Synthesis of the tricyclic skeleton of cyathins using Brook rearrangement-mediated [3 + 4] annulation

Article abstract of DOI:10.1021/ol0059753

(Formula presented) The tricyclic core of cyathins has been synthesized using a Brook rearrangement-mediated [3 + 4] annulation that we previously developed.

Full text of DOI:10.1021/ol0059753

ORGANIC
LETTERS
2000
Vol. 2, No. 13
1903-1905
Synthesis of the Tricyclic Skeleton of
Cyathins Using Brook
Rearrangement-Mediated [3 + 4]
Annulation
Kei Takeda,* Daisuke Nakane, and Mika Takeda
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical UniVersity,
2630 Sugitani, Toyama 930-0194, Japan
takedak@ms.toyama-mpu.ac.jp
Received April 20, 2000
ABSTRACT
The tricyclic core of cyathins has been synthesized using a Brook rearrangement-mediated [3 + 4] annulation that we previously developed.
Cyathins,1 isolated from bird nest fungi, and other members2-4
of this family, including erinacins (1, 2),5 which are
collectively called cyathins, continue to be of interest because
of their unusual 5-6-7 tricyclic ring system coupled with
their important biological activities (Figure 1). Recently,
erinacine E (2), one of the complex members of the cyathin
(1) (a) Allbutt, A. D.; Ayer, W. A.; Brodie, H. J.; Johri, B. N.; Taube,
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Figure 1.
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family, was shown to have potent nerve growth factor (NGF)
synthesis-stimulating activity5 and to be a k opioid receptor
agonist.6 Synthetic efforts have been described by several
groups,7 and two total syntheses of allocyathin B2 (3) have
been reported.8,9
We have recently developed a Brook rearrangement-
mediated [3 + 4] annulation for the stereoselective synthesis
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Ohizumi, Y.; Takaya, Y.; Oshima, Y. Tetrahedron Lett. 1998, 39, 6229-
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Sakamoto, H.; Ishiguro, Y.; Furukawa, S. Tetrahedron Lett. 1994, 35, 1569-
1572. (b) Kawagishi, H.; Shimada, A.; Shizuki, K.; Mori, H.; Okamoto,
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J. Antibiot. 1998, 51, 983-990.
10.1021/ol0059753 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/03/2000

of seven-membered carbocycles by the reaction of R,â-
unsaturated acylsilanes with the lithium enolates of alkenyl
methyl ketones.10 To demonstrate the effectiveness of the
methodology for the synthesis of functionalized cyclohep-
tenones, we decided to apply this method to the synthesis
of the tricyclic skeleton of the cyathin ring system. As a
target we selected the tricyclic compounds 4 and 5 bearing
the appropriate functionalities necessary for their conversion
to natural products, and we addressed two retrosynthetic
pathways defined as A and B that use the 5-6 ring systems
6 and 8 as three-carbon and four-carbon units in the key [3
+ 4] annulation, respectively (Scheme 1).
Scheme 2
by oxidation of the generated R-silyl alcohol. Oxidation with
DMSO/(COCl)2, PCC, and MnO2 resulted in a low yield of
14 with the concomitant formation of 12. The best result
was obtained when 1 equiv of n-Pr4NRuO4 (TPAP)14 was
used to provide 13 in 57% yield along with 14% of 12. The
use of a catalytic amount of TPAP and/or a longer reaction
time resulted in increased formation of 12.
Scheme 1
As a four-carbon unit in the [3 + 4] annulation, we initially
examined several vinyl methyl ketone derivatives 7 which
have a leaving group such as a phenylthio or phenylsulfonyl
group at the â-position, anticipating that facile elimination
of LiX would occur to lead to an enone derivative in the
annulation product. Not unexpectedly, significant decom-
position of the substrate occurred during the formation of
the enolate. Next, we turned to the use of the lithium enolate
of 4-methoxy-3-buten-2-one. When the lithium enolate was
added to a THF solution of 13 at 0 °C and the solution was
then warmed to room temperature, tricycliclic ketone 14 was
obtained as an epimeric mixture at C(9) in 47% yield along
with recovery of 13 (14%) (Scheme 3).
Path A. Acylsilane 13 was prepared by a four-step
sequence starting with known enone 1011 (Scheme 2). When
10 was reacted with Me3SiCN in the presence of ZnI2
followed by elimination of silanol with POCl3,12 unsaturated
nitrile 11 was obtained in 65% yield. Reduction of 11 with
DIBAL followed by an acid quench afforded aldehyde 12
in 76% yield. Conversion of 12 into acylsilane 13 was carried
out by reaction with dimethyl(phenyl)silyllithium13 followed
Scheme 3
(7) (a) Ayer, W. A.; Ward, D. E.; Browne, L. M.; Delbaere, L. T. J.;
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Sato, T.; Yoshii, E.; Koizumi, T.; Shiro, M. J. Am. Chem. Soc. 1998, 120,
4947-4959. (d) Takeda, K.; Nakajima, A.; Takeda, M.; Yoshii, E.; Zhang,
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The structures were assigned by analogy with structurally
related compounds,10c and the 5,10-cis stereochemistry of
(14) (a) Griffith, W. P.; Ley, S. V.; Whitecombe, G. P.; White, A. D. J.
Chem. Soc., Chem. Commun. 1987, 1625-1627. (b) Griffth, W. P.; Ley,
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1 1981, 2520-2526.
1904
Org. Lett., Vol. 2, No. 13, 2000

