Enantioselective total synthesis of (-)-α-kainic acid

Article abstract of DOI:10.1021/ol1001076

(Figure Presented) An enantioselective total synthesis of (-)-α-kainic acid is described. Key steps are an lr-catalyzed allylic amination with a propargyllc amine to provide an enyne and a diastereoselective intramolecular Pauson-Khand reaction. Subsequent steps involve a Baeyer-Villiger reaction, reduction of the resulting lactone, and direct Jones oxidation of a silyl ether.

Full text of DOI:10.1021/ol1001076

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1108-1111
Enantioselective Total Synthesis of
(-)-r-Kainic Acid
Andreas Farwick and Gu¨nter Helmchen*
Organisch-Chemisches Institut der Ruprecht-Karls-UniVersita¨t Heidelberg,
Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
g.helmchen@oci.uni-heidelberg.de
Received January 15, 2010
ABSTRACT
An enantioselective total synthesis of (-)-r-kainic acid is described. Key steps are an Ir-catalyzed allylic amination with a propargylic amine
to provide an enyne and a diastereoselective intramolecular Pauson-Khand reaction. Subsequent steps involve a Baeyer-Villiger reaction,
reduction of the resulting lactone, and direct Jones oxidation of a silyl ether.
In 1953 (-)-R-kainic acid (Figure 1) was first isolated from
the marine alga Digenea simplex.1 Kainic acid is the
structurally simplest member of the kainoid family2 of
alkaloids. These nonproteogenic amino acids show anthel-
mintic3 and neurotransmitting activities.4 (-)-R-Kainic acid
is being widely used as a tool in neuropharmacology5 for
mimicry of various stages of neuronal disorders such as
epilepsy,6 Alzheimer’s disease, and Huntington’s chorea.7
Figure 1. Generation of the stereogenic centers of (-)-R-kainic
acid (1).
A shortage in the commercial extraction of natural kainic
acid led to an impediment of neuroscience.8
As a consequence, the synthesis of (-)-R-kainic acid has
received particular attention, and more than 20 total syntheses
have been reported.9–11 Most of the syntheses start with an
enantiomerically pure compound from the chiral pool, for
example, serine or glutamic acid. The number of true
enantioselective syntheses, i.e., with an achiral compound
as starting material, is small; still smaller is the number of
syntheses based on enantioselective catalysis.10
We herein present a concise enantioselectiVe total synthesis
of (-)-R-kainic acid. The enantiomeric purity of the target
of 99% ee is based on the Ir-catalyzed allylic amination,
which provides for the chirality center C2 (Figure 1 and
Scheme 1). Chirality centers C3 and C4 were introduced by
an intramolecular Pauson-Khand reaction and catalytic
hydrogenation, respectively.
(1) Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn. 1953,
73, 1026–1028.
(2) Reviews: (a) Parsons, A. F. Tetrahedron 1996, 52, 4149–4174. (b)
Moloney, M. G. Nat. Prod. Rep. 1998, 15, 205–219. (c) Moloney, M. G.
Nat. Prod. Rep. 2002, 19, 597–616.
(3) Watase, H.; Tomiie, Y.; Nitta, I. Nature (London) 1958, 181, 761–
762.
(4) (a) Watkins, J. C.; Krogsgaard-Larsen, P.; Honore´, T. Trends
Pharmacol. Sci. 1990, 11, 25–33. (b) Cantrell, B. E.; Zimmerman, D. M.;
Monn, J. A.; Kamboj, R. K.; Hoo, K. H.; Tizzano, J. P.; Pullar, I. A.; Farell,
L. N.; Bleakman, D. J. Med. Chem. 1996, 39, 3617–3624.
(5) MacGeer, E. G.; Olney, J. W.; MacGeer, P. L. Kainic Acid as a
Tool in Neurobiology; Raven: New York, 1978.
(6) (a) Sperk, G. Prog. Neurobiol. (Oxford) 1994, 42, 1–32. (b) Gluck,
M. R.; Jayatilleke, E.; Shaw, S.; Rowan, A. J.; Haroutunian, V. Epilepsy
Res. 2000, 39, 63–71.
