A bioinspired approach to Tri-nor-guaianes. Synthesis of (-)-clavukerin A

Article abstract of DOI:10.1021/np060184g

A bioinspired approach to tri-nor-guaianes by degradation of the C-7 side chain of related guaia-11-enes is described. In this approach (-)-clavukerin A (1) is obtained by selective ozonolysis-Criegge rearrangement of (+)-1α H,7αff,10αH-guaia-4,11-dien-3-one (4) to afford 7β-hydroxy and 7β-acetoxy tri-nor-guaiane derivatives 6 and 7, respectively, which after elimination and deoxygenation give the title compound. The starting guaiadienone is readly obtained from commercially available santonin or (+)-dihydrocarvone.

Full text of DOI:10.1021/np060184g

1234
J. Nat. Prod. 2006, 69, 1234-1236
A Bioinspired Approach to Tri-nor-guaianes. Synthesis of (-)-Clavukerin A
Gonzalo Blay, Begon˜a Garc´ıa, Eva Molina, and Jose´ R. Pedro*
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica, UniVersitat de Vale`ncia, Dr. Moliner 50, E-46100, Burjassot, Vale`ncia, Spain
ReceiVed April 26, 2006
A bioinspired approach to tri-nor-guaianes by degradation of the C-7 side chain of related guaia-11-enes is described.
In this approach (-)-clavukerin A (1) is obtained by selective ozonolysis-Criegge rearrangement of (+)-1RH,7RH,10RH-
guaia-4,11-dien-3-one (4) to afford 7â-hydroxy and 7â-acetoxy tri-nor-guaiane derivatives 6 and 7, respectively, which
after elimination and deoxygenation give the title compound. The starting guaiadienone is readly obtained from
commercially available santonin or (+)-dihydrocarvone.
Natural tri-nor-guaianes are rare metabolites that have been
isolated from terrestrial as well as marine sources.1 One of their
most representative members is (-)-clavukerin A (1), an unstable
diene isolated from the Okinawan soft coral ClaVularia koellikeri
(stolonifer) by Kitagawa and co-workers.2 Its structure was assigned
as shown on the basis of spectral, chemical, and X-ray crystal-
lographic analysis of its diepoxide, and its absolute configuration
was also proposed following a CD study.2 Bowden and co-workers
reported the isolation of a terpenoid from an Australian soft coral
Cespitularia sp.,3a which was later identified as 1.3b The terpenoid
origin of tri-nor-guaianes has been confirmed by Takeda and Katoh
on the biosynthesis of 3,10-dihydro-1,4-dimethylazulene in cultured
cells of Calypogeia granulate (liverwort)4a and by Dai and
co-workers in the biosynthesis of 1 in a Heteroxenia sp.4b Their
formation is presumably closely related to guaiane biosynthesis with
loss of the isopropyl side chain at an unknown stage of the
biosynthetic pathway.2b,4 The syntheses of 13b,5,6 and other tri-nor-
guaianes7 have been challenging due to the difficulties of construc-
tion of the perhydroazulene framework with appropriate function-
alization and configuration. Several total syntheses of clavukerin
A (1), in racemic5 as well as in enantiomeric pure form,3b,6 have
been reported. Two general strategies have been used for the
synthesis of its carbon framework: either starting from a suitable
cycloheptane derivative and further construction of the five-
membered ring3b,5a,8 or starting from a cyclopentane derivative
followed by construction of the seven-membered ring.5b,6 However,
no biomimetic syntheses of tri-nor-guaianes via degradation of the
isopropenyl side chain of guaianes have been reported. De Groot’s
group9 has reported the formation of tri-nor-guaiadiene 3 in 20%
yield when R-epoxyisoledene was treated with TsOH‚H2O in
acetone at room temperature. Its formation was explained by acetone
elimination from allylic carbocation 2. Herein we report a bio-
inspired approach to the synthesis of (-)-clavukerin A (1) from
guaiadienone 4 via degradation of the isopropenyl side chain.
