Total synthesis of (-)-α-kainic acid by (-)-sparteine-mediated asymmetric deprotonation-cycloalkylation

Article abstract of DOI:10.1021/ol0485666

(Chemical Equation Presented) We report a new enantioselective synthesis of (-)-α-kainic acid from D-serine methyl ester hydrochloride, based on a (-)-sparteine-mediated asymmetric deprotonation of an intermediate carbamate that, by stereospecific anti S_N′S_E′ intramolecular cycloalkylation, leads to the pyrrolidine ring precursor of (-)-α-kainic acid, in high yield and diastereoselectivity. The intermediate pyrrolidine was further transformed to (-)-α-kainic acid in three steps.

Full text of DOI:10.1021/ol0485666

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3743-3746
Total Synthesis of (
)-Sparteine-Mediated Asymmetric
Deprotonation
Cycloalkylation†
−)-r-Kainic Acid by
(−
−
M. Montserrat Martinez and Dieter Hoppe*
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t Mu¨nster,
Corrensstrasse 40, D-48149 Mu¨nster, Germany
dhoppe@uni-muenster.de
Received July 23, 2004
ABSTRACT
We report a new enantioselective synthesis of (
asymmetric deprotonation of an intermediate carbamate that, by stereospecific anti S
ring precursor of ( )- -kainic acid, in high yield and diastereoselectivity. The intermediate pyrrolidine was further transformed to (
acid in three steps.
−
)-
r
-kainic acid from
D
-serine methyl ester hydrochloride, based on a (
N SE intramolecular cycloalkylation, leads to the pyrrolidine
)- -kainic
−)-sparteine-mediated
′
′
−
r
− r
The natural marine product (-)-R-kainic acid (1), a potent
neurotransmitting activity inhibitor for the central nervous
system,1 is the parent member of kainoids, an important class
of compounds with interesting biological properties.
acid carried out by Oppolzer,2 several total syntheses of this
compound were published,3 although only a few lead to the
enantiopure product. Here, we report a new diastereoselective
(-)-sparteine-mediated total synthesis of (-)-R-kainic acid.
Recently, we have reported that sparteine-mediated car-
bocyclizations of allyllithium compounds lead to cyclopen-
tanes with the favored cis stereochemistry at the newly
formed bond.4 Later, this method was extended to the
synthesis of a cis-3,4-divinylpyrrolidine with high enantio-
and diastereoselectivity.5 We now report the use of this
(2) Oppolzer, W.; Thirring, K. J. Am. Chem. Soc. 1982, 104, 4978.
(3) (a) Williams, M. R. Synthesis of Optical ActiVe R-Amino Acids;
Pergamon: Oxford, 1989; p 306. Reviews: (b) Parsons, A. F. Tetrahedron
1996, 52, 4149. For selected recently syntheses: (c) Nakagawa, H.;
Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2, 3181. (d) Xia, Q.; Ganem,
B. Org. Lett. 2001, 3, 485. (e) Clayden, J.; Menet, C. J.; Tchabanenko, K.
Tetrahedron 2002, 58, 4727. (f) Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito,
T. Tetrahedron 2000, 56, 6199. (g) Trost, B. M.; Rudd, M. T. Org. Lett.
2003, 5, 1467. (h) Chevliakov, M. V.; Montgomery, J. J. Am. Chem. Soc.
1999, 121, 11139. (i) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K.
J. Chem. Soc., Perkin Trans. 1 2000, 19, 3194. (j) Hirasawa, H.; Taniguchi,
T.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 7587.
Synthesis of kainoids needs to address the formation of a
pyrrolidine-2-carboxylic acid with defined stereochemistry
at the three continuous chiral centers of the ring, where is
essential to achieve a cis stereochemistry for the 3- and
4-positions. Subsequent to the first synthesis of (-)-R-kainic
† Dedicated to Professor Th. Kauffmann on the occasion of his 80th
birthday.
(1) (a) Foster, A. C.; Fagg, G. E. Brain Res. ReV. 1984, 7, 103. (b)
Watkins, J. C.; Olverman, H. J. Trends Neurosci. 1987, 10, 265. (c) Hansen,
J. J.; Krogsgaard-Larsen, P. Med. Res. ReV. 1990, 10, 55.
(4) Deiters, A.; Hoppe, D. J. Org. Chem. 2001, 66, 2842.
(5) Deiters, A.; Wibbeling, B.; Hoppe, D. AdV. Synth. Catal. 2001, 343,
181.
10.1021/ol0485666 CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/21/2004

