Synthetic studies on cyathins: Enantioselective total synthesis of (+)-allocyathin B2

Article abstract of DOI:10.1021/ol048010i

(Chemical Equation Presented) The enantioselective total synthesis of (+)-allocyathin B₂ has been achieved. Our approach features a convergent enantioselective construction of the 5-6-7 tricyclic core system using the originally developed chira

Full text of DOI:10.1021/ol048010i

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4897-4900
Synthetic Studies on Cyathins:
Enantioselective Total Synthesis of
(+)-Allocyathin B2
Masashi Takano, Akinori Umino, and Masahisa Nakada*
Department of Chemistry, School of Science and Engineering, Waseda UniVersity,
3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
mnakada@waseda.jp
Received September 29, 2004
ABSTRACT
The enantioselective total synthesis of (
of the 5 7 tricyclic core system using the originally developed chiral building blocks via asymmetric catalysis, the intramolecular aldol
reaction in high yield, successful samarium diiodide-mediated ring expansion, and a newly developed double-bond installation method.
+)-allocyathin B2 has been achieved. Our approach features a convergent enantioselective construction
−6−
Since the first isolation and structure elucidation of cyathins
from bird nest fungi by Ayer and co-workers in 1970,1k-m
numerous compounds possessing the cyathane skeleton, that
is, cyathins,1 allocyathins,1a,1d,1f-j,2 striatins,1c,3 cyafrins,1d-f,4
sarcodonins,1a,2,5b erinacines (cyathane-xylosides),5 and sca-
bronins,6 have been isolated and characterized. With the
exception of a few compounds such as allocyathin B2,
erinacine A, and sarcodonin A, all cyathins possess an
(1) (a) Shibata, H.; Tokunaga, T.; Karasawa, D.; Hirota, A.; Nakayama,
M.; Nozaki, H.; Tada, T. Agric. Biol. Chem. 1989, 53, 3373-3375. (b)
Ayer, W. A.; Lee, S. P. Can. J. Chem. 1979, 57, 3332-3337. (c) Hecht, H.
J.; Hoefle, G.; Steglich, W.; Anke, T.; Oberwinkler, F. J. Chem. Soc. Chem.
Commun. 1978, 15, 665-666. (d) Ayer, W. A.; Browne, L. M.; Fernandez,
S.; Ward, D. E.; Yoshida, T. ReV. Latinoameric. Quim. 1978, 9, 177-184.
(e) Ayer, W. A.; Nakashima, T. T.; Ward, D. E. Can. J. Chem. 1978, 56,
2197-2199. (f) Ayer, W. A.; Yoshida, T.; Van Schie, D. M. J. Can. J.
Chem. 1978, 56, 2113-2120. (g) Ayer, W. A.; Browne, L. M.; Mercer, J.
R.; Taylor, D. R.; Ward, D. E. Can. J. Chem. 1978, 56, 717-721. (h) Ayer,
W. A.; Taube, H. Can. J. Chem. 1973, 51, 3842-3854. (i) Ayer, W. A.;
Carstens, L. L. Can. J. Chem. 1973, 51, 3157-3160. (j) Ayer, W. A.; Taube,
H. Tetrahedron Lett. 1972, 19, 1917-1920. (k) Allbutt, A. D.; Ayer, W.
A.; Brodie, H. J.; Johri, B. N.; Taube, H. Can. J. Microbiol. 1971, 17,
1401-1407. (l) Johri, B. N.; Brodie, H. J. Can. J. Microbiol. 1971, 17,
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Taube, H. Experientia 1971, 27, 853.
(5) (a) Kenmoku, H.; Tanaka, K.; Okada, K.; Kato, N.; Sassa, T. Biosci.
