Studies on the Synthesis of Gymnodimine. Construction of the Spiroimine Portion via Diels-Alder Cycloaddition

Article abstract of DOI:10.1021/ol035939e

(Equation Presented) An azaspiro[5.5]undecadiene corresponding to a subunit of the shellfish toxin gymnodimine was synthesized by Diels-Alder cycloaddition. One member of the pair of stereoisomeric adducts was transformed to a spiroimine, which will serve

Full text of DOI:10.1021/ol035939e

ORGANIC
LETTERS
2003
Vol. 5, No. 26
4983-4986
Studies on the Synthesis of
Gymnodimine. Construction of the
Spiroimine Portion via Diels−Alder
Cycloaddition
James D. White,* Guoqiang Wang, and Laura Quaranta
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331-4003
james.white@orst.edu
Received October 3, 2003
ABSTRACT
An azaspiro[5.5]undecadiene corresponding to a subunit of the shellfish toxin gymnodimine was synthesized by Diels−Alder cycloaddition.
One member of the pair of stereoisomeric adducts was transformed to a spiroimine, which will serve as the core around which the macrocyclic
portion of the toxin will be assembled.
Gymnodimine (1) is a biotoxin isolated from oysters (Tios-
trea chilensis) collected in New Zealand and has been found
Scheme 1
to exhibit neurotoxic shellfish poisoning in a mouse biossay.1
Our strategy for the synthesis of 1 relies upon the assembly
of two subunits, 2 and 3, to create the macrocyclic core of
the toxin’s structure. Progress toward the tetrahydrofuran
portion 3 has been reported by us2 and others,3-5 and we
now describe a route to the azaspiro[5.5]undecadiene seg-
ment4,5 that can serve as a progenitor of 1. Our approach
employs a Diels-Alder cycloaddition to conjugated diene
4, which is prepared from the (S)-glyceraldehyde derivative
5 (Scheme 1). The latter is the enantiomer of the starting
material we used to gain access to fragment 3.
The commercially available ester 6 was saponified, and
the lithium carboxylate was converted via its mixed anhy-
(1) (a) Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H.; 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.
(2) White, J. D.; Wang, G.-Q.; Quaranta, L. Org. Lett. 2003, 5, 4109.
(3) Rainier, J. D.; Xu, Q. Org. Lett. 1999, 1, 27.
(4) (a) Ishihara, J.; Miyakawa, J.; Tsujimoto, T.; Murai, A. Synlett 1997,
1417. (b) Tsujimoto, T.; Ishihara, J.; Horie, M.; Murai, A. Synlett 2002,
399.
(5) (a) Yang, J.; Cohn, S. T.; Romo, D. Org. Lett. 2000, 2, 763. (b)
Ahn, Y.; Cardenas, G. I.; Yang, J.; Romo, D. Org. Lett. 2001, 3, 751.
dride to Weinreb amide 7.6 Treatment of 7 with the lithio
alkene prepared from (E)-stannane 87 gave unsaturated
10.1021/ol035939e CCC: $25.00 © 2003 American Chemical Society
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ketone 9, which underwent smooth Wittig methylenation to
furnish conjugated diene 10 (Scheme 2). The selection of a
moiety. Fortunately, 14 and 15 were readily separable by
chromatography and the latter was crystalline, thus allowing
firm relative and absolute stereochemical assignments to be
made to the pair of cycloadducts through X-ray crystal-
lographic analysis (Figure 1).
Scheme 2
Figure 1. X-ray crystal structure of 15.
Our initial experiments designed to lead to the spiroimine
portion of gymnodimine were carried out with 14. Cleavage
of the p-methoxybenzyl ether from this adduct with 2,3-
dichloro-5,6-dicyanobenzoquinone resulted in spontaneous
formation of a γ-lactone (Scheme 4), and subsequent
suitable dienophilic partner for a Diels-Alder reaction with
10 was complicated by the fact that all of the unsymmetrical
dienophiles we tested resulted in a sluggish reaction that
produced mixtures of regioisomers and stereoisomers.
It was clear from these experiments that a symmetrical
doubly activated dienophile would be the preferred Diels-
Alder partner for 10, and this reasoning led us to examine
the methylene derivative 118 of Meldrum’s acid 12. The
unstable dienophile 11, obtained by elimination of pyridine
from the zwitterion 13 and used in situ, was reacted with 10
in ethanol to give 14 and 15 in a 1.2:1 ratio as the only two
cycloadducts (Scheme 3). Thus, there is complete regio-
selectivity in the reaction of 10 with 11 but only poor
asymmetric induction from the stereocenter in the dioxalane
Scheme 4
Scheme 3
methylation of the carboxylic acid liberated in this process
yielded the crystalline ester 16. The structure of 16 was
confirmed by X-ray crystallographic analysis (Figure 2).
The lactone moiety of 16 was selectively reduced with
diisobutylaluminum hydride, and the resulting cyclic hemi-
acetal 17 was condensed with phosphonate 18.9 The transient
R,â-unsaturated nitrile underwent immediate cyclization to
tetrahydrofuran 19, affording a heterocycle that was resistant
to ring opening and consequently prevented further advance
toward 2.
(6) Lee, C. E.; Kick, E. K.; Ellman, J. A. J. Am. Chem. Soc. 1998, 120,
9735.
(7) Stannane 8 was prepared from methyl butynoate by modification of
a method reported by Piers (Piers, E.; Wong, T.; Ellis, K. A. Can. J. Chem.
1992, 70, 2058).
(8) Zia-Ebrahimi, M.; Huffman, G. W. Synthesis 1996, 215.
(9) Deschamps, B.; Lefebvre, G.; Seyden-Penne, J. Tetrahedron 1972,
28, 4209.
4984
Org. Lett., Vol. 5, No. 26, 2003

