Enantio- and stereocontrolled formation of the bisspiroacetal core of spirolide B

Article abstract of DOI:10.1016/j.tetlet.2004.08.156

The bisspiroacetal core of spirolide B, a marine natural toxin, was synthesized from triketone 10 via one-step bisspiroacetalization, methylation, and silylation accompanied by isomerization of the C-15 spirocenter. The equilibrium of two isomers under ac

Full text of DOI:10.1016/j.tetlet.2004.08.156

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7855–7858
Enantio- and stereocontrolled formation of the bisspiroacetal
core of spirolide B
Jun Ishihara,a,* Tomoko Ishizaka,b Takanori Suzukib and Susumi Hatakeyamaa
aGraduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan
bGraduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 28 July 2004;revised 26 August 2004;accepted 26 August 2004
Available online 11 September 2004
Abstract—The bisspiroacetal core of spirolide B, a marine natural toxin, was synthesized from triketone 10 via one-step bisspiro-
acetalization, methylation, and silylation accompanied by isomerization of the C-15 spirocenter. The equilibrium of two isomers
under acidic conditions was also examined.
Ó 2004 Elsevier Ltd. All rights reserved.
Recently, a new class of marine toxins containing an
azaspirocyclic moiety such as spirolides,1 pinnatoxins,2
gymnodimines,3 and pteriatoxins,4 has been isolated
from shellfish and dinoflagellate. The toxicological
properties of these compounds would be attributed to
the spirocyclic imine moiety,5 which would be biogenet-
ically constructed by an intramolecular Diels–Alder
reaction via exo-addition.2,3 In the course of our syn-
thetic studies of the azaspirocyclic compounds, we have
successfully constructed the azaspirocyclic moiety based
on asymmetric Diels–Alder reaction of a N-carbamate
a-methylene-lactam.6 Spirolides were isolated from the
digestive glands of mussels Mytilus edulis and scallops
Placopecten magellanicus, and its origin was known to
be the dinoflagellate Alexandrium ostenfeldii.7,8 The
structure was featured by the macrocyclic framework
containing the azaspirocyclic moiety and the bisspiroac-
etal. The biological properties are characterized by the
rapid onset of symptoms in the mouse bioassay, and
the potential effects of spirolides are evaluated with re-
spect to an acetylcholine receptor.9 Although the rela-
tive stereochemistry of spirolides has been investigated
on the basis of NMR and molecular modeling method,
the stereochemistries at C-2 and C-4 have remained
uncertain except for their syn-relationship.7a Since spiro-
lides bear a very close structural resemblance to pinna-
toxin, the absolute structure is predicted to be similar
to that of pinnatoxin.10 The unique structural feature
and biological activity prompted us to synthesize spiro-
lide B. Herein we disclosed the enantio- and stereo-
controlled synthesis of the C-10/C-24 segment,
bisspiroacetal core of spirolide B.
Our synthetic strategy of spirolide B involves one-step
formation of bisspiroacetal 1 from acyclic triketone 2
(Scheme 1). We assumed that methylation of 1 would
proceed with high diastereoselectivity due to the axial
attack of nucleophile to the cyclic ketone.11 The bisspi-
roacetal moiety appears in some polyether ionophores
Keywords: Spirolide;Bisspiroacetal.
*
Corresponding author. Tel./fax: +81 95 819 2427;e-mail: jishi@
net.nagasaki-u.ac.jp
Scheme 1. Spirolide B and its retrosynthetic analysis.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.156

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J. Ishihara et al. / Tetrahedron Letters 45 (2004) 7855–7858
and marine natural products.12 However, the stereo-
selective formation of 1,7,9-trioxadispiro[5.1.4.2]tetra-
decane moiety occurring in spirolides has not been
established yet. Since bisspiroacetalization of 2 might
produce eight possible isomers including four 6,5,5-tri-
cyclic acetals and four 5,6,5-ones, it is very much chal-
lenging to construct the desired tricyclic bisspiroacetal
core stereoselectively.13
Cleavage of epoxide 314 with Me2CuCNLi215 afforded a
mixture of desired 1,3-diol 4 and the corresponding 1,2-
diol, which was easily removed by treatment with NaIO4
(Scheme 2). Selective iodination of the primary alcohol
in 4, followed by sulfonylation, gave 5 in good yield.
