New access to kainic acid via intramolecular palladium-catalyzed allylic alkylation

Article abstract of DOI:10.1055/s-2007-982542

The formal synthesis of kainic acid was carried out in eleven steps. The key cyclization step was accomplished through an intramolecular palladium-catalyzed allylic alkylation of an allylic sulfone. Further functionalization of the resulting pyrrolidone f

Full text of DOI:10.1055/s-2007-982542

LETTER
1521
New Access to Kainic Acid via Intramolecular Palladium-Catalyzed Allylic
Alkylation
New
F
ormal Synthesis
aof Kainic At
cid hieu Bui The Thuong,a Silvia Sottocornola,a Guillaume Prestat,a Gianluigi Broggini,b David Madec,*a
Giovanni Poli*a
a
Université Pierre et Marie Curie-Paris 6, Laboratoire de Chimie Organique (UMR CNRS 7611), Institut de Chimie Moléculaire
(FR 2769), case 183, 4 place Jussieu, 75252 Paris cedex 05, France
b
Dipartimento di Scienze Chimiche e Ambientali, Università dell'Insubria, via Valleggio 11, 22100 Como, Italy
Fax +33(1)44277567; E-mail: giovanni.poli@upmc.fr; E-mail: madec@ccr.jussieu.fr
Received 22 March 2007
Dedicated to Dr. Pierre Mangeney in honor of his 60th birthday
molecular 5-exo interaction between a stabilized acet-
Abstract: The formal synthesis of kainic acid was carried out in
amide enolate anion and a properly tethered h3-allyl-
eleven steps. The key cyclization step was accomplished through an
intramolecular palladium-catalyzed allylic alkylation of an allylic
sulfone. Further functionalization of the resulting pyrrolidone
palladium appendage (Scheme 1).10 Moreover, we subse-
quently showed that this reaction could take place under
featured, inter alia, a N-heterocyclic carbene–copper hydride biphasic conditions, which are milder and higher yielding
than those previously reported in monophasic media.11
(NHC–CuH)-mediated stereoconvergent conjugate reduction.
Key words: kainic acid, synthesis, palladium, allylic alkylation,
ring closure
OAc
[Pd(C3H5)Cl]2
dppe
n-Bu4NBr
EWG
O
EWG
O
KOH (aq)
CH2Cl2, H2O
N
N
(–)-a-Kainic acid is the parent member of kainoids, an
important class of natural nonproteinogenic amino acids
(Figure 1). It was first isolated in 1953 from Digenea
simplex.1 In addition to its insecticidal and anthelmintic
properties, it has been shown to display powerful neuro-
excitatory activity in the mammalian central nervous sys-
tem, where it acts as conformationally restricted analogue
of L-glutamate. For these reasons, it has found funda-
mental applications in the study of neurodegenerative
disorders2 such as Alzheimer’s disease,3 Huntington’s
chorea4 and epilepsy.5 Since the first synthesis of (–)-kain-
ic acid, carried out by Oppolzer,6 numerous total synthe-
ses of this compound have been described, most of them
being of chiral pool derivation.7,8 Interest in the synthesis
of such a target amazingly increased in recent years, due
to a temporary halt on the extraction from the above alga,
which brought about shortage of this natural product.9
Bn
Bn
EWG = CO2Me, COMe, CN, SPh, SO2Ph
72–96%
Scheme 1 Palladium-catalyzed intramolecular allylic alkylation
under biphasic conditions
In order to further test the value of the above methodolo-
gy, we next envisioned to exploit our strategy in the syn-
thesis of kainic acid. Accordingly, since one of the most
efficient total syntheses reported to date entails pyrroli-
done 1 as an advanced intermediate,12 we focused on the
latter structure as our synthetic goal. We report herein the
formal synthesis of ( )-kainic acid according to the
retrosynthetic path depicted in Scheme 2.
HOOC
HOOC
EtO2C
Following our ongoing interest in the synthesis of nitro-
gen-based heterocycles, we reported that pyrrolidones
could be built up regio- and stereoselectively via the intra-
ref. 12
O
N
H
N
H
kainic acid
1
LG
HOOC
HOOC
HOOC
HOOC
(RO)2(O)P
O
(RO)2(O)P
O
COOH
Pd-AA
N
N
H
H
N
N
(–)-α-kainic acid
(–)-domoic acid
PG
PG
Figure 1 (–)-a-Kainic acid and (–)-domoic acid structures
3
2
Scheme 2 Retrosynthetic approach to kainic acid; Pd-AA = palladi-
um-catalyzed allylic alkylation
SYNLETT 2007, No. 10, pp 1521–1524
1
8
.0
6
.2
0
0
7
Advanced online publication: 07.06.2007
DOI: 10.1055/s-2007-982542; Art ID: G09307ST
© Georg Thieme Verlag Stuttgart · New York

