Studies on the stability of 1,7,9-trioxadispiro[5.1.5.2]pentadecane system: The common tricyclic acetal moiety in pinnatoxins

Article abstract of DOI:10.1055/s-1998-1742

The stability of the common dispiroacetal moiety in pinnatoxins, the 1,7,9-trioxadispiro[5.1.5.2]pentadecane system, was investigated. The tricyclic keto acetal, of the natural form, was most favored among the possible isomers, however, its methylated for

Full text of DOI:10.1055/s-1998-1742

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Studies on the Stability of 1,7,9-Trioxadispiro[5.1.5.2]pentadecane System:
The Common Tricyclic Acetal Moiety in Pinnatoxins
Jun Ishihara, Tetsuya Sugimoto, and Akio Murai*
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo, 060-0810, Japan
FAX 011-706-2714; e-mail amurai@sci.hokudai.ac.jp
Received 24 February 1998
6)
Abstract
: The stability of the common dispiroacetal moiety in
2
2
corresponding tricyclic ketone
.
Compound was rather stable in the
1
pinnatoxins, the 1,7,9-trioxadispiro[5.1.5.2]pentadecane system, was
investigated. The tricyclic keto acetal, of the natural form, was most
favored among the possible isomers, however, its methylated form was
not so preferential to be isomerized readily in the presence of acid.
These stability results were supported by MM2 and AM1.
presence of acid, whereas the methylation product, , was labile under
the same condition. In this paper, we describe the stability studies of the
1,7,9-trioxadispiro[5.1.5.2]pentadecane system.
6)
3
In our previous studies, when triketone was subjected to HF in
CH CN, cleavage of the silyl groups and the subsequent cyclization
3
2
proceeded stereoselectively to afford the desired tricyclic compound in
78% yield, along with several isomers. The isomers could be
The trioxadispiroacetal moieties usually appear in nature in polyether
ionophores, and the construction of these tricyclic systems, linked in a
1)
2
transformed into on further treatment under the same conditions, thus
3
2
the total conversion yield of to amounted to 86% (Scheme 1). The
spiro fashion, represents
a synthetic challenge. The favored
3
acetalization of
could provide eight possible isomers, which
conformation of the spiroacetal would be predictable on the basis of
5
includefour 6,5,6-tricyclic keto-acetals and four 6,6,5-tricyclic ketones
(Scheme 2). The predominant product indicated that
thermodynamically most preferable in CH CN. In order to investigate
stabilizing anomeric and exo-anomeric effects that direct C-O bonds to
2)
6
2
would be
axial positions on the respective rings. Although several syntheses of
3)
the dispiroacetal systems were reported, the formation of spiroacetals
3
the stability of the trioxadispiro-acetal system, we reviewed the
additional acidic conditions. First, for the purpose of elucidating
provided low selectivity to afford a mixture of anomers due to the
cumulative stereoelectronic and steric effects of the isomers. Very
recently, we have reported the construction of the common
7)
3
solvent effects, the similar treatment of with HF in THF for 24 h was
2
attempted (Table 1). The cyclization provided as a major spiroacetal in
1
trioxadispiro-acetal moiety of pinnatoxins, shellfish poisons, isolated
4, 5)
63%, however, removal of the TBS group proceeded slowly to be
from Pinna muricata,
with high selectivity via methylation of the
Scheme 1
Scheme 2

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accompanied with decomposition products (entries 1 and 2). On the
other hand, when purified 2 was treated with aqueous HCl in THF, the
starting material was recovered in 69%, along with a mixture of dicyclic
products (entry 3). Under a nonaqueous condition, exposure of 2 to
predominance of 7. Accordingly, it is accepted that naturally occurring
acetal 2 would be the most stable among the possible isomers.
PTS·H O in THF provided 2 (quant.) without any isomerization (entry
2
5). It was clarified that 2 would be the thermodynamically most favored
tricyclic acetal in both CH CN and THF, and the energy differences
3
between 2 and the isomers would be significant. Next, we explored the
energy calculation of the dispiro compounds.
The tricyclic ketone 2 was converted to 1 in 90 % yield as a single
To simplify the calculation, we selected dimethyl compound 7 as a
8)
stereoisomer. Unexpectedly, when 1 was allowed to stand in old CDCl
3
model. Table 2 depicts the energy of the possible isomers relative to 7.
in an NMR tube for 12 h, the isomerization occurred to give a mixture of
Most of the 6,5,6-tricylic acetals would be more favored than the 6,6,5-
tricyclic ketones. There might be significant 1,3-diaxial repulsion in the
central ring of 6,6,5-tricyclic systems. It should be noted that the
optimal conformations of α-keto acetal in all isomers came from the
consequence of the stabilizing anomeric effect. The anomer effect
would be increased by the carbonyl group in the α-keto spiroacetal,
which can be attributed to the stereoelectronic effect of the carbonyl π-
10)
11)
two isomers (3:2); one was recovered 1, another was compound 9.
Similar transformations were observed by treatment with fresh CDCl in
3
the presence of a trace of HCl (Table 1, entry 6). The evidence of
destabilization was so intriguing that we examined the isomerization of
1 (Table 1). Exposure to HCl or PTS in THF provided a mixture of 1 and
9 in a ratio of 3:1 (entries 7 and 9). Since analogous operation of pure 9
furnished a mixture of 1 and 9 in the same ratio (entry 10), the
isomerization was suggested to be in thermodynamic equilibrium. It was
apparent that 1 would be unstable under acidic conditions, compared to
the precursor 2. Next, the calculations of the relative energy of the
possible isomers was evaluated again (Table 3). MM2 calculation
predicted that 10 would be the most favored isomer, however, the
differential energy was estimated to be only 0.5-1.1 kcal/mol (entries 1,
9)
orbital. Based on the calculations by MM2, cis-6,5,6-tricyclic isomer 7
was most preferred energetically, and the difference in potential energy
from the next stable isomer, 8 was evaluated as more than 1.8 kcal/mol
(entries 1 and 5). It could be rationalized that the structure of 7 would
maximize the anomeric stabilization and minimize any destabilizing
1,3-diaxial and dipole repulsion. AM1 calculations also suggested the