The secondary alcohol in 5 was inverted by a three-step
sequence involving mesylation, displacement with acet-
oxy anion, and removal of the acetyl group to afford 6
in good yield. For this purpose, Mitsunobu inversion
turned out to be unsuccessful. Silylation of 6 afforded
sulfone 7 quantitatively. Another subunit 8 was pre-
pared from 3-butyn-1-ol according to the procedure
we have established earlier.16 Coupling of both subunits
7 and 8, followed by oxidation and desulfurization, fur-
nished compound 9 in 86% overall yield (Scheme 2).
Ruthenium tetraoxide oxidation of the alkyne in 9 led
to triketone 10 in 74% yield.17
Scheme 2. Reagents and conditions: (a) Me2CuCNLi2, THF–Et2O
(2:1), ꢀ20°C, 19h (4:1,2-diol = 6.7:1);(b) NaIO 4, MeOH–pH5.5 buffer
(2:1), 23°C, 30min (68% for two steps);(c) I , PPh3, imidazole, THF,
2
0°C, 1.5h (77%);(d) NaSO 4PhÆ2H2O, DMF, 23°C, 10h (85%);(e)
MsCl, Et3N, DMAP, CH2Cl2, 23°C, 2.5h;(f) Bu 4NOAc, PhMe,
reflux, 18h;(g) K 2CO3 MeOH, 23°C, 10h (90% for three steps);(h)
TBSOTf, 2,6-lutidine, CH2Cl2, 0°C, 1.5h (100%);(i) BuLi, THF,
ꢀ78°C, 30min then 7;(j) DMPI, NaHCO 3, CH2Cl2, 23°C, 40min;(k)
SmI2, MeOH, THF, 0°C, 40min (86% for three steps);(1) RuO 2ÆH2O,
NaIO4, CCl4–MeCN–H2O (1:1:1:5), 23°C, 10h (74%).
With the required triketone 10 in our hands, we then
investigated its one-step bisspiroacetalization (Scheme
3). When 10 was exposed to HF–pyridine in MeCN at
23°C for 8.5h, the acetalization proceeded smoothly
to generate a 1:4 mixture of the desired compound 11
and its C-15 epimer 11a in 81% yield, along with a small
amount of other spiro-isomers. These unidentified spiro-
isomers were also converted to 11 and 11a under the
above-mentioned acetalization conditions. As a result,
a 1:4 mixture of 11 and 11a was obtained in 85% total
yield. It is interesting to note that, in this particular reac-
tion, the corresponding 5,6,5-membered bisspiroacetals
were not produced at all. Although 11 and 11a were sep-
arable by HPLC, this mixture was directly subjected to
the subsequent methylation to afford a 1:4 mixture of
12 and 12a.18 It should be noted that the methylation
proceeded exclusively by virtue of the axial attack to
11 as well as 11a. Silylation of the carbinol in 12 and
12a with TBSOTf and 2,6-lutidine resulted in the iso-
merization of the C-15 spirocenter to give a 2:1 mixture
of 13 and 13a.19 Eventually desired acetal 13 was
obtained as a major isomer in spite of the possibility
of production of eight bisspiroacetals. It is rationalized
that the protection of the methyl carbinol in 12a would
deprive the stabilization of the intramolecular hydrogen
bonding between the tert-hydroxyl group and the acetal
oxygen. X-ray crystallographic analysis of di-p-bromo-
benzoate 14 derived from 13 confirmed its stereochemis-
try as shown in Figure 1. The stereochemistry of 13a
Scheme 3. Reagents and conditions: (a) HFÆpy, MeCN, 23°C, 8.5h, 85% (one recycle);(b) MeLi, THF, ꢀ78°C, 30min, 99%;(c) TBSOTf,
2,6-lutidine, CH2Cl2, 0°C ! 20°C, 1h, 13: 53%, 13a: 29%.

