Stereocontrolled total synthesis of (-)-kainic acid. Regio- and stereoselective lithiation of pyrrolidine ring with the (+)-sparteine surrogate

Article abstract of DOI:10.1021/ol051408+

(Chemical Equation Presented) A stereocontrolled total synthesis of (-)-kainic acid is described. cis-3,4-Disubstituted pyrrolidine ring was constructed by [3 + 2] cycloaddition of azomethine ylide with chiral butenolide. The crucial introduction of carboxyl group at the C-2 position was executed by regio- and stereoselective lithiation of the pyrrolidine ring in the presence of a (+)-sparteine surrogate followed by trapping with carbon dioxide.

Full text of DOI:10.1021/ol051408+

ORGANIC
LETTERS
2
005
Vol. 7, No. 20
337-4340
Stereocontrolled Total Synthesis of
)-Kainic Acid. Regio- and
Stereoselective Lithiation of Pyrrolidine
4
(−
Ring with the (
Yasuhiro Morita, Hidetoshi Tokuyama, and Tohru Fukuyama*
+
)-Sparteine Surrogate
†
†,‡
,†
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo,
PRESTO-JST, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
fukuyama@mol.f.u-tokyo.ac.jp
Received June 17, 2005
ABSTRACT
A stereocontrolled total synthesis of (
−)-kainic acid is described. cis-3,4-Disubstituted pyrrolidine ring was constructed by [3 + 2] cycloaddition
of azomethine ylide with chiral butenolide. The crucial introduction of carboxyl group at the C-2 position was executed by regio- and
stereoselective lithiation of the pyrrolidine ring in the presence of a (
+
)-sparteine surrogate followed by trapping with carbon dioxide.
8
(
-)-Kainic acid (1), first isolated in 1953 from the Japanese
Huntington’s chorea. On the other hand, the structural
1
marine alga Digenea simplex and later found in the related
algae as well, is the parent member of the kainoids that
display potent anthelmintic properties and neurotransmitting
activities in the mammalian central nervous system. Thus,
feature of 1, namely, a highly functionalized trisubstituted
pyrrolidine ring with three contiguous chiral centers, has
received considerable attention from synthetic chemists.
2
3
4
5
9
Since Oppolzer’s first enantioselective total synthesis, a
kainic acid has been widely used as a tool in neuropharma-
number of total syntheses and synthetic approaches have been
reported to date.
6
10
cology for the stimulation of the nerve cells and the mimicry
7
of disease states such as epilepsy, Alzheimer’s disease, and
In view of the recent depletion of supply of the natural
1
1
kainic acid, we developed a research program to develop
an efficient synthetic route to 1. Our synthetic strategy is
outlined in Scheme 1. The carboxyl group on the C-3
substituent would be introduced in the last stage of the
synthesis. We planned to construct the R-amino acid moiety
by regio- and diastereoselective lithiation at the C-2 posi-
tion of the pyrrolidine 3 followed by carboxylation. The
propenyl group at the C-4 position would be installed by
nucleophilic addition to the γ-lactone. Stereoselective con-
struction of the lactone-fused pyrrolidine ring would be
performed by a substrate-controlled diastereoselective 1,3-
†
University of Tokyo.
PRESTO-JST.
‡
(
1) Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn. 1953,
3, 1026.
2) (a) Impellizzeri, G.; Mangiafico, S.; Oriente, G.; Piatelli, M.; Sciuto,
S.; Fattorusso, E.; Magno, S.; Santacroce, C.; Sica, D. Phytochemistry 1975,
4, 1549. (b) Balansard, G.; Gayte-Sorbier, A.; Cavalli, C. Ann. Pharm.
7
(
1
Fr. 1982, 40, 527. (c) Balansard, G.; Pellegrini, M.; Cavalli, C.; Timon-
David, P.; Gasquet, M.; Boudon, G. Ann. Pharm. Fr. 1983, 41, 77.
(3) (a) Maloney, M. G. Nat. Prod. Rep. 1998, 15, 205. (b) Maloney, M.
G. Nat. Prod. Rep. 1999, 16, 485. (c) Parsons, A. F. Tetrahedron 1996, 52,
4
149.
(4) Nitta, I.; Watase, H.; Tomiie, Y. Nature (London) 1958, 181, 761.
5) (a) Hashimoto, K.; Shirahama, H. J. Synth. Org. Chem. Jpn. 1989,
(
4
7, 212. (b) Hashimoto, K.; Shirahama, H. Trends Org. Chem. 1991, 2, 1.
(
c) Cantrell, B. E.; Zimmerman, D. M.; Monn, J. A.; Kamboj, R. K.; Hoo,
(7) Sperk, G. Prog. Neurobiol. (Oxford) 1994, 42, 1.
(8) Coyle, J. T.; Schwarcz, R. Nature (London) 1976, 263, 244.
(9) (a) Racemic synthesis: Oppolzer, W.; Andres, H. HelV. Chim. Acta
1979, 62, 2282. (b) Enantioselective synthesis: Oppolzer, W.; Thirring, K.
J. Am. Chem. Soc. 1982, 104, 4978.
K. H.; Tizzano, J. P.; Pullar, I. A.; Farrell, L. N.; Bleakman, D. J. Med.
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(6) MacGeer, E. G.; Olney, J. W.; MacGeer, P. L. Kainic Acid as a
Tool in Neurogiology; Raven: New York, 1978.
1
0.1021/ol051408+ CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/08/2005

