Stereocontrolled Synthesis of 5α- and 5β-Substituted Kainic Acids

Article abstract of DOI:10.1021/jo982109j

A general and efficient method for the stereoselective synthesis of racemic 5β- and 5α-substituted kainic acids 3 and 4 has been developed starting from the bicyclic pyroglutamate derivative 6, readily available on a large scale. Compound 6 proved to be a versatile synthon from which straightforward functionalizations at both C-5β and C-5α were accomplished in a stereoselective manner without compromising the stereogenic integrity of the potentially labile C-2 center. The key steps involved the stereoselective nucleophilic addition of organocopper reagents to the N-acyliminium ion I, and the stereoselective hydrogenation of the cyclic imine 9 derived from 6. Transformations of the bicyclic intermediates 7 and 8 into the final substituted kainic acids 3 and 4 were accomplished via stepwise sequences that avoid the facile and undesirable intramolecular Claisen and epimerization reactions. Compounds 3 and 4 have shown no significant binding affinity for the kainate receptors, which reflects the sensitivity of the recognition site to steric and conformational factors.

Full text of DOI:10.1021/jo982109j

4304
J . Org. Chem. 1999, 64, 4304-4314
Ster eocon tr olled Syn th esis of 5r- a n d 5â-Su bstitu ted Ka in ic Acid s
Iva´n Collado, J esu´s Ezquerra, Ana I. Mateo, Concepcio´n Pedregal, and Almudena Rubio*
Centro de Investigacio´n Lilly, S. A. Avda de la Industria, 30. 28108 Alcobendas, Madrid, Spain
Received October 19, 1998
A general and efficient method for the stereoselective synthesis of racemic 5â- and 5R-substituted
kainic acids 3 and 4 has been developed starting from the bicyclic pyroglutamate derivative 6,
readily available on a large scale. Compound 6 proved to be a versatile synthon from which
straightforward functionalizations at both C-5â and C-5R were accomplished in a stereoselective
manner without compromising the stereogenic integrity of the potentially labile C-2 center. The
key steps involved the stereoselective nucleophilic addition of organocopper reagents to the
N-acyliminium ion I, and the stereoselective hydrogenation of the cyclic imine 9 derived from 6.
Transformations of the bicyclic intermediates 7 and 8 into the final substituted kainic acids 3 and
4 were accomplished via stepwise sequences that avoid the facile and undesirable intramolecular
Claisen and epimerization reactions. Compounds 3 and 4 have shown no significant binding affinity
for the kainate receptors, which reflects the sensitivity of the recognition site to steric and
conformational factors.
In tr od u ction
regarding the structural requirements for activating
kainate receptors and with the ultimate goal of discover-
ing potent and selective kainate receptor antagonists, we
have developed a novel and general approach to the
stereocontrolled introduction of substituents at positions
5â and 5R in the pyrrolidine ring system of kainic acid
that culminated in the total synthesis of 5â- and 5R-
substituted kainic acids (3 and 4).
Kainic acid1 (1) and its analogues have attracted
considerable interest due to their potent and specific
neuroexcitatory activity at the glutamate receptors.2 This
important property along with its unique structure has
motivated the development of stereocontrolled approaches
for the synthesis of either the naturally occurring kain-
oids3 or their chemically modified analogues.4 Although
a number of structure-activity relationship studies on
kainic acid have revealed that the unsaturation at C-4
as well as the relative stereochemistry of the three
stereocenters are crucial for the high affinity to the
kainate receptor,5 little was known on the structural
modification at the pyrrolidine core. Recently we have
reported an efficient stereocontrolled route to 4-substi-
tuted kainic acids 2.6 To provide further information
(1) Murukami, S.; Takemoto, T.; Shimizu, Z. J . Pharm. Soc. J pn.
1953, 73, 1026.
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J . C.; Krogsgaard-Larsen, P.; Honore´, T. Trends Pharmacol. Sci. 1990,
11, 25. (c) Lodge, D., Ed. Excitatory Amino Acids in Health and Disease;
J ohn Wiley & Sons: New York, 1988. (d) Krogsgaard-Larsen, P.;
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New York, 1992. (e) Michaelis, E. K. Progr. Neurobiol. 1998, 54, 369.
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Gallagher, P. T. J . Chem. Soc., Perkin Trans. 1 1992, 553. (f) Barco,
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Org. Chem. 1992, 57, 6279. (g) Takano, S.; Inomata, K.; Ogasawara,
K. J . Chem. Soc., Chem. Commun. 1992, 169. (h) Hatakeyama, S.;
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Valli, M. J . J . Org. Chem. 1994, 59, 2773. (k) Bachi, M. D.; Melman,
A. Synlett 1996, 60. (l) Bachi, M. D.; Bar-Ner, N.; Melman, A. J . Org.
Chem. 1996, 61, 7116. (m) Hanessian, S.; Ninkovic, S. J . Org. Chem.
1996, 61, 5418. (n) Nakada, Y.; Sugahara, T.; Ogasawara, K. Tetra-
hedron Lett. 1997, 38, 857. (o) Rubio, A.; Ezquerra, J .; Remuin˜a´n, M.
J .; Vaquero, J . J . Tetrahedron Lett. 1998, 39, 2171. For rewiews, see:
Synthesis of Optically Active R-Amino Acids: Williams, R. M., Ed.;
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Resu lts a n d Discu ssion
In light of our synthetic approach to the 4-substituted
kainic acids 2 (Scheme 1) based on the stereocontrolled
C-4 alkylation on the pyroglutamate derivative 6, the
most notable difficulty of achieving our targets resided
in the stereoselective functionalization of C-5 on the same
bicyclic pyroglutamate 6. Recently, we7 and others8,9 have
reported on the stereoselective functionalization of N-BOC
ethyl pyroglutamate as one of the most useful routes to
the synthesis of 5-substituted prolines. On the basis of
these results and taking into account the high degree of
stereocontrol exercised by the 3-azabicyclo[3.3.0]octane
nucleus, it was argued that bicyclic pyroglutamate 6
could be transformed into the 5â-substituted prolinate 7
by diastereoselective addition of organocopper reagents
to the N-acyliminium ion I whereas the 5R epimer 8
10.1021/jo982109j CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/26/1999

Synthesis of 5R- and 5â-Substituted Kainic Acids
J . Org. Chem., Vol. 64, No. 12, 1999 4305
Sch em e 1
Sch em e 2
would be the result of the hydrogenation of the cyclic
imine 9 (Scheme 2). After the stereoselective introduction
of the substituent in the desired position, the side chains
at C-3 and C-4 would be generated by dehydration of the
tertiary alcohol followed by oxidative cleavage of the
double bond. Methyl and phenyl substituents at C-5 were
chosen on the basis of their distinctive size and properties
compared with a hydrogen atom.
Sch em e 3
(4) (a) Goldberg, O.; Luini, A.; Teichberg, V. I. Tetrahedron Lett.
1980, 21, 2355. (b) Conway, G. A.; Park, J . S.; Maggiora, L.; Mertes,
M. P.; Galton, N.; Michaelis, E. K. J . Med. Chem. 1984, 27, 52. (c)
Goldberg, O.; Teichberg, V. I. J . Med. Chem. 1985, 28, 1957. (d)
Yanagida, M.; Hashimoto, K.; Ishida, M.; Shinozaki, H.; Shirahama,
H. Tetrahedron Lett. 1989, 30, 3799. (e) Hashimoto, K.; Horikawa, M.;
Shirahama, H. Tetrahedron Lett. 1990, 31, 7047. (f) Kozikowski, A.
P.; Fauq, A. H. Tetrahedron Lett. 1990, 31, 2967. (g) Hanssen, J . J .;
Krogsgaard-Larsen, P. Med. Res. Rev. 1990, 10, 55. (h) Hashimoto,
K.; Shirahama, H. Tetrahedron Lett. 1991, 32, 2625. (i) J efferies, I.
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M.; Ishida, M.; Shinozaki, H.; Shirahama, H. Bioorg. Med. Chem. Lett.
1992, 2, 743. (k) Tabcheh, M.; Pappalardo, L.; Roumestant, M. L.;
Viallefont, P. Amino Acids 1992, 2, 191. (l) Baldwin, J . E.; MacKenzie
T. S. C.; Moloney, M. G. Synlett 1994, 925. (m) Baldwin, J . E.; Rudolph,
M. Tetrahedron Lett. 1994, 35, 6163. (n) Baldwin, J . E.; Bamford, S.
J .; Fryer, A. M.; Wood, M. E. Tetrahedron Lett. 1995, 36, 4869. (o) Gill,
P.; Lubell, W. D. J . Org. Chem. 1995, 60, 2658. (p) Ezquerra, J .;
Escribano, A.; Rubio, A.; Remuin˜a´n, M. J .; Vaquero, J . J . Tetrahedron
Lett. 1995, 36, 6149. (q) Hashimoto, K.; Ofhune, Y.; Shirahama, H.
Tetrahedron Lett. 1995, 36, 6235. (r) Horikawa, M.; Shima, Y.;
Hashimoto, K.; Shirahama, H. Heterocycles 1995, 40, 1009. (s) Hash-
imoto, K.; Hashimoto, M.; Shirahama, H. Tetrahedron 1996, 52, 1931.
(t) Hanessian, S.; Ninkovic, S.; Reinhold: U. Tetrahedron Lett. 1996,
37, 8971. (u) 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. (v) Ezquerra, J .; Escribano, A.; Rubio,
A.; Remuin˜a´n, M. J .; Vaquero, J . J . Tetrahedron Asymmetry 1996, 7,
2613. (w) Maeda, H.; Kraus, G. A. J . Org. Chem. 1997, 62, 2314.
(5) (a) Tsai, C.; Schinider, J . A.; Lehmann, J . Neurosci. Lett. 1988,
92, 298. (b) Ishida, M.; Shinozaki, H. Br. J . Pharmacol. 1991, 104, 873.
(c) Sonnenberg, J . D.; Koch, H. P. K.; Willis, C. L.; Bradbury, F.;
Dauenhauer, D.; Bridges, R.; Chamberlin, A. R. Bioorg. Med. Chem.
Lett. 1996, 6, 1607.
The key bicyclic intermediate 6 was obtained from the
azabicyclooctanone derivative 5 in 70% yield after pro-
tecting group exchange, C-4 oxidation, and further
protection of the hydroxyl group.6 Compound 5, in turn,
was prepared via a [3 + 2] cycloaddition reaction of a
thiazolium ylide with 2-cyclopentenone in a four-step
sequence in 45% overall yield as reported by Monn and
Valli3j (Scheme 1). The synthesis of the 5â-substituted
kainic acids 3 is shown in Scheme 3. Partial reduction
with DIBAL10 of the lactam carbonyl on 6, followed by
treatment of the resulting hemiaminal with PTSA in
MeOH resulted in the formation of 10 as a single
diastereomer. The stereochemistry of the newly gener-
ated center is not relevant, but it was presumably
assigned as 5â on the basis of the steric hindrance
imposed by the 3-azabicyclo[3.3.0]octane nucleus. The
generation of the N-acyliminium ion intermediate I by
(6) Collado, I.; Ezquerra, J .; Mateo, A. I.; Rubio, A. J . Org. Chem.
1998, 63, 1995.
(7) (a) Ezquerra, J .; Rubio, A.; Pedregal, Cc.; Sanz, G.; Rodr´ıguez,
J . H.; Garc´ıa-Ruano, J . L. Tetrahedron Lett. 1992, 34, 4989. (b)
Ezquerra, J .; Pedregal, C.; Rubio, A.; Valenciano, J .; Garc´ıa Nav´ıo, J .
L.; Alvarez-Builla, J .; Vaquero, J . J . Tetrahedron Lett. 1993, 34, 6317.
(c) Collado, I.; Ezquerra, J .; Vaquero, J . J .; Pedregal, C. Tetrahedron
Lett. 1994, 35, 8037. (d) Collado, I.; Ezquerra, J .; Pedregal, C. J . Org.
Chem. 1995, 60, 5011.
(8) (a) Skrinjar, M.; Wistrand, L.-G. Tetrahedron Lett. 1990, 31,
1775. (b) Wistrand, L.-G.; Skrinjar, M. Tetrahedron 1991, 47, 573. (c)
Thaning, M.; Wistrand, S.-G. Acta Chem. Scand. 1992, 46, 194. (d)
Skrinjar, M.; Nilsson, C.; Wistrand, L.-G.; Tetrahedron: Asymmetry
1992, 3, 1263. (f) Yoda, H.; Kitayama, H.; Yamada, W.; Katagiri, T.;
Takabe, K. Tetrahedron: Asymmetry 1993, 4, 1451.
(9) Petersen, J . S.; Fels, G.; Rapoport, H. J . Am. Chem. Soc. 1984,
106, 4539. (b) Shiosaki, K.; Papoport, H. J . Org. Chem. 1985, 50, 1229.
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(10) Langlois, N.; Rojas, A. Tetrahedron Lett. 1993, 34, 2477.

4306 J . Org. Chem., Vol. 64, No. 12, 1999
Collado et al.