J. Ishihara et al. / Tetrahedron Letters 45 (2004) 7855–7858
7857
Figure 1. X-ray crystallography of acetal compounds.
was deduced by X-ray crystallographic analysis of diol
15.20
instance, the potential energy of 12 was 3.2kcal/mol
higher than 12a, and silyl ether 13 has 1.8kcal/mol
higher energy than 13a. Notably, the differential poten-
tial energy between 13 and 13a is lower than that be-
tween 12 and 12a. In the event, the hydrogen bonding
of the C-15 hydroxyl group with the spiroacetal oxygen
play an important role for stabilization of 12a. On the
other hand, treatment of 13a either with TBSOTf and
2,6-lutidine (run 8) or with TfOH and 2,6-lutidine (run
9) caused no isomerization. These results suggest that
the isomerization of the C-15 acetal would proceed be-
fore silylation of the tertiary alcohol. One explanation
for the results is that silylation of 12 would take place
faster than that of 12a, so that 13 would be preferen-
tially produced through equilibrated isomerization of 12.
We next examined acid-catalyzed isomerization of ace-
tals (Table 1). When 13a was exposed to a catalytic
amount of CSA, a 1:2 mixture of 13 and 13a was ob-
tained (run 1). Treatment of 13 with CSA also afforded
the same 1:2 mixture (run 7), suggesting that these reac-
tions were thermodynamically controlled. The equilib-
rium ratio of 13 and 13a could be evaluated to be ca.
1:2 in the presence of either Brønsted acid or Lewis acid
capable of coordinating to the acetal oxygens (runs 2–6).
Molecular mechanics calculation was performed on the
possible spiroacetal isomers, using AMBER force field.
The calculations show that unnatural isomers at C-15
11a, 12a, and 13a were preferred energetically to other
isomers including natural isomers (11, 12, 13). For
In conclusion, we have established the formation of bis-
spiroacetal core of spirolide B involving one-step bisspi-
roacetalization, and further studies toward the synthesis
of spirolide B are in progress in our laboratory.
Table 1. Isomerization of spiroacetals
Crystallographic data (excluding structure factors) for
the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC 245421 and
245422. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK [fax: +44 (0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
Run Sub-
strate
Condition
13:13a
This work was financially supported by Grants-in-Aid
for Scientific Research from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan
(14044001).
1
2
3
4
5
6
7
8
9
13a
13a
13a
13a
13a
13a
13
CSA (0.1equiv), MeCN, 23°C, 15h
ZnBr2 (0.2equiv), CH2Cl2, 23°C, 4d
36:64
33:67
Et2AlCl (1.0equiv), CH2Cl2, ꢀ60°C, 19h 25:75
SnCl2 (0.1equiv), CH2Cl2, 23°C, 5.5h
CuCl2 (excess), CH2Cl2, 23°C, 5.5h
HFÆpy (excess), MeCN, 23°C, 2.5h
CSA (0.1equiv), MeCN, 23°C, 1.5h
33:67
33:67
40:60
36:64
References and notes
13a
13a
TBSOTf, 2,6-lutidine, CH2Cl2, 23°C, 3d ꢁ0:100
1. Hu, T.;Curtis, J. M.;Oshima, Y.;Qillilam, M. A.;Walter,
J. A.;Watson-Wright, W.;Wright, J. L. C. J. Chem. Soc.,
Chem. Commun. 1995, 2159.
TfOH, 2,6-lutidine, CH2Cl2, 23°C, 1d ꢁ0:100
All reactions proceeded quantitatively.

7858
J. Ishihara et al. / Tetrahedron Letters 45 (2004) 7855–7858
2. (a) Uemura, D.;Chou, T.;Haino, T.;Nagatsu, A.;
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RuO2ÆxH2O (20,883-3) from Aldrich was effective for the
oxidation, whereas the reaction with RuO2ÆxH2O 99.99%
(46,376-0) from Aldrich failed in this case.
18. The stereochemistries of 11, 11a, 12, 12a were determined
by H NMR analysis as well as the chemical conversion.
1
3. (a) Seki, T.;Satake, M.;Mackenzie, L.;Kaspar, H. F.;
Yasumoto, T. Tetrahedron Lett. 1995, 36, 7093;(b)
Stewart, M.;Blunt, J. W.;Munro, M. H. G.;Robinson,
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Miles, C. O.;Wilkins, A. L.;Stirling, D. J.;MacKenzie, A.
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Tetrahedron Lett. 2001, 42, 3495.
