A Stereoselective synthesis of the C10-C31 (BCDEF ring) portion of pinnatoxin A

Article abstract of DOI:10.1021/ol0168364

(matrix presented) An efficient synthesis of the C10-C31 (BCDEF ring) portion of pinnatoxin A has been achieved. The key step is a highly stereoselective construction of the dispiroketal (BCD ring) system employing an intramolecular hetero-Michael reaction of a reversibly formed hemiketal alkoxide through the use of LiOMe.

Full text of DOI:10.1021/ol0168364

ORGANIC
LETTERS
2001
Vol. 3, No. 25
4075-4078
A Stereoselective Synthesis of the
C10−C31 (BCDEF Ring) Portion of
Pinnatoxin A
Seiichi Nakamura, Jun Inagaki, Tomohiro Sugimoto, Masashi Kudo,
Makoto Nakajima, and Shunichi Hashimoto*
Graduate School of Pharmaceutical Sciences, Hokkaido UniVersity,
Sapporo 060-0812, Japan
hsmt@pharm.hokudai.ac.jp
Received September 29, 2001
ABSTRACT
An efficient synthesis of the C10−C31 (BCDEF ring) portion of pinnatoxin A has been achieved. The key step is a highly stereoselective
construction of the dispiroketal (BCD ring) system employing an intramolecular hetero-Michael reaction of a reversibly formed hemiketal
alkoxide through the use of LiOMe.
Recently, several novel, marine-derived macrocycles con-
taining a spiro-linked cyclic imine moiety have been
isolated.1,2 These natural products have been considered as
culprits in shellfish poisoning, and a number of them have
also been found to be Ca2+ channel activators.2a,3 Pinnatoxins,
the first and most prominent members of this class, were
isolated from the shellfish Pinna muricata and characterized
by Uemura and co-workers in 1995.1a Their unprecedented
molecular architecture, combined with the associated biologi-
cal activity and scarcity of natural supply, has prompted a
major effort toward the synthesis of pinnatoxins.4,5 In 1998,
Kishi and co-workers accomplished the first total synthesis
of (-)-pinnatoxin A utilizing a biomimetic intramolecular
Diels-Alder reaction to construct the G ring as well as the
macrocycle, establishing the absolute stereochemistry of
natural pinnatoxin A, as shown in 1.6 As part of a program
(1) (a) Uemura, D.; Chou, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.;
Zheng, S. Z.; Chen, H. S. J. Am. Chem. Soc. 1995, 117, 1155. (b) Chou,
T.; Kamo, O.; Uemura, D. Tetrahedron Lett. 1996, 37, 4023.
(2) (a) Hu, T.; Curtis, J. M.; Oshima, Y.; Quilliam, M. A.; Walter, J. A.;
Watson-Wright, W. M.; Wright, J. L. C. Chem. Commun. 1995, 2159. (b)
Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H. F.; Yasumoto, T.
Tetrahedron Lett. 1995, 36, 7093. (c) Lu, C.-K.; Lee, G.-H.; Huang, R.;
Chou, H.-N. Tetrahedron Lett. 2001, 42, 1713.
directed toward the total synthesis of pinnatoxin A (1), we
report herein a highly stereoselective synthesis of 2, corre-
sponding to the C10-C31 (BCDEF ring) portion of this
(4) (a) Sugimoto, T.; Ishihara, J.; Murai, A. Tetrahedron Lett. 1997, 38,
7379. (b) Ishihara, J.; Sugimoto, T.; Murai, A. Synlett 1998, 603. (c)
Sugimoto, T.; Ishihara, J.; Murai, A. Synlett 1999, 541. (d) Ishihara, J.;
Tojo, S.; Kamikawa, A.; Murai, A. Chem. Commun. 2001, 1392.
(3) Zheng, S. Z.; Huang, F. L.; Chen, S. C.; Tan, X. F.; Zuo, J. B.; Peng,
J.; Xie, R. W. Chin. J. Mar. Drugs 1990, 33, 33.
10.1021/ol0168364 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/14/2001

molecule, exploiting an intramolecular hetero-Michael reac-
tion of a reversibly formed hemiketal alkoxide as the key
step in creating the BCD ring system.
