Total synthesis of (-)-kainic acid via intramolecular michael addition: A second-generation route

Article abstract of DOI:10.1021/ol800328q

A total synthesis of (-)-kainic acid starting from the commercially available 2-azetidinone is described. The key δ-lactone intermediate was concisely prepared from the commercially available azetidinone through the Reformatsky-type reaction and an introduction of a glycine moiety. The construction of the functionalized pyrrolidine ring was executed by a one-pot sequential elimination-Michael addition protocol of a β-amino-δ- lactone intermediate with high diastereoselectivity.

Full text of DOI:10.1021/ol800328q

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1711-1714
Total Synthesis of (-)-Kainic Acid via
Intramolecular Michael Addition: A
Second-Generation Route
Hiroshi Sakaguchi,† Hidetoshi Tokuyama,‡ and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
fukuyama@mol.f.u-tokyo.ac.jp
Received February 13, 2008 (Revised Manuscript Received March 19, 2008)
ABSTRACT
A total synthesis of (-)-kainic acid starting from the commercially available 2-azetidinone is described. The key δ-lactone intermediate was
concisely prepared from the commercially available azetidinone through the Reformatsky-type reaction and an introduction of a glycine moiety.
The construction of the functionalized pyrrolidine ring was executed by a one-pot sequential elimination-Michael addition protocol of a ꢀ-amino-
δ-lactone intermediate with high diastereoselectivity.
(-)-Kainic acid (1), the parent member of the kainoid
family,1 was isolated in 1953 from the Japanese marine alga
Digenea simplex2 and has also been found in the related
algae.3 Since kainoids display potent anthelminthic proper-
ties4 and neurotransmitting activities5 in the mammalian
central nervous system, kainic acid in particular has been
widely used as a tool in neuropharmacology6 for stimulation
of nerve cells and the mimicry of disease states such as
epilepsy,7 Alzheimer’s disease, and Huntington’s chorea.8
Despite its importance in the neurosciences, this compound
is costly due to the limited supply from natural resources
and the lack of practical synthesis.9
In addition to its irreplaceable utility, the structural features
of 1, namely, a highly functionalized trisubstituted pyrrolidine
ring with three contiguous chiral centers, have attracted
considerable attention to 1 as a synthetic target. Accordingly,
a number of total syntheses and synthetic approaches have
so far been reported,10,11 including two from this labora-
tory.12,13
† Visiting researcher from Sumitomo Chemical Co., Ltd.
‡ Current Address: Graduate School of Pharmaceutical Sciences, Tohoku
University, Aramaki, Aoba, Sendai, 980-8578, Japan.
(1) (a) Maloney, M. G. Nat. Prod. Rep. 1998, 15, 205. (b) Maloney,
M. G. Nat. Prod. Rep. 1999, 16, 485. (c) Maloney, M. G. Nat. Prod. Rep.
2002, 19, 597. (d) Parsons, A. F. Tetrahedron 1996, 52, 4149. (e) Hashimoto,
K.; Shirahama, H. J. Syn. Org. Chem., Jpn. 1989, 47, 212.
(2) Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn. 1953,
73, 1026.
After completion of our earlier total synthesis of 1
utilizing a regio- and stereoselective lithiation of pyrro-
lidine ring,12 we established a more efficient route to 1,13
as outlined in Scheme 1. A diastereoselective Evans-type
(3) (a) Impellizzeri, G.; Mangiafico, S.; Oriente, G.; Piatelli, M.; Sciuto,
S.; Fattorusso, E.; Magno, S.; Santacroce, C.; Sica, D. Phytochemistry 1975,
14, 1549. (b) Balansard, G.; Gayte-Sorbier, A.; Cavalli, C.; Timond-David,
P.; Gasquent, M. Ann. Pharm. Fr. 1982, 40, 527. (c) Balansard, G.;
Pellegrini, M.; Cavalli, C.; Timon-David, P.; Gasquet, M.; Boudon, G. Ann.
Pharm. Fr. 1983, 41, 77.
(6) MacGeer, E. G.; Olney, J. W.; MacGeer, P. L. Kainic Acid as a
Tool in Neurogiology; Raven: New York, 1978.
(7) Sperk, G. Prog. Neurobiol. (Oxford) 1994, 42, 1.
(8) Coyle, J. T.; Schwarcz, R. Nature (London) 1976, 263, 244.
(9) (a) Tremblay, J.-F. Chem. Eng. News 2000, 3, 14. (b) Tremblay,
J.-F. Chem. Eng. News 2000, 6, 31. (c) Tremblay, J.-F. Chem. Eng. News
2001, 29, 19.
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(b) Cantrell, B. E.; Zimmerman, D. M.; Monn, J. A.; Kamboj, R. K.; Hoo,
K. H.; Tizzano, J. P.; Pullar, I. A.; Farrell, L. N.; Bleakman, D. J. Med.
Chem. 1996, 39, 3617.
(10) For recent reviews, see: ref. 3.
10.1021/ol800328q CCC: $40.75
Published on Web 04/11/2008
2008 American Chemical Society