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Tetrahedron Lett. 1996, 37, 7671.
At first, we converted 12 and 12a to the corresponding
TES ethers, using TESCl and imidazole in DMF. The TES
ethers were reconvertible to parent 12 and 12a by
treatment with Bu4NF, respectively. The 1H NMR spectra
of the TES ethers of 12 was quite similar to that of TBS
ethers 13, and the TES ether of 12a was corresponding
to 13a. These results suggested that the stereochemistry at
C-15 of 11, 12, and the TES ether of 12 should be
corresponding to 13, and 11a, 12a, and the TES ether of
6. (a) Tsujimoto, T.;Ishihara, J.;Horie, M.;Murai, A.
Synlett 2002, 399;(b) Ishihara, J.;Horie, M.;Shimada, Y.;
Tojo, S.;Murai, A. Synlett 2002, 403.
7. (a) Falk, M.;Burton, I. W.;Hu, T.;Walter, J. A.;Wright,
J. L. C. Tetrahedron 2001, 57, 8659;(b) Hu, T.;Burton, I.
W.;Cembella, A. D.;Curtis, J. M.;Quilliam, M. A.;
Walter, J. A.;Wright, J. L. C. J. Nat. Prod. 2001, 64, 308;
(c) Cembella, A. D.;Bauder, A. G.;Lewis, N. I.;Quilliam,
M. A. J. Plankton Res. 2001, 23, 1413.
8. For the synthetic studies of spirolide, see: (a) Brimble, M.
A.;Fares, F. A.;Turner, P. Aust. J. Chem. 2000, 53, 845;
(b) Caprio, V.;Brimble, M. A.;Furkert, D. P. Tetrahedron
2001, 57, 4023;(c) Furkert, D. P.;Brimble, M. A. Org.
Lett. 2002, 4, 3655;(d) Trzoss, M.;Brimble, M. A. Synlett
2003, 2042;(e) Brimble, M. A.;Trzoss, M. Tetrahedron
2004, 60, 5613.
9. Gill, S.;Murphu, M.;Clause, J.;Richard, D.;Quilliam,
M.;MacKinnon, S.;LaBlanc, P.;Mueller, R.;Pulido, O.
Neurotoxicology 2003, 24, 593.
12a should have the same configuration to 13a.
27
19. For compound 13: a colorless oil; ½aŠ þ19:8 (c 0.64,
D
MeOH); 1H NMR (500MHz, CD3OD) d 7.32–7.19
(5H, m), 7.21 (2H, d, J = 8.5Hz), 6.85 (2H, d,
J = 8.5Hz), 4.55 (1H, d, J = 11.5Hz), 4.42 (1H, d,
J = 11.5Hz), 4.36 (2H, s), 4.09–4.05 (1H, m), 4.01–3.95
(1H, m), 3.75 (3H, s), 3.62–3.52 (3H, m), 3.48–3.44 (1H,
m), 2.28 (1H, quint, J = 6.7Hz), 2.21–2.06 (4H, m), 1.99
(1H, dd, J = 6.0, 13.0Hz), 1.98–1.94 (1H, m), 1.88–1.77
(1H, m), 1.75–1.67 (4H, m), 1.65–1.53 (4H, m), 1.41 (1H,
ddd, J = 4.0, 11.3, 14.7Hz), 1.28 (3H, s), 1.06 (3H, d,
J = 7.0Hz), 0.88 (9H, s), 0.09 (6H, s); 13C NMR
(125MHz, CD3OD) d 160.75, 139.95, 131.85, 130.51,
128.79, 128.70, 128.58, 117.66, 114.72, 111.49, 80.77,
74.48, 73.96, 73.61, 69.44, 68.92, 68.50, 55.68, 46.34,
37.57, 36.93, 36.88, 26.45, 24.83, 18.99, 14.74, ꢀ1.52,
ꢀ1.71;IR (neat) mmax (cmꢀ1) 2943, 2859, 1612, 1510, 1458,
1369, 1248, 1173, 1099, 1943, 931, 829;EI-MS-LR m/z
(Int. %) 654 (M+, 4.1), 597 (M+ꢀtBu, 10), 121 (100);EI-
MS-HR, found 654.3945, calcd for C38H58O7Si (M+)
10. The absolute stereochemistry of pinnatoxin B was deter-
mined by Kishi et al. see: McCauley, J. A.;Nagasawa, K.;
Lander, P. A.;Mischke, S. G.;Semones, M. A.;Kishi, Y.