Scheme 2a
Apart from constructing the 6,7-spiro-linked cyclic imine
(AG ring) system, building the 6,5,6-dispiroketal (BCD ring)
system presents a major challenge in the synthesis of 1 as
mentioned by the Kishi,6 Murai,4 and Hirama5 groups.
Although a number of methods have been developed to
synthesize bicyclic spiroketal subunits,7 the formation of
tricyclic dispiroketals has been less thoroughly investigated.8,9
The majority of reported synthetic strategies in either case
rely on the acid-catalyzed cyclization of open-chain hydroxy-
ketones. In this context, Kishi and co-workers demonstrated
that treatment of an appropriate tetrahydroxy diketone with
CSA led to the formation of a 2:3 mixture of C19 epimeric
dispiroketals, and the undesired isomer epimerized exclu-
sively to the natural series under silylation conditions.6 An
alternative approach to spiroketals involves the intramolecular
hetero-Michael reaction of a hemiketal alkoxide,10 which has
the advantage of generating a chiral center from an enone
in the conjugate addition step as well as a chiral spirocenter.
This elegant approach, however, has not yet been applied to
the synthesis of dispiroketals. It was readily apparent that
the strategy based on this approach would not only benefit
from the construction of the BCD ring system but also from
the direct assembly of the EF ring system (Scheme 1).
Scheme 1. Synthetic Plan for the C10-C31 Fragment 2
a Reagents and conditions: (a) BuLi, THF-HMPA (10:1), -78
°C, 1 h, 95%; (b) TsOH, MeOH-H2O, 35 h, 98%; (c) anisaldehyde
dimethyl acetal, PPTS, CH2Cl2, 6 h, 75%; (d) TESCl, imidazole,
CH2Cl2, 2 h, 98%; (e) DIBAL-H, CH2Cl2, -78 to -20 °C, 1 h,
87%; (f) SO3‚pyridine, Et3N, DMSO, 1 h, 96%; (g) MeMgI, THF-
Et2O, -78 to -50 °C, 2 h, 92%; (h) SO3‚pyridine, Et3N, DMSO,
1 h, 93%; (i) LiHMDS, ZnCl2, THF, -78 °C, then 9, 1.5 h, 98%;
(j) Ac2O, pyridine, DMAP, 20 h; (k) DBU, CH2Cl2, 0 °C, 1 h,
96% (two steps); (l) [(Ph3P)CuH]6, benzene, 10 h, 91%; (m)
MeMgI, Et2O, -78 °C, 1 h, 95%; (n) TBSOTf, 2,6-lutidine, CH2Cl2,
4 h 93%; (o) Bu4NF (1.05 equiv), THF-AcOH (10:1), 0 °C, 1 h,
88%; (p) SO3‚pyridine, Et3N, DMSO, 1 h, 94%; (q) 12, LiHMDS,
THF, -78 to -50 °C, 1.5 h, 88%; (r) Ac2O, pyridine, DMAP, 16
h; (s) DBU, CH2Cl2, 1 h, 89% (two steps); (t) DDQ, CH2Cl2-H2O
(10:1), 1 h, 93%; (u) Dess-Martin periodinane, CH2Cl2-pyridine,
0 °C, 1 h, 84%; (v) NCS, AgNO3, γ-collidine, CH3CN-H2O (4:
1), 0.5 h, 87%.
Focusing primarily on the two anomeric stabilization effects
due to the axial-type orientation of the C ring oxygen atom
with respect to both the B and D ring pyrans, we were thus
intrigued by the feasibility of the tandem hemiketal forma-
tion/hetero-Michael reaction initiated by selective desilylation
of 4 under thermodynamic conditions.
The synthetic sequence to the envisaged potential dispiroket-
al precursor 4 is detailed in Scheme 2. Alkylation of the
dithiane 611 with the iodide 512 and concurrent removal of
the acetal protective groups were followed by reprotection
(5) (a) Noda, T.; Ishiwata, A.; Uemura, S.; Sakamoto, S.; Hirama, M.
Synlett 1998, 298. (b) Ishiwata, A.; Sakamoto, S.; Noda, T.; Hirama, M.