14 was based on J5,10 (ca. 0 Hz for both isomers) and NOESY
experiments.
Scheme 5
Path B. Bicyclic methyl ketone 16 was prepared from 10
via a two-step sequence: (1) addition of ethynylmagnesium
bromide and (2) Rupe rearrangement15 (Scheme 4).
Scheme 4
The key [3 + 4] annulation proceeded smoothly when 16
was added to a solution of acryloylsilane 17a at -80 °C
and allowed to warm to 0 °C to afford 20a as a single
diastereomer in 60% yield (Scheme 5). The 6,5,10-cis
stereochemistry was assigned on the basis of J5,6 ) 7.3 Hz,
J5,10 ) 6.6 Hz, and a NOESY correlation between H-6 and
H-10. The relative stereochemisty of Me-15 was tentatively
assigned as trans to H-5 and H-6 since no NOESY correlation
between the 9-Me and H-5 was observed. The observed
stereoselectivity can be rationalized by a concerted pathway
of the anionic oxy-Cope rearrangement of the cis-1,2-
divinylcyclopropanediolate intermediate 19 which was ste-
reoselectively derived from 1,2-adduct 18 by Brook rear-
rangement, followed by internal trapping of the generated
carbanion by the ketone carbonyl.10c The stereoselectivity,
which is different from that in the reaction of 13, remains
unclear at the present time. Although the trimethylsilyl group
at C-10 could be removed by exposure to NBS followed by
n-Bu4NF to give an enone derivative,10c the reaction turned
out to produce a low yield and to have poor reproducibility.
We then decided to use trimethylsilyl derivative 17b,
anticipating a more facile conversion into the enone deriva-
tive. The [3 + 4] annulation using 17b proceeded in a similar
manner to give 20b as a single isomer in 50% yield.
Oxidative desilylation of 20b was realized after DIBAL
reduction to alcohol 21 to afford enone 22 in 79% yield.
The configuration of 9-Me was assigned on the basis of a
NOESY correlation between 9-Me and H-10 and a com-
parison of 1H NMR of its O-silylated derivative 23 with that
of 6-methyl derivative of 23, which is known.8b
In summary, we have demonstrated the synthetic utility
of our Brook rearrangement-mediated [3 + 4] annulation
by application to the synthesis of the tricyclic ring system
of cyathins.
Acknowledgment. This research was partially supported
by a grant-in-aid for Scientific Research (Grant 10671986)
from the Japanese Ministry of Education, Sciences, Sports
and Culture.
Supporting Information Available: Full experimental
details and characterization data for all new compounds
described. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Swaminathan, S.; Narayanan, K. V. Chem. ReV. 1971, 71, 429-
438.
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