Total synthesis of pinnatoxin A

Article abstract of DOI:10.1002/anie.200802729

A familiar ring: A ruthenium-catalyzed cycloisomerization of an enyne, synthesized by an exo-selective Diels-Alder reaction with an α-methylene lactone as the dienophile, proved to be highly effective for the construction of the 27-membered carbocycle of pinnatoxin A. The total synthesis was completed upon the formation of the seven-membered cyclicimine by self-catalyzed dehydration. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200802729

Angewandte
Chemie
DOI: 10.1002/anie.200802729
Natural Product Synthesis
Total Synthesis of Pinnatoxin A**
Seiichi Nakamura,* Fumiaki Kikuchi, and Shunichi Hashimoto*
Dedicated to Professor E. J. Corey on the occasion of his 80th birthday
Pinnatoxins and pteriatoxins are structurally related marine
toxins which were isolated and characterized by Uemura and
co-workers.[1,2] Pinnatoxin A (1), isolated along with pinna-
toxins B–D from the shellfish Pinna muricata in 1995, is the
first and most prominent member of the marine iminium
alkaloid family; it was reported to activate Ca2+ channels,[3]
although the scarcity of a natural supply has prevented
additional biological evaluation. Pinnatoxin A (1) possesses a
striking array of structural features, including a 27-membered
carbocycle incorporating a [6,5,6]-dispiroketal (BCD rings), a
[5,6]-bicycloketal (EF rings), and a cyclic imine (A ring)
spirolinked to a cyclohexene ring (G ring), which suggests
that it originates biosynthetically from an intramolecular
[4+2] cycloaddition event.[1a,2] Owing to its structural com-
plexity, biological properties, and limited availability, 1 has
been a target of considerable synthetic interest. In 1998, Kishi
and co-workers[4] accomplished the first total synthesis of
(À)-1 by utilizing a biomimetic intramolecular Diels–Alder
reaction to construct the G ring and the macrocycle, estab-
lishing that the absolute stereochemistry was enantiomeric to
that illustrated by Uemura and co-workers. A formal total
synthesis of 1 was documented by the group of Hirama in
2004,[5] and very recently a total synthesis was completed by
the group of Zakarian.[6] Other studies directed toward the
synthesis of the pinnatoxin framework have also been
reported by several groups, including ours.[7–9] In this com-
munication, we disclose a route to the synthesis of pinnatox-
in A (1), capitalizing on the exo-selective intermolecular
Diels–Alder reaction devised by the Roush group[10,11] and the
Ru-catalyzed cycloisomerization methodology developed by
the Trost group.[12–14]
In our retrosynthetic strategy, we envisioned the late-stage
formation of the cyclic imine and a Ru-catalyzed cyclo-
isomerization of the appropriate enyne 3 to construct the
27-membered carbocycle in 2 (Scheme 1). Since the stereo-
chemical arrangement of the G ring would require an exo-
selective Diels–Alder reaction with diene 5, we decided to
take advantage of the striking exo preference of the con-
formationally restricted s-cis enone and enoate dieno-
philes.[10,11] a-Methylene lactone 6 was then chosen as the
[*] Dr. S. Nakamura, Dr. F. Kikuchi, Prof. Dr. S. Hashimoto
Faculty of Pharmaceutical Sciences
Hokkaido University
Sapporo 060-0812 (Japan)
Fax: (+81) 11-706-3236
E-mail: hsmt@pharm.hokudai.ac.jp
nakamura@pharm.hokudai.ac.jp
[**] This research was supported in part by a Grant-in-Aid for Scientific
Research on Priority Areas (A) “Exploitation of Multi-Element Cyclic
Molecules” and Priority Areas 17035002 and 18032002 from the
Ministry of Education, Culture, Sports, Science and Technology
(MEXT) and the Akiyama Foundation. We are grateful to Prof.
Daisuke Uemura of Keio University for helpful advice. We also thank
Seiko Oka, Hiroko Matsumoto, Akiko Maeda, Miwa Kiuchi, and
Tomohiro Hirose of the Center for Instrumental Analysis, Hokkaido
University and Dr. Eri Fukushi of the Faculty of Agriculture,
Hokkaido University for technical assistance in NMR, mass, and
elemental analyses. The early stages of our pinnatoxin A synthesis
were developed by Dr. Jun Inagaki, Tomohiro Sugimoto, and
Masashi Kudo.
