Synthetic study of pinnatoxin A: Stereoselective synthesis of the BCD-ring unit, a novel 6,5,6-bis-spiroketal system

Article abstract of DOI:10.1055/s-1998-1648

The bis-spiroketal unit of pinnatoxin A was constructed via a catalytic asymmetric epoxidation and dihydroxylation reaction followed by thermodynamically controlled acetalization.

Full text of DOI:10.1055/s-1998-1648

298
LETTERS
SYNLETT
Synthetic Study of Pinnatoxin A: Stereoselective Synthesis of the BCD-ring Unit, a Novel
6,5,6-Bis-spiroketal System
a,b
a
a
a
a,b
Takeshi Noda , Akihiro Ishiwata , Satoshi Uemura , Satoshi Sakamoto , and Masahiro Hirama*
a
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-77, Japan
b
CREST, Japan Science and Technology Corporation (JST)
Fax +81(22)217-6566; E-mail hirama@ykbsc.chem.tohoku.ac.jp
Received 18 December 1997
®
Abstract: The bis-spiroketal unit of pinnatoxin A was constructed via a
catalytic asymmetric epoxidation and dihydroxylation reaction followed
by thermodynamically controlled acetalization.
epoxidation followed by reduction with Red-Al gave 10 as a sole
10
product in a 86% overall yield from 9. After protecting the diol groups
11
selectively, catalytic asymmetric dihydroxylation of 11 afforded a
13.4:1 mixture of 12 and the diastereomer in a 89% overall yield from
10. Oxidation of the secondary hydroxy group of 12 with SO ·pyridine
gave the ketol 13 in a 82% yield.
3
Pinnatoxin A (1), a marine toxin recently isolated from Pinna muricata,
2+
1
exhibits characteristic activity toward the Ca channel. The structure,
including the relative stereochemistry, was determined based on the
Treatment of 13 with TsOH (0.1 equiv.) in t-BuOH, however, gave an
unexpected ratio (1:2.6) of the desired bis-spiroketal 14 (27%) and the
undesired isomer 15 (70% yield). This unfavorable selectivity is likely
due to the dipole interaction between the C-O bonds in the B and D
2,3
NMR data. Several unique structural features are (i) 27-membered
carbocyclic framework, (ii) 19-membered polyether ring, (iii) 14 chiral
centers, (iv) bis-spiroketal, (v) imminium and carboxylate functionality.
However the absolute stereochemistry has not yet been established.
12
rings. Use of toluene as a less polar aprotic solvent improved the
equilibration ratio of 14 and 15 to 1.3:1. These isomers were easily
separated by florisil chromatography. Each isolated isomer gave the
same equilibration mixture (14:15 = 1.3:1) upon treatment with TsOH
in toluene. The stereochemistry of 14 and 15 was determined by NOE
13
14
experiments using the corresponding acetate 17
and 18,
respectively. The improved ratio can be explained by the enhanced
5
anomeric effect in less polar solvent. When 13 was treated with TsOH
(0.1 equiv.) in MeOH, triol 16 was formed more selectively in a 52%
yield (other isomers: 25%). Moreover, the ratio was improved
dramatically by stirring the triol mixture with TsOH in toluene. The triol
16 was obtained in a 74% yield together with a small amount of a
15
mixture of inseparable isomers (12%), which yielded 16 as a major
product upon retreatment with TsOH in toluene. The structure of 16 was
16
unambiguously established by X-ray analysis (Figure 1), which
indicates the existence of an intramolecular hydrogen bond between the
terminal diol groups. This hydrogen bond must play an important role in
stereoselective formation of 16 in toluene.
Scheme 1
We describe herein an enantioselective route to the spiroketal (BCD-
4
ring) unit (2). The synthesis strategy is outlined in Scheme 1. The
MM2* calculation (MacroModel version 4.5) and accounting for the
anomeric effect suggest that the bis-spiroketal 2 is the most stable
Thus, the enantioselective route to 16 can be established. Since the
enantiomer of 7 is readily available, the present method can also
5
17
diastereomer among the four possible ketal diastereomers. Thus we
provide ent-14. Further synthetic studies of the AGEF ring fragment and
total synthesis of 1 will be reported in due course.
envisioned that an acid-promoted spiroketalization of acyclic ketol 3
6
would lead predominantly to the formation of 2. Dienone 4, which has
an entire carbon framework corresponding to 2, was synthesized as
shown in Scheme 2. Aldehyde 5, which is readily available from
Acknowledgments. We are grateful to Dr. Chizuko Kabuto, Dr.
Masako Ueno, and Mr. Kazuo Sasaki (Instrumental Analysis Center for
Chemistry, Tohoku University) for their assistance with X-ray analysis
and NMR measurement. This work was supported partially by the
Ministry of Education, Science, Sports and Culture, Japan.
7
geraniol, was converted to allylic chloride 6 in a 74% overall yield. β-
8
Ketoester 8 prepared from alcohol 7 was alkylated with 6 using
tetraethylammonium fluoride in the presence of tetrabutylammonium
9
iodide followed by alkaline hydrolysis and decarboxylation to give
dienone 4. Internal ketalization of 4 and the subsequent reduction gave
the allylic alcohol 9 in a 64% overall yield from 8. Catalytic asymmetric