Compound 4 has been reported in Baccharis boliViensis10a and
Wikstroemia lanceolada10b and is readily available from santonin11b
or (+)-dihydrocarvone.11a
in 92% yield for the two steps. The elimination of acetate 7 was
achieved with p-TsOH-SiO2 in benzene14 at 60 °C (bath temper-
ature) for 6 h. From the 1H NMR spectrum starting material 7 and
Scheme 1. Synthesis of (-)-Clavukerin A (1)a
Removal of the isopropenyl side chain of 4 was carried out by
Schreiber and Liew’s method.12 Guaiadienone 4 (Scheme 1) was
treated with O3 in CH2Cl2-MeOH to give a monomethoxy
hydroperoxide, which was acetylated in situ to obtain compound
5. Criegge rearrangement12,13 afforded tri-nor-guaiane derivatives
6 (48%) and 7 (28%) and methyl ketone 8 (17%). A â-disposition
for the oxygenated function at C-7 of 6 and 7 was established by
the positive NOE between H-7 and H-1 in 7. Dehydration of
compound 6 was carried out by treatment of 6 with MsCl-Et3N
followed by elimination (Li2CO3, DMF, 100 °C) to give dienone 9
a Reagents and conditions: (a) (i) O3, CH2Cl2-MeOH, -78 °C, (ii) Ac2O,
Et3N, DMAP, rt; (b) CH2Cl2-MeOH, 60 °C, 48% 6 + 28% 7 + 17% 8; (c) (i)
MsCl, Et3N, CH2Cl2, 0 °C f rt 100%; (ii) Li2CO3, DMF, 100 °C, 92%; (d)
p-TsOH-SiO2, benzene, 60 °C, 70% 9 + 12% 7; (f) LiAlH4-AlCl3, Et2O, -20
°C, 45%.
* Corresponding author. Phone: +34-96-3544329. Fax: +34-96-
3544328. E-mail: Jose.R.Pedro@uv.es.
10.1021/np060184g CCC: $33.50
© 2006 American Chemical Society and American Society of Pharmacognosy
Published on Web 07/15/2006

Notes
Journal of Natural Products, 2006, Vol. 69, No. 8 1235
(100), 161 (17), 137 (30); HRMS (EI) calcd for C14H20O3 [M+•
236.1412, found 236.1409.
(+)-7â-Acetyl-1rH,10rH-tri-nor-guai-4-en-3-one (8): colorless oil;
]
tri-nor-guaiadienone 9 and its diastereomer 10 were detected in a
7.5:1 ratio.15 Column chromatography separated compounds 7
(12%) and 9 (70%). Compound 9 was thus obtained in 63% yield
from compound 4. One-step deoxygenation of tri-nor-guaiadienone
[R]D +128.8 (c 0.74, CHCl3); IR (NaCl) νmax 1684, 1623 cm-1; H
NMR (300 MHz, CDCl3) δ 3.06-3.00 (1H, m, H-1), 2.88 (1H, br d,
J ) 19.4 Hz, H-6), 2.72 (1H, br t, J ) 11.7 Hz, H-7), 2.60-2.44 (2H,
m, H-2, H-6′), 2.20 (3H, s, CH3CO), 2.16-2.08 (1H, m, H-10), 2.06-
1.82 (3H, m, H-2′, H-8, H-9), 1.74 (tt, J ) 3.4, 17.3 Hz, H-9′), 1.64
(3H, d, J ) 1.5 Hz, 3 H-15), 1.60-1.40 (1H, m, H-8′), 0.62 (3H, d, J
) 7.1 Hz, 3 H-14); 13C NMR (75 MHz, CDCl3) δ 210.5, 207.8, 172.8,
138.4 (C), 50.3, 45.9 (CH), 41.1, 36.4 (CH2), 35.1 (CH), 33.5 (CH2),
28.2 (CH3), 27.7 (CH2), 11.9, 7.9 (CH3); EIMS m/z 220 (M+•, 100),
205 (13), 177 (44), 163 (17), 110 (17), 107 (19); HRMS (EI) m/z calcd
for C14H20O2 [M+•] 220.1463, found 220.1474.
24
1
16
9 with LiAlH4-AlCl3 at -20 °C afforded compound 1 in 45%
yield, as a colorless unstable oil and having the same physical and
spectroscopic features as (-)-clavukerin A from C. koellikeri.2
In summary, we have developed a bioinspired approach to tri-
nor-guaianes through degradation of the isopropenyl side chain of
guai-11-enes by tandem selective ozonolysis-Criegge rearrange-
ment, which introduces oxygenation at C-7. Elimination of that
oxygenated function and deoxygenation of the C-3 carbonyl group
afforded (-)-clavukerin A (1) from guaiadienone 4 in three steps
and 29% yield.
