Synthetic studies on (+)-ophiobolin A: Asymmetric synthesis of the spirocyclic CD-ring moiety

Article abstract of DOI:10.1021/ol060437x

Asymmetric synthesis of the spirocyclic CD-ring moiety of (+)-ophiobolin A is described. Fragment A, which was prepared via pig liver esterase (PLE)-mediated kinetic resolution, and fragment B, which was prepared via diastereoselective allylation and subs

Full text of DOI:10.1021/ol060437x

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2039-2042
Synthetic Studies on (+)-Ophiobolin A:
Asymmetric Synthesis of the Spirocyclic
CD-Ring Moiety
Naoyoshi Noguchi and Masahisa Nakada*
Department of Chemistry, Faculty of Science and Engineering, Waseda UniVersity,
3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
mnakada@waseda.jp
Received February 19, 2006
ABSTRACT
Asymmetric synthesis of the spirocyclic CD-ring moiety of (+)-ophiobolin A is described. Fragment A, which was prepared via pig liver
esterase (PLE)-mediated kinetic resolution, and fragment B, which was prepared via diastereoselective allylation and subsequent kinetic
iodolactonization, were coupled to afford the allylsilane 2, which was successfully cyclized to the desired spirocyclic CD-ring moiety 1a in the
presence of a Lewis acid.
(+)-Ophiobolin A (Scheme 1) was first isolated as a
metabolite from the culture broth of the pathogenic plant
fungus Ophiobolus miyabeanus,1a and from its absolute
structure proof, the first naturally occurring sesterterpene was
identified.1b Since then, several congeners, including ophiobo-
lin B,1c C,1d D,1e,f F,1g G,1h H,1h I,2 J,2b K,3a L,3b M,3c 6-epi-
ophiobolin G,3d and 6-epi-ophiobolin N,3d have been isolated.4a
(+)-Ophiobolin A possesses eight stereogenic centers on
the unique tricyclic 5-8-5-5 ring system. The five-membered
A-ring incorporates three successive stereogenic centers
including a chiral tertiary alcohol and two contiguous
stereogenic centers at the cis-fused AB-ring juncture. The
CD-ring is a spirocyclic ether, possessing a total of five
(+)-Ophiobolin A shows a broad spectrum of bioactivity
against nematodes, fungi, and bacteria.4a It was reported to
inhibit calmodulin-activated cyclic nucleotide phospho-
diesterase4b and also to induce apoptotic cell death in the
L1210 cell line.4c Recent studies disclosed that (+)-ophiobo-
lin A is cytotoxic to the cancer cell lines A-549, Mel-20,
and P-335 with IC50 values ranging from 62.5 to 125 nM.4d
Scheme 1. Retrosynthetic Analysis of (+)-Ophiobolin A
(1) (a) Ishibashi, K.; Nakamura, R. J. Agric. Chem. Soc. Jpn. 1958, 32,
739-744. (b) Nozoe, S.; Morisaki, M.; Tsuda, K.; Iitaka, Y.; Tokahashi,
N.; Tamura, S.; Ishibashi, K.; Shirasaka, M. J. Am. Chem. Soc. 1965, 87,
4968-4970. (c) Canonica, L.; Friecchi, A.; Galli Kienle, U.; Scala, A.
Tetrahedron Lett. 1966, 7, 1329-1333. (d) Nozoe, S.; Hirai, K.; Tsuda, K.
Tetrahedron Lett. 1966, 7, 2211-2216. (e) Itai, A.; Nozoe, S.; Tsuda, K.;
Okuda, S.; Iitaka, Y.; Nakayama, Y. Tetrahedron Lett. 1967, 8, 4111-
4112. (f) Nozoe, S.; Itai, A.; Tsuda, K.; Okuda, S. Tetrahedron Lett. 1967,
8, 4113-4117. (g) Nozoe, S.; Morisaki, K.; Fukushima, K.; Okuda, S.
Tetrahedron Lett. 1968, 9, 4457-4458. (h) Culter, H. G.; Crumley, F. G.;
Cox, R. H.; Springer, J. P.; Arrendale, R. F.; Cole, R. J.; Cole, P. D. J.
Agric. Food Chem. 1984, 32, 778-782.
