Formal total synthesis of the trinorguaiane sesquiterpenes (+/-)-clavukerin A and (+/-)-isoclavukerin

Article abstract of DOI:10.1016/S0040-4039(02)00402-1

A formal total synthesis of racemic (+/-)-clavukerin A and (+/-)-isoclavukerin from 4-methylcyclohept-2-en-1-one is presented. The key step involved a Danheiser (trimethylsilyl)cyclopentene annulation.

Full text of DOI:10.1016/S0040-4039(02)00402-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2683–2685
Formal total synthesis of the trinorguaiane sesquiterpenes
(+/−)-clavukerin A and (+/−)-isoclavukerin
Jan C. Friese, Stefan Krause and Hans J. Scha¨fer*
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-Universita¨t Mu¨nster, Corrensstrasse 40, D-48149 Mu¨nster, Germany
Received 17 January 2002; accepted 26 February 2002
Abstract—A formal total synthesis of racemic (+/−)-clavukerin A and (+/−)-isoclavukerin from 4-methylcyclohept-2-en-1-one is
presented. The key step involved a Danheiser (trimethylsilyl)cyclopentene annulation. © 2002 Published by Elsevier Science Ltd.
The trinorguaiane sesquiterpenes clavukerin A1 1 and
isoclavukerin2 3 are marine natural products that have
been isolated from the Okinawan soft coral Clavularia
koellikeri during a search for biologically active com-
pounds from marine sources. So far three total synthe-
ses of isoclavukerin3,4 and five total syntheses of
clavukerin A have been described,4,5 including three
enantiocontrolled routes and two for the racemate.
with peracetic acid gave the corresponding epoxide 6,6
which in turn was converted to methylcycloheptenol 7
by conjugate addition of methyl cuprate generated in
situ from methyl lithium and CuCN.7 Oxidation of 7
with Jones reagent gave 4-methylcyclohept-2-en-1-one
(8)8 (Scheme 1). The Danheiser (trimethylsi-
lyl)cyclopentene annulation9 involving the (trimethylsi-
lyl)allene 9 and methylcycloheptenone 8 was carried out
with the use of 1.7 equivalents of titanium tetrachloride
in dichloromethane at −78°C.10 The annulation pro-
ceeded smoothly to afford a 1:1 mixture of the cis fused
diastereoisomers 10 and 11 (Scheme 2). Compounds 10
and 11 could easily be separated by HPLC and the
relative configuration of 11 was determined by NOE
relationships.
Honda et al.,5c Asaoka et al.4a and Pak et al.5a utilized
the skeleton 2 (Scheme 1) as a key fragment in their
syntheses of clavukerin A and converted it to the
natural product in a two-step procedure. In addition 4
has been converted into isoclavukerin by Asaoka et al.
previously.4a Therefore, any synthesis of 2 or 4 consti-
tutes a formal synthesis of the natural products clavuk-
erin A 1 and isoclavukerin 3. Herein we wish to report
an efficient and very direct two-step synthesis of
racemic fragments 2 and 4 based upon a Danheiser
(trimethylsilyl)cyclopentene annulation, employing
methyl cycloheptenone as a starting material.
As shown in Scheme 3, treatment of 10 or 11 with
K2CO3 in methanol followed by addition of tetrabutyl
ammonium fluoride generated rac-2 or rac-4. Charac-
1
terization of 2 and 4 by H and 13C NMR spectroscopy
showed them to be identical to those reported.4a The
elaboration of 2 to (+/−)-clavukerin A and 4 to (+/−)-
isoclavukerin has been reported earlier and thus a
formal synthesis of 1 and 3 has been achieved. The
4-Methylcyclohept-2-en-1-one (8) was prepared in a
three-step synthesis. Epoxidation of cycloheptadiene 5
Scheme 1.
* Corresponding author. Tel.: +49 251-83 33 23 1; fax: +49 251-83 36 52 3; e-mail: schafeh@uni-muenster.de
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00402-1