Sch em e 4
Sch em e 5
for 12b). Noteworthy, all the chemical transformations
from 6 to 12a ,b were performed without further purifica-
tion of the intermediates.
treatment of the aminal 10 with BF3‚OEt2, and its
reaction with 2 equiv of a Grignard-derived organocopper
reagent7d RCu‚MgBr2 gave rise to the single diastereo-
mers 7a ,b in excellent yields (92% for 7a and 88% for
7b for the three steps from 6). The stereochemistry of
7a ,b could not be deduced unambiguously at this stage
due to the presence of rotamers that highly complicates
the NMR spectra. Treatment of 7a ,b with BF3‚OEt2
resulted in the alcohol deprotection and elimination with
simultaneous removal of the N-BOC protecting group
giving 11a ,b (96% for 11a and 94% for 11b). NOE
experiments recorded on compounds 11 allowed us to
firmly establish the stereochemistry as 5â,11 confirming
that the stereochemical outcome of the organocopper
addition is governed by the steric congestion imposed by
the bicyclic system and the OTBDMS group. Nitrogen
protection in 11a ,b gave 12a ,b (91% for 12a and 90%
Once the desired functionalization at C-5 was achieved,
the next steps in the synthesis were directed to the
elaboration of the side chains at C-3 and C-4 (Scheme
4). Keto ester 13a was prepared from 12a by ruthenium
oxidation followed by esterification with (trimethylsilyl)-
diazomethane (54% for the two steps). The Wittig reac-
tion on 13a was shown to compete with the intramolec-
ular Claisen cyclization resulting in a low yield of the
corresponding olefin 14a . Since other methylenation
methods were unsuccessful, we explored the route previ-
ously reported for the synthesis of 4-substituted kainic
acids.6 Thus, osmylation of 12a ,b followed by periodate
cleavage gave the keto aldehydes 15a ,b which were
chemoselectively reduced with Zn(BH4)2 to the keto
alcohols 16a ,b. Characterization of 16a and 16b was not
possible since they exist as an equilibrium mixture with
their corresponding lactols. The Wittig methylenation on
16a ,b gave the desired olefins 17a ,b in good overall yields
and without purification of the intermediates (61% for
17a and 64% for 17b). It is noteworthy that no evidence
of epimerization at C-4 was observed under these basic
conditions. The synthesis of 3 was then completed after
J ones oxidation and hydrolysis of the ester and BOC
groups. The stereochemistry of the final amino acids 3a ,b
was unambiguously confirmed by NOE experiments
performed on the hydrochlorides.11
(11) The NOEs observed in 11 and 3 are shown below:
The synthesis of the 5R-substituted kainic acids started
from the same common intermediate 6. In this case, the
stereoselective introduction of substituents at C-5 re-
quired the nucleophilic ring opening7d of the pyro-
glutamate derivative 6 with a suitable Grignard reagent
and further cyclization of the resulting keto N-BOC
derivative to the imines 9a ,b. The R-configuration of the

Synthesis of 5R- and 5â-Substituted Kainic Acids
J . Org. Chem., Vol. 64, No. 12, 1999 4307
Sch em e 6
Sch em e 7
C-5 substituent would then be the result of the hydro-
genation of 9 from the less-hindered face. Reaction of 6
with a Grignard reagent (R ) CH3, C6H5) took place
exclusively at the lactam carbonyl group giving the
ketones 20a ,b in quantitative yield (Scheme 5). Surpris-
ingly, the conditions for the isolation of the intermediates
20a ,b greatly influence the ratio of the two epimeric
ketones. Thus, when the reactions were quenched with
a saturated ammonium chloride solution, the nonepimer-
ized ketones were isolated as single products, whereas
quenching the reaction mixture with a MeOH/AcOH (1:
1) solution gave rise to an equimolecular mixture of
epimeric ketones. In both cases, further treatment with
trifluoroacetic acid gave exclusively the cyclic imines
9a ,b. This transformation proceeded in excellent yields
(95% for 9a and 84% for 9b), but only when the reaction
was carried out with a large excess (30 equiv) of trifluoro-
acetic acid. These conditions were determined after it was
realized that smaller excess of trifluoroacetic acid retards
the removal of the BOC group and favors the R,â-
elimination of the OTBDMS group giving mixtures of the
desired imines 9a ,b along with varying amounts of side
products resulting from the elimination of the OTBDMS
group.
Hydrogenation of the cyclic imines 9a ,b proceeded
quantitatively to give, as expected, the prolinate deriva-
tives 8a ,b as single isomers. The stereochemistry of C-5
was confirmed by NOE experiments performed on the
elimination products 21a ,b resulting from the treatment
of 8a ,b with BF3‚OEt2. Nitrogen protection on 21a ,b
allowed us to isolate the N-BOC derivatives 22a ,b in
excellent overall yields for the five steps from 6 (70% for
22a and 59% for 22b ). Oxidative ring opening of 22a
followed by chemoselective reduction of the resulting keto
aldehyde 23a afforded the keto alcohol 24a . Owing to the
lability of the C-4 stereocenter of 24a , it was not surpris-
ing that attempts to apply the same synthetic route as
described above for the elaboration of the side chains
resulted in the exclusive formation of the allokainic acid
derivative 28a .
was the thermodynamically more stable 16a . These
assumptions were discerned by performing the Wittig re-
actions with dideuterated triphenylphosphonium meth-
ylide (Scheme 6). In both cases, introduction of deuterium
at C-4 indicated that ketone enolization occurred prior
to the Wittig reaction and therefore the more stable
trans-C4/C5 olefins 17a and 25a were obtained.
Since the Wittig reaction proceeded with epimerization
at C-4 and other nonbasic methylenation reagents proved
to be ineffective, an alternative approach was devised for
the conversion of 22a ,b into the R-substituted kainic
acids 4 (Scheme 7). Hydroxylation of the double bond
followed by Swern oxidation afforded the hydroxy ketones
29a ,b, which were dehydrated with the Burgess reagent12
to give the unsaturated ketones 30a ,b. Several attempts
to generate the thermodynamic enolate II by treatment
of the enones 30a ,b with a complex prepared from
diisobutylaluminum hydride and copper iodide in a
mixture of THF and HMPA,3g,13 resulted in the recovery
of the unreacted enone. However, when the copper iodide
At this point, there was an intriguing aspect to the
Wittig reaction. The fact that no evidence of C-4 epimer-
ization was observed when the Wittig reaction was
carried out on 16a , whereas such epimerization on the
isomer 24a was complete, led us to study in more detail
these reactions. There were two possible explanations to
this different behavior: (a) the substituent at C-5â was
preventing the enolization of the ketone 16a or (b)
enolization occurred but, the result of the equilibration
(12) (a) Atkins, G. M.; Burgess, E. M. J . Am. Chem. Soc. 1968, 90,
4744. (b) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J . Org. Chem.
1973, 38, 26.
(13) (a) Tsuda, T.; Fuji, T.; Kawasaki, T.; Saegusa, T. J . Chem. Soc.
Chem. Commun. 1980, 1013. (b) Tsuda, T.; Satomi, H.; Hayashi, T.;
Saegusa, T. J . Org. Chem. 1987, 52, 439.

4308 J . Org. Chem., Vol. 64, No. 12, 1999
Collado et al.
diethyl ether were distilled from sodium/benzophenone ketyl
prior to use. HMPA was distilled under CaH2 and collected
was replaced by methyl copper (prepared from methyl-
lithium and copper bromide dimethyl sulfide complex),
the enolate II was formed, and, after addition of an excess
of paraformaldehyde, the hydroxy ketones 31a ,b were
isolated in very good yields. The alcohols 31a ,b were
tosylated and further reduced with lithium triethylboro-
hydride. Treatment of the resulting monotosylated diols
with potassium tert-butoxide14 gave the Wharton frag-
mentation’s products 33a ,b in moderate yields. Finally,
J ones oxidation followed by ester hydrolysis and BOC
removal allowed to isolate the 5R-substituted kainic acids
4a ,b. The stereochemistry of 4a ,b was ascertained by
comparison of their NMR spectra15 with those of 3a ,b and
by the NOE results.16
Compounds 3 and 4 were evaluated for their binding
as agonists and antagonists in cells expressing hum-
GluR6 kainate receptors and in the rat forebrain kainate
receptors. Unfortunately, no significant binding affinity
was found compared with kainic acid itself. This lack of
activity reflects the sensitivity of the kainate receptors
recognition site to steric and conformational factors.
1
over 4 Å molecular sieves. H NMR and 13C NMR data were
recorded at 200 and 50 MHz, respectively. Analytical TLC was
performed on Merck TLC glass plates precoated with F254
silica gel 60 (UV (254 nm), PMA and iodine). Chromatographic
separations were performed by using 230-400 mesh silica gel
(Merck).
Eth yl (1SR,2SR,4SR,5SR,6RS)-N-(ter t-Bu toxyca r bon -
yl)-3-aza-6-[(ter t-bu tyldim eth ylsilyl)oxy]-6-m eth yl-4-m eth -
oxybicyclo[3.3.0]octa n e-2-ca r boxyla te (10). To a solution
of 6 (3.0 g, 6.8 mmol) in 50 mL of THF at -78 °C was added
10.2 mL (10.2 mmol) of a 1 M solution of diisobutylaluminum
hydride in THF. The mixture was stirred at -78 °C for 30 min
and then quenched with methanol (15 mL). The reaction
mixture was poured into a mixture of ethyl acetate (50 mL)
and a sodium tartrate solution (40 mL) and stirred at room
temperature for 1 h. The aqueous layer was extracted with
ethyl acetate (3 × 20 mL) and the organic phase was dried
(Na2SO4) and evaporated to dryness. The residue was dissolved
in methanol (25 mL), and 130 mg (0.68 mmol) of p-toluene-
sulfonic acid was added. After the solution was stirred at room-
temperature overnight, a saturated NaHCO3 solution (10 mL)
was added. The methanol was evaporated in vacuo, and the
aqueous phase was extracted with ether (3 × 25 mL). The
organic phase was dried (Na2SO4) and concentrated to dryness
to give 3.1 g of 10 which was used in subsequent reaction
without further purification: 1H NMR (CDCl3, doubling due
to rotamers) δ 5.29 and 5.28 (2s, 1H), 4.22-4.02 (m, 3H), 3.40
and 3.35 (2s, 3H), 2.96-2.82 (m, 1H), 2.29-2.19 (m, 1H), 2.05-
1.53 (m, 4H), 1.46-1.20 (m, 15H), 0.86 and 0.83 (2s, 9H), 0.09
and 0.06 (2s, 6H); 13C NMR (CDCl3, doubling due to rotamers)
δ 173.0, 172.4, 153.6, 153.4, 90.3, 90.0, 81.4, 81.3, 80.6, 80.1,
68.3, 67.7, 62.9, 62.0, 60.8, 60.7, 55.2, 55.1, 45.8, 43.9, 41.9,
40.8, 30.8, 30.7, 28.6, 28.1, 28.3, 28.2, 26.0, 18.0, 14.2, 14.1,
-2.2, -2.3; IR (film) 2957, 1709, 1390, 1367, 1179 cm-1; HRMS
(m/z): calcd for C23H43NO6Si (M+): 457.2860, found: 457.2861.
Eth yl (1SR,2SR,4SR,5RS,6RS)-N-(ter t-Bu toxyca r bon -
yl)-3-a za -6-[(ter t-bu tyld im eth ylsilyl)oxy]-4,6-d im eth ylbi-
cyclo[3.3.0]octan e-2-car boxylate (7a) an d Eth yl (1SR,2SR,4
RS,5RS,6RS)-N-(tert-Butoxycarbonyl)-3-aza-6-[(tert-butyldi-
methylsilyl)oxy]-4-phenyl-6-methylbicyclo[3.3.0]octane-2-car-
boxyla te (7b). To a suspension of CuBr‚Me2S (3.0 g, 14.6
mmol) in 30 mL of diethyl ether at -40 °C was added a
solution of the Grignard reagent (MeMgBr or PhMgBr) (14.6
mmol). The reaction mixture was stirred at -40 °C for 30 min
and then cooled to -78 °C prior to the addition of 1.8 mL (14.6
mmol) of boron trifluoride etherate. After the mixture was
stirred for 15 min, a solution of 10 (3.0 g, 6.6 mmol) in diethyl
ether (15 mL) was added. The reaction mixture was stirred at
-78 °C for 15 min and then allowed to warm to room
temperature and remain there for 1 h at which time TLC
analysis (hexane/ethyl acetate 7:1) revealed complete con-
sumption of 10. The reaction mixture was quenched with 30
mL of a (1:1) mixture of a saturated NH4OH solution and a
saturated solution of NH4Cl. After stirring for 1 h, the layers
were separated and the aqueous layer was extracted with
diethyl ether (3 × 25 mL). The combined organic phases were
washed with a saturated NaHCO3 solution, dried (Na2SO4) and
concentrated in vacuo to give 7a ,b, which were purified by
chromatography (7a : hexane/ethyl acetate 7:1; 7b: hexane/
ethyl acetate 8:1) 7a : 2.7 g (92% yield from 6); colorless oil;
1H NMR (CDCl3, doubling due to rotamers) δ 4.16-3.91 (m,
4H), 2.78-2.62 (m, 1H), 2.04-1.11 (m, 23H), 0.81 (s, 9H), 0.05
(s, 6H); 13C NMR (CDCl3, doubling due to rotamers) δ 173.8,
173.3, 153.7, 152.7, 82.0, 79.2, 68.9, 68.4, 63.4, 63.1, 60.5, 54.6,
46.0, 44.8, 41.5, 40.7, 29.9, 28.3, 27.9, 27.2, 25.9, 22.1, 21.4,
18.0, 14.1, -2.2, -2.4; IR (film) 2963, 2932, 1699, 1391, 1182
cm-1. Anal. Calcd for C23H43NO5Si: C, 62.54; H, 9.81; N, 3.17.