10.1021/ol060437x CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/13/2006

stereogenic centers, four of which are successive, as well as
a quaternary stereogenic center at the trans-fused BC-ring
juncture.
Total synthesis of (+)-ophiobolin A has not been achieved
nor have synthetic studies on the spirocyclic CD-ring moiety
been reported.5,6 Recent studies on its potent bioactivity4 as
well as on its complex structural features led us to commence
synthetic studies on (+)-ophiobolin A.
this reaction8 would simultaneously construct the 1-oxaspiro-
[4.4]nonane framework as well as the two requisite stereo-
genic centers at C10 and C14. Because this cyclization
proceeds via an oxonium ion, the allylsilane was expected
to react at the C14 position from the less-hindered side to
afford 1a as a major product. A coupling reaction of
fragments A and B would provide 2. Consequently, we first
prepared these two fragments.
We selected pig liver esterase (PLE)-mediated asymmetric
hydrolysis of 3 to prepare 4 for the synthesis of fragment A
(Scheme 2) because fragment A possesses a quaternary
We envisioned that (+)-ophiobolin A could be synthesized
from the CD-ring moiety 1a and fragment C, which we
expected to derive from the chiral building block we had
reported earlier.7 Consequently, we first examined the
synthesis of 1a and report herein the asymmetric synthesis
of the spirocyclic CD-ring moiety of (+)-ophiobolin A.
As outlined in Scheme 1, we selected a Lewis acid
promoted cyclization reaction of 2 to construct 1a because
Scheme 2. Kinetic Resolution of 4 with PLE
(2) (a) Sugawara, F.; Strobel, G.; Strange, R. N.; Siedow, J. N.; Duyne,
G. D. V.; Clardy, J. Proc. Natl. Acad. Sci. 1987, 84, 3081-3085. (b)
Sugawara, F.; Takahashi, N.; Strobel, G.; Yun, C.; Gray, G.; Fu, Y.; Clardy,
J. J. Org. Chem. 1988, 53, 2170-2172.
(3) (a) Singh, S. B.; Smith, J. L.; Sabnis, G. S.; Dombrowski, A. W.;
Schaeffer, J. M.; Goetz, M. A.; Bills, G. F. Tetrahedron 1991, 47, 6931-
6938. (b) Li, E.; Clark, A. M.; Rotella, D. P.; Hufford, C. D. J. Nat. Prod.
1995, 58, 74-81. (c) Tsipouras, A.; Adefarati, A. A.; Tkacz, J. S.; Frazier,
E. G.; Rohrer, S. P.; Birzin, E.; Rosegay, A.; Zink, D. L.; Geotz, M. A.;
Singh, S. B.; Schaeffer, J. M. Bioorg. Med. Chem. 1996, 4, 531-536. (d)
Wei, H.; Itoh, T.; Kinoshita, M.; Nakai, Y.; Kurotaki, M.; Kobayashi, M.
Tetrahedron 2004, 60, 6015-6019.
(4) (a) Au, T. K.; Chick, Wallace S. H.; Leung, P. C. Life Sci. 2000, 67,
733-742. (b) Fujiwara, H.; Matsunaga, K.; Kumagai, H.; Ishizuka, M.;
Ohizumi, Y. Pharm. Pharmacol. Commun. 2000, 6, 427-431. (c) Leung,
P. C.; Taylor, W. A.; Wang, J. H.; Tipton, C. L. J. Biol. Chem. 1984, 259,
2742-2747. (d) Shen, X.; Krasnoff, S. B.; Lu, S.-W.; Dunbar, C. D.;
O’Neal, J.; Turgeon, B. G.; Yoder, O. C.; Gibson, D. M.; Hamann, M. T.
J. Nat. Prod. 1999, 62, 895-897.
(5) Several research groups reported synthetic studies on ophiobolins.
See: (a) Dauben, W. G.; Hart, D. J. J. Org. Chem. 1977, 42, 922-923. (b)
Das, T. K.; Dutta, P. C.; Kartha, G.; Bernassau, J. M. J. Chem. Soc., Perkin
Trans. 1 1977, 1287-95. (c) Boeckman, R. K., Jr.; Bershas, J. P.; Clardy,
J.; Solheim, B. J. Org. Chem. 1977, 42, 3630-3633. (d) Paquette, L. A.;
Andrews, D. R.; Springer, J. P. J. Org. Chem. 1983, 48, 1147-1149. (e)
Paquette, L. A.; Colapret, J. A.; Andrews, D. R. J. Org. Chem. 1985, 50,
201-205. (f) Coates, R. M.; Muskopf, J. W.; Senter, P. A. J. Org. Chem.
