohol 26 (175 mg, 0.69 mmol) in 1 mL of
THF, followed by a catalytic amount of imidazole (∼10 mg).
The reaction mixture was heated to 60 °C for 1 h. It was then
cooled to room temperature, and dry CS2 (0.42 mL, 6.9 mmol)
was added and heated to 60 °C for 15 min. It was recooled to
room temperature, MeI (0.42 mL, 6.9 mmol) was added, and
the reaction mixture was refluxed for 3 h. It was then cooled
to room temperature, diluted with 5 mL of water, and
extracted with ether. Evaporation of the solvent and rapid
purification of the product on a short silica gel column using
ethyl acetate-hexane (1:20) as eluent furnished the xanthate
27 (190 mg, 80%). IR: νmax/cm-1 1730, 1283, 1218. 1H NMR
(300 MHz): δ 5.77 (1 H, dd, J ) 9.5 and 3.5 Hz), 3.69 (3 H, s),
2.56 (3 H, s), 2.50-2.30 (2 H, m), 2.05-1.90 (2 H, m), 1.80-
1.60 (2 H, m), 1.50-1.00 (3 H, m), 1.32 (3 H, s), 0.98 (3 H, d,
J ) 7.2 Hz), 0.89 (3 H, d, J ) 6.3 Hz), 0.81 (3 H, d, J ) 6.6
Hz). 13C NMR (75 MHz): δ 215.8 (C), 178.5 (C), 83.1 (CH),
52.1 (CH3), 45.0 (C), 41.9 (CH), 39.8 (CH), 35.6 (CH2), 33.8
(CH), 33.3 (CH), 31.9 (CH), 26.5 (CH3), 22.9 (CH2), 22.1 (CH3),
21.2 (CH3), 19.1 (CH3), 13.2 (CH3). A solution of the xanthate
1
128 °C. [R]22D: -46.9 (c 1.45, CHCl3). IR: νmax/cm-1 1737. H
NMR (300 MHz): δ 3.32 (3 H, s), 3.02 (1 H, d, J ) 3.6 Hz),
2.28 (1 H, d, J ) 18.6 Hz), 2.18 (1 H, br s), 2.04 (1 H, d, J )
18.6 Hz), 2.00-1.75 (2 H, m), 1.65-1.50 (1 H, m), 1.49 (1 H,
dd, J ) 14.5 and 3.5 Hz), 1.35 (1 H, m), 1.22 (1 H, dd, J ) 14.5
and 3.5 Hz), 1.15 (3 H, s), 1.05 (3 H, s), 1.00-0.85 (1 H, m),
0.90 (3 H, d, J ) 6.6 Hz), 0.86 (3 H, d, J ) 6.6 Hz). 13C NMR
(75 MHz): δ 219.6 (C), 89.1 (CH), 59.1 (CH3), 54.3 (CH2), 47.9
(C), 47.3 (CH), 43.4 (CH), 40.4 (C), 38.7 (CH2), 33.0 (CH), 31.3
(CH), 22.4 (CH2), 21.7 (CH3), 21.5 (CH3), 19.7 (CH3), 19.4 (CH3).
Mass: m/z 250 (M+). Anal. Calcd for C16H26O2: C, 76.75; H,
10.47, found C, 76.83; H, 10.66. Reaction of the xanthate 22
(30 mg, 0.08 mmol) with nBu3SnH (0.05 mL, 0.19 mmol) and
a catalytic amount of AIBN (∼5 mg) in refluxing toluene (3
mL) followed by hydrolysis gave exclusively 4-neopupukeanone
10 (13 mg, 73%).