(-)-1rH,10rH-Tri-nor-guaia-4,6-dien-3-one (9). From Alcohol
6. To a solution of compound 6 (31 mg, 0.160 mmol) in CH2Cl2 (1
mL) at 0 °C under argon were added 134 µL (0.954 mmol) of Et3N
and 57 µL (0.699 mmol) of MsCl. The resulting mixture was stirred at
0 °C for 40 min and then was allowed to warm to room temperature
for 45 min. Then, the solution was acidified to pH 1 with 10% aqueous
HCl, diluted with EtOAc, washed with aqueous saturated NaHCO3 and
brine, and dried (MgSO4) Evaporation of solvents in vacuo afforded a
colorless oil (43 mg, 100%).
Experimental Section
General Experimental Procedures. Compound 4 was obtained
following the procedure described by us.11a All reactions involving air-
or moisture-sensitive materials were carried out under argon atmosphere.
Commercial reagents and solvents were analytical grade or were purified
by standard procedures prior to use. Melting points were recorded on
a Bu¨chi B-545 digital melting point apparatus and are uncorrected.
Optical rotations were measured with a Perkin-Elmer 243 apparatus in
CHCl3 using sodium light (D line, 589 nm). IR spectra were recorded
as liquid films in NaCl for oils and as KBr disks for solids. NMR spectra
were run in CDCl3, and for compound 1 the solvent was filtered through
basic alumina prior to use. The spectra were recorded at 300 or 400
MHz for 1H and at 75 or 100 MHz for 13C and referenced to the solvent
as internal standard. Carbon types were assigned by DEPT experiments.
1H-1H decoupling and NOE experiments were used in selected cases
to aid assignment. Low- and high-resolution mass spectra were recorded
on an Autospec GC 8000 apparatus. Reactions were monitored by TLC
analysis using Merck silica gel 60 F-254 thin-layer plates. Flash column
chromatography was performed on Merk silica gel 60, 0.040-0.063
mm.
A mixture of the crude oil and Li2CO3 (100 mg, 1.325 mmol) in
DMF (4 mL) under argon was heated at 100 °C (bath temperature) for
22 h. Then, the reaction was quenched with saturated aqueous NH4Cl,
and the mixture was diluted with H2O and extracted with EtOAc as
usual. The combined organic layers were washed with brine and dried
(MgSO4), and the solvent was removed in vacuo to give 26 mg (92%)
of tri-nor-guaiadienone 9: white crystals, mp 34-36 °C (hexanes-
EtOAc); [R]D24 -337 (c 1.36, CHCl3); IR (KBr) νmax 3080, 1695, 1634
cm-1; 1H NMR (400 MHz, CDCl3) δ 6.48 (1H, br d, J ) 12 Hz, H-6),
6.15 (1H, ddd, J ) 4.1, 6.2, 12.1 H, H-7), 3.06-3.02 (1H, m, H-1),
2.55 (1H, dd, J ) 6.8, 18.8 Hz, H-2), 2.52-2.42 (1H, m, H-8), 2.41-
2.30 (1H, m, H-8′), 2.20 (1H, dd, J ) 2.8, 18.8 Hz, H-2′), 2.22-2.12
(1H, m, H-10), 1.96-1.78 (2H, m, 2 H-9), 1.75 (3H, d, J ) 1.6 Hz, 3
H-15), 0.71 (3H, d, J ) 6.8 Hz, 3 H-14); 13C NMR (75 MHz, CDCl3)
δ 209.0, 166.8 (C), 140.3 (CH), 137.5 (C), 124.7, 46.6 (CH), 39.7,
34.2 (CH2), 33.2 (CH), 27.0 (CH2), 11.2, 8.1 (CH3); EIMS m/z 176
(M+•, 100), 161 (22), 147 (13), 133 (29), 105 (32), 91 (47); HRMS
(EI) m/z calcd for C12H16O [M+•] 176.1201, found 176.1193.
