Synthesis of (-)-kainic acid using chiral lithium amides in an asymmetric dearomatizing cyclization

Article abstract of DOI:10.1016/S0040-4020(02)00379-4

Chiral lithium amide bases are able to deprotonate N-benzyl-N-cumyl anisamides enantioselectively to yield enantiomerically enriched benzylic organolithiums. These spontaneously undergo dearomatising cyclisation to yield, in high enantiomeric excess enantiomerically enriched partially saturated isoindolones, which in some cases may be recrystallised to enantiomeric purity. These isoindolone derivatives are converted in nine steps, among them a surprisingly regioselective Baeyer-Villiger reaction, to (-)-kainic acid.

Full text of DOI:10.1016/S0040-4020(02)00379-4

TETRAHEDRON
Pergamon
Tetrahedron 58 )2002) 4727±4733
Synthesis of ꢀ2)-kainic acid using chiral lithium amides
in an asymmetric dearomatizing cyclization
Jonathan Clayden,p Christel J. Menet and Kirill Tchabanenko
Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Received 12 March 2002; accepted 21 March 2002
AbstractÐChiral lithiumamide bases are able to deprotonate N-benzyl-N-cumyl anisamides enantioselectively to yield enantiomerically
enriched benzylic organolithiums. These spontaneously undergo dearomatising cyclisation to yield, in high enantiomeric excess enantio-
merically enriched partially saturated isoindolones, which in some cases may be recrystallised to enantiomeric purity. These isoindolone
derivatives are converted in nine steps, among them a surprisingly regioselective Baeyer±Villiger reaction, to )2)-kainic acid. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
our recently published14 synthesis of )^)-kainic acid the
relative stereochemistry was controlled by maintaining the
C3 and C4 substituents as part of a six-membered ring until
late in the synthesis. The 5,6-fused isoindolinone ring
systemrequired for this synthesis was formed frombenz-
amide 5a by a dearomatizing cyclization of the type we ®rst
reported in 1998,21±24 and which we now interpret as a six-
electron electrocyclization.25 Recently, we found that
replacement of the t-BuLi/HMPA or LDA used for the
racemic cyclisation with a chiral lithium amide base allows
control over the absolute stereochemistry of the product.26
As far as we are aware, this reaction is the ®rst use of a chiral
lithium amide base to deprotonate a prochiral methylene
group enantioselectively and thus forman enantiomerically
enriched organolithium compound. Previous asymmetric
functionalisation a to nitrogen has employed the much
more basic s-BuLi-)2)-sparteine combination.27±30 We
now report in full31 the application of our chiral lithium
amide-protomated asymmetric cyclisation to the synthesis
of 10 and the conversion of 10 to )2)-kainic acid in nine
steps.12
)2)-Kainic acid 1 is the parent member of a class of substi-
tuted prolines known as the kainoids.1±3 The kainoids have
a common substitution pattern and stereochemistry, and
members of the class differ only in the nature of the
unsaturated substituent at C4.4 Kainic acid, like other
kainoids, exhibits a wide variety of biological activity,
and has been used as an anthelmintic and as an insecticide.5,6
It is widely used as a tool in neuropharmacology,7 and binds
strongly to the class of neurotransmitter receptors, the
kainate receptors, which take its name.8,9 Kainic acid was,
until recently, readily available fromits most abundant
natural source, the alga Digenea simplex.10 Supplies were
interrupted in 1999,11 leading to a ®fty-fold increase in the
cost of kainic acid and enhancing the desirability of a
synthetic route to this useful natural product.
2. Results and discussion
Over two dozen syntheses of )2)-kainic acid have been
published12 since Oppolzer's 1982 route from l-glutamic
acid,13 and many more syntheses provide )^)-kainic
acid14 or its analogues.1,15±18 One of the main challenges
in kainoid chemistry is the C3±C4 stereochemistry,
which, in biologically active kainoids is always cis.19,20 In
The cyclisation starting materials, 5, were made in one of
two ways. Acylation of cumylamine 232,33 with p-methoxy-
benzoyl chloride gave 3, whose slow benzylation gave the
tertiary amide 5a. Alternatively, alkylation of cumylamine 2
with m-methoxybenzyl chloride gave the secondary amine 4
which was acylated with p-methoxybenzoyl chloride to
yield 5b. We have found that N-cumyl amides are ideal
starting materials for dearomatising cyclisations because
they carry a bulky N-substituent )a prerequisite for good
diastereoselectivity) and the cumyl group may be removed
later under acid conditions )Schemes 1 and 2).23
Keywords: kainic acid; stereoselective; cyclization; lithiumamide; organo-
lithium.
p
Corresponding author. Tel.: 144-161-275-4612; fax: 144-161-275-
4939; e-mail: j.p.clayden@man.ac.uk
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)02)00379-4

4728
J. Clayden et al. / Tetrahedron 58 )2002) 4727±4733
Scheme 1.
