Enantiospecific total synthesis of both enantiomers of 2-thiocyanatoneopupukeanane from (R)-carvone

Article abstract of DOI:10.1039/b005943i

Enantiospecific total synthesis of both enantiomers of 2-thiocyanatoneopupukeanane from (R)-carvone, employing an intramolecular rhodium carbenoid C-H insertion reaction as the key step, was discussed. Reduction of ketone using either sodium borohydride o

Full text of DOI:10.1039/b005943i

View Article Online / Journal Homepage / Table of Contents for this issue
Enantiospecific total synthesis of both enantiomers
of 2-thiocyanatoneopupukeanane from (R)-carvone
A. Srikrishna* and Santosh J. Gharpure
1
The readily available4 isotwistane dione 4 was chosen as
the requisite starting material. It was readily identified that for
the generation of 2-thiocyanatoneopupukeanane 1b, the
isopropenyl group in the isotwistane dione 4 needs to be epi-
merised. As isomerisation to the isopropylidene group and
hydrogenation sequence was unsuccessful, we resorted to the
conversion of the isopropenyl group into an acetyl group. The
synthetic sequence is depicted in Scheme 1. Thus, ozonolysis of
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received (in Cambridge, UK) 24th July 2000, Accepted 18th August 2000
First published as an Advance Article on the web 6th September 2000
Enantiospecific synthesis of both enantiomers of the
marine sesquiterpene 2-thiocyanatoneopupukeanane
starting from (R)-carvone, employing an intramolecular
rhodium carbenoid C–H insertion reaction as the key step,
is described.
from the sponge Ciocalypta sp.,3 is the presence of a unique 9-
isopropyl-3,6-dimethyltricyclo[4.3.1.03,7]decane carbon frame-
work (an isotwistane) incorporating two quaternary carbon
atoms and the presence of a rare thiocyanate functionality
making them challenging synthetic targets. In 1998, we accom-
plished the first synthesis of a neopupukeanane 4 based on
a rhodium carbenoid C–H insertion reaction,4 and herein,
we describe the first enantiospecific total synthesis of both
enantiomers of 2-thiocyanatoneopupukeanane 1b starting
from (R)-carvone 5.
In 1991, the research groups of Scheuer and Higa reported the
isolation of two sesquiterpene thiocyanates, 2-thiocyanatoneo-
pupukeanane 1a from the sponge Phycopsis terpnis (from
Okinawa) and 4-thiocyanatoneopupukeanane
2 from an
unidentified species from Pohnpei.1 Subsequently,2 Faulkner
et al. have reported the isolation of 2-thiocyanatopupukeanane
3 from the sponge Axinyssa aplysinoides along with 2-thio-
cyanatoneopupukeanane, which was identical to that reported
by Scheuer and Higa, and established its stereostructure as endo
isomer 1b on the basis of 2D NMR studies. A characteristic of
the structure of these neopupukeananes, whose first member
9-isocyanoneopupukeanane was reported by Scheuer et al.
Scheme 1 Reagents, conditions and yields: (a) i. O3–O2,CH2Cl2–MeOH (5:1), Ϫ70 ЊC; ii. Me2S, rt, 12 h, 95%; (b) DBU, C6H6, rt, 4 h 85%, 1:1; (c) Zn,
TiCl4, CH2Br2, THF, CH2Cl2, rt, 4 h, 60% (80% conversion); (d) H2 (1 atm), 10% Pt/C, EtOH, 4 h, 96%; (e) HS(CH2)2SH, BF3ؒEt2O, C6H6, 0 ЊC to rt,
8 h, 80%; (f) Raney Ni, EtOH, reflux, 12 h, 85%; (g) DIBAL-H, PhMe, Ϫ78 ЊC, 1 h, 95%; (h) Li, liq. NH3, Ϫ78 ЊC, 0.5 h, 85%; (i) MsCl, Py, DMAP,
10 h; (j) NH4SCN, BnNEt3Cl, THF, reflux, 4 h, 75% (2 steps), 1b:14 1:4.
