Stereoselective synthesis of (-)-α-kainic acid and (+)-α-allokainic acid via trimethylstannyl-mediated radical carbocyclization and oxidative destannylation

Article abstract of DOI:10.1021/jo9604088

(-)-α-Kainic acid (1) and its C4 epimer (+)-α-allokainic acid (2) have been prepared from L-serine. The requisite stereochemical array in (-)-α-kainic acid (1) was introduced using a trimethylstannyl radical carbocyclization of a diene, which gave the 2,3-trans/3,4-cis and 2,3-trans/3,4-trans componnds in a 2.8:1 ratio and in high yield. The destannylation of the trisubstituted pyrrolidine nucleus was achieved via an oxidative cleavage of the C-Sn bond with ceric ammonium nitrate. This provided a dimethyl acetal that was further transformed into the intended α-kainic acid. When the same radical carbocyclization was attempted on a triene, the 2,3-trans/3,4-trans and the 2,3-trans/3,4-cis adducts were obtained in a 2.5:1 ratio, respectively. This approach was used to synthesize (+)-α-allokainic acid.

Full text of DOI:10.1021/jo9604088

5418
J . Org. Chem. 1996, 61, 5418-5424
Ster eoselective Syn th esis of (-)-r-Ka in ic Acid a n d (+)-r-Allok a in ic
Acid via Tr im eth ylsta n n yl-Med ia ted Ra d ica l Ca r bocycliza tion a n d
Oxid a tive Desta n n yla tion
Stephen Hanessian* and Sacha Ninkovic
Department of Chemistry, Universite´ de Montre´al, P.O. Box 6128, Station Centre-ville,
Montre´al P.Q., Canada, H3C 3J 7
Received February 28, 1996X
(-)-R-Kainic acid (1) and its C4 epimer (+)-R-allokainic acid (2) have been prepared from L-serine.
The requisite stereochemical array in (-)-R-kainic acid (1) was introduced using a trimethylstannyl
radical carbocyclization of a diene, which gave the 2,3-trans/3,4-cis and 2,3-trans/3,4-trans
compounds in a 2.8:1 ratio and in high yield. The destannylation of the trisubstituted pyrrolidine
nucleus was achieved via an oxidative cleavage of the C-Sn bond with ceric ammonium nitrate.
This provided a dimethyl acetal that was further transformed into the intended R-kainic acid. When
the same radical carbocyclization was attempted on a triene, the 2,3-trans/3,4-trans and the 2,3-
trans/3,4-cis adducts were obtained in a 2.5:1 ratio, respectively. This approach was used to
synthesize (+)-R-allokainic acid.
The marine product (-)-R-kainic acid (1)1 has attracted
considerable interest since it was first isolated by Take-
moto in 1953,1a principally because of its potent neu-
rotransmitting activity in the central nervous system2
(Figure 1). Other naturally occurring kainoids, like
acromelic acid3 and domoic acid,4 possess powerful bio-
logical properties as well, and they seem to exert their
action by mimicking glutamic acid.2a,5 Several total
syntheses of such kainoids have been achieved during
the last decade.3b-d,4c,d,6
Oppolzer's enantioselective synthesis of R-kainic acid6l
by an intramolecular ene reaction stands as the first and,
as yet, the most efficient approach in terms of steps and
overall yields (10 steps, 4.8% overall yield starting from
ethyl glutamate). This work also led to the unequivocal
establishment of absolute configuration of R-kainic acid.
A related synthesis of allokainic acid was also reported
by Oppolzer and co-workers.6f More recently, Baldwin
and co-workers have reported the synthesis of several
kainoids using a cobalt-mediated free radical intramo-
lecular cyclization reaction.3d,6h,k The intramolecular
Pauson-Khand reaction6a,d,f and a tandem Micheal
F igu r e 1.
reaction7b were also used for the construction of the C3-
C4 bond. An interesting approach that involves the
simultaneous formation of C2-C3 and C4-C5 bonds
utilizes an intramolecular azomethine ylide cycloaddition
X Abstract published in Advance ACS Abstracts, J uly 1, 1996.
(1) Isolation from Digenea simplex : (a) Murukami, S.; Takemoto,
T.; Shimizu, Z. J . Pharm. Soc. J pn. 1953, 73, 1026. (b) Morimoto, H.
J . Pharm. Soc. J pn. 1955, 75, 766, 937. (c) Watase, H. Bull. Chem.
Soc. J pn. 1958, 31, 932 and references cited therein. Isolation from
Centocerus clavulatrum: (d) Impellizzeri, G.; Mangiafico, S.; Oriente,
G.; Piatelli, M.; Sciuto, S. Santacroce, C.; Sico, D. Phytochemistry 1975,
14 , 1549. Isolation from Alsidium helmintrocarton: (e) Balansard, G.;
Gayte-Sorbier, A.; Cavalli, C. Ann. Pharm. Fr., 1982, 40, 527.
(2) (a) Kainic Acid as a Tool in Neurobiology; McGeer, E. G., Olney,
J . W., McGeer, P. L., Eds.; Raven Press: New York, 1978. (b) Ishida,
M.; Shinozaki, H. Brain Res. 1988, 474, 386.
(3) Isolation: (a) Konno, K.; Shirahama, H.; Matsumoto, T. Tetra-
hedron Lett. 1983, 24, 939. Synthesis: (b) Konno, K.; Hoshimoto, K.;
Ohfune, Y.; Shirahama, H.; Matsumoto, T. J . Am. Chem. Soc. 1988,
100, 4807. (c) Fushija, S.; Sato; Kanazawa, T.; Kusana, G.; Nozoe, S.
Tetrahedron Lett. 1990, 31, 3901. (d) Baldwin, J . E.; Li, C.-S. J . Chem.
Soc., Chem. Commun. 1988, 261.
(4) Isolation: (a) Daigo, K. J . Pharm. Soc. J pn. 1959, 79, 350. (b)
Takemoto, T.; Daigo, K.; Kondo, Y.; Kondo, K. J . Pharm. Soc. J pn.
1966, 86, 874. Synthesis: (c) Ohfune, Y.; Tomita, M. J . Am. Chem.
Soc. 1982, 104, 3511. (d) Maeda, M.; Kodama, T.; Tanoka, T.;
Yashimuzu, H.; Takemoto, T.; Nomoto, K.; Fujito, T. Tetrahedron Lett.
1987, 28, 633.
(5) (a) Glutamate: Transmitter in the Central Nervous System;
Roberts, P. J ., Storm-Mathesen, J ., J ohnson, G. A. R., Eds.; Wiley: New
York, 1981. (b) Goldberg, O.; Luini, A.; Teichberg, V. I. J . Med. Chem.
1983, 26, 39.
that generates three chiral centers in a single step.6j
A
number of other approaches have been reported.8 The
above cited syntheses have involved 10-21 steps in
overall yields ranging from 0.7% to 6%. The synthesis
(6) (a) Yoo, S.; Lee, S. H. J . Org. Chem. 1994, 59, 6968. (b) (Racemic)
Monn, J . A.; Valli, M. J . J . Org. Chem. 1994, 59, 2773. (c) Hatakeyama,
S.; Sugawara, K.; Takano, S. J . Chem. Soc., Chem. Commun. 1993,
125. (d) Yoo, S.-E.; Lee, S-H.; J eong, N.; Cho, I. Tetrahedron Lett. 1993,
34, 3435. (e) Cooper, J .; Knight, D. W.; Gallagher, P. T. J . Chem. Soc.,
Perkin Trans. 1 1992, 553. (f) Takano, S.; Inomata, K.; Ogasawara, K.
J . Chem. Soc., Chem. Commun. 1992, 169. (g) Yoo, S.-E.; Lee, S.-H.;
Yi, K.-Y.; J eong, N. Tetrahedron Lett. 1990, 31, 6877. (h) Baldwin, J .
E.; Moloney, M. G.; Parsons, A. F. Tetrahedron 1990, 46, 7263. (i)
Takano, S.; Sugihara, T.; Shigeki, S.; Ogasawara, K. J . Am. Chem.
Soc. 1988, 110, 6467. (j) Takano, S.; Iwabuchi, Y.; Ogasawara, K. J .
