Total synthesis of pinnatoxin A

Full text of DOI:10.1021/ja981257o

J. Am. Chem. Soc. 1998, 120, 7647-7648
7647
Scheme 1a
Total Synthesis of Pinnatoxin A
John A. McCauley, Kazuo Nagasawa, Peter A. Lander,
Steven G. Mischke, Marcus A. Semones, and Yoshito Kishi*
Department of Chemistry and Chemical Biology
HarVard UniVersity, Cambridge, Massachusetts 02138
ReceiVed April 14, 1998
In 1995, Uemura and co-workers isolated pinnatoxin A (1) from
the shellfish Pinna muricata, determined its gross structure and
relative stereochemistry, and proposed a biosynthetic pathway,
i.e., 2 f 1.1 Pinnatoxin A is one of the major toxic principles
responsible for outbreaks of Pinna shellfish intoxication in China
and Japan.2 Its unique molecular architecture, accompanied by
a Reagents and yields: (a) CSA, MeOH, 5 (51%) + 4 (30%); (b)
TBSOTf, 2,6-lutidine, 95%; (c) OsO4, NMO; NaIO4, 85%; (d) (i)
4-iodobutyl-p-methoxybenzyl ether, t-BuLi, Et2O, -78 °C, 88%; (ii)
Swern oxidation, 92%; (iii) PPh3CH3Br, n-BuLi, 0 °C, 89%; (e) (i) TBAF,
rt, quantitative; (ii) I2, PPh3, imidazole, 92%; (f) (i) 1,3-dithiane, t-BuLi,
10% HMPA/THF, 92%; (ii) TBAF, 70 °C, 95%.
its pronounced biological activity as a Ca2+-channel activator,
makes pinnatoxin A an intriguing synthetic target.3 In this paper,
we report the first total synthesis of pinnatoxin A, which allowed
the assignment of its absolute configuration as the antipode of 1.
Our retrosynthetic analysis of pinnatoxin A is based on
Uemura’s biosynthetic proposal, entailing an intramolecular
Diels-Alder reaction to construct the G-ring as well as the
macrocycle, followed by imine formation to establish the 6,7-
spiro-ring system. Functional group arrangements similar to the
AG-ring system of pinnatoxin A are found in other natural
products, including the spirolides4 and gymnodimine,5 and perhaps
arise via a similar biogenetic pathway, i.e., an intramolecular
Diels-Alder reaction followed by imine formation or vice versa.6
To investigate these key cyclizations, we envisioned the requisite
diene 2 as available via a dithiane-based coupling to form the
C.25-C.26 bond and sequential Ni(II)/Cr(II)-mediated couplings
between vinyl iodides with suitable advanced C.6 and C.32
aldehydes, cf. structure 2. At the outset of this work, the absolute
stereochemistry of pinnatoxin A had not been determined.
As the entry point into the bis-spiroketal system, we chose the
acid-catalyzed cyclization of diketone 3, prepared from 1-pentynol
in 12 steps.7 Treatment with camphorsulfonic acid (CSA)
afforded primarily a 2:3 mixture of C.19 epimeric bis-spiroketals
4 and 5 whose structures were determined by X-ray analysis of
their corresponding mono-p-nitrobenzoate derivatives (Scheme
1).8 The ratio of 4 and 5 was affected by choice of acids, solvents,
and addition of metal ions. In fact, the desired bis-spiroketal 5
completely epimerized to the undesired bis-spiroketal 4 in the
presence of magnesium bromide, whereas the undesired bis-
spiroketal 4 epimerized back exclusively to the natural series under
standard silylation conditions, i.e., 4 f 6. Once silylated at the
tertiary hydroxyl, the bis-spiroketal system became configuration-
ally stable9 and could be transformed into dithiane 10 via standard
synthetic methods without loss of its stereochemical integrity.
Dithiane 10 and iodide 117 were coupled under t-BuLi in 10%
HMPA/THF conditions10 and converted to diol 12 in two steps
(Scheme 2). Following oxidation, Ni(II)/Cr(II)-mediated cou-
pling11 of the aldehyde with vinyl iodide 137 proceeded smoothly
to generate a mixture of C.6-diastereomeric allylic alcohols.
Removal of the primary TBS group and oxidation then furnished
a single diketo-aldehyde 14. Completion of the pinnatoxin carbon
skeleton, cf. 16, entailed a second Ni(II)/Cr(II)-mediated coupling
between aldehyde 14 and iodide 15,7 in the presence of a
bispyridinyl ligand.12 It is noteworthy that the vinylchromium
species adds selectively to the C.32 aldehyde in the presence of
a carbamate carbonyl, an enone, and a ketone.
(1) (a) Uemura, D.; Chuo, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.; Zheng,
S.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155. (b) Chuo, T.; Kamo, O.;
Uemura, D. Tetrahedron Lett. 1996, 37, 4023.