Two chiral lithiumamide bases, 6´Li and 7´Li,34 were used
to promote the asymmetric cyclisation of 5a and b to yield
the partially saturated isoindolones 10a and b. The hydro-
chloride salt 6´HCl35±37 or 7´HCl38 was dissolved in THF,
and 2 equiv. of BuLi were added to forma solution of chiral
lithiumamide 6´Li or 7´Li plus lithiumchloride. Once the
amide 5a or b had been added the mixture was allowed to
warm, promoting asymmetric deprotonation26 to 8 and
cyclisation23 to the enolate 9. An aqueous quench and acidic
work-up returned the enones 10a or b in good yield and
enantiomeric excess.39 The ee of 10a )but not 10b) could
be improved to .99% by one recrystallisation fromEtOAc.
Scheme 3.
12a and b. At this stage, the enantiomeric excess of 12b was
improved by recrystallisation from ethyl acetate, returning
material of 98% ee, which was carried through the synthesis
)Scheme 3).40
Few N-protecting groups are compatible with the harshly
oxidising conditions required for the formation of the
C2-carboxylic acid substituent,41,42 but Boc withstands the
oxidation well. Treatment with Boc2O in the presence of
DMAP and then catalytic RuCl3 in the presence of stoichio-
metric NaIO4 gave 14 which was isolated as its methyl ester
after treatment with diazomethane )Scheme 4).
Conjugate addition of Me2CuLi to 10a or b in the presence
of Me3SiCl gave single diastereoisomers of the enol ethers
11a and b, which were subjected without puri®cation to
tri¯uoroacetic acid, which both removed the cumyl group
and hydrolysed the enol ether to yield deprotected ketones
Baeyer±Villiger oxidation of 14 expands the cyclohexanone
ring to a seven-membered lactone with a remarkable level of
regioselectivity. Although we have not determined precisely
the origin of this regioselectivity, it appears to be conforma-
tional in origin.43 The presence of the methyl group b to the
ketone is essential: the un-methylated analogue of 14 is
oxidised without regioselectivity to give a mixture of
lactones.44
The ring opening of the lactone must be carried out carefully
to avoid epimerisation of the centre a to the amide carbonyl
group.16 We have found that the most reliable way to avoid
unwanted epimerisation to the allokainic acid series is to
carry out a methanolysis )sodium methoxide in methanol)
of 15 at 2788C. Alcohol 16 may then be isolated as a single
diastereoisomer. The use of LiOMe or higher temperatures
risks signi®cant epimerisation.
Elimination of water from 16 is best performed by ®rst
Scheme 2.
Scheme 4.

J. Clayden et al. / Tetrahedron 58 )2002) 4727±4733
4729
gel 60H )230±300 mesh) as the stationary phase. Thin layer
chromatography was performed using Merck silica 60 F254
aluminium-backed plates.
4.1.1. N-ꢀ1-Methyl-1-phenylethyl)-4-methoxybenzamide
3. p-Anisoyl chloride )1.39 g, 8.14 mmol) was added drop-
wise to a solution of cumylamine 2 )1 g, 7.4 mmol) and
triethylamine )1.12 g, 11.1 mmol) in DCM )10 mL). After
12 h, water was added to the reaction mixture which was
extracted with DCM, washed with brine, dried with MgSO4,
and evaporated under reduced pressure. Puri®cation by
recrystallisation )ethyl acetate) afforded the title compound
1 as a white solid )1.73 g, 87%). Mp 60±628C. Found: M1,
269.1419; C17H19NO2 requires M, 269.14157; dH )300
MHz, CDCl3) 7.78 )2H, d, Jˆ9 Hz, H3, H5), 7.5±7.2 )5H,
m, ArH), 6.95 )2H, d, Jˆ9 Hz, H2, H6), 6.43 )1H, br s, NH),
3.88 )3H, s, MeO), 1.86 )6H, s, CH3); dC )75 MHz, CDCl3)
165.89, 161.96, 146.99, 128.38, 127.65, 126.59, 124.68,
113.60, 56.07, 55.34, 29.21; m/z )EI) 269 )M1, 35%), 135
)100%); nmax)®lm)/cm21 3279 )NH), 1632 )CvO), 1607
)Ar).