Biotechnol. Biochem. 2004, 68, 1786-1789. (b) Kamo, T.; Imura, Y.; Hagio,
T.; Makabe, H.; Shibata, H.; Hirota, M. Biosci. Biotechnol. Biochem. 2004,
68, 1362-1365. (c) Kenmoku, H.; Shimai, T.; Toyomasu, T.; Kato, N.;
Sassa, T. Biosci. Biotechnol. Biochem. 2002, 66, 571-575. (d) Kenmoku,
H.; Kato, N.; Shimada, M.; Omoto, M.; Mori, A.; Mitsuhashi, W.; Sassa,
T. Tetrahedron Lett. 2001, 42, 7439-7442. (e) Lee, E. W.; Shizuki, K.;
Hosokawa, S.; Suzuki, M.; Suganuma, H.; Inakuma, T.; Li, J.; Ohnishi-
Kameyama, M.; Nagata, T.; Furukawa, S.; Kawagishi, H. Biosci. Biotechnol.
Biochem. 2000, 64, 2402-2405. (f) Kenmoku, H.; Sassa, T.; Kato, N.
Tetrahedron Lett. 2000, 41, 4389-4393. (g) Omori-Satoh, T.; Yamakawa,
Y.; Mebs, D. Toxicon 2000, 38, 1561-1580. (h) Saito, T.; Aoki, F.; Hirai,
H.; Inagaki, T.; Matsunaga, Y.; Sakakibara, T.; Sakemi, S.; Suzuki, Y.;
Watanabe, S.; Suga, O.; Sujaku, T.; Smogowicz, A. A.; Truesdell, S. J.;
Wong, J. W.; Nagahisa, A.; Kojima, Y.; Kojima, N. J. Antibiot. 1998, 51,
983-990. (i) Mebs, D.; Omori-Satoh, T.; Yamakawa, Y.; Nagaoka, Y.
Toxicon 1996, 34, 1313-1316. (j) Kawagishi, H.; Shimada, A.; Hosokawa,
S.; Mori, H.; Sakamoto, H.; Ishiguro, Y.; Sakemi, S.; Bordner, J.; Kojima,
N.; Furukawa, S. Tetrahedron Lett. 1996, 37, 7399-7402. (k) Kawagishi,
H.; Shimada, A.; Shizuki, K.; Mori, H.; Okamoto, K.; Sakamoto, H.;
Furukawa, S. Heterocycl. Commun. 1996, 2, 51-54. (l) Kawagishi, H.;
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Y.; Furukawa, S. Tetrahedron Lett. 1994, 35, 1569-1572.
(2) Shibata, H.; Irie, A.; Morita, Y. Biosci. Biotechnol. Biochem. 1998,
62, 2450-2452.
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30, 221-225.
(4) Hirota, M.; Morimura, K.; Shibata, H. Biosci. Biotechnol. Biochem.
2002, 66, 179-184.
10.1021/ol048010i CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/26/2004

unusual 5-6-7 tricyclic carbon skeleton, including a trans-
fused 6-7 ring system, and a common structural feature is
two stereogenic quaternary carbons existing at its ring
junctures.
On the other hand, the structural complexity and diversity
arise from the different degrees of oxidation not only around
the five-membered and seven-membered rings but also at
the C19 position of sarcodonins and the C17 position of
scabronins (Scheme 1). Furthermore, the striatins and eri-
approaches to construct these attractive natural products.8
To date, four total syntheses of cyathins have been reported;
however, three of them, allocyathin B2,8i-k B3,8a,d and
sarcodonin G,8f have been synthesized as a racemate. Snider
reported the first synthesis of (+)-erinacine A,8j,k which was
derived from (()-allocyathin B2 and (+)-xylose. Thus, no
enantioselective synthesis of cyathins has been accomplished.
We report herein the enantioselective total synthesis of (+)-
allocyathin B2 (1) through highly convergent and enantio-
selective construction of the 5-6-7 tricyclic core system
using chiral building blocks prepared via asymmetric ca-
talysis.
Scheme 1
Since 1 has been derived from 2,8j,k our own strategy for
the synthesis of 1 is based on the retrosynthetic analysis of
2 illustrated in Scheme 1. We envisioned that 2 could be
derived from 3 via installation of the ester group, followed
by iodomethylation, samarium diiodide-mediated ring expan-
sion, and subsequent introduction of the double bond.