Scheme 1. Retrosynthetic analysis of pinnatoxin A (1). Bn=benzyl;
TBDPS=tert-butyldiphenylsilyl; TBS=tert-butyldimethylsilyl; TES=tri-
ethylsilyl; TMS=trimethylsilyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802729.
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dienophile to give cycloadduct 4 with the correct stereo-
fered with pyridine. The aldehyde was then homologated by a
Horner–Wadsworth–Emmons reaction with b-ketophospho-
nate 12[16] under Masamune conditions[18] to provide enone 13
in 78% overall yield in three steps. Enone 13 was subjected to
a Wittig reaction to yield diene 5 in 92% yield, which set the
stage for the crucial Diels–Alder reaction.
chemistry at both C5 and C31. Bicycloketal 7 could be derived
from the internal ketalization of ketone 8, which could be
constructed by removal of the C12 TES protecting group of
the open-chain precursor 9, and a subsequent double hemi-
ketal formation/hetero-Michael addition reaction.
We previously developed a route to access the C10–C31
fragment (7),[9] wherein a tandem double hemiketal forma-
tion/intramolecular hetero-Michael addition sequence was
employed for the stereoselective construction of the BCD
ring system. Since Kishi and co-workers suggested that the
C15 TBS protecting group could not be removed during the
later stages of the synthesis,[4b] a protecting group exchange
appeared to be the first task to advance intermediate 7 to 1.
Thus, removal of the silyl protecting groups with Bu4NF in
THF at reflux and subsequent selective reprotection of the
hydroxy groups at C28 and C31 as TBS ethers afforded
alcohol 10 in 95% yield in two steps; 10 was then silylated
with TESOTf to give 11 in 94% yield (Scheme 2). After
selective removal of the C31 TBS ether with Bu4NF in THFat
08C, the alcohol, which is prone to isomerization, was
immediately oxidized with Dess–Martin periodinane[15] buf-
The cycloaddition of 5 with a-methylene lactone 6[19] in
p-xylene at 1608C in a sealed tube proceeded with complete
regioselectivity to provide a mixture of four of the eight
possible stereoisomers in a 45:27:18:10 ratio and a total yield
of 83%. Modest exo selectivity (72:28) was obtained as
expected from known precedent,[11b] albeit with a poor
diastereofacial selection (63:37). After separation of the
isomers, desired adduct 4 was isolated in 35% yield along with
23% of adduct 14. At this stage, we were faced with the task
of removing the benzyl group at C10 without affecting the
olefin functionality. After considerable experimentation, it
was found that the desired transformation could be achieved
by addition of 4 to a premixed suspension of Pd/C and
HCO2H[20] in EtOH. The resultant alcohol 15 was unevent-
fully converted into alkyne 16 in 77% yield by Dess–Martin
oxidation, and subsequent treatment with the Ohira–Best-
Scheme 2. Synthesis of cyclization precursor 3. a) B uNF, THF, reflux, 72 h; b) TBSCl, imidazole, DMF, 3.5 h, 95% (2 steps); c) TESOTf, 2,6-
4
lutidine, CH2Cl2, 15 min, 94%; d) Bu4NF (1.05 equiv), THF, 08C, 4 h, 91%; e) Dess–Martin periodinane, pyridine, CH2Cl2, 3 h; f) phosphonate 12,
LiCl, iPr2NEt, MeCN, 18 h, 86% (2 steps); g) MePPh3Br, BuLi, THF, 08C, 30 min, 92%; h) lactone 6 (10 equiv), 4 Š molecular sieves, p-xylene,
1608C, 12 h, 35% of 4, 23% of 14, and 23% of endo isomers; i) 10% Pd/C, HCO2H, EtOH, 12 h, 81%; j) Dess–Martin periodinane, pyridine,
CH2Cl2, 1 h, 95%; k) (MeO)2P(O)C(N2)COMe, K2CO3, MeOH, 72 h, 82%; l) LiAlH4, THF, À78 to 08C, 6 h, 90%; m) TBSCl, imidazole, CH2Cl2, 1 h,
98%; n) Dess–Martin periodinane, pyridine, CH2Cl2, 1 h, 96%; o) CH2 =CHCH2MgBr, THF, À78 to 08C, 2 h, 97%; p) 1-(trimethylsilyl)imidazole,
THF, reflux, 48 h, 98%.