March 1998
SYNLETT
299
2.
3.
4.
Uemura, D.; Chou, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.;
Zheng, S.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155.
Chou, T.; Kamo, O. and Uemura, D. Tetrahedron Lett. 1996, 37,
4023.
Synthesis of the spiroketal unit has been reported very recently:
Sugimoto, T.; Ishihara, J. and Murai, A. Tetrahedron Lett. 1997,
38, 7379.
5.
Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon Press: Oxford, 1983; Juaristi, E.; Cuevas,
G. The Anomeric Effect; CRC Press: Boca Raton, 1995.
6.
7.
For reviews of spiroketal, see: Perron, F.; Albizati, K. F. Chem.
Rev. 1989, 89, 1617.
Corey, E. J.; Achiwa, K.; Katzenellenbogen, J. A. J. Am. Chem.
Soc. 1969, 91, 4318; McMurry, J. E.; Erion, M. D. J. Am. Chem.
Soc. 1985, 107, 2712.
8.
9.
Masamune, S.; Ma, P.; Okumoto, H.; Ellingboe, J. W.; Ito, Y.
J. Org. Chem. 1984, 49, 2834.
References and Notes
Clark, J. H. and Miller, J. M. J. Chem. Soc., Perkin Trans. 1 1977,
1743.
1.
Zheng, S. Z.; Huang, F. L.; Chen, S. C.; Tan, X. F.; Zuo, J. B.;
Peng, J. and Xie, R. W. Zhongguo HaiyangYaowu (Chinese J. of
Marine Drugs). 1990, 33, 33.
10. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765; Finan, J.
M.; Kishi, Y. Tetrahedron Lett. 1982, 23, 2719.