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2, and 3) and the preference for naturally occurring isomer, 10, would be
small. Based on AM1 level calculations, 11 was found to be the most
preferential isomer. These results were coincident to the experimental
observation of 1. It is considered that the keto-acetal 2 would be
stabilized by the anomeric effect enhanced by the presence of α-ketone,
while methyl compound 1 would be destabilized by the repulsion of the
central ring against the methyl or the hydroxyl group at C-15, as well as
the lack of above α-keto enhanced anomeric effect. Furthermore, the
Fehr, T.; Keller-Juslen, C.; King, H. D.; Hans-Rudolf, L; Kuhn,
M.; Wartburg, A. J. Antibiot. 1979, 32, 535. e) Liu, C.-M.;
Hermann, T. E.; Prosser, B. L. T.; Palleroni, N. J.; Westley, J. W.;
Miller, P. A. J. Antibiot. 1981, 34, 133. f) Westley, J. W.; Evans, R.
H., Jr.; Sello, L. H.; Troupe, N.; Liu, C.; Blount, J. F.; Pitcher, R.
G.; Williams, T. H.; Miller, P. A. J. Antibiot. 1981, 34, 139. g) Hu,
T.; Curtis, J. M.; Oshima, Y.; Quilliam, M. A.; Walter, J. A.;
Watson-Wright, J. L. C. J. Chem. Soc., Chem. Commun. 1995,
2159. Hu, T.; Curtis, J. M.; Walter, J. A.; Wright, J. L. C.
Tetrahedron Lett. 1996, 37, 7671.
hydrogen bonding of the hydroxyl group at C-15 with the
12)
tetrahydropyranyl oxygen atom might probably exist in 9.
The
isomerization ratios between 1 and 9 were slightly different in CDCl
and THF due to the difference in solvation effect. It was realized that 9
3
2)
3)
Delongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon Press: Oxford, pp. 4-53, 1983.
increased in relatively low dielectric solvent CDCl (ε=4.7), compared
3
a) Horita, K.; Nagato, S.; Oikawa, Y.; Yonemitsu, O. Tetrahedron
Lett. 1987, 28, 3253. b) Perron, F.; Albizati, K. F. J. Org. Chem.
1989, 54, 2047. c) Brimble, M. A.; Williams, G. M. Tetrahedron
Lett. 1990, 31, 3043. Brimble, M. A.; Williams, G. M. J. Org.
Chem. 1992, 57, 5818. d) McGarvey, G. J.; Stepanian, M. W.
Tetrahedron Lett. 1996, 37, 5461. McGarvey, G. J.; Stepanian, M.
W.; Bressette, A. R.; Ellena, J. F. Tetrahedron Lett. 1996, 37,
5465. e) For a review, see: Vaillancourt, V.; Pratt, N. E.; Perron, F.;
Albizati, K. F. The Total Synthesis of Natural Products 1992, 8,
533-691.
to THF (ε=7.4). In consequence, extreme predominance of 1 would be
lost over the isomers and would be isomerized partly to 9 easily.
4)
a) Uemura, D; Chou, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.;
Zheng, S.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155. b) Chou,
T.; Haino, T.; Kuramoto, M.; Uemura, D. Tetrahedron Lett. 1996,
37, 4027.
5)
6)
7)
Noda, T; Ishiwata, A.; Uemura, S.; Sakamoto, S.; Hirama, M.
Synlett 1998, 298.
Sugimoto, T.; Ishihara, J.; Murai, A. Tetrahedron Lett. 1997, 38,
7379.
Exposure of 3 to a mixture of Bu NF (3.4 eq) and AcOH (10 eq)
4
in THF at 25 °C for 1.5 h resulted in no reaction, whereas
treatment with Bu NF (10 eq) and AcOH (10 eq) afforded
4
complex mixtures.
8)
9)
All structures in the Table show the optimum conformations.
Based on the calculation, the central five-membered ring is able to
have two envelope conformations, which are estimated to have
almost the same energy. The H-NMR measurements at variable
temperatures supported the existence of two conformers of the
tetrahydrofuran ring in equilibrium.
1
Kirby, A. J The Anomeric Effect and Related Stereoelectronic
Effects at Oxygen; Springer-Verlag, Berlin Heidelberg New York
pp. 20-23, 1983.
1
10) The ratios of the mixture were determined by H-NMR analysis.
1
13
It was thus concluded that the ketone 2 would be more available as a
synthetic key intermediate, whereas the corresponding methyl
compound 1 has an ability to isomerize readily in the presence of
11) The structure of 9 was determined by H- and C-NMR, NOE,
COSY, HMBS, and HSQC spectra. The selected NOE correlations
of 9 are shown as follows:
13)
acid.
Acknowledgements. We are grateful to Dr. H. Yamada, Tokyo Institute
of Technology for helpful discussions.
References and Notes
22
1
1)
a) Kinashi, H.; Otake, N.; Yonehara, H.; Sato, S.; Saito, Y.
Tetrahedron Lett. 1973, 4955. b) Occolowitz, J. L.; Berg, D. H.;
Dobono, M.; Hamill, R. L. Biomed. Mass. Spectrosc. 1976, 3, 272.
c) Westley, J. W.; Blount, J. F.; Evans, R. H.; Liu, C. M. J.
Antibiot. 1977, 30, 610. d) Keller-Juslen, C.; King, H. D.; Kuhn,
M.; Loosli, H. R.; Von Wartburg, A. J. Antibiot. 1978, 31, 820.
9: colorless oil, [α]
-34 (c 0.17, CH OH); H-NMR (400 MHz,
3
D
CDCl ), δ 1.20 (3H, s, H-37), 1.36 (1H, m, H-22), 1.45 (1H, m, H-
3
13ax), 1.47 (1H, m, H-13eq), 1.54 (1H, m, H-22), 1.58 (1H, m, H-
14eq), 1.59 (1H, m, H-11), 1.64 (1H, m, H-17α), 1.64 (1H, m, H-
20), 1.67 (1H, m, H-21), 1.68 (1H, m, H-11), 1.77 (1H, m, H-21),
1.79 (1H, m, H-18α), 1.93 (1H, dt, J= 4.9, 13.2 Hz, H-14ax), 2.24