(7) (a) Hampson, D. R.; Manalo, J. L. Nat. Toxins 1998, 6, 153–158.
(b) Coyle, J. T.; Schwarcz, R. Nature (London) 1976, 263, 244–246.
(8) (a) Tremblay, J.-F. Chem. Eng. News 2000, 78 (1), 14–15. (b)
Tremblay, J.-F. Chem. Eng. News 2000, 78 (10), 31.
The Pauson-Khand reaction has been employed in
syntheses of (-)-R-kainic acid.11 However, the reported
syntheses are complicated by low diastereoselectivity in the
10.1021/ol1001076  2010 American Chemical Society
Published on Web 02/11/2010

Scheme 1
.
Retrosynthetic Analysis
Scheme 2.
Ir-Catalyzed Allylic Aminationa
Pauson-Khand step,11a interchange of protecting groups,11b
or very high numbers of steps.11c The protecting group at
nitrogen of intermediate D of Scheme 1 is of crucial
importance for the diastereoselectivity with respect to centers
C3 and C3a. In a series of tests, we found that an N-Boc
group generally gave rise to high diastereoselectivity.12 This
group appeared also compatible with all other planned
synthetic operations. The Si(t-Bu)Me2 (TBDMS) group was
selected as the O-protecting group because of the possibility
to directly oxidize a CH2OSi(t-Bu)Me2 group to a carboxyl
group.13
a TBD: 1,5,7-triazabicyclo[4.4.0]dec-5-ene. b The term b/l denotes the
ratio of branched and linear product of the allylic amination.
synthesis, one would like to carry out a substitution at the
carbonate 215b (Scheme 2) using N-Boc-but-2-inylamine as
nucleophile. However, so far conditions have not been
developed that allow N-alkyl-amides to be employed.
Therefore, two related nucleophiles were probed.
The Ir-catalyzed allylic amination has been developed into
a reliable tool over the past few years.14 In the present
(9) (a) Oppolzer, W.; Thirring, K. J. Am. Chem. Soc. 1982, 104, 4978–
4979. (b) Takano, S.; Sugihara, T.; Satoh, S.; Ogasawara, K. J. Am. Chem.
Soc. 1988, 110, 6467–6471. (c) Takano, S.; Iwabuchi, Y.; Ogasawara, K.
J. Chem. Soc., Chem. Commun. 1988, 1204–1206. (d) Baldwin, J. R.;
Moloney, M. G.; Parsons, A. F. Tetrahedron 1990, 46, 7263–7282. (e)
Cooper, J.; Knight, D. W.; Gallagher, P. T. J. Chem. Soc., Perkin Trans. 1
1992, 553–559. (f) Hatakeyama, S.; Sugawara, K.; Takano, S. J. Chem.
Soc., Chem. Commun. 1993, 125–127. (g) Hanessian, S.; Ninkovic, S. J.
Org. Chem. 1996, 61, 5418–5424. (h) Rubio, A.; Ezquerra, J.; Escribano,
A.; Remuinan, M. J.; Vaquerro, J. J. Tetrahedron Lett. 1998, 39, 2171–
2174. (i) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Chem.
Commun. 1999, 245–246. (j) Cheliakov, M. V.; Montgomery, J. J. Am.
Chem. Soc. 1999, 121, 11139–11143. (k) Nakagawa, H.; Sugahara, T.;
Ogasawara, K. Org. Lett. 2000, 2, 3181–3183. (l) Miyata, O.; Ozawa, Y.;
Ninomiya, I.; Naito, T. Tetrahedron 2000, 56, 6199–6207. (m) Clayden,
J.; Menet, C. J.; Tchabanenko, K. Tetrahedron 2002, 58, 4727–4733. (n)
Montserrat Martinez, M.; Hoppe, D. Org. Lett. 2004, 6, 3743–3746. (o)
Montserrat Martinez, M.; Hoppe, D. Eur. J. Org. Chem. 2005, 1427–1443.
