Stereocontrolled synthesis of (-)-kainic acid from trans-4-hydroxy-L- proline

Article abstract of DOI:10.1021/jo051508t

A highly stereoselective synthesis of (-)-kainic acid has been achieved in 14 steps and > 7% overall yield starting from inexpensive trans-4-hydroxy-L-proline. The key steps are diastereoselective enolate alkylation and cuprate substitution reactions.

Full text of DOI:10.1021/jo051508t

Stereocontrolled Synthesis of (-)-Kainic
Acid from trans-4-Hydroxy-L-proline†
Jean-Franc¸ois Poisson,* Arturo Orellana, and
Andrew E. Greene
Chimie Recherche (LEDSS), Universite´ Joseph Fourier,
FIGURE 1.
38041 Grenoble, France
the often problematic C3-C4 cis substitution. Other
approaches have made use of a 3 + 2 cyclization or have
started from pyroglutamic acid. Surprisingly, inexpensive
trans-4-hydroxy-L-proline (2, eq 1) has not been used to
date as the starting material for a preparation of (-)-
kainic acid.6 While the structure and absolute configu-
ration of this hydroxy amino acid would seem to make it
an ideal substance for this purpose, the difficulty in
controlling the relative stereochemistry at the three
contiguous stereogenic centers on the pyrrolidine has
apparently so far thwarted or dissuaded synthetic chem-
ists.7
We hoped to be able to achieve such a synthesis
through regio- and stereoselective alkylation of a keto
derivative of hydroxyproline (I), followed by stereoselec-
tive reduction of the keto function and displacement of a
derivative of the resulting hydroxyl group by an isopro-
jean-francois.poisson@ujf-grenoble.fr
Received July 20, 2005
A highly stereoselective synthesis of (-)-kainic acid has been
achieved in 14 steps and >7% overall yield starting from
inexpensive trans-4-hydroxy-L-proline. The key steps are
diastereoselective enolate alkylation and cuprate substitu-
tion reactions.
Isolated in 1953 from Digenea simplex,1 (-)-kainic acid
(1, Figure 1) is the parent member of the kainoid class
of marine natural products. This class of compounds
exhibits a wide range of biological activities, and mem-
bers have found use as anthelmintics and insecticides.2
Kainic acid, itself, is currently used by brain researchers
to reproduce neuronal death for the study of important
neuronal disorders such as Alzheimer’s disease and
epilepsy.3 A halt in the commercial extraction of kainic
acid in 1999 created a shortage,4a which led to the
development of numerous total syntheses, thus adding
significantly to the many already existent in 1999.5 The
natural product, however, is once again available from
algae, and the supply problem appears to be largely
resolved.4b
(5) Total synthesis of (-)-kainic acid: (a) Oppolzer, W.; Thirrring,
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) Takano, S.;
Inomata, K.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1992,
169-170. (f) Cooper, J.; Knight, D. W.; Gallagher, P. T. J. Chem. Soc.,
Perkin Trans. 1 1992, 553-559. (g) Hatakeyama, S.; Sugawara, K.;
Takano, S. J. Chem. Soc., Chem. Commun. 1993, 125-127. (h) Yoo,
S.-E.; Lee, S. H. J. Org. Chem. 1994, 59, 6968-6972. (i) Hanessian,
S.; Ninkovic, S. J. Org. Chem. 1996, 61, 5418-5424. (j) Bachi, M. D.;
Melman, A. J. Org. Chem. 1997, 62, 1896-1898. (k) Rubio, A.;
Ezquerra, J.; Escribano, A.; Rmuinan, M. J.; Vaquerro J. J. Tetrahe-
dron Lett. 1998, 39, 2171-2174. (l) Campbell, A. D.; Raynham, T. M.;
Taylor, R. J. K. J. Chem. Soc., Chem. Commun. 1999, 245-246. (m)
Cheliakov, M. V.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 11139-
11143. (n) Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000,
2, 3181-3183. (o) Miyata, O.; Ozawa, Y.; Ninomiya, I.; Naito, T.
Tetrahedron 2000, 56, 6199-6207. (p) Xia, Q.; Ganem, B. Org. Lett.
2001, 3, 485-487. (q) Clayden, J.; Menet, C. J.; Tchabanenko, K.
