Synthesis of the BCD ring system of azaspiracid: Construction of the trispiro ring structure by the thioether approach

Article abstract of DOI:10.1016/j.tetlet.2003.10.161

The synthesis of the BCD ring system of azaspiracid 1 has been attained. Construction of the stereochemistry of the C₁₃ position was successfully controlled by connection between the B ring and the C ring with a sulfur atom.

Full text of DOI:10.1016/j.tetlet.2003.10.161

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 351–354
Synthesis of the BCD ring system of azaspiracid: construction of the
trispiro ring structure by the thioether approach
Yuichi Ishikawa and Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku,
Yokohama 223-8522, Japan
Received 24 September 2003; revised 20 October 2003; accepted 24 October 2003
Abstract—The synthesis of the BCD ring system of azaspiracid 1 has been attained. Construction of the stereochemistry of the C13
position was successfully controlled by connection between the B ring and the C ring with a sulfur atom.
Ó 2003 Elsevier Ltd. All rights reserved.
40
Azaspiracid 1 and its congeners 2–5, a family of marine
polyethers isolated from the blue mussel Mytilus edulis
in Killary Harbor, Ireland, are known as novel shellfish
poisons (Fig. 1).1 Azaspiracids share a unique structure
R2
I
HN
H
R4
R1
O
R3
H
H
13 C
O
H
A
O
O
B
O
H
HO
1
O G
E
26
20
D
O
O
F
H
O
consisting of an azaspiro ring,
a 2,9-dioxabicy-
H
OH
H
HO
clo[3.3.1]nonane ring, and trispiro ring units. However,
the relative stereochemistry of the molecules and details
of their biological mode of action are still obscure.
Accordingly, azaspiracids are attractive synthetic targets
for organic chemists. Although several groups are
working toward their total synthesis, no accomplish-
ment has been reported.2;3 The challenging framework
of azaspiracids as well as their biological activity
therefore prompted us to initiate a synthetic study to
determine the complete structure and to understand the
structure–activity relationship.
R1 R2 R3 R4
H Me H
H MeMe H
H
OH H
azaspiracid
:
:
:
:
:
1
H
2
3
4
5
azaspiracid-2
azaspiracid-3
azaspiracid-4
azaspiracid-5
H
H
H
H
H
H
H H OH
Figure 1. Azaspiracids.
would be controlled by connecting the B ring to the C
ring with a sulfur atom. After cyclization, a mild
removal of the sulfur atom would afford the desired
trispiro-ring system of azaspiracid 1. We describe herein
the construction of the BCD ring system, having the
desired stereochemistry of the spirocenter at C13 posi-
tion (6), as a model of the natural molecule.
Although synthesis of the FGHI ring part of 1 was
reported by several groups,2i;j;l only the Nicolaou group
has constructed the ABCD ring system using an intra-
molecular hydrogen bonding.2k It was described in sev-
eral papers that construction of the correct structure of
the ABCD ring system was unsuccessful under usual
acetalization conditions.2b;g;k Therefore, we planned a
new access to the stereochemistry of the spirocenter at
the C13 position in the BC ring, the stereochemical
control of which might be impeded by an anomeric effect
and steric hindrance. In the strategy, the spirocenter
In our synthetic strategy (Scheme 1), spiroacetal 6 would
be reductively produced from acetal 7 with simultaneous
introduction of a methyl group at the C14 position.
Compound 7 would be obtained by stepwise manipu-
lation of tetrahydrothiofuran 8, which would be pro-
duced from alcohol 11 through 9 and 10. Compound 11
would be constructed by cyclization of 12, easily pre-
pared from L-malic acid.
Keywords: Mytilus edulis; Marine polyether; azaspiracid; trispiro ring.
* Corresponding author. Tel./fax: +81-45-566-1717; e-mail: nisiyama@
chem.keio.ac.jp
The synthesis commenced with selective protection of
134 (Scheme 2). Thus, hydroxyl groups of 13 were
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.161

