An approach to the imine ring system of pinnatoxins

Article abstract of DOI:10.1021/ol050321l

(Chemical Equation Presented) A concise stereoselective approach to the spirobicyclic imine fragment of pinnatoxins and pteriatoxins is described. The approach relies on a tandem reaction sequence involving consecutive sigmatropic rearrangements to build

Full text of DOI:10.1021/ol050321l

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1629-1631
An Approach to the Imine Ring System
of Pinnatoxins
Matthew J. Pelc and Armen Zakarian*
Department of Chemistry and Biochemistry, Florida State UniVersity,
Tallahassee, Florida 32306-4390
zakarian@chem.fsu.edu
Received February 15, 2005
ABSTRACT
A concise stereoselective approach to the spirobicyclic imine fragment of pinnatoxins and pteriatoxins is described. The approach relies on
a tandem reaction sequence involving consecutive sigmatropic rearrangements to build the quaternary chiral center at the core of the spirobicyclic
ring system.
The imine group is typically considered to be a reactive
functional group sensitive to hydrolysis. For this reason, its
presence in the structure of an emerging group of natural
products exemplified by pinnatoxins (1)1 and gymnodimine2
is intriguing. These natural products incorporate an imine
group as a part of a spirobicyclic ring system within their
molecular framework. The seven-membered cyclic imine in
closely related spirolides C and D has been shown to be
completely stable to hydrolysis upon treatment with aqueous
acids.3 This atypical chemical behavior of the cyclic imines
has been linked to the biological profile of the natural
products3a and has also been observed during the pioneering
total synthesis of pinnatoxin A by Kishi and in a recent
insightful study described by Romo.4,5
In addition to the presence of the imine group, perhaps a
more significant challenge for synthesis is posed by the
quaternary chiral center at the core of the spirobicyclic ring
system. A number of synthetic studies toward gymnodimine
and pinnatoxins that address this problem have been de-
scribed.6 A recent formal synthesis of pinnatoxin A relies
on an intramolecular epoxide opening by a nitrile anion to
form the A,G-ring portion of the target molecule.7
In this communication, we report a new approach to the
A,G-spirobicyclic ring system (2) of pinnatoxins and
pteriatoxins based on a cascade sigmatropic rearrangement
of vinylic sulfoxide 3 (Scheme 1).
(1) (a) Uemura, D.; Chuo, T.; Haino, T.; Nagatsu, A.; Fukuzawa, S.;
Zheng, S.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155-1156. (b) Takada,
N.; Umemura, N.; Suenaga, K.; Chou, T.; Nagatsu, A.; Haino, T.; Yamada,
K.; Uemura, D. Tetrahedron Lett. 2001, 42, 3491-3494. Pteriatoxins: (c)
Takada, N.; Umemura, N.; Suenaga, K.; Chou, T.; Nagatsu, A.; Haino T.;
Yamada, K.; Uemura, D. Tetrahedron Lett. 2001, 42, 3495-3498.
(2) (a) Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H. F.; Yasumoto,
T. Tetrahedron Lett. 1995, 36, 7093-7096. (b) Stewart, M.; Blunt, J. W.;
Munro, M. H. G.; Robinson, W. T.; Hannah, D. T. Tetrahedron Lett. 1997,
38, 4889-4890.
(3) (a) Hu, T.; Burton, I. W.; Cembella, A. D.; Curtis, J. M.; Quilliam,
M. A.; Walter, J. A.; Wright, J. L. C. J. Nat. Prod. 2001, 64, 308-312. (b)
Hu, T.; Curtis, J. M.; Walter, J. A.; Wright, J. L. C. Tetrahedron Lett. 1996,
37, 7671-7674.
(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) Ahn, Y.; Cardenas, J. Y.; Yang, J.; Romo, D. Org. Lett. 2001, 3,
751-754.
10.1021/ol050321l CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/15/2005