Scheme 1
.
Outline of Total Synthesis of (-)-Kainic Acid (1)
Scheme 2. Strategy for Second-Generation Synthesis
high diastereoselectivity. Finally, formation of the iso-
propenyl group and manipulation of the functional groups
furnished kainic acid 1. While the key intramolecular
Michael addition proved to be highly effective for the
formation of the fully elaborated pyrrolidine ring, synthetic
accessibility of the precursor 6 was not efficient since it
requires the chiral auxiliary-controlled construction of the
framework and the intramolecular olefin metathesis under
dilute reaction conditions. In this letter, we disclose our
second-generation intramolecular Michael addition route
with improved in situ preparation of the precursor 6. This
scalable route allowed us to synthesize (-)-kainic acid
in a 12-step longest linear sequence in 14% overall yield
from the commercially available, inexpensive azetidinone
13.
The strategy of our second-generation synthesis is il-
lustrated in Scheme 2. We planned to maintain the intramo-
lecular Michael addition to the key intermediate 8 and the
end game sequence established for the first-generation
synthesis. Retrosynthetically, if we were to append an amino
group to the intermediate 8, the resultant 9 would be easily
prepared from the azetidinone 11 by reductive opening of
the ꢀ-lactam ring, followed by installation of a glycine moiety
and lactone formation. Compound 11 could be obtained from
the commercially available azetidinone derivative 12,14 which
has been manufactured on an industrial scale as a starting
material for ꢀ-lactam antibiotic drugs such as imipenem.
Our synthesis commenced with the introduction of a
carbobutoxymethyl group on [3R(1′R, 4R)-4-acetoxy-3-[1-
(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone (13, Kaneka
Corporation) using t-butyl bromozincacetate 1415 under
improved literature conditions15b (Scheme 3). Activation of
the ꢀ-lactam ring with a Cbz group followed by reduction
with NaBH4 afforded amino alcohol 17. Introduction of the
glycine moiety was then carried out by Mitsunobu reaction16
of 17 with Nosyl (Ns)-activated glycine ester 18 to provide
19.17 Upon treatment with trifluoroacetic acid, 19 underwent
cyclization to give lactone 20. Finally, switching from the
Ns group to the Boc group in one-pot furnished the desired
21 in 46% overall yield from 13.
aldol reaction between crotonamide detivative 3 and
acetaldehyde afforded an aldol product 4 as a single
isomer, which was converted to an acrylate derivative 5
by a six-step sequence. The fully functionalized trisub-
stituted pyrrolidine ring 7 was constructed by the ring-
closing metathesis followed by an intramolecular Michael
addition of the resultant R,ꢀ-unsaturated lactone 6 with
(11) For selected examples, see:(a) Ueno, Y.; Tanaka, K.; Ueyanagi,
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Chem. 1997, 62, 1896. (o) Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito, T.
Synlett 1997, 275. (p) Rubio, A.; Ezquerra, J.; Escribano, A.; Remuinan,
M. J.; Vaquero, J. J. Tetrahedron Lett. 1998, 39, 2171. (q) Cossy, J.; Cases,
M.; Pardo, D. G. Tetrahedron 1999, 55, 6153. (r) Campbell, A. D.; Taylor,
R. J. K.; Raynham, T. M. Chem. Commun. 1999, 245. (s) Chevliakov, M. V.;
Montgomery, J. J. Am. Chem. Soc. 1999, 121, 11139. (t) Miyata, O.; Ozawa,
Y.; Ninomiya, I.; Naito, T. Tetrahedron 2000, 56, 6199. (u) Nakagawa,
H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2, 3181. (v) Xia, Q.;
Ganem, B. Org. Lett. 2001, 3, 485. (w) Hirasawa, H.; Taniguchi, T.;
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C. J.; Tchabanenko, K. Tetrahedron 2002, 58, 4727. (y) Mart´ınez, M. M.;
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Org. Lett., Vol. 10, No. 9, 2008
1712