Scheme 1. Retrosynthesis of (-)-R-Kainic Acid by Using an
Intramolecular Anti SN′SE′ Reaction
Scheme 2. Synthesis of Cyclization Precursor 12a
methodology to synthesize (-)-R-kainic acid following the
strategy described in Scheme 1.
In our synthesis, the desired configuration of (-)-R-kainic
acid, is achieved via asymmetric anti SN′SE′ cycloalkylation
reaction of key precursor C, synthesized from building blocks
A and B.6
Synthesis of key precursor C (12 in Scheme 2) has been
carried out starting from N-benzyl-protected D-serine methyl
ester hydrochloride,7 first transformed into silyl ether 3 ([R]D
+3.9, c 0.94, CHCl3) in 89% yield. Reduction of ester 3
with LiBH4 led to alcohol 4 ([R]D -8.2 (c 1.10, CHCl3)) in
47%.8 Further, the synthesis required the elaboration of
intermediate 6 from 4 containing two stereogenic double
bonds, both achieved with an E/Z ratio >99% (determined
by 1H NMR). N-Alkylation of alcohol 4 was carried out by
refluxing (E)-configured isoprenoid 219 using NaHCO3 in
acetonitrile, yielding alcohol 5 ([R]D -3.6 (c 0.91, CHCl3))
in 82%. 5 was converted to 6 with 75% overall yield by
Swern oxidation followed in situ olefination using (carb-
ethoxymethylene)triphenylphosphorane, in a single operation
to avoid racemization. The next step of the synthesis
consisted of the selective removal of TES group in 6 with
TBAF, which was achieved in 81% yield. Allylic alcohol 7
([R]D +14.7 (c 0.61, CHCl3)) was then submitted to chlorine-
substitution, giving (E,E)-allylic chloride 8 ([R]D +22.0 (c
0.78, CHCl3)) in 71%. An optical purity of g95% enantio-
a Conditions: (a) TBSCl, NEt3, DMAP, CH2Cl2, rt, 12 h. (b)
LiBH4, THF/toluene, reflux, 20 min. (c) CH3CN, NaHCO3, rt, 30
min, 21, reflux, 3 h. (d) (COCl)2, DMSO, CH2Cl2, -78 °C, NEt3,
-15 °C, 1 h. (e) (Carbethoxymethylene)triphenylphosphorane, -15
°C to room temperature, 3 h. (f) TBAF, THF, 0 °C, 5 min. (g)
NEt3, CH2Cl2, -40 °C, MsCl, 1 h, LiCl, THF, rt, 3 h. (h) DIBAL-
H, CH2Cl2, -78 °C, 2 h. (i) NaH, CbCl,THF, reflux, 12 h.
Intramolecular anti SN′SE′ cycloalkylation of (E,E)-car-
bamate 12 (Scheme 3), the key step for the synthesis of (-)-
R-kainic acid, commenced with R-deprotonation by means
of n-BuLi/(-)-sparteine at -78 °C in toluene.11 This reaction
took place under kinetic control, providing after 1 h the
cyclization products 13a ([R]D -22.6 (c 0.57, CHCl3)) and
13b ([R]D -6.4 (c 0.75, CHCl3)) in 83% yield12 (13a:13b,
1
dr 80:20, as determined by H NMR). As expected, a high
1
meric excess was determined for 8 by H NMR analysis of
the corresponding (-)-MPTA ester 10.10
Desired carbamate 12 was prepared from 8 via 1,2-
reduction of its ester moiety by treatment with DIBAL-H
(70% yield), followed by standard carbamoylation of 11,
yielding 12 ([R]D +9.7 (c 0.71, CHCl3)) in 53%.
C3-C4 cis selectivity was achieved giving the two separable
diastereomers 13a and 13b, without formation of trans
products with respect to the C3-C4 bond, as evidenced by
1H NMR.
Since the relative configuration of pyrrolidines 13a and
13b could not be determined by NOE studies, the stereo-
chemical assignment of structures to 13a and 13b is based
on the fact that the two olefinic protons of the isopropenyl
(6) This synthetic route could be also applicable for the synthesis of (-)-
domoic acid by modifying precursor A with a dienoic side chain.
(7) N-Benzylation was carried out first by reductive amination; see:
Barco, A.; Benetti, S.; Spalluto, G. J. Org. Chem. 1992, 57, 6279.
(8) Low yield was obtained due to simultaneous occurrence of depro-
tection of silyl ether. Other reducing agents were checked (LiAlH4, NaBH4)
unsuccessfully.
1
chain appear as two singlets in the H NMR spectra, as is
typical for similar kainoids.13 In addition, experimental
3
vicinal coupling constants (3J2,3 and J3,4) observed for 13a
(9) Synthesized from hydroxyacetone in 67% overall yield over four
steps: silylation followed by Horner-Wadsworth-Emmons reaction, 1,2-
reduction of the ester moiety, and bromination.
(10) (-)-MPTA ester 10 was derived from racemic and enantiomerically
enriched 9 by esterification using (-)-MPTACl in 70% overall yield.
(11) Deiters, A.; Mu¨ck-Lichtenfeld, C.; Fro¨hlich, R.; Hoppe, D. Org.
Lett. 2000, 2, 2415.
(12) Other conditions for the asymmetric cyclization, as well as other
key precursors, were tried with less success.
3744
Org. Lett., Vol. 6, No. 21, 2004