Tetrahedron 2002, 58, 4727-4733. (r) Montserrat Martinez, M.; Hope,
D. Eur. J. Org. Chem. 2005, 1427-1443. (s) Scott, M. E.; Lautens, M.
Org. Lett. 2005, 7, 3045-3047. Formal syntheses of (-)-kainic acid:
(t) Barco, A.; Benetti, S.; Spalluto, G. J. Org. Chem. 1992, 57, 6279-
6286. (u) Nakada, Y.; Sugahara, T.; Ogasawara, K. Tetrahedron Lett.
1997, 38, 857-860. (v) Cossy, J.; Cases, M.; Gomez Pardo, D.
Tetrahedron 1999, 55, 6153-6166. (w) Hirasawa, H.; Taniguchi, T.;
Ogasawara, K. Tetrahedron Lett. 2001, 42, 7587-7590. (x) Anderson,
J. C.; O’Loughlin, J. M. A.; Tornos, J. A. Org. Biomol. Chem. 2005, 3,
2741-2749. Racemic syntheses: (y) Yoo, S.-E.; Lee, S.-H.; Yi, K.-Y.;
Jeong, N. Tetrahedron Lett. 1990, 31, 6877-6880. (z) Monn, J. A.; Valli,
M. J. J. Org. Chem. 1994, 59, 2773-2778. (aa) Anderson, J. C.;
Whiting, M. J. Org. Chem. 2003, 68, 6160-6163. (ab) Hodgson, D. M.;
Hachisu, S.; Andrews, M. D. Org. Lett. 2005, 7, 815-817. Total
synthesis of (+)-kainic acid: (ac) Trost, B. M.; Rudd, M. T. Org. Lett.
2003, 5, 1467-1470.
Many of the successful kainic acid syntheses have
relied on a Pauson-Khand, Ireland-Claisen, ene, or
radical reaction for the formation of the C3-C4 bond with
† This paper is dedicated to a friend and colleague, Dr. Yanyun Wang,
deceased March 5, 2005.
(1) Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn.
1953, 73, 1026-1028. (-)-Kainic acid has also been isolated from
Centrocerus clavulatum (Impellizzeri, G.; Mangiafico, G.; Oriente, G.;
Piattelli, M.; Sciuto, S.; Fattorusso, E.; Magno, S.; Santacroce, C.; Sica,
D. Phytochemistry 1975, 14, 1549-1557) and from Alsidum helmitho-
corton (Balansard, G.; Pellegrini, M.; Cavalli, C.; Timon-David, P. Ann.
Pharm. Fr. 1983, 41, 77-86).
(2) For reviews on the kainoids, see: (a) Parsons, A. F. Tetrahedron
1996, 52, 4149-4174. (b) Moloney, M. G. Nat. Prod. Rep. 2002, 19,
597-616 and previous reports.
(3) (a) Gluck M. R.; Jayatilleke, E.; Shaw, S.; Rowan, A. J.;
Haroutunian, V. Epilepsy Res. 2000, 39, 63-71. (b) Hampson, D. R.;
Manalo, J. L. Nat. Toxins 1998, 6, 153-158.
(6) trans-4-Hydroxy-L-proline, however, has been employed for the
synthesis of congeners. See: Remuzon, P. Tetrahedron 1996, 52,
13803-13835.
(4) (a) Shortage of Kainic Acid Hampers Neuroscience Research.
Chem. Eng. News 2000, 78 (1), 14-15. (b) Producers Strive to Bring
Kainic Acid Back on the Market. Chem. Eng. News 2000, 78 (10), 31.
(7) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis: Construc-
tion of Chiral Molecule using Amino Acids; Wiley-Interscience: New
York, 1987.