352
Y. Ishikawa, S. Nishiyama / Tetrahedron Letters 45 (2004) 351–354
H
O
H
H
H
O
H
B
O
O
H
13C
D
S
O
O
7
H
OTBDPS
OTBDPS
6
OTBS
OTBS
O
MEMO
OH
H
MEMO
H
PivO
PivO
O
H
OTBDPS
H
S
H
H
OTBDPS
OH
8
9
OTBS
OH
H
H
PMBO
MeO2C
O
H
O
OTBDPS
H
OTBDPS
BnO
10
11
OTBDPS
O
OH
MeO2C
OH
OH
13
MeO2C
12
Scheme 1. Our strategy for construction of the BCD ring system.
b, c
a
d
MeO2C
OTBDPS
OTES
MeO2C
OH
OH
14
13
OTBDPS
e
i
OTBDPS
OTES
OTES
MeO2C
HO
O
16
15
OTBDPS
f, g
OTBDPS
O
OR
OTES
HO
MeO2C
17
18: R= TES
12: R= H
h
OH
H
MeO2C
O
H
OTBDPS
11
Scheme 2. Reagents and conditions: (a) TBDPSCl, Imid., DMF, then TESCl, 95%; (b) DIBAL, toluene, )78 °C; (c) Ph3P@CHCO2Me, benzene, 80%
in twosteps; (d) DIBAL, CH 2Cl2, )78 °C, 87%; (e) Ti(OiPr)4,
-())-DET, TBHP, CH2Cl2, 81%; (f) SO3ÆPyr, DMSO, Et3N, CH2Cl2;
(g) Ph3P@CHCO2Me, benzene, 79% in twosteps; (h) CSA, MeOH, 0 °C, 82%; (i) Pd2(dba)3ÆCHCl3, Ph3P, CH2Cl2, rt, 90%.
D
protected stepwise to afford silylether 14 in 95% yield.
Reduction of 14 with DIBAL, followed by the Wittig
reaction, gave a,b-unsaturated ester 15 in good yield,
which on DIBAL reduction gave allyl alcohol 16.
Asymmetric epoxidation of 16 by the Sharpless protocol
generated epoxy alcohol 17 in 90% yield. Oxidation of
17 with SO3ÆPyr–DMSO, followed by Wittig reaction
yielded ester 18. The TES group of 18 was selectively
deprotected under acidic conditions (CSA/MeOH) to
afford alcohol 12 in 81% yield. Tocnostruct highly
substituted tetrahydrofuran 11 from 12, Hiramaꢀs
method was used at this stage.5 Thus, treatment of 12
with Pd2(dba)3 and Ph3P in CH2Cl2 at room tempera-
ture provided tetrahydrofuran 11 as a single isomer in
excellent yield.
Protection of 11 as a TBS ether was followed by
hydrogenation and saponification to give carboxylic
acid 19 (Scheme 3). Condensation of 19 with (R)-4-
benzyl-2-oxazolidinone6 produced oxazolidinone 20,
which on introduction of a benzyloxymethyl group gave
benzyl ether 21, as a single diastereomer. Reductive
removal of the oxazolidinone with LiBH4 afforded
alcohol 22. After TPAP oxidation of 22, the result-

