Total synthesis of (-)-(α)-kainic acid via a diastereoselective methylenecyclopropane ring expansion

Article abstract of DOI:10.1021/ol051003p

(Chemical Equation Presented) A concise and enantioselective synthesis of (-)-(α)-kainic acid in 13 steps with an overall yield of 15% is reported. The pyrrolidine kainoid precursor with the required C2/C3 trans stereochemistry was prepared with excellent diastereoselectivity (>20:1) via a Mgl ₂-mediated ring expansion of a tertiary methylenecyclopropyl amide. A selective hydroboration was then employed to set the remaining stereochemistry at the C4 position en route to (-)-(α)-kainic acid.

Full text of DOI:10.1021/ol051003p

ORGANIC
LETTERS
2005
Vol. 7, No. 14
3045-3047
Total Synthesis of (
via a Diastereoselective
−)-(r)-Kainic Acid
Methylenecyclopropane Ring Expansion
Mark E. Scott and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
mlautens@chem.utoronto.ca
Received May 3, 2005
ABSTRACT
A concise and enantioselective synthesis of (−)-(r)-kainic acid in 13 steps with an overall yield of 15% is reported. The pyrrolidine kainoid
precursor with the required C2/C3 trans stereochemistry was prepared with excellent diastereoselectivity (>20:1) via a MgI2-mediated ring
expansion of a tertiary methylenecyclopropyl amide. A selective hydroboration was then employed to set the remaining stereochemistry at the
C4 position en route to (−)-(r)-kainic acid.
The kainoid amino acids are a potent class of neuroexcitant
compounds whose biological activity stems from their ability
to function as a conformationally restricted analogue of
glutamic acid. For this reason, these amino acids have been
used extensively by the neurological community in the study
of Huntington’s chorea and Alzheimer’s disease.1 Typically,
these amino acids are composed of a trans-C2,C3/cis-C3,C4
pyrrolidine core which differs solely in the nature of the
substituent at the 4-position.
synthetic methodology outlined in Scheme 1. Scheme 2
shows the synthesis of (-)-kainic acid.
Scheme 1. Retrosynthetic Analysis
Recently, we reported a highly diastereoselective route to
trans-C2,C3-pyrrolidines using a magnesium iodide-mediated
ring expansion of methylenecyclopropanes in the presence
of a chiral sulfinimines.2 Enantiopure pyrrolidines could then
be obtained upon deprotection of the chiral auxiliary. We
now report the use of this methodology toward the total
synthesis of the (-)-(R)-kainic acid3 1 using the retro-
MgI2-mediated ring expansion of N,N-diphenylmethylene-
cyclopropyl amide 2 in the presence of chiral sulfinimine 3
gave the expected pyrrolidine 4 ([R]D -55.2° (c 1.11,
10.1021/ol051003p CCC: $30.25
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Oxidation of the primary alcohol using a buffered TEMPO/
NaOCl oxidation4 furnished the expected aldehyde 6 ([R]24
D
Scheme 2. Synthesis of (-)-Kainic Acid
+10.4° (c 0.8, CHCl3)) in 91% total yield as a 98:2 ratio of
C4-epimers. Next, installation of the methyl group to give
the secondary alcohol 7 was achieved in near quantitative
yield as a 3:2 ratio of diastereomers by slow addition of the
aldehyde to MeMgBr at -78 °C. We found that the rate
and order of addition was crucial in minimizing the amount
of competing side products for this step.
Subsequent removal of the tertiary amide proved difficult
under classical hydrolytic conditions, due in part to the
lability of the chiral sulfoxyl group. This problem was
circumvented by treating alcohol 7 with catalytic KOtBu in
THF at 0 °C to afford lactone 8 in 86% yield as a 3:2 mixture
of diastereomers. Reduction of 8 using DIBAL-H, followed
by Wittig olefination of the lactol 9, gave the vinyl methyl
ether 10 in 95% yield over two steps as an inseparable
mixture of diastereomers (dr ) 3:2 and E:Z ) 5.4:1). Dess-
Martin oxidation of 10 afforded the vinyl methyl ether ketone
11 in 87% yield as an inseparable mixture of E/Z isomers,
with no evidence of epimerization by 1H NMR. Deprotection
of 11 using Hg(OAc)2 followed by KI workup then gave
the desired aldehyde 12 in 91% yield ([R]24D -19.8° (c 0.4,
CHCl3)).
The next key step in the synthesis was a global oxidation
of the aldehyde, sulfoxyl, and para-methoxy phenyl groups
using RuCl3/NaIO4.5 Gratifyingly, oxidation of 12 using these
conditions, followed by diazomethane workup, afforded the
dimethyl ester 13 in 75% ([R]24 -15.5° (c 0.8, CHCl3)).
D
We then set out to install the exo-methylene group. On the
basis of previous studies by other groups,6 we expected