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mann reagent in the presence of K2CO3 in MeOH.[21] To set up
the three-carbon homologation, the lactone moiety was
reduced with LiAlH4 to diol 17, which was monosilylated at
the C1 hydroxy group with TBSCl to provide alcohol 18 in
88% yield in two steps. Dess–Martin oxidation of 18 and then
addition of allylmagnesium bromide furnished alcohol 19 in
93% yield in two steps, which, upon silylation with
1-(trimethylsilyl)imidazole in THF at reflux, gave enyne 3 in
98% yield.
With the cyclization precursor in hand, we then inves-
tigated the key cycloisomerization reaction. Gratifyingly, the
reaction of enyne 3 occurred with complete regioselectivity by
application of the Trost procedure[12,14] (10 mol% of [CpRu-
(MeCN)3]PF6, acetone, 508C) to provide desired cyclization
product 20 in 79% yield with no signs of dimerization
(Scheme 3). Exposure of 27-membered ring compound 20 to
pyridinium p-toluenesulfonate (PPTS) in EtOH resulted in
selective removal of the silyl protecting groups at C1 and C6
to afford diol 21, which, upon tosylation of the liberated
primary alcohol gave 22 in 82% yield over two steps. The
C7–C8 double bond was saturated by oxidation of the allylic
alcohol at C6 with Dess–Martin periodinane and subsequent
conjugate reduction with the Stryker reagent in wet ben-
zene,[22] providing ketone 23 in 93% yield in two steps. After
displacement of tosylate 23 with NaN3 in DMF at 708C, the
C34 TBDPS ether was selectively removed with Bu4NF in
THF at 08C to give alcohol 2 in 88% yield over two steps; 2
was then transformed into carboxylic acid 25 by two
successive oxidations (Dess–Martin periodinane; NaClO2).
The azide group at C1 in 25 was chemoselectively reduced to
amine 26 under a hydrogen atmosphere in the presence of
Lindlarꢀs catalyst in preparation for formation of the cyclic
imine. In the total syntheses of the pinnatoxins and pteria-
toxins, Kishi and co-workers reported that e-aminoketones
could be converted into the corresponding seven-membered
cyclic imines either by heating at 2008C without a solvent
under high vacuum,[4a] or by treatment with the Et3N salt of
2,4,6-triisopropylbenzoic acid in xylene at 808C.[4c,e] We found
that the carboxy group in the molecule facilitated the
formation of the cyclic imine from e-aminoketone 26 under
thermolysis conditions: iminoacid 27 was obtained in 74%
yield upon heating in chlorobenzene at 1208C for 18 hours.
Scheme 3. Completion of the total synthesis of pinnatoxin A (1). a) [CpRu(MeCN)3]PF6 (10 mol%), acetone, 508C, 15 min, 79%; b) PPTS, EtOH,
72 h, 89%; c) TsCl, pyridine, CH2Cl2, 2 h, 92%; d) Dess–Martin periodinane, pyridine, CH2Cl2, 6 h; e) [{(Ph3P)CuH}6], wet benzene, 12 h, 93%
(2 steps); f) NaN3, DMF, 708C, 18 h, 93%; g) Bu4NF, THF, 08C, 10 h, 95%; h) Dess–Martin periodinane, pyridine, CH2Cl2, 1 h; i) NaClO2,
NaH2PO4, 2-methyl-2-butene, tBuOH/H2O (4:1), 6 h, 80% (2 steps); j) H2, Lindlar’s catalyst, EtOH, 36 h, 83%; k) chlorobenzene, 1208C, 18 h,
74% (84% based on recovered ketoamino acid 26); l) 46% aqueous HF/MeCN (1:9), 12 h, 91%. Cp=cyclopentadienyl; Ts=p-toluenesulfonyl.
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Finally, removal of the silyl groups with HF in aqueous MeCN
completed the total synthesis of pinnatoxin A (1), which was
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In conclusion, the total synthesis of pinnatoxin A was
completed in 53 steps for the longest linear sequence from a
known compound and in 0.21% overall yield. Late stages of
the synthesis feature the exo-selective Diels–Alder reaction
by using a-methylene lactone 6 as a dienophile for construc-
tion of the G ring, the Ru-catalyzed cycloisomerization to
fashion the 27-membered carbocyclic ring, and the formation
of the seven-membered cyclic imine by self-catalyzed dehy-
dration of ketoamino acid 26. Notably, the successful
application of the Trost protocol attests to the power and
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Received: June 10, 2008
Published online: July 30, 2008
Keywords: cyclization · cycloaddition · macrocycles ·
.
natural products · ruthenium
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