Found: C, 62.90; H, 9.98; N, 3.52. 7b: 2.92 g (88% yield from
6); colorless oil; 1H NMR (CDCl3, doubling due to rotamers) δ
7.55-7.50 (m, 2H), 7.32-7.12 (m, 3H), 4.96 and 4.92 (2s, 1H),
4.36-4.06 (m, 3H), 2.96-2.81 (m, 1H), 2.23-1.83 (m, 4H),
1.68-1.47 (m, 1H), 1.42-1.19 (m, 6H), 1.32 and 1.11 (2s, 9H),
0.88 (s, 9H), 0.17 and 0.15 (2s, 6H); 13C NMR (CDCl3, doubling
Su m m a r y
We have described in this paper highly efficient routes
to the synthesis of 5â- and 5R-substituted kainic acids.
The introduction of substituents at C-5â and C-5R, and
the elaboration of the stereogenic centers to the final
kainoids can be accomplished with full control over its
relative configuration from the common intermediate 6.
The key functionalization steps comprised organocopper
addition to the N-acyliminium ion I and hydrogenation
of the cyclic imine 9, both of which proceeded with
excellent yields and diastereoselectivities. Transforma-
tions of the bicyclic intermediates 7 and 8 into the final
substituted kainic acids were accomplished via stepwise
sequences that avoid the undesirable facile intramolecu-
lar Claisen and epimerization reactions. In summary,
pyroglutamate derivative 6 proved to be a versatile
synthon from which straightforward access to both 4-,6
5â-, and 5R-substituted kainic acids could be achieved
with complete stereocontrol.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. All solvents and reagents were
purchased from commercial sources and used as received,
unless otherwise indicated. Tetrahydrofuran, dioxane, and
(14) (a) Wharton, P. S.; Hiegel, G. A.; Coombs, R. V. J . Org. Chem.
1963, 28, 3217. (b) Grob, C. A. Angew. Chem., Int. Ed. Engl. 1969, 8,
535. (c) Caine, D. Org. Prep. Proced. Int. 1988, 25, 3.
(15) Hashimoto, K.; Konno, K.; Shirahama, H. J . Org. Chem. 1996,
61, 4685.
(16) The NOEs observed in 21 and 4 are shown below:

Synthesis of 5R- and 5â-Substituted Kainic Acids
J . Org. Chem., Vol. 64, No. 12, 1999 4309
due to rotamers) δ 173.8, 173.4, 153.5, 152.8, 146.0, 145.2,
128.3, 128.0, 126.2, 126.1, 125.9, 125.6, 82.2, 79.8, 79.4, 69.5,
69.2, 65.9, 65.5, 62.5, 62.4, 60.7, 60.6, 46.5, 45.7, 42.2, 42.1,
28.7, 28.4, 28.1, 27.9, 26.7, 26.5, 26.1, 25.9, 18.0, -2.0, -2.1,
-2.2, -2.3; IR (film) 1750, 1699, 1391, 1256, 1181 cm-1. Anal.
Calcd for C28H45NO5Si: C, 66.76; H, 9.00; N, 2.78. Found: C,
66.68; H, 8.92; N, 2.58.
The black-colored mixture was stirred at room temperature
for 4 h and then partitioned between ether (20 mL) and H2O
(20 mL). The layers were separated, and the aqueous phase
was extracted with ether (2 × 20 mL). The combined organic
phases were washed with H2O (10 mL), dried (Na2SO4), filtered
through Celite, and concentrated in vacuo. The crude carbox-
ylic acid was dissolved in ether (100 mL) and treated sequen-
tially with EtOH (3.6 mL) and a 2 M solution of (trimethyl-
silyl)diazomethane in hexane (3.6 mL, 7.2 mmol). The reaction
mixture was stirred at room temperature for 30 min, and then
the solvents were evaporated in vacuo. The reaction crude was
purified by chromatography (hexane/ethyl acetate 2:1) to afford
0.68 g of 13a (54% yield) colorless oil; 1H NMR (CDCl3,
doubling due to rotamers) δ 4.23-3.96 (m, 4H), 3.64 (s, 3H),
3.19-3.14 (m, 1H), 2.92-2.49 (m, 3H), 2.17 (s, 3H), 1.47-1.19
(m, 15H); 13C NMR (CDCl3, doubling due to rotamers) δ 207.2,
172.3, 172.0, 172.1, 171.9, 153.7, 153.0, 80.2, 64.6, 64.3, 61.1,
60.3, 58.9, 57.4, 55.8, 55.0, 51.7, 40.1, 39.3, 32.8, 32.2, 30.9,
30.6, 28.2, 28.1, 20.6, 20.3, 14.1; IR (film) 1747, 1720, 1699,
E t h yl (1SR,2SR,4SR,5SR)-3-Aza -4,6-d im et h ylbicyclo-
[3.3.0]oct-6-ene-2-carboxylate(11a)and Ethyl(1SR,2SR,4RS,5SR)-
3-Aza -4-p h en yl-6-m eth ylbicyclo[3.3.0]oct-6-en e-2-ca r box-
yla te (11b). To a solution of 7a ,b (6.5 mmol) in CHCl3 (35
mL) was added 16.0 mL (130 mmol) of boron trifluoride
etherate. The mixture was heated in a sealed tube at 100-
110 °C for 24 h, and then it was quenched with a saturated
solution of NaHCO3. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The
combined organic phases were washed with
a saturated
solution of NaHCO3 (25 mL), dried (Na2SO4), and concentrated
in vacuo to give 11a ,b which were used in subsequent reaction
without further purification. 11a : colorless oil; 1H NMR
(CDCl3) δ 5.13 (s, 1H), 4.18 (c, 2H, J ) 7.1 Hz), 3.22 (d, 1H, J
) 8.5 Hz), 2.95-2.82 (m, 1H), 2.79-2.58 (m, 2H), 2.51-2.17
(m, 2H), 2.04 (s broad, 1H), 1.64 (s, 3H), 1.27 (d, 3H, J ) 6.4
Hz), 1.24 (t, 3H, J ) 7.1 Hz); 13C NMR (CDCl3) δ 173.8, 140.5,
122.8, 67.8, 62.7, 60.7, 60.0, 48.9, 35.8, 21.3, 14.7, 14.2; IR (film)
2963, 2928, 2855, 1736, 1200 cm-1; HRMS (m/z): calcd for
1684 cm-1
.
Met h yl (2SR,3SR,4SR,5SR)-N-(ter t-Bu t oxyca r b on yl)-
2-(eth oxyca r bon yl)-4-isop r op en yl-5-m eth yp yr r olid in e-3-
a ceta te (14a ). To a suspension of methyltriphenylphosphon-
ium bromide (1.8 g, 5 mmol) in toluene (25 mL) was added at
room temperature under nitrogen, a 0.5 M solution of potas-
sium bis(trimethylsilyl)amide in toluene (8.8 mL, 4.4 mmol),
and the reaction was allowed to continue at room temperature
for 1 h. To a stirred solution of 13a (740 mg, 2 mmol) in toluene
(12 mL) at room temperature under nitrogen was added via
cannula the foregoing solution of methyltriphenylphosphonium
ylide until the reaction was complete (TLC; hexane/ethyl
acetate 2:1). The reaction mixture was partitioned between
ether (50 mL) and H2O (50 mL), and the layers were separated.
The aqueous phase was extracted with ether (2 × 25 mL), and
the combined organic phases were dried (Na2SO4) and evapo-
rated in vacuo. The crude was purified by chromatography
(hexane/ethyl acetate 4:1) affording 214 mg of 14a as a
colorless oil (29% yield): 1H NMR (CDCl3, doubling due to
rotamers) δ 4.87 (s, 1H), 4.65 (s, 1H), 4.26-3.74 (m, 4H), 3.66
(s, 3H), 2.98-2.82 (m, 1H), 2.68-260 (m, 1H), 2.48-2.25 (m,
2H), 1.64 (s, 3H), 1.45-1.23 (m, 15H); 13C NMR (CDCl3,
doubling due to rotamers) δ 172.5, 172.2, 172.3, 154.0, 153.2,
142.3, 142.3, 114.0, 113.9, 80.1, 64.6, 64.3, 61.2, 56.8, 54.4, 53.7,
51.7, 40.5, 39.6, 33.2, 28.4, 28.3, 22.0, 21.8, 20.2, 19.6, 14.2,
14.1.
C
12H18NO2: (M+ - 1): 208.1338, found: 208.1343. 11b:
colorless oil; 1H NMR (CDCl3) δ 7.47-7.21 (m, 5H), 5.24 (s,
1H), 4.22 (c, 2H,J ) 7.1 Hz), 3.93 (d, 1H, J ) 5.8 Hz), 3.43 (d,
1H, J ) 8.7 Hz), 3.20-3.13 (m, 1H), 3.03-2.89 (m, 1H), 2.62-
2.30 (m, 2H), 2.36 (s broad, 1H), 1.67 (s, 3H), 1.28 (t, 3H, J )
7.1 Hz); 13C NMR (CDCl3) δ 173.5, 143.6, 140.5, 128.5, 127.2,
123.1, 68.1, 67.8, 63.0, 60.7, 48.3, 35.6, 15.0, 14.1. IR (film)
2924, 1738, 1194 cm-1. HRMS (m/z): calcd for C17H21NO2:
(M+): 271.1572, found: 271.1575.
Eth yl (1SR,2SR,4SR,5SR)-N-(ter t-Bu toxyca r bon yl)-3-
aza-4,6-dim eth ylbicyclo[3.3.0]oct-6-en e-2-car boxylate (12a)
a n d Eth yl (1SR,2SR,4RS,5SR)-N-(ter t-Bu toxyca r bon yl)-
3-a za -4-p h en yl-6-m eth ylbicyclo[3.3.0]oct-6-en e-2-ca r box-
yla te (12b). To a solution of 11a ,b (6 mmol), Et3N (2.19 mL,
15 mmol) and DMAP (732 mg, 6 mmol) in CH2Cl2 (15 mL) was
added a solution of di-tert-butyl dicarbonate (2.64 g, 12 mmol)
in CH2Cl2 (5 mL). The reaction mixture was stirred at room
temperature until completion. The mixture was then poured
into a 1:1 mixture of CH2Cl2 and a 1 N solution of HCl. The
organic phase was separated, washed several times with 1 N
HCl, dried (Na2SO4), and evaporated to dryness. The crude
was purified by chromatography (hexane/ethyl acetate 8:1) to
give 12a ,b (1.75 g of 12a , 87% yield from 7a ; 2.05 g of 12b,
85% yield from 7b). 12a : colorless oil; 1H NMR (CDCl3,
doubling due to rotamers) δ 5.29 (s, 1H), 4.21-3.76 (m, 4H),
2.93-2.83 (m, 1H), 2.72-2.69 (m, 1H), 2.57-2.29 (m, 2H), 1.69
(s, 3H), 1.51-1.21 (m, 15H); 13C NMR (CDCl3, 333 K) δ 173.1,
153.2, 140.1, 123.8, 79.2, 67.2, 60.2, 60.1, 56.5, 45.6, 37.6, 28.1,
21.0, 14.1, 13.9; IR (film) 2976, 1751, 1696, 1451, 1392, 1257,
1186 cm-1. Anal. Calcd for C17H27NO4: C, 65.99; H, 8.79; N,
4.53. Found: C, 65.62; H, 9.07; N, 4.67. 12b: white solid, mp
92-94 °C (hexane); 1H NMR (CDCl3, doubling due to rotamers)
δ 7.57-7.53 (m, 2H), 7.36-7.16 (m, 3H), 5.35 (s, 1H), 5.05 and
4.84 (2s, 1H), 4.24 (c, 2H, J ) 7.1 Hz), 4.00 and 3.92 (2d, 1H,
(2SR,3SR,4SR,5SR)-N-(ter t-Bu t oxyca r b on yl)-2-(et h -
oxyca r b on yl)-4-a cet yl-5-m et h ylp yr r olid in e-3-a cet a ld e-
h yd e (15a ) a n d (2SR,3SR,4SR,5RS)-N-(ter t-Bu toxyca r -
bon yl)-2-(eth oxyca r bon yl)-4-a cetyl-5-p h en ylp yr r olid in e-
3-a ceta ld eh yd e (15b). A stirred solution of 12a ,b (2 mmol)
and N-methylmorpholine N-oxide (515 mg, 4.4 mmol) in
acetone (20 mL) and H2O (6 mL) was treated with a 4%
solution of OsO4 in H2O (37 mL, 0.003 mmol), and the resulting
mixture was stirred at room temperature for 24 h. The reaction
mixture was partitioned between ether (40 mL) and H2O (40
mL). The layers were separated, and the aqueous layer was
extracted with ether (3 × 20 mL). The combined organic phases
were washed with H2O, dried (Na2SO4), and evaporated to
dryness. The crude diols were dissolved in THF (12 mL), and
a solution of NaIO4 (642 mg, 3 mmol) in H2O (8 mL) was added.