(-)-(1S,3R,6R,7R,9S,10R)-9-Isop r op yl-10-m eth oxy-3,6-
d im eth yltr icyclo[4.3.1.03,7]d eca n -4-on e (23). To a magneti-
cally stirred suspension of NaH (20 mg, 55% dispersion in oil,
0.42 mmol, washed with dry hexane) and tetrabutylammonium
iodide (∼10 mg) in THF (1 mL) was added a solution of the
alcohol 21 (50 mg, 0.18 mmol) in THF (1 mL) and DMF (0.5
mL), and the reaction mixture was stirred for 1 h at room
temperature. To the reaction mixture was then added MeI (0.1
mL, 1.61 mmol) and stirred for 20 h at room temperature. It
was then quenched with a few drops of water and extracted
with ether. Evaporation of the solvent and purification of the
residue on a silica gel column using ethyl acetate-hexane (1:
20) as eluent furnished the methyl ether (25 mg, 48%) as an
oil. [R]22D: -83.3 (c 0.90, CHCl3). 1H NMR (300 MHz): δ 3.90-
3.75 (4 H, m), 3.27 (3 H, s), 2.96 (1 H, d, J ) 4.5 Hz), 2.12 (1
H, m), 1.90-1.65 (3 H, m), 1.82 (1 H, d, J ) 14.1 Hz), 1.70 (1
n
27 (150 mg, 0.44 mmol), Bu3SnH (0.3 mL, 1.12 mmol), and a
catalytic amount of AIBN (∼5 mg) in 10 mL of benzene was
refluxed for 4 h. The reaction mixture was cooled, diluted with
ether, and washed successively with 1% aqueous NH4OH
solution and water. Evaporation of the solvent and purification
of the residue on a silica gel column using ethyl acetate-
hexane (1:20) as eluent furnished the ester 28 (65 mg, 63%)
as an oil. [R]24D: -121.0 (c 1.08, CHCl3). IR: νmax/cm-1 1732.
1H NMR (300 MHz): δ 3.66 (3 H, s), 2.39 (1 H, dd, J ) 14.0
and 2.6 Hz), 1.85-1.65 (2 H, m), 1.65-1.55 (1 H, m), 1.55-
1.35 (3 H, m), 1.26 (3 H, s), 1.30-1.10 (2 H, m), 1.05-0.90 (2

Synthesis of (-)-4-Thiocyanatoneopupukeanane
J . Org. Chem., Vol. 66, No. 12, 2001 4385
H, m), 0.93 (3 H, d, J ) 6.6 Hz), 0.90 (3 H, d, J ) 6.6 Hz), 0.82
(3 H, d, J ) 6.6 Hz). 13C NMR (75 MHz): δ 179.4 (C), 51.8
(CH3), 45.5 (C), 42.7 (CH), 39.2 (CH), 37.1 (CH2), 31.7 (CH),
28.6 (CH), 28.5 (CH2), 28.4 (CH), 26.8 (CH3), 22.8 (CH2), 21.4
(CH3), 21.3 (CH3), 20.4 (CH3). Mass: 238 (M+, C15H26O2).
Further elution of the column with the same solvent gave
methoxy ester 29 (32 mg, 27%) as an oil. [R]24D: -64.2 (c 1.76,
CHCl3). IR: νmax/cm-1 1732. 1H NMR (300 MHz): δ 3.66 (3 H,
s), 3.29 (1 H, dd, J ) 13.2 and 4.5 Hz), 3.27 (3 H, s), 2.28 (1 H,
dd, J ) 14.1 and 2.4 Hz), 2.15 (1 H, m), 1.90-1.60 (4 H, m),
1.40 (1 H, ddd, J ) 13.5, 8.7 and 1.2 Hz), 1.28 (3 H, s), 1.20 (1
H, dd, J ) 14.1 and 4.0 Hz), 1.10-0.90 (1 H, m), 0.95 (3 H, d,
J ) 7.2 Hz), 0.89 (3 H, d, J ) 6.3 Hz), 0.82 (3 H, d, J ) 6.6
Hz). 13C NMR (75 MHz): δ 179.3 (C), 81.0 (CH), 58.3 (CH3),
51.9 (CH3), 45.3 (C), 42.6 (CH), 40.3 (CH), 36.3 (CH2) 33.7 (CH),
32.5 (CH), 30.8 (CH), 26.4 (CH3), 22.4 (CH2), 21.8 (CH3), 21.7
(CH3), 13.1 (CH3). Mass: m/z 268 (M+, C16H28O3). Reaction of
the xanthate 27 (50 mg, 0.14 mmol) with nBu3SnH (0.1 mL,
0.37 mmol) and a catalytic amount of AIBN (∼5 mg) in
refluxing toluene (10 mL) for 4 h furnished the esters 28 (28
mg, 81%) and 29 (6 mg, 15%).