1522
M. B. T. Thuong et al.
LETTER
SO2Ph
Key precursor 1 would arise from the trans-substituted
pyrrolidone 2 via Horner–Wadsworth–Emmons olefina-
tion with ethyl glyoxalate, followed by reduction of the
electron-poor double bond. Pyrrolidone 2 could in turn be
derived from an intramolecular palladium-catalyzed allyl-
ic alkylation of the unsaturated a-phosphonoamide 3.
(MeO)2(O)P
O
(MeO)2(O)P
O
a
quantitative
N
N
PMB
PMB
6
7
1-Acetoxy-4-chloro-2-methyl-2-butene was first recog-
nized as a reasonable intermediate in the synthesis of the
cyclization precursor 6.13 However, in view of the diffi-
culties in preparing and isolating this reagent in satis-
factory yield14 we decided to look for an alternative
precursor. A quick perusal of the literature suggested that
chlorosulfone (E)-4 could be an ideal choice. Indeed,
allylic sulfones are known to generate h3-allyl-palladium
complexes, although their use is still rather underdevel-
oped with respect to the more popular allyl acetates or
carbonates.15 Copper-catalyzed condensation between
phenylsulfonyl chloride and isoprene afforded 4 in 61%
yield on multigram scale.16 Reaction of the latter with ex-
cess p-methoxybenzylamine afforded allylic amine 5 in
trans/cis > 95:5
Scheme 4 Reagents and conditions: (a) [Pd(C3H5)Cl]2 (5 mol%),
dppe (12.5 mol%), n-Bu4NBr (10 mol%), aq KOH (4 equiv), CH2Cl2–
H2O (1:1), r.t., 16 h.
(MeO)2(O)P
O
EtO2C
a
O
54%
N
N
PMB
PMB
7
8
E/Z = 1:1
80% yield. Subsequent acylation with dimethylphos- Scheme 5 Reagents and conditions: (a) NaH (1.2 equiv), THF, 0 °C
then ethyl glyoxalate (50% solution in toluene, 2 equiv), r.t., 1 h.
phonoacetic acid gave the cyclization precursor 6 in 98%
yield (Scheme 3).
yield (52%) of the desired pyrrolidone 9 with a poor 65:35
cis/trans diastereomeric ratio, when starting from (Z)-8.
a
PhSO2
PhSO2Cl
+
Cl
61%
Conversely, N-heterocyclic carbene–copper hydride
(NHC–CuH) efficiently promoted the reduction step.19 In-
deed, treatment of (Z)-8 or (E)-8 with 1,3-bis(2,6-diiso-
propylphenyl)imidazol-2-ylidene (IPr)-CuCl (2 mol%), t-
BuONa (10 mol%), and excess poly(methylhydrosilox-
ane) (PMHS) as the hydride source, gave the cis-pyrroli-
done 9 as the only product in 84% and 67% yields,
respectively (Scheme 6). A similar result was obtained
starting from an equimolar E/Z mixture of 8 (72% yield).20
4
b
80%
SO2Ph
(MeO)2(O)P
O
c
98%
PhSO2
PMB
N
H
N
6
5
PMB
Scheme 3 Reagents and conditions: (a) CuCl (5 mol%), Et3NHCl
(5 mol%), MeCN, 60 °C, 16 h; (b) p-MeOC6H4CH2NH2 (3 equiv),
MeCN, reflux, 4 h; (c) (MeO)2P(O)CH2COOH (1.2 equiv), DCC (1.5
equiv), DMAP (5 mol%), THF, r.t., 16 h.
EtO2C
a
O
N
84%
PMB
Intramolecular palladium-catalyzed allylic alkylation of
the phosphonoacetamide 6 was next tested (Scheme 4).
Much to our satisfaction, treatment of the substrate 6
with [Pd(C3H5)Cl]2 (5 mol%), 1,2-bis(diphenylphosphi-
no)ethane (dppe; 12.5 mol%), n-Bu4NBr (10 mol%) and
KOH (4.0 equiv) in 1:1 CH2Cl2–H2O gave, after 16 hours
at room temperature, the expected pyrrolidone 7 in quan-
titative yield and a >95:5 trans/cis diastereomeric ratio.17
EtO2C
(Z)-8
O
CO2Et
N
67%
PMB
9
a
cis/trans > 95:5
O
N
PMB
(E)-8
Horner–Wadsworth–Emmons olefination was next un-
dertaken. Deprotonation of 7 with NaH at 0 °C in THF fol-
lowed by condensation with excess ethyl glyoxalate in
toluene afforded the expected diene pyrrolidone 8 (54%
yield) as a 1:1 E/Z mixture, separable by flash chromatog-
raphy (Scheme 5).