The mixture was stirred at room temperature for 5 h and then
partitioned between ether (40 mL) and H2O (40 mL). The
layers were separated and the aqueous phase was extracted
with ether (3 × 40 mL). The combined organic phases were
washed with H2O (20 mL), dried (Na2SO4) and evaporated to
dryness to afford 15a ,b which were used without further
purification. 15a : colorless oil; 1H NMR (CDCl3, doubling due
to rotamers) δ 9.67 (s, 1H), 4.18-3.95 (m, 4H), 3.21-3.18 (m,
2
1J ) 6.3 Hz, J ) 6.6 Hz), 2.99-2.90 (m, 2H), 2.52-2.32 (m,
2H), 1.87 (s, 3H), 1.36-1.16 (m, 12H); 13C NMR (CDCl3,
doubling due to rotamers) δ 173.4, 172.9, 153.9, 153.3, 144.6,
143.9, 139.8, 128.2, 128.0, 126.4, 125.8, 125.6, 123.9, 80.1, 79.9,
67.2, 66.9, 65.0, 64.4, 62.6, 62.2, 60.7, 45.7, 45.1, 36.4, 36.1,
27.9, 14.7, 14.1; IR (KBr) 1752, 1699, 1385, 1368, 1181 cm-1
.
Anal. Calcd for C22H29NO4: C, 71.13; H, 7.87; N, 3.77. Found:
C, 71.22; H, 7.83; N, 3.55.
Meth yl (2SR,3SR,4RS,5SR)-N-(ter t-Bu toxyca r bon yl)-
4-a cetyl-2-(eth oxyca r bon yl)-5-m eth ylp yr r olid in e-3-a ce-
ta te (13a ). A mixture consisting of RuO2‚H2O (97 mg, 0.73
mmol) and NaIO4 (3.2 g, 15.0 mmol) in CH3CN (6.5 mL), CCl4
(6.5 mL), and H2O (9.5 mL) was vigorously stirred at room
temperature for 15 min. To this mixture was added a solution
of 12a (1.11 g, 3.6 mmol) in CH3CN (5 mL) and CCl4 (5 mL).
1H), 2.95-2.74 (m, 3H), 2.12 (s, 3H), 1.41-1.21 (m, 15H); 13
C
NMR (CDCl3, doubling due to rotamers) δ 207.7, 207.4, 200.0,
199.7, 172.3, 171.8, 153.7, 153.0, 80.3, 64.7, 64.4, 61.1, 58.9,
57.5, 55.9, 55.3, 43.0, 42.5, 37.6, 36.9, 30.8, 30.5, 28.2, 28.1,
20.6, 20.3, 14.1; IR (film) 2979, 1745, 1711, 1693, 1392, 1257
cm-1. Anal. Calcd for C17H27NO6.1/3H2O: C, 58.77; H, 8.03; N,
4.03. Found: C, 58.90; H, 8.09; N, 4.39. 15b: colorless oil; 1H

4310 J . Org. Chem., Vol. 64, No. 12, 1999
Collado et al.
NMR (CDCl3, doubling due to rotamers) δ 9.68 and 9.66 (2s,
1H), 7.60-7.53 (m, 2H), 7.37-7.21 (m, 3H), 5.07-4.92 (m, 1H),
4.34-4.18 (m, 3H), 3.56-3.49 (m, 1H), 3.20-2.65 (m, 3H),
2.23-2.08 (2s, 3H), 1.38 and 1.09 (2s, 9H), 1.34 (t, 3H, J ) 7.1
Hz); 13C NMR (CDCl3, doubling due to rotamers) δ 207.6, 206.8,
199.5, 199.2, 172.0, 171.7, 154.0, 153.5, 141.9, 141.2, 128.6,
128.2, 127.3, 127.1, 126.3, 125.7, 80.9, 80.6, 65.3, 64.9, 63.4,
62.9, 61.5, 61.3, 61.1, 59.8, 43.4, 42.3, 37.1, 31.5, 31.0, 28.1,
27.8, 14.1; IR (film) 2980, 1747, 1700, 1393, 1171 cm-1. Anal.
Calcd for C22H29NO6: C, 65.49; H, 7.24; N, 3.47. Found: C,
65.18; H, 7.09; N, 3.22.
min. The product was extracted with ethyl acetate (3 × 20
mL), the organic phase was dried (Na2SO4) and concentrated,
affording 18a ,b which were used without further purification.
18a : colorless oil; 1H NMR (CDCl3, doubling due to rotamers)
δ 4.88 (s, 1H), 4.66 (s, 1H), 4.22-3.80 (m, 4H), 2.92-2.82 (m,
1H), 2.65-2.28 (m, 3H), 1.63 (s, 3H), 1.43-1.22 (m, 15H); 13
C
NMR (CDCl3, doubling due to rotamers) δ 176.5, 172.3, 172.0,
154.0, 153.2, 142.1, 114.2, 80.2, 64.5, 64.1, 61.1, 56.9, 54.3, 53.6,
40.2, 39.4, 33.0, 28.2, 28.1, 21.9, 21.7, 20.0, 19.5, 14.0; IR (film)
3230, 2977, 1732, 1682, 1651, 1454, 1392 cm-1; HRMS (m/z):
calcd for C18H29NO6 (M+): 355.1995, found: 355.1997. 18a :
1
white foam; mp 52-54 °C; H NMR (CDCl3, doubling due to
Eth yl (2SR,3SR,4SR,5SR)-N-(ter t-Bu toxyca r bon yl)-3-
(2-h yd r oxyet h yl)-4-isop r op en yl-5-m et h ylp yr r olid in e-2-
ca r boxyla te (17a ) a n d Eth yl (2SR,3SR,4SR,5RS)-N-(ter t-
Bu t oxyca r b on yl)-5-p h e n yl-3-(2-h yd r oxye t h yl)-4-iso-
p r op en ylp yr r olid in e-2-ca r boxyla te (17b). To a stirred
solution of 15a ,b (2.0 mmol) in THF (20 mL) at -10 °C and
under argon was added 11.0 mL (2.2 mmol) of a 0.2 M solution
of Zn(BH4)2 in THF. The mixture was stirred at -10 °C for 30
min and then quenched with H2O (5 mL). The THF was
eliminated in vacuo, and the aqueous phase was diluted with
H2O (10 mL) and extracted with ether (3 × 20 mL). The
combined organic phase was dried (Na2SO4) and evaporated
in vacuo. The crude keto alcohols were dissolved in dioxane
(12 mL) and added to a solution of triphenylphosphonium
methylide (8 mmol) in dioxane (50 mL). The mixture was
stirred until the reaction was judged complete (TLC: hexane/
ethyl acetate 2:1). The reaction mixture was partitioned
between ether (100 mL) and H2O (100 mL), and the layers
were separated. The aqueous phase was extracted with ether
(2 × 50 mL), and the combined organic phases were dried
(Na2SO4) and evaporated in vacuo affording a yellow oil. Flash
chromatography (hexane/ethyl acetate 2:1) gave 17a ,b (61%
for 17a and 64% for 17b, overall yields from 12a and 12b,
respectively). 17a : 1H NMR (CDCl3, doubling due to rotamers)
δ 4.87 (s, 1H), 4.68 (s, 1H), 4.24-4.02 (m, 3H), 3.97-3.75 (m,
1H), 3.71-3.65 (m, 2H), 2.58-2.48 (m, 2H), 1.76-1.49 (m, 2H),
rotamers) δ 7.65-7.51 (m, 2H), 7.30-7.16 (m, 3H), 4.96-4.71
(m, 3H), 4.32-4.07 (m, 3H), 3.03-2.83 (m, 2H), 2.59-2.31 (m,
2H), 1.71 and 1.66 (2s, 3H), 1.38 and 1.11 (2s, 9H), 1.32 and
1.31 (2t, 3H, J ) 7.1 Hz); 13C NMR (CDCl3, doubling due to
rotamers) δ 177.2, 172.2, 172.0, 154.2, 153.5, 142.7, 142.3,
142.1, 141.1, 128.3, 128.0, 126.8, 126.1, 126.8, 115.1, 114.5,
80.9, 80.6, 65.4, 64.6, 64.9, 64.5, 61.3, 56.6, 56.3, 39.8 y 39.3,
33.2, 32.9, 28.1, 27.9, 22.8, 22.0, 14.1; IR (KBr) 3210, 1740,
1709, 1393, 1368 cm-1. Anal. Calcd for C23H31NO6: C, 66.17;
H, 7.48; N, 3.36. Found: C, 65.97; H, 7.31; N, 3.35.
(2SR,3SR,4SR,5SR)-N-(ter t-Bu toxycar bon yl)-2-car boxy-
4-isop r op en yl-5-m eth ylp yr r olid in e-3-a cetic Acid (19a )
a n d (2SR,3SR,4SR,5RS)-N-(ter t-Bu toxyca r bon yl)-2-ca r -
b oxy-5-p h en yl-4-isop r op en ylp yr r olid in e-3-a cet ic Acid
(19b). To a solution of 18a ,b (1 mmol) in THF (8 mL) was
added a 2.5 N solution of LiOH (16 mL, 40 mmol), and the
reaction mixture was stirred at room temperature for 48 h.
The THF was evaporated in vacuo, and the aqueous phase was
washed with ether (2 × 10 mL) prior to the addition of a 1 N
solution of HCl until pH 2. The aqueous phase was extracted
with ether (3 × 25 mL), dried (Na2SO4), and evaporated to
dryness to afford 19a ,b, which were used without further
purification. 19a : colorless oil; 1H NMR (CDCl3, doubling due
to rotamers) δ 9.56 (br s, 2H), 4.90 (s, 1H), 4.67 (s, 1H), 4.16-
3.69 (m, 2H), 3.04-2.96 (m, 1H), 2.66-2.36 (m, 3H), 1.65 (s,
3H), 1.45-1.29 (m, 12H); 13C NMR (CDCl3, 333 K) δ 176.6,
176.1, 154.6, 142.1, 114.0, 81.2, 64.6, 57.2, 54.6, 39.8, 33.2, 28.4,
22.1, 20.0; IR (film) 3410, 1745, 1713, 1655, 1410 cm-1. 19b:
1.65 (s, 3H), 1.44 and 1.39 (2s, 9H), 1.36 and 1.22 (m, 6H); 13
C
NMR (CDCl3, doubling due to rotamers) δ 173.2, 172.9, 154.2,
153.2, 142.6, 142.4, 113.5, 113.1, 79.8, 64.8, 64.4, 61.0, 60.4,
56.7, 56.3, 55.2, 54.5, 40.9, 40.1, 31.2, 31.1, 28.3, 28.2, 22.0,
21.7, 20.0, 19.4, 14.0, 13.9; IR (film) 3458, 2977, 1747, 1694,
1393, 1258 cm-1; HRMS (m/z): calcd for C18H31NO5 (M+):
341.2202, found: 341.2205. 17b: colorless oil; 1H NMR (CDCl3,
doubling due to rotamers) δ 7.65-7.51 (m, 2H), 7.32-7.14 (m,
3H), 4.92-4.67 (m, 3H), 4.32-4.12 (m, 3H), 3.70-3.52 (m, 2H),
2.92-2.80 (m, 1H), 2.59-2.46 (m, 1H), 1.82 (br s, 1H), 1.71
and 1.65 (2s, 3H), 1.73-1.40 (m, 2H), 1.37 and 1.08 (2s, 9H),
1.34 and 1.32 (2t, 3H, J ) 7.1 Hz); 13C NMR (CDCl3, doubling
due to rotamers) δ 173.0, 172.8, 154.4, 153.5, 143.1, 142.7,
142.5, 141.2, 128.2, 127.9, 127.1, 126.2, 126.8, 126.7, 114.6,
113.8, 80.6, 80.2, 65.5, 64.3, 65.3, 64.3, 61.2, 60.6, 57.4, 57.0,
40.9, 40.2, 30.9, 28.2, 27.9, 22.8, 22.0, 14.1; IR (film) 3460, 1746,
1
mp 196-198 °C; H NMR (DMSO-d6, doubling due to rotam-
ers) δ 7.63-7.57 (m, 2H), 7.31-7.19 (m, 3H), 4.93-4.71 (m,
2
3H), 4.09 and 3.98 (2d, 1J ) 8.1 Hz and J ) 3.9 Hz, 1H), 2.87-
2.59 (m, 2H), 2.44-2.16 (m, 2H), 1.66 and 1.60 (2s, 3H), 1.33
and 1.04 (2s, 9H). 13C NMR (DMSO-d6, doubling due to
rotamers) δ 173.5, 173.3, 173.0, 172.8, 153.6, 153.1, 143.4,
143.2, 142.8, 140.6, 128.1, 127.8, 127.1, 126.2, 126.7, 114.3,
114.1, 79.7, 79.1, 65.0, 64.2, 64.0, 63.5, 56.6, 56.0, 40.6, 40.2,
33.4, 32.5, 27.9, 27.7, 22.9, 21.9; IR (KBr) 3420, 1748, 1713,
1655, 1410 cm-1
.