Chem. Soc., Chem. Commun. 1988, 1204. (k) Baldwin, J . E.; Li, C.-S.
J . Chem. Soc., Chem. Commun. 1987, 166. (l) Oppolzer, W.; Thirring,
K. J . J . Am. Chem. Soc. 1982, 104, 4978. (m) For reviews see: Synthesis
of Optically Active R-Amino Acids; Williams, R. M., Ed.; Pergamon
Press: New York, 1989; pp 305-380. Parsons, A. F. Tetrahedron 1996,
52, 4145.
S0022-3263(96)00408-2 CCC: $12.00 © 1996 American Chemical Society

Synthesis of (-)-R-Kainic Acid and (+)-R-Allokainic Acid
J . Org. Chem., Vol. 61, No. 16, 1996 5419
Sch em e 1
of allokainic acid 2 has also been the subject of several
reports,6c,g,k,7 mostly in conjunction with methods in-
tended for the synthesis of R-kainic acid itself.
Resu lts a n d Discu ssion
Of the above-mentioned total syntheses of R-kainic acid
and allokainic acid, three use a free-radical carbocycliza-
tion strategy6c,h,k to construct the heterocyclic ring system.
Our approach to the trisubstituted pyrrolidine ring
comprising the kainic acids relied on the trimethylstan-
nyl-mediated carbocyclization of terminal dienes and
related systems, followed by a chemoselective oxidative
cleavage of the C-Sn bond.9 A disconnective analysis is
shown in Figure 1 for R-kainic acid. Past experience in
our group9,10 has shown that such free-radical carbocy-
clizations favor the cis-stereochemistry at the newly
formed bond, which argued well for the R-kainic acid
series. The prospects of internal stereochemical control
by a resident group on an adjacent stereogenic center
during the radical-induced carbocyclization was expected
to offer an added element of interest in overall stereose-
lectivity.
The synthesis commenced with L-serine, which was
transformed into compound 6 in a four-step procedure
without the need for purification (Scheme 1). Formation
of the oxazolidinone ring as well as in situ N-allylation
was efficently carried out leading to 7. It is noteworthy
that when a tert-butyldiphenylsilyl ether was used
instead of the MOM protecting group, racemization
occurred during the formation of the oxazolidinone ring.
This is most probably due to a 1,3-silyl shift in a
precursor related to 6 prior to ring formation. Depro-
tection of 7 and Swern oxidation of the resulting alcohol,
followed by a Wittig olefination,11 gave the chiron 9,
which was subjected to carbocyclization.
When diene 9 was treated with trimethyltin hydride
generated under Stork’s conditions,12 the resulting mix-
ture of stannylated compounds was obtained in only 50%
yield, favoring the cis stereochemistry at the C3-C4
centers in a ratio of 2.8:1. However, a slow addition of
sodium cyanoborohydride over a period of 1 h to a
refluxing solution containing the substrate 9 and trim-
ethyltin chloride afforded the cyclized products 10 and
its C4 isomer as an inseparable mixture in 88% yield
without compromising the cis/ trans ratio. We have
previously shown9,10 that the carbon-tin bond in alkyl-
trimethylstannanes can be selectively cleaved in the
presence of ceric ammonium nitrate (CAN) to give an
aldehyde or its dialkyl acetal from the carbon atom
bearing the longer alkyl chain. In the present case,
treatment of the mixture containing 10 and its C4 isomer
with excess CAN in methanol gave the dimethyl acetals
11 and 12 in 38% and 14% yields, respectively, after
chromatographic separation. It is of practical importance
to point out that the cis/ trans ratio was maintained in
the products 11 and 12 during the oxidative cleavage.
The in situ transformation of the initially formed alde-
hyde into the corresponding dimethyl acetals is a form
of temporary protection from the risk of epimerization.
Nevertheless, the problem of epimerization emerged
during the deprotection of the acetal and its further
elaboration into the intended 2-propenyl side chain. Our
initial attempts to obtain the desired aldehyde 13 using
TsOH or SnCl2‚H2O13 led in fact to epimerization at the
C4 center. However, treatment of 11 with bromodim-
ethylborane14 at -78 °C for 30 min led to the aldehyde
13 in quantitative yield based on the crude product
without any detectable epimerization. Treatment of 13
(7) (a) Agami, C.; Cases, M.; Couty, F. J . Org. Chem. 1994, 59, 7937.
(b) Barco, A.; Benetti, S.; Pollini, G. P.; Spalluto, G.; Casolari, A.;
Zanirato, V. J . Org. Chem. 1992, 57, 6279. (c) Murakami, M.;
Hasegawa, N.; Hayashi, M.; Ito, Y. J . Org. Chem. 1991, 56, 7356. (d)
Mooiweer, H. H.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1991,
47, 3451 and references cited therein. (e) De Shong, P.; Kell, D.
Tetrahedron Lett. 1986, 27, 3979. (f) Oppolzer, W.; Robbiani, C.; Ba¨ttig,
K. Tetrahedron 1984, 40, 1391. (g) Kraus, G. A.; Nagy, J . O. Tetrahe-
dron Lett. 1983, 24, 3427.
(8) (a) Yoo, S.-E.; Lee, S.-H.; Kim, N.-J . Tetrahedron Lett. 1988, 29,
2195. (b) Kraus, G. A.; Nagy, J . O. Tetrahedron 1985, 41, 3537. (c)
Husinec, S.; Porter, A. E. A.; Roberts, J . S.; Strachan, C.-H. J . Chem.
Soc., Perkin Trans. 1 1984, 2517. (d) Kennewell, P. D.; Matharu, S.
S.; Taylor, J . B.; Sammes, P. G. J . Chem. Soc., Perkin Trans. 1 1980,
2542.
(9) Hanessian, S.; Leger, R. J . Am. Chem. Soc. 1992, 114, 3115.
(10) Hanessian, S.; Leger, R. Synlett 1992, 402.
(11) Ireland, R. E.; Norbeck, D. W. J . Org. Chem. 1985, 50, 2198.
(12) Stork, G.; Sher, P. M. J . Am. Chem. Soc. 1986, 108, 303.
(13) Ford, K. L.; Roskamp, E. J . Tetrahedron Lett. 1992, 33 , 1135.
(14) Guindon, Y.; Yoakim, C.; Morton, H. E. J . Org. Chem. 1984,
49, 3912.

5420 J . Org. Chem., Vol. 61, No. 16, 1996
Hanessian and Ninkovic
Sch em e 2
under the mildest possible conditions with methylmag-
nesium chloride or methyllithium led to addition ac-
companied by epimerization at C4. We were successful
in obtaining the intended methyl carbinol 14 in 65% yield
using the less basic and more oxophilic methyl cerium
chloride.15 Oxidation of alcohol 14 with tetra-n-propy-
lammonium perruthenate16 afforded ketone 15, which
could be purified by chromatography without any detect-
able epimerization at C-4. There remained to effect a
methylenation reaction on 15 in order to complete the
elaboration of the side chain. Wittig reactions are known
to produce significant epimerization on analogous
ketones.6b In a thiazolium ylide approach to racemic
R-kainic acid, Monn and Valli6b were able to avoid
epimerization by using the nonbasic Nozaki reagent,17
CH2I2-Zn-TiCl4. Thus, when ketone 15 was treated
with this reagent combination in THF at 0 °C, compound
16 was formed in excellent yield without evidence of
formation of the trans C3/C4 allokainate diastereoisomer.
Although 16 has already been synthesized by Baldwin
and co-workers,6h no spectral data were reported since
the mentioned compound was isolated as a mixture of
its C4 isomers and purified at a later stage. We were
able to obtain 16 as a crystalline solid and to characterize
it by NOE as well as by X-ray crystallography. Cleavage
of the oxazolidinone ring in 16 was effected with aqueous
base with simultaneous removal of the tert-butyl ester
essentially as described by Baldwin.6h At this juncture
in the synthesis, it was necessary to protect the nitrogen
atom as the tert-butyloxycarbonyl derivative before oxi-
dation of the primary hydroxyl group.
