Oxidative cyclization of a seco-cladiellane diterpenoid

Article abstract of DOI:10.1016/j.tetlet.2005.01.080

A short and efficient synthesis of a diterpenoid with a 1,2-seco-cladiellane carbon skeleton is described, starting from geraniol and carvone. One-step oxidative cyclization with a RuO₂/NaIO₄ system leads to two diastereomeric, bicyc

Full text of DOI:10.1016/j.tetlet.2005.01.080

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1623–1626
Oxidative cyclization of a seco-cladiellane diterpenoid
Manuel Friedel, Gregor Golz, Peter Mayer and Thomas Lindel*
Ludwig-Maximilians-Universita¨t, Department of Chemistry and Biochemistry, D-81377 Munich, Germany
Received 1 December 2004; revised 14 January 2005; accepted 18 January 2005
Available online 1 February 2005
Abstract—A short and efficient synthesis of a diterpenoid with a 1,2-seco-cladiellane carbon skeleton is described, starting from
geraniol and carvone. One-step oxidative cyclization with a RuO2/NaIO4 system leads to two diastereomeric, bicyclic triols, which
contain six stereogenic centers and will be helpful in the synthesis of eleutherobin. The stereochemical outcome of this cyclization
has been determined by X-ray analysis.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In 1997 Fenical et al. reported the marine natural prod-
uct eleutherobin, isolated from the soft coral Eleuthero-
bia sp. (1, Fig. 1).1 Eleutherobin and the sarcodictyins A
(2) and B (3)2 have been shown to possess antimitotic
activity and to stabilize microtubuli in a similar way to
paclitaxel.3 Currently, there are only two completed to-
tal syntheses of eleutherobin (1) by Nicolaou et al.4 and
by Danishefsky and co-workers5 each of which needs
about 25 single conversions. Different groups have iso-
lated and synthesized eleutherobin and sarcodictyin
analogs.6,7
Recently, Andersen and co-workers have shown that the
dihydrofuran and the cyclohexene double bonds may be
hydrogenated with tolerable loss of activity.8 This
Figure 1. Structures of eleutherobin (1) and sarcodictyins A (2) and B
(3) with their ABC pharmacophor.
encouraged us to investigate the synthesis of saturated
analogs. We wish to report on an efficient approach to
a cladiellane, which is cut between C1 and C2 and,
therefore, named 1,2-seco-cladiellane. It was our
hypothesis that the C20 skeleton should be accessible
starting from two C10 building blocks.
2. Results and discussion
Cyclizations of 1,5-dienes to tetrahydrofurans using per-
manganate have been described in various natural prod-
ucts syntheses.9 However, the closely related reaction
with RuO2/NaIO4, a system that was first described by
Djerassi and co-workers,10 has only rarely been used,
although better yields should be expected.11
Introduction of the tetrahydrofuran system was envis-
aged in a one-step oxidative cyclization. Moreover, we
had to learn something about the stereochemical out-
come of that oxidation.
In a first experiment we treated geranyl acetate (5) with
KMnO4 under conditions first described by Klein and
Rojahn.12 We found that the desired tetrahydrofuran 6
was formed in only 35% isolable yield. As major side
products, hemiketals 7 and 8 were formed in 10% and
5% yield (Scheme 1). The hitherto unreported formation
Keywords: Eleutherobin; Oxidative cyclization; Ruthenium tetroxide;
Sarcodictyins; 1,2-seco-Cladiellane.
*
Corresponding author. Tel.: +49 89 218077733; fax: +49 89 2180
77734; e-mail: thomas.lindel@cup.uni-muenchen.de
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.080