Tricyclic compound 3 would arise from diketone 4 via the
intramolecular aldol reaction, followed by dehydration,
installation of the isopropyl group, and dehydration. Then,
4 was disconnected to two chiral fragments, Fragments A
(5) and B (6). Fragments A and B would be readily prepared
via our established asymmetric catalysis for chiral building
blocks;9,10 hence, we started to prepare Fragment A via the
catalytic asymmetric intramolecular cyclopropanation reac-
tion9 and Fragment B via baker’s yeast reduction.10
Enantiomerically pure 7 (Scheme 2),11 which had been
prepared by the catalytic asymmetric intramolecular cyclo-
propanation of the corresponding R-diazo-â-keto sulfone, was
reacted with thiophenol (99%), and the mesityl sulfonyl
group was selectively removed by lithium naphthalenide12
with the thiophenyl group remaining intact to generate 8
(86%). Formation of ethylene ketal (91%), following oxida-
tion with m-chloroperbenzoic acid to the corresponding
sulfoxide (quantitative), and Pummerer rearrangement af-
forded Fragment A (5) (87%).
nacines possess a unique structure categorized as xylose
conjugates of cyathins.
Some compounds in this large cyathin family show strong
antibiotic activity, and the erinacines5j-l and scabronines6
have been shown to exhibit significant nerve growth factor
(NGF) synthesis-stimulating activity. Moreover, erinacine E,
one of the complex members of this family, was recently
shown to have not only potent NGF synthesis-stimulating
activity but also κ-opioid receptor agonist activity.5h Since
NGF does not cross the blood-brain barrier (BBB) and this
native peptide is rapidly metabolized in vivo,7a the use of
small nonpeptide stimulators of NGF synthesis is perceived
as a promising way to treat such neurodegenerative diseases
as Alzheimer, Parkinson, and Huntington diseases.7b-d
The structural complexity and biological activity of the
cyathins described above have drawn much attention to their
synthesis, and several groups have developed different
As shown in Scheme 3, preparation of Fragment B (6)
commenced with diol 9 (>99% ee), which was available by
(8) (a) Ward, D. E.; Gai, Y.; Qiao, Q.; Shen, J. Can. J. Chem. 2004, 82,
254-267. (b) Thominiaux, C.; Chiaroni, A.; Desmaele, D. Tetrahedron
Lett. 2002, 43, 4107-4110. (c) Wender, P. A.; Bi, F. C.; Brodney, M. A.;
Gosselin, F. Org. Lett. 2001, 3, 2105-2108. (d) Ward, D. E.; Gai, Y.; Qiao,
Q. Org. Lett. 2000, 2, 2125-2127. (e) Takeda, K.; Nakane, D.; Takeda,
M. Org. Lett. 2000, 2, 1903-1905. (f) Piers, E.; Gilbert, M.; Cook, K. L.
Org. Lett. 2000, 2, 1407-1410. (g) Wright, D. L.; Whitehead, C. R.;
Sessions, E. H.; Ghiviriga, I.; Frey, D. A. Org. Lett. 1999, 1, 1535-1538.
(h) Magnus, P.; Shen, L. Tetrahedron 1999, 55, 3553-3560. (i) Tori, M.;
Toyoda, N.; Sono, M. J. Org. Chem. 1998, 63, 306-313. (j) Snider, B. B.;
Vo, N. H.; O’Neil, S. V. J. Org. Chem. 1998, 63, 4732-4740. (k) Snider,
B. B.; Vo, N. H.; O’Neil, S. V.; Foxman, B. M. J. Am. Chem. Soc. 1996,
118, 7644-7645. (l) Piers, E.; Cook, K. L. Chem. Commun. 1996, 16,
1879-1880. (m) Dahnke, K. R.; Paquette, L. A. J. Org. Chem. 1994, 59,
885-899. (n) Ward, D. E. Can. J. Chem. 1987, 65, 2380-2384. (o) Ayer,
W. A.; Ward, D. E.; Browne, L. M.; Delbaere, L. T. J.; Hoyano, Y. Can.
J. Chem. 1981, 59, 2665-2672.
(6) (a) Obara, Y.; Nakahata, N.; Kita, T.; Takaya, Y.; Kobayashi, H.;
Hosoi, S.; Kiuchi, F.; Ohta, T.; Oshima, Y.; Ohizumi, Y. Eur. J. Pharm.