The oxidation of 17 has been previously carried out
using PDC at 60 °C.6h In our case, we opted for a J ones
oxidation at 0 °C, which after esterification with diaz-
omethane afforded 18 in 57% overall yield. Hydrolysis
of the N-Boc group and the ester function afforded
crystalline (-)-R-kainic acid (1).
An alternative route to the kainoid skeleton was sought
on the basis of the trimethyltin carbocyclization of a
terminal diene, which would directly lead to a methyl
ketone by oxidative cleavage of an intermediate olefin.
Thus, triene 21 was synthesized essentially by the same
reaction sequence used for the preparation of 9 from
L-serine as shown in Scheme 2. N-Alkylation with
5-bromo-3-methylpenta-1,3-diene gave the diene 19, which
was deprotected in the presence of bromotrimethylsi-
lane.18 Oxidation of the resulting alcohol 20 and chain
extension then gave the triene intermediate 21.
When triene 21 was subjected to the trimethyltin
radical addition-carbocyclization conditions, compound
22 and its C4 isomer were isolated in 52% yield as a 2.5:1
ratio, favoring the all-trans stereochemistry. The ster-
eochemistry of the double bond was ascertained by NMR
studies. Ozonolyzis afforded the ketones 23 and 24 in
47% and 22% yield, respectively, after separation by
column chromatography. Ketone 24 could then be epimer-
ized to the all-trans isomer 23 in high yield by treatment
with DBU. Methylenation of 23 gave the olefin 25 in
excellent yield. The remainder of the sequence was
similar to that of 1 and proceeded uneventfully to give
intermediate 26, which was further transformed to (+)-
allokainic acid.
Although the preponderance of the cis-isomer in the
carbocyclization of 9 can be rationalized on the basis of
a favored early transition state19 (Figure 2A), the reversal
in stereochemistry in the case of diene 21, which affords
the trans isomer 22 as the major product, is less evident.
It is likely that the cisoid and transoid disposition of the
allylic trimethyltin branch affect the relative reactivity
of the ensuing radicals in the corresponding transition
states. The thermodynamically more stable all-trans
product could thus predominate in the mixture of isomers
contained in 22 as depicted in Figure 2B.
We have described the synthesis of (-)-R-kainic acid
(1) and (+)-allokainic acid (2) in 2% and 3% overall yields,
respectively, from L-serine based on a novel free-radical
carbocyclization route comprising less then 20 steps in
each case. Related studies involving the synthesis of
unnatural, conformationnally constrained bicyclic kain-
oids will be reported in due course.
Exp er im en ta l Section 20
Gen er a l P r oced u r e. All reactions were carried out under
a positive atmosphere of dry argon unless otherwise indicated.
Solvents were distilled prior to use: THF and Et2O were
(15) (a) Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett.
1984, 25, 4233. (b) Imamoto, T.; Takiyama, N.; Nakamura, K.;
Hatayima, T.; Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392.
(16) (a) Griffith, W. P.; Ley, S. V.; Whitecombe, G. P.; White, A. D.
J . Chem. Soc., Chem. Commun. 1987, 1625. (b) Griffith, W. P.; Ley, S.
V. Aldrichim. Acta 1990, 23, 13.
(17) (a) Hibino, J .-I.; Okazoe, T.; Kazuhiko, T.; Nozaki, H. Tetrahe-
dron Lett. 1985, 26, 5579. (b) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki,
H. Tetrahedron Lett. 1978, 27, 2417.
(19) (a) Beckwith, A. L. J .; Blair, I.; Phillipou, G. J . Am. Chem. Soc.
1973, 96, 1614. (b) Beckwith, A. L. J . Tetrahedron 1981, 37, 3073. (c)
Rajanbabu, T. V. Acc. Chem. Res. 1991, 24, 139. (d) Giese, B. Radicals
in Organic Synthesis: Formation of Carbon-Carbon Bonds; Baldwin,
J . E., Ed.; Pergamon Press: Toronto, 1986.
(20) 1H and 13C NMR spectra were determined at 300 and 400 MHz.
For typical experimental protocols, see: Hanessian,S.; Benalil, A.;
Laferrie`re, C. J . Org. Chem. 1995, 60, 4786.
(18) Hanessian, S.; Delorme, D.; Dufresne, Y. Tetrahedron Lett.
1984, 25, 2515

Synthesis of (-)-R-Kainic Acid and (+)-R-Allokainic Acid
J . Org. Chem., Vol. 61, No. 16, 1996 5421
g, 122 mmol) in THF (0.3 M, 300 mL) at 0 °C was added over
10 min a solution of 6 (12 g, 51 mmol in 50 mL of THF). The
reaction mixture was stirred at room temperature for 15 h,
after which time freshly distilled allyl bromide (3 equiv, 13
mL) was added and the solution was stirred for another 15 h
at room temperature. Quenching with NH4Cl (saturated) (50
mL) and usual workup as described above gave a syrup that
was chromatographed (50% ethyl acetate in hexane) to afford
9.54 g (93%) of 7: [R]D -30.2° (c 1.0, CHCl3); 1H NMR (CDCl3)
δ 5.82-5.68 (m, 1H), 5.25-5.17 (m, 2H), 4.58 (s, 2H), 4.34 (dd,
1H, J ) 8.8 and 8.7 Hz), 4.15-4.08, 3.95-3.87 and 3.67-3.52
(m, 6H), 3.32 (s, 3H); 13C NMR (CDCl3) δ 157.9, 132.1, 118.3,
96.5, 66.4, 64.8, 45.0, 55.5, 54.1; IR υmax 2890, 1720, 1390, 1200,
1100-1000, 890, 740 cm-1; HRMS for C9H15O4N calcd 201.1003,
found 201.1001.
(4S)-3-Allyl-4-(h yd r oxym eth yl)oxa zolid in -2-on e (8). To
a solution of oxazolidinone 7 (2.79 g, 13.9 mmol) in THF (1.3
mL) and water (12 mL) was slowly added a solution of 6 N
HCl (28 mL). The mixture was stirred at 40 °C for 5 h and
then poured into an equal volume of brine. Extraction with
dichloromethane (10 × 40 mL) and ethyl acetate (5 times, 40
mL), drying over MgSO4, and chromatography (ethyl acetate)
gave alcohol 8 (2.1 g, 96%): [R]D -44.1° (c 1.0, CHCl3); 1H NMR
(CDCl3) δ 5.79-5.71 (m, 1H), 5.29-5.20 (m, 2H), 4.34 (dd, 1H,
J ) 8.9, 8.8 Hz), 4.23 (dd, 1H, J ) 8.7, 5.8 Hz), 4.12-4.05,
3.87-3.66 (m, 4H), 3.60 (dd, 1H, J ) 11.9, 3.2 Hz), 3.30-3.10
(broad s, 1H); 13C NMR (CDCl3) δ 158.2, 131.6, 118.0, 64.3 and
59.7, 55.4, 44.3; IR υmax 3380, 2880, 1420, 1230, 1060, 1015,
945, 905, 740 cm-1; HRMS for C7H11O3N + H calcd 158.0817,
found 158.0812; MS (FAB+) m/ z 158 (M+ + H). Anal. Calcd
for C7H11NO3: C, 53.49; H, 7.05; N, 8.91. Found: C, 53.49;
H, 7.26; N, 8.87.
F igu r e 2.
distilled from sodium benzophenenone; CH2Cl2 was distilled
from CaH2. All new compounds are homogeneous on TLC, and
their purities were further verified by 1H NMR at 300 and 400
MHz and by 13C NMR spectroscopy at 75 MHz. Optical
rotations were recorded at 22 °C.