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M. Friedel et al. / Tetrahedron Letters 46 (2005) 1623–1626
Scheme 1. Oxidative cyclization with KMnO4 and RuO2/NaIO4.
of 7 and 8 can be explained by initial dihydroxylation of
the terminal double bond of geranyl acetate, followed by
oxidation to the acyloin. Subsequent dihydroxylation of
the allyl acetate sets the stage for the two possibilities of
cyclization to the tetrahydrofuran resp. tetrahydropyran
rings. In each case only one diastereomer was formed.
The stereochemistry of the generated anomeric carbon
atom has not been elucidated.
Scheme 2. Synthesis of seco-cladiellane 14 and biomimetic, oxidative
cyclization to 15 and 16.
A much cleaner reaction was observed on oxidative
cyclization of 5 with RuO2/NaIO4. Under the conditions
described by Sica and co-workers the desired product 6
was isolated in satisfying 54% yield, along with 21%
of overoxidized tetrahydrofuran 9 (Scheme 1).13 The
relative stereochemistry of 6 has been determined by
X-ray analysis.
We next turned to the diterpenoid case. Our synthesis of
the cyclization precursor 14 starts with the reduction of
(S)-(+)-carvone (12) to tetrahydrocarvone (13), which is
possible stereoselectively, although not completely che-
moselectively, by the Zn/NiCl2-system developed by
Petrier and Luche (Scheme 2).14 Overreduction occurs
to a certain extent and makes re-oxidation of the alcohol
necessary. SmI2-mediated reductive coupling of 13 with
allylic phosphate 11, synthesized in quantitative yield
from geraniol (10), by a method described by Butsugan
and co-workers,15 led to the seco-cladiellane 14 in 63%
yield. Interestingly, prolonged reaction times in this step
led to a decrease in isolated yield. SN2-selective SmI2-in-
duced Barbier-type reactions have been used in a num-
ber of natural products syntheses. However, the
method employing phosphates as coupling reagents is
less common.16
seco-Cladiellane 14 with S-configuration at C-10is the
only diastereomer formed in this reaction. Later, we
could show that nucleophilic SN2 attack occurred from
the si face of the carbonyl group.
Figure 2. SCHAKAL plots of 15 and 16 showing the configuration of
the newly formed stereocenters. H-atoms at nonstereogenic centers are
omitted for clarity.
Treatment of seco-cladiellane 14 with the RuO2/NaIO4
system finally led to oxidized and cyclized, diastereo-