1999, 370, 79-84. (b) Kita, T.; Takaya, Y.; Oshima, Y.; Ohta, T.; Aizawa,
K.; Hirano, T.; Inakuma, T. Tetrahedron 1998, 54, 11877-11886. (c) Ohta,
T.; Kita, T.; Kobayashi, N.; Obara, Y.; Nakahata, N.; Ohizumi, Y.; Takaya,
Y.; Oshima, Y. Tetrahedron Lett. 1998, 39, 6229-6232.
(7) (a) Dijkhuizen, P. A.; Verhaagen, J. Neurosci. Res. Commun. 1999,
24, 1-10. (b) Rosenberg, S. Annu. Rep. Med. Chem. 1992, 27, 41-48. (c)
Bigge, C. F.; Boxer, P. A. Annu. Rep. Med. Chem. 1994, 29, 13-22. (d)
Saragovi, H. U.; Burgess, K. Exp. Opin. Ther. Patents 1999, 9, 737-751.
(9) 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.
(10) Iwamoto, M.; Kawada, H.; Tanaka, T.; Nakada, M. Tetrahedron
Lett. 2003, 44, 7239-7243.
(11) Enantiomerically pure 7 was easily obtained by recrystallization due
to its highly crystalline nature.
(12) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924-
1930. Sodium amalgam, magnesium, and SmI2 gave fruitless results.
4898
Org. Lett., Vol. 6, No. 26, 2004

both reaction points in the electrophile moiety and in the
nucleophile moiety are next to the quaternary carbon. The
preliminary studies on this reaction using a base in protic
solvent15 revealed that this reaction attained equilibrium
between 4 and 15 probably due to the retro-aldol reaction.
Accordingly, the reaction in aprotic solvent was next
examined. Although no reaction occurred with amines,16 use
of potassium t-butoxide in benzene gratifyingly improved
the yield to 94%.17
Scheme 2
Dehydration of 15 with thionyl chloride and pyridine
afforded a separable mixture of 16 (71%) and 17 (11%),18
and 16 was reacted with isopropenyllithium to afford 18
(72%, at 61% conversion). Hydrogenation of the isopropenyl
group and hydrogenolysis of the MPM group took place in
a one-pot operation (96%), and the following Dess-Martin
oxidation generated 19 (92%). Dehydration of 19 with thionyl
chloride and pyridine afforded a mixture of regioisomeric
alkenes; however, refluxing this mixture in benzene in the
presence of p-toluenesulfonic acid successfully caused
complete isomerization of the nonconjugated diene to afford
3 (77%, two steps).
Ring expansion of the cyclohexenone moiety of 3 em-
ployed Hasegawa’s method8f,19 because this method could
easily generate the requisite ring-expanded γ-keto ester 21.
For this purpose, 3 was first converted to the corresponding
â-keto ester using Mander’s reagent (87%),20 followed by
iodomethylation21 to produce 20 as a single stereoisomer
(86%).22 Exposure of 20 to samarium diiodide effectively
caused ring expansion to furnish the desired γ-keto ester 21
as a mixture of diastereomers (91%, 1.9:1).
our established method,10 that is, baker’s yeast-mediated
reduction and subsequent stereoselective reduction with Me4-
NBH(OAc)3. Removal of the benzyl ether of 9 by hydro-
genolysis (quantitative) and subsequent formation of ani-
sylidene gave 10 as the sole product (90%).10 Formation of
TBS ether (quantitative) and subsequent regioselective
reduction of the anisylidene group by DIBAL-H afforded
11 (97%). Finally, alcohol 11 was converted to Fragment B
(6) under the conventional conditions (93%).
Scheme 3
To introduce the double bond into 21, such known one-
pot methods as those using (PhSeO)2O23 or IBX24 were
examined; however, no products were obtained. Hence, we
decided to find new conditions for the conversion from 21
to 2. After several attempts, we successfully found that the
dienolate formed from the keto-ester 21 could be converted
to 2. That is, 21 was first treated with excess LDA (5.0 equiv)
in THF, and then the generated dienolate of 21 was treated
with iodine (2.0 equiv) to afford 2 in a one-pot operation
(71%). This one-pot reaction would involve the isomerization
(15) Intramolecular aldol reaction of 4 by K2CO3 in ethanol at reflux
temperature afforded a mixture of 4 (42%) and 15 (47%).