(4S)-3′-(3-Allyl-2-oxooxa zolid in -4-yl)a cr ylic Acid ter t-
Bu tyl Ester (9). To a solution of oxalyl chloride (0.67 mL,
1.15 equiv) in dichloromethane (20 mL) at -65 °C was added
freshly distilled DMSO (1.13 mL, 2.4 equiv in 5 mL of CH2-
Cl2) over 2 min, and the reaction mixture was stirred for 5
more min at the same temperature. The alcohol 8 (1.04 g. in
5 mL of CH2Cl2) was then added into the reaction mixture over
5 min, and the stirring was continued for another 20 min after
which triethylamine (3.7 mL, 4 equiv) was added and the
solution brought to -15 °C over 1.5 h. [(tert-Butoxycarbonyl)-
methylene]triphenylphosphorane (3.5 g, 1.4 equiv in 5 mL of
CH2Cl2) was added to the mixture, and the temperature was
allowed to reach 25 °C over 1.5 h. The reaction mixture was
poured into brine (30 mL), and the solution was extracted with
CH2Cl2 (3 × 50 mL), dried over MgSO4, and chromatographed
using 40% ethyl acetate in hexane to afford diene 9 (1.43g,
(2S )-2-[(t er t -B u t o x y c a r b o n y l)a m in o ]-3-(m e t h o x y -
m eth oxy)p r op ion ic Acid Meth yl Ester (5). To a solution
of N-(tert-butoxycarbonyl)-L-serine methyl ester (4) (40 g) in
dichloromethane (300 mL) at 0 °C were slowly added diiso-
propylethylamine (65 mL, 2 equiv) and a solution of meth-
oxymethyl chloride (27.7 mL, 2 equiv) in dichloromethane (50
mL, over 20 min). The reaction mixture was stirred at room
temperature for 18 h and then diluted with water (100 mL).
The mixture was then poured into a separatory funnel
containing ethyl acetate (800 mL), and the organic phase was
washed with 5% HCl (100 mL), saturated NaHCO3 (100 mL),
and brine (100 mL), dried over MgSO4, and concentrated to
afford crude 5 (45 g). Flash chromatography (30% ethyl
acetate in hexane) gave 5 as an oil: [R]D +5.9° (c 1.0, CHCl3);
1H NMR (CDCl3) δ 5.43 (d, 1H, J ) 8.3 Hz), 4.46 (s, 2H), 4.34-
4.31 (m, 1H), 3.86 (dd, 1H, J ) 10.2 and 3.3 Hz), 3.64-3.59
(m, 4H), 3.19 (s, 3H), 1.32 (s, 9H); 13C NMR (CDCl3) δ 170.7,
155.1, 96.3, 79.5, 67.7, 54.9, 53.7, 52.0, 28.0 ; IR (neat) υmax
1
85%): [R]D +2.3° (c 1.4, CHCl3); H NMR (CDCl3) δ 6.52 (dd,
1H, J ) 15.6, 8.2 Hz), 5.84 (d, 1H, J ) 15.6 Hz), 5.70-5.57
(m, 1H), 5.15-5.07 (m, 2H), 4.40-4.25, 4.06-3.99, 3.92, 3.41
(m, m, dd and dd 5H, first dd: J ) 8.2, 5.7 Hz, second dd: J
) 15.6, 7.5 Hz), 1.39 (s, 9H); 13C NMR (CDCl3) δ 163.9, 157.9,
141.0, 131.2, 127.7, 118.8, 81.0, 66.1, 55.8, 44.7, 27.7; IR υmax
2990, 2930, 1760, 1715, 1410, 1370, 1305, 1255, 1225, 1155,
1060, 980, 930, 850, 765 cm-1; MS (FAB+) m/ z 254 (M+ + H),
198 (M+ + H - CdC(CH3)2).
3300, 2900, 1700, 1575, 1350, 1140, 1090, 1010, 900 cm-1
;
HRMS calcd for C11H22O6N + H 264.1447, found 264.1432; MS
(CI, isobutane) m/ e 208.1 (M+ - (CH3)2CdCH2), 164.1 (M+
(CH3)2CdCH2 - CO2), 132.1 (M+ - (CH3)2CdCH2 - CO2
MeOH).
-
-
(7S ,8S )-3-O x o -6-[(t r im e t h y ls t a n n y l)m e t h y l]t e t r a -
h yd r op yr r olo[1,2-c]oxa zol-7-yl]a cetic Acid ter t-Bu tyl Es-
ter (10). To a refluxing solution of diene 9 (1.24 g) and
trimethyltin chloride (1.28 g, 1.3 equiv) in 2-methyl-2-propanol
(85 mL) were added a solution of sodium cyanoborohydride
(1.28 g, 4.1 equiv) with a syringe pump and AIBN (90 mg, 10%)
in methanol (15 mL) over a period of 2 h. After completion of
the addition, the reaction mixture was heated under reflux
for 30 min and then cooled to room temperature. Ammonium
hydroxide (10% solution) was added until the solution became
clear. The reaction mixture was then poured into a separatory
funnel containing 200 mL of ether. The organic phase was
washed two times with brine (30 mL), dried (MgSO4), and
concentrated. Flash chromatography (30% ethyl acetate in
hexane) gave 1.81 g (88%) of compound 10 and its C-4 isomer
as a 2.8:1 cis/ trans mixture: 1H NMR (CDCl3) δ 4.44 (dd, 1H,
J ) 9.1, 8.3 Hz, cis), 4.25 (dd, 1H, J ) 9.3, 4.9 Hz, trans), 4.13
(dd, 1H, J ) 9.1, 4.3 Hz, cis), 3.76-3.63 (m, 2H, cis), 3.33 (dd,
1H, J ) 10.6, 8.5 Hz, trans), 2.96 (dd, 1H, J ) 10.5, 9.2 Hz,
(2R )-2-[(t er t -B u t o x y c a r b o n y l)a m in o ]-3-(m e t h o x y -
m eth oxy)p r op a n -1-ol (6). To a solution of crude ester 5 (45
g) in THF (260 mL, 0.7 M) was added at 0 °C a solution of
lithium borohydride (2.0 M in THF, 91 mL, 1 equiv). The
reaction mixture was stirred for 12 h at room temperature and
then treated at 0 °C with saturated NH4Cl. Extraction with
ethyl acetate (600 mL) and usual workup gave a syrup that
was chromatographed (60% ethyl acetate in hexane) to give 6
(34 g, 75% yield from serine) as a white solid: [R]D -3.2° (c
1.1, CHCl3); 1H NMR (CDCl3) δ 5.25-5.15 (broad s, 1H), 4.50
(s, 2H), 3.71-3.31 (m, 6H), 3.24 (s, 3H), 1.32 (s, 9H); 13C NMR
(CDCl3) δ 155.8, 96.4 79.2, 66.9, 62.1, 55.0, 51.6, 28.1; IR υmax
3330, 2910, 1685, 1510, 1365, 1245, 1165, 1110, 1040 cm-1
;
MS (FAB+) m/ e 236 (M+ + H), 180 (M+ - (CH3)2CdCH2), 148
(M+ - (CH3)2CdCH2 - CO2).
(4S)-3-Allyl-4-[(m eth oxym eth oxy)m eth yl]oxa zolid in -2-
on e (7). To a suspension of sodium hydride (2.4 equiv, 4.90

5422 J . Org. Chem., Vol. 61, No. 16, 1996
Hanessian and Ninkovic
trans), 2.65-1.95, 1.78-1.55 (m, 5H, cis/ trans), 1.36 (s, 9H),
1.19-0.58 (m, 2H, cis/ trans), 0.03 (s, 9H, cis/ trans); 13C NMR
(CDCl3) δ cis 171.3, 161.1, 80.8, 68.0, 62.5, 44.8, 40.2, 53.6,
33.8, 27.8, 10.7, -9.9; trans 171.1, 160.7, 80.9, 68.2, 64.6, 50.0,
45.8, 52.4, 36.3, 13.4, -9.8; MS (NBA) m/ z 364 (M+ + H -
CdC(CH3)2), 348 (M+ + H - CdC(CH3)2 - Me). Anal. Calcd
for C16H29NO4Sn: C, 45.96; H, 6.99; N, 3.35. Found: C, 46.31;
H, 7.08; N, 3.38.