Hz), 1.74 (1 H, ddd, J ) 14.4, 9.9 and 4.5 Hz), 1.66 (1 H, br s),
1.58 (1 H, br s), 1.40 (1 H, d, J ) 15.0 Hz), 1.35-0.80 (7 H,
m), 1.01 (3 H, s), 0.96 (3 H, s), 0.89 (3 H, d, J ) 6.6 Hz), 0.83
(3 H, d, J ) 6.6 Hz). 13C NMR (75 MHz): δ 78.8 (CH), 50.4
(CH2), 46.7 (CH), 44.6 (CH), 42.9 (C), 39.6 (CH2), 38.2 (C), 34.7
(CH2), 31.9 (CH), 27.5 (CH), 26.8 (CH3), 24.5 (CH3), 23.0 (CH2),
21.2 (CH3), 21.0 (CH3). Mass: m/z 222 (M+, C15H26O). To a
magnetically stirred solution of the alcohol 32 (44 mg, 0.19
mmol) in 1 mL of pyridine were added MsCl (0.02 mL, 0.26
mmol) and a catalytic amount of DMAP. The reaction mixture
was stirred for 10 h at room temperature. It was then diluted
with 5 mL of water and extracted with CH2Cl2. The organic
extract was washed successively with 3 N aqueous HCl and
saturated aqueous NaHCO3 solution. Evaporation of the
solvent and purification of the product on a silica gel column
using ethyl acetate-hexane (1:10) as eluent furnished the
mesylate 33 (50 mg, 84%) as a white solid, which was
recrystallized from a mixture of hexane and ether. Mp: 52-
54 °C. [R]22D: -21.0 (c 1.49, CHCl3). IR: νmax/cm-1 1350, 1170.
1H NMR (300 MHz): δ 4.44 (1 H, dd, J ) 9.9 and 6.3 Hz),
3.00 (3 H, s), 2.17 (1 H, dd, J ) 14.4 and 9.9 Hz), 1.95 (1 H,
dd, J ) 13.8 and 3.6 Hz), 1.77 (1 H, ddd, J ) 14.4, 9.9 and 4.5
Hz), 1.68 (1 H, br s), 1.61 (1 H, dd, J ) 14.4 and 6.3 Hz), 1.45
(1 H, d, J ) 14.1 Hz), 1.40-1.10 (4 H, m), 1.10 (3 H, s), 0.99
(3 H, s), 0.95-0.85 (2 H, m), 0.89 (3 H, d, J ) 6.3 Hz), 0.83 (3
H, d, J ) 6.3 Hz). 13C NMR (75 MHz): δ 87.9 (CH), 47.8 (CH2),
45.6 (CH), 44.0 (CH), 43.0 (C), 39.2 (CH2), 38.6 (C), 38.1 (CH3),
35.6 (CH2), 31.9 (CH), 27.1 (CH), 26.5 (CH3), 24.3 (CH3), 22.6
(CH2), 21.1 (CH3), 21.0 (CH3). Mass: m/z 205 (M - OMs). Anal.
Calcd for C16H28O3S: C, 63.96; H, 9.39. Found: C, 64.19; H,
9.76%.
(-)-(1S,3R,6R,7R,9S)-9-Isop r op yl-3,6-d im eth yltr icyclo-
[4.3.1.03,7]d eca n -4-on e (10). A magnetically stirred solution
of the ester 28 (50 mg, 0.21 mmol) in 1 mL of 2 M methanolic
KOH was refluxed for 15 h. It was then cooled, diluted with
water, and washed with CH2Cl2. The aqueous phase was
acidified with 3 N aqueous HCl and extracted with CH2Cl2.
Evaporation of the solvent gave acid 30 (43 mg, 91%). IR: νmax
/
cm-1 1697. 1H NMR (300 MHz): δ 2.37 (1 H, dd, J ) 14.0 and
2.2 Hz), 1.90-1.10 (9 H, m), 1.34 (3 H, s), 1.05-0.95 (2 H, m),
0.96 (3 H, d, J ) 6.6 Hz), 0.91 (3 H, d, J ) 6.3 Hz), 0.83 (3 H,
d, J ) 6.3 Hz). 13C NMR (75 MHz): δ 186.1 (C), 45.5 (C), 42.7
(CH), 39.0 (CH), 36.8 (CH2), 31.7 (CH), 28.6 (CH), 28.54 (CH2),
28.49 (CH), 26.9 (CH3), 22.8 (CH2), 21.4 (CH3), 21.3 (CH3), 20.4
(CH3). To a magnetically stirred solution of the acid 30 (20
mg, 0.09 mmol) in dry benzene (1 mL) was added oxalyl
chloride (0.04 mL, 0.45 mmol). The reaction mixture was
stirred for 2 h at room temperature. Evaporation of benzene
and the excess oxalyl chloride under reduced pressure fur-
nished the acid chloride, which was taken in dry ether (2 mL)
and added, dropwise, to a cold (0 °C) magnetically stirred
solution of diazomethane (5 mL, prepared from 500 mg of
N-nitroso-N-methylurea and 10 mL of 60% aqueous KOH
solution). The reaction mixture was slowly warmed to room
temperature and stirred for 2 h, and the excess diazomethane
and ether were carefully evaporated on a water bath. Rapid
purification of the crude product through a neutral alumina
column using CH2Cl2 as eluent furnished the diazo ketone 31
(12 mg, 54%) as a yellow oil. IR: νmax/cm-1 2094, 1624. To a
magnetically stirred, refluxing solution of rhodium acetate (2
mg) in dry CH2Cl2 (5 mL) was added, dropwise, a solution of
the diazo ketone 31 (12 mg, 0.048 mmol) in CH2Cl2 (1 mL).