1985, 50, 3541-3557. (g) Mehta, G.; Krishnamurthy, N. J. Chem. Soc.,
Chem. Commun. 1986, 1319-1321. (h) Umehara, M.; Hishida, S.; Okumoto,
S.; Ohba, S.; Ito, M.; Saito, Y. Bull. Chem. Soc. Jpn. 1987, 60, 4474-
4476. (i) Rigby, J. H.; Senanayake, C. J. Org. Chem. 1987, 52, 4634-
4635. (j) Rowley, M.; Kishi, Y. Tetrahedron Lett. 1988, 29, 4909-4912.
(k) Dauben, W. G.; Warshawsky, A. M. J. Org. Chem. 1990, 55, 3075-
3087. (l) Paquette, L. A.; Liang, S.; Galatsis, P. Synlett 1990, 663-665.
(m) Snider, B. B.; Yang, K. J. Org. Chem. 1992, 57, 3615-3626. (n) Rigby,
J. H.; McGuire, T.; Senanayake, C.; Khemani, K. J. Chem. Soc., Perkin
Trans.1 1994, 3449-3457. (o) Paquette, L. A.; Liang, S.; Wang, H.-L. J.
Org. Chem. 1996, 61, 3268-3279. (p) Blake, A. J.; Highton, A. J.; Majid,
T. N.; Simpkins, N. S. Org. Lett. 1999, 1, 1787-1789. (q) McGee, K. F.,
Jr.; Al-Tel, T. H.; Sieburth, S. M. Synthesis 2001, 1185-1196. (r) Ruprah,
P. K.; Cros, J.-P.; Pease, J. E.; Whittingham, W. G.; Williams, J. M. J.
Eur. J. Org. Chem. 2002, 3145-3152. (s) Salem, B.; Suffert, J. Angew.
Chem., Int. Ed. 2004, 43, 2826-2830.
stereogenic center, which could not be derived from a
commercially available compound. PLE-mediated asym-
metric hydrolysis of 3 in 0.01 M KPB8 (pH 8, potassium
phosphate buffer) successfully generated 4 with 96% ee via
kinetic resolution. Specifically, monoester 4, prepared with
89% ee via PLE-mediated asymmetric hydrolysis in the
initial 9 h reaction, was again treated with PLE, and after a
week, 4 was recovered in 88% yield. HPLC analysis of the
corresponding anilide revealed that the ee of 4 was increased
from 89 to 96% ee.9
The synthesis of fragment A began with the conversion
of chiral starting material 4 to the corresponding acid chloride
(Scheme 3), which was then reduced with NaBH4 to afford
5 (86%).10 Alcohol 5 was protected as a MOM ether,
followed by reduction with LiAlH4 (99%) to produce 6,
which was acetylated and subjected to ozonolysis followed
by reductive workup affording 7 (100%). Protection of 7 as
an ethoxyethyl ether, removal of the acetyl group, and Swern
oxidation gave aldehyde 8 (84%). Horner-Wadsworth-
Emmons reaction of 8, followed by DIBAL-H reduction, and
treatment of the resulting allylic alcohol with lithium chloride
and methanesulfonyl chloride11 afforded 9 (97%). Still’s
protocol successfully introduced the allyltrimethylsilane,12
and the following removal of the ethoxyethyl group and
subsequent conversion furnished fragment A (81%).
(6) For the total synthesis of ophiobolin C, see: (a) Rowley, M.;
Tsukamoto, M.; Kishi, Y. J. Am. Chem. Soc. 1989, 111, 2735-2737. For
the total synthesis of (+)-albolic acid and (+)-ceroplastol II, see: (b) Kato,
N.; Kataoka, H.; Ohbuchi, S.; Tanaka, S.; Takeshita, H. J. Chem. Soc.,
Chem. Commun. 1988, 354-356. (c) Kato, N.; Takeshita, H.; Kataoka, H.;
Ohbuchi, S.; Tanaka, S. J. Chem. Soc., Perkin Trans. 1 1989, 165-174.