4.1.2. N-ꢀ3-Methoxybenzyl)-N-ꢀ1-methyl-1-phenylethyl)-
amine 4. 3-Methoxybenzyl bromide )0.37 g, 1.85 mmol)
was added to a solution of cumylamine 2 )0.25 g, 1.85
mmol) and potassium carbonate )2.4 mmol) in DMF
)10 mL). The reaction mixture was stirred for 12 h. Water
was added, and the mixture was extracted with ether,
washed with brine, dried over MgSO4, and evaporated
under reduced pressure. Puri®cation by ¯ash chroma-
tography )1:1 ethyl acetate±petroleumether) afforded the
title compound 4 as a colourless oil )0.48 g, 100%). Found:
M1, 255.1628; C17H21NO requires M, 255.1623; dH )300
MHz, CDCl3) 7.7±7.2 )9H, m, ArH), 3.84 )3H, s, CH3O),
3.51 )2H, s, CH2), 1.59 )2H, br s, NH2), 1.57 )6H, s, CH3);
dC )75 MHz, CDCl3) 159.60, 147.71, 142.95, 129.23,
128.14, 126.20, 125.80, 125.35, 113.68, 112.06, 56.04,
55.10, 47.52, 29.68; m/z )CI) 256 )M1H1, 100%), 138
)30%); nmax)®lm)/cm21 1601 )Ar).
Scheme 5.
converting the alcohol to a selenide. We found N-phenyl-
selenenylphthalimide45 to be the most consistently reliable
seleniumsource, though we have also had success
with o-nitrophenylselenocyanate.14,46 Treatment with the
seleniumreagent in the presence of Bu 3P at roomtempera-
ture, followed by oxidation to the selenoxide with hydrogen
peroxide at 2408C gave, after spontaneous elimination, the
alkene 17. Reduction of the Boc-protected amide was
achieved by the method of Rubio47 )DIBAL followed by
triethylsilane and boron tri¯uoride etherate). The ®nal
deprotections take place on treatment with LiOH and
tri¯uoroacetic acid,48 and after puri®cation a sample of
)2)-kainic acid was obtained with spectroscopic data and
optical rotation identical with the natural product )Scheme
5).48
4.1.3. N-1-Benzyl-N-ꢀ1-methyl-1-phenylethyl)-4-methoxy-
benzamide 5a. A solution of amide 1 )2.18 g, 8.1 mmol) in
DMF )20 mL) was added dropwise to dry NaH )0.65 g,
16.2 mmol) under N2. After 12 h, benzyl bromide )12.15
mmol, 2.08 g) was added to the reaction mixture. After
24 h, the reaction was quenched with water at 08C, extracted
with ether, washed with brine, dried over MgSO4, and
evaporated under reduced pressure. Puri®cation by recrys-
tallisation )ethyl acetate) afforded the title compound 5a as a
white solid )2.38 g, 82%). Mp 118±1198C. Found: M1
359.1879; C24H25NO2 requires M, 359.1885; dH )300
MHz, CDCl3) 7.39 )12H, m, ArH), 6.85 )2H, d, Jˆ9 Hz,
H1, H2), 5.82 )2H, s, CH2), 3.81 )3H, s, CH3), 1.75 )6H, s,
CH3), dC )75 MHz, CDCl3) 172.95, 160.35, 148.72, 139.77,
139.77, 130.70, 128.61, 128.45, 128.17, 127.03, 126.73,
126.06, 124.37, 113.48, 62.29, 55.19, 52.25, 28.50; m/z
)CI) 360 )M1H1, 90%); nmax)®lm)/cm21 1638 )CvO),
1606 )Ar).
3. Conclusion
Chiral lithiumamide bases are valuable reagents for
promoting a new type of dearomatising asymmetric
cyclisation. A product of this cyclisation is a valuable inter-
mediate for the synthesis of )2)-kainic acid, and we are
currently seeking to apply similar cyclisations to the syn-
thesis of other members of the kainoid family.
4. Experimental
4.1. General methods
Diethyl ether )referred to as `ether') and tetrahydrofuran
)THF) were distilled under nitrogen fromsodiumbenzo-
phenone ketyl. Dry solvents were transferred to reaction
vessels by syringe. `Petrol' refers to redistilled petroleum
ether )bp 40±608C). Melting points are uncorrected.
Column chromatography was performed with Merck silica
4.1.4. N-ꢀ3-Methoxybenzyl)-N-ꢀ1-methyl-1-phenylethyl)-
4-methoxybenzamide 5b. By the procedure used for 3,
amine 4 )0.93 g, 3.65 mmol) and p-anisoyl chloride )0.87,
4.7 mmol) gave, after puri®cation by recrystallisation )ethyl

4730
J. Clayden et al. / Tetrahedron 58 )2002) 4727±4733
acetate), the title compound 5b as a white solid )1.23 g,
87%). Mp 124±1268C. Found: M1, 390.2068; C25H28NO3
requires M, 390.2069; dH )300 MHz, CDCl3) 7.20 )13H, m,
ArH), 5.83 )2H, s, CH2), 3.85 )3H, s, CH3O), 3.81 )3H,
s, CH3O), 1.81 )6H, s, CH3); dC )75 MHz, CDCl3)
172.91, 160.40, 159.74, 148.78, 141.53, 131.76, 130.69,
129.56, 128.61, 128.47, 128.30, 126.79, 127.04, 126.09,
119.03, 113.55, 112.46, 112.42, 62.36, 55.21, 55.14,
52.22, 28.57; m/z )CI) 390 )M1, 100%), 272 )M12
C6H5C)CH3)2); nmax)®lm)/cm21 1639 )CvO), 1606 )Ar).