(16) DBU and 1,1,3,3-tetramethylguanidine were tested.
(17) Molecular modeling suggests that this dramatic change could arise
from the chelate formed between the hydroxyl and the keto groups of 15
with a potassium cation. Structure of 15 was elucidated as shown in Scheme
4 by X-ray crystallographic analysis. The CIF file is available; see
Supporting Information.
(18) Dehydration of 15 with PTSA (cat.) produced only the MPM-
deprotected 17 (45%).
(19) (a) Hasegawa, E.; Kitazume, T.; Suzuki, K.; Tosaka, E. Tetrahedron
Lett. 1998, 39, 4059-4062. For extensive studies, see: (b) Chung, S. H.;
Cho, M. S.; Choi, J. Y.; Kwon, D. W.; Kim, Y. H. Synlett. 2001, 1266-
1268.
With Fragments A and B in hand, coupling of these
fragments was executed (Scheme 4). Fragments B was
treated with t-BuLi in Et2O, and the resulting organolithium
compound was reacted with Fragment A to generate 12
(41%); use of a mixture of Et2O/THF (10:1) as a solvent
greatly improved the yield to 79%.13 12 was converted to
methyl xantate 13 (91%), followed by tin-hydride reduction14
to produce 14 (89%). Both protective groups in 14, TBS
ether and ethylene ketal, were cleanly removed under the
acidic conditions (quantitative), and subsequent Dess-Martin
oxidation formed diketone 4 (93%).
(20) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425-5428.
(21) Clark, J. H.; Miller, J. M. J. Chem. Soc., Perkin Trans. 1 1977,
1743-1745.
Now, the stage was set for the intramolecular aldol reaction
to form the six-membered ring, which is the central part of
the cyathane skeleton. This reaction was challenging because
(22) Configuration was elucidated by NOE.
(23) Barton, D. H. R.; Lester, D. J.; Ley, S. V. J. Chem. Soc., Chem.
Commun. 1978, 130-131.
(24) (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc.
2000, 122, 7596-7597. (b) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.
Angew. Chem., Int. Ed. 2002, 41, 993-996. (c) Nicolaou, K. C.; Gray, D.
L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem., Int. Ed. 2002, 41,
996-1000.
(13) 12 was obtained as a mixture of diastereomers in ratios of 1.3:1 in
Et2O and 1:2 in Et2O/THF.
(14) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574-1586.
Org. Lett., Vol. 6, No. 26, 2004
4899

Scheme 4
from the initially formed R,â-unsaturated ketone to the
mediated ring expansion, and a newly developed double-
bond installation method. Now envisioned in our laboratory
is the development of a new access to the trans-fused 6-7
ring system of cyathins, which is surmised to be possible
via the intermediate prepared in this synthesis. Further
progress of our studies will be reported in due course.
thermodynamically more stable â,γ-unsaturated ketone 2 via
the enolate. This transformation is clean and easy to operate
and, hence, would be advantageous for preparative purposes.
The known transformations from 2 to 1,8j,k that is,
stereoselective reduction of ketone and ester in 2 (89%) and
selective oxidation of the resultant allylic alcohol with MnO2
(90%), were successfully employed to complete the total
synthesis of (+)-allocyathin B2. Synthetic (+)-allocyathin
B2 proved to be identical in all respects to the reported
spectral data (1H NMR,8j,k IR,1b MS,1b [R]D,1b and 13C
NMR8j,k).
In summary, the enantioselective total synthesis of (+)-
allocyathin B2 has been achieved. This approach features the
convergent enantioselective construction of the 5-6-7
tricyclic core system using the originally developed chiral
building blocks via asymmetric catalysis, the intramolecular
aldol reaction in high yield, successful samarium diiodide-
Acknowledgment. We thank Ms. Yuri Fujisawa for early
experiments. This work was financially supported in part by
The Sumitomo Foundation, Uehara Memorial Foundation,
and Waseda University Grant for Special Research Projects.
We are also indebted to 21COE “Practical Nano-Chemistry”.
Supporting Information Available: Spectral data for all
new compounds and X-ray data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
OL048010I
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Org. Lett., Vol. 6, No. 26, 2004