65%): 1H NMR (CDCl3) δ 4.40 (dd, 1H, J ) 9.2, 7.8 Hz), 4.17
(dd, 1H, J ) 9.2, 3.5 Hz), 4.01 (ddd, 1H, J ) 8.4, 6.3, 2.1 Hz),
3.85 (ddd, 1H, J ) 9.8, 7.8, 3.5 Hz), 3.70 (dd, 1H, J ) 11.7, 8.8
Hz), 3.35 (dd, 1H, J ) 11.8, 4.2 Hz), 2.58 (dd, 1H, J ) 16.0,
7.6 Hz), 2.47-2.31, 2.28-2.14 (m, 3H), 1.42 (s, 9H), 1.16 (d,
3H, J ) 6.4 Hz); 13C NMR (CDCl3) δ 171.6, 161.5, 81.1, 67.5,
65.5, 63.1, 46.8, 43.1, 44.5 33.3 , 27.9, 22.6; HRMS for C14H23
-
NO5 + H calcd 286.1654, found 286.1664; MS (FAB+) 286 (M+
+ H), 230 (M+ + H - CH2dC(CH3)2).
(6R,7S,8S)-[6-(Dim eth oxym eth yl)-3-oxotetr a h yd r op y-
r r olo[1,2-c]oxa zol-7-yl]a cetic Acid ter t-Bu tyl Ester (11)
a n d (6S,7S,8S)-[6-(Dim eth oxym eth yl)-3-oxotetr a h yd r o-
p yr r olo[1,2-c]oxa zol-7-yl]a cet ic Acid ter t-Bu t yl E st er
(12). To a solution of 10 and its C-4 isomer (2.6 g) in methanol
(125 mL) at 0 °C was added ceric ammonium nitrate (34 g, 10
equiv), portionwise over 30 min. The reaction mixture was
stirred at room temperature for 15 h, poured into a separatory
funnel containing 350 mL of ethyl acetate, and extracted with
water (6 × 50 mL) and brine (2 × 50 mL). The organic phase
was dried (MgSO4) and concentrated. Flash chromatography
(40% ethyl acetate in hexane, slow elution) gave the cis-
dimethyl acetal 11 (733 mg, 38%) and trans-isomer 12 (335
mg, 17%). For 12: [R]D +5.2° (c 1.0, CHCl3); 1H NMR (CDCl3)
δ 4.46 (dd, 1H, J ) 9.2, 8.0 Hz), 4.32 (dd, 1H, J ) 9.2, 4.2 Hz),
4.20 (d, 1H, J ) 5.9 Hz), 3.73 (ddd, 1H, J ) 11.9, 7.8, 4.1 Hz),
3.56 (dd, 1H, J ) 12.3, 5.1 Hz), 3.36, 3,34 (2 × s, 6H), 3.21
(dd, 1H, J ) 12.2, 8.7 Hz), 2.68 (dd, 1H, J ) 15.5, 3.1 Hz),
2.29-2.05 (m, 3H), 1.40 (s, 9H); 13C NMR (CDCl3) δ 171.2,
160.8, 107.0, 81.0, 68.5, 64.7, 55.5, 54.8, 48.6, 46.5, 42.2, 38.2,
27.9; MS (FAB+) 316 (M+ + H) 284 (M+ + H - MeOH), 228
(M+ + H - MeOH - CH2dC(CH3)2). For 11: [R]D +35.0° (c
1.1, CHCl3); 1H NMR (CDCl3) δ 4.38 (dd, 1H, J ) 9.1, 7.8 Hz),
4.18 (d, 1H, J ) 4.5 Hz), 4.13 (dd, 1H, J ) 9.1, 3.4 Hz), 3.75-
3.63 (m, 2H), 3.31, 3.30 (2 × s, 6H), 3.20 (dd, 1H, J ) 12.1, 4.7
Hz), 2.73-2.64, 2.49, 2.30-2.16 (m, dd, m, 4H, J ) 15.8, 7.6
Hz), 1.40 (s, 9H); 13C NMR (CDCl3) δ 171.2, 161.3, 105.2, 80.9,
67.2, 63.1, 55.5, 54.3, 43.0, 41.6, 46.2, 33.2, 27.9; IR υmax 2960,
2810, 1745, 1370, 1355, 1200, 1145, 1080, 1050 cm-1; HRMS
for C15H25NO6 + H calcd 316.1760, found 316.1741; MS (FAB+)
(6R,7S,8S)-(6-Acetyl-3-oxotetr a h yd r op yr r olo[1,2-c]ox-
a zol-7-yl)a cetic Acid ter t-Bu tyl Ester (15). To a solution
of 14 (74 mg) in dichloromethane (3 mL, 0.1 M) and molecular
sieves (3 Å) was added at room temperature N-methylmor-
pholine N-oxide (76 mg, 2.5 equiv) and tetrapropylammonium
perruthenate (cat.). The reaction mixture was stirred for 30
min, filtered over Celite-silica gel, and concentrated. Flash
chromatography (ethyl acetate) afforded ketone 15 (58 mg,
80%): [R]D
+57.0° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 4.45 (dd,
1H, J ) 9.3, 7.7 Hz), 4.20 (dd, 1H, J ) 9.2, 3.2 Hz), 3.87-3.80,
3.62-3.55 (m, 3H), 3.24 (dd, 1H, J ) 12.0, 4.8 Hz), 2.43-2.23
(m, 3H), 2.19 (s, 3H), 1.40 (s, 9H);
13C NMR (CDCl3) δ 209.5,
170.8, 161.1, 81.5, 66.8, 63.0, 52.3, 42.9, 32.1, 48.6, 33.2, 27.9;
HRMS for C14H21NO5 + H calcd 284.1498, found 284.1499; MS
(FAB
+) m/ z 284 (M+ + H), 228 (M+ + H - CH2dC(CH3)2).
(6S,7S,8S)-(6-Isop r op en yl-3-oxotetr a h yd r op yr r olo[1,2-
c]oxa zol-7-yl)a cetic Acid ter t-Bu tyl Ester (16). To a
suspension of zinc dust (110 mg, 12 equiv) in THF (1 mL) was
added diiodomethane (75 µL, 6.5 equiv). After the mixture
was stirred for 30 min, a solution TiCl4 in dichloromethane
(1.0 M, 240 µL, 2 equiv) was added, and the resulting dark
brown solution was stirred for another 30 min at room
temperature. Ether (5 mL) was added to the mixture, and
the organic phase was washed with 10% HCl (1 mL) and brine
(1 mL), dried over MgSO4, and concentrated. Flash chroma-
tography (60% ethyl acetate in hexane) afforded 16 (23 mg,
63%) as a white solid. Recrystallization from petroleum ether
afforded crystals suitable for X-ray analysis: mp 87 °C; [R]D
-8.8° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 4.95, 4.76 (2 × s, 2H),
4.56 (dd, 1H, J ) 9.1, 8.3 Hz), 4.24 (dd, 1H, J ) 9.2, 4.8 Hz),
3.86-3.79 (m, 2H), 3.18 (dd, 1H), 3.02, 2.43-2.10 (dd, m, 4H,
J ) 14.0, 7.7 Hz), 1.74 (s, 3H), 1.45 (s, 9H); 13C NMR (CDCl3)
δ 171.4, 161.4, 142.3, 114.4, 81.2, 68.8, 63.5, 49.2, 43.2, 49.7,
34.4, 28.0, 22.5; X-ray crystal structure data have been
deposited with the Cambridge Crystallographic Data Centre.22
(2S,3R,4S)-2-(Hyd r oxym eth yl)-4-isop r op en yl-3-[(m eth -
oxyca r bon yl)m eth yl]p yr r olid in e-1-ca r boxylic Acid ter t-
Bu tyl Ester (17). Compound 16 (34 mg) was dissolved in
dioxane (0.75 mL) and an aqueous solution of NaOH (3N, 0.3
mL). The reaction mixture was brought to 70 °C and kept at
that temperature for 16 h. After the mixture was cooled to 0
°C, a solution of Boc2O (70 mg, 2.4 equiv) in dioxane (0.75 mL)
was added and the reaction mixture stirred at room temper-
ature for 2 h. After water (2.5 mL) was added, citric acid (10%
solution) was used to adjust the pH to around 3-4 and the
product was extracted with ethyl acetate (15 mL). The organic
m/ z 316 (M+ + H), 260 (M+ + H - CH2dC(CH3)2), 228 (M+
+
H - CH2dC(CH3)2 - MeOH). Anal. calcd for C7H11NO3: C,
57.13; H, 7.99; N, 4.44. Found: C, 57.00; H, 8.19; N, 4.45.