10.1021/jo051508t CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/18/2005
10860
J. Org. Chem. 2005, 70, 10860-10863

SCHEME 1. Diastereoselective Alkylation and
Reductiona
penyl. The choice of the nitrogen protecting group loomed
crucial to the success of the approach: the N-benzoyl
enamine was known to undergo selective alkylation, but
in modest yield,8 and the N-phenylfluorenyl ketone
efficient regioselective alkylation, but with little diaste-
reoselectivity.9,10 A further consideration was that with
carbamate derivatives cuprate substitution with reten-
tion of configuration had been reported and carbamate
participation was proposed to explain the unusual
result.5aa,11
a Reaction conditions: (a) (i) MeOH, SOCl2, reflux; (ii) TMSCl,
Et3N, CH2Cl2, 35 °C, then MeOH, 0 °C, then PfBr, Pb(NO3)2, Et3N,
20 °C; (b) IBX, EtOAc, reflux. (c) n-BuLi, HMPA, THF, -78 °C,
then BrCH2CO2CH3, cat. NaI, -40 °C (dr 16:1); (d) L-Selectride,
THF, -78 °C; (e) NaBH4, EtOH, 0 °C.
Since alkylation attempts on the N-Boc ketone failed
to produce satisfactory results, the corresponding phen-
ylfluorenyl (Pf) derivative 412 was prepared (Scheme 1).
This ketone could be easily obtained from trans-4-
hydroxy-L-proline in good yield on a multigram scale by
sequential esterification (99%), phenylfluorenyl introduc-
tion (82%), and oxidation (89%). Although achievable
under Swern conditions, the oxidation was more conve-
niently carried out with IBX in refluxing ethyl acetate.13
Concordant with Sardina and co-workers’ results,10b it
was initially found that the enolate of 4 in the presence
of bromoacetate at -40 °C slowly formed the desired
alkylation product, but on prolonged reaction or allowing
the reaction mixture to warm to 0 °C, it underwent
epimerization. Fortunately, however, by keeping the
reaction temperature at -40 °C and using a catalytic
amount of sodium iodide to generate in situ the more
reactive iodoacetate, the desired trans product 5 could
be secured highly selectively (dr 16:1) and in 80% yield.14
Similar diastereoselectivity was observed with benzyl and
tert-butyl bromoacetates and methyl and allyl iodides.15
The next difficulty was to regenerate selectively the
C-4 hydroxyl group with the R configuration. Sodium
borohydride afforded the undesired C-4 S isomer as a
single product.16 L-Selectride (2.1 equiv), however, se-
lectively produced a lactol (not shown), which could be
further reduced with sodium borohydride to give cleanly
diol 6 in 70% yield on a gram scale. The use of 3 equiv of
L-Selectride led directly to the diol, but in lower yield.
The sterochemistry in diol 6 was confirmed by X-ray
analysis.17
In preparation for the upcoming cuprate substitution,
the bulky phenylfluorenyl protecting group, having played
its crucial role in the alkylation, was replaced with a
benzyloxycarbonyl (Cbz) group. This was accomplished
through palladium-catalyzed hydrogenolysis of the phen-
ylfluorenyl group in 6, followed by carbamate formation
with BCN,18 which provided 7a in 76% overall yield
(Scheme 2). Selective acetylation of the primary hydroxyl
in 7a to give 7b (82%) then allowed tosylation of the
secondary hydroxyl to be efficiently achieved through
reaction with tosylimidazole activated with MeOTf (79%).19
Treatment of the resultant tosylate 8 with sodium
hydroxide produced double ester cleavage to afford 9 in
92% yield.
The substitution reaction using a high order cyanocu-
prate proved very sensitive to reaction conditions, as
reported previously.5aa However, by strictly following the
procedure reported in the Experimental Section, repro-
ducible yields of the substitution product 10 could be
realized. The mechanism of this intriguing reaction is
unclear and deserves study.
(8) Baldwin, J. E.; Bamford, S. J.; Fryer, A. M.; Rudolph, M. P. W.;
Wood, M. E. Tetrahedron 1997, 53, 5233-5254.
(9) The N-phenylfluorenyl bromide is easily prepared from unex-
pensive starting material on a 200-g scale by a two-step procedure:
Jamison, T. F.; Lubell, W. D.; Dener, J. M.; Krische´, M. J.; Rapoport,
H. Org. Synth. 1993, 71, 220-225.
(10) (a) Sharma, R.; Lubell, W. D. J. Org. Chem. 1996, 61, 202-
209. (b) Blanco, M.-J.; Paleo, M. R.; Penide, C.; Sardina, F. J. J. Org.
Chem. 1999, 64, 8786-8793. For early references on the utility of the
phenylfluorenyl group, see: (c) Lubell, W. D.; Rapoport, H. J. Am.
