First total synthesis and stereochemical definition of isodomoic acid G

Article abstract of DOI:10.1021/ol0355783

(Matrix Presented) The first total synthesis and stereochemical definition of isodomoic acid G has been achieved. The key nickel-catalyzed coupling of an alkynyl enone with an alkenylzirconium allows formation of the pyrrolidine ring and most of the stere

Full text of DOI:10.1021/ol0355783

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3771-3773
First Total Synthesis and
Stereochemical Definition of Isodomoic
Acid G
Yike Ni, Kande K. D. Amarasinghe, Bashar Ksebati, and John Montgomery*
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202-3489
jwm@chem.wayne.edu
Received August 21, 2003
ABSTRACT
The first total synthesis and stereochemical definition of isodomoic acid G has been achieved. The key nickel-catalyzed coupling of an alkynyl
enone with an alkenylzirconium allows formation of the pyrrolidine ring and most of the stereochemical features in a single step. This report
provides the first total synthesis application of this new reaction and illustrates its utility in the stereoselective preparation of highly substituted
1,3-dienes.
The kainoid amino acids have attracted intense interest over
recent years due to their potent neuroexcitatory activity, their
Scheme 1
utility as pharmacological probes, and their scarcity from
natural sources.1,2 The epimeric natural products kainic acid
(1) and allokainic acid are the simplest members of this group
of pyrrolidine di- and tricarboxylic acids,3 and domoic acid
(2)4 and acromelic acid5 are representative of the more
complex members of this group (Scheme 1). Domoic acid
was originally isolated from a marine algae in 1958,4 and
its structure was redefined in the first and only total synthesis
reported by Ohfune and Tomita in 1982.6 Numerous isomers
(1) (a) Tremblay, J.-F. Chem. Eng. News 2000, January 3rd, 14. (b)
Tremblay, J.-F. Chem. Eng. News 2001, January 29th, 19.
(2) (a) Monaghan, D. T.; Bridges, R. J.; Cotman, C. W. Annu. ReV.
Pharmacol. Toxicol. 1989, 29, 365. (b) Moloney, M. G. Nat. Prod. Rep.
1998, 205. (c) Chamberlin, R.; Bridges, R. In Drug Design For Neuro-
science; Kozikowski, A. P., Ed.; Raven Press, Ltd.: New York, 1993; pp
231-259. (d) McGeer, E. G.; Olney, J. W.; McGeer, P. L. Kainic Acid as
a Tool in Neurobiology; Raven Press: New York, 1978.
(3) Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn. 1953,
73, 1026.
(4) Takemoto, T.; Daigo, K. Chem. Pharm. Bull. 1958, 6, 578.
(5) Konno, K.; Shirahama, H.; Matsumoto, T. Tetrahedron Lett. 1983,
24, 939.
of domoic acid have been isolated, and the observed
structural variations include the position of the C4 side chain
unsaturation and the chirality at the C5′ position.7 No reports
(6) Ohfune, Y.; Tomita, M. J. Am. Chem. Soc. 1982, 104, 3511.
10.1021/ol0355783 CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/06/2003