)3H, m, ArH, H7), 6.15 )1H, dd, Jˆ10, 1.5 Hz, H6), 4.44
)1H, d, Jˆ2 Hz, H3), 3.84 )3H, s, CH3O), 3.68 )1H, m,
H7a), 2.64 )3H, m, H4, H3a), 1.86 )3H, s, CH3), 1.54 )3H,
s, CH3); dC )75 MHz, CDCl3) 196.52, 171.51, 160.08,
145.90, 144.34, 143.15, 130.25, 130.12, 128.09, 126.90,
125.22, 117.99, 113.22, 111.56, 67.21, 59.91, 55.22,
42.41, 41.42, 39.10, 28.25, 27.80; nmax 2942 )CH), 1679
)CvO), 1600 )Ar), 1586 )Ar); m/z )CI) 376 )M1H1,
90%), 258 )70%), 119 )100%).
4.2.3. ꢀ3R,3aR,7R,7aS)-3-ꢀ3-Methoxyphenyl)-7-methyl-
perhydro-isoindole-1,5-dione 12b. Methyl lithium)7.04
mmol, 1.6 M solution in hexane) was added to a suspension
of copper bromide )0.5 g, 3.52 mmol) in THF )5 mL) at
2788C. The solution was stirred for 30 min and allowed
to warmto 0 8C. Isoindole 10b )0.66 g, 1.76 mmol) in
THF )10 mL) and trimethylsilylchloride )0.45 mL, 3.52
mmol) were added dropwise at 2788C. The resulting
mixture was stirred for 3 h at 2788C. Saturated ammonium
chloride solution was added, and the mixture allowed to
warmto roomtemperature. The layers were separated and
the aqueous layer was extracted with ethyl acetate. The
combined organic fractions were washed with saturated
ammonium chloride, dried over MgSO4 and evaporated
under reduced pressure to give a crude sample of silyl
4.2. General procedure for cyclisation using a chiral
lithium amide
The benzamide 5a or b )1 equiv.) was added to a freshly
prepared solution of the chiral lithiumamide )HCl salt
6´HCl or 7´HCl )1.3 equiv.) and BuLi )2.6 equiv.) in THF
)10 mL) at 2788C. The mixture was allowed to warm to
room temperature. Saturated ammonium chloride solution
was added. The aqueous layer was extracted with ether. The
combined organic layers were washed with dilute hydro-
chloric acid and brine, dried over MgSO4 and evaporated
under reduced pressure to afford the crude product.
4.2.1. 2-ꢀ1-Methyl-1-phenylethyl)-3-phenyl-2,3,3a,4,5,7a-
hexahydro-1H-1,5-isoindoledione 10a. By this method,
amide 5a )0.25 g, 0.696 mmol), 7´HCl )0.24 g, 0.90 mmol)
and n-BuLi )1.8 mmol) in THF )20 mL) gave, after puri®-
cation by ¯ash chromatography )7:3 petroleum ether±ethyl
acetate), the title compound 10a as a white solid )0.157 g,
66%). Mp 127±1288C. Analytical HPLC )b-GEM, Regis),
eluting with IPA and hexane )30:70), showed it to consist
of a 86.5:13.5 mixture of two enantiomers, tR 8.16 and
20
enol ether 11b. [a]D ˆ117 )cˆ1.17, CHCl3); Found:
M1, 463.2546; C28H37NO3Si requires M, 463.25426; dH
)300 MHz, CDCl3) 7.3±6.5 )9H, m, ArH), 4.61 )1H,
d, Jˆ2.5 Hz, H6), 4.21 )1H, s, H3), 3.62 )3H, s, MeO),
2.6±2.0 )4H, m, H4, H3a, H7a), 1.85±1.7 )1H, m, H7),
1.62 )3H, s, CH3-cumyl), 1.37 )3H, s, CH3-cumyl), 0.80
)3H, d, Jˆ7.0 Hz, CH3), 0.0 )9H, s, TMS); dC )75 MHz,
CDCl3) 175.88, 159.87, 146.78, 146.15, 143.83, 129.74,
127.89, 126.56, 125.54, 118.22, 118.22, 112.67, 111.71,
108.83, 68.60, 58.96, 55.17, 44.60, 39.52, 32.39, 27.86,
27.42, 27.30, 23.28, 0.25; nmax 2953 )CH3), 1688 )CvO).