(2SR,3SR,4SR,5SR)-2-Ca r boxy-4-isop r op en yl-5-m eth -
ylp yr r olid in e-3-a cetic Acid (3a ) a n d (2SR,3SR,4SR,5RS)-
2-Ca r b oxy-5-p h en yl-4-isop r op en ylp yr r olid in e-3-a cet ic
Acid (3b). A solution of 19a ,b (1 mmol) in a 1 N HCl solution
in ethyl acetate (5 mL) was stirred at room temperature for 8
h. The solvent was evaporated to dryness, and the resulting
precipitate was washed with ether and filtered to afford the
hydrochlorides of 3a ,b as white solids (83% for 3a and 87%
for 3b, overall yields from 17a and 17b, respectively. 3a : mp
193 °C; 1H NMR (CD3OD) δ 5.13 (s, 1H), 4.81 (s, 1H), 4.43 (d,
1H, J ) 4.0), 3.95-3.79 (m, 1H), 3.23-3.10 (m, 1H), 2.70-
2.60 (m, 1H), 2.54-2.31 (m, 2H), 1.78 (s, 3H), 1.43 (d, 3H, J )
6.4 Hz); 13C NMR (CD3OD) δ 174.8, 171.2, 140.4, 115.0, 64.2,
58.2, 54.0, 41.5, 34.1, 24.0, 16.5; IR (KBr) 3430, 1740, 1217
cm-1. Anal. Calcd for C11H18NO4Cl: C, 50.10; H, 6.89; N, 5.31.
Found: C, 50.08; H, 6.67; N, 5.04. 3b: mp 170-172 °C; 1H
NMR (CD3OD) δ 7.57-7.44 (m, 5H), 5.02 (s, 1H), 4.88 (d, 1H,
J ) 11.6), 4.78 (s, 1H), 4.54 (d, 1H, J ) 2.4 Hz), 3.45-3.28 (m,
2H), 2.64-2.42 (m, 2H), 1.75 (s, 3H); 13C NMR (CD3OD) δ
174.7, 171.3, 139.4, 134.1, 131.1, 130.4 (2C), 129.9 (2C), 116.2,
65.0, 64.3, 52.1, 41.9, 34.1, 23.8; IR (KBr) 3410, 1759, 1723,
1194 cm-1. Anal. Calcd for C16H20NO4Cl: C, 58.99; H, 6.19;
N, 4.30. Found: C, 58.90; H, 6.09; N, 4.19.
1694, 1682, 1393, 1368 cm-1; HRMS (m/z): calcd for C23H33
-
NO5 (M+): 403.2359, found: 403. 2360. Deuterated compound
17a -d6 was prepared from 15a following the same procedure
as for 17a , but using Ph3PCD3I instead of Ph3PCH3I. The
major isolated product in these conditions was 17a -d6 produced
from the equilibrium reactions of the corresponding ketone
1
enolate with Ph3PCD2H+. H NMR (CDCl3, 333 K) δ 4.87 and
4.68 (residual olefinic protons), 4.24-4.10 (m, 3H), 3.97-3.75
(m, 1H), 3.71-3.65 (m, 2H), 2.58-2.48 (m, 1.3H), 1.76-1.49
(m, 2H), 1.43 (s, 9H), 1.36 (d, J ) 6.3 Hz, 3H) and 1.2 (t, J )
7.1 Hz, 3H); 13C NMR (CDCl3, doubling due to rotamers) δ
same as for 17a , but carbons at 142.6, 142.4, 55.2, 54.5, 22.0,
and 21.7 appear as residual signals.
(2SR,3SR,4SR,5SR)-N-(ter t-Bu t oxyca r b on yl)-2-(et h -
oxycar bon yl)-4-isopr open yl-5-m eth ylpyr r olidin e-3-acetic
Acid (18a ) a n d (2SR,3SR,4SR,5RS)-N-(ter t-Bu t oxyca r -
bon yl)-2-(eth oxycar bon yl)-5-ph en yl-4-isopr open ylpyr r oli-
d in e-3-a cetic Acid (18b). To a solution of 17a ,b (1.0 mmol)
in acetone (7 mL) cooled to 0 °C was added freshly prepared
J ones reagent (1.7 mL). After the solution was stirred at 0 °C
for 1 h and at room temperature for 2 h, 2-propanol (15 mL)
and H2O (15 mL) were added and the mixture stirred for 15
E t h yl (1SR,2SR,5RS,6RS)-3-Aza -6-(ter t-bu t yld im et h -
ylsilyloxy)-4,6-d im eth ylbicyclo[3.3.0]oct-3-en e-2-ca r box-

Synthesis of 5R- and 5â-Substituted Kainic Acids
J . Org. Chem., Vol. 64, No. 12, 1999 4311
yla te (9a ) a n d Eth yl (1SR,2SR,5RS,6RS)-3-Aza -6-(ter t-
bu tyldim eth ylsilyloxy)-4-ph en yl-6-m eth ylbicyclo[3.3.0]oct-
3-en e-2-ca r boxyla te (9b). To a solution of 6 (3 g, 6.8 mmol)
in THF (50 mL) at -40 °C and under argon was added an
ether solution of the corresponding Grignard reagent (8.1
mmol). The reaction mixture was stirred at -40 °C for 2 h
and then partitioned between a saturated NH4Cl solution (30
mL) and ether (50 mL). The aqueous phase was extracted with
ether (3 × 25 mL), and the combined organic phases were
washed with H2O, dried (Na2SO4), and evaporated to dryness.
The crude ketones were dissolved in CH2Cl2 (35 mL) and added
dropwise to 15.6 mL (204 mmol) of TFA. The reaction mixture
was stirred at room temperature for 1-2 h and then quenched
with a saturated NaHCO3 solution till pH ∼ 8. The layers were
separated, and the aqueous phase was extracted with CH2Cl2
(2 × 25 mL). The combined organic phases were washed with
a saturated NaHCO3 solution (25 mL), dried (Na2SO4), and
evaporated in vacuo. Flash chromatography (hexane/ethyl
acetate 4:1) afforded 9a ,b (95% for 9a and 84% for 9b). 9a :
1H NMR (CDCl3) δ 4.33-4.28 (m, 1H), 4.17 (dc, 2H, J ) 7.1
Hz), 3.09-2.87 (m, 2H), 2.07 (d, J ) 1.9 Hz, 3H), 2.02-1.53
(m, 4H), 1.48 (s, 3H), 1.25 (t, 3H, J ) 7.1 Hz), 0.79 (s, 9H),
0.07 and 0.06 (2s, 6H); 13C NMR (CDCl3) δ 176.2, 173.5, 82.2,
81.2, 69.9, 60.8, 46.6, 43.8, 30.4, 27.7, 25.6, 20.1, 17.9, 14.1,
-2.3, -2.6; IR (film) 2957, 2932, 1740, 1173 cm-1. Anal. Calcd
for C18H33NO3Si: C, 63.67; H, 9.79; N, 4.13. Found: C, 63.48;
H, 9.61; N, 4.36. 9b: mp 52-54 °C; 1H NMR (CDCl3) δ 7.83-
7.78 (m, 2H), 7.38-7.28 (m, 3H), 4.51 (dd, 1H, J ) 6.6 and 2.1
Hz), 4.20 (c, 2H, J ) 7.1 Hz), 3.71 (dd, 1H, J ) 10.1 y 2.1 Hz),
3.21-3.06 (m, 1H), 2.11-1.69 (m, 4H), 1.42 (s, 3H), 1.27 (t,
3H, J ) 7.1 Hz), 0.64 (s, 9H), -0.05 and -0.37 (2s, 6H); 13C
NMR (CDCl3) δ 175.4, 173.6, 135.0, 130.2, 128.9 (2C), 127.9
(2C), 82.7, 81.7, 66.0, 61.0, 47.7, 44.2, 29.6, 27.9, 25.6, 17.9,
a saturated NaHCO3 solution (20 mL), dried (Na2SO4), and
evaporated in vacuo to give 21a ,b which were used without
further purification. 21a : colorless oil; 1H NMR (CDCl3) δ 5.35
(s, 1H), 4.16 (c, 2H, J ) 7.1 Hz), 3.53 (d, 1H, J ) 3.1 Hz), 3.51-
3.38 (m, 1H), 3.16-2.93 (m, 2H), 2.73-2.58 (m, 1H), 2.28-
2.14 (m, 1H), 1.99 (br s, 1H), 1.71 (s, 3H), 1.25 (t, 3H, J ) 7.1
Hz), 1.11 (d, 3H, J ) 6.6 Hz); 13C NMR (CDCl3) δ 174.9, 138.8,
127.3, 66.7, 60.7, 57.1, 56.0, 47.6, 39.9, 17.7, 17.0, 14.2; IR (film)
2967, 2924, 1732, 1194, 1179 cm-1; HRMS (m/z): calcd for
C
12H19NO2: (M+): 209.1416. Found: 209.1414. 21b: colorless
1
oil; H NMR (CDCl3) δ 7.38-7.14 (m, 5H), 5.27 (s, 1H), 5.51
(d, 1H, J ) 7.2 Hz), 4.18 (c, 2H, J ) 7.1 Hz), 3.71 (s, 1H), 3.28-
3.13 (m, 2H), 2.82-2.64 (m, 1H), 2.44-2.30 (m, 1H), 2.42 (br
s, 1H), 1.27 (t, 3H, J ) 7.1 Hz), 0.74 (s, 3H); 13C NMR (CDCl3)
δ 175.2, 141.2, 139.5, 127.8 (2C), 127.5 (2C), 126.9, 126.7, 66.3,
63.8, 60.7, 57.5, 46.1, 40.2, 15.8, 14.2; IR (film) 2912, 1732,
1198, 1179 cm-1; HRMS (m/z): calcd for C17H21NO2: (M+):
271.1572, found: 271.1566.
Eth yl (1SR,2SR,4RS,5SR)-N-(ter t-Bu toxyca r bon yl)-3-
aza-4,6-dim eth ylbicyclo[3.3.0]oct-6-en e-2-car boxylate (22a)
a n d Eth yl (1SR,2SR,4SR,5SR)-N-(ter t-Bu toxyca r bon yl)-
3-a za -4-p h en yl-6-m eth ylbicyclo[3.3.0]oct-6-en e-2-ca r box-
yla te (22b). To a solution of 21a ,b (5 mmol), Et3N (1.75
mL,12.5 mmol), and DMAP (610 mg, 5 mmol) in CH2Cl2 (15
mL) was added a solution of di-tert-butyl dicarbonate (2.2 g,
10 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred
at room temperature until completion. The mixture was then
poured into a 1:1 mixture of CH2Cl2 and a 1 N solution of HCl.
The organic phase was separated, washed several times with
1N HCl, dried (Na2SO4), and evaporated to dryness. The crude
was purified by chromatography (hexane/ethyl acetate 7:1) to
give 22a ,b (70% yield for 22a and 59% yield for 22b, overall
1
yields from 6). 22a : colorless oil; H NMR (CDCl3, doubling
14.2, -2.6, -2.7; IR (KBr) 2955, 2939, 1736, 1256, 1175 cm-1
.
due to rotamers) δ 5.37 (s, 1H), 4.23-4.04 (m, 4H), 3.24-3.10
(m, 1H), 2.94-2.80 (m, 1H), 2.64-2.51 (m, 1H), 2.23-2.11 (m,
1H), 1.68 (s, 3H), 1.44 and 1.37 (2s, 9H), 1.25 and 1.23 (2t,
3H, J ) 7.1 Hz), 1.06 and 1.00 (2d, 3H, J ) 6.6 Hz); 13C NMR
(CDCl3, doubling due to rotamers) δ 173.4, 173.0, 154.6, 153.9,
139.2, 139.0, 126.5 126.2, 79.7, 64.1, 63.7, 60.7, 55.1, 54.0, 55.0,
54.7, 49.6, 48.6, 38.7, 28.3, 28.2, 17.4, 16.9, 16.8, 16.7, 14.2,
14.1; IR (film) 2978, 1746, 1705, 1366, 1188 cm-1. Anal. Calcd
for C17H27NO4: C, 65.99; H, 8.79; N, 4.53. Found: C, 65.79;
H, 9.14; N, 4.76. 22b: mp 85-87 °C (hexane); 1H NMR (CDCl3,
doubling due to rotamers) δ 7.26-7.07 (m, 5H), 5.18-5.02 (m,
2H), 4.50 and 4.41 (m, 1H), 4.28-4.13 (m, 2H), 3.48-3.39 (m,
1H), 3.10-2.96 (m, 1H), 2.76-2.63 (m, 1H), 2.45-2.34 (m, 1H),
1.35-0.94 (m, 15H); 13C NMR (CDCl3, doubling due to rota-
mers) δ 173.5, 173.1, 155.1, 154.1, 141.5, 140.5, 140.3, 127.6,
127.3 (2C), 127.3, 127.0 (2C), 126.6, 126.4, 126.1, 79.8, 66.0,
65.7, 65.2, 65.0, 60.9, 57.2, 56.1, 48.3, 47.0, 39.0, 28.1, 27.7,
15.9, 14.1; IR (KBr) 2978, 1744, 1696, 1379, 1186 cm-1. Anal.