From Acetate 7. To a solution of compound 7 (42 mg, 0.178 mmol)
in benzene (3.62 mL) was added 268 mg of p-TsOH-SiO2,14 and the
mixture was heated at 60 °C under argon for 6 h. Flash chromatography
on silica gel eluting with hexanes-EtOAc (95:5 to 6:4) separated 5
mg (12%) of starting material 7 and 22 mg (70%) of dienone 9 with
physical and spectroscopic features identical to the dienone obtained
from alcohol 6.
Ozonolysis-Criegge Rearrangement of Guaiadienone 4. Through
a solution of compound 4 (100 mg, 0.459 mmol) in CH2Cl2-MeOH
(5:1, 8.4 mL) was bubbled O3 at -78 °C until disappearance of the
starting material (54 min). The solution was purged with argon, and
Ac2O (2.28 mL, 24.16 mmol), Et3N (2.28 mL, 16.36 mmol), and DMAP
(17 mg, 0.140 mmol) were added via syringe. The resulting solution
was stirred at room temperature for 19 h, diluted with EtOAc, and
washed with 2 N aqueous HCl, saturated aqueous NaHCO3, and brine,
and the organic layer was dried over anhydrous MgSO4. Removal of
the solvent afforded an oil, which was diluted with CH2Cl2-MeOH
(5:1, 10 mL) and stirred at reflux for 2 h 30 min and then concentrated
in vacuo. Flash column chromatography (hexanes-EtOAc, 9:1 to 5:5)
of the crude residue separated 17 mg (17%) of methyl ketone 8, 30
mg (28%) of acetate 7, and 43 mg (48%) of alcohol 6.
(-)-1rH,10rH-Tri-nor-guaia-4,6-diene [(-)-clavukerin A] (1). A
solution of AlCl3 (758 mg, 5.675 mmol) in Et2O (1 mL) at 0 °C was
added to a suspension of LiAlH4 (48 mg, 1.261 mmol) in Et2O (3.3
mL) at 0 °C and stirred until bubbling stopped. The mixture was cooled
at -20 °C, and a solution of compound 9 (37 mg, 0.210 mmol) in
Et2O (1 mL) was added via syringe. After 9 min the reaction was
quenched with ice and extracted with Et2O, washed with brine, and
dried over MgSO4. Removal of the solvent gave an oil, which was
chromatographed on silica gel (pentane) to afford 15.4 mg (45%) of
an unstable, colorless, volatile oil, which was identified as (-)-
(+)-7â-Hydroxy-1rH,10rH-tri-nor-guai-4-en-3-one (6): colorless
24
oil; [R]D +98.3 (c 1.75, CHCl3); IR (NaCl) νmax 3500-3250, 1694,
1
1622, 1037 cm-1; H NMR (400 MHz, CDCl3) δ 4.08-3.94 (1H, m,
H-7), 2.94 (1H, br d, J ) 19.2 Hz, H-6), 2.91 (1H, br s, H-1), 2.60
(1H, br dd, J ) 10.5, 18.6 Hz, H-6′), 2.54 (1H, dd, J ) 7.2, 18.3 Hz,
H-2), 2.12-2.05 (1H, m, H-10), 2.02 (1H, br d, J ) 18.4 Hz, H-2′),
1.45-1.86 (1H, m, H-8), 1.86-1.75 (1H, m, H-8′), 1.75-1.68 (2H,
m, 2 H-9), 1.66 (3H, br s, 3 H-15), 0.70 (3H, d, J ) 6.9 Hz, 3 H-14);
13C NMR (75 MHz, CDCl3) δ 208.1, 171.2, 138.5 (C), 70.0, 46.4 (CH),
40.7, 40.5, 35.7 (CH2), 34.7 (CH), 32.2 (CH2), 12.9, 8.0 (CH3); EIMS
m/z 194 (M+•, 44), 176 (8), 166 (18), 137 (100), 110 (61); HRMS (EI)
calcd for C12H18O2 [M+•] 194.1307, found 194.1306.