of the total synthesis of the naturally occurring isomers of
domoic acid have appeared, although Baldwin has reported
the synthesis of domoic acid analogues.8 In 1997, two new
isomers of domoic acid were isolated that were the first
naturally occurring members of the kainoid amino acid group
to possess a C4 exocyclic double bond.9 These natural
products, termed isodomoic acids H (3) and G (4), are
identical aside from the E to Z variation of the exocyclic
tetrasubstituted alkene stereochemistry (Scheme 1). Neither
the relative stereochemistry of the C5′ position nor the overall
absolute stereochemistry was established in the initial report.
Given the structural novelty and the potentially interesting
biological activity of isodomoic acids G and H, we set out
to develop a synthetic strategy for their preparation. Herein,
we report the first total synthesis of isodomoic acid G and
establish its side chain stereochemistry as 5′(R).
Scheme 2 a
A recent report from our laboratory described the first
examples of nickel-catalyzed cyclization of alkynyl enones
with organozirconium reagents.10 This new procedure ef-
ficiently assembles exocyclic dienes with a tetrasubstituted
alkene component, and it appeared that the process was
ideally suited to address the challenging issue of stereose-
lective diene introduction required in a total synthesis of
isodomoic acid G. To assemble the required cyclization
precursor, D-serine methyl ester was converted to the
corresponding oxazolidinone upon treatment with triphos-
gene, and N-alkylation with butynyl mesylate followed by
ester reduction with NaBH4 afforded compound 5 (Scheme
2).11 A Swern oxidation/Wittig olefination sequence then
afforded substrate 6. The requisite alkenylzirconium precur-
sor 9 was then assembled by an Evans alkylation of
acyloxazolidinone 7.12 Lithium borohydride reduction of the
product of diastereoselective methylation followed by sily-
lation provided TIPS-protected alkyne 8. Hydrozirconation
of 8 with Cp2ZrHCl in THF to afford 9 in situ, followed by
treatment with substrate 6 in the presence of 10 mol %
Ni(COD)2 and 20 mol % ZnCl2, then afforded pyrrolidine
10 in 74% isolated yield with complete control of the
C2-C3 relative stereochemistry (Scheme 3).10,13 It should
be stressed that this single step addresses most of the
challenges associated with this total synthesis, including
formation of the pyrrolidine ring, control of the C2-C3
a Reagents and conditions: (a) triphosgene, THF, reflux, 99%.
(b) KHMDS, butynyl mesylate, THF, 0 °C to rt, 72%. (c) NaBH4,
ethyl alcohol, 0 °C to rt, 90%. (d) (i) (COCl)2, DMSO, Et3N,
CH2Cl2, -78 °C; (ii) 4,4-dimethyl-3-[2-(triphenyl-phosphinio)-
acetyl]-oxazolidin-2-one bromide, DMAP, 74% (two steps). (e)
NaHMDS, MeI, THF, -78 ∼ -40 °C, 78% (dr > 98:2). (f) (i)
LiBH4, EtOH/H2O; (ii) TIPSCl, imidazole, DMAP, CH2Cl2, 81%
(two steps).
Scheme 3 a
a Reagents and conditions: (a) 8, Cp2ZrHCl, THF, rt; then 6,
Ni(COD)2 (10 mol %), ZnCl2 (20 mol %), THF, 0 °C, 74%. (b)
MeOMgBr, MeOH, rt, 80%.
(7) (a) Maeda, M.; Kodama, T.; Tanaka, T.; Yoshizumi, H.; Takemoto,
T.; Nomoto, K.; Fujita, T. Chem. Pharm. Bull. 1986, 34, 4892. (b) Wright,
J. L. C.; Falk, M.; McInnes, A. G.; Walter, J. A. Can. J. Chem. 1990, 68,
22. (c) Walter, J. A.; Falk, M.; Wright, J. L. C. Can. J. Chem. 1994, 72,
430.
(8) (a) Baldwin, J. E.; Moloney, M. G.; Parsons, A. F. Tetrahedron 1991,
47, 155. For representative synthetic approaches to other kainoid amino
acids, see: (b) Parsons, A. F. Tetrahedron 1996, 52, 4149. (c) Xia, Q.;
Ganem, B. Org. Lett. 2001, 3, 485, and references therein.
(9) Zaman, L.; Arakawa, O.; Shimosu, A.; Onoue, Y.; Nishio, S.; Shida,
Y.; Noguchi, T. Toxicon 1997, 35, 205.
(10) Ni, Y.; Amarasinghe, K. K. D.; Montgomery, J. Org. Lett. 2002,
4, 1743.
(11) For our earlier approaches to other members of the kainoid amino
acids, see: (a) Chevliakov, M. V.; Montgomery, J. Angew. Chem., Int. Ed.
1998, 37, 3144. (b) Chevliakov, M. V.; Montgomery, J. J. Am. Chem. Soc.
1999, 121, 11139.
relative stereochemistry, formation of the 1,3-diene, and con-
trol of stereochemistry of the C4-C1′ and C2′-C3′ alkenes.
Methanolysis of the acyl oxazolidinone linkage of 10 with
MeOMgBr afforded ester 11.
The selective formation of compound 11 as a single isomer
was complicated by the partial epimerization of the C2
stereocenter during the conversion of 5 to 6. The extent of
epimerization varied in amounts up to 20-30%. The most
straightforward, albeit inelegant, way to avoid this complica-
tion was to employ a chiral oxazolidinone during the
conversion, since the minor epimer of 12 was easily separated
(12) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(13) Negishi, E.; Okukado, N.; King, A. O.; Van Horn, D. E.; Spiegel,
B. I. J. Am. Chem. Soc. 1978, 100, 2254.
3772
Org. Lett., Vol. 5, No. 20, 2003