Chem. Soc. 1987, 109, 236-239. (d) Lubell, W. D.; Rapoport, H. J. Am.
Chem. Soc. 1988, 110, 7447-7455.
(11) (a) Thottathil, J. K.; Moniot, J. L. Tetrahedron Lett. 1986, 27,
151-154. (b) Hashimoto, K.; Shirahama, H. Tetrahedron Lett. 1991,
32, 2625-2628.
(12) (a) Gill, P.; Lubell, W. D. J. Org. Chem. 1995, 60, 2658-2659.
(b) Blanco, M.-J.; Sardina, F. J. J. Org. Chem. 1996, 61, 4748-4755.
(13) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001-3003.
(14) Epimerization of 5 is so facile that purification on silica gel
pretreated with triethylamine (2.5%, v/v) was sufficient to produce the
cis isomer.
(15) The following yields and disatereoselectivities were obtained:
benzyl bromoacetate (92%, 14:1), tert-butyl bromoacetate (83%, 16:1),
methyl iodide (66%, 8:1), allyl iodide (80%, 14:1).
The denouement of the synthesis was straightfor-
ward: oxidation of the primary alcohol with Jones re-
(17) Crystal data for C27NO4H27‚H2O: monoclinic P21, a ) 9.921(5)
Å, b ) 27.47(1) Å, c ) 10.021(5) Å, â ) 118.67(5)°, V ) 2396(2) Å3, Z
) 4, dcalcd ) 1.241 mg/m3, F(000) ) 952.00, λ Cu KR ) 1.54178 Å, Θmax
range 3.22-74.89°, 5344 measured reflections, 4438 [R(int) ) 0.03897]
independent reflections, R(1) [1 > 2σ(I)] ) 0.0652, wR2 [all data] )
0.0924, GoF (all data) ) 1.962. The crystallographic information file
(CIF) has been deposited at the Cambridge Crystallographic Data
Centre as CCDC 276163. These data can be obtained from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CBZ 1EZ, UK.; fax (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk.
(18) Benzyl 5-norborbene-2,3-dicarboximido carbonate. Henklein, P.;
Heyne, H.-U.; Halatsch, W.-R.; Niedrich, H. Synthesis 1987, 166-167.
(19) O’Connell, J. F.; Rapoport, H. J. Org. Chem. 1992, 57, 4775-
4777.
(16) The C-4 S isomer (benzyl acetate) could be converted to diol 6
by hydrogenolysis, lactonization under Mitsunobu conditions, and
reduction.
J. Org. Chem, Vol. 70, No. 26, 2005 10861

SCHEME 2. Synthesis of (-)-Kainic Acida
organic phase was washed with brine and dried over MgSO4,
and the volatiles were removed under reduced pressure to leave
a pale yellow oil. The oil was taken up in ethanol, the solution
was cooled to 0 °C, and NaBH4 (171 mg, 4.51 mmol) was then
added. After being stirred at 0 °C for 2.0 h, the mixture was
treated with water, followed by a few drops of HCl (1 N). The
aqueous phase was extracted with EtOAc, which was washed
with brine and dried over MgSO4. The volatiles were removed
under reduced pressure. Purification of the crude product by
silica gel flash chromatography (eluent CH2Cl2/EtOAc, 3/7)
afforded diol 6 (1.25 g, 70%) as a white solid: mp 56-57 °C;
[R]20 +230 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.29
D
(m, 1H), 1.61 (m, 1H), 2.25 (m, 1H), 2.96 (d, J ) 8.8 Hz, 1H),
3.14 (dd, J ) 2.3, 11.7 Hz, 1H), 3.21 (s, 3H), 3.50 (ddd, J ) 4.0,
8.6, 10.5 Hz, 1H), 3.59 (ddd, J ) 4.7, 5.5, 10.5 Hz, 1H), 3.69 (dd,
J ) 4.7, 11.7 Hz, 1H), 4.32 (dt, J ) 2.3, 4.7 Hz, 1H), 7.23-7.61
(m, 13H); 13C NMR (75 MHz, CDCl3) δ 28.7, 48.5, 51.3, 61.2,
65.5, 71.3, 119.7, 119.9, 126.6, 127.0, 127.26, 127.34, 127.47,
127.53, 128.27, 128.32, 128.8, 139.6, 141.7, 142.9, 146.2, 147.4,
a Reaction conditions: (a) (i) H2, Pd/C, AcOH, EtOAc, 20 °C;
(ii) BCN,18 Et3N, dioxane-H2O, 20 °C; (b) AcCl, collidine, CH2Cl2,
-78 °C; (c) tosylimidazole, MeOTf, N-methylimidazole, THF, 30
°C; (d) NaOH, THF-H2O, 20 °C; (e) [CH2dC(CH3)]2CuCNLi2,
THF, -78 f 25 °C; (f) Jones reagent, acetone, 20 °C, 87%; (g)
NaOH, reflux, 86%.