Scheme 6 Reagents and conditions: (a) IPr-CuCl (2 mol%),
t-BuONa (10 mol%), PMHS (4 equiv), toluene, r.t., 16 h.
PMB deprotection completed the formal synthesis of
kainic acid. Thus, treatment of 9 with CAN in MeOH gave
rise to Ganem’s intermediate 1 (47% yield, i.e. 6 steps and
14% overall yield from the known chlorosulfone 4),
whose spectroscopic data were in agreement with those
reported in the literature.12 According to Ganem’s
Reduction of the conjugate double bond was next tackled
for each isomer, separately. The use of L-Selectride®18
was rather disappointing, leading to complete degradation
of starting material in the case of (E)-8, and to a moderate
Synlett 2007, No. 10, 1521–1524 © Thieme Stuttgart · New York

LETTER
New Formal Synthesis of Kainic Acid
1523
(8) For some recent syntheses of kainic acid: (a)Nakagawa, H.;
Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2, 3181.
(b) Clayden, J.; Menet, C. J.; Mansfield, D. J. Chem.
Commun. 2002, 38. (c) Clayden, J. C.; Menet, C. J.;
Tchabanenko, K. Tetrahedron 2002, 58, 4727. (d) Trost, B.
M.; Rudd, M. T. Org. Lett. 2003, 5, 1467. (e) Hoppe, D.;
Montserrat Martinez, M. Org. Lett. 2004, 6, 3743.
(f) Hodgson, D. M.; Hachisu, S.; Andrews, M. D. Org. Lett.
2005, 7, 815. (g) Lautens, M.; Scott, M. E. Org. Lett. 2005,
7, 3045. (h) Anderson, J. C.; O’Loughlin, J. M. A.; Tornos,
J. A. Org. Biomol. Chem. 2005, 3, 2741. (i) Morita, Y.;
Tokuyama, H.; Fukuyama, T. Org. Lett. 2005, 7, 4337.
(j) Hodgson, D. M.; Hachisu, S.; Andrews, M. D. J. Org.
Chem. 2005, 70, 8866. (k) Poisson, J.-F.; Orellana, A.;
Greene, A. E. J. Org. Chem. 2005, 70, 10860. (l) Pandey, S.
K.; Orellana, A.; Greene, A. E.; Poisson, J.-F. Org. Lett.
2006, 8, 5665. (m) Chalker, J.; Yang, A.; Deng, K.; Cohen,
T., unpublished results; private communication from T.
Cohen in the form of a lecture in Paris, 2006.
procedure, a four-step sequence can convert pyrrolidone 1
into kainic acid in an overall 73% yield (Scheme 7).
Moreover, the two enantiomers may be further separated
via a (+)-ephedrine-mediated resolution, according to
Oppolzer’s protocol.21
EtO2C
EtO2C
a
O
47%
O
N
N
H
PMB
9
1
4 steps
73% overall
ref. 12
HOOC
(9) (a) Tremblay, J.-F. Chem. Eng. News 2000, 78, 14.
(b) Tremblay, J.-F. Chem. Eng. News 2000, 78, 131.
(10) Poli, G.; Giambastiani, G.; Pacini, B.; Porcelloni, M. J. Org.
Chem. 1998, 63, 804.
HOOC
N
H
kainic acid
(11) Madec, D.; Prestat, G.; Martini, E.; Fristrup, P.; Poli, G.;
Norrby, P.-O. Org. Lett. 2005, 7, 995.
(12) Compound 1 (66% ee) was obtained in seven steps and 16%
global yield from commercially available compounds: Xia,
Q.; Ganem, B. Org. Lett. 2001, 3, 485.
(13) Hecht, S.; Amslinger, S.; Jauch, J.; Kis, K.; Trentinaglia, V.;
Adam, P.; Eizenreich, W.; Bacher, A.; Rohdich, F.
Tetrahedron Lett. 2002, 43, 8929.
(14) (a) Large-scale preparation of 4-chloro-2-methylbut-2-en-1-
ol from 2-methyl-2-vinyl oxirane and TiCl4 (see ref. 13)
afforded a poor (27%) yield. Alternatively, treatment of the
same oxirane with CuCl2–LiCl (see ref. 13) gave the
corresponding aldehyde in 68% yield. NaBH4 reduction of
the latter gave the desired alcohol in 43% yield, see: Fox, T.
