Total synthesis of (+)-pinnatoxin A

Article abstract of DOI:10.1021/ja800435j

A convergent enantioselective total synthesis of (+)-pinnatoxin A is described. The synthesis capitalizes on the highly diastereoselective Ireland-Claisen rearrangement of an acyclic alpha-branched allylic ester to set the quaternary stereogenic center at the core of the spiroimine ring system along with the adjacent tertiary stereocenter. The all-carbon macrocyclic ring system was formed by ring-closing metathesis. Copyright

Full text of DOI:10.1021/ja800435j

Published on Web 03/01/2008
Total Synthesis of (+)-Pinnatoxin A
Craig E. Stivala and Armen Zakarian*
Department of Chemistry and Biochemistry, Florida State UniVersity, Tallahassee, Florida 32306-4390
Received January 25, 2008; E-mail: zakarian@chem.ucsb.edu
Scheme 1. Synthesis Plan
The remarkable and intricate structure of pinnatoxin A secured
its place as a compelling target for chemical synthesis.1 In a report
published in 1990, Zheng and co-workers linked massive human
intoxication following the consumption of shellfish of the Pinna
species to the presence of a neurotoxin.2 A few years later, the
group of Uemura isolated two toxins from 45 kg of the viscera of
Pinna muricata and elucidated the structure of pinnatoxin A, which
is comprised of a 27-membered carbocycle incorporating a unique
A,G-spiroimine and B,C,D-spirotricyclic bis-ketal fragments.3,5 The
mechanism of bioactivity of the marine toxins remains unknown,
although it has been suggested that pinnatoxin A is a calcium
channel activator.2a The biosynthetic pathway to the natural product
proposed by Uemura invokes a notable intramolecular Diels-Alder
cycloaddition that forms ring G and installs the macrocycle. The
proposed biosynthesis served as the basis for the pioneering total
synthesis of (-)-pinnatoxin A by the group of Kishi,4 an extension
of which has recently provided a complete stereochemical assign-
ment for pinnatoxins B, C, and related pteriatoxins A-C.5,6
Here, we describe our studies that culminated in the total
synthesis of the natural enantiomer of pinnatoxin A. In terms of
strategy, a major focus of our effort was the assembly of the
cyclohexene ring (ring G) including the quaternary stereocenter C5
at the core of the A,G-spirocyclic imine (Scheme 1). In an attempt
to achieve improved stereocontrol, we chose to depart from the
apparent Diels-Alder approach in favor of the Ireland-Claisen
rearrangement-based strategy, which prompted the development of
a method for stereoselective enolization of acyclic alpha-branched
esters.7 This analysis identified two subtargets, 1 and 2, with allylic
ester 3 as the key precursor to the advanced building block 2.
Ester 3 was prepared in a convergent manner from the corre-
sponding allylic alcohol and carboxylic acid, underscoring the power
of the Ireland-Claisen strategy. The synthesis of the allylic alcohol
commenced with D-ribose thioacetal 4 (Scheme 2).8 After instal-
lation of the protecting groups,9 the dithiane ring was cleaved and
the exposed aldehyde was used in the Horner-Emmons olefination
to afford 6 (80%). The ester was advanced to unsaturated aldehyde
7 in two steps in 85% yield. The diastereoselective addition of
diethylzinc catalyzed by 1,2-aminoalcohol 910 delivered 8 in 79%
yield along with its diastereomer (10%).
Scheme 2
Scheme 3
Previously, we described a 10-step synthesis of carboxylic acid
10 from (S)-citronellic acid.7b Acid 10 was combined with allylic
alcohol 8 using EDC in the presence of DMAP to form ester 3 in
high yield (Scheme 3). In the key event, ester 3 was subjected to
stereoselective enolization using chiral Koga-type chiral lithium
amide 11. The resulting lithium enolate was intercepted as silyl
ketene acetal 12, which underwent a highly diastereoselective [3,3]-
sigmatropic shift delivering carboxylic acid 13 in high yield. Thus,
two challenging stereogenic centers, C5 and C31, were established
efficiently by this transformation.
was performed under the conditions developed by Dussault and
co-workers.11 Direct oxidation of the resulting hydroxy aldehyde
using a variety of protocols was unproductive; therefore, reduction
to diol 15 was carried out. Double oxidation of 15 under Swern
conditions provided the dialdehyde, which underwent a smooth
regioselective aldol cyclization to 16 in the presense of dibenzy-
lammonium trifluoroacetate in 80% yield over two steps,12 installing
the requisite cyclohexene ring. The aldehyde was masked as the
allylic MOM ether (16 f 17). Removal of the silyl protecting
group, oxidation, and Wittig olefination gave the C27 olefin 18
(82%). Deprotection of the primary alcohol and oxidation with the
Dess-Martin periodinane13 delivered aldehyde 2.