Scheme 3
.
Synthesis of the Key Intermediate 21
Scheme 4. Synthesis of the Pyrrolidine Ring by Hofmann
Elimination and Intramolecular Michael Addition
As a significant improvement, the above elimination and
Michael addition sequence was executed in a single operation
involving treatment of Cbz-protected amine 21 first with
LiHMDS (1.0 equiv) and CbzCl (1.1 equiv), and then with
by additional LiHMDS (2.5 equiv) (Scheme 5). The sequen-
tial elimination-Michael addition cascade by way of di-Cbz
imide intermediate proceeded quite nicely to give a mixture
of the desired pyrrolidine derivative 7 and its C-2 epimer in
high diastereoselectivity (ratio of 7 to its C-2 epimer was
92:8) in 94% yield. Finally, the five-step end game strategy,
which we developed in the first- generation route,13 was
applied to 7 to provide (-)-kainic acid (1).
In summary, we have achieved a second-generation total
synthesis of (-)-kainic acid (1) utilizing our intramolecular
Michael addition strategy. The highlights of this improved
synthesis include (1) a facile preparation of the key lactone
intermediate 21 from the commercial available, inexpensive
azetidinone derivative 13 and (2) a highly efficient one-pot
cascade reaction including acylation, ꢀ-elimination, and
intramolecular Michael addition to construct the fully func-
tionalized pyrrolidine ring with high diastereoselectivity.
With this improved and scalable route, (-)-kainic acid (1)
was synthesized from 13 in 12 steps in 14% overall yield.
With the desired ꢀ-amino-δ-lactone 21 in hand, we next
examined the elimination of the amino group and the key
intramolecular Michael addition reaction to form the pyrro-
lidine ring. After removal of the Cbz group of 21 by
hydrogenolysis, the resultant primary amine was treated with
a 10-fold molar excess of iodomethane in the presence of
cesium carbonate. The Hofmann elimination18 proceeded as
expected to give the desired R,ꢀ-unsaturated lactone 6 in
64% in two steps (Scheme 4). The key stereoselective
construction of the 2,3-cis-pyrrolidine ring was carried out
as reported previously.13 Thus, upon treatment of 6 with
LiHMDS in DMF at -78 °C, intramolecular Michael
addition took place smoothly to afford a diastereomeric
mixture of the desired pyrrolidine derivative 7 and its C-2
epimer in a 91:9 ratio.
Scheme 5
. One-pot Sequential Elimination-Michael Addition
Protocol and End Game of Total Synthesis
(13) Sakaguchi, H.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2007, 9,
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Org. Lett., Vol. 10, No. 9, 2008
1713

Acknowledgment. We thank Dr. Kenji Inoue of Kaneka
Corporation for a generous gift of [3R(1′R, 4R)-4-acetoxy-
3-[1-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone. This
work was financially supported in part by a Grant-in-Aid
from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan.
Supporting Information Available: Experimental details
1
and H and 13C NMR spectra for all new compounds. This
material is available free of charges via the Internet at
http://pubs.acs.org.
OL800328Q
1714
Org. Lett., Vol. 10, No. 9, 2008