176.1, 221.7; MS (ESI+) m/z 430 (MH+). Anal. Calcd for C27H27
-
NO4: C, 75.50; H, 6.34; N, 3.26. Found: C, 75.18; H, 6.43; C,
3.22.
(2S,3R,4R)-1-Benzyl 2-Methyl 4-Hydroxy-3-(2-hydroxy-
ethyl)pyrrolidine-1,2-dicarboxylate (7a). A mixture of diol
6 (1.00 g, 2.33 mmol) and 10% Pd/C (500 mg) in 0.4 mL of acetic
acid and 20 mL of ethyl acetate was placed under 5 atm of
hydrogen and stirred at 20 °C for 24 h. The reaction mixture
was filtered over Celite, which was then washed with methanol
and water. The filtrate was concentrated to dryness and the
resulting residue dissolved in 20 mL of 4:1 dioxane-water and
treated with triethylamine (1.60 mL, 11.5 mmol) followed by
BCN18 (1.40 g, 4.60 mmol). After being stirred for 24 h at 20 °C,
the mixture was treated with water and the aqueous phase was
extracted with EtOAc. The organic phase was washed with brine
and dried over MgSO4, and the volatiles were removed under
reduced pressure. Purification of the crude product by silica gel
flash chromatography (eluent EtOAc) gave the Cbz derivative
agent led in 87% yield to the corresponding acid, which
was refluxed in aqueous sodium hydroxide to afford
(-)-kainic acid (mp 239-243 °C, [R]20 -13.9 (c 0.35,
D
H2O)), indistinguishable spectroscopically and chromato-
graphically from an authentic sample of the natural
product (mp 241-243 °C, [R]20 -13.9 (c 0.31, H2O)).
D
In summary, we have described the first synthesis of
(-)-kainic acid starting from trans-4-hydroxy-L-proline.
The synthesis proceeds in >7% yield for 14 steps with
essentially total stereochemical control at the three
contiguous stereogenic centers, which places it among the
most effective reported to date. A highlight of the work
is the diastereoselective alkylation of ketone 4, the
apparent generality of which should make trans-4-
hydroxy-L-proline an even more attractive starting mate-
rial for synthesis.
7a (574 mg, 76%, two steps) as a thick oil: [R]20 -29.5 (c 1.0,
D
CHCl3); 1H NMR (300 MHz, CDCl3, mixture of rotamers) δ 1.80-
1.98 (m, 2H), 2.22-2.30 (m, 1H), 3.51 (s, 1.5H), 3.60-3.70 (m,
2.5H), 3.75 (s, 1.5H), 3.76-3.85 (m, 1.5H), 4.07 (d, J ) 9.2 Hz,
0.5H), 4.10 (d, J ) 9.1 Hz, 0.5H), 4.37 (m, 1H), 4.96 (A of AB q,
J ) 13.7 Hz, 0.5H), 5.09 (app d, J ) 1.5 Hz, 1H), 5.19 (B of AB
q, J ) 13.7 Hz, 0.5H), 7.27-7.35 (m, 5H); 13C NMR (75 MHz,
CDCl3, mixture of rotamers) δ 29.0, 48.2, 48.9, 52.0, 52.3, 54.4,
54.8, 60.8, 60.9, 62.9, 63.2, 67.2, 67.3, 70.4, 71.3, 127.8, 127.9,
128.3, 128.4, 136.2, 136.3, 154.4, 154.9, 173.0, 173.2; MS (ESI+)
m/z 346 (M + Na)+. Anal. Calcd for C16H21NO6‚0.5H2O: C, 57.82;
H, 6.67; N, 4.21. Found: C, 57.87; H, 6.69; N, 4.15.