(6R,7S,8S)-(6-F or m yl-3-oxotetr a h yd r op yr r olo[1,2-c]ox-
a zol-7-yl)a cetic Acid ter t-Bu tyl Ester (13). To a solution
of 11 (676 mg) in dichloromethane (25 mL, 0.08 M) was slowly
added bromodimethylborane (0.42 mL, 2 equiv) at -78 °C. The
reaction mixture was stirred at the same temperature for 45
min and then transferred via canula into a solution of
saturated sodium bicarbonate-THF (10 and 20 mL, respec-
tively) with vigorous stirring. The solution was poured into a
separatory funnel containig ethyl acetate (100 mL), and the
organic phase was washed with saturated ammonium chloride
(20 mL), and brine (25 mL), dried over MgSO4, and concen-
trated to afford the crude aldehyde 13 (575 mg, quantitative),
which was used as such in the next step: 1H NMR (CDCl3) δ
9.85, (d, 1H, J ) 1.7 Hz), 4.50 (dd, 1H, J ) 9.4, 7.7 Hz), 4.28
(dd, 1H, J ) 9.4, 3.0 Hz), 3.75-3.63 (m, 2H), 3.61 (dd, 1H, J
) 12.1, 4.1 Hz), 2.73-2.64, 2.49, 2.30-2.16 (m, dd, m, 4H, J
) 15.8, 7.6 Hz), 1.40 (s, 9H); 13C NMR (CDCl3) δ: 198.4, 170.2,
160.3, 81.4, 67.3, 64.1, 57.5, 40.9, 44.8, 36.6, 27.7.
(6R,7S,8S)-[6-(1′-Hydr oxyeth yl)-3-oxotetr ah ydr opyr r olo-
[1,2-c]oxa zol-7-yl]a cetic Acid ter t-Bu tyl Ester (14). Ce-
rium trichloride (400 mg, 3.0 equiv, obtained by drying cerium
chloride heptahydride at 160 °C and 1 mmHg for 6 h) was
mixed with THF (10 mL), and the mixture was stirred at room
temperature for 1 h. The suspension was cooled to -78 °C, a
solution of MeLi (1.2M in ether, 1.31 mL, 2.9 equiv) was slowly
added, and the resulting yellowish mixture was stirred for
another 45 min. A solution of aldehyde 13 (143 mg) in THF
(4 mL) was then added to the reaction mixture over 1 min.
After the mixture was stirred at -78 °C for 25 min, saturated
ammonium chloride (3 mL) was added and the mixture was
extracted with ethyl acetate (30 mL). The organic phase was
washed with saturated ammonium chloride (4 mL), saturated
sodium bicarbonate (4 mL), and brine (5 mL), dried over
MgSO4, and concentrated. Flash chromatography (10-15%
methanol in dichloromethane) afforded alcohol 14 (32mg,
phase was dried (MgSO4
) and concentrated. The crude acid
was then redissolved in ether (10 mL), and diazomethane was
added at 0 °C. After the reaction was completed, the excess
diazomethane was removed, the solvent was evaporated under
reduced pressure, and the residue was chromatographed (60%
ethyl acetate in hexane) to afford compound 17 (16 mg, 43%):
[R]D -41.7° (c 0.69, CHCl3) [lit.6h [R]D -38.0° (c 0.2, CHCl3)];
1H NMR (CDCl3) δ 4.91, 4.67 (m, 2H), 3.80-3.50, 3.46 (m, d,
8H, J ) 7.7 Hz), 2.96-2.88, 2.56-2.42 (m, 2H), 2.33-2.16, (m,
2H), 1.70 (s, 3H), 1.48 (s, 9H); 13C NMR (CDCl3) δ 172.8, 156.8,
142.0, 113.0, 80.6, 66.9, 65.1, 51.8, 48.9, 45.6, 39.3, 33.1, 28.4,
22.2; HRMS for C16H27NO5 + H calcd 314.1968, found 314.1954;
MS (FAB+) m/ z 314.2 (M+ + H), 282.2 (M+ + H - MeOH),
258.3 (M+ + H - CH2dC(CH3)2), 226.1 (M+ + H - MeOH -
CH2dC(CH3)2), 214.1 (M+ + H - CH2dC(CH3)2 - CO2).
1-(ter t-Bu tyloxyca r bon yl)-r-k a in ic Acid Dim eth yl Es-
ter (18). Compound 17 (15 mg, 0.05 mmol) was dissolved in
acetone (0.05 M, 1 mL) and the solution cooled to 0 °C prior to
the addition of freshly prepared J ones reagent (8 equiv). After
the solution was stirred for 1 h, 2-propanol (few drops) was
added and the mixture stirred for 15 min. The product was

Synthesis of (-)-R-Kainic Acid and (+)-R-Allokainic Acid
J . Org. Chem., Vol. 61, No. 16, 1996 5423
extracted with ethyl acetate (5 mL). The organic phase was
dried (MgSO4) and concentrated. The crude acid was redis-
solved in ether (10 mL), and diazomethane was added at 0
°C. After the reaction was completed, the excess diazomethane
removed, and the solvent was evaporated under reduced
pressure. Flash chromatography (40% ethyl acetate in hexane)
afforded compound 18 (9 mg, 56%): [R]D 18.9° (c 0.45, CHCl3);
1H NMR (CDCl3) δ 4.93, 4.70 (2 × s, 2H), 4.17, 4.07 (2 × d,
1H, J ) 3.4, 3.6 Hz), 3.77-3.62 (m, 7H), 3.51-3.40 (m, 1H),
3.08-2.97 and 2.91-2.81 (2 × m, 2H), 2.42-2.25 (m, 2H), 1.70
(s, 3H), 1.48 and 1.41 (2 x s, 9H); 13C NMR (CDCl3) δ 172.6,
172.4, 172.3, 172.2, 154.2, 153.6, 141.3, 141.2, 113.4, 113.1,
80.2, 63.9, 63.6. 52.3, 52.1, 51.7, 47.8, 47.5, 45.9, 45.2, 41.8,
40.8, 32.9, 28.3, 28.1, 27.9, 22.3, 22.1; MS (EI) m/ z 342.3 (M+
+ H), 286.3 (M+ + H - (CH3)2dCH2), 242 (M+ + H -
(CH3)2dCH2 - CO2); HRMS calcd for C17H27O6N + H 342.1916,
found 342.1902.
and 3.90-3.53 (m, 8H), 1.76 (s, 3H); 13C NMR (CDCl3) δ: 158.7,
140.0, 125.1, 137.8, 113.2, 64.7, 60.4, 55.9, 39.9, 11.6.
(4′S,2E)-3′′-[3′-(3-Meth ylp en ta -2,4-d ien yl)-2′-oxooxa zo-
lid in -4′-yl]a cr ylic Acid Meth yl Ester (21). To a solution
of oxalyl chloride (0.47 mL, 1.15 equiv) in dichloromethane (15
mL) at -65 °C was added freshly distilled DMSO (0.70 mL,
2.2 equiv in 3 mL of CH2Cl2) over 2 min, and the reaction
mixture was then stirred for 5 min more at the same temper-
ature. The alcohol 20 (920 mg, 4.7 mmol) in CH2Cl2 (5 mL)
was then added to the reaction mixture over 5 min, and
stirring was continued for another 20 min, after which time
triethylamine (2.35 mL, 3.7 equiv) was added and the solution
cooled to -15 °C over 1.5 h. Methyl (triphenylphosphora-
nylidene)acetate (2.34 g, 1.5 equiv) was added to the mixture
and the temperature brought to 25 °C over 1.5 h. The reaction
mixture was poured into brine (30 mL), extracted with CH2-
Cl2 (3 × 50 mL), and dried over MgSO4, and the residue was
chromatographed with 60% ethyl acetate in hexane to afford
21 (940 mg, 80%): 1H NMR (CDCl3) δ 6.74 (dd, 1H, J ) 15.6,
8.3 Hz), 6.33 (dd, 1H, J ) 17.4, 10.7 Hz), 6.00 (d, 1H, J ) 15.6
Hz), 5.38 (dd, 1H, J ) 7.1, 7.1 Hz), 5.20, 5.06 (2 × d, 2H, J )
17.4, 10.7 Hz), 4.46-4.31, 4.29-4.12, 4.01-3.96, 3.76-3.68 (m,
dd, dd and m, 8H, first dd: J ) 15.6 and 6.2 Hz, second dd:
J ) 8.2, 6.4 Hz), 1.73 (s, 3H); 13C NMR (CDCl3) δ 165.3, 157.5,
142.9, 140.1, 125.5, 124.3, 138.6, 113.8, 66.2, 56.3, 51.9, 40.2,
11.9.