Synlett 1999, 692. (c) Nitta, A.; Ishiwata, A.; Noda, T.; Hirama, M. Synlett
1999, 695.
(6) McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.;
Semones, M. A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647.
(7) For a review on the synthesis of spiroketals, see: Perron, F.; Albizati,
K. F. Chem. ReV. 1989, 89, 1617.
(8) (a) Kishi, Y.; Hatakeyama, S.; Lewis, M. D. In Frontiers of
Chemistry; Laidler, K. J., Ed.; Pergamon Press: Oxford, 1982; pp 287-
304. (b) Baker, R.; Brimble, M. A. J. Chem. Soc., Chem. Commun. 1985,
78. (c) Perron, F.; Albizati, K. F. J. Org. Chem. 1989, 54, 2047.
(9) For a review on the synthesis of dispiroketals, see: Brimble, M. A.;
Fare`s, F. A. Tetrahedron 1999, 55, 7661.
(10) (a) Smith, A. B., III; Schow, S. R.; Bloom, J. D.; Thompson, A. S.;
Winzenberg, K. N. J. Am. Chem. Soc. 1982, 104, 4015. (b) Williams, D.
R.; Barner, B. A. Tetrahedron Lett. 1983, 24, 427. (c) Negri, D. P.; Kishi,
Y. Tetrahedron Lett. 1987, 28, 1063. (d) Aicher, T. D.; Buszek, K. R.;
Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola,
P. M.; Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162. (e)
Toshima, H.; Aramaki, H.; Furumoto, Y.; Inamura, S.; Ichihara, A.
Tetrahedron 1998, 54, 5531.
(11) McGarvey, G. J.; Stepanian, M. W. Tetrahedron Lett. 1996, 37,
5461.
4076
Org. Lett., Vol. 3, No. 25, 2001

of the vicinal diol as its 4-methoxybenzylidene (MP) acetal
and that of the C23 hydroxyl group as its TES ether to give
the advanced dithiane 7 in 68% yield. Reductive cleavage
of the MP acetal group with DIBAL-H was followed by
sequential Parikh-Doering oxidation,13 addition of MeMgI,
and reoxidation, affording the methyl ketone 8 in 71% yield.
Aldol fragment coupling of the C14-C23 ketone 8 with the
C10-C13 aldehyde 914 using LiHMDS-ZnCl2 followed by
successive acetylation, elimination, and conjugate reduction16
produced ketone 10 in 86% yield. Chelation-controlled
alkylation of 10 with MeMgI and protection of the resulting
hydroxyl group as its TBS ether were followed by selective
removal of the primary TES ether and subsequent oxidation
to furnish aldehyde 11 in 73% yield. At this juncture,
installation of the C24-C31 fragment 1217 was accomplished
by aldol coupling of 11 with 12 and dehydration to give the
C10-C31 enone 13 in 78% yield. Deprotection of the MPM
ether with DDQ followed by Dess-Martin oxidation and
removal of the dithiane protective group afforded the targeted
triketone 4 in 68% yield.
Scheme 3a
With a viable route to the dispiroketal precursor 4 secured,
the stage was now set for the hemiketal formation/intra-
molecular hetero-Michael addition sequence. Prior to experi-
mentation in the actual system with 4, we explored the
reaction of triketone 14,19 which is devoid of the C27- C31
subunit, to simplify structure determination of the products
(Scheme 3). Initial attempts at a direct conversion of 14 to
dispiroketals triggered by desilylation with Bu4NF met with
failure. Thus, we examined a stepwise procedure as follows.