24
20
clavukerin A (1): [R]
-43.3 (c 0.09, CHCl3) [lit.2a [R]D -53 (c
D
0.30, CHCl3)]; IR (NaCl) νmax 1660, 1600 cm-1; 1H NMR (400 MHz,
CDCl3) δ 6.21 (1H, br d, J ) 12.0 Hz, H-6), 5.54 (1H, dt, J ) 4.9,
12.4 Hz, H-7), 2.84-2.81 (1H, m, H-1), 2.37-2.14 (4H, m, 2 H-3, 2
H-8), 2.00-1.82 (2H, m), 1.73 (3H, s, 3 H-15), 1.82-1.47 (3H, m),
0.75 (3H, d, J ) 6.8 Hz, 3 H-14); 13C NMR (75 MHz, CDCl3) δ 138.8,
134.9 (C), 128.8, 123.7 (CH), 54.5 (CH), 37.8, 34.4 (CH2), 34.2 (CH),
27.2, 26.7 (CH2), 14.5, 11.4 (CH3); EIMS (EI) m/z 162 (M+•, 100),
147 (76), 133 (31), 119 (37), 105 (76); HRMS (EI) m/z calcd for C12H18
[M+•] 162.1408, found 162.1417.
(+)-7â-Acetoxy-1rH,10rH-tri-nor-guai-4-en-3-one (7): colorless
oil; [R]D24 +151.5 (c 1.30, CHCl3); IR (NaCl) νmax 1740, 1700, 1641,
1
1249 cm-1; H NMR (300 MHz, CDCl3) δ 5.08-4.94 (1H, m, H-7),
3.02-2.94 (1H, m, H-1), 2.90 (1H, br d, J ) 18.4 Hz, H-6), 2.66 (1H,
br dd, J ) 11.0, 18.2 Hz, H-6′), 2.54 (1H, dd, J ) 6.6, 18.6 Hz, H-2),
2.16-1.90 (2H, m, H-2′, H-10), 2.04 (3H, s, CH3CO), 1.92-1.74 (2H,
m, 2 H-8), 1.74-1.66 (2H, m, 2 H-9), 1.64 (3H, br s, 3 H-15), 0.69
(3H, d, J ) 7.2 Hz, 3 H-14); 13C NMR (75 MHz, CDCl3) δ 207.7,
170.1, 169.4, 138.9 (C), 72.2, 46.2 (CH), 40.6, 36.9 (CH2), 34.6 (CH),
32.1, 31.9 (CH2), 21.3, 13.1, 8.0 (CH3); EIMS m/z 236 (M+•, 8), 176
Acknowledgment. E.M. thanks the Universitat de Valencia for a
grant (V Segles Program).
Supporting Information Available: 1H NMR and 13C NMR spectra
of compounds 1 and 6-9. This material is available free of charge via
the Internet at http://pubs.acs.org.

1236 Journal of Natural Products, 2006, Vol. 69, No. 8
Notes
(8) (a) Friese, J. C.; Krause, S.; Scha¨fer, H. J. Tetrahedron Lett. 2002,
43, 2683-2685. (b) Alexakis, A.; March, S. J. Org. Chem. 2002,
67, 8753-8757.
(9) Moreno-Dorado, F. J.; Lamers, Y. M. A. W.; Mironov, G.; Wijnberg,
J. B. P. A.; de Groot, A. Tetrahedron 2003, 59, 7743-7750.
(10) (a) Zdero, C.; Bohlmann, F.; Solomon J. C.; King, R. M.; Robinson,
H. Phytochemistry 1989, 28, 531-542. (b) Lin, R.-W.; Tsai, I.-L.;
Duh, C.-Y.; Lee, K.-H.; Chem, I.-S. Planta Med. 2004, 70, 234-
238.
References and Notes
(1) (a) Connolly, J. D.; Hill, R. A. In Dictionary of Terpenoids Vol 1,
Mono- and Sesquiterpenoids; Chapman & Hall: London, 1991; pp
476-523. (b) Fraga, B. M. Nat. Prod. Rep. 2004, 21, 669-693, and
previous reports.
(2) (a) Kobayashi, M.; Son, B. W.; Kido, M.; Kyogoku, Y.; Kitagawa,
I. Chem. Pharm. Bull. 1983, 31, 2160-2163. (b) Kobayashi, M.;
Son, B. W.; Kyogoku, Y.; Kitagawa, I. Chem. Pharm. Bull. 1984,
32, 1667-1670.