Experimental Section
(2S,3R)-Methyl 3-(2-Methoxy-2-oxoethyl)-4-oxo-1-(9-phen-
yl-9H-fluoren-9-yl)pyrrolidine-2-carboxylate (5). A solution
of n-butyllithium (1.6 M in hexane, 3.4 mL, 5.5 mmol) was added
dropwise to a solution of ketone 412 (2.00 g, 5.22 mmol) in 10
mL of THF and 2.0 mL of HMPA at -78 °C under argon. The
resulting solution was stirred at -78 °C for 0.5 h and then
rapidly transferred with a cannula to a solution of sodium iodide
(240 mg, 1.60 mmol) and methyl bromoacetate (1.50 mL, 15.84
mmol) in 10 mL of THF at -55 °C. The reaction mixture was
allowed to warm to -40 °C, stirred for an additional 1.0 h, and
then treated with 10 mL of a 30% aqueous solution of H3PO4.
Water (10 mL) was added, and the aqueous phase was extracted
with EtOAc, which was washed with water and brine and dried
over MgSO4. The volatiles were removed under reduced pres-
sure. Purification of the crude product by silica gel flash
chromatography (eluant hexane/EtOAc, 7/3) gave keto diester
5 (1.89 g, 80%, dr 16:1) as a pale yellow oil. The spectral data
were in accord with the literature values.10b
(2S,3R,4R)-Methyl 4-Hydroxy-3-(2-hydroxyethyl)-1-(9-
phenyl-9H-fluoren-9-yl)pyrrolidine-2-carboxylate (6). A
solution of L-Selectride (1 M in THF, 8.7 mL, 8.7 mmol) was
added to a solution of keto diester 5 (1.89 g, 4.15 mmol) in THF
at -78 °C under argon. The reaction mixture was stirred for 1
h at -78 °C and then treated with 3 N NaOH (2.9 mL, 8.7 mmol),
followed by 30% H2O2 (2.9 mL, 26.1 mmol), and allowed to warm
to 20 °C. After the mixture was stirred for 15 min, water was
added and the aqueous phase extracted with ethyl acetate. The
(2S,3R,4R)-1-Benzyl 2-Methyl 3-(2-Acetoxyethyl)-4-(tos
yloxy)pyrrolidine-1,2-dicarboxylate (8). Methyl triflate (0.278
mL, 2.46 mmol) was added dropwise to tosylimidazole (556 mg,
2.50 mmol) in 7 mL of THF at 0 °C under argon. After being
stirred for 5 min, a solution of acetate 7b (415 mg, 1.14 mmol)
and N-methylimidazole (0.200 mL, 2.51 mmol) in 7 mL of THF
was added. The reaction mixture was warmed to 30 °C and
stirred for 72 h. The reaction was then quenched by addition of
a 5% solution of aqueous KHSO4, diluted with water, and
extracted with EtOAc. The organic phase was washed brine and
dried over MgSO4, and the volatiles were removed under reduced
pressure. The crude product was purified by flash silica gel
chromatography (eluent EtOAc/hexane, 6/4 to 1/1) to afford
tosylate 8 (464 mg, 79%) as a white powder: mp 91.5 °C; [R]20
D
+49.0 (c 1.0, CHCl3); IR 2957, 1732, 1711, 1417, 1360, 1240,
1170, 896 cm-1; 1H NMR (300 MHz, CDCl3, mixture of rotamers)
δ 1.80-2.00 (m, 2H), 2.04 (s, 1.5H), 2.05 (s, 1.5H), 2.37-2.54
(m, 1H), 2.44 (s, 1.5H), 2.48 (s, 1.5H), 3.50 (s, 1.5H), 3.59 (dd, J
) 3.2, 9.7 Hz, 0.5H), 3.63 (dd, J ) 3.2, 9.5 Hz, 0.5H), 3.71-3.85
(m, 1H), 3.78 (s, 1.5H), 3.99 (dq, J ) 1.4, 6.2 Hz, 2H), 4.06 (d, J
) 9.7 Hz, 0.5H), 4.11 (d, J ) 9.5 Hz, 0.5H), 4.98 (A of AB q, J )
12.2 Hz, 0.5H), 5.07 (app t, J ) 3.7 Hz, 1H), 5.08 (A′ of A′B′ q,
J ) 12.5 Hz, 0.5H), 5.13 (B′ of A′B′ q, J ) 12.5 Hz, 0.5H), 5.18
(B of AB q, J ) 12.2 Hz, 0.5H), 7.28-7.41 (m, 7H), 7.76 (d, J )