The synthesis of aldehyde 2 was accomplished as illustrated in
Scheme 4. Reduction of the acid, acylation of the resulting alcohol,
and removal of the PMB group was followed by ozonolysis, which
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C O M M U N I C A T I O N S
Scheme 4
Scheme 6
Aldehyde 20, prepared previously,14 was employed in the
preparation of iodide 1 for the fragment coupling (Scheme 5).
Addition of 3-(p-methoxybenzyloxy)-1-propyllithium followed by
oxidation with the Dess-Martin periodinane furnished ketone 21
in high yield. Takai methylenation,15 removal of the PMB group,
and iodo-dehydroxylation afforded iodide 1.
The fragment coupling was accomplished directly by the addition
of complex organollithium reagent 22, generated by an iodine-
Scheme 5
lithium exchange from 1, to aldehyde 2 in good yield. When the
corresponding Grignard reagent was used, a significant reduction
of 2 to alcohol 19 was observed (up to 30%).
Once the silyl protecting groups (TIPS, TES) were removed from
the diastereomeric mixture of the alcohols 23 with TBAF, the
primary and secondary hydroxyl groups were oxidized to provide
the keto aldehyde. This keto aldehyde was converted to tetraene
24 upon chemoselective addition of vinylmagnesium bromide.
Compound 24 served as the substrate for the formation of the
27-membered all-carbon macrocycle of the target molecule by ring-
closing metathesis. Under a variety of reaction conditions with either
Grubbs II16 or Hoveyda-Grubbs II17 (25) catalysts, a ∼3:1 ratio
of two products, desired macrocycle 26-a and undesired isomer
26-b, was produced. The formation of 26-b is a result of a
competitive cyclization involving the 1,1-disubstituted alkene at
C10-C38. Catalyst 25 generally gave cleaner reactions. No reaction
was detected when the first-generation catalysts were employed.
When the order of ring-closing metathesis and oxidation with Dess-
Martin periodinane was reversed, the regioselectivity remained the
same. Installation of the triethylsilyl protecting group on the allylic
hydroxyl group in substrate 24 made it unreactive in the RCM
reaction.
After oxidation, enone 26-a was isolated in 57% overall yield.
The completion of the total synthesis was achieved following a
series of transformations depicted in Scheme 6. Lewis acid mediated
anti-addition of MeCu(CN)Li installed the stereogenic center at
C27.18 After extensive experimentation, we found that the two
methoxymethyl (MOM) groups and the benzylidene acetal could
be cleaved using the modified Lipshutz conditions with the
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C O M M U N I C A T I O N S
concomitant formation of the EF-ketal in a reasonable yield.19
Silylation and reductive debenzylation gave 29, which was con-
verted to azide 31 in three steps. Physical data for 31 (1H, 13C NMR,
[R]D, HRMS) matched those reported by Inoue/Hirama and co-
workers, who previously used this intermediate in a formal synthesis
of pinnatoxin A.1a Direct oxidation of the allylic hydroxyl group
to the carboxylic acid was observed upon prolonged exposure of
31 to a suspension of manganese(IV) oxide in CH2Cl2,20 which
was followed by treatment with trimethylsilyl diazomethane to
obtain methyl ester 32.21 The Staudinger reduction of the azide at
C1 with trimethylphosphine in aqueous THF afforded the corre-
sponding primary amine. In the absence of water, attempted direct
cyclization of the intermediate iminophosphorane resulted in no
imine formation, and only decomposition was observed under
forcing conditions (∼130 °C). The challenging imine formation was
carried out by heating the amino ketone in the presence of
triethylammonium 2,4,6-triisopropylbenoate in xylenes at 85 °C
employing the reaction conditions developed previously by Kishi
and co-workers.6 Thus, pinnatoxin A methyl ester was formed in
70% overall yield.22
Hydrolysis of the methyl ester occurred cleanly upon exposure
of 33 to lithium hydroxide in aqueous tetrahydrofuran at ambient
temperature, affording (+)-pinnatoxin A in 80% yield. The cyclic
imine proved to be stable under these basic reaction conditions.
