Synthesis of (±)-kainic acid by dearomatising cyclisation of a lithiated N-benzyl p-anisamide

Article abstract of DOI:10.1039/a909325g

N-Benzyl p-anisamide 6, on lithiation with Bu(t)Li in the presence of HMPA, undergoes a stereoselective anionic cyclisation with loss of aromaticity to give a bicyclic enone which may be converted in nine steps to (±)-kainic acid.

Full text of DOI:10.1039/a909325g

Synthesis of (±)-kainic acid by dearomatising cyclisation of a lithiated N-benzyl
p-anisamide
Jonathan Clayden* and Kirill Tchabanenko
Department of Chemistry, University of Manchester, Oxford Road, Manchester, UK M13 9PL.
E-mail: j.p.clayden@man.ac.uk
Received (in Liverpool, UK) 24th November 1999, Accepted 12th January 2000
N-Benzyl p-anisamide 6, on lithiation with ButLi in the
presence of HMPA, undergoes a stereoselective anionic
cyclisation with loss of aromaticity to give a bicyclic enone
which may be converted in nine steps to ( )-kainic acid.
We recently described1 the dearomatising cyclisation reaction
of lithiated N-benzyl benzamides 1 to give bicyclic cyclohexa-
dienes 2 and 3 (Scheme 1).2 The reaction is stereoselective,
creating three new stereogenic centres, and it is noticeable that
the pyrrolidine ring of the major product 2 has the relative
stereochemistry of kainic acid 4. (2)-Kainic acid3 4 was first
isolated in 1953 from the Japanese marine alga Digenea
simplex.4 It has diverse biological activity: as an anthelmintic,
D. simplex is a traditional remedy in which kainic acid is the
active component.5 Kainic acid is an extremely potent neuro-
excitor, binding specifically at the kainate receptor and leading
to specific neuronal death.6,7 Both the anthelmintic and
neuroexcitatory properties of kainic acid are dependent on the
cis C-3–C-4 relative stereochemistry: allokainic acid, the C-4
Scheme 2 Reagents and conditions: (a) p-anisoyl chloride, Et3N, CH2Cl2;
epimer, is inactive as an anthelmintic8 and has lower neuro-
(b) NaH, DMF, BnBr, 18 h; (c) ButLi (2 equiv.), HMPA (12 equiv.), THF,
excitatory activity than kainic acid.9
240 °C, 60 h; (d) NH4Cl; (e) THF, 1 M HCl (aq).
Scheme 1 Reagents and conditions: (a) ButLi (1.3 equiv.), HMPA (6
equiv.), THF, 278 °C, 16 h; (b) NH4Cl.
A number of syntheses of (2)-kainic acid10 and (±)-kainic
acid11 have been reported, several of which10g–k,p,s,11a achieve
control over the C-3–C-4 stereochemistry by forming these
substituents from a cyclic precursor. Our approach to (±)-kainic
acid, presented in Schemes 2 and 3, also uses this strategy,
exploiting the relative stereochemistry of the dearomatising
cyclisation reaction.
Acylation of cumylamine 512 with p-anisoyl chloride,
Scheme 3 Reagents and conditions: (a) Me2CuLi, Me3SiCl, THF, 278 °C,
1 h; (b) CF3CO2H, reflux, 6 h; (c) Boc2O, Et3N, DMAP, CH2Cl2, (d) NaIO4,
cat. RuCl2, 1+1 acetone–H2O; (e) Me3SiCHN2, PhH, MeOH; (f) MCPBA,
CH2Cl2; (g) NaOH (2.2 equiv.), MeOH, reflux, 2 h; (h) o-NO2C6H4SeCN,
Bu3P, THF, rt; (i) H2O2, Py, THF, 240 °C; (j) NaBH(OMe)3 (2 equiv.),
THF, reflux; (k) 10+1 CF3CO2H–H2O, reflux, 4 h.
followed by alkylation of the secondary amide with benzyl
bromide, gave the cyclisation substrate 6. Tertiary N-sub-
stituents are necessary for good yields in the cyclisation step,
and our early studies had all used N-But amides. However, we
had considerable difficulty removing the tert-butyl group from
the cyclised products: we turned to the cumyl group for ease of
removal under acid conditions.13 The N-cumyl-N-benzyl amide
6 was lithiated with ButLi in the presence of HMPA, but the
more bulky group slowed the reaction considerably and the
cyclisation of 6 via 7 required 60 h at 240 °C to reach
completion. The initial product of the cyclisation was the
enolate 8, which was protonated to give the dienyl ether 9 as a
single regioisomer. This was hydrolysed in situ to the bicyclic
Chem. Commun., 2000, 317–318
This journal is © The Royal Society of Chemistry 2000
317

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enone 10, whose pyrrolidinone ring has the relative stereo-
chemistry of kainic acid.
Lithium dimethyl cuprate, in the presence of trimethylsilyl
chloride, attacked solely the exo face of the enone 10: TFA
catalysed both hydrolysis of the product silyl enol ether and
removal of the cumyl group, and the lactam 11 was reprotected
as its Boc derivative 12.
The phenyl ring of 12 was oxidised with catalytic RuO4, and
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may favour a conformation with the breaking O–O bond
antiperiplanar to the C–C bond shown in bold, rather than the
C–C bond to the other side of the former ketone.
Seven-membered lactone 14 was converted to diester 15 by
hydrolysis with methanolic NaOH (slow addition of base
avoided cleavage of the Boc protecting group) and esterification
with trimethylsilyldiazomethane.15 The elimination of water to
give the isopropenyl group of 16 was achieved in one step by
direct formation of a selenide16 which was oxidised and
eliminated under mild conditions.
Sodium trimethoxyborohydride selectively reduced the lac-
tam carbonyl group of 16 in the presence of the two esters,17 and
wet trifluoroacetic acid both deprotected the amino group and
hydrolysed the esters of the product 17. The racemic product
(±)-4 was recrystallised from methanol and had spectroscopic
properties (1H and 13C NMR) identical with those of natural
kainic acid.
12 D. Balderman and A. Kalir, Synthesis, 1978, 24.
13 The use of cumyl as an organolithium-resistant acid labile protecting
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We are grateful to the Leverhulme Trust for a grant.
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Notes and references
1 A. Ahmed, J. Clayden and S. A. Yasin, Chem. Commun., 1999, 231.
2 Dearomatising anionic cyclisations are also known in the naphthamide
series: A. Ahmed, J. Clayden and M. Rowley, Chem. Commun., 1998,
297; A. Ahmed, J. Clayden and M. Rowley, Tetrahedron Lett., 1998, 39,
6103; R. A. Bragg and J. Clayden, Tetrahedron Lett., 1999, 40, 8323;
Tetrahedron Lett., 1999, 40, 8327. There are reports of similar reactions
17 We are not aware of other uses of this reagent to reduce lactams in the
presence of esters. See, however, M. E. Kuehne and P. J. Shannon,
J. Org. Chem., 1977, 42, 2082.
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