(8′S,1E)-[6′-[1-Met h yl-3-(t r im et h ylst a n n yl)p r op en yl]-
3′-oxot et r a h yd r op yr r olo[1′,2′-c]oxa zol-7′-yl]a cet ic Acid
Meth yl Ester (22). To a refluxing solution of triene 21 (268
mg, 1.07 mmol) and trimethyltin chloride (280 mg, 1.3 equiv)
in 2-methyl-2-propanol (30 mL) was added a solution of sodium
cyanoborohydride (280 mg, 4.1 equiv) and AIBN (20 mg, 10%)
in methanol (5 mL) over a period of 1 h with a syringe pump.
After completion of the addition, the reaction mixture was kept
under reflux for 2 h then cooled to room temperature. Am-
monium hydroxide (10% solution) was added until the solution
became clear. The reaction mixture was poured into a sepa-
ratory funnel containing 100 mL of ether. The organic phase
was washed twice with brine (20 mL), dried (MgSO4), and
concentrated. Flash chromatography (40% ethyl acetate in
hexane) gave 22 and its C-4 epimer (257 mg, 52%) as an
unseparable 2.8:1 mixture of trans and cis isomers: 1H NMR
(CDCl3) δ 5.49-5.32 (m, 1H, cis/trans), 4.48-4.10 (m, 2H, cis/
trans), 3.75-3.52, 3.32-1.92 (m, 10H), 1.68-1.37 (m, 5H),
+0.18 to -0.10 (m, 9H); 13C NMR (CDCl3) δ 172.6 (cis), 172.3
(trans), 161.1 (cis), 160.6 (trans), 128.3 (trans), 127.9 (cis),
125.9 (cis), 124.3 (trans), 68.6 (cis), 67.6 (trans), 64.3, 63.5, 56.8,
51.6, 51.2 43.6, 42.9 (cis and trans), 49.4 (cis), 48.2 (trans),
34.5 (trans), 33.0 (cis), 15.3 (cis), 12.8 (trans), 12.7 (cis), 11.4
(trans), -9.8 (cis), -9.9 (trans); HRMS for C16H27O4NSn +H
calcd 416.0884, found 416.0904.
(6S,7R,8S)-(6-Acetyl-3-oxotetr a h yd r op yr r olo[1,2-c]ox-
a zol-7-yl)a cetic Acid Meth yl Ester (23) a n d (6R,7R,8S)-
(6-Acetyl-3-oxotetr a h yd r op yr r olo[1,2-c]oxa zol-7-yl)a ce-
tic Acid Meth yl ester (24). Ozone was bubbled through a
solution containing 22 and its C-4 isomer (210 mg, 0.5 mmol)
in methanol/dichloromethane (1:1, 5 mL total) at -78 °C for
20 min. After removal of excess O3, by bubbling argon through
the reaction mixture for 5 min, methyl sulfide (1 mL) was
added, and the solution was stirred at 0 °C for 1 h. The solvent
was removed under reduced pressure and the residue chro-
matographed (60% ethyl acetate in hexane) to give 57 mg
(47%) of the trans-ketone 23 and 27 mg (22%) of the cis-ketone
24. For 23: [R]D -17.9° (c 1.1, CHCl3); 1H NMR (CDCl3) δ
4.51 (dd, 1H, J ) 9.3, 7.8 Hz), 4.39 (dd, 1H, J ) 9.3, 3.8 Hz),
3.82-3.65 (m, 5H), 3.52 (dd, 1H, J ) 11.8, 9.8 Hz), 3.10-3.04
(m, 1H), 2.61-2.53 (m, 2H), 2.37 (dd, 1H, J ) 17.3, 9.8 Hz),
2.20 (s, 3H); 13C NMR (CDCl3) δ 205.5, 171.7, 160.5, 67.8, 64.2,
57.8, 51.9, 41.8, 29.0, 47.2 , 35.5; IR υmax 2940, 2905, 1740,
1385, 1350, 1200, 1165, 1075, 995 cm-1; HRMS for C11H15NO5
M + H calcd 242.1028, found 242.1041; MS (EI) m/ e 242 (M+
+ H).
(-)-r-Ka in ic Acid (1). Compound 18 (9 mg) was dissolved
in a mixture of THF (0.25 mL) and a 2.5% solution of KOH (1
mL). The reaction mixture was stirred for 12 h at room
temperature, and a solution of citric acid (10%) was added
untill pH ∼3. The diacid was extracted with ethyl acetate and
the solvent dried (Na2SO4) and removed under reduced pres-
sure. Dichloromethane (1 mL) and TFA (12 equiv) were added,
and the reaction mixture was stirred for 12 h. After removal
of the solvent, the crude product was added, to a column
containing Dowex-50 H+ (WX8-200, 8% cross-linking, 100-
200 wet mesh). Elution with NH4OH (1 N), evaporation, and
treatment with Amberlite CG-50 (100-200 dry mesh)6e af-
forded after recrystallization R-kainic acid (1) (4.5 mg, 80%):
mp 242-244 °C (lit.6i mp 243-244); [R]D -13.9° (c 0.18, H2O)
[lit.6i [R]D -14.2° (c 0.18, H2O)]; 1H NMR (D2O) δ 5.02, 4.73 (2
× s, 2H), 4.06 (d, 1H, J ) 3.1 Hz) 3.61 (dd, 1H, J ) 11.6, 7.3
Hz), 3.43 (dd, 1H, J ) 11.7, 10.7 Hz), 3.08-2.94 (m, 2H), 2.31
(dd, 1H, J ) 15.7, 6.4 Hz), 2.19 (dd, 1H, J ) 15.7, 8.1 Hz),
1.76 (s, 3H); 13C NMR (D2O) δ 179.6, 174.3, 141.0, 113.9, 66.7,
47.2, 46.6, 42.4, 36.1, 23.0; MS (EI) m/ z 214 (M+ + H).
(4′S,2E)-4′-[(Meth oxym eth oxy)m eth yl]-3′-(3-m eth ylpen -
ta -2,4-d ien yl)-2′-oxooxa zolid in -2-on e (19). To a suspension
of sodium hydride (3 equiv, 1.65 g, 41.2 mmol) in THF (0.1 M,
140 mL) at 0 °C was added over 10 min a solution of 6 (3.26
g, 13.9 mmol) in 10 mL of THF. The reaction mixture was
stirred at room temperature for 15 h, after which time freshly
prepared 5-bromo-3-methylpenta-1,3-diene (3 equiv, 13 mL)21,22
was added and the solution was stirred for another 15 h at
room temperature. Quenching with NH4Cl (saturated) (10
mL) and usual workup (ethyl acetate, brine) followed by
chromatography (40% ethyl acetate in hexane) gave 19 (2.06
1
g, 62%): [R]D -17.2° (c 1.54, CHCl3); H NMR (CDCl3) δ 6.31
(dd, 1H, J ) 17.4, 10.7 Hz), 5.42 (dd, 1H, J ) 7.3, 7.3 Hz),
5.17, 5.02 (2 × d, 2H, J ) 17.4, 10.7 Hz), 4.57 (s, 2H), 4.30
(dd, 1H, J ) 8.8, 8.7 Hz), 4.20-4.06, 3.90-3.82 and 3.56-3.53
(m, 6H), 3.31 (s, 3H), 1.78 (s, 3H); 13C NMR (CDCl3) δ 158.1,
140.2, 125.5, 137.8, 113.3, 96.6, 66.8, 64.8, 40.3, 55.5, 54.3, 11.8;
IR υmax 2900, 1740, 1420, 1410, 1240, 1210, 1140, 1100-1030,
903, 750 cm-1
.