In conclusion, an enantioselective total synthesis of (+)-
pinnatoxin A has been accomplished. The essential features of the
synthesis are the highly convergent strategy enabled by the success
of the Ireland-Claisen rearrangement of alpha-branched ester 3.
The key Ireland-Claisen rearrangement allowed for the assembly
of the challenging quaternary stereogenic center at C5 and the
adjacent tertiary stereocenter at C31 in high yield and with a high
level of stereocontrol.
(f) Nakamura, S.; Inagaki, J.; Kudo, M.; Sugimoto, T.; Obara, K.;
Nakajima, M.; Hashimoto, S. Tetrahedron 2002, 58, 10353-10374. (g)
Nakamura, S.; Inagaki, J.; Sugimoto, T.; Ura, Y.; Hashimoto, S.
Tetrahedron 2002, 58, 10375-10386. (h) Nakamura, S.; Inagaki, J.;
Sugimoto, T.; Kudo, M.; Nakajima, M.; Hashimoto, S. Org. Lett. 2001,
3, 4075-4078. Murai group: (i) Ishihara, J.; Horie, M.; Shimada, Y.;
Tojo, S.; Murai, A. Synlett 2002, 403-406. (j) Ishihara, J.; Tojo, S.;
Kamikawa, A.; Murai, A. Chem. Commun. 2001, 1392-1393. (k)
Sugimoto, T.; Ishihara, J.; Murai, A. Synlett 1999, 541-544. (l) Ishihara,
J.; Sugimoto, T.; Murai, A. Synlett 1998, 603-606. (m) Sugimoto, T.;
Ishihara, J.; Murai, A. Tetrahedron Lett. 1997, 38, 7379-7382. Kitching
group: (n) Suthers, B. D.; Jacobs, M. F.; Kitching, W. Tetrahedron Lett.
1998, 39, 2621-2624. Zakarian group: (o) Pelc, M. J.; Zakarian, A. Org.
Lett. 2005, 7, 1629-1631.
(2) (a) Zheng, S. Z.; Huang, F. L.; Chen, S. C.; Tan, X. F.; Zuo, J. B.; Peng,
J.; Xie, R. W. Zhongguo Haiyang Yaowu (Chin. J. Mar. Drugs) 1990,
33, 33-35. (b) Otofuji, T.; Ogo, A.; Koishi, J.; Matsuo, K.; Tokiwa, H.;
Yasumoto, T.; Nishihara, K.; Yamamoto, E.; Saisho, M.; Kurihara, Y.;
Hayashida, K. Food Sanit. Res. 1981, 31, 76-83. (c) Department of Public
Health, Fukuoka Prefecture. Food Sanit. Res. 1976, 26, 11-20.
(3) (a) Uemura, D.; Chuo, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.; Zheng,
S.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155-1156. (b) Chuo, T.;
Kamo, O.; Uemura, D. Tetrahedron Lett. 1996, 37, 4023-4026. (c) Chou,
T.; Haino, T.; Kuramoto, M.; Uemura, D. Tetrahedron Lett. 1996, 37,
4027-4030.
(4) McCauley, J. A.; Nagasawa, K.; Lander, P. A.; Mischke, S. G.; Semones,
M. A.; Kishi, Y. J. Am. Chem. Soc. 1998, 120, 7647-7648.
(5) (a) Takada, N.; Umemura, N.; Suenaga, K.; Chou, T.; Nagatsu, A.; Haino,
T.; Yamada, K.; Uemura, D. Tetrahedron Lett. 2001, 42, 3491-3494.
(b) Takada, N.; Umemura, N.; Suenaga, K.; Uemura, D. Tetrahedron Lett.
2001, 42, 3495-3497.
(6) (a) Matsuura, F.; Peters, R.; Anada, M.; Harried, S. S.; Hao, J.; Kishi, Y.
J. Am. Chem. Soc. 2006, 128, 7463-7465. (b) Hao, J.; Matsuura, F.; Kishi,
Y.; Kita, M.; Uemura, D.; Asai, N.; Iwashita, T. J. Am. Chem. Soc. 2006,
128, 7742-7743. (c) Matsuuda, F.; Hao, J.; Reents, R.; Kishi, Y. Org.
Lett. 2006, 8, 3327-3330.
(7) (a) Qin, Y.-c.; Stivala, C. E.; Zakarian, A. Angew. Chem., Int. Ed. 2007,
46, 7466-7469. (b) Stivala, C. E.; Zakarian, A. Tetrahedron Lett. 2007,
48, 6845-6848.