(p) Scott, M. E.; Lautens, M. Org. Lett. 2005, 7, 3045–3047. (q) Poisson,
J.-F.; Orellana, A.; Greene, A. E. J. Org. Chem. 2005, 70, 10860–10863.
(r) Morita, Y.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2005, 7, 4337–
4340. (s) Anderson, J. C.; O’Loughlin, J. M. A.; Tornos, J. A. Org. Biomol.
Chem. 2005, 3, 2741–2749. (t) Hodgson, D. M.; Hachisu, S.; Andrews,
M. D. Org. Lett. 2005, 7, 815–817. (u) Pandey, S. K.; Orellana, A.; Greene,
A. E.; Poisson, J.-F. Org. Lett. 2006, 8, 5665–5668. (v) Sakaguchi, H.;
Tokuyama, H.; Fukuyama, T. Org. Lett. 2007, 9, 1635–1638. (w) Jung,
Y. C.; Yoon, C. H.; Turos, E.; Yoo, K. S.; Jung, K. W. J. Org. Chem.
2007, 72, 10114–10122. (x) Chalker, J. M.; Yang, A.; Deng, K.; Cohen, T.
Org. Lett. 2007, 9, 3825–3828. (y) Sakaguchi, H.; Tokuyama, H.; Fukuyama,
T. Org. Lett. 2008, 10, 1711–1714.
The N,N-diacylamine 3 is an ammonia equivalent, which
is known to provide both excellent regioselectivity, i.e., a
high ratio of branched to linear substitution product, as well
as high enantiomeric excess.15 The reaction with carbonate
2 under “salt-free” conditions15a gave the branched product
4 in 87% yield with enantiomeric purity of 97.5% ee (Scheme
2).
Amines are also excellent nucleophiles for the Ir-catalyzed
allylic amination.16 In the present case, the primary amine
but-2-ynylamine (5) appeared as a logical choice. However,
so far no example of a reaction with a propargylic amine
has been reported.17 Accordingly, we were pleased to find
that the reaction proceeded with a very good regioselectivity,
ratio b/l ) 94:6, and an excellent enantiomeric excess of
99% (Scheme 2).
(13) (a) Evans, P. A.; Roseman, J. D.; Garber, L. T. Synth. Commun.
1996, 26, 4685–4692. (b) Evans, P. A.; Murthy, V. S.; Roseman, J. D.;
Rheingold, A. L. Angew. Chem., Int. Ed. 1999, 38, 3175–3177. (c) Liu,
H.-J.; Han, I.-S. Synth. Commun. 1985, 15, 759–764.
(14) Reviews: (a) Takeuchi, R. Synlett 2002, 1954–1965. (b) Helmchen,
G.; Dahnz, A.; Du¨bon, P.; Schelwies, M.; Weihofen, R. Chem. Commun.
2007, 675–691. (c) Miyabe, H.; Takemoto, Y. Synlett 2005, 1641–1655.
(d) Helmchen, G. In Iridium Complexes in Organic Synthesis; Oro, A.,
Claver, C., Eds.; Wiley-VCH: Weinheim, Germany, 2009; pp 211-250.
(15) Ir-catalyzed allylic amination with N,N-diacylamines: (a) Weihofen,
R.; Tverskoy, O.; Helmchen, G. Angew. Chem., Int. Ed. 2006, 45, 5546–
5549. (b) Gnamm, C.; Franck, G.; Miller, N.; Stork, T.; Bro¨dner, K.;
Helmchen, G. Synthesis 2008, 3331–3350. (c) Singh, O. V.; Han, H.
Tetrahedron Lett. 2007, 48, 7094–7098.
(10) Asymmetric catalysis: (a) Bachi, M. D.; Melman, A. J. Org. Chem.
1997, 62, 1896–1898. (b) Xia, Q.; Ganem, B. Org. Lett. 2001, 3, 485–487.
(c) Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 1467–1470.
(11) Syntheses based on a Pauson-Khand reaction: (a) Yoo, S.-E.; Lee,
S. H.; Jeong, N.; Cho, I. Tetrahedron Lett. 1991, 34, 3435–3438. (b) Yoo,
S.-E.; Lee, S. H. J. Org. Chem. 1994, 59, 6968–6972. (c) Takano, S.;
Inomata, K.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1992, 169–
170.