Upon exposure of 14 to 1 N aqueous HCl in THF, selective
liberation of the C12 hydroxyl group provided an equilibrium
mixture of hydroxytriketone 15 and stereoisomers of hemi-
ketals 16 and 17.20 After considerable experimentation, we
were gratified to find that treatment of this mixture with
LiOMe (1.0 equiv) in THF-MeOH (10:1) at room temper-
ature for 4 h afforded the desired dispiroketal 18 as the major
product out of the eight possible stereoisomers in 72% yield
from 14, together with 13% combined yield of some
undesired stereoisomers. Monitoring of this reaction by TLC
analysis showed that the intramolecular hetero-Michael
addition took place immediately to predominantly form the
a Reagents and conditions: (a) 1 N aqueous HCl-THF (1:10),
0 °C, 1 h; (b) LiOMe (1.0 equiv), THF-MeOH (10:1), 4 h, 72%;
(c) NaBH4, MeOH, 0 °C, 2 h, 93%; (d) Bu4NF, THF, reflux, 12 h,
91%; (e) SO3‚pyridine, Et3N, DMSO, 2 h, 90%; (f) H2, 20%
Pd(OH)2/C, AcOEt, 13 h, 85%; (g) H2NNHCONH2‚HCl, NaOAc,
EtOH, 8 h, 98% (syn:anti ) 1:1.6).
undesired stereoisomer 19, which was then slowly consumed
to give the desired isomer 18 as a major product. Since all
the stereochemistry of the newly formed chiral centers in
19 were opposite to those in 18, the isomerization was
presumed to proceed via the reaction sequence of retro-
Michael reaction, dissociation to 15, double hemiketalization,
and hetero-Michael reaction. However, no explanation for
the significant kinetic preference for the formation of 19 can
be offered at present. Use of NaOMe or KOMe in place of
LiOMe also gave 18 as a major product via a similar process
within 5 min, which was gradually isomerized to the C19,
C23 epimeric dispiroketal 20 via a retro-Michael-Michael
reaction process until the 18:20 ratio21 of 52:48 and 54:46,
respectively, was established (3-5 h). Molecular mechanics
calculations using MacroModel MM2* indicate that the
(16R,19S,23S)-isomer 20, which is stabilized by two ano-
meric effects as well as by relief from the dipole-dipole
(12) Toshima, H.; Ichihara, A. Biosci., Biotechnol., Biochem. 1995, 59,
497.
(13) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505.
(14) Compound 9 was prepared from (4R)-4-benzyl-3-(4-benzyloxy-1-
oxobutyl)-2-oxazolidinone15 by the following sequence: (1) NaHMDS,
2-benzenesulfonyl-3-phenyloxaziridine, THF, -90 °C, 81%; (2) TESCl,
imidazole, CH2Cl2, 86%; (3) LiBH4, H2O, THF, 83%; (4) (COCl)2, DMSO,
Et3N, CH2Cl2, -78 to 0 °C, 93%.
(15) Lafontaine, J. A.; Leahy, J. W. Tetrahedron Lett. 1995, 36, 6029.
(16) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291.
(17) Compound 12 was prepared from (3aS,6S,7S,7aS)-6-benzyloxy-2,2-
dimethyl-7-hydroxytetrahydro-1,3-dioxolo[4,5-c]pyran18 by the following
sequence: (1) TBSCl, imidazole, DMF, 97%; (2) H2, 20% Pd(OH)2/C,
AcOEt; (3) Ph3PdCHCON(Me)OMe, benzene, reflux, 83% (two steps);
(4) TBDPSCl, imidazole, DMF, 94%; (5) MeMgI, Et2O, 0 °C, 94%; (6)
MeCu(CN)Li (4 equiv), BF3‚OEt2, THF-Et2O, -78 °C, 80%.
(18) Schmidt, R. R.; Gohl, A. Chem. Ber. 1979, 112, 1689.
(19) Compound 14 was prepared from 11 by the following sequence:
(1) Ph3PdCHCOMe, benzene, reflux, 98%; (2) DDQ, CH2Cl2-H2O (10:
1), 94%; (3) Dess-Martin periodinane, CH2Cl2-pyridine, 0 °C, 96%; (4)
NCS, AgNO3, γ-collidine, CH3CN-H2O (4:1), 93%.
(21) The ratio of isomers was determined by HPLC analysis (column,
Zorbax Sil, 4.6 × 250 mm; eluent, 9% AcOEt in hexane; flow rate, 1.0
mL/min).
(20) In the infrared spectrum of the mixture, absorbance at 1713 cm-1
indicated the existence of a nonconjugated ketone carbonyl.