(8) Ko¨lln, O.; Redlich, H. Synthesis 1995, 1376-1382.
(9) See Supporting Information for experimental details.
(10) Sola`, L.; Reddy, K. S.; Vidal-Ferran, A.; Moyano, A.; Perica`s, M. A.;
Riera, A.; Alvarez-Larena, A.; Piniella, J.-F. J. Org. Chem. 1998, 63,
7078-7082.
(11) Schwartz, C.; Raible, J.; Mott, K.; Dussault, P. H. Org. Lett. 2006, 8,
3199-3201.
(12) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret, P.; Keck, G. E.;
Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8031-8034.
Acknowledgment. Financial support for this work was provided
by the Petroleum Research Fund, administered by the American
Chemical Society (43838-G1) and the Department of Chemistry
and Biochemistry, Florida State University. We thank the Holton
group for the extensive use of their IR and NMR spectrometers
and, with Tom Gedris, for the assistance with NMR spectroscopy.
The McQuade group is thanked for the use of their HPLC
instrument. We also thank Dr. Umesh Goli and Dr. Christelle Guillo
for the assistance with the high-resolution mass spectroscopy.
Professor Alexei Novikov (the University of North Dakota) is
thanked for stimulating discussions.
(13) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(14) Lu, C.-D.; Zakarian, A. Org. Lett. 2007, 9, 3161-3163.
(15) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem. 1994,
59, 2668-2670. We observed significant epimerization at C12 when the
Wittig reaction was employed.
(16) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-
956.
(17) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168-8179. (b) Gessler, G.; Randl, S.; Blechert,
S. Tetrahedron Lett. 2000, 41, 9973-9976.
(18) (a) Yamamoto, Y.; Maruyama, K. J. Am. Chem. Soc. 1978, 100, 3240-
3241. (b) Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Ishihara, Y.;
Maruyama, K. J. Org. Chem. 1982, 47, 119-126. (c) Hanessian, S.; Sumi,
K. Synthesis 1991, 1083. (d) Yamamoto, Y.; Chounan, Y.; Nishii, S.;
Ibuka, T.; Kitahara, H. J. Am. Chem. Soc. 1992, 114, 7652-7660.
(19) (a) Lipshutz, B. H.; Pegram, J. J.; Morey, M. C. Tetrahedron Lett. 1981,
22, 4603-4606. (b) Lipshutz, B. H.; Harvey, D. F. Synth. Commun. 1982,
12, 267-277. (c) Ireland, R. E.; Varney, M. D. J. Org. Chem. 1986, 51,
635-648.
Supporting Information Available: Experimental details, char-
acterization data, and copies of 1H and 13C NMR spectra for synthetic
intermediates. This material is available free of charge via the Internet
at http://pubs.acs.org.
(20) The corresponding aldehyde can be isolated in good yield if the reaction
time is about 1 h; an analogous transformation was used by Hirama and
co-workers (see ref 1a).
(21) For a recent review, see: Ku¨hnel, E.; Laffan, D. D.; Lloyd-Jones, G. C.;
del Campo, T. M.; Shepperson, I. R.; Slaughter, J. L. Angew. Chem., Int.
Ed. 2007, 46, 7075-7078.
References
(1) For the synthetic studies targeting pinnatoxins, see: Hirama group: (a)
Sakamoto, S.; Sakazaki, H.; Hagiwara, K.; Kamada, K.; Ishii, K.; Noda,
T.; Inoue, M.; Hirama, M. Angew. Chem., Int. Ed. 2004, 43, 6505-6510.
(b) Wang, J.; Sakamoto, S.; Kamada, K.; Nitta, A.; Noda, T.; Oguri, H.;
Hirama, M. Synlett 2003, 891-894. (c) Ishiwata, A.; Sakamoto, S.; Noda,
T.; Hirama, M. Synlett 1999, 692-694. (d) Nitta, A.; Ishiwata, A.; Noda,
T.; Hirama, M. Synlett 1999, 695-696. (e) Noda, T.; Ishiwata, A.; Uemura,
S.; Sakamoto, S.; Hirama, M. Synlett 1998, 298-300. Hashimoto group:
(22) Pinnatoxin A methyl ester was prepared previously from the natural (+)-
pinnatoxin A by Uemura and co-workers (ref 3a). The physical data of
the synthetic material match those reported for the methyl ester derived
from the natural product. See Supporting Information for details.
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