M. Friedel et al. / Tetrahedron Letters 46 (2005) 1623–1626
1625
Ofwegen, L.; Castro, C. B.; Andersen, R. J. Org. Lett.
2000, 2, 257–260.
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meric triols 15 and 16 along with minor amounts of dia-
stereomeric overoxidized products (Scheme 2).17 Diaste-
reomers 15 and 16 are formed as an easily separable 1:1
mixture in 40% combined yield.
´
Bayon, P.; Telser, J.; Gennari, C. Tetrahedron Lett. 2003,
We were able to obtain X-ray data of both diastereo-
mers, which allowed us to assign their absolute configu-
rations.18 Both diastereomers show syn configuration at
the tetrahydrofuran moiety. The newly formed stereo-
centers possess 4R, 7S, 8S configuration in 15 and 4S,
7R,8R in 16 (Fig. 2). The stereochemical outcome
of this reaction is consistent with mechanistic
considerations.13,19
44, 7913–7919; (c) Kaliappan, K.; Kumar, N. Tetrahedron
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2000, 2, 1835–1837.
In summary, we have shown that a 1,2-seco-cladiellane
may be easily synthesized from geraniol in two steps
with an overall yield of 62%. We have also shown that
the tetrahydrofuran ring, three stereocenters, as well as
two of the oxygen atoms present in sarcodictyins may
be introduced in a single step.
8. Britton, R.; de Silva, E. D.; Bigg, C. M.; McHardy, L. M.;
Roberge, M.; Andersen, R. J. J. Am. Chem. Soc. 2001,
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Tetrahedron 1994, 50, 4835–4852; (b) Carlsen, P. H. J.;
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Chem. Soc. 1953, 75, 3838–3840.
A pharmacophor consisting of three subunits A–C has
been proposed by Ojima et al. (Fig. 1).20 Open-ring
1,2-seco-cladiellanes derived from 15 and 16 will be use-
ful in testing that pharmacophor model.
11. Piccialli, V.; Cavallo, N. Tetrahedron Lett. 2001, 42, 4695–
4699.
Acknowledgements
12. Klein, E.; Rojahn, W. Tetrahedron 1965, 21, 2353–
2358.
13. Albarella, L.; Musumeci, D.; Sica, D. Eur. J. Org. Chem.
2001, 997–1003.
M.F. thanks the Fonds der Chemischen Industrie for a
doctoral stipend.
14. Petrier, C.; Luche, J.-L. Tetrahedron Lett. 1987, 28, 2351–
2352.
References and notes
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Patent 5473057, 1995; Chem. Abstr. 1996, 124, 194297z;
(b) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.;
Casazza, A. M.; Carboni, J.; Fairchild, C. R. J. Am.
Chem. Soc. 1997, 119, 8744–8745.
2. DÕAmbrosio, M.; Guerriero, A.; Pietra, F. Helv. Chim.
Acta 1987, 70, 2019–2027.
3. Long, B. H.; Carboni, J. M.; Wasserman, A. J.; Cornell,
L. A.; Casazza, A. M.; Jensen, P. R.; Lindel, T.; Fenical,
W.; Fairchild, C. R. Cancer Res. 1998, 58, 1111–
1115.
4. (a) Nicolaou, K. C.; van Delft, F.; Ohshima, T.; Vourlo-
umis, D.; Xu, J.; Hosokawa, S.; Pfefferkorn, J.; Kim, S.;
Li, T. Angew. Chem. 1997, 109, 2630–2634; Angew.
Chem., Int. Ed. 1997, 36, 2520–2524; (b) For a related
formal total synthesis, see: Ritter, N.; Metz, P. Synlett
2003, 15, 2422–2424.
5. (a) Chen, X.-T.; Zhou, B.; Bhattacharya, S. K.; Gutter-
idge, C. E.; Pettus, T. P. R.; Danishefsky, S. J. Angew.
Chem. 1998, 110, 835–838; Angew. Chem., Int. Ed. 1998,
37, 789–792; (b) Castoli, D.; Caggiano, L.; Panigada, L.;
Sharon, O.; Costa, A. M.; Gennari, C. Angew. Chem.
2005, 117, 594–597; Angew. Chem. Int. Ed. 2005, 44, 588–
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16. (a) Kagan, H. B. Tetrahedron 2003, 59, 10351–10372, and
references cited therein; (b) Molander, G. A.; Harris, C. R.
Chem. Rev. 1996, 96, 307–338.
17. Selected physical and spectroscopical data. 15: Mp 115.1–
c 1.9 mg/mL in CHCl3). IR
20
D
115.3 °C. ½aŠ
À20(
~
(KBr) m ¼ 3447 (s, br), 2955 (s), 2924 (s), 2872 (m), 1636
(m, br), 1466 (m), 1381 (m), 1368 (m), 1344 (w), 1319 (w),
1278 (w), 1241 (w), 1184 (w), 1150 (w), 1099 (m), 1062 (m),
1021 (w), 983 (w), 951 (w), 920(w), 884 (w), 850(w), 798
(w), 616 (w), 530(w). UV/vis (CHCl 3): kmax(e) = 207 nm
(8136 molÀ1 dm3 cmÀ1), 262 (11740mol À1 dm3 cmÀ1), 285
(12736 molÀ1 dm3 cmÀ1). 1H NMR (400 MHz, CDCl3):
d = 3.86 (t, 3J = 6.96 Hz, 1H), 3.75 (dd, 3J = 9.34 Hz,
3J = 1.47 Hz, 1H), 2.2 (s, br, 3H), 1.97–1.88 (m, 3H), 1.78
2
3
(td, J = 13.55 Hz, J = 2.56 Hz, 1H), 1.69–1.62 (m, 3H),
1.53 (dd, J = 14.65 Hz, J = 9.34 Hz, 1H), 1.49–1.27 (m,
5H), 1.25 (s, 3H), 1.17 (s, 3H), 1.12 (s, 3H), 1.13 (td,
2
3
3
2J = 13.55 Hz, J = 2.56 Hz, 1H), 0.92–0.89 (m, 1H), 0.91
3
3
(d, J = 6.23 Hz, 3H), 0.86 (d, J = 6.59 Hz, 3H), 0.84 (d,
3J = 6.96 Hz, 3H). 13C NMR (100 MHz, CDCl3): d = 86.1,
85.4, 74.4, 73.1, 71.5, 43.1, 42.7, 40.2, 38.8, 34.8, 32.6, 31.1,
28.9, 27.5, 26.6, 25, 21.0, 20.1, 19.4, 15.5. MS (FAB+): m/z
(%): 686 (3) [2M+H]+, 343 (23) [M+H]+, 325 (14), 307
(47), 155 (29), 143 (12), 95 (14), 75 (20), 71 (14), 57 (15).
HRFABMS C20H39O4 [M+H]+: calcd 343.2848; found
6. (a) Nicolaou, K. C.; Winssinger, N.; Vourloumis, D.;
Ohshima, T.; Kim, S.; Pfefferkorn, J.; Xu, J.-Y.; Li, T. J.
Am. Chem. Soc. 1998, 120, 10814–10826; (b) Beumer, R.;
20
D
343.2821. 16: Mp 92–95.6 °C. ½aŠ +8 (c 1.6 mg/mL in
CHCl3). IR (film) ~m ¼ 3420(s, br), 2967 (s), 2931 (s), 2873
(s), 1771 (w), 1634 (w), 1464 (m), 1416 (w), 1367 (m), 1249
(w), 1166 (m), 1109 (m), 1083 (m),1028 (w), 994 (w), 949
(w), 888 (w), 788 (w), 552 (w). 1H NMR (400 MHz,
´
Bayon, P.; Bugada, P.; Ducki, S.; Monelli, N.; Sirtori, F.
R.; Telser, J.; Gennari, C. Tetrahedron 2003, 59, 8803–
8820; (c) Cinel, B.; Roberge, M.; Behrisch, H.; van