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J. C. Friese et al. / Tetrahedron Letters 43 (2002) 2683–2685
Scheme 2.
Scheme 3.
synthesis of 2 and 4, respectively, required five steps
from commercially available cycloheptadiene 5 and
proceeded in 15 and 13% overall yield, respectively.
4. (a) Asaoka, M.; Kosaka, T.; Itahana, H.; Takei, H.
Chem. Lett. 1991, 1295–1298; (b) Shimizu, I.; Ishikawa,
T. Tetrahedron Lett. 1994, 35, 1905–1908.
5. (a) Kim, S. K.; Pak, S. J. Org. Chem. 1991, 56, 6829–
6832; (b) Lee, E.; Yoon, C. H. Tetrahedron Lett. 1996,
33, 5929–5930; (c) Honda, T.; Ishige, H.; Nagase, H. J.
Chem. Soc., Perkin Trans. 1 1994, 3305–3310.
6. Crandall, J. K.; Banks, D. B.; Coyler, R. J.; Watkins, R.
J.; Arrington, J. P. J. Org. Chem. 1968, 33, 423–425.
7. Marino, J. P.; Floyd, D. M. Tetrahedron Lett. 1979, 8,
675–678.
In conclusion, we have described the formal total syn-
thesis of (+/−)-clavukerin A and (+/−)-isoclavukerin
employing a new potent route. The key fragments rac-2
and rac-4 could be obtained in two steps from enone 8.
Acknowledgements
8. Rasmusson, G. H.; House, H. O.; Zawesky, E. F.;
Depuy, C. H. Org. Synth. 1968, 42, 36–38.
9. (a) Danheiser, R. L.; Carini, D. J.; Basak, A. J. Am.
Chem. Soc. 1981, 103, 1604–1606; (b) Danheiser, R. L.;
Carini, D. J.; Finf, D. M.; Basak, A. Tetrahedron 1983,
39, 935–947.
This work was supported by the Fonds der Chemischen
Industrie. J.C.F. gratefully acknowledges a fellowship
of the Fonds der Chemischen Industrie.
10. To a solution of 4-methycyclohept-2-en-1-one (8) (500
mg, 4.03 mmol) and 1-methyl-1-(trimethylsilyl)-allene (9)
(768 mg, 6.98 mmol) in CH2Cl2 (20 ml) at −78°C was
added dropwise TiCl4 (0.69 ml, 6.98 mmol). The resulting
dark red solution was stirred at −78°C for 1 h and then
transferred into a mixture of water (100 ml) and diethyl
ether (100 ml). The aqueous phase was extracted with
diethyl ether (3×100 ml), the combined organic layers
were washed with brine (2×20 ml), dried over anhydrous
MgSO4 and filtered. The solvent was evaporated under
reduced pressure and the crude product was purified by
flash chromatography (petroleum ether:diethyl ether=
References
1. (a) Kobayashi, M.; Son, B. W.; Kidom, M.; Kyogoku,
Y.; Kitagawa, I. Chem. Pharm. Bull. 1983, 31, 6; (b)
Kobayashi, M.; Son, B. W.; Kidom, M.; Kyogoku, Y.;
Kitagawa, I. Chem. Pharm. Bull. 1984, 32, 1667.
2. Kusumi, T.; Hamada, T.; Hara, M.; Ishitsuka, M. O.;
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3. Trost, B. M.; Higuchi, R. I. J. Am. Chem. Soc. 1996, 118,
10094–10105.