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 (1:20) as eluent furnished the
4-neopupukeanone 10 (8 mg, 75%), which exhibited TLC, IR,
(-)-(1S,3R,4R,6R,7R,9S)-4-Th iocya n a t on eop u p u k ea -
n a n e (6). A solution of the mesylate 33 (25 mg, 0.08 mmol)
and KSCN (50 mg, 0.51 mmol) in acetone (1 mL) was placed
in a Carius tube and heated to 80 °C for 5 days. The reaction
mixture was then cooled, diluted with CH2Cl2, and washed
with water. Evaporation of the solvent and purification of the
residue on a silica gel column using ethyl acetate-hexane (1:
40) as eluent furnished 4-thiocyanatoneopupukeanane 6 (6 mg,
27%, 68% based on the starting material consumed) as an oil.
The synthetic sample exhibited spectral data identical to that
of the natural product reported by Scheuer and Higa.5a [R]28
:
D
-117.6 (c 1.08, CHCl3) [lit.5a [R]23D: -120.5 (c 1.44, CHCl3)].
1
IR: νmax/cm-1 2160. H NMR (300 MHz): δ 3.47 (1 H, dd, J )
8.4 and 3.3 Hz), 2.24 (1 H, dd, J ) 15.3 and 8.1 Hz), 1.76 (1 H,
ddd, J ) 14.4, 10.2 and 4.5 Hz), 1.70-1.60 (1 H, m), 1.68 (1 H,
dd, J ) 15.3 and 3.3 Hz), 1.50-1.10 (7 H, m), 1.21 (3 H, s),
1.05 (3 H, s), 0.90-0.80 (1 H, m), 0.90 (3 H, d, J ) 6.6 Hz),
0.81 (3 H, d, J ) 6.6 Hz). 13C NMR (75 MHz): δ 113.8 (C),
60.1 (CH), 50.5 (CH2), 45.7 (CH2), 45.1 (CH), 44.8 (C), 43.1
(CH), 39.1 (C), 37.8 (CH2), 31.8 (CH), 27.8 (CH), 26.7 (CH3),
24.0 (CH3), 22.4 (CH2), 21.0 (2 C, CH3). Mass: m/z 205 (M -
SCN, C15H25). Further elution of the column with ethyl
acetate-hexane (1:10) furnished the unreacted mesylate 33
(15 mg, 60%).
1
and H NMR spectra identical to those of the sample obtained
Ack n ow led gm en t. We thank Professor T. Higa,
University of Ryukyus, and Professor P. J . Scheuer,
University of Hawaii at Manoa for providing the copies
of the 1H and 13C NMR spectra of natural (-)-4-
thiocyanatoneopupukeanane, the Department of Science
and Technology, New Delhi for financial support, and
the Council of Scientific and Industrial Research, New
Delhi, for the award of a research fellowship to SJ G.
earlier.
(-)-(1S,3R,4S,6R,7R,9S)-9-Isop r op yl-3,6-d im et h ylt r i-
cyclo[4.3.1.03,7]d ec-4-yl m eth a n esu lfon a te (33). To a cold
(0 °C), magnetically stirred solution of the ketone 10 (48 mg,
0.22 mmol) in 1 mL of MeOH was added NaBH4 (10 mg, 0.26
mmol). The reaction mixture was stirred for 15 min at the
same temperature, and then solvent was evaporated under
reduced pressure. It was then diluted with water and extracted
with ether. Evaporation of the solvent and purification of the
product on a silica gel column using ethyl acetate-hexane (1:
10) as eluent furnished the alcohol 32 (44 mg, 91%). Mp: 57-
59 °C. [R]27D: -66.1 (c 1.12, CHCl3). IR: νmax/cm-1 3360. 1H
NMR (300 MHz): δ 3.62 (1 H, dd, J ) 9.9 and 6.6 Hz), 2.03 (1
H, dd, J ) 13.8 and 9.9 Hz), 1.91 (1 H, dd, J ) 13.8 and 3.5
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 21 and 28. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0102765