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-1
(1H, m, H-18β), 2.25 (1H, m, H-17b), 3.43 (1H, dd, J= 6.3, 10.3
Hz, H-24), 3.46-3.54 (2H, m, H-10), 3.59 (1H, dd, J= 6.3, 10.3
Hz, H-24), 3.77 (3H, s, MPM), 3.79-3.84 (1H, m, H-23), 3.94-
4.01 (1H, m, H-12), 4.39 (2H, s, MPM), 4.88 (2H, s, Bn), 6.87
cm ; IR (CHCl ), 3520, 3018, 3005, 2947, 2866, 1612, 1514,
3
1456, 1364, 1302, 1248, 1194, 1175, 1148, 1096, 1036, 1003,
-1
957, 860, 826, 766, 748, 700, and 671 cm .
12) On measurement of IR analysis of 9 in 0.03 M CHCl , a broad
3
(2H, d, J= 8.8 Hz, MPM), 7.22 (2H, d, J= 8.8 Hz, MPM), and
-1
signal was observed at 3520 cm , which was assignable to the
13
7.25-7.36 (5H, m, Bn); C-NMR (100 MHz, CDCl ), δ 21.32
3
hydrogen bonded hydroxyl group, whereas IR absorption of 1 in
(C21), 22.15 (C37), 27.87 (C22), 30.67 (C17), 31.51 (C13), 32.58
(C18), 36.43 (C14), 36.79 (C11), 37.24 (C20), 55.66 (MPM),
67.73 (C10), 68.14 (C12), 70.41 (C15), 73.68 (MPM), 74.06
(C24), 74.18 (Bn), 75.00 (C23), 110.49 (C19), 112.15 (C16),
114.67, 128.70, 128.95, 129.38, 130.53, 131.64, 139.53, and
160.79 (Ar); IR (neat), 3544, 3064, 2938, 2860, 1614, 1518, 1458,
1365, 1302, 1248, 1149, 1098, 1035, 1002, 960, 822, 735, and 696
-1
0.03 M CHCl solution displayed a sharp signal at 3568 cm ,
3
corresponding to a free hydroxyl group.
13) It was also reported that the unexpected rearrangements of the
trioxadispiroacetal compounds proceeded in the presence of acid.
see: Dorta, R. L.; Martín, A.; Suárez, E.; Betancor, C. J. Org.
Chem. 1997, 62, 2273.