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LETTERS
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11. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang,
Z.-M.; Xu, D. and Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.
J=11.3, 7.2Hz, C24-Ha), 4.05 (dd, 1H, J=11.3, 4.0Hz, C24-Hb),
4.03 (m, 1H, C12-H), 3.78 (dddd, 1H, J=11.2, 7.2, 4.0, 3.5Hz,
C23-H), 3.79 (ddd, 1H, J=10.3, 7.2, 6.0Hz, C10-Ha), 3.71 (dt, 1H,
J=10.3, 6.0Hz, C10-Hb), 2.93 (brs, 1H, C15-OH), 2.29 (td, 1H,
J=12.2, 7.6Hz, C17-Ha), 2.12 (dd, 1H, J=12.6, 7.6Hz, C18-Ha),
2.07 (s, 3H, Ac), 1.89 (td, 1H, J=13.5,4.8Hz, C14-Hax), 1.83 (dtt,
1H, J=13.2, 4.7, 4.3Hz, C21-Heq), 1.74 (td, 1H, J=12.6, 8.0Hz,
C18-Hb), 1.70 (m, 1H, C20-Heq), 1.68 (m, 1H, C11-Ha), 1.67 (m,
1H, C20-Hax), 1.64 (dd, 1H, J=12.2, 8.0Hz, C17-Hb), 1.63 (m,
1H, C14-Heq), 1.60 (m, 1H, C11-Hb), 1.56 (m, 1H, C22-Heq),
1.54 (m, 1H, C13-Heq), 1.48 (tdt, 1H, J=13.2, 12.0, 4.0Hz, C21-
Hax), 1.41 (tdd, 1H, J=13.5, 12.0, 4.2Hz, C13-Hax), 1.30 (dddd,
1H, J=13.5, 11.5, 10.0, 4.0Hz, C22-Hax), 1.22 (s, 3H, C15-Me),
1.04 (s, 9H, tBu).
12. Brimble, M. A.; Rush, C. J. J. Chem. Soc., Perkin Trans. I 1994,
497; 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.
25
1
13. 17 ([α]
–4.7° (c 0.13, CHCl )) : H NMR (CDCl , 600MHz)
3 3
D
7.68-7.63 (m, 4H, Ph), 7.44-7.36 (m, 6H, Ph), 4.04 (dddd, 1H,
J=11.2, 5.8, 3.8, 2.3Hz, C23-H), 3.98 (dd, 1H, J=11.2, 5.8Hz,
C24-Ha), 3.88 (dtd, 1H, J=11.8, 6.5, 2.5Hz, C12-H), 3.86 (dd, 1H,
J=11.2, 3.8Hz, C24-Hb), 3.79 (ddd, 1H, J=10.3, 7.8, 7.0Hz, C10-
Ha), 3.71 (ddd, 1H, J=10.3, 8.0, 5.5Hz, C10-Hb), 2.24 (s, 1H,
C15-OH), 2.16 (m, 1H, C17-Ha), 2.12 (m, 1H, C18-Ha), 2.00 (s,
3H, Ac), 1.87 (dddd, 1H, J=14.0, 8.0, 7.0, 6.5Hz, C11-Ha), 1.83
(m, 1H, C21-Heq), 1.82 (m, 1H, C18-Hb), 1.80 (m, 1H, C17-Hb),
1.78 (m, 1H, C14-Hax), 1.73 (m, 1H, C21-Hax), 1.72 (m, 1H,
C20-Heq), 1.70 (m, 7H, C11-Hb), 1.67 (m, 1H, C14-Heq), 1.62
(m, 1H, C20-Hax), 1.57 (m, 1H, C13-Heq), 1.52 (m, 1H, C22-
Heq), 1.41 (tdd, 1H, J=13.5, 12.0, 4.2Hz, C13-Hax), 1.28 (tdd,
1H, J=13.0, 12.0, 4.2Hz, C22-Hax), 1.22 (s, 3H, C15-Me), 1.05
(s, 9H, tBu).
15. The structures of the minor isomers were not determined.
25
16. Crystal data for 16 [mp 126°C from AcOEt–hexane; [α]
–6.0°
D
(c 0.26, CHCl )] : C
a = 12.252(2), b = 14.297(3), c = 9.622(3) Å, V = 1685.5(6) Å , Z
H O , M = 316.39, orthorhombic P2 2 2 ,
16 28 6 1 1 1
3
3
-3
= 4, D = 1.247 g cm , R = 0.037.
C
17. Gao, Y.; Zepp, C. M. Tetrahedron Lett. 1991, 32, 3155; Mori, K.;
Takigawa, T.; Matsuo, T. Tetrahedron 1979, 35, 933.
25
1
14. 18 ([α]
–9.0° (c 1.09, CHCl )) ; H NMR (CDCl , 600MHz)
3 3
D
7.68-7.63 (m, 4H, Ph), 7.44-7.35 (m, 6H, Ph), 4.17 (dd, 1H,