DOI: 10.1039/b005943i
J. Chem. Soc., Perkin Trans. 1, 2000, 3191–3193
This journal is © The Royal Society of Chemistry 2000
3191

View Article Online
Scheme 2 Reagents, conditions and yields: (a) H2 (1 atm), (Ph3P)3RhCl, C6H6, 5 d, 100%; (b) LiHMDS, H2C᎐C(Me)COOMe, Ϫ78 ЊC–rt, 55%,
᎐
16:17 3:1; (c) i. 5% NaOH, MeOH–H2O (1:1), reflux, 12 h, 95%; ii. (COCl)2, C6H6, rt, 2 h; iii. CH2N2, Et2O, 0 ЊC, 2 h; iv. Rh2(OAc)4, CH2Cl2, reflux,
2 h, 65%, 20:9 3:1; (d) i. NaBH4, MeOH, 0 ЊC, 15 min; ii. silica gel chromatography; (e) PCC, silica gel, CH2Cl2, rt, 2 h, 95%.
the dione 4 furnished the trione 6. 1,8-Diazabicyclo[5.4.0]-
undec-7-ene (DBU) catalysed isomerisation of the trione 6
furnished a ~1:1 mixture of the triones 6 and 7,† which were
separated by silica gel column chromatography. As the
attempted Wittig methylenation of the trione 7 furnished a mix-
ture of the diones 4 and 8, obviously via equilibration of 7
during the Wittig reaction, the methylene group was introduced
using Lombardo’s procedure.5 Consequently, reaction of the
trione 7 with titanium tetrachloride, methylene bromide and
zinc generated the isopropenyl compound 8, mp 71–72 ЊC, [α]D26
Ϫ34 (c 1, CHCl3), in a regiospecific manner, which on hydro-
genation using 10% Pt/C as the catalyst furnished neo-
pupukeanane-2,5-dione (Ϫ)-9.† The less hindered C-5 ketone
was deoxygenated via its thioketal. Reaction of the dione 9 with
ethane-1,2-dithiol in the presence of boron trifluoride–diethyl
ether generated the thioketal (Ϫ)-10, which on treatment with
Raney Ni in refluxing ethanol furnished neopupukeanan-2-one
(Ϫ)-11.† Reduction of the ketone 11 using either sodium boro-
hydride or lithium aluminium hydride furnished a mixture of
the exo and endo alcohols 12a,b. On the other hand, reduction
of the ketone 11 using lithium in liquid ammonia conditions
furnished exclusively the endo isomer 12b.† Reduction of the
ketone 11, however, using diisobutylaluminium hydride fur-
nished predominantly the exo alcohol 12a† along with minor
amounts of the endo alcohol. Treatment of the alcohol 12a with
methanesulfonyl chloride in pyridine in the presence of a
catalytic amount of 4-(N,N-dimethylamino)pyridine (DMAP)
furnished the mesylate 13a, which was found to be unstable.
Reaction of the mesylate 13a with ammonium thiocyanate in
the presence of a catalytic amount of benzyltriethylammonium
chloride in refluxing THF furnished 2-thiocyanatoneo-
pupukeanane (ϩ)-1b, [α]D23 65 (c 0.6, CHCl3), along with the
rearranged eliminated compound 14. The synthetic sample of
(ϩ)-1b, contaminated with trace amounts of its epimer, was
found to be the antipode of the natural 2-thiocyanatoneo-
pupukeanane and exhibited the 1H and 13C NMR spectral data
identical to that of the natural product.1,2 It is worth noting that
the replacement of the mesylate by a thiocyanato group
proceeded via an SN1 mechanism. This was established by the
reaction of the epimeric mesylate 13b, obtained from the alco-
hol 12b, with ammonium thiocyanate, which also furnished the
same mixture of 1b and 14.
hydrolysis of the ester, formation of the corresponding acid
chloride and reaction with ethereal diazomethane. Rhodium
acetate catalysed intramolecular C–H insertion of the diazo
ketones 18 and 19 in refluxing methylene chloride furnished a
~3:1 mixture of the neopupukeananediones 20 and 9. Treat-
ment of a mixture of the diones 20 and 9 with sodium boro-
hydride furnished a mixture of the ketol 21 and the diol 22,
which were separated by silica gel column chromatography.
Oxidation of the ketol 21 with pyridinium chlorochromate
(PCC) and silica gel furnished the dione (Ϫ)-20, which was
found to be identical to the compound obtained by hydrogen-
ation of the dione 4 in all respects. Similarly, oxidation of the
diol 22 furnished the dione (ϩ)-9, [α]D23 16.7 (c 1, CHCl3), which
exhibited IR, 1H and 13C NMR spectra identical to its enantio-
mer obtained via the dione 4. Repetition of the same sequence
of reactions on (ϩ)-9 furnished the natural enantiomer of
2-thiocyanatoneopupukeanane (Ϫ)-1b, via 2-neopupukeanone
(ϩ)-11, [α]D23 24.4 (c 1.3, CHCl3).
In conclusion, we have accomplished the first enantiospecific
synthesis of both enantiomers of the marine sesquiterpene
2-thiocyanatoneopupukeanane starting from a single enantio-
mer of carvone, employing an intramolecular rhodium
carbenoid C–H insertion as the key reaction.