Swern oxidation of the angular primary alcohol furnished
the crystalline aldehyde 22 whose structure was established
by X-ray crystallographic analysis (Figure 3).
Figure 2. X-ray crystal structure of 16.
Figure 3. X-ray crystal structure of 22.
An alternative route to an amine that could serve as a
precursor to 2 appeared to lie through the dihydroxy
carboxylic acid 21. The latter was prepared by reduction of
the cis-fused lactone acid 20 (Scheme 5), a substance
obtained previously by cleavage of the p-methoxybenzyl
ether from 14 (Scheme 4). Activation of carboxylic acid 21
via its mixed anhydride led to a trans-fused γ-lactone, and
The aldehyde of 22 was now positioned for elaboration
to the requisite nitrile 24, and this was accomplished by
Horner-Wadsworth-Emmons condensation with phospho-
Scheme 6
Scheme 5
Org. Lett., Vol. 5, No. 26, 2003
4985

nate 18, followed by selective hydrogenation of the resulting
R,â-unsaturated nitrile 23. When 24 was reacted with
vinyllithium, reaction took place selectively at the lactone
carbonyl as expected, but this was followed by a second rapid
addition of vinyllithium to the intermediate vinyl ketone 25
to give 26 after silylation of the alkoxide. Apparently, the
trans ring fusion of 24 imparts strain sufficient to trigger
opening of the lactol after the first equivalent of vinyllithium
has been added. While the double vinylation of 24 is a
potentially solvable problem, difficulties in reducing the
nitrile of 26 in the presence of the ketone function prompted
us to examine a parallel sequence with Diels-Alder cy-
cloadduct 15. Although the center at C7 of 15 is inverted
from that required for gymnodimine, a later correction of
this stereogenic center can be envisioned to attain the
(presumably) more stable configuration of 1.
triethylsilyl chloride resulted in silylation of the primary
alcohol formed upon opening of the lactol and led to vinyl
ketone 30. This substance underwent conjugate addition with
the reagent prepared from vinyllithium and thienylcuprate
31,11 and the resulting enolate was trapped with trimethylsilyl
chloride to afford 32. Reduction of the nitrile followed by
treatment of the intermediate primary amine 33 with sodium
hydroxide resulted in spontaneous intramolecular condensa-
tion to furnish the cyclic imine 34.
The sequence leading to 34 provides a template upon
which a viable approach to the spiroimine nucleus of
gymnodimine can now be framed. Further studies that will
assemble the full macrocyclic core of 1 from a substance
similar to 30 and a tetrahydrofuran subunit already in hand
will be reported in due course.
Removal of the p-methoxybenzyl group from 15 again led
to spontaneous lactonization, in this case yielding a cis-fused
γ-lactone stereoisomeric with 20 (Scheme 6). The angular
carboxyl function was reduced to primary alcohol 27, and
Swern oxidation followed by condensation with phosphonate
18 produced R,â-unsaturated nitrile 28. This substance did
not respond well to catalytic hydrogenation, but reduction
of the conjugated double bond was accomplished efficiently
with magnesium in methanol.10 Treatment of the resulting
lactone with vinyllithium allowed isolation of 29 without
the complication of double vinylation seen with 24, confirm-
ing that strain associated with the trans ring fusion in the
latter is responsible for its opening to 25. Exposure of 29 to
Acknowledgment. We thank Professor Alexandre F. T.
Yokochi of this department for the X-ray crystal structures
of 15, 16, and 22. L.Q. is grateful to the Swiss National
Science Foundation for a Postdoctoral Fellowship. Financial
support for this work was provided by the National Institute
of General Medical Sciences through Grant GM58889.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds and
crystallographic data for 15, 16, and 22. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL035939E
(10) Profitt, J. A.; Watt, D. S.; Corey, E. J. J. Org. Chem. 1975, 40,
127.
(11) Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett. 1987,
28, 945.
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Org. Lett., Vol. 5, No. 26, 2003