to afford the desired cycloadduct 10 in 83% yield with high
diastereoselectivity (20:1). After a one-pot conversion of the
N-benzyl group into the N-carbomethoxy group, the optically
pure γ-lactone 11 (>99% ee) was obtained by recrystalli-
Scheme 1. Synthetic Strategy for (-)-Kainic Acid (1)
3
zation. Subsequent reduction of the acetal with Et SiH and
TFA furnished lactone 12. Construction of the 4-propenyl
group was then achieved by a three-step transformation
involving a modified Julia olefination. Thus, after treatment
of 12 with methyllithium in toluene, a THF solution of
R-lithiated methyl phenyl sulfone 13 was added to the
reaction mixture to provide the desired diol 14 as a
diastereomeric mixture. Neither epimerization at the C-4
position nor a formation of dimethylcarbinol was observed.
TMSOTf-catalyzed acetylation of 14 to the corresponding
diacetate, followed by reductive treatment with catalytic
16
amount of mercury chloride and magnesium powder, gave
dipolar cycloaddition of an azomethine ylide to the chiral
butenolide 5.
1
5 bearing the isopropenyl group in high yield (Scheme 2).
Synthesis of (-)-kainic acid (1) commenced with a large-
scale preparation of chiral butenolide 8 by a modification
of the reported methods. We have found that photooxygen-
ation of furfural (6) proceeded with bubbling air under
sunlight instead of bubbling oxygen under irradiation with
Scheme 2. Synthesis of the Disubstituted Pyrrolidine Ring
12
a high-pressure mercury lamp. Thus, bubbling air through
an ethanolic solution of furfural in the presence of Rose
Bengal under the sun gave the desired butenolide 7. We have
also improved the subsequent enzymatic dynamic kinetic
resolution of 7.13 When the reaction was carried out with
lipase AK in a higher concentration of 7 in vinyl acetate as
solvent, the reaction time was dramatically shortened and
the desired acetoxy butenolide 8 (93% ee) was obtained in
a quantitative yield.
The crucial 1,3-dipolar cycloaddition of the chiral buten-
14
olide 8 with the azomethine ylide took place smoothly upon
1
5
treatment of a mixture of 8 and 9 with 10 mol % of TFA
(
10) For a recent review, see ref 3. For selected examples, see: (a)
Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Chem. Soc., Chem. Commun.
988, 1204. (b) Takano, S.; Sugihara, T.; Satoh, S.; Ogasawara, K. J. Am.
1
Chem. Soc. 1988, 110, 6467. (c) Baldwin, J. E.; Moloney, M. G.; Parsons,
A. F. Tetrahedron 1990, 46, 7263. (d) Jeong, N.; Yoo, S.-E.; Lee, S. J.;
Lee, S. H.; Chung, Y. K. Tetrahedron Lett. 1991, 32, 2137. (e) Barco, A.;
Benetti, S.; Pollini, G. P.; Spalluto, G.; Zanirato, V. J. Chem. Soc., Chem.
Commun. 1991, 390. (f) Cooper, J.; Knight, D. W.; Gallagher, P. T. J. Chem.
Soc., Perkin Trans. 1 1992, 553. (g) Takano, S.; Inomata, K.; Ogasawara,
K. J. Chem. Soc., Chem. Commun. 1992, 169. (h) Hatakeyama, S.;
Sugawara, K.; Takano, S. J. Chem. Soc., Chem. Commun. 1993, 125. (i)
Yoo, S.-E.; Lee, S. H. J. Org. Chem. 1994, 59, 6968. (j) Hanessian, S.;
Ninkovic, S. J. Org. Chem. 1996, 61, 5418. (k) Nakada, Y.; Sugahara, T.;
Ogasawara, K. Tetrahedron Lett. 1997, 38, 857. (l) Bachi, M. D.; Melman,
A. J. Org. Chem. 1997, 62, 1896. (m) Miyata, O.; Ozawa, Y.; Ninomiya,
I.; Naito, T. Synlett 1997, 275. (n) Rubio, A.; Ezquerra, J.; Escribano, A.;
Remuinan, M. J.; Vaquero, J. J. Tetrahedron Lett. 1998, 39, 2171. (o) Cossy,
J.; Cases, M.; Pardo, D. G. Tetrahedron 1999, 55, 6153. (p) Campbell, A.
D.; Taylor, R. J. K.; Raynham, T. M. Chem. Commun. 1999, 245. (q)
Chevliakov, M. V.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 11139.
With the key cis-3,4-disubstituted pyrrolidine intermediate
in hand, we next focused our attention on the stereoselective
introduction of carboxyl group at the C-2 position. For this
purpose, we initially tested a directing effect of the C-3
substituent on the selective lithiation of N-Boc-protected
1
7
(
r) Hirasawa, H.; Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2001,
2, 7587. (s) Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron 2002,
8, 4727. (t) Trost. B. M.; Rudd, M. T. Org. Lett. 2003, 5, 1467. (u)
pyrrolidine. Thus, the nitrogen and hydroxyl groups of 15
4
5
were protected with Boc and MOM groups, respectively, and
Anderson, J. C.; Whiting, M. J. Org. Chem. 2003, 68, 6160.
11) (a) Tremblay, J.-F. Chem. Eng. News 2000, 78(1), 14. (b) Tremblay,
J.-F. Chem. Eng. News 2000, 78(10), 31.
12) (a) Moradei, O. M.; Paquette, L. A. Org. Synth. 2003, 80, 66. (b)
Gollnick, K.; Griesbeck, A. Tetrahedron 1985, 41, 2057.
13) (a) Brinksma, J.; Deen van der, H.; Oeveren van, A.; Feringa, B.
L. J. Chem. Soc., Perkin Trans. 1 1998, 4159. (b) Deen van der, H.; Cuiper,
A. D.; Hof, R. P.; Oeveren van, A.; Feringa, B. L.; Kellogg, R. M. J. Am.
Chem. Soc. 1996, 118, 3801.
(
(14) (a) Hosomi, A.; Sakata, Y.; Sakurai, H. Chem. Lett. 1984, 1117.
(b) Padwa, A.; William, D. Organic Syntheses; Wiley: New York, 1993;
Collect. Vol. VIII, p 231.
(15) Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K. Chem. Pharm. Bull.
1985, 33, 2762.
(16) (a) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 14, 4833. (b)
Lee, G. H.; Lee, H. K.; Choi, E. B.; Kim, B. T.; Pak, C. S. Tetrahedron
Lett. 1995, 36, 5607.
(
(
4338
Org. Lett., Vol. 7, No. 20, 2005