8.95 min )eeˆ73%). Recrystallisation fromethyl acetate
20
gave material )0.081 mg, 34%) of ee .99%, [a]D
ˆ
2224 )cˆ0.17, CHCl3). Found: M1, 345.1732;
C23H23NO2 requires M, 345.17287; dH )300 MHz, CDCl3)
7.34 )10H, m, ArH), 6.92 )1H, dd, Jˆ10, 5 Hz, H7), 6.16
)1H, dd, Jˆ10, 2 Hz, H6), 4.47 )1H, d, Jˆ2.5 Hz, H3), 3.67
)1H, m, H7a), 2.66 )3H, m, H41H3a), 1.85 )3H, s, CH3),
1.52 )3H, s, CH3); dC )75 MHz, CDCl3) 196.52, 171.48,
145.87, 144.33, 141.46, 130.25, 128.99, 128.09, 126.90,
125.80, 125.20, 67.25, 59.91, 42.38, 41.47, 39.04, 28.21,
27.14; m/z )CI) 346 )M1H1, 100%), nmax 2978 )CH),
1680 )CvO).
Without further puri®cation, tri¯uoroacetic acid )5 mL) was
added to isoindole 11b )1.76 mmol). The mixture was
heated to re¯ux for 4 h and concentrated under reduced
pressure. Puri®cation by ¯ash chromatography )1:2 petro-
leumether±ethyl acetate) afforded the title compound 12b
as a white solid )0.32 g, 67% for the two steps).
19
[a]D ˆ137 )cˆ1.08, CHCl3). Recrystallisation from
20
ethyl acetate gave a white solid )0.23 g, 48%), [a]D
ˆ
148 )cˆ9.1 mg/mL in CHCl3). Analytical GC, showed
this material to consist of a 1.03:98.97 mixture of two
enantiomers, tR 34.57 and 35.58 min )eeˆ98%). Mp
175±1778C, Found: M1 273.1371; C16H19NO3 requires M,
273.1365; dH )300 MHz, CDCl3) 7.4±6.8 )4H, m, ArH), 6.2
)1H, br s, NH), 4.34 )1H, d, Jˆ4.4 Hz, H3), 4.34 )3H, s,
MeO), 3.0±2.0 )7H, m, H3a, H4, H6, H7, H7a), 1.22 )3H, s,
CH3); dC )75 MHz, CDCl3) 209.75, 160.04, 141.91, 129.99,
117.98, 113.27, 111.44, 61.92, 55.21, 46.48, 44.94, 41.06,
30.36, 20.51; nmax 3250 )NH), 2900 )CH3), 1695 )CvO).
By the same method, amide 5a )0.25 g, 0.696 mmol),
6´HCl )0.24 g, 0.90 mmol) and n-BuLi )1.8 mmol) in THF
)20 mL) afforded the title compound 10a as a white solid
)0.211 g, 88, 81% ee).
4.2.2. 3-ꢀ3-Methoxyphenyl)-2-ꢀ1-methyl-1-phenylethyl)-
2,3,3a,4,5,7a-hexahydro-1H-1,5-isoindoledione 10b. By
the same method, amide 5b )0.17 g, 0.44 mmol), 6´HCl
)0.12 g, 0.60 mmol) and n-BuLi )0.60 mmol) in THF
)15 mL) gave, after puri®cation by ¯ash chromatography
)7:3 petroleumether±ethyl acetate) the title compound
10b as a yellow oil )0.14 g, 87%). Analytical HPLC
)b-GEM, Regis), eluting with isopropanol and hexane
)30:70), showed it to consist of a 7.9:92.1 mixture of two
4.2.4. ꢀ3R,3aR,7R,7aS)-7-Methyl-3-phenylperhydro-iso-
indole-1,5-dione 12a. By the same method, enone 10a
)0.56, 1.72 mmol) gave title compound 12a )0.42 g,
100%) as a white solid. Mp 170±1718C. [a]Dˆ151
)cˆ0.63 in CHCl3). Found: M1, 243.1263; C15H17NO2
requires M, 243.1259; dH )300 MHz, CDCl3) 7.45±7.10
)5H, m, ArH), 4.32 )1H, d, Jˆ4.5 Hz, H3), 2.81±2.22
20
enantiomers, tR 8.45 and 8.93 min )eeˆ84%). [a]D ˆ2159
)cˆ1.4, CHCl3). Found: M1, 375.1838; C24H25NO3 requires
375.1834. dH )300 MHz, CDCl3) 7.30 )6H, m, ArH), 6.89

J. Clayden et al. / Tetrahedron 58 )2002) 4727±4733
4731
)7H, m, H3a, H4, H6, H7, H7a), 2.06 )1H, dd, Jˆ11, 4.8 Hz,
H4), 1.11 )3H, d, Jˆ6.2 Hz, CH3); dC )75 MHz, CDCl3)
209.9, 178.1, 140.0, 128.9, 126.1, 125.7, 61.9, 46.4,
45.8, 44.9, 40.9, 30.4, 20.5; m/z )CI) 244 )M1H1100%);
t-Bu); dC )75 MHz, CDCl3) 207.95, 172.75, 170.34, 149.41,
84.08, 62.65, 52.73, 47.09, 44.97, 42.05, 34.54, 29.34,
27.78, 20.30; m/z )CI) 343 )M1NH41, 100%), 326 )M1
H1, 25%), 226 )M1H12Boc, 60%), 243 )M1NH412
Boc, 70%); nmax)®lm)/cm21 1789, 1746, 1729, 1713
)4£CvO).