D.; Poulter, C. D. J. Org. Chem. 2002, 67, 5009.
Scheme 7 Reagents and conditions: (a) (NH4)2Ce(NO3)6 (4 equiv),
MeOH, 0 °C then r.t., 16 h.
In summary, the above described sequence represents a
successful eleven-step formal synthesis of kainic acid.
The key cyclization step was accomplished through an in-
tramolecular palladium-catalyzed allylic alkylation from
an allylic sulfone. Further functionalization of the result-
ing pyrrolidone exploited a stereoconvergent NHC–CuH-
mediated conjugate reduction. Extension of the present
strategy to an enantioselective synthesis of (–)-kainic acid
is currently under investigation.
(b) Acetylation with Ac2O–Et3N gave 1-acetoxy-4-chloro-2-
methyl-2-butene in 29% yield (Scheme 8).
Acknowledgment
TiCl4, CH2Cl2
O
CNRS and UPMC are acknowledged for financial support. We
thank also Dr S. Roland (UPMC) for fruitful discussions concerning
NHC–copper chloride catalyzed conjugate reductions. The spon-
sorship of COST Action D40 ‘Innovative Catalysis: New Processes
and Selectivities’ is kindly acknowledged.
HO
Cl
–80 °C
27%
THF
–20 °C
43%
80 °C
AcOEt
68%
CuCl2
LiCl
NaBH4
O
Cl
Scheme 8
References and Notes
(1) Murukami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc.
Jpn. 1953, 73, 1026.
(2) Hollmann, M.; Heinemann, S. Annu. Rev. Neurosci. 1994,
17, 31.
(15) For some examples concerning the use of allylic sulfones in
palladium-catalyzed allylic alkylation, see: (a) Trost, B. M.;
Schmuff, N. R.; Miller, J. M. J. Am. Chem. Soc. 1980, 102,
5979. (b) Clayden, J.; Julia, M. J. Chem. Soc., Chem.
Commun. 1994, 1905. (c) Orita, A.; Watanabe, A.;
(3) 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.
(4) Coyle, J. T.; Schwarcz, R. Nature (London) 1976, 263, 244.
(5) Sperk, G. Prog. Neurobiol. (Oxford) 1994, 42, 1.
(6) Oppolzer, S.; Thirring, K. J. J. Am. Chem. Soc. 1982, 104,
4978.
(7) For reviews concerning previous syntheses of kainic acid,
see: (a) Parsons, A. F. Tetrahedron 1996, 52, 4149.
(b) Clayden, J.; Read, B.; Hebditch, K. R. Tetrahedron 2005,
61, 5713. (c) Rosini, G. Chim. Ind. (Milan) 2001, 83, 75.
Tsuchiya, H.; Otera, J. Tetrahedron 1999, 55, 2889.
(d) Cheng, W.-C.; Halm, C.; Evarts, J. B.; Olmstead, M. M.;
Kurth, M. J. J. Org. Chem. 1999, 64, 8557. (e) Deng, K.;
Chalker, J.; Yang, A.; Cohen, T. Org. Lett. 2005, 7, 3637.
(16) (a) Truce, W. E.; Goralski, C. T.; Christensen, L. W.; Bavry,
R. H. J. Org. Chem. 1970, 35, 4217. (b) Min, J. H.; Lee, J.
S.; Yang, J. D.; Koo, S. J. Org. Chem. 2003, 68, 7925.
(17) Procedure for the Palladium-Catalyzed Cyclization
Reaction: To a solution of tetrabutylammonium bromide
(10 mol%) in CH2Cl2 (1 mL) were added in this order
allylpalladium chloride dimer (5 mol%) and dppe (12.5
mol%). After 5 min stirring, to the thus formed catalytic
Synlett 2007, No. 10, 1521–1524 © Thieme Stuttgart · New York