For the total synthesis of (()-ceroplastol I, see: (d) Boeckman, R. K., Jr.;
Arvanitis, A.; Voss, M. E. J. Am. Chem. Soc. 1989, 111, 2737-2739. For
the total synthesis of (+)-ceroplastol I, see: (e) Paquette, L. A.; Wang, T.
Z.; Vo, N. H. J. Am. Chem. Soc. 1993, 115, 1676-1683.
(7) (a) Honma, M.; Sawada, T.; Fujisawa, Y.; Utsugi, M.; Watanabe,
H.; Umino, A.; Matsumura, T.; Hagihara, T.; Takano, M.; Nakada, M. J.
Am. Chem. Soc. 2003, 125, 2860-2861. (b) Takano, M.; Umino, A.;
Nakada, M. Org. Lett. 2004, 6, 4897-4900. (c) Miyamoto, H.; Iwamoto,
M.; Nakada, M. Heterocycles 2005, 66, 61-68.
(8) For oxonium ion mediated cyclizations using dihydropyrans, see:
Paquette, L. A.; Tae, J. J. Org. Chem. 1996, 61, 7860-7866. For a recent
review of allylsilane chemistry, see: (a) Fleming, I.; Barbero, A.; Walter,
W. Chem. ReV. 1997, 97, 2063-2192. (b) Hosomi, A.; Miura, K. Bull.
Chem. Soc. Jpn. 2004, 77, 835-851. (c) Chabaud, L.; James, P.; Landais,
Y. Eur. J. Org. Chem. 2004, 3173-3199.
(9) To the best of our knowledge, this kinetic resolution of monoester
has never been reported. For details, see Supporting Information.
(10) Soai, K.; Yokoyama, S.; Mochida, K. Synthesis 1987, 647-648.
(11) Meyers, A. I.; Collington, E. W. J. Org. Chem. 1971, 36, 3044-
3045.
(12) (a) Still, W. C. J. Org. Chem. 1976, 41, 3063-3064. (b) Smith, J.
G.; Drozda, S. E.; Petraglia, S. P.; Quinn, N. R.; Rice, E. M.; Taylor, B.
S.; Viswanathan, M. J. Org. Chem. 1984, 49, 4112-4120.
2040
Org. Lett., Vol. 8, No. 10, 2006

Scheme 3. Synthesis of Fragment A
Scheme 5. Coupling of Fragment A with Fragment B
corresponding organolithium intermediate, which was then
reacted with fragment B at the same temperature, successfully
affording 2 in 84% yield as a mixture of two diastereomers.
Now, the stage was set for the Lewis acid promoted
cyclization reaction of 2. Table 1 compares the effect of
several Lewis acids on the generation of 1a as well as three
other possible products. EtAlCl2 generated three products,
1a, 1b, and 1c, in 20, 40, and 40% yields, respectively. Less
acidic Et2AlCl required an elevated temperature to produce
1a, 1b, and 1c with yields of 25, 36, and 36%, respectively.
SnCl4 similarly afforded a mixture of the same three products,
but the ratio of 1c was slightly higher, representing 49% of
the product yield. Although TiCl4 merely decomposed 2
because of its strong acidity, TiCl3(OiPr) afforded 1a, 1b,
and 1c in 29, 31, and 40% yields, respectively. TiCl2(OiPr)2
gave rather different results, however, producing 1a and 1c
in 18 and 19% yields, respectively, and a major new product,
1d, which formed in 57% yield. Interestingly, 1d was the
sole product (84% yield) when the less acidic TiCl(OiPr)3
was used. The acidity of Ti(OiPr)4 was too weak to promote
this reaction. In contrast to the above results, BF3‚OEt2
produced 1a in 45% yield.