Scheme 3. Cyclization to the Pyrrolidines 13a and 13ba
Scheme 4. Completion of the Synthesis to (-)-R-Kainic Acid
and Synthesis of Lactone 18ba
a Conditions: (a) MeLi or TMSOTf. (b) t-BuLi, TMEDA, THF,
-78 °C, 1 h, MeSSMe, 1 h, rt. (c) MeOC(dO)Cl, ClCH2CH2Cl,
reflux, 3 h. (d) MeSO3H, MeOH, H2O, reflux, 16 h. (e) Jones
reagent. (f) 40% NaOH aq, reflux, 18 h. (g) Dowex 50WX-200
(elution with NH4OH (1 N)), Amberlite CG- 50 (elution with H2O).
(h) Recrystallization, EtOH aq.
a Conditions: (a) n-BuLi/sp (2.2 equiv), toluene, -78 °C, 1 h.
regioselective C-C bond formation between both γ,γ′-
positions and simultaneous elimination of lithium chloride.5
Although these (-)-sparteine-lithium ion pairs of primary
allyl carbamates have been recognized to have limited
configurational stability, the cycloalkylation is more rapid
than epimerization. (2) An endo conformation of the allylic
moiety in an anti mode is required for the SN′SE′ cycloalky-
lation.16 The chairlike transition state E allows the π-π*
overlap of the electron-rich and electron-deficient allyl
moieties, presumably being the origin of the high cis
diastereoselectivity. Compound 13b is most probably formed
by intramolecular cycloalkylation of the (R)-configured
lithium derivative F‚sp.
(b) MeOH.
were within the range of calculated ones from computational
studies based on the Karplus-Conroy equation.14
The (Z)-geometry of the enol carbamate moiety is based
on the small olefinic coupling constant (5.6 Hz) observed,
in agreement with previous studies in our group.4,5
Further support to this assignment is provided by the
conversion of 13a to (-)-R-kainic acid (1).
The stereochemical outcome of the asymmetric cycloalky-
lation reaction is supported by the following mechanistic
considerations: (1) The chiral base n-BuLi/(-)-sparteine
enantioselectively removes the R-pro-S-proton15 of carbamate
12, generating the configurationally labile intermediate
E‚sp. Intramolecular cycloalkylation of E occurs under
To complete the synthesis of (-)-R-kainic acid, oxidative
removal of the carbamate group in 13a is necessary (Scheme
4).
The usual oxidative methods17 are not applicable to vinyl
carbamates 13a and 13b due to the reactive additional
trisubstituted double bond. Moreover, attempts to convert
the vinyl carbamate 13a into aldehyde 14a by using
methyllithium18 or TMSOTf19 failed. In light of these results,
we used an indirect oxidation method consisting in a vinylic
deprotonation with t-BuLi followed by quench with MeSS-
Me.20 The obtained ketene monothioacetal 15a was submitted
(13) (a) Kondo, K.; Kondo, Y.; Takemoto, T.; Kenoue, T. Bull. Chem.
Soc. Jpn. 1962, 35, 1899. (b) For a discussion of the rotameric distributions
of several kainoids: (c) Conway, G. A.; Park, J. S.; Maggiora, L.; Mertes,
M. P.; Galton, N.; Michaelis, E. K. J. Med. Chem. 1984, 27, 52. (d)
Kozikowski, A. P.; Fauq, A. H. Tetrahedron Lett. 1990, 31, 2967 and
references therein.
(14) NMR-Spectroscopie; Gu¨nther, H., Ed.; Georg Thieme Verlag
Stuttgart: New York, 1992. The coupling constants were obtained with
the use of the packet of programs TURBOMOLE (version 5.6) (University
Karlsruhe: Karlsruhe, Germany, 2003). The structures were optimized with
the theoretical function at the DFT level using the pure B-P functional [DFT-
(B-P)] and the basis set TZVP (triple-valence-polarized).
(15) In all known examples, deprotonation of O-allylic carbamates with
n-BuLi/sp led to the (S)-configured organolithium compound. For re-
views: (a) Hoppe, D. Angw. Chem. 1984, 96, 930; Angw. Chem., Int. Ed.
Engl. 1984, 23, 932. (b) Hoppe, D.; Hense, T. Angw. Chem., Int. Ed. Engl.
1997, 36, 2282 and references therein.
(16) Hoppe, D.; Bro¨nneke, A. Tetrahedron Lett. 1983, 24, 1687. For
review about SN reactions, see: Magid, M. R. Tetrahedron 1980, 31, 1901.
(17) (a) Rehders, F.; Hoppe, D. Synthesis 1992, 859. (b) Grieco, A. P.;
Oguri, T.; Yokoyama, Y. Org. Lett. 1978, 5, 419.
(18) Madec, D.; Henryon, V.; Fe´re´zou, P. J. Tetrahedron Lett. 1999,
40, 8103.
Org. Lett., Vol. 6, No. 21, 2004
3745