the compound thus obtained was treated with s-BuLi at -78
C and then with gaseous carbon dioxide. Disappointingly,
°
Scheme 4. (-)-Sparteine-Mediated Lithiation/Silylation of
meso-3,4-Disubstituted N-Boc-pyrrolidine1
7d
however, the trisubstituted pyrrolidine derivative 17 was
obtained as an inseparable mixture of regio- and diastereo-
isomers. At this point, we could epimerize the undesired
R-carboxyl isomers to the thermodynamically more stable
â-epimers via their mixed anhydrides and then converted to
methyl esters 18a and 18b. After removal of the MOM
group, the regioisomers could be separated to give the desired
19a and the undesired 19b in a 2.6:1 ratio (51% and 20%
overall yield from 16). This result indicated that the directing
effects of the substituents at the 3-position were not sufficient
for the differentiation of the regio- and stereochemistry in
the lithiation process (Scheme 3).
Scheme 3. MOM Group-Directed Lithiation of 19a
O’Brien and co-workers reported that the diamine 25 could
serve as a surrogate for (+)-sparteine for enantioselective
1
8
lithiation of N-Boc-pyrrolidine. Thus, we examined the
lithiation-carboxylation protocol in the presence of the (+)-
sparteine surrogate 25. To our delight, the reaction in the
presence of 2.5 equiv of 25 only gave a mixture of the desired
isomer 26a and its regioisomer 26b (81:19). Thus, we have
successfully controlled the diastereoselectivity, albeit with
similar regioselectivity. After conversion to the ester and
deprotection of the MOM group, the desired isomer 19a was
chromatographically separated (Scheme 5).
Scheme 5. Lithiation with the (+)-Sparteine Surrogate 25a
We then decided to utilize external chiral ligands to
achieve regio- and diastereoselective lithiation. However,
(-)-sparteine (20), the most representative chiral amine
established by Beak and co-workers, could not be adopted
in our case. Beak reported that (-)-sparteine-mediated
lithiation/silylation of bicyclic cis-3,4-disubstituted N-Boc-
pyrrolidine 21 gave the corresponding silylated product 22
with excellent diastereo- and enantioselectivity although the
stereochemistry of the product is opposite to what we desired
(
Scheme 4). In addition, rather poor diastereo- and enantio-
a
selectivity was observed with the monocyclic compound 23.
The ratio of regioisomers (*) was determined by HPLC analysis
after conversion to the corresponding benzyl ester (BnBr, K
2 3
CO ,
(
17) (a) For a review, see: Beak, P.; Zajdel, W. J. Chem. ReV. 1984, 84,
DMF, rt, 15 min, quant).
4
71. (b) Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1991, 113, 9708. (c)
Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc.
Chem. Res. 1996, 29, 552. (d) Johnson, T. A.; Jang, D. O.; Slafer, B. W.;
Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2002, 124, 11689, references
therein.
The remaining task toward a total synthesis of (-)-kainic
acid was to construct the carboxylmethyl group at the C-3
Org. Lett., Vol. 7, No. 20, 2005
4339