n
max)®lm)/cm21 3300 )NH), 1710 )CvO), 1670 )CvO).
4.2.5. ꢀ1R,3aS,4R,7aR)-1-ꢀ3-Methoxyphenyl)-4-methyl-
3,6-dioxo-octahydro-isoindole-2-carboxylic acid tert-
butyl ester 13b. Triethylamine )0.14 mL, 0.99 mmol),
Boc-anhydride )0.44 g, 1.96 mmol) and DMAP )0.12 g,
0.99 mmol) were added to a solution of isoindole 12b
)0.27 g, 0.99 mmol) in CH2Cl2 )15 mL). The mixture was
stirred for 12 h and concentrated under reduced pressure.
The residue was puri®ed by ¯ash chromatography )2:1
petroleumether±ethyl acetate) to afford the title compound
Isoindole 13a )1.03 g, 3 mmol) was treated in the same way
to give, after puri®cation by ¯ash chromatography, the ester
21
14 )0.56 g, 57%). [a]D ˆ167 )cˆ0.62, CHCl3).
4.2.8. ꢀ1R,3aR,4S,8aR)-4-Methyl-3,7-dioxoperhydrooxe-
pino[4,5-c]pyrrole-1,2-dicarboxylic acid 2-tert-butyl
ester 1-methyl ester 15. mCPBA )70%) )0.76 g,
3.1 mmol) was added in one portion to a stirred solution
of ketone 14 )0.53 g, 1.55 mmol) in CH2Cl2 )10 mL). The
mixture was stirred for 48 h. Sodium sul®te )5 mL of satu-
rated aqueous solution) was added and the mixture was
extracted with ethyl acetate. The combined extracts were
washed with sodiumhydrogen carbonate )10 mL of satu-
rated aqueous solution), water )10 mL), dried )MgSO4) and
evaporated under reduced pressure to afford the crude
product. Puri®cation by ¯ash chromatography, eluting
with 2:1 Pet±EtOAc, gave the lactone 15 )0.46 g, 88%) as
19
13b as a colourless oil )0.37 g, quant.). [a]D ˆ130
)cˆ1.19, CHCl3). Found: M1 373.1894, C21H27NO4
requires M, 373.18891; dH )300 MHz, CDCl3) 7.4±6.6
)4H, m, ArH), 4.77 )1H, s, H3), 3.83 )3H, s, MeO), 2.8±
2.4 )6H, m, H7a, H3a, H7, H6, H4), 2.10 )1H, dd, Jˆ15.0,
7.5 Hz, H4), 1.38 )9H, s, t-Bu), 1.17 )3H, d, Jˆ6.5 Hz,
CH3); dC )75 MHz, CDCl3) 208.92, 173.97, 160.10,
149.58, 141.43, 130.01, 117.06, 113.08, 110.76, 83.39,
65.25, 55.24, 46.63, 45.46, 42.12, 40.61, 29.93, 27.65,
20.31; m/z )CI) 374 )M1H1, 5%), 291 )M1NH4±Boc,
25%, 274 )M1H±Boc 100%); nmax 2975 )CH3), 1782 and
1718 )2£CvO).