without further purification to N-debenzylation by treatment
with methyl chloroformate,21 providing 16a ([R]D -19.0 (c
0.5, CHCl3)) in 84% overall yield. Similar results were
obtained when the minor diastereomer 13b was treated under
the same conditions to provide 16b.
Treatment of monothioketene acetal 16a with an excess
of methanesulfonic acid resulted in the deprotection of the
hydroxyl group and simultaneous hydrolysis of the ketene
monothioacetal moiety, giving alcohol 17a in 55% overall
yield. In a similar fashion, lactone 18b resulted from
deprotection of silyl ether in 16b followed by cyclization of
both C-2 and C-3 chains in 48% yield.
The final steps to the natural product were carried out
following literature precedents:4i Jones oxidation of the
primary alcohol 17a, followed by hydrolysis with 40%
aqueous sodium hydroxide, and purification by using ion-
exchange chromatography afforded enantiopure (-)-R-kainic
acid as colorless needles after recrystallization from aqueous
ethanol (38% overall yield). Our final product possessed
physical properties identical to those of the authentic
material: mp 243-245 °C (decomp) versus lit.3i mp 241-
244 °C (decomp); [R]D -14.3 (c 0.40, H2O) versus lit.4i [R]D
-14.6 (c 0.25, H2O).
In conclusion, we have reported a new method to prepare
(-)-R-kainic acid via (-)-sparteine-mediated asymmetric
lithiation and cycloalkylation synthesis.
Elucidation of the structure of 17a and 18b was carried
1
out by H NMR spectra and NOE studies.22 The absolute
configuration was confirmed by comparing their respective
Acknowledgment. This work was supported by the
Deutsche Forschunsgemeinschaft (Sonderforschungs-bereich
424) and the Fonds der Chemischen Industrie. M. Mart´ınez
thanks Spanish “Ministerio de Educacio´n Cultura y Deporte”
for a grant. We thank Mrs. E. Izgorodina for theoretical
calculation of NMR coupling constants.
[R]D values with published ones: for 17a ([R]D -41.2 (c
3i
0.52, CH2Cl2)) versus ([R]D -43.0 (c 1.25, CH2Cl2)) and
3j
for 18b ([R]D -28.1 (c 0.30, CHCl3)) versus ent-18b ([R]D
+32.1 (c 1.20, CHCl3)).
(19) Seppi, M.; Kalkofen, R.; Reupohl, J.; Fro¨hlich, R.; Hoppe, D. Angew.
Chem. 2004, 116, 1447.
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.
(20) Paulsen, H.; Hoppe, D. Tetrahedron 1992, 48, 5667.
(21) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Chem. Commun.
1999, 245.
(22) 1H NMR exhibits two broad singlets at 4.62 and 4.91 ppm for the
alkene protons, indicating the C3-C4 cis relationship (see refences 4i and
12). The NOE studies were carried out at low temperature because of the
broad signals.
OL0485666
3746
Org. Lett., Vol. 6, No. 21, 2004