(2) (a) 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. (b) 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.
(3) For synthetic studies, see: (a) Sugimoto, T.; Ishihara, J.; Murai, A.
Tetrahedron Lett. 1997, 38, 7379. (b) Zhang, X.; McIntosh, M. C. 215th
National Meeting of the American Chemical Society, Dallas, TX; March 29-
April 2, 1998; ORGN 188.
(4) (a) Hu, T.; Curtis, J. M.; Oshima, Y.; Quilliam, M. A.; Walter, J. A.;
Watson-Wright, W. M.; Wright, J. L. C. J. Chem. Soc., Chem. Commun. 1995,
2159. (b) In the case of the spirolides, the imino group has been shown to be
essential for bioactivity: Hu, T.; Curtis, J. M.; Walter, J. A.; Wright, J. L. C.
Tetrahedron Lett. 1996, 37, 7671.
Our first attempt directed at the biomimetic Diels-Alder
reaction began with removal of the acetonide and formation of
(7) Experimental details for the synthesis of 3, 11, 13 and 15, and the
structures of 18b-c are included in Supporting Information.
(8) Bis-spiroketals 4 and 5 can be distinguished readily from the chemical
1
shifts of the C.12 and C.23 resonances in H NMR.
(9) For similar examples, see: Guo, J.; Duffy, K. J.; Stevens, K. L.; Dalko,
P. I.; Roth, R. M.; Hayward, M. M.; Kishi, Y. Angew. Chem., Int. Ed. 1998,
37, 187, and references therein.
(5) (a) Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H. F.; Yasumoto, T.
Tetrahedron Lett. 1995, 36, 7093. (b) Stewart, M.; Blunt, J. W.; Munro, M.
H. G.; Robinson, W. T.; Hannah, D. J. Tetrahedron Lett. 1997, 38, 4889.
(6) Prorocentrolides possess a fused cyclohexene/cyclic imine ring system
which may also arise through an intramolecular Diels-Alder reaction: (a)
Torigoe, K.; Murata, M.; Yasumoto, T. J. Am. Chem. Soc. 1988, 110, 7876.
(b) Hu, T.; deFreitas, S. W.; Curtis, J. M.; Oshima, Y.; Walter, J. A.; Wright,
J. L. C. J. Nat. Prod. 1996, 59, 1010.
(10) Smith, A. B., III.; Condon, S. M.; McCauley, J. A.; Leazer, J. L., Jr.;
Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1997, 119, 947.
(11) (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644. (b) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.;
Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048. (c) Stamos, D.
P.; Sheng, X. C.; Chen, S. S.; Kishi, Y. Tetrahedron Lett. 1997, 38, 6355,
and references therein.
(12) Chen, C.; Tagami, K.; Kishi, Y. J. Org. Chem. 1995, 60, 5386.
S0002-7863(98)01257-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/15/1998

7648 J. Am. Chem. Soc., Vol. 120, No. 30, 1998
Communications to the Editor
Scheme 2a
underwent complete dimerization via an intermolecular cyclo-
addition of the diene with the C.33-C.35 olefin.13
In contrast, heating a 0.2 mM solution of the diene in a variety
of solvents led to the desired intramolecular Diels-Alder reac-
tion.14 For example, heating the diene in toluene at 100 °C for
24 h gave a 1:1:1 mixture of three out of the eight possible
intramolecular Diels-Alder products, which were separated by
HPLC to yield pure adducts 18a-c.7 2D NMR experiments
established the structures of 18a-c: desired exo product (18a),
undesired exo product (18b), and one endo product (18c), all
possessing the desired regiochemistry.15 Interestingly, the exo/
endo ratio was enhanced by changing the solvent to dodecane
and reducing the temperature to 70 °C. Under these conditions,
the ratio of 18a:18b:18c was 1.0:0.9:0.4, with a ca. 5:1 exo:endo
ratio in a 78% combined yield. It is worthwhile to note that the
facial selectivity leading to the exo products depended on the
arrangement of functional groups around the C.25-C.32 moiety.16
The desired Diels-Alder product 18a was converted to amino
ketone 19 in two steps. However, attempts to form the imine
between the C.1 amine and C.6 ketone under a variety of acidic
conditions were unsuccessful. This observation, along with the
fact that pinnatoxin A exists as a stable imine in dilute aqueous
acid,1 led us to hypothesize a large energy barrier present for the
imine formation/hydrolysis due to the steric strain in generating
a tetrahedral intermediate adjacent to a quaternary center. To
overcome this obstacle, we heated the neat amino ketone 19 to
200 °C under high vacuum for 1 h and obtained a 70% yield of
the desired imine. Finally, the tert-butyl ester was cleaved with
1:1 TFA/CH2Cl2 treatment17 to furnish synthetic pinnatoxin A
[RD -9° (c 0.5, MeOH)], identical in all respects to natural
pinnatoxin A18 [RD +2.5° (c 0.3, MeOH)] except for the sign of
optical rotation. From this information, we conclude that the
absolute stereochemistry of natural pinnatoxin A is the antipode
of structure 1. This conclusion was further supported by the
biological tests of synthetic (-)-pinnatoxin A in reference to
natural (+)-pinnatoxin A.18
a Reagents and yields: (a) (i) 10, t-BuLi, 10% HMPA/THF, then
addition of 11, 71%; (ii) (CF3CO2)2IPh, CaCO3, 82%; (iii) DDQ, 85%;
(b) (i) Dess-Martin oxidation, 90%; (ii) 13, 1% NiCl2/CrCl2, DMSO,
55%; (iii) HF‚pyridine, pyridine, THF, 91%; (iv) Dess-Martin oxidation,
91%; (c) 15, 33% NiCl2/CrCl2, bispyridinyl ligand, THF, 88%.