1626
M. Friedel et al. / Tetrahedron Letters 46 (2005) 1623–1626
CDCl3): d = 3.88 (dd, 3J = 9.89 Hz, 3J = 1.47 Hz, 1H),
3.87 (t, J = 6.96 Hz, 1H), 2.82–2.61 (s, br, 3H), 2.1–1.90
73 (12), 71 (40), 69 (25), 67 (11), 55 (25). HRFABMS
C20H39O4 [M+H]+: calcd 343.2848; found 343.2853.
18. CCDC-256464 (15) and CCDC-256465 (16) contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.
ac.uk/conts/retrieving.html (or from the Cambridge Crys-
tallographic Data Centre, 12, Union Road, Cambridge
CB21EZ, UK; fax: (+44) 1223-336-033; or deposit@
ccdc.cam.ac.uk).
19. Albarella, L.; Lasalvia, M.; Piccialli, V.; Sica, D. J. Chem.
Soc., Perkin Trans. 2 1998, 737–743, and references cited
therein.
20. Ojima, I.; Chakravarty, S.; Inoue, T.; Lin, S.; He, L.;
Horwitz, S. B.; Kuduk, S. D.; Danishefsky, S. J. Proc.
Natl. Acad. Sci. U.S.A. 1999, 96, 4256–4261.
3
(m, 5H), 1.66 (td,2J = 12.82 Hz, 3J = 2.75 Hz, 1H), 1.6
(ddd, 2J = 14.65 Hz, 3J = 8.06 Hz, 3J = 6.96 Hz, 1H),
1.50–1.36 (m, 3H), 1.33 (m, 1H), 1.26 (m, 2H), 1.26 (s,
3H), 1.15 (s, 3H), 1.11 (s, 3H), 0.95–0.89 (m, 2H), 0.91 (d,
3J = 6.23 Hz, 3H), 0.88 (d, 3J = 6.23 Hz, 3H), 0.85 (d,
3J = 6.23 Hz, 3H). 13C NMR (100 MHz, CDCl3): d = 85.5,
85.5, 73.8, 73.6, 71.8, 40.8, 40.0, 40, 38.6, 34.6, 32.6, 30.6,
28.7, 27.7, 26.4, 25.2, 22.3, 20.1, 19.3, 15. MS (FAB+): m/z
(%): 707 (3) [2M+Na]+, 686 (2) [2M+H]+, 365 (48)
[M+Na]+, 343 (26) [M+H]+, 325 (30), 323 (12), 308 (21),
301 (100), 263 (12), 173 (17), 155 (78), 154 (11), 151 (13),
143 (61), 137 (31), 136 (13), 127 (21), 125 (24), 111 (11),
109 (17), 107 (12), 97 (10), 95 (32), 85 (18), 83 (13), 81 (28),