Calcd for C22H29NO4: C, 71.13; H, 7.87; N, 3.77. Found: C,
71.48; H, 8.19; N, 3.62.
(2SR,3SR,4RS,5RS)-N-(ter t-Bu toxycar bon yl)-2-(eth oxy-
ca r bon yl)-4-a cetyl-5-m eth ylp yr r olid in e-3-a ceta ld eh yd e
(23a ). Compound 23a was obtained 22a following the same
procedure as for 15a : 1H NMR (CDCl3, doubling due to
rotamers) δ 9.74 (s, 1H), 4.43-4.03 (m, 4H), 3.64-3.55 (m, 1H),
3.27-3.13 (m, 1H), 2.93-2.56 (m, 2H), 2.15 (s, 3H), 1.63-1.22
(m, 15H); 13C NMR (CDCl3, doubling due to rotamers) δ 207.6,
206.9, 199.9, 119.7, 172.5, 172.0, 154.2, 153.5, 80.7, 80.5, 65.7,
61.4, 61.3, 55.4, 54.6, 54.9, 54.5, 44.4, 44.1, 37.7, 36.7, 32.5,
32.2, 28.3, 28.2, 18.1, 17.1, 14.2, 14.1; IR (film) 1744, 1709,
1393, 13681173 cm-1; HRMS (m/z): calcd for C17H27NO6
(M+): 341.1838; Found: 341.1839.
Anal. Calcd for C23H35NO3Si: C, 68.78; H, 8.78; N, 3.49.
Found: C, 68.81; H, 8.82; N, 3.36.
Eth yl (1SR,2SR,4RS,5RS,6RS)-3-Aza -6-(ter t-bu tyld i-
m eth ylsilyloxy)-4,6-d im eth ylbicyclo[3.3.0]octa n e-2-ca r -
boxyla te (8a ) a n d Eth yl (1SR,2SR,4SR,5RS,6RS)-3-Aza -
6-(ter t-bu tyld im eth ylsilyloxy)-4-p h en yl-6-m eth ylbicyclo-
[3.3.0]octa n e-2-ca r boxyla te (8b). To a solution of 9a ,b (5
mmol) in EtOH (30 mL) was added 110 mg (0.5 mmol) of PtO2,
and the mixture was stirred at room temperature under H2
overnight. The suspension was filtered off through a pad of
Celite, and the solvent was evaporated in vacuo to give 8a ,b
which were used without further purification. 8a : colorless
oil; 1H NMR (CDCl3) δ 4.12 (c, 2H, J ) 7.1 Hz), 3.48 (d, 1H, J
) 3.8 Hz), 3.30-3.15 (m, 1H), 2.98-2.83 (m, 1H), 2.39 (br s,
1H), 2.18-1.97 (m, 2H), 1.86-1.38 (m, 3H), 1.43 (d, 3H, J )
6.9 Hz), 1.42 (s, 3H), 1.23 (t, 3H, J ) 7.1 Hz), 0.85 (s, 9H),
0.11 and 0.10 (2s, 6H); 13C NMR (CDCl3) δ 175.2, 84.9, 68.7,
60.5, 59.2, 57.5, 50.6, 44.6, 31.5, 27.2, 26.2, 18.0, 14.4, 14.2,
-1.8, -2.0; IR (film) 2957, 2932, 1732 cm-1; HRMS (m/z): calcd
for C18H35NO3Si: (M+): 341.2386. Found: 341.2383. 8b: mp
1
62-64 °C; H NMR (CDCl3) δ 7.41-7.38 (m, 2H), 7.30-7.12
(m, 3H), 4.52 (d, 1H, J ) 6.2 Hz), 4.16 (c, 2H, J ) 7.1 Hz),
3.71 (d, 1H, J ) 4.1 Hz), 3.11-2.97 (m, 1H), 2.53 (dd, 1H, J )
6.2 and 9.2 Hz), 2.22-2.07 (m, 1H), 1.86-1.67 (m, 2H), 1.54-
1.35 (m, 1H), 1.25 (t, 3H, J ) 7.1 Hz), 0.99 (s, 3H), 0.86 (s,
9H), -0.02 and -0.40 (2s, 6H); 13C NMR (CDCl3) δ 175.1,
139.0, 127.5 (2C, 127.4 (2C), 125.9, 84.7, 68.1, 64.1, 60.9, 59.5,
50.5, 44.7, 30.7, 26.9, 26.5, 18.1, 14.2, -1.8, -2.3; IR (KBr)
2957, 2930, 1732, 1256, 1204 cm-1. Anal. Calcd for C23H37NO3-
Si: C, 68.44; H, 9.24; N, 3.47. Found: C, 68.08; H, 9.08; N,
3.37.
Eth yl (1SR,2SR,4RS,5SR)-3-Aza -4,6-d im eth ylbicyclo-
[3.3.0]oct-6-en e-2-ca r boxyla te (21a ) a n d Eth yl (1SR,2SR,
4SR,5SR)-3-Aza-4-ph en yl-6-m eth ylbicyclo[3.3.0]oct-6-en e-
2-ca r boxyla te (21b). To a solution of 8a ,b (5 mmol) in CHCl3
(25 mL) was added 12.3 mL (100 mmol) of boron trifluoride
etherate. The reaction mixture was heated at 100 °C in a
sealed tube for 24 h. The reaction was quenched with a
saturated NaHCO3 solution till pH ∼ 8, and the layers were
separated. The aqueous phase was extracted with CH2Cl2 (2
× 40 mL), and the combined organic phases were washed with
Eth yl (2SR,3SR,4SR,5RS)-N-(ter t-Bu toxyca r bon yl)-3-
(2-h yd r oxyet h yl)-4-isop r op en yl-5-m et h ylp yr r olid in e-2-
ca r boxyla te (25a ). Compound 25a was obtained from 23a
following the same procedure as for 17a . Flash chromatogra-
phy (hexane/ethyl acetate 2:1) afforded 25a (49% yield from
22a ). 1H NMR (CDCl3, doubling due to rotamers) δ 4.88 (s,
1H), 4.84 (s, 1H), 4.28-3.98 (m, 3H), 3.73-3.55 (m, 3H), 2.19-
1.98 (m, 3H), 1.78-1.50 (m, 2H), 1.69 (s, 3H), 1.43-1.21 (m,
15H); 13C NMR (CDCl3, doubling due to rotamers) δ 173.7,
173.1, 154.3, 153.4, 141.5, 115.7, 79.9, 79.8, 65.8, 62.1, 61.5,

4312 J . Org. Chem., Vol. 64, No. 12, 1999
Collado et al.
60.9, 59.8, 56.8, 56.2, 41.8, 41.0, 35.3, 35.0, 28.1, 28.0, 19.4,
with CH2Cl2 (2 × 5 mL), and the combined organic phases were
washed with brine, dried (Na2SO4), and evaporated to dryness.
Flash chromatography (hexane/ethyl acetate 1:1) gave the keto
alcohols 29a ,b (82% for both 29a and 29b). 29a : colorless oil;
1H NMR (CDCl3, doubling due to rotamers) δ 4.32-4.01 (m,
4H), 3.08-2.75 (m, 4H), 2.26-2.13 (m, 1H), 1.41 and 1.34 (2s,
9H), 1.40 and 1.39 (2s, 3H), 1.28-1.10 (m, 6H); 13C NMR
(CDCl3, doubling due to rotamers) δ 214.3, 214.1, 172.5, 172.1,
154.1, 153.3, 80.6, 80.5, 77.7, 64.5, 61.3, 53.8, 53.5, 52.5, 41.0,
39.8, 39.7, 28.3, 28.2, 18.7, 17.8, 17.1, 14.2, 14.1; IR (film) 3410,
18.2, 17.7, 13.8; IR (film) 3490, 1744, 1694, 1393, 1368 cm-1
;
HRMS (m/z): calcd for C18H31NO5 (M+): 341.2202, found:
341.2203. Deuterated compound 25a -d6 was prepared from
22a following the same procedure as for 25a using Ph3PCD3I
instead of Ph3PCH3I. The major isolated product in these
conditions was 25a -d6 produced from the equilibrium reactions
of the corresponding ketone enolate with Ph3PCD2H+. 1H NMR
(CDCl3, 333 K) δ 4.8 and 4.84 (residual olefinic protons), 4.19
(m, 2H), 4.01 (d, J ) 7.7 Hz, 1H), 3.73-3.55 (m, 3H), 2.25-
2.00 (m, 1.3H), 1.80-1.55 (m, 2H), 1.69 (s, 3H), 1. 40 (s, 9H),
1.32-1.22 (m, 6H); 13C NMR (CDCl3, doubling due to rotamers)
δ same as for 25a but carbons at 141.5, 62.1, 61.5, and 17.7
appear as residual signals.
1748, 1693, 1682, 1393, 1192 cm-1. Anal. Calcd for C17H27
-
NO6: C, 59.81; H, 7.93; N, 4.10. Found: C, 59.51; H, 7.82; N,
3.99. 29b: mp 64-67 °C; 1H NMR (CDCl3, doubling due to
rotamers) δ 7.24-7.05 (m, 5H), 5.28-5.15 (m, 1H), 4.59 and
4.48 (2s, 1H), 4.30-4.16 (m, 2H), 3.30-3.17 (m, 2H), 3.09-
2.94 (m, 1H), 2.50-2.36 (m, 1H), 1.73 (s, 1H), 1.32-1.03 (m,
12H), 0.64 (s, 3H); 13C NMR (CDCl3, doubling due to rotamers)
δ 213.1, 172.6, 172.2, 155.0, 154.4, 139.8, 138.8, 128.5, 128.2,
127.9, 127.7, 80.8, 80.6, 78.8, 65.6, 65.0, 63.1, 62.8, 61.5, 55.1,
54.2, 41.3, 40.2, 40.1, 28.1, 27.8, 18.2, 14.3, 14.2; IR (KBr) 3422,
2978, 1745, 1695, 1388, 1188 cm-1. Anal. Calcd for C22H29NO6‚
1/2H2O: C, 64.06; H, 7.33; N, 3.40. Found: C, 64.11; H, 7.37;
N, 3.36.
(2SR,3SR,4RS,5RS)-N-(ter t-Bu toxycar bon yl)-2-(eth oxy-
ca r b on yl)-4-isop r op en yl-5-m et h ylp yr r olid in e-3-a cet ic
Acid (26a ). Compound 26a was obtained from 25a following
the same procedure as for 18a and was used in the subsequent
reaction without further purification: 1H NMR (CDCl3, dou-
bling due to rotamers) δ 4.89 (s, 1H), 4.85 (s, 1H), 4.26-3.86
(m, 3H), 3.79-3.61 (m, 1H), 2.61-2.34 (m, 3H), 2.18-2.02 (m,
1H), 1.65 (s, 3H), 1.43-1.20 (m, 15H); 13C NMR (CDCl3,
doubling due to rotamers) δ 176.0, 172.6, 171.8, 154.1, 153.2,
140.4, 116.7, 80.1, 65.3, 61.0, 61.0, 60.4, 56.4, 56.0, 40.6, 39.8,
35.2, 28.0, 19.3, 18.1, 17.4, 13.8; IR (film) 3190, 1748, 1713,
1699, 1395, 1370 cm-1; HRMS (m/z): calcd for C18H29NO6
(M+): 355.1995, found: 355.1980.