In conclusion, an enantioselective total synthesis of
(-)-kainic acid (1) has been accomplished. The synthesis
Scheme 6. Total Synthesis of (-)-Kainic Acid
features (1) a facile construction of the cis-3,4-disubstituted
pyrroridine ring by a TFA-catalyzed stereoselective 1,3-
dipolar cycloaddition of the azomethine ylide and the
optically active butenolide prepared by enzymatic dynamic
kinetic resolution, (2) a modified Julia olefination for
construction of the propenyl group, and (3) the construction
of R-amino acid moiety of the trisubstituted pyrrolidine ring
by a regio- and stereoselective lithiation-carboxylation
sequence.
Acknowledgment. We thank Dr. Yoshihiko Hirose of
Amano Enzyme for a generous supply of Amano lipase AK.
This work was financially supported in part by Grant-in-
Aid from The Ministry of Education, Culture, Sports, Science
and Technology, Japan.
Supporting Information Available: Experimental details
1
13
position of the pyrrolidine ring. After transformation of
alcohol 19a to bromide 27, nucleophilic substitution with
KCN afforded nitrile 28. Conversion of the nitrile to the
carboxylic acid was then executed in a stepwise manner.
Thus, treatment of nitrile 28 with alkaline hydrogen peroxide
gave amide 29 and the subsequent hydrolysis of both the
amide and the methyl ester led to N-Boc-kainic acid (30).
Finally, deprotection of the Boc group with TFA yielded
and H and C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL051408+
(
18) (a) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R. O’Brien, P. J.
Am. Chem. Soc. 2002, 124, 11870. (b) Hermet, J.-P. R.; Porter, D. W.;
Dearden, M. J.; Harrison, J. R.; Koplin, T.; O’Brien, P.; Parmene, J.; Tyurin,
V.; Whitwood, A. C.; Gilday, J.; Smith, N. M. Org. Biomol. Chem. 2003,
1, 3977.
(
-)-kainic acid (1), which was spectroscopically identical
10a,j
with the natural product
(Scheme 6).
4340
Org. Lett., Vol. 7, No. 20, 2005