1524
M. B. T. Thuong et al.
LETTER
system were added successively a CH2Cl2 (5 mL) solution of
6 (795 mg, 1.6 mmol), H2O (6.0 mL), and a 50% aq KOH
solution (6.4 mmol). The resulting biphasic system was
stirred vigorously at r.t. for 16 h. The aqueous phase was
extracted with CH2Cl2 (3 ×). The collected organic phases
were dried over MgSO4 and the solvent was removed in
vacuo. The crude product was purified by flash
(20) Procedure for the Hydride Conjugate Addition: An oven-
dried flask under an argon atmosphere was charged with IPr-
CuCl (2 mol%), t-BuONa (10 mol%) and anhydrous toluene
(1 mL). After 10 min stirring at r.t., PMHS (90 mL) was
added and the resulting orange solution was stirred at r.t. for
5 min. Then toluene (1 mL), and further PMHS (270 mL)
were added. A solution of 8 (1:1 E/Z mixture) (508 mg, 1.54
mmol) in toluene (8 mL) was added via cannula to the thus
generated reducing system and the reaction mixture was
stirred at r.t. for 16 h. H2O was added, the aqueous phase was
extracted with EtOAc (3 ×). The collected organic phases
were washed with brine, dried over MgSO4 and the solvents
were removed in vacuo. The crude product was purified by
flash chromatography to afford pure 9 as an oil (72%). 1H
NMR (400 MHz, CDCl3): d = 7.16 (d, J = 8.6 Hz, 2 H), 6.83
(d, J = 8.6 Hz, 2 H), 4.74 (br s, 1 H), 4.65 (br s, 1 H), 4.39 (d,
J = 14.2 Hz, 1 H), 4.35 (d, J = 14.2 Hz, 1 H), 4.11 (q, J = 7.1
Hz, 2 H), 3.77 (s, 3 H), 3.36–3.42 (m, 1 H), 3.10–3.15 (m, 2
H), 3.03 (dd, J = 1.3, 10.1 Hz, 1 H), 2.83 (dd, J = 3.5, 17.2
Hz, 1 H), 2.21–2.32 (m, 1 H), 1.42 (s, 3 H), 1.23 (t, J = 7.1
Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 174.1, 172.5,
159.2, 143.1, 130.0, 128.1, 114.9, 114.0, 60.6, 55.3, 49.0,
46.3, 42.0, 41.6, 31.0, 19.8, 14.3. IR: 2936, 1731, 1687,
1513, 1246, 1175, 1032 cm–1.
chromatography to afford 7 in quantitative yield as an oil. 1H
NMR (400 MHz, CDCl3): d = 7.19 (d, J = 8.6 Hz, 2 H), 6.86
(d, J = 8.6 Hz, 2 H), 4.78 (br s, 2 H), 4.46 (d, J = 14.6 Hz, 1
H), 4.40 (d, J = 14.6 Hz, 1 H), 3.87 (d, J = 10.8 Hz, 3 H), 3.81
(d, J = 10.8 Hz, 3 H), 3.80 (s, 3 H), 3.55 (dd, J = 8.3, 9.6 Hz,
1 H), 3.20–3.32 (m, 1 H), 2.98–3.07 (m, 1 H), 2.94 (dd, J =
4.5, 22.8 Hz, 1 H), 1.63 (s, 3 H). 13C NMR (100 MHz,
CDCl3): d = 168.3, 159.2, 144.3, 129.6, 127.4, 114.1, 112.3,
55.3, 53.5 (J = 100 Hz), 50.1, 46.4, 46.0 (J = 140 Hz), 39.7,
19.2. IR: 2955, 2360, 1688, 1514, 1247, 1031 cm–1. MS
(ESI+): m/z = 392 [M + K+], 376 [M + Na+], 354 [M + H+].
(18) (a) Fortunato, J. M.; Ganem, B. J. Org. Chem. 1976, 41,
2194. (b) Oppolzer, W.; Poli, G. Tetrahedron Lett. 1986, 27,
4717.
(19) For pioneering work concerning reduction reactions by
copper hydride, see: (a) Mahoney, W. S.; Brestensky, D. M.;
Stryker, J. M. J. Am. Chem. Soc. 1988, 110, 291. For
copper-catalyzed examples using PMHS as hydride source,
see: (b) Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R.
Tetrahedron Lett. 1998, 39, 4627. (c) Lipshutz, B. H.;
Chrisman, W.; Noson, K.; Papa, P.; Sclafani, J. A.; Vivian,
R. W.; Keith, J. M. Tetrahedron 2000, 56, 2779.
(21) Oppolzer, W.; Andres, H. Helv. Chim. Acta 1979, 62, 2282.
(d) Lipshutz, B. H.; Chrisman, W.; Noson, K. J. Organomet.
Chem. 2001, 624, 367. (e) For the first example reporting
the use of NHC-copper catalyst, see: (f) Jurkauskas, V.;
Sadighi, J. P.; Buchwald, S. L. Org. Lett. 2003, 5, 2417.
Synlett 2007, No. 10, 1521–1524 © Thieme Stuttgart · New York

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