The synthesis of fragment B was initiated from 10
(Scheme 4), which had been stereoselectively prepared.13
X-ray crystallographic analysis of the crystalline derivative
of 1a confirmed the whole structure of 1a as the desired
product shown in Table 1.16 Products 1b, 1c, and their
derivatives were not suitable for the X-ray crystallographic
analysis; however, NMR studies including NOESY experi-
ments of their derivatives successfully elucidated their
structures.16
Scheme 4. Synthesis of Fragment B
X-ray crystallographic analysis of 1d disclosed that it was
an unexpected product because the configuration of the C15
stereogenic center was clearly reversed. Because no epimer-
ization at the C15 position can occur except in the spiroether
formation step, the oxonium ion derived from 2 or the
hydroxyl ketone which arose from 2 must have epimerized
under the reaction conditions, and the epimerized oxonium
ion, which was more reactive than the sterically hindered,
unepimerized species, reacted with the allylsilane from the
less-hindered side to afford 1d. This key epimerization to
form 1d occurs only under the reaction conditions in entries
6 and 7 of Table 1, and the isopropoxy ligand of the
employed titanium catalysts could play a crucial role in this
reaction.
Iodolactonization of 10 under the optimized conditions14
cleanly afforded iodolactone 11 as the sole product (92%).
Compound 11 was converted to the corresponding trifluo-
roacetate, followed by removal of the trifluoroacetate with
diethylamine and subsequent protection of the resulting
alcohol with BPSCl to generate fragment B (61%).15
To couple fragments A and B (Scheme 5), fragment A
was treated with t-BuLi in Et2O at -78 °C to generate the
Admittedly, the yields of the desired precursor 1a were
relatively low in several of the reactions in Table 1. However,
stereogenic centers generated at C10 in 1b and at C14 in 1c
(13) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737-1739.
(14) (a) Moon, H.-S.; Eisenberg, S. W. E.; Wilson, M. E.; Schore, N.
E.; Kurth, M. J. J. Org. Chem. 1994, 59, 6504-6505. (b) Maligres, P. E.;
Upadhyay, V.; Rossen, K.; Cianciosi, S. J.; Purick, R. M.; Eng, K. K.;
Reamer, R. A.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett.
1995, 36, 2195-2198. (c) Williams, D. R.; Cortez, G. S. Tetrahedron Lett.
1998, 39, 2675-2678.
(15) For the alternate approach to fragment B, see: Herdeis, C.; Luetsch,
K. Tetrahedron: Asymmetry 1993, 4, 121-131.
(16) For details, see Supporting Information.
Org. Lett., Vol. 8, No. 10, 2006
2041

Table 1. Intramolecular Cyclization Reaction of 2
yield (%)b
entry
Lewis acid
temp (°C)
-78
-78, -50, -20
-78
time (h)a
1a
1b
1c
1d
1
2
3
4
5
6
7
EtAlCl2
Et2AlCl
SnCl4
TiCl3(OiPr)
TiCl2(OiPr)2
TiCl(OiPr)3
BF3‚OEt2
6
20
25
25
29
18
0
40
36
24
31
0
40
36
49
40
19
0
0
0
0
5, 8, 12
2
4
4, 1.5
2, 2, 12
4
-78
0
-78, -50
-78, -50, -20
-78
57
84
0
0
25
45
27
a Time at the corresponding reaction temperature. b Isolated yields.
are correct, suggesting that further optimization of the
cyclization reaction of 2 would improve the diastereoselec-
tivity, and the transformations from 1b and 1c to the
compounds possessing correct stereochemistry could be
possible.
In conclusion, the spiro CD-ring moiety 1a possessing the
correct stereochemistry has been successfully constructed via
a Lewis acid promoted cyclization reaction of 2, which had
been prepared by the coupling of fragments A and B in a
convergent manner. Further studies toward the asymmetric
total synthesis of (+)-ophiobolin A, which include efficient
access to fragment A, and the improved stereoselectivity in
the cyclization of 2 are now in progress.
determination of compound 1d. This work was financially
supported in part by a Waseda University Grant for Special
Research Projects and a Grant-in-Aid for Scientific Research
on Priority Areas (Creation of Biologically Functional
Molecules (No. 17035082)) from The Ministry of Education,
Culture, Sports, Science, Sports and Technology (MEXT),
Japan. We are also indebted to 21COE Practical Nano-
Chemistry.
Supporting Information Available: Spectral data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. We thank Dr. Motoo Shiro of Rigaku
X-ray Research Laboratory for the X-ray crystal structure
OL060437X
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Org. Lett., Vol. 8, No. 10, 2006