Acknowledgements
We thank Professors T. Higa of Ryukyus University and D. J.
Faulkner of University of California for providing the copies
of the spectra of the natural 2-thiocyanatoneopupukeanane.
We are grateful to the Council of Scientific and Industrial
Research for the award of a research fellowship to S. J. G.
Notes and references
† All the compounds exhibited spectral data consistent with their struc-
tures. Selected spectral data for the trione 6: mp 76–78 ЊC. [α]D26 Ϫ78.3
(c 1.15, CHCl3). νmax/cmϪ1 1735, 1720, 1700. δH (300 MHz, CDCl3
ϩ CCl4) 2.91 (1 H, t of d, J 8.1 and 3.0 Hz), 2.60–2.45 (2 H, m), 2.37
(1 H, d, J 18.9 Hz), 2.13 (3 H, s, COCH3), 2.02 (1 H, d, J 18.9 Hz), 1.95–
1.70 (2 H, m), 1.82 (1 H, d, J 14.7 Hz), 1.54 (1 H, d, J 14.4 Hz), 1.22
(3 H, s), 1.16 (3 H, s). δC (75 MHz, CDCl3 ϩ CCl4) 216.2 (C), 215.2 (C),
205.9 (C), 51.5 (CH), 51.2 (C), 48.8 (CH), 48.3 (C), 47.8 (CH2), 44.9
(CH), 34.0 (CH2), 28.0 (CH3), 19.6 (CH3), 18.0 (CH3), 15.5 (CH2). m/z:
234 (Mϩ, 48%). For the trione 7: mp 102–104 ЊC. [α]D25 30.8 (c 0.91,
CHCl3). νmax/cmϪ1 1735, 1720, 1700. δH (300 MHz, CDCl3 ϩ CCl4) 2.96
(1 H, dd, J 10.8 and 6.9 Hz), 2.59 (1 H, br s), 2.50–2.40 (1 H, m), 2.44
(1 H, d, J 18.6 Hz), 2.19 (3 H, s, COCH3), 2.10 (1 H, d, J 18.6 Hz), 1.95–
1.80 (2 H, m), 1.52 (1 H, d, J 15.0 Hz), 1.45 (1 H, d, J 15.0 Hz), 1.33
(3 H, s), 1.18 (3 H, s). δC (75 MHz, CDCl3 ϩ CCl4) 216.2 (C), 215.7 (C),
204.9 (C), 50.4 (C), 49.0 (CH), 48.9 (C), 47.7 (CH2), 47.3 (CH), 44.0
(CH), 28.4 (CH3), 27.8 (CH2), 19.0 (CH3), 18.9 (CH3), 15.5 (CH2). m/z:
234 (Mϩ, 100%). For the neopupukeananedione 9: mp 93–95 ЊC. [α]D23
Ϫ15.6 (c 1.8, CHCl3). νmax/cmϪ1 1735, 1710. δH (300 MHz,
CDCl3 ϩ CCl4) 2.40 (1 H, d, J 18.6 Hz), 2.35–2.30 (1 H, m), 2.20–2.10
For the generation of the natural enantiomer of 2-thio-
cyanatoneopupukeanane (Ϫ)-1b, dihydrocarvone 15 was
chosen as the starting material (Scheme 2). Wu and co-workers
have reported that the reaction of the enone 15 with LiHMDS
and methyl methacrylate provides a 3:1 mixture of the bicyclic
compounds 16 and 17 via the approach of methacrylate from
the anti and syn faces of the isopropyl group, respectively, dur-
ing a Michael–Michael reaction.6 As the isomers were not easily
separable, the sequence was carried out with a mixture of 16
and 17. Consequently, the esters 16 and 17 were transformed
into the diazo ketones 18 and 19, via a standard sequence, i.e.
3192
J. Chem. Soc., Perkin Trans. 1, 2000, 3191–3193

View Article Online
J 14.4, 11.0 and 3.5 Hz), 1.55–1.25 (8 H, m), 1.20–0.95 (1 H, m), 1.17
(1 H, ddd, J 14.4, 5.7 and 2.7 Hz), 1.06 (3 H, s), 1.00 (3 H, s), 0.92 (3 H,
d, J 6.6 Hz), 0.82 (3 H, d, J 6.3 Hz), 0.95–0.85 (1 H, m). δC (75 MHz,
CDCl3 ϩ CCl4) 81.1 (CH), 51.0 (CH), 45.8 (C), 43.2 (CH), 41.4 (CH2),
39.7 (C), 36.7 (CH), 32.3 (CH2), 31.7 (CH), 29.5 (CH2), 26.7 (CH3), 26.6
(CH3), 22.4 (CH2), 21.4 (CH3), 21.2 (CH3). m/z: 222 (Mϩ, 4%).