Y. Ishikawa, S. Nishiyama / Tetrahedron Letters 45 (2004) 351–354
353
OH
OTBS
H
H
a-c
d
MeO2C
HO2C
O
O
H
H
OTBDPS
OTBDPS
11
OTBS
19
OTBS
O
O
O
O
H
H
e
f
N
O
N
O
O
O
H
OTBDPS
H
OTBDPS
OBn
Bn
Bn
20
21
OTBS
OTBS
H
H
g, h
PMBO
Ph
HO
BnO
O
O
H
OTBDPS
H
OTBDPS
BnO
O O
S
N
10
22
PMBO
N
N N
23
Scheme 3. Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2, 86%; (b) H2, Pd–C, EtOH; (c) LiOH, MeOH–THF–H2O, 98% in twosteps;
(d) PivCl, Et3N, THF, 0 °C, then (R)-4-benzyl-2-oxazolidinone, LiCl, 0 °C tort, 88%; (e) LHMDS, THF, )78 °C, then BOMCl, LiI, )78 to )30 °C,
ꢀ
78%; (f) LiBH4, THF–EtOH–H2O, 91%; (g) TPAP, NMO, MS4A, CH2Cl2; (h) 23, LHMDS, THF, )78 °C, 90% in twosteps.
ing aldehyde was subjected to the Julia olefination7
with sulfone 23,8 to afford olefin 10 in 90% yield (two
steps).
In the next stage, removal of an MEM ether from 8 gave
alcohol 27,10 which was oxidized with SO3ÆPyr–DMSO
togive ketone 28 in 89% yield (Scheme 5). Reaction of
28 with CSA in MeOH afforded methylacetal 29 (86%),
as a single isomer, which was reprotected with a TBDPS
group. Reductive removal of the ester gave alcohol 30
Introduction of a sulfur atom to control the spirocenter
at the C13 position is shown in Scheme 4. Thus, di-
hydroxylation of 10 under the Sharpless conditions9
gave diol 24. DDQ oxidation of 24, followed by pro-
tection with an MEM group, gave 25. After removal of
the anisilidene group of 25 under acidic conditions, the
resulting alcohol was protected as a pivalate ester, fol-
lowed by hydrogenolysis to afford diol 9. Dimesylation
of 9 gave 26 in 95% yield. Finally, treatment of 26 with
Na2S at 100 °C afforded tetrahydrothiofuran 8 in 70%
yield.
11
(79% in twosteps). Treatment of 30 with Yb(OTf)3 in
CH3CN gave acetal 7 in 98% yield. Desulfurization of 7
with Raney Ni W-4 in EtOH afforded the desired
spiroacetal 612 in 95% yield. The acetal structure of 6
was determined by the NOE experiments.
In conclusion, we have accomplished the synthesis of the
BCD ring system of azaspiracid 1, based on the struc-
tural control of the spirocenter at the C13 position by
OTBS
OTBS
OH
OH
H
H
a
PMBO
PMBO
O
O
H
OTBDPS
H
OTBDPS
BnO
OBn
10
b,c
24
OTBS
MEMO
H
d-f
O
H
O
O
OTBDPS
OBn
MP
25
OTBS
O
OTBS
MEMO
MEMO
H
H
h
PivO
PivO
O
H
S
H
H
H
OTBDPS
OR
OTBDPS
OR
8
9: R= H
26: R= Ms
g
t
i
ꢀ
Scheme 4. Reagents and conditions: (a) AD-mix-a, MeSO2NH2, BuOH–H2O, 68%; (b) DDQ, MS4A, CH2Cl2, 61%; (c) MEMCl, Pr2NEt, CH2Cl2,
88%; (d) 80% AcOH aq, rt, 92%; (e) PivCl, Pyr, 0 °C tort, 88%; (f) H , Pd(OH)2–C, EtOAc, 77%; (g) MsCl, Et3N, CH2Cl2, 95%; (h) Na2S, DMF,
2
100 °C, 70%.