(4′S,2E)-4′-(Hyd r oxym eth yl)-3′-(3-m eth ylp en ta -2,4-d i-
en yl)-2′-oxooxa zolid in -2-on e (20). Bromotrimethylsilane (6
mL, 6 equiv, 45 mmol) was added at -35 °C into a solution of
19 (1.87 g, 7.8 mmol) in dichloromethane (80 mL, 0.1 M), and
the reaction mixture was stirred for 1.5 h at the same
temperature. It was left for another 0.5 h at 0 °C and then
added into a saturated solution of NaHCO3 with a cannula
with vigorous stirring. Extraction with ethyl acetate (200 mL)
and usual processing of the organic phase, evaporation, and
chromatography (60% ethyl acetate in hexane to 100% ethyl
acetate) afforded 20 (904 mg, 59%) and starting material 19
(493 mg, 26%): [R]D -30.0° (c 1.45, CHCl3); 1H NMR (CDCl3)
δ 6.29 (dd, 1H, J ) 17.4, 10.7 Hz), 5.40 (dd, 1H, J ) 7.0, 6.9
Hz), 5.16 and 5.00 (2 × d, 2H, J ) 17.4, 10.7 Hz), 4.30-4.02
(21) Oroshnik, W. J . Am. Chem. Soc. 1956, 78, 2651.
(6S,7R,8S)-(6-Isop r op en yl-3-oxotetr a h yd r op yr r olo[1,2-
c]oxa zol-7-yl)a cetic Acid Meth yl Ester (25). BuLi in
hexane (2.5 M, 0.165 mL) was added at -78 °C to a suspension
of Ph3PMeBr (154 mg) in THF (2.5 mL). The mixture was
(22) The author has deposited atomic coordinates for 16 with the
Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

5424 J . Org. Chem., Vol. 61, No. 16, 1996
Hanessian and Ninkovic
stirred at room temperature for 20 min and then brought to
-60 °C prior the addition of a solution of ketone 23 (52 mg) in
THF (2.5 mL). The reaction mixture was kept at -60 °C for
1 h and warmed to 25 °C over a period of 0.5 h, after which
time it was filtered over Celite-silica gel. The solvent was
removed under reduced pressure and the crude product
chromatographed (60% ethyl acetate in hexane) to afford a
1-(ter t-Bu tyloxyca r bon yl)a llok a in ic Acid Dim eth yl Es-
ter (27). Compound 26 was oxidized and esterified following
the same procedure described above for kainic acid. Flash
chromatography (30% ethyl acetate in hexane) afforded 27 (36
mg, 84%): [R]D -37.6° (c 0.37, CHCl3); 1H NMR (CDCl3) δ
4.89-4.82 (m, 2H), 3.96 and 3.91 (2 × d, 1H, J ) 8.2, 8.8 Hz,
2 rotamers), 3.74-3.61 (m, 7H), 3.31 (dd, 1H, J ) 10.9, 10.7
Hz), 2.66-2.39 (m, 4H), 1.71 (s, 3H), 1.44 and 1.39 (2 × s, 9H);
13C (400 MHz, CDCl3) δ 172.3, 172.0, 171.1, 152.8, 140.5, 140.4,
114.1, 79.8, 79.7, 64.0, 63.6, 51.7, 51.5, 51.2, 51.1, 50.4, 50.3,
49.8, 49.3, 42.7, 42.0, 35.2, 35.0, 29.2, 28.0, 27.8, 27.7, 27.5,
18.3, 18.2; HRMS for C17H27NO6 + H calcd 342.1916, found
342.1906.
Allok a in ic Acid (2). Allokainic acid (2) was obtained
following the same procedure as for kainic acid (1). Thus, 33
mg of compound 27 was subjected to the same reactions
described for 18. The crude product was passed through a
column containing Dowex-50(H+). Elution with NH4OH (1 N),
evaporation, and treatment with Amberlite CG-506e gave 2 (13
mg, 65%): mp 239-240 °C (lit.7f mp 238-242 °C); [R]D 7.0° (c
0.2, H2O) [lit.7f [R]D 7.4° (c 0.7, H2O)]; 1H NMR (D2O) δ 5.01 (s,
2H), 3.96 (d, 1H, J ) 8.7 Hz) 3.56 (dd, 1H, J ) 10.9, 8.1 Hz),
3.36 (dd, 1H, J ) 11.4, 11.0 Hz), 2.95-2.57 (m, 4H), 1.77 (s,
3H); 13C NMR (400 MHz, D2O) δ 177.4, 174.0, 141.0, 116.0,
65.4, 52.1, 48.7, 42.6, 37.5, 18.2; MS (EI) m/ z 214 (M+ + H);
HRMS for C10H16O4N calcd 214.1079, found 214.1069.
1
white solid (43 mg, 83%): [R]D +4.0° (c 1.0, CHCl3); H NMR
(CDCl3) δ 4.87-4.85, 4.83 (broad s and s, 2H), 4.50 (dd, 1H, J
) 9.4, 7.9 Hz), 4.38 (dd, 1H, J ) 9.4, 4.2 Hz), 3.82-3.73 (m,
1H), 3.65 (s, 3H,), 3.47-3.33 (m, 2H), 2.71, 2.55, 2.24-2.04
(dd, dd, m, 4H, first dd: J ) 19.4, 7.7 Hz, second dd: J )
15.6, 3.6 Hz), 1.68 (s, 3H); 13C NMR (CDCl3) δ 172.2, 160.7,
141.1, 114.7, 67.7, 64.6, 54.9, 51.8, 43.1, 48.5, 34.8, 18.0; HRMS
for C12H17NO4 + H calcd 240.1236, found 240.1240; MS (EI)
m/ e 240 (M+ + H).
(2S,3R,4S)-2-(Hyd r oxym eth yl)-4-isop r op en yl-3-[(m eth -
oxyca r bon yl)m eth yl]p yr r olid in e-1-ca r boxylic Acid ter t-
Bu tyl Ester (26). Compound 25 (39 mg) was dissolved in a
mixture of dioxane (0.5 mL) and aqueous NaOH (3 N, 0.4 mL).
The reaction mixture was kept at 60 °C for 16 h. After the
mixture was cooled to 0 °C, a solution of Boc2O (85 mg, 2.4
equiv) in dioxane (0.7 mL) was added, and the reaction mixture
was stirred at room temperature for 2 h. After the addition
of water (2.5 mL), citric acid (10% solution) was used to bring
the pH to around 3-4, and the product was extracted with
ethyl acetate (10 mL). The organic phase was dried (MgSO4)
and concentrated. The crude acid was then redissolved in
ether (10 mL), and diazomethane was added at 0 °C. After
the reaction was completed, excess diazomethane was removed
and the solvent was evaporated under reduced pressure. Flash
chromatography (40% ethyl acetate in hexane) afforded com-
Ack n ow led gm en t. We acknowledge generous fi-
nancial assistance given by NSERC, the Medicinal
Chemistry Chair program, FCAR, and Merck Frosst. We
thank Dr. M. Simard for X-ray crystallographic analysis.
1
pound 26 (45 mg, 88%): [R]D -27.8° (c 0.6, CHCl3); H NMR
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
(CDCl3) δ 4.86-4.84 (m, 2H), 3.81-3.60 and 3.12 (m, dd, 8H,
J ) 11.0, 10.9 Hz), 2.54-2.41, 2.23-2.19 (m, 4H), 1.69 (s, 3H),
1.45 (s, 9H); 13C NMR (CDCl3) δ 172.2, 156.3, 141.5, 114.2,
80.4, 66.1, 65.7, 51.5, 50.8, 40.3, 50.4, 35.9, 18.5; MS (EI) m/ z
314.5 (M+ + H), 282.5 (M+ + H - MeOH), 258.3 (M+ + H -
CH2dC(CH3)2), 226.1 (M+ + H - MeOH - CH2dC(CH3)2),
214.1 (M+ + H - CH2dC(CH3)2 - CO2).
and 13C NMR spectra of 8-13, 15, 16, 1, 20, 21, 23, 25, and 2
(29 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
J O9604088