(1 H, m), 2.04 (1 H, d, J 18.6 Hz), 1.82 (1 H, m), 1.70–1.35 (5 H, m),
1.30 (3 H, s), 1.14 (3 H, s), 0.98 (3 H, d, J 6.6 Hz), 0.88 (3 H, d, J 6.6
Hz). δC (75 MHz, CDCl3 ϩ CCl4) 218.1 (C), 217.6 (C), 50.2 (C), 49.5
(CH), 49.2 (C), 48.0 (CH2), 44.6 (CH), 41.6 (CH), 30.9 (CH), 27.1
(CH2), 22.2 (CH2), 20.9 (CH3), 20.8 (CH3), 19.4 (CH3), 18.9 (CH3). m/z:
234 (Mϩ, 54%). For 2-neopupukeanone 11: [α]D23 Ϫ24.6 (c 2.4, CHCl3).
νmax/cmϪ1 1720. δH (300 MHz, CDCl3 ϩ CCl4) 2.25–2.15 (1 H, m), 1.86
(1 H, ddd, J 14.4, 10.8 and 4.8 Hz), 1.80–1.15 (10 H, m), 1.12 (6 H, s),
0.92 (3 H, d, J 6.6 Hz), 0.84 (3 H, d, J 6.6 Hz). δC (75 MHz,
CDCl3 ϩ CCl4) 221.4 (C), 54.7 (C), 51.9 (CH), 45.0 (CH), 41.6 (CH),
40.4 (C), 40.2 (CH2), 35.3 (CH2), 33.0 (CH2), 31.1 (CH), 26.5 (CH3),
22.5 (CH2), 21.2 (CH3), 21.1 (CH3), 19.6 (CH3). m/z: 220 (Mϩ, 11%).
For the exo alcohol 12a: νmax/cmϪ1 3380. δH (300 MHz, CDCl3 ϩ CCl4)
3.51 (1 H, d, J 3.7 Hz), 1.75 (1 H, ddd, J 14.2, 10.2 and 4.1 Hz), 1.70–
1.65 (1 H, m), 1.55–0.80 (11 H, m), 1.03 (3 H, s), 1.00 (3 H, s), 0.93 (3 H,
d, J 6.3 Hz), 0.82 (3 H, d, J 6.3 Hz). δC (75 MHz, CDCl3 ϩ CCl4) 79.0
(CH), 49.6 (CH), 44.5 (C), 41.0 (CH2), 40.5 (CH2), 39.7 (C), 36.5 (CH2),
35.3 (CH), 32.8 (CH), 31.3 (CH), 26.8 (CH3), 22.3 (CH2), 21.5 (CH3),
21.2 (CH3), 19.5 (CH3). m/z: 222 (Mϩ, 3%). For the endo alcohol 12b:
[α]D24 43.2 (c 0.9, CHCl3). νmax/cmϪ1 3340. δH (300 MHz, CDCl3 ϩ CCl4)
3.36 (1 H, br s), 2.09 (1 H, ddd, J 14.0, 9.0 and 5.0 Hz), 1.68 (1 H, ddd,
1 A. T. Pham, T. Ichiba, W. Y. Yoshida, P. J. Scheuer, T. Uchida, J.-i.
Tanaka and T. Higa, Tetrahedron Lett., 1991, 32, 4843.
2 H.-y. He, J. Salva, R. F. Catalos and D. J. Faulkner, J. Org. Chem.,
1992, 57, 3191.
3 P. Karuso, A. Poiner and P. J. Scheuer, J. Org. Chem., 1989, 54, 2095.
4 A. Srikrishna and S. J. Gharpure, Chem. Commun., 1998, 1589. For
the first enantiospecific synthesis of (Ϫ)-4-thiocyanatoneo-
pupukeanane employing an intramolecular cyclopropanation as the
key reaction, see: A. Srikrishna and S. J. Gharpure, Tetrahedron Lett.,
1999, 40, 1035.
5 L. Lombardo, Tetrahedron Lett., 1982, 23, 4293; S. H. Pine, in Organic
Reactions, ed. L. A. Paquette, 1993, vol. 43, p. 1.
6 R.-B. Zhao, Y.-F. Zhao, G.-Q. Song and Y.-L. Wu, Tetrahedron Lett.,
1990, 31, 3559.
J. Chem. Soc., Perkin Trans. 1, 2000, 3191–3193
3193