354
Y. Ishikawa, S. Nishiyama / Tetrahedron Letters 45 (2004) 351–354
2. (a) Carter, R. G.; Weldon, D. J. Org. Lett. 2000, 2, 3913–
OTBS
O
RO
S
H
3916; (b) Carter, R. G.; Graves, D. E. Tetrahedron Lett.
2001, 42, 6035–6039; (c) Carter, R. G.; Campbell Bour-
land, T.; Graves, D. E. Org. Lett. 2002, 4, 2177–2179; (d)
Carter, R. G.; Graves, D. E.; Gronemeyer, M. A.;
Tschumper, G. S. Org. Lett. 2002, 4, 2181–2184; (e)
Aiguade, J.; Hao, J.; Forsyth, C. J. Tetrahedron Lett. 2001,
42, 817–820; (f) Hao, J.; Aiguade, J.; Forsyth, C. J.
Tetrahedron Lett. 2001, 42, 821–824; (g) Dounay, A. B.;
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Diedrichs, N.; Zou, N.; Bernal, F. Angew. Chem., Int. Ed.
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Iwamuro, Y.; Nemoto, J.; Oikawa, M. Tetrahedron Lett.
2003, 44, 6199–6201.
b
OTBS
PivO
O
H
H
H
H
PivO
OTBDPS
O
H
H
S
H OTBDPS
8:
R= MEM
R= H
a
27:
28
OMe
O
H
R2O
H
c
H
f
S
O
H
H
OR1
29: R1 = H, R2 = Piv
d, e
30: R1 = TBDPS, R2 = H
NOESY
H
H
O
O
H
H
g
H
S
H
S
O
O
O
H
OTBDPS
OTBDPS
H
O
3. Recently, the Nicolaou group has accomplished a total
synthesis of the proposed azaspiracid structure. However,
spectroscopic data of the synthetic sample was not
identical with those of the natural 1: (a) Nicolaou, K.
C.; Li, Y.; Uesaka, N.; Koftis, T. V.; Vyskocil, S.; Ling,
T.; Govindasamy, M.; Qian, W.; Bernal, F.; Chen, D.
Y.-K. Angew. Chem., Int. Ed. 2003, 42, 3643–3648; (b)
Nicolaou, K. C.; Chen, D.Y.-K.; Li, Y.; Qian, W.; Ling,
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N. Angew. Chem., Int. Ed. 2003, 42, 3649–3653.
4. Saito, A.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.;
Nomizu, S.; Moriwake, T. Chem. Lett. 1984, 1389–
1392.
7
NOE
15%
H
H
1%
H
O
H
H
O
H
O
O
O
Me
OTBDPS
OTBDPS
O
H
6
Scheme 5. Reagents and conditions: (a) ZnBr2, CH2Cl2, 83%; (b)
i
SO3ÆPyr, DMSO, Pr2NEt, CH2Cl2, 89%; (c) CSA, MeOH, 86%; (d)
TBDPSCl, Et3N, DMAP, CH2Cl2; (e) DIBAL, CH2Cl2, )78 °C, 79%
in twosteps; (f) Yb(OTf) 3, CH3CN, rt, 98%; (g) Raney Ni W-4, EtOH,
reflux, 95%.
5. Suzuki, T.; Sato, O.; Hirama, M. Tetrahedron Lett. 1990,
31, 4747–4750.
connection between the B ring and the C ring with a
sulfur atom. Further synthetic studies toward azaspir-
acid 1 are in progress.
6. Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem.
Soc. 1982, 104, 1737–1739.
7. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 1, 26–28.
8. Sulfone 23 was prepared from 1,3-propanediol in three
steps: (a) NaH, PMBCl, TBAI, THF; (b) DEAD, PBu3, 1-
phenyl-1H-tetrazole-5-thiol, THF; (c) Mo7O24(NH4)6Æ
4H2O, H2O2 aq, EtOH.
9. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547.
10. Corey, E. J.; Gras, J.-L.; Ulrich, P. Tetrahedron Lett. 1976,
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11. Kobayashi, S.; Sugiura, M.; Kitagawa, M.; Lam, W.
Acknowledgements
This research was financially supported by a Grant-in-
Aid for the 21st Century COE program ꢁKEIO Life
Conjugate Chemistryꢀ, as well as Young Scientists from
the Ministry of Education, Culture, Sports, Science and
Technology of Japan (to Y.I., No. 15710167), and the
Sasakawa Scientific Research Grant from The Japan
Science Society (to Y.I.).
Chem. Rev. 2002, 102, 2227–2302.
23
D
12. 7: colorless oil; ½aŠ )16.0 (c 0.37, CHCl3); IR (film) m
2929, 1427, 1113, 1074, 1020 cmÀ1
;
1H NMR (400 MHz,
References and Notes
C6D6) d 7.85–7.79 (complex, 4H), 7.24–7.21 (complex,
6H), 4.56 (m, 1H), 4.02 (ddd, 1H, J ¼ 8.3, 7.8, 5.4 Hz), 3.76
(dd, 1H, J ¼ 10.8, 3.9 Hz), 3.75 (br s, 1H), 3.70 (br d, 1H,
J ¼ 2.4 Hz), 3.67 (m, 1H), 3.55 (dd, 1H, J ¼ 10.8, 4.4 Hz),
2.54 (ddd, 1H, 13, 6.8, 4 Hz), 2.09–2.03 (complex, 2H),
1.91 (ddd, 1H, J ¼ 12.7, 9.3, 4.4 Hz), 1.75 (m, 1H), 1.61
(ddd, 1H, J ¼ 12.7, 7.9, 3.4 Hz), 1.45 (m, 1H), 1.31 (m,
1H), 1.17 (s, 1H), 1.13 (m, 1H), 0.31 (d, 1H, J ¼ 6.8 Hz);
13C NMR (100 MHz, C6D6) d 136.1, 134.2, 129.9, 128.5,
110.5, 79.2, 76.3, 76.1, 67.8, 66.8, 36.5, 34.5, 31.0, 27.2,
25.4, 24.5, 19.7, 15.9; HREIMS calcd for C28H38O4Si
(Mþ): 466.2536, found: m=z 466.2530.
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(c) Ito, E.; Satake, M.; Ofuji, K.; Kurita, N.; McMahon,
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