19
a colourless oil. [a]D ˆ15 )cˆ0.57, CHCl3). Found: M1,
341.1480; C16H23NO7 requires M, 341.1474; dH )300 MHz,
CDCl3) 4.29 )1H, s, H1), 4.26 )1H, dd, Jˆ14.2, 4.4 Hz, H5),
4.10 )1H, dd, Jˆ14.2, 7.0 Hz, H5), 3.83 )3H, s, CO2Me),
3.0±2.7 )5H, m, H3a, H4, H8, H8a), 1.51 )9H, s, )CH3)3),
1.3 )3H, d, Jˆ7.5 Hz, CH3); dC )75 MHz, CDCl3) 171.5,
171.3, 169.7, 149.2, 84.4, 68.9, 63.0, 52.9, 48.7, 36.5,
32.5, 29.8, 27.8, 15.5; m/z )CI) 342 )M1H1, 5%), 242
)M1H12Boc, 60%); nmax)®lm)/cm21 1780 )CvO), 1755
)CvO), 1748 )CvO), 1723 )CvO).
4.2.6.
ꢀ1R,3aS,4R,7aR)-4-Methyl-3,6-dioxo-1-phenyl-
octahydro-isoindole-2-carboxylic acid tert-butyl ester
13a. By the same method, amide 12a )0.42 g, 1.72 mmol)
gave 13a )0.53 g, 90%) as a white solid. Mp 133±1358C.
Found: M1, 343.1778; dH )300 MHz, CDCl3) 7.41±7.16
)5H, m, ArH), 4.79 )1H, s, H3), 2.74±2.34 )6H, m, H3a,
H4, H6, H7, H7a), 2.09 )1H, dd, Jˆ14.8, 8.8 Hz, H4), 1.3
)9H, t-Bu), 1.13 )3H, d, Jˆ6.7 Hz, CH3); dC )75 MHz,
CDCl3) 208.9, 174.1, 149.5, 139.7, 128.9, 127.9, 124.9,
83.3, 65.3, 46.6, 45.5, 41.9, 40.7, 29.9, 27.6, 20.3; m/z )CI)
344 )M1H1, 20%), 244 )M1H12Boc, 100%); nmax)®lm)/
cm21 1786 )CvO), 1745 )CvO), 1713 )CvO).
4.2.9. 1-ꢀtert-Butyl) 2-methyl ꢀ2R,3R,4R)-4-[ꢀ1S)-2-
hydroxy-1-methylethyl]-3-ꢀ2-methoxy-2-oxoethyl)-5-oxo-
tetrahydro-1H-1,2-pyrroledicarboxylate 16. Sodium
methoxide )5.44 mmol, 1 M in methanol) was added drop-
wise over 0.5 h to a solution of the lactone 15 )0.46 g,
1.36 mmol) in methanol )10 mL) at 2788C. The reaction
mixture was stirred for 1 h. Saturated ammonium chloride
solution was added and the mixture was extracted with ethyl
acetate, washed with brine, dried over MgSO4 and evapo-
rated under reduced pressure to afford the crude product.
Puri®cation by ¯ash chromatography, eluting with 1:1 pet.
ether±EtOAc, gave the alcohol 16 )0.50 g, 99%) as a
4.2.7.
ꢀ1R,3aS,4R,7aR)-4-Methyl-3,6-dioxooctahydro-
isoindole-1,2-dicarboxylic acid 2-tert-butyl ester 1-methyl
ester 14. A solution of isoindole 13b )0.37 g, 0.99 mmol) in
ethyl acetate )15 mL) was added dropwise to a solution of
sodium periodate )3.64 g, 17 mmol) and ruthenium tri-
chloride hydrate )0.025 g, 0.12 mmol) in water )30 mL)
and acetonitrile )15 mL). The mixture was stirred for 4 h,
after which time a white precipitate had formed. The
mixture was ®ltered and the ®ltrate was extracted with
ethyl acetate, dried over MgSO4, ®ltered through Celitew,
and evaporated under reduced pressure and dissolved in
ether. Freshly prepared diazomethane was added, followed
by a sodiumbicarbonate solution, and the ether was evapo-
rated under reduced pressure. Puri®cation by ¯ash chroma-
tography )2:1 petroleumether±ethyl acetate) afforded the
22
colourless oil. [a]D ˆ28 )cˆ4.71, CHCl3). Found:
M1H1, 374.1816; C17H28NO8 requires M, 374.1814; dH
)300 MHz, CDCl3) 4.24 )1H, d, Jˆ5 Hz, H3), 3.74 )3H, s,
CO2Me), 3.65 )3H, s, CO2Me), 3.62 )2H, m, CH2OH), 2.90
)2H, m, H4, H5), 2.59 )1H, dd, Jˆ17, 6 Hz, CHaHbCOMe),
2.45 )1H, dd, Jˆ17, 8 Hz, CHaHbCO2Me), 1.87 )1H, q,
Jˆ5 Hz, CHCH3), 1.42 )9H, s, )CH3)3), 1.02 )3H, d,
Jˆ7 Hz, CH3); dC )75 MHz, CDCl3) 173.6, 171.5, 170.6,
149.1, 83.9, 66.3, 62.6, 52.6, 52.1, 46.3, 35.1, 33.3, 32.9,
27.8, 13.6; m/z )CI) 374 )M1H1, 15%), 274 )M1H12Boc,
100%); nmax)®lm)/cm21 3527 )OH), 1786, 1742 )CvO).