Org. Lett., Vol. 3, No. 25, 2001
4077

repulsion, but experiences the severe steric interaction
between the C15 TBS ether and the C23 side chain, is 0.27
kcal/mol lower in energy than the desired (16R,19R,23R)-
isomer 18.22-24 Thus, it is of interest to note that only small
amounts of 20 were observed with the use of LiOMe even
after prolonged reaction times.25 The origin of the sluggish
isomerization of 18 to 20 under this condition is currently
unclear. Stereochemical assignments of 18, 19, and 20 were
Scheme 4a
1
obtained from H NOE experiments. The stereochemistry
of 18 was further established from the X-ray crystal structure
of the derived semicarbazone 21 as shown in Figure 1.
a Reagents and conditions: (a) 1 N aqueous HCl-THF (1:10),
0 °C, 1 h; (b) LiOMe, THF-MeOH (10:1), 5 h, 73% (two steps);
(c) CSA (1.0 equiv), CH2Cl2, 5 h, 68%.
Figure 1. X-ray crystal structure of 21, rendered in Chem3D. For
the purpose of clarity, only protons attached to stereogenic centers
are shown.
is based on an intramolecular hetero-Michael reaction of a
reversibly formed hemiketal alkoxide through the use of
LiOMe. This novel process should be useful in the construc-
tion of other dispiroketals. Further efforts toward a total
synthesis of pinnatoxin A are currently underway.
Encouraged by the success of the crucial spirocyclization
in a model system, we then proceeded to complete the
BCDEF ring system. Removal of the TES group in 4
followed by the intramolecular hetero-Michael reaction using
LiOMe as a base furnished the desired dispiroketal 3 in 73%
overall yield as expected from the model studies (Scheme
4). Finally, internal ketalization of 3 with CSA in CH2Cl2
gave the bicycloketal 2 in 68% yield.26 The stereochemistries
of 327 and 2 were verified by the diagnostic 1H NOE
correlation between C12-H and C23-H.
Acknowledgment. This research was supported in part
by a Grant-in-Aid for Scientific Research on Priority Areas
(A) Exploitation of Multi-Element Cyclic Molecules from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Supporting Information Available: Characterization
data for the compounds 2-4, 7-14, and 18-21 and an X-ray
crystallographic file (CIF) for 21. This material is available
free of charge via the Internet at http://pubs.acs.org.
In summary, we have achieved a highly stereoselective
synthesis of the C10-C31 portion of pinnatoxin A. The key
step, generating the 6,5,6-dispiroketal (BCD ring) system,
OL0168364
(26) The isomerization of 2 to its C19 epimer, if any, could not be found
under the ketalization conditions (CSA in CH2Cl2). In this respect, Murai
and co-workers reported that the C19 epimer of the closely related
dispiroketal compound isomerized under similar conditions to give a 4.3:1
mixture of C19 epimeric dispiroketals, with the undesired configuration
favored.4c However, they did not mention the result of epimerization of the
desired isomer.
(27) The stereochemistry of 3 was further confirmed by comparison of
the 1H NMR spectrum with the sample obtained from 18 by the following
sequence: (1) LiHMDS, THF, -78 °C, then C27-C31 aldehyde; (2) Ac2O,
pyridine, CH2Cl2; (3) DBU, CH2Cl2, 0 °C, 20% (three steps); (4) MeCu-
(CN)Li (4 equiv), BF3‚OEt2, THF-Et2O, -78 °C, 73%.
(22) Molecular mechanics calculations indicate that the (16S,19S,23S)-
isomer 19 is 2.0 kcal/mol higher in energy than 18.
(23) The other five stereoisomers were estimated to be 3.0-7.6 kcal/
mol higher in energy than 18.
(24) In the case of 1,7,9-trioxadispiro[5.1.5.3]hexadecane, the cis-isomer,
wherein both O1 and O9 are axially disposed about the central ring, is
reported to be less stable by 0.3-0.7 kcal/mol than the trans-isomer without
the destabilizing dipole repulsion: McGarvey, G. J.; Stepanian, M. W.;
Bressette, A. R.; Ellena, J. F. Tetrahedron Lett. 1996, 37, 5465.
(25) The ratios of 18, 19, 20, and another unidentified isomer after 4
and 48 h were 85:8:3:4 and 82:8:6:4, respectively.
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Org. Lett., Vol. 3, No. 25, 2001