(16) (a) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164–
15165. (b) Welter, C.; Koch, O.; Lipowsky, G.; Helmchen, G. Chem.
Commun. 2004, 896–897. (c) Welter, C.; Dahnz, A.; Brunner, B.; Streiff,
S.; Du¨bon, P.; Helmchen, G. Org. Lett. 2005, 7, 1239–1242. (d) Polet, D.;
Alexakis, A.; Tissot-Croset, K.; Corminboeuf, C.; Ditrich, K. Chem.sEur.
J. 2006, 12, 3596–3609.
(12) We have tested Ts, SO2t-Bu, Boc, and Cbz as N-protecting groups.
Excepting Boc, in all cases the diastereoselectivity was in the range of 66:
34 to 82:18. This observation is in accordance with results described in:
Yoo, S.-E.; Lee, S.-H.; Jeong, N.; Cho, I. Tetrahedron Lett. 1993, 34, 3435–
3438, and in ref 11b.
Org. Lett., Vol. 12, No. 5, 2010
1109

Scheme 3
.
Synthesis of the 1,6-Enyne 8
Scheme 4
.
Completion of the Total Synthesis of (-)-R-Kainic
Acid (1)a
The 1,6-enyne 8 was prepared from both 4 and 6 (Scheme
3). The formyl group of 4 was removed with methanol and
a catalytic amount of KOH. Subsequent N-alkylation with
1-bromobut-2-yne (7) needed careful control of reaction
conditions in order to avoid a shift of the double bond;
alkylation at -30 °C in DMF in the presence of 15-crown-5
turned out to give good results. No reaction occurred in the
absence of crown ether. In the second route, Boc-protection
of 6 was carried out with a biphasic mixture of CH2Cl2 and
1 M NaOH in the presence of the phase transfer catalyst
n-Bu4NHSO4.Theenyne8,thesubstrateforthePauson-Khand
reaction, was obtained in high yield.
a TPAP: tetrapropylammonium perruthenate.
The further steps of the total synthesis of (-)-R-kainic
acid are described in Scheme 4. A protocol of the intramo-
lecular Pauson-Khand reaction18 using molecular sieves 4
Å as additive19 was followed for generation of the key
cyclopentenone intermediate 9 from the 1,6-enyne 8. The
reaction proceeded with 65% yield and a trans:cis diastere-
omer ratio of 88:12 with respect to the moiety C3/C3a. Pure
trans-9 was isolated by chromatography in 57% yield.
Catalytic hydrogenation of the tetrasubstituted olefin 9 with
H2/Pd(OH)2/C gave 10 as a 60:40 mixture of epimers. As
the newly formed stereogenic center would be destroyed
later, separation of the diastereomers was not necessary.
Subsequent Baeyer-Villiger rearrangement20 with m-CPBA,
buffered with Na2HPO4, in CH2Cl2 gave the lactone 11 in
86% yield.
the reversibility of the reaction,9v we decided to reduce the
lactone. This was cleanly effected with in situ formed
Ca(BH4)2 in ethanol to give the corresponding dialcohol,
21
which in crude form was reacted with t-BuMe2SiCl (TB-
DMSCl) selectively at the primary OH group to give the
monoalcohol 12 in 92% yield. Ley-Griffith oxidation22
furnished the methylketone 13, which was transformed under
nonbasic conditions into the olefin 14 by reaction with
Tebbe’s reagent.23 No epimerization occurred in the build-
up of the propenyl group.