Scheme 1
Scheme 3
The synthesis of iodide 4 commenced with a known
diimide 6 obtained by oxidative dimerization of the lithium
enolate of commercially available 4-(S)-isopropyl-3-propio-
nyl-2-oxazolidinone (Scheme 2).8 Conversion of 5 to diol
Scheme 2
conditions, the reaction proved to be sluggish (5 mol %
Pd(dppf)Cl2, 14% conversion after 12 h at 60 °C). However,
when the reaction conditions developed by Fu were em-
ployed, the desired product 10 was formed in a 75% yield
after 30 min at 30 °C.10
Further elaboration required deprotection of the primary
hydroxyl group to 11, oxidation of 11 to the aldehyde, and
a three-step transformation of the aldehyde into vinyl
sulfoxide 3.
At this stage, we set out to examine the key tandem
sigmatropic reorganization of 3 and of its epimer at the sulfur
center (epi-3, Scheme 4).11 Heating of each diastereomer in
the presence of triethyl phosphite and s-collidine as a buffer
in a high-boiling alcohol resulted in a clean rearrangement
to the predicted product, allylic alcohol 12.12 Thus, the
designed reaction cascade holds a promise for efficient
formation of the quaternary chiral center at C-5, addressing
one of the major challenges posed by the target spirobicyclic
structure. In addition, the reaction accomplishes a stereose-
lective introduction of the tertiary allylic alcohol within the
six-membered ring that will serve as a template for the
7, its monoprotection with pivaloyl chloride, and iodo-
dehydroxylation afforded 4 in only five steps.
Ketone 8, readily available from ascorbic acid, served as
the starting material for the preparation of lactone 5 (Scheme
3).9 Addition of 4-pentenylmagnesium bromide proceeded
with 8:1 diastereoselectivity, giving the desired stereoisomer
as the major product.9 Cleavage of the double bond followed
by oxidation of the lactol afforded 5. Alkylation of the zinc-
ate enolate generated from the lactone with iodide 4 gave a
5:1 epimeric mixture of the desired products in an excellent
yield. Triflate 9 formed from the alkylation products served
as the substrate for Negishi coupling. Under the standard
(6) (a) Yang, J.; Cohn, S. T.; Romo, D. Org. Lett. 2000, 2, 763-766.
(b) White, J. D.; Wang, G.; Quaranta, L. Org. Lett. 2003, 5, 4983-4986.
(c) Tsujimoto, T.; Ishihara, J.; Horie, M.; Murai, A. Synlett 2002, 399-
402. (d) Ishihara, J.; Horie, M.; Shimada, Y.; Tojo, S.; Murai, A. Synlett
2002, 403-406. (e) Nitta, A.; Ishiwata, A.; Noda, M.; Hirama, M. Synlett
1999, 695-696. (f) Wang, J.; Sakamoto, S.; Kamada, K.; Nitta, A.; Noda,
T.; Oguri, H.; Hirama, M. Synlett 2003, 891-893. (g) Brimble, M. A.;
Trzoss, M. Tetrahedron 2004, 60, 5613-5622. (h) Trzoss, M.; Brimble,
M. A. Synlett 2003, 2042-2046.
(7) Sakamoto, S.; Sakazaki, H.; Hagiwara, K.; Kamada, K.; Ishii, K.;
Noda, T.; Inoue, M.; Hirama, M. Angew. Chem., Int. Ed. 2004, 43, 6505-
6510.
(8) Kise, N.; Ueda, T.; Kumada, K.; Terao, Y.; Ueda, N. J. Org. Chem.
2000, 65, 464-468.
(9) Marco, J. A.; Carda, M.; Gonzalez, F.; Rodriguez, S.; Castillo, E.;
Murga, J. J. Org. Chem. 1998, 63, 698-707.
(10) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719-2724.
(11) R)-Sulfoxide, epi-3, was prepared from 11 by the same method using
(R)-methyl p-tolyl sulfoxide.
(12) Stereochemical configuration is supported by HMBC and NOE
correlations in a model study (see Supporting Information).
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Org. Lett., Vol. 7, No. 8, 2005

this reaction resulted in decomposition, and no desired imine
could be identified.
Scheme 4
On the other hand, the initial rearrangement product 12
was readily transformed into 2 (Scheme 6). Removal of the
Scheme 6
protecting group from the primary alcohol followed by
tosylation and substitution with azide afforded 16. Acetyla-
tion of the tertiary allylic alcohol gave 17. Staudinger re-
duction of the azide with Me3P resulted in smooth cyclization
to imine 2 upon reflux in toluene.
In conclusion, we developed a reaction tandem for the
assembly of the spirobicyclic imine ring system of pinna-
toxins and pteriatoxins. The reaction sequence is initiated
by a [3,3]-sigmatropic shift that is followed by a Mislow-
Evans rearrangement and introduces the chiral quaternary
center at the core of the spirobicyclic ring system with a
high level of stereocontrol. The allylic acetate functionality
in 2, that also resulted from the tandem reaction, is favorably
set up for further elaboration to introduce the side chain at
C-31. We plan to exploit the π-allyl palladium methodology14
or allylic substitutions with cuprate reagents15 to achieve this
goal. Studies to evaluate the viability of cyclic imine 2 as
an intermediate for the synthesis of pinnatoxins are underway
in our laboratory.
required chain extension at C-31. We speculate that this
tandem reaction sequence is initiated by a [3,3]-sigmatropic
shift to form intermediate 13, which then undergoes a fast
Mislow-Evans rearrangement under the reaction conditions.
At this point, we wished to incorporate the aza-Wittig
azepine ring closure into the reaction cascade.13 Conse-
quently, azide 14 was prepared from 3 by reductive depro-
tection of the primary alcohol, tosylation, and substitution
with sodium azide in DMF (Scheme 5). The azido group in
Scheme 5
Acknowledgment. This work was supported by the
Department of Chemistry and Biochemistry, Florida State
University. We are grateful to Dr. Umesh Goli of the De-
partment of Chemistry for performing the HRMS experi-
ments and Farhan Bou-Hamdan for assistance with the two-
dimensional NMR experiments.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds and
1
copies of H NMR and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL050321L
thus obtained 14 was reduced with triphenylphosphine to
the corresponding iminophosphorane, which was subjected
in situ to the rearrangement reaction conditions. However,
(14) Tsuji, J. Palladium Reagents and Catalysts; New PerspectiVes for
the 21st Century; John Wiley & Sons: Chichester, England, 2004; Chapter
4.3, p 469.
(15) Lipshutz, B. H.; Sengupta, S. Organic Reactions; John Wiley &
Sons: New York, 1992; Vol. 42, Chapter 1, p 135.
(13) Similar azepine ring closure was reported by Hirama; see ref 6f.
Org. Lett., Vol. 7, No. 8, 2005
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