Eth yl (1SR,2SR,4RS,5SR)-N-(ter t-Bu toxyca r bon yl)-
3-a z a -4-m e t h y l-6-m e t h y li d e n e -7-o x o b i c y c lo [3.3.0]-
oct a n e-2-ca r b oxyla t e (30a ) a n d E t h yl (1SR,2SR,4SR,
5SR)-N-(ter t-Bu toxyca r bon yl)-3-a za -4-p h en yl-6-m eth yli-
d en e-7-oxobicyclo[3.3.0]octa n e-2-ca r boxyla te (30b). To a
solution of 29a ,b (2 mmol) in toluene (2 mL) was added 620
mg (2.6 mmol) of the Burgess reagent. The reaction mixture
was stirred at 60-65 °C for 2 h, and then the solvent was
evaporated in vacuo. Flash chromatography (hexane/ethyl
acetate 2:1) of the crude gave the enones 30a ,b (45% for 30a
and 42% for 30b). 30a : colorless oil; 1H NMR (CDCl3, doubling
due to rotamers) δ 6.12 (s, 1H), 5.36 and 5.33 (2s, 1H), 4.40-
4.05 (m, 4H), 3.77-3.64 (m, 1H), 2.83-2.64 (m, 2H), 2.36-
2.21 (m, 1H), 1.42 and 1.36 (2s, 9H), 1.29-1.20 (m, 3H), 1.07-
0.99 (m, 3H); 13C NMR (CDCl3, doubling due to rotamers) δ
204.7, 172.5, 172.2, 155.1, 154.3, 145.1, 144.9, 120.9, 120.5,
80.5, 80.4, 64.6, 61.2, 56.5, 56.0, 47.8, 46.7, 42.7, 41.8, 40.9,
28.2, 19.2, 18.6, 14.2; IR (film) 2978, 1732, 1703, 1368, 1194
cm-1; HRMS (m/z): calcd for C12H16NO3 (M+ - CO2tBu):
(2SR,3SR,4RS,5RS)-N-(ter t-Bu toxycar bon yl)-2-car boxy-
4-isop r op en yl-5-m eth ylp yr r olid in e-3-a cetic Acid (27a ).
Compound 27a was obtained from 26a following the same
procedure as for 19a and was used without further purifica-
tion: 1H NMR (CDCl3, doubling due to rotamers) δ 8.59 (br s,
2H), 4.97 (s, 1H), 4.88 (s, 1H), 3.92-3.64 (m, 2H), 2.74-2.50
(m, 2H), 2.32-1.97 (m, 2H), 1.68 (s, 3H), 1.44-1.24 (m, 12H);
13C NMR (CDCl3, doubling due to rotamers) δ 178.4, 177.2,
177.1, 176.9, 154.3, 153.0, 140.1, 117.3, 80.9, 65.8, 65.3, 60.9,
60.3, 56.3, 56.0, 41.1, 40.5, 35.3, 35.0, 28.3, 28.1, 19.3, 18.1,
17.5; IR (film) 1715,1410 cm-1
.
(2SR,3SR,4RS,5RS)-2-Ca r boxy-4-isop r op en yl-5-m eth -
ylp yr r olid in e-3-a cetic Acid (28a ). Compound 28a was
obtained from 27a following the same procedure as for 3a . The
hydrochloride was dissolved in the minimum amount of
methanol and was added the same volume of propylene oxide.
After stirring overnight at room temperature the white
precipitate was filtered and washed with ether affording
compound 28a (86% from 25a ) as the zwitterion: mp > 200
1
222.1130. Found: 222.1126. 30b: mp 111-114 °C; H NMR
(CDCl3, doubling due to rotamers) δ 7.29-6.95 (m, 5H), 5.77
(s, 1H), 5.44-5.29 (m, 1H), 5.01-4.93 (2s, 1H), 4.63-4.53 (2s,
1H), 4.32-4.20 (m, 2H), 4.00-3.91 (m, 1H), 3.00-2.87 (m, 1H),
2.78-2.36 (m, 2H), 1.61-1.04 (m, 12H); 13C NMR (CDCl3, 333
K) δ 202.9, 172.0, 154.3, 144.3, 139.8, 127.9 (2C), 126.8, 126.7
(2C), 121.3, 80.4, 65.8, 65.6, 61.1, 49.4, 42.4, 41.3, 27.8, 14.0;
IR (KBr) 2977, 1734, 1699, 1374, 1186 cm-1. Anal. Calcd for
1
°C; H NMR (D2O/KOD) δ 4.83 (s, 1H), 4.80 (s, 1H), 3.23 (dc,
J ) 6.2 and 10.0 Hz, 1H), 3.17 (d, J ) 7.2 Hz, 1H), 2.58 (dd,
J ) 4.2 and 13.1 Hz, 1H), 2.48-2.37 (m, 1H), 2.15 (dd, J ) 9.2
and 13.1 Hz, 1H), 1.99-1.94 (m, 1H), 1.66 (s, 3H), 1.03 (d, J )
6.2 Hz, 3H); 13C NMR (D2O/KOD) δ 183.2, 182.0, 145.1, 114.7,
67.1, 63.5, 57.6, 45.9, 43.7, 19.4, 18.7; IR (KBr) 3420, 1716,
1617, 1389, 1321 cm-1. Anal. Calcd for C11H17NO4‚1/3CH3OH:
C, 56.78; H, 7.87; N, 5.76. Found: C, 56.59; H, 8.08; N, 6.09.
Eth yl (1SR,2SR,4RS,5RS,6RS)-N-(ter t-Bu toxycar bon yl)-
3-a za -4,6-d im eth yl-6-h yd r oxy-7-oxobicyclo[3.3.0]octa n e-
2-ca r boxyla te (29a ) a n d Eth yl (1SR,2SR,4SR,5RS,6RS)-
N -(t er t -Bu t oxyca r b on yl)-3-a za -4-p h e n yl-6-h yd r oxy-6-
m eth yl-7-oxobicyclo[3.3.0]octa n e-2-ca r boxyla te (29b). To
a solution of 22a ,b (2 mmol) and N-methylmorpholine N-oxide
(515 mg, 4.4 mmol) in acetone (20 mL) and H2O (6 mL) were
added 37 mL (0.003 mmol) of a 4% solution of OsO4 in H2O.
The reaction mixture was stirred at room temperature for 48
h and then partitioned between ether (40 mL) and H2O (40
mL). The layers were separated, and the aqueous phase was
extracted with ether (3 × 20 mL). The combined organic phases
were dried (Na2SO4) and evaporated to dryness. To a solution
of oxalyl chloride (206 µL, 2.4 mmol) in CH2Cl2 (6 mL) at -78
°C and under argon were added 355 µL of DMSO (5 mmol).
This mixture was stirred at -78 °C for 30 min and then was
added a solution of the foregoing crude diol (2 mmol) in CH2Cl2
(2 mL). After stirring at -78 °C for 45 min, Et3N (1.4 mL, 10
mmol) was added and the reaction was allowed to reach rt.
The reaction mixture was stirred for 30 min and then
quenched with H2O (15 mL). The aqueous phase was extracted
C
22H27NO5‚2/3H2O: C, 66.48; H, 7.18; N, 3.52. Found: C, 66.50;
H, 7.28; N, 3.60.
Eth yl (1SR,2SR,4RS,5SR,6SR)-N-(ter t-Bu toxyca r bon -
yl)-3-a za -4,6-d im et h yl-6-(h yd r oxym et h yl)-7-oxob icyclo-
[3.3.0]octan e-2-car boxylate (31a) an d Eth yl (1SR,2SR,4SR,
5SR,6SR)-N-(tert-Butoxyarbonyl)-3-aza-4-phenyl-6-(hydroxy-
m eth yl)-6-m eth yl-7-oxobicyclo[3.3.0]octan e-2-car boxylate
(31b). To a suspension of CuBr‚Me2S (62 mg, 0.3 mmol) in
THF (4 mL) at -40 °C was added a 1.6 M solution of MeLi in
ether (188 mL, 0.3 mmol), and the mixture was stirred at -40
°C for 10 min. The mixture was cooled to -50 °C and then
was sequentially added a 1 M solution of diisobutylaluminum
hydride in hexane (2.2 mL, 2.2 mmol) and HMPA (1 mL). The
reaction mixture was stirred for 30 min prior to the addition
of a solution of 30a ,b (1.0 mmol) in THF (1 mL). After stirring
at -50 °C for 2 h, paraformaldehyde (150 mg, 5 mmol) was
added and the mixture stirred at -50 °C for 5 min. The
reaction mixture was stirred at room temperature overnight
and then partitioned between ether (10 mL) and a 1 N HCl
solution (10 mL). The layers were separated, and the aqueous
phase was extracted with ether (3 × 10 mL). The combined
organic phases were dried (Na2SO4) and concentrated to
dryness. Flash column chromatography (hexane/ethyl acetate
1:1) gave compounds 31a ,b (80% for 31a and 81% for 31b)
31a : colorless oil; 1H NMR (CDCl3, doubling due to rotamers)

Synthesis of 5R- and 5â-Substituted Kainic Acids
J . Org. Chem., Vol. 64, No. 12, 1999 4313
δ 4.38-4.05 (m, 4H), 3.61-3.44 (m, 2H), 3.05-2.83 (m, 2H),
2.77-2.59 (m, 1H), 2.43-2.27 (m, 1H), 1.43 and 1.37 (2s, 9H),
1.33-1.21 (m, 6H), 1.17 (s, 3H); 13C NMR (CDCl3, doubling
due to rotamers) δ 219.8, 219.6, 172.7, 172.3, 153.8, 153.0, 80.5,
80.4, 68.2, 65.2, 65.0, 61.2, 56.3, 55.8, 54.2, 54.1, 50.2, 49.1,
42.1, 42.0, 41.3, 40.2, 28.3, 28.2, 18.1, 17.2, 15.8, 15.6, 14.2,
14.1; IR (film) 3450, 1742, 1699, 1393, 1368, 1192 cm-1. Anal.
Calcd for C18H29NO6: C, 60.83; H, 8.22; N, 3.94. Found: C,
60.53; H, 8.16; N, 3.71. 31b: colorless oil; 1H NMR (CDCl3,
doubling due to rotamers) δ 7.24-7.13 (m, 5H), 5.40-5.25 (m,
1H), 4.48-4.19 (m, 3H), 3.46-2.48 (m, 6H), 1.79 (br s, 1H),
1.35-1.07 (m, 12H), 0.53 (s, 3H); 13C NMR (CDCl3, doubling
due to rotamers) δ 219.7, 219.4, 172.7, 172.3, 154.5, 153.5,
139.8, 138.3, 128.0, 127.9, 127.7, 127.2, 80.7, 80.5, 68.3, 68.1,
66.8, 66.3, 64.9, 64.8, 61.4, 55.5, 55.1, 50.5, 49.3, 41.6, 41.4,
41.2, 40.5, 28.0, 27.7, 15.8, 15.7; IR (film) 3418, 2976, 2934,
1740, 1695, 1390, 1171 cm-1. Anal. Calcd for C23H31NO6‚1/
3H2O: C, 65.22; H, 7.55; N, 3.31. Found: C, 65.46; H, 7.95; N,
3.47.
Eth yl (1SR,2SR,4RS,5SR,6SR)-N-(ter t-Bu toxycar bon yl)-
3-a za -4,6-d im e t h yl-6-(p -t olu e n e su lfon yloxym e t h yl)-7-
oxobicyclo[3.3.0]octa n e-2-ca r boxyla te (32a ) a n d Eth yl
(1SR,2SR,4SR,5SR,6SR)-N-(ter t-Bu toxyca r bon yl)-3-a za -
4-p h e n yl-6-m e t h yl-6-(p -t olu e n e su lfon yloxym e t h yl)-7-
oxobicyclo[3.3.0]octa n e-2-ca r boxyla te (32b). To a solution
of 31a ,b (1 mmol) in pyridine (5 mL) was added 286 mg (1.5
mmol) of tosyl chloride, and the reaction mixture was stirred
at 0 °C for 2 h and at room temperature overnight. The
mixture was partitioned between ether (20 mL) and a 1 N HCl
solution (10 mL). The layers were separated, and the organic
phase was washed with 1 N HCl solution till pH ∼ 1, dried
(MgSO4), and evaporated to dryness. Flash column chroma-
tography (hexane/ethyl acetate 3:1) afforded 32a ,b (72% for
32a and 63% for 32b). 32a : colorless oil; 1H NMR (CDCl3,
doubling due to rotamers) δ 7.74-7.68 (m, 2H), 7.36-7.32 (m,
2H), 4.33-3.98 (m, 4H), 3.91-3.76 (m, 2H), 3.09-2.96 (m, 1H),
2.90-2.74 (m, 1H), 2.67-2.30 (m, 2H), 2.43 (s, 3H), 1.43 and
1.36 (2s, 9H), 1.32-1.22 (m, 6H), 1.09 and 1.08 (2s, 3H); 13C
NMR (CDCl3, doubling due to rotamers) δ 216.0, 215.8, 172.2,
171.7, 153.6, 152.8, 145.2, 131.9, 129.8, 127.7, 80.4, 80.2, 72.6,
65.5, 65.3, 61.1, 56.3, 55.7, 51.7, 51.5, 49.2, 48.1, 41.0, 40.9,
40.6, 39.6, 28.1, 28.0, 21.4, 17.4, 16.3, 16.1, 16.0, 14.0; IR (film)
1747, 1705, 1699, 1393, 1368, 1179 cm-1; HRMS (m/z): calcd
for C20H26NO6S (M+ - CO2tBu): 408.1481, found: 408.1482.