Next, oxidation of 14 to the dicarboxylic acid and
N-deprotection were required. Evans et al. have demonstrated
that TBDMS ethers of primary alcohols can be directly
oxidized with Jones’ reagent to give carboxylic acids.13
However, the oxidation of the silyl ether 14 under standard
conditions proceeded with partial cleavage of the Boc group
to give mixtures of chromium salts from which kainic acid
could not be obtained in reasonable yield. Extensive experi-
mentation with careful control of temperature, concentration,
and amount of oxidant led to conditions mainly yielding
N-Boc-kainic acid, which could be isolated free of chromium
impurities. Despite the sensitivity of the 2-propenyl moiety
to acid, N-deprotection under carefully controlled conditions
proceeded smoothly. Analytically pure (-)-R-kainic acid (1)
was obtained after ion exchange chromatography (DOWEX
As opening of lactones of this type with methoxide or
MeOH/Et3N is known to proceed with low yield because of
(17) A large number of highly selective Ir-catalyzed allylic aminations
with N-tosyl-propargylamines have been carried out by S.-L. You and co-
workers at the Shanghai Institute of Organic Chemistry, private communica-
tion of Prof. S.-L. You. In our group, Ir-catalyzed alkylations of cinnamyl
methyl carbonate with the pronucleophiles R-Ct C-CH2-CH(COOMe)2,
R ) H and Me, have been studied (ligand L2). In the case R ) Me, excellent
results were obtained (98.5% ee), in the case R ) H the reaction proceeded,
but the ee was low, only 12%.
(18) (a) Khand, U. I.; Knox, G. R.; Pauson, P. L.; Watts, W. E. J. Chem.
Soc., Chem. Commun. 1971, 36a. First intramolecular version: (b) Schore,
N. E.; Croudace, M. C. J. Org. Chem. 1981, 46, 5436–5438. Reviews: (c)
Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263–3283. (d)
Gibson, S. E.; Stevenazzi, A. Angew. Chem., Int. Ed. 2003, 42, 1800–1810.
(e) Blanco-Urgoiti, J.; An˜orbe, L.; Pe´rez-Serrano, L.; Dom´ınguez, G.; Pe´rez-
Castells, J. Chem. Soc. ReV. 2004, 33, 32–42. (f) Shibata, T. AdV. Synth.
Catal. 2006, 348, 2328–2336.
(21) Helmchen, G.; Prelog, V. HelV. Chim. Acta 1972, 55, 2599–2611.
(22) Review: (a) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639–666. (b) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.;
White, A. D. J. Chem. Soc., Chem. Commun. 1987, 1625–1627.
(23) (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611–3613. (b) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs,
R. H. J. Am. Chem. Soc. 1980, 102, 3270–3272.
(19) Pe´rez-Serrano, L.; Casarrubios, L.; Dom´ınguez, G.; Pe´rez-Castells,
J. Org. Lett. 1999, 1, 1187–1188.
(20) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.; Bendall, J. G.;
Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483–7498.
1110
Org. Lett., Vol. 12, No. 5, 2010

50WX8) in 76% yield over two steps; the spectral data
matched those reported for the natural product.24
Overall, our synthesis from the carbonate 2 via 4 or 6
required 13 or 12 steps and gave a total yield of 16% or
12%, respectively.
In summary, we are reporting a straightforward enantiose-
lective total synthesis of (-)-R-kainic acid (1). Key steps are
an Ir-catalyzed allylic amination with a propargylic amine,
which proceeded with very high enantio- and regioselectivity,
and an intramolecular, highly diastereoselective Pauson-Khand
reaction. No exchange of protecting groups was required.
der Chemischen Industrie. We thank Olena Tverskoy of our
group for experimental assistance. We are also grateful for
a continued supply of chiral amines by Prof. Ditrich of BASF
SE, Ludwigshafen. We thank Prof. Shu-Li You, SIOC,
Shanghai, for sending us a manuscript describing his work
on Ir-catalyzed allylic substitutions with N-tosylpropargy-
lamines. Finally, we are obliged to Prof. W. J. Kerr, Univer-
sity of Strathclyde, Glasgow, for advice on the Pauson-Khand
reaction.
Supporting Information Available: Experimental details
including spectral and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (SFB 623) and the Fonds
(24) Maeda, M.; Kodama, T.; Tanaka, T.; Yoshizumi, H.; Takemoto,
T.; Nomoto, K.; Fujita, T. Chem. Pharm. Bull. 1986, 34, 4892–4895.
OL1001076
Org. Lett., Vol. 12, No. 5, 2010
1111