21
ester 14 )0.21 g, 67%). [a]D ˆ167 )cˆ0.62, CHCl3).
Found: M1H1, 325.1522; C16H23NO6 requires 325.1525;
dH )300 MHz, CDCl3) 4.2 )1H, d, Jˆ1.3 Hz, H3), 3.72
)3H, s, CO2Me), 2.82±2.72 )1H, m, H7), 2.62 )1H, dd, Jˆ
7.5, 5 Hz, H7a), 2.53 )1H, dd, Jˆ10, 6 Hz, H6), 2.50 )1H, m,
H3a), 2.38 )dd, Jˆ9.5, 4.5 Hz, H4), 2.24 )1H, dd, Jˆ10,
7.5 Hz, H6), 2.0 )1H, dd, Jˆ9.6, 7.5 Hz, H4), 1.42 )9H, s,
4.2.10. ꢀ2R,3R,4S)-4-Isopropenyl-3-methoxycarbonyl-
methyl-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-
butyl ester 2-methyl ester 17. Tri-n-butylphosphine
)0.57 g, 2.8 mmol) was added dropwise to a stirred solution

4732
J. Clayden et al. / Tetrahedron 58 )2002) 4727±4733
of pyrrolidinone 16 )0.50, 1.34 mmol) and phenyl-
selenophthalimide )0.6 g, 2.0 mmol) in THF at room
temperature. After 2 h, the solution was cooled to 2408C.
Pyridine )50 mL) was added followed by dropwise addition
of an aqueous solution of hydrogen peroxide )0.5 mL). The
mixture was allowed to warm to room temperature and
stirred for further 12 h. A saturated solution of sodium
bisul®te )5 mL) was added and the reaction mixture was
extracted with ethyl acetate. The combined extracts were
washed with water, dried over MgSO4, and evaporated
under reduced pressure to afford the crude product. Puri®-
cation by ¯ash chromatography, eluting with 5:1 petroleum
ether±EtOAc, gave the title compound 17 )0.31 g, 65%) as a
was extracted with ethyl acetate, dried over MgSO4 and
evaporated under reduced pressure. CH2Cl2 and tri¯uoro-
acetic acid were added and the reaction mixture was heated
to re¯ux for 2 h. After removal of the solvent, the crude
product was added to a column containing Dowex-50 H1
)WX8-200, 8% cross-linking, 100±200 wet mesh). Elution
with NH4OH )1N), evaporation, and treatment with
Amberlite CG-50 afforded )2)-kainic acid 1 )0.015 g,
19
80%) as a white solid. [a]D ˆ213.8 )cˆ0.39, CHCl3)
[lit.,48 213.9], with spectroscopic data as reported in the
literature.48
22
colourless oil. [a]D ˆ211 )cˆ0.95, CHCl3). Found:
Acknowledgements
M1H, 356.1701; C17H25NO7 requires M, 355.16309; dH
)300 MHz, CDCl3) 5.19 )1H, s, CvCHaHb), 5.05 )1H, s,
CvCHaHb), 4.36 )1H, d, Jˆ4 Hz, H2), 3.85 )3H, s,
CO2CH3), 3.73 )3H, s, CO2CH3), 3.51 )1H, d, Jˆ8.5 Hz,
H4), 2.97 )1H, m, H3), 2.50 )1H, dd, Jˆ17, 6 Hz,
CHaHbCO2Me), 2.40 )1H, dd, Jˆ17, 8.5 Hz,
CHaHbCO2Me), 1.75 )3H, s, CH3), 1.52 )9H, s, )CH3)3);
dC )75 MHz, CDCl3) 171.5, 171.2, 170.7, 149.3, 136.6,
117.9, 83.9, 62.0, 52.7, 51.9, 51.7, 34.9, 33.8, 27.8, 22.7;
m/z )CI) 356 )M1H1, 20%), 273 )M1NH412Boc, 50%),
256 )M1H12Boc, 100%); nmax)®lm)/cm21 1792 )CvO),
1740 )CvO).
We are grateful to the EPSRC and to the Leverhulme Trust
for research grants, to Aventis Cropscience )Lyon) for
support, and to Dr Darren Mans®eld for helpful discussions.
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21
compound 18 )0.03 g, 44%) as colourless oil. [a]D
ˆ
219.1 )cˆ0.62, CHCl3). dH )300 MHz, CDCl3) 4.95 )1H,
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