(3) (a) Bowden, B. F.; Coll, J. C.; Tapiolas, D. M. Aust. J. Chem. 1983,
36, 211-214. (b) Asaoka, M.; Kosaka, T.; Itahana, H.; Takei, H.
Chem. Lett. 1991, 1295-1298.
(4) (a) Takeda, R.; Katoh, K. J. Am. Chem. Soc. 1983, 105, 4056-4058.
(b) Dai, M. C.; Garson, M. J.; Coll, J. C. Comp. Biochem. Physiol.
1991, 99B, 775-783. (c) Dickschat, J. S.; Bode, H. B.; Mahmud,
T.; Mu¨ller, R.; Schulz, S. J. Org. Chem. 2005, 70, 5174-5182.
(5) (a) Kim, S. K.; Pak, C. S. J. Org. Chem. 1991, 56, 6829-6832. (b)
Shimizu, I.; Ishikawa T. Tetrahedron Lett. 1994, 35, 1905-1908.
(6) (a) Honda, T.; Ishige, H.; Nagase, H. J. Chem. Soc., Perkin Trans.
1 1994, 3305-3310, and references therein. (b) Lee, E.; Yoon, C.
H. Tetrahedron Lett. 1996, 37, 5929-5930. (c) Grimm, E. L.; Methot,
J.-L.; Shamji, M. Pure. Appl. Chem. 2003, 75, 231-234.
(7) (a) Koike, T.; Yamazaki, K.; Fukumoto, N.; Yashiro, K.; Takeuchi,
N.; Tobinaga, S. Chem. Pharm. Bull. 1996, 44, 646-652. (b) Piet,
D. P.; Orruˆ, R. V. A.; Jenniskens, L. H. D.; van de Haar, C.; van
Beek, T. A.; Franssen, M. C. R.; Wijnberg, J. B. P. A.; de Groot, A.
Chem. Pharm. Bull. 1996, 44, 1400-1403. (c) Trost, B. M.; Higuchi,
R. I. J. Am. Chem. Soc. 1996, 118, 10094-10105. (d) Lange, G. L.;
Gottardo, C.; Merica, A. J. Org. Chem. 1999, 64, 6738-6744. (e)
Wender, P. A.; Fuji, M.; Husfeld, C. O.; Love, J. A. Org. Lett. 1999,
1, 137-139.
(11) (a) Blay, G.; Garcia, B.; Molina E.; Pedro, J. R. Tetrahedron 2005,
61, 11156-11162. (b) Blay, G.; Bargues, V.; Cardona, L.; Garcia,
B.; Pedro, J. R. Tetrahedron 2001, 57, 9719-9725.
(12) (a) Schreiber, S. L.; Liew, W.-F. Tetrahedron Lett. 1983, 24, 2363-
2366. (b) Gijsen, H. J. M.; Kanai, K.; Stork, G. A.; Wijnberg, J. B.
P. A.; Orru, R. V. A.; Seelen, C. G. J. M.; van der Kerk, S. M.; de
Groot, A. Tetrahedron 1990, 46, 7237-7246, and references therein.
(13) Treatment of the ozonolysis mixtures with Cu(OAc)2-FeSO4 could
afford dealkylated elimination products (Schreiber, S. L. J. Am. Chem.
Soc. 1980, 102, 6163-6165), but under these conditions compound
4 gave a complex mixture with significant loss of mass.
(14) Blay, G.; Bargues, V.; Cardona, L. Garcia, B.; Pedro, J. R. J. Org.
Chem. 2000, 65, 6703-6707.
(15) Structure 10 was deduced by comparison of the chemical shifts of
1
H-6, H-7, and H-14 in its H NMR spectrum [6.44 δ (d, J ) 11.8
Hz, 1H), 6.30 δ (1H, ddd, J ) 5.5, 11.8 Hz, 1H), and 1.06 δ (d, J
) 6.4 Hz, 3H), respectively] with those of compound 9 (see
Experimental Section) and related guaiadienones.11a
(16) (a) Brewster, J. H.; Bayer, H. O. J. Org. Chem. 1964, 29, 116-121.
(b) Brown, B. R. J. Chem. Soc. 1952, 2756-2759.
NP060184G