J. Am. Chem. Soc. 1998, 120, 7647.
11. Sugimoto, T.;Ishihara, J.;Murai, A. Tetrahedron Lett.
1997, 38, 7379.
12. (a) Perron, F.;Albizati, K. M. Chem. Rev. 1989, 89, 1617;
27
654.3952. For compound 13a: a colorless oil; ½aŠ þ48:4 (c
0.63, MeOH); 1H NMR (125MHz, C6D6) dD7.38–7.09
(5H, m), 7.25 (2H, d, J = 8.5Hz), 6.81 (2H, d, J = 8.5Hz),
4.45 (1H, d, J = 12.0Hz), 4.36 (1H, d, J = 11.5Hz), 4.33
(1H, d, J = 11.5Hz), 4.30 (1H, dd, J = 7.5, 14.0Hz), 4.10
(1H, ddd, J = 4.0, 7.6, 15.6Hz), 3.68–3.55 (3H, m), 3.49–
3.45 (1H, m), 3.31 (3H, s), 2.49–2.39 (2H, m), 2.28 (1H,
dd, J = 7.0, 12.5Hz), 2.26–2.19 (2H, m), 1.88 (1H, dd,
J = 8.0, 12.0Hz), 1.77–1.65 (5H, m), 1.54–1.48 (2H, m),
1.49 (1H, dd, J = 9.5, 13.0Hz), 1.38–1.20 (2H, m), 1.32
(3H, s), 1.12 (9H, s), 0.74 (3H, d, J = 7.0Hz), 0.26 (3H, s),
0.19 (3H, s); 13C NMR (125MHz, C6D6) d 159.67, 139.56,
131.35, 129.26, 128.46, 127.50, 114.89, 114.02, 110.09,
78.22, 73.18, 73.03, 72.85, 68.61, 67.02, 66.19, 54.74, 46.08,
36.50, 35.20, 34.88, 34.64, 32.30, 31.77, 31.00, 30.81, 30.16,
26.33, 25.11, 23.08, 18.58, 14.54, 14.32, ꢀ1.66, ꢀ1.83;IR
`
(b) Brimble, M. A.;Fare s, F. A. Tetrahedron 1999, 55,
7661.
13. (a) Ishihara, J.;Sugimoto, T.;Murai, A. Synlett 1998, 603;
(b) Sugimoto, T.;Ishihara, J.;Murai, A. Synlett 1999, 541.
14. The chiral epoxide 3 was readily prepared from 3-butyn-
1-ol for four steps.
(neat) mmax (cmꢀ1
) 2943, 2856, 1610, 1516, 1458,
1362, 1248, 1155, 1101, 1038, 966, 827;EI-MS-LR m/z
(Int. %) 654 (M+), 597 (M+ꢀtBu, 6.7), 121 (100);EI-MS-
HR, found 654.3930, calcd for C38H58O7Si (M)+ 654.3952.
20. Crystal data for 14: C37H50Br2O8Si, M 810.69, mono-
˚
clinic, P21, a = 8.052 (1), b = 11.788 (2), c = 20.548 (3) A,
3
˚
b = 97.625 (1)°, U = 1933.0 (5) A , Dc (Z = 2) =
1.393gcmꢀ3, l = 21.82cmꢀ1, T = 153K. The final R value
is 0.043 for 4672 independent reflections with I > 3rI and
414 parameters. For 15: C23H44O6Si, M 444.68, ortho-
rhombic, P212121, a = 7.354 (2), b = 18.909 (5), c = 37.967
3
˚
˚
(10) A, U = 5279.6 (2) A , Dc (Z = 8, two independent
molecules) = 1.119gcmꢀ3, l = 1.21cmꢀ1, T = 293K. The
final R value is 0.073 for 2967 independent reflections with
I > 1.5rI and 542 parameters.
15. Johnson, M. R.;Nakata, T.;Kishi, Y. Tetrahedron Lett.
1979, 4343.