32b: mp 151-155 °C; 1H NMR (CDCl3, doubling due to
rotamers) δ 7.66 (d, 2H, J ) 8.3 Hz), 7.32 (d, 2H, J ) 8.3
Hz),7.24-7.09 (m, 5H), 5.44-5.28 (m, 1H), 4.36-4.20 (m, 3H),
3.63 (d, 1H, J ) 9.3 Hz), 3.53-3.45 (m, 1H), 3.25-3.02 (m,
2H), 2.68-2.44 (m, 2H), 2.43 (s, 3H), 1.36-1.10 (m, 12H), 0.49
(s, 3H); 13C NMR (CDCl3, doubling due to rotamers) δ 216.1,
215.9, 172.3, 171.7, 154.4, 153.5, 145.2, 138.6, 137.0, 132.0,
129.9, 127.9, 127.7, 127.4, 127.2, 80.9, 80.8, 72.8, 67.2, 66.8,
64.7, 64.5, 61.5, 52.6, 52.2, 49.2, 48.2, 41.6, 40.6, 40.2, 28.0,
27.8, 21.6, 16.6, 14.1; IR (KBr) 2978, 2930, 1744, 1697, 1368,
1180 cm-1. Anal. Calcd for C30H37NO8S‚2H2O: C, 59.29; H,
6.80; N, 2.31. Found: C, 59.38; H, 6.46; N, 2.18.
(Na2SO4), and evaporated to dryness. Flash chromatography
(hexane/ethyl acetate 3:1) gave 33a ,b (37% for 33a and 25%
1
for 33b). 33a : colorless oil; H NMR (CDCl3, doubling due to
rotamers) δ 9.72 (s, 1H), 4.94 (s, 1H), 4.65 (s, 1H), 4.24-3.92
(m, 4H), 2.96-2.68 (m, 4H), 1.69 (s, 3H), 1.46-1.19 (m, 15H);
13C NMR (CDCl3, doubling due to rotamers) δ 199.9, 199.8,
172.8, 172.3, 154.6, 152.4, 141.0, 117.7, 80.4, 80.1, 65.7, 61.2,
61.1, 57.3, 56.7, 53.7, 52.9,43.2, 38.8, 38.1, 28.3, 28.2, 22.6, 22.5,
16.8, 15.7, 14.1; IR (film) 1748, 1715, 1393, 1368, 1184 cm-1
.
Anal. Calcd for C18H29NO5: C, 63.70; H, 8.62; N, 4.13. Found:
C, 63.54; H, 8.90; N, 4.05. 33b: 1H NMR (CDCl3, doubling due
to rotamers) δ 9.69 (s, 1H), 7.24-7.10 (m, 5H), 5.25-5.13 (m,
1H), 4.82 and 4.78 (2s, 1H), 4.46 and 4.38 (2s, 1H), 4.31-4.13
(m, 3H), 3.27-3.20 (m, 1H), 3.12-2.95 (m, 1H) 2.93-2.66 (m,
2H), 1.36-1.05 (m, 15H); 13C NMR (CDCl3, doubling due to
rotamers) δ 199.7, 172.7, 172.2, 154.6, 153.4, 140.5, 139.3,
137.9, 127.4, 127.1, 126.8, 126.6, 126.4, 117.2, 117.1, 80.6, 80.3,
66.5, 66.2, 66.1, 61.4, 53.8, 53.1, 43.3, 43.0, 40.1, 39.5, 28.1,
27.6, 24.8, 24.5, 14.2; IR (film) 2976, 2931, 1743, 1725, 1696,
1392, 1369, 1174 cm-1. Anal. Calcd for C23H31NO5: C, 68.81;
H, 7.78; N, 3.49. Found: C, 68.50; H, 7.91; N, 4.42.
(2SR,3SR,4SR,5RS)-N-(ter t-Bu t oxyca r b on yl)-2-(et h -
oxyca r bon yl)-4-isop r op en yl-5-m eth ylp yr r olid in -3-a cetic
Acid (34a ) a n d (2SR,3SR,4SR,5SR)-N-(ter t-Bu t oxyca r -
b on yl)-2-(et h oxyca r b on yl)-5-p h en yl-4-isop r op en ylp yr -
r olid in e-3-a cetic Acid (34b). Compounds 34a ,b were ob-
tained from 33a ,b following the same procedure as for 18a ,b
and were used in next reaction without further purification.
34a : 1H NMR (CDCl3, doubling due to rotamers) δ 4.99 (s,
1H), 4.71 (s, 1H), 4.24-3.94 (m, 4H), 2.98-2.89 (m, 1H), 2.77-
2.56 (m, 3H), 1.71 (s, 3H), 1.44-1.20 (m, 15H); 13C NMR
(CDCl3, doubling due to rotamers) δ 177.1, 172.8, 172.3, 154.6,
153.4, 141.7, 117.5, 80.4, 80.2, 65.5, 61.1, 57.2, 56.6, 53.5, 52.8,
40.7, 39.9, 33.1, 28.3, 28.2, 22.6, 16.8, 15.7; IR (film) 1744, 1713,
1395, 1370, 1186 cm-1, HRMS (m/z): calcd for C13H20NO4 (M+
- CO2tBu): 254.1392, found: 254.1387. 34b: 1H NMR (CDCl3,
doubling due to rotamers) δ 7.24-7.06 (m, 5H), 5.24-5.11 (m,
1H), 4.85 and 4.81 (2s, 1H), 4.48 and 4.42 (2s, 1H), 4.33-4.15
(m, 3H), 3.25-3.18 (m, 1H), 3.01-2.86 (m, 1H) 2.78-2.55 (m,
2H), 1.36-1.04 (m, 15H); 13C NMR (CDCl3, doubling due to
rotamers) δ 176.8, 172.7, 172.2, 154.6, 153.4, 140.1, 139.3,
137.8, 127.3, 127.1, 126.8, 126.5, 117.1, 80.6, 80.3, 66.4, 66.0,
66.0, 65.9, 61.4, 53.7, 53.2, 42.0, 41.4, 33.1, 32.8, 28.1, 27.6,
25.0, 24.7, 14.1. IR (film) 3255, 2973, 2925, 1740, 1697, 1393,
1258 cm-1
.
(2SR,3SR,4SR,5RS)-N-(ter t-Bu toxycar bon yl)-2-car boxy-
4-isop r op en yl-5-m eth ylp yr r olid in e-3-a cetic Acid (35a )
a n d (2SR,3SR,4SR,5SR)-N-(ter t-Bu toxyca r bon yl)-2-ca r -
b oxy-5-p h en yl-4-isop r op en ylp yr r olid in e-3-a cet ic Acid
(35b). Compounds 35a ,b were obtained from 34a ,b folowing
the same procedure as for 19a ,b and were used in next reaction
without further purification. 35a : colorless oil; 1H NMR
(CDCl3, doubling due to rotamers) δ 10.06 (br s, 2H), 4.99 (s,
1H), 4.72 (s, 1H), 4.14-3.95 (m, 2H), 2.97-2.72 (m, 2H), 2.60-
2.54 (m, 2H), 1.71 (s, 3H), 1.43-1.21 (m, 12H); 13C NMR
(CDCl3, doubling due to rotamers) δ 179.2, 178.1, 177.7, 154.9,
153.4, 140.6, 140.5, 117.9, 117.8, 81.1, 80.8, 65.4, 65.3, 57.3,
56.8, 53.9, 53.3, 40.8, 40.0, 33.1, 28.3, 28.2, 22.6, 16.7, 15.5;
IR (film) 2980, 2934, 1719, 1408, 1150 cm-1. 35b: 1H NMR
(CDCl3, doubling due to rotamers) δ 8.07 (br s, 2H), 7.24-7.10
(m, 5H), 5.27-5.13 (m, 1H), 4.85 and 4.79 (2s, 1H), 4.51 (s,
1H), 4.42-4.24 (m, 1H), 3.24-3.06 (m, 2H) 2.75-2.60 (m, 2H),
1.37 (s, 3H), 1.33 and 1.04 (2s, 9H); 13C NMR (CDCl3, doubling
due to rotamers) δ 178.6, 177.5, 177.3, 154.8, 153.4, 140.3,
140.1, 139.0, 137.6, 127.4, 127.2, 127.1, 126.7, 126.6, 117.4,
81.3, 80.9, 66.4, 66.1, 65.9, 65.7, 54.4, 54.1, 42.2, 41.7, 33.4,
28.1, 27.6, 24.9, 24.3; IR (film) 2976, 2931, 1726, 1713, 1695,
(2SR,3SR,4SR,5RS)-N-(ter t-Bu t oxyca r b on yl)-2-(et h -
oxyca r bon yl)-4-isop r op en yl-5-m eth ylp yr r olid in e-3-a cet-
a ld eh yd e (33a ) a n d (2SR,3SR,4SR,5SR)-N-(ter t-Bu toxy-
ca r b on yl)-2-(et h oxyca r b on yl)-4-isop r op en yl-5-p h en yl-
p yr r olid in e-3-a ceta ld eh yd e (33b). To a solution of 32a ,b
(1 mmol) in THF (7 mL) at -78 °C and under argon was added
a 1 M solution of LiBEt3H in THF (1.1 mL, 1.1 mmol), and
the mixture was stirred at -78 °C for 30 min. Then the
reaction was quenched with a saturated NaHCO3 solution (1
mL), and the mixture was allowed to reach 0 °C. H2O2 (33%)
(10 drops) was added, and the mixture stirred at 0 °C for 20
min. The solvent was eliminated in vacuo, and the residue was
extracted with ether (3 × 10 mL). The combined organic phases
were dried (Na2SO4) and evaporated to dryness. To a solution
of the crude alcohols in tert-butyl alcohol (20 mL) was added
potassium tert-butoxide (135 mg). The mixture was stirred at
25-30 °C for 2 h and then partitioned between a mixture of
ether (40 mL) and a saturated NH4Cl solution (10 mL). The
organic phase was washed with H2O (3 × 10 mL), dried
1403, 1156 cm-1
.
(2SR,3SR,4SR,5RS)-2-Ca r boxy-4-isop r op en yl-5-m eth -
ylpyr r olidin e-3-acetic Acid Hydr och lor ide (4a) an d (2SR,
3SR,4SR,5SR)-2-Ca r boxy-5-p h en yl-4-isop r op en ylp yr r oli-
d in e-3-a cetic Acid Hyd r och lor id e (4b). A solution of 35a ,b
(1 mmol) in a 1 N HCl solution in ethyl acetate (5 mL) was
stirred at room temperature for 8 h. The solvent was elimi-
nated in vacuo, and the resulting solid was washed with ether

4314 J . Org. Chem., Vol. 64, No. 12, 1999
Collado et al.
and dried to give 4a ,b (94% for both 4a and 4b, overall yields
from 35a ,b. 4a : mp > 200 °C; 1H NMR (CD3OD) δ 5.23 (s,
1H), 4.78 (s, 1H), 4.32 (d, 1H, J ) 11.3 Hz), 4.06-3.92 (m,
1H), 3.32-3.24 (m, 1H), 3.13-2.55 (m, 3H), 1.81 (s, 3H), 1.38
(d, 3H, J ) 6.8 Hz); 13C NMR (CD3OD) δ 174.6, 171.0, 140.3,
119.2, 63.0, 60.8, 53.0, 44.1, 33.5, 24.7, 13.6; IR (KBr) 3424,
2926, 1725, 1410, 1258, 1208 cm-1. Anal. Calcd for C11H18NO4-
Cl: C, 50.10; H, 6.89; N, 5.31. Found: C, 50.18; H, 6.87; N,
5.23. 4b: mp > 200 °C; 1H NMR (CD3OD) δ 7.52-7.23 (m,
5H), 5.19 (d, 1H, J ) 6.1 Hz), 5.12 (s, 1H), 4.80 (s, 1H), 4.45
(d, 1H), 3.72-3.65 (m, 1H), 3.36-3.20 (m, 1H), 3.05-2.64 (m,
2H), 1.32 (s, 3H); 13C NMR (CD3OD) δ 174.5, 170.9, 140.3,
133.6, 129.8, 129.7, 127.7, 118.9, 67.4, 63.4, 53.8, 44.0, 33.9,
24.9; IR (KBr) 3427, 3056, 2972, 2928, 1723, 1405, 1260, 1226
cm-1. Anal. Calcd for C16H20NO4Cl: C, 58.99; H, 6.19; N, 4.30.
Found: C, 58.87; H, 6.25; N, 4.18.
Ack n ow led gm en t. This research was supported by
a CDTI program (Plan concertado 94/0036) and the
Spanish PROFARMA program (Ministerio de Industria
and Ministerio de Sanidad). A.I.M. and I.C. are grateful
to Ministerio de Educacio´n for a fellowship. We are also
grateful to Dr. Chafiq Hamdouchi and Dr. Carlos Lamas
(Centro de Investigacio´n Lilly) for useful suggestions.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of all compounds lacking elemental analysis (10,
11a ,b, 13a ,b, 14a , 17a ,b, 18a , 19a ,b, 8a , 21a ,b, 23a , 25a , 26a ,
27a , 30a , 32a , 34a ,b, 35a ,b) and NOE experiments (11a ,b,
21a ,b, 3a ,b, 4a ,b). This material is available free of charge
via the Internet at http://pubs.acs.org.
J O982109J