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2685
3:2) to give a 1:1 mixture of 10 and 11 as a colorless oil
(914 mg, 3.66 mmol, 91%). 10 and 11 could be separated
by HPLC (petroleum ether:diethyl ether=9:1, Nucleosil
100-7).
(100) [(CH3)3Si+], 59 (10), 45 (10), 41 (4) [C3H+5].—
C15H26Osi (250.46): calcd C, 71.94; H, 10.64; found C,
72.07; H, 10.51%. rac-(3aS,8S,8aR)-3,8-Dimethyl-2-
(trimethylsilyl)-3a,5,6,7,8,8a-hexahydroazulene-4(1H)-one
(rac-11): Rf=0.41 (petroleum ether:diethyl ether=9:1).—
FT-IR (Film): w˜ (cm−1)=2954 (s, CH), 1705 (s, CꢀO),
1628 (m, CꢀC), 1456 (m), 1405 (m, CH-def.), 1377 (m),
1328 (m), 1247 (s), 1202 (w), 1181 (w), 1160 (w), 1130 (w),
1077 (w), 997 (w), 931 (w), 836 (s), 754 (s), 690 (s).—1H
NMR (CDCl3, 300.1 MHz): l (ppm)=0.22 (s, 9H, TMS),
0.84 (d, 3H, 3J=6.4 Hz, 8-CH3), 1.12–1.74 (m, 5H,
rac-(3aS,8R,8aR)-3,8-Dimethyl-2-(trimethylsilyl)-3a,5,6,
7,8,8a-hexahydroazulene-4(1H)-one (rac-10): Rf=0.45
(petroleum ether:diethyl ether=9:1)—FT-IR (Film): w˜
(cm−1)=2955 (s), 2929 (s), 2859 (s), 1699 (s), 1617 (m),
1455 (m), 1380 (w), 1338 (w), 1248 (s), 1197 (w), 1181 (w),
1120 (w), 171 (w), 1008 (w), 975 (w), 942 (w), 837 (s), 753
(s), 624 (s).—1H NMR (CDCl3, 300.1 MHz): l (ppm)=
0.17 (s, 9H, TMS), 0.81 (d, 3H, 3J=7.2 Hz, 8-CH3),
1.15–1.38, 1.48–1.57 (2m, 5H, je 2×6-H, 7-H, 1×8-H),
1.71 (ddd, 3H, 4Ja=1.0 Hz, 4Jb=1.9 Hz, 4Jc=2.4 Hz,
3-CH3), 2.19 (mc, 2H, 2×1-H), 2.32 (ddd, 1H, 3Ja=2.2
4
4
1×1-Ha, 2×6-H, 7-H), 1.84 (ddd, 3H, Ja=0.7 Hz, Jb=
1.4 Hz, 4Jc=2.2 Hz, 3-CH3), 2.08 (ddd, 4J=1.6 Hz,
3Ja=10.4 Hz, 3Jb=18.6 Hz, 8a-H), 2.15–2.35 (m, 3-H,
3
3
1×1-Hb, 2×5-H), 2.59 (mc, 1H, Ja=1.6 Hz, Jb=8.5 Hz,
4
3
3
3
1×8-H), 3.58 (dd, 1H, J=2.2 Hz, J=10.4 Hz, 3a-H).—
13C NMR (CDCl3, 75.5 MHz): l (ppm)=−0.4 (q, TMS),
16.9, 21.3 (2q, 8-CH3, 3-CH3), 22.4, 34.6, 41.6, 43.8 (4t,
C-1, C-5, C-6, C-7), 36.1 (d, C-8), 47.3 (d, C-8a), 66.3 (d,
C-3a), 137.1 (s, C-2), 147.6 (s, C-3), 209.7 (s, C-4).—MS
(GC/MS 70 eV): m/z (%)=250 (15) [M+], 235 (18) [M+−
CH3], 221 (6) [M+−CO−H], 207 (12) [235-CO], 194 (15),
177 (12) [M+−(CH3)3Si], 160 (8), 145 (25) [M+−
HOSi(CH3)3−CH3], 133 (14), 117 (6), 105 (12), 97 (8), 73
(100) [(CH3)3Si+], 59 (10), 45 (10).
Hz, Jb=9.3 Hz, Jc=18.4 Hz, 8a-H), 2.39–2.54 (m, 2H,
2×5-H), 3.43 (mc, 1H, 3a-H).—13C NMR (CDCl3, 75.5
MHz): l (ppm)=0.8 (q, TMS), 15.9 (q, 3-CH3), 24.1 (q,
8-CH3), 25.4, 31.9 (2t, C-6, C-7), 34.4 (d, C-8), 36.7 (t,
C-1), 40.5 (t, C-5), 44.0 (d, C-8a), 72.5 (d, C-3a), 139.2 (s,
C-2), 146.4 (s, C-3), 213.7 (s, C-4).—MS (GC/MS 70 eV):
m/z (%)=250 (15) [M+], 235 (18) [M+−CH3], 225 (1), 207
(12) [M+−CH3−CO], 194 (15) [M+−C2H4−CO], 177 (12)
[M+−(CH3)3Si], 160 (4) [M+−HOSi(CH3)3], 145 (18) [M+−
HOSi(CH3)3−CH3], 133 (6), 117 (6), 106 (12), 93 (8), 73