standard Wittig olefination approaches to give a substantial
amount of the epimerized product. Use of the nonbasic Zn/
TiCl4/CH2I27,8 reagent furnished the desired olefin 14 cleanly
in 71% yield with no evidence of the epimerized allo-isomer.
All spectroscopic properties of the resulting olefin 14 were
in accord with those previously reported ([R]25 -45.1° (c
D
CHCl3)) in 78% yield.2 Hydroboration from the least
hindered face of the pyrrolidine ring using 9-BBN, followed
by standard oxidative workup, afforded the primary alcohol
1.3, CHCl3), lit. ([R]15 -48.1° (c 1.0, CHCl3)).6a,9
D
Conversion of 14 to 1 was then carried out as previously
reported by Yoo and co-workers.6a,9 Ester hydrolysis followed
by tosyl deprotection using Birch conditions afforded crude
1 from 14. Purification of 1 was then carried out using an
ion-exchange resin (Amberlite CG50) followed by recrys-
5 ([R]24 +33.4° (c 0.8, CHCl3)) as a single diastereomer.
D
(1) (a) Kainic Acid as a Tool in Neurobiology; McGeer, E. G., Olney, J.
W., McGeer, P. L., Eds.; Raven: New York, 1978. (b) Excitatory Amino
Acids; Simon, R. P., Ed.; Thieme Medical: New York, 1992. (c) Moloney,
M. G. Nat. Prod. Rep. 1990, 16, 485. (d) Moloney, M. G. Nat. Prod. Rep.
1998, 15, 205.
tallization to afford optically pure (-)-(R)-kainic acid ([R]23
D
(2) Scott, M. E.; Han, W.; Lautens, M. Org. Lett. 2004, 6, 3309.
(3) For a review of previous syntheses of kainic acid, see: (a) Parsons,
A. F. Tetrahedron 1996, 52, 4149. For some recent syntheses of kainic
acid, see: (b) Hodgson, D. M.; Hachisu, S.; Andrews, M. D. Org. Lett.
2005, 7, 815. (c) Martinez, M. M.; Hoppe, D. Org. Lett. 2004, 6, 3743. (d)
Anderson, J. C.; Whiting, M. J. Org. Chem. 2003, 68, 6160. (e) Trost, B.
M.; Rudd, M. T. Org. Lett. 2003, 5, 1467. (f) Clayden, J.; Menet, C. J.;
Mansfield, D. J. Chem. Commun. 2002, 1, 38. (g) Clayden, J.; Menet, C.
J.; Tchabanenko, K. Tetrahedron 2002, 58, 4727. (h) Hirasawa, H.;
Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 7587. (i) Xia,
Q.; Ganem, B. Org. Lett. 2001, 3, 485. (j) Campbell, A. D.; Raynham, T.
M.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 2000, 19, 3194. (k)
Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2, 3181. (l)
Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito, T. Tetrahedron 2000, 56, 6199.
(m) Clayden, J.; Tchabanenko, K. Chem. Commun. 2000, 4, 317. (n) Cossy,
J.; Cases, M.; Pardo, D. G. Synlett 1998, 507. (o) Bachi, M. D.; Melman,
A. J. Org. Chem. 1997, 62, 1896.
(4) Leanna, M. R.; Sowin, T. J.; Morton, H. E. Tetrahedron Lett. 1992,
33, 5029.
(5) (a) Kasai, M.; Ziffer, H. J. Org. Chem. 1983, 48, 2346. (b) Carlsen,
P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981,
46, 3936. (c) Caputo, J. A.; Fuchs, R. Tetrahedron Lett. 1967, 8, 4729. (d)
Chakraborti, A. K.; Ghatak, U. R. Synthesis 1983, 746.
(6) (a) Yoo, S.; Lee, S.; Jeong, N.; Cho, I. Tetrahedron Lett. 1993, 34,
3435. (b) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 5418. (c)
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(8) Use of Lombardo’s reagent also gave the methylenated product in
comparible yield: (a) Lombardo, L. Tetrahedron Lett. 1982, 23, 4293. (b)
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(9) Yoo, S.; Lee, S. H. J. Org. Chem. 1994, 59, 6968.
3046
Org. Lett., Vol. 7, No. 14, 2005

-14.3° (c 0.8, H2O), natural (-)-(R)-kainic acid [R]23
-14.6° (c 0.9, H2O))10 in 70% yield over two steps.
Acknowledgment. We thank Merck-Frosst Canada, the
National Sciences and Engineering Research Council (NSERC)
of Canada, and the University of Toronto for funding. We
also thank Dr. Wooseok Han for helpful discussions. M.S.
thanks NSERC (PGS-B) as well as the Sumner Foundation
for scholarship funding.
D
In conclusion, we have successfully synthesized (-)-(R)-
kainic acid in enantiopure form in 13 linear steps. Initial ring
expansion of the methylenecyclopropyl amide in the presence
of a chiral sulfinimine set the first two stereocenters in one
convienent step. A highly selective hydroboration using the
bulky tertiary amide to control facial selectivity then set the
remaining stereocenter en route to the final product.
Supporting Information Available: Experimental pro-
cedures for the preparation of new compounds and charac-
terization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(10) An authentic sample of natural (-)-(R)-kainic acid was obtained
from Ocean Produce International, NS, Canada.
OL051003P
Org. Lett., Vol. 7, No. 14, 2005
3047