Scheme 3a
In conclusion, we have completed the first total synthesis of
pinnatoxin A utilizing a biomimetic intramolecular Diels-Alder
reaction. This synthesis has also established the absolute stereo-
chemistry of pinnatoxin A as the antipode of the structure 1.
Acknowledgment. Financial support from the National Institutes of
Health (NS12108) is gratefully acknowledged. J.A.M. and P.A.L. thank
the NIH/NCI for postdoctoral fellowships (5 F32 CA72201 and 1 F32
CA68701, respectively). K.N. thanks the Uehara Memorial Foundation
for a postdoctoral fellowship. S.G.M. thanks the NIH/NIGMS for a
postdoctoral fellowship (1 F32 GM17061).
Supporting Information Available: The experimental details for the
synthesis reported, including the synthesis of diketone 3, and iodides 11,
13, and 15 (26 pages, print/PDF). See any current masthead page for
ordering information and Web access instructions.
JA981257O
a Reagents and yields: (a) (i) TFA, CH2Cl2, H2O, 71%; (ii) MsCl,
TEA, -78 °C, 85%; (iii) TESOTf, 2,6-lutidine, 79%; (b) DABCO, TEA,
benzene; 70 °C, 0.2 mM diene in dodecane, 78%; (c) (i) HF‚pyridine,
pyridine, THF, 94%; (ii) Pd(PPh3)4, AcOH, toluene, 82%; (d) (i) 200
°C, 1-2 Torr, 70%; (ii) 1:1 TFA/CH2Cl2, 95%.
(14) The C.19-epi-ketal derived from TFA treatment of acetonide 16 was
transformed into a Diels-Alder precursor without exposure to TESOTf,
furnishing a cyclization precursor with the diene and dieneophile on opposite
faces of the molecule. Considering that this compound cannot meet the
geometrical arrangement required for the intramolecular Diels-Alder reaction,
one expects this compound would not undergo the desired intramolecular
cycloaddition. Indeed, this substrate was found only to dimerize under all
conditions tested.
the bicyclic ketal (Scheme 3). Under the acidic conditions
employed, the C.19 bis-spiroketal stereocenter almost completely
epimerized to the undesired configuration. However, as demon-
strated previously, we could epimerize the C.19 stereocenter of
the mesylate derived from 16 back to the desired configuration,
cf. 17, under silylation conditions. The diene was then formed
via SN2′ displacement of the C.32 allylic mesylate with DABCO13
followed by removal of a C.31 proton by treatment with
triethylamine. However, upon concentration, this diene readily
(15) We thank Dr. Yuan Wang, Eisai Research Institute, Andover, MA,
for the 2D NMR experiments.
(16) For example, treatment of 16 with MsCl, followed by DABCO, gave
a Diels-Alder precursor with the C.29-C.30 acetonide intact. The intramo-
lecular Diels-Alder reaction [toluene (0.2 mM), 100 °C] then furnished a
single product in 60% yield. 2D COSY and NOESY NMR experiments
indicated that this product possessed the desired stereochemistry. However,
all attempts to remove the acetonide have been fruitless thus far.
(17) The configuration of the C.19 spiroketal center is stable once the
macrocycle is formed. For a similar example, see ref 9.
(18) We thank Professor Uemura for a generous gift of natural pinnatoxin
A. We also thank him for performing biological tests which indicated that
synthetic pinnatoxin A was inactive in a mouse assay at 100 µg dosage,
whereas the LD99 for natural pinnatoxin A is 2.7 µg per mouse.
(13) (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1983,
22, 795. (b) Jung, M. E.; Zimmerman, C. N. J. Am. Chem. Soc. 1991, 113,
7813.