Scheme 4 a
Scheme 6
a Reagents and conditions: (a) 8, Cp2ZrHCl, THF, rt; then 12,
Ni(COD)2 (10 mol %), ZnCl2 (20 mol %), THF, 0 °C, 70%.
By repeating the entire sequence, starting from D-serine
methylester and (S)-valine-derived 15, we then prepared the
5′(S)-isomer of isodomoic acid G in essentially identical
fashion (Scheme 6). Although the NMR spectra of the 5′(R)
Scheme 5 a
1
and 5′(S) synthetic samples were extremely similar, the H
NMR spectrum of a mixed sample of the synthetic 5′(S)-
isomer and the natural product possessed subtle differences
when compared with the pure natural product. A mixed
sample of the 5′(R)-isomer and the natural product were
indistinguishable from the pure natural product; thus, the
natural product side chain stereochemistry can be assigned
as 5′(R). The absolute stereochemistry of isodomoic acid G
was confirmed to be that shown on the basis of comparing
CD spectra of synthetic 5′(R)-4 and the natural product.
In summary, the first total synthesis and stereochemical
definition of isodomoic acid G has been achieved. The key
nickel-catalyzed coupling of an alkynyl enone with an
alkenylzirconium allows formation of the pyrrolidine ring
and most of the stereochemical features in a single step. This
report provides the first total synthesis application of this
new reaction and illustrates its utility in the stereoselective
preparation of highly substituted 1,3-dienes.
a Reagents and conditions: (a) (i) MeONa, MeOH, rt; (ii) TBAF,
THF, rt, 95% (two steps). (b) (i) Dess Martin periodinane, CH2Cl2,
rt; (ii) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O, rt; (iii)
NaOH, MeOH, H2O, rt; (iv) ion-exchange chromatography (38%
from 14).
from the desired isomer (Scheme 4). The configuration of
the chiral oxazolidinone does not affect the diastereoselec-
tivity in the conversion of 12 to 13.14
Acknowledgment. We are extremely grateful to Professor
Osamu Arakawa for providing an authentic sample of
isodomoic acid G and to Professor Christine Chow and Helen
Chui for helpful suggestions. We thank the National Institutes
of Health (GM-57014) for generous support of this research
and Boulder Scientific for a generous gift of Cp2ZrHCl.
With compound 11 in hand, methanolysis of the remaining
internal oxazolidinone with MeONa was accomplished
(Scheme 5).11 After n-Bu4NF-mediated deprotection, the
resulting diol 14 was oxidized to the corresponding diacid
(Dess Martin followed by NaClO2). Exhaustive hydrolysis
and sequential ion exchange chromatographic separations
afforded synthetic 5′(R)-isodomoic acid G (4) that displayed
1H NMR spectral characteristics identical to the data provided
in the original isolation report from Arakawa.9
Supporting Information Available: Full experimental
details and copies of NMR spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) See Supporting Information for complete details.
OL0355783
Org. Lett., Vol. 5, No. 20, 2003
3773