8.4 Hz, 1H), 7.80 (d, J ) 8.3 Hz, 1H); 13C NMR (75 MHz, CDCl3,
10862 J. Org. Chem., Vol. 70, No. 26, 2005

mixture of rotamers) δ 20.8, 21.6, 25.6, 44.7, 45.6, 52.2, 52.3,
52.5, 52.6, 61.2, 61.3, 62.2, 62.5, 67.4, 67.5, 79.5, 80.0, 127.6,
127.7, 127.8, 127.9, 128.1, 128.4, 128.5, 130.0, 130.1, 133.3, 133.4,
135.9, 136.1, 145.4, 145.5, 153.6, 154.2, 170.7, 172.0, 172.2; MS
(CI+) m/z 537 (M + NH4)+. Anal. Calcd for C25H29NO9S: C, 57.79;
H, 5.63; N, 2.70. Found: C, 57.50; H, 5.61; N, 2.66.
adduct 10 (115.8 mg, 54%, 64% brsm) as a clear oil and a second,
blue product, which gave acid 9 (42.8 mg, 15% recovery) after
base-acid extraction. The spectroscopic data of 10 ([R]20D -51.5
(c 1.0, CHCl3) were in full agreement with those reported.5aa
(2S,3S,4S)-4-(Prop-1-en-2-yl)pyrrolidine-2,3-dicarboxy-
lic Acid ((-)-Kainic Acid) (1). The final hydrolysis was
performed as previously described:5aa 86% yield; [R]20D -13.9 (c
0.35, H2O). The synthetic material was spectroscopically and
chromatographically identical with an authentic sample of the
natural product obtained from a commercial source.
(2S,3S,4S)-1-(Benzyloxycarbonyl)-3-(hydroxymethyl)-4-
(prop-1-en-2-yl)pyrrolidine-2-carboxylic Acid (10). The pub-
lished procedure5aa was slightly modified. tert-Butyllithium (1.7
M in pentane, 7.50 mL, 12.7 mmol) was added dropwise to a
solution of freshly distilled 2-bromopropene (0.567 mL, 6.4 mmol)
in 30 mL of THF under argon, while the internal temperature
was maintained below -70 °C. The reaction mixture was stirred
at this temperature for an additional 0.5 h and then rapidly
transferred with a cannula to a suspension of 286 mg (3.2 mmol)
of CuCN (99.99%, dried twice by warming under high vacuum
and then kept under argon) in 3 mL of THF at -78 °C. The
resulting mixture was stirred for 5 min, after which time it was
allowed to warm until complete dissolution of the CuCN (ca. 2
min at -30 °C), which produced a pale yellow, homogeneous
solution. A solution of acid 9 (296 mg, 0.64 mmol) in 3 mL of
THF was then added at -78 °C, and the reaction mixture was
stirred for 5 min before being allowed to warm to 25 °C. After
2.0 h, the reaction mixture was treated with dilute HCl and
diluted with water. The aqueous phase was extracted with
EtOAc, which was washed with brine and dried over MgSO4.
The volatiles were removed under reduced pressure. The crude
product was purified by flash silica gel chromatography (gradient
hexane/EtOAc/AcOH, 49.5/49.5/1 to EtOAc/AcOH, 99/1) to give
Acknowledgment. We are grateful to Prof. P. Dumy
for his interest in our work, Drs. C. Philouze and A.
Durif for the X-ray structure determination, Prof. J. C.
Anderson for his most useful advice on the crucial
cuprate reaction, and a reviewer for helpful comments.
We are also grateful to the French Ministry for a
Chateaubriand Fellowship (to A.O.) and the Universite´
Joseph Fourier and the CNRS (UMR 5616, FR 2607)
for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 7b and 9;
1H and 13C NMR spectra for compound 7b; CIF and ORTEP
diagram for compound 6. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO051508T
J. Org. Chem, Vol. 70, No. 26, 2005 10863