Synthesis of a potent (±)-4-(2-hydroxyphenyl) analogue of the acromelic acids by dearomatising cyclisation of a lithiated N-p-methoxybenzyl-4-methoxy-1-naphthamide

Article abstract of DOI:10.1016/S0040-4039(01)00501-9

Dearomatising anionic cyclisation of N-cumyl-N-p-methoxybenzyl-4-methoxy-1-naphthamide 8 diastereoselectively generates a pyrrolidinone-fused tetralone 12 which may be transformed in seven steps to the racemic form of a known non-natural member of the aryl kainoid family 4 having potent biological activity. Key steps of the synthesis are ruthenium-catalysed oxidation of the C2-p-methoxybenzyl ring of 12 to a carboxylic acid and Baeyer-Villiger cleavage of the tetralone to a lactone whose hydrolysis reveals the two-carbon substituent at C3 and the 2-hydroxyphenyl substituent at C4. Selective reduction of the lactam yields the kainoid 4. Control of epimerisation at the C-4 centre during the lactone hydrolysis leads to either the (active) 3,4-cis or the (inactive) 3,4-trans epimers of the target.

Full text of DOI:10.1016/S0040-4039(01)00501-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3407–3410
Synthesis of a potent ( )-4-(2-hydroxyphenyl) analogue of the
acromelic acids by dearomatising cyclisation of a lithiated
N-p-methoxybenzyl-4-methoxy-1-naphthamide
Anjum Ahmed, Ryan A. Bragg, Jonathan Clayden* and Kirill Tchabanenko
Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Received 22 February 2001; revised 15 March 2001; accepted 19 March 2001
Abstract—Dearomatising anionic cyclisation of N-cumyl-N-p-methoxybenzyl-4-methoxy-1-naphthamide 8 diastereoselectively
generates a pyrrolidinone-fused tetralone 12 which may be transformed in seven steps to the racemic form of a known non-natural
member of the aryl kainoid family 4 having potent biological activity. Key steps of the synthesis are ruthenium-catalysed
oxidation of the C2-p-methoxybenzyl ring of 12 to a carboxylic acid and Baeyer–Villiger cleavage of the tetralone to a lactone
whose hydrolysis reveals the two-carbon substituent at C3 and the 2-hydroxyphenyl substituent at C4. Selective reduction of the
lactam yields the kainoid 4. Control of epimerisation at the C-4 centre during the lactone hydrolysis leads to either the (active)
3,4-cis or the (inactive) 3,4-trans epimers of the target. © 2001 Elsevier Science Ltd. All rights reserved.
Many members of the aryl kainoid family1 of natural
and non-natural products, represented by the general
structure 2, are powerful neuroexcitatory agents.2 The
natural acromelic acids such as acromelic acid A 33 and
their unnatural analogues4 including 4 and 55,6 show
greater biological activity even than kainic acid 1. Until
recently, kainic acid was widely used as a tool in
neuropharmacology7 for the stimulation of nerve cells
and the mimicry of disease states such as Alzheimer’s
and Huntington’s diseases. However, a current shortage
of naturally extracted kainic acid8 has led to an acute
need for efficient synthetic routes both to kainic acid9
and its potent aryl kainoid analogues.10
In this Letter, we report a short synthesis of a potent
aryl kainoid 4 which uses, as a key step, the dearoma-
tising anionic cyclisation of a 1-naphthamide 8.11 We
recently published12 a short synthesis of ( )-kainic acid
1 which employed a similar dearomatising anionic cycli-
sation of an N-benzyl-p-anisamide.13 Our retrosynthetic
Scheme 1. Retrosynthetic analysis of kainoid 4.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00501-9

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A. Ahmed et al. / Tetrahedron Letters 42 (2001) 3407–3410
analysis of 4 is shown in Scheme 1. We aimed to form
the carboxylate substituent at C2 by oxidation of the
aromatic ring required for the cyclisation, and the two
cis-related substituents at C3 and C4 of the pyrrolidi-
none ring by a Baeyer–Villiger cleavage of the tetralone
generated on cyclisation of the 4-methoxy-1-naph-
thamide. The 3,4-cis stereochemistry of all members of
the kainoid class is essential for their biological activity:
our strategy uses the six-membered ring as a means of
ensuring the groups remain cis for the duration of the
synthesis—a strategy also employed by Shirahama5 in
the first synthesis of 4.
Although Ar=Ph has served us well both in the cyclisa-
tions and in subsequent oxidation to a carboxylic acid,12
we hoped to improve the aryl oxidation by choosing the
more electron-rich p-methoxyphenyl group as Ar.16
The starting material for the cyclisation was made from
the commercially available aldehyde 5 by oxidation17 to
6 and coupling with cumylamine. Alkylation of the
resulting secondary amide 7 with p-methoxybenzyl chlo-
ride gave the cyclisation precursor 8 (Scheme 2).
Amide 8 was deprotonated by t-BuLi in THF at −78°C
to afford a benzylic organolithium 9 which cyclised over
a period of 16 h at −78°C on addition of DMPU18
(Scheme 3). The resulting enolate 10 was protonated to
yield the tricyclic lactam 11 as a single diastereoiso-
mer.19 Refluxing in wet trifluoroacetic acid both depro-
tected the amide group and the hydrolysed the enol
ether to yield the amidoketone 12a. Hydrolysis without
deprotection to give 12b could be accomplished with 1
M HCl.
Our choice of R and Ar was influenced by the function
of these groups in the cyclisation and in later stages of
the synthesis. The most high-yielding cyclisations are
those in which the non-cyclising substituent at N is
branched and bulky,14 and difficulties removing t-Bu
from the cyclised products have meant that we now
prefer cumyl as a base-stable, strong acid-labile protect-
ing group for nitrogen during the cyclisation.12,15
Scheme 2. Synthesis of the cyclisation precursor 8. (i) NaClO2, NaH2PO4, H2O, t-BuOH, 2-methyl-2-butene, 20 h, 96%; (ii)
(COCl)2, DMF, CHCl3, 20 h, 100%; (iii) cumylamine, CH2Cl2, NaOH, H2O, 16 h, 92%; (iv) NaH, DMF, 4-methoxybenzyl
chloride, 2 days, 74%.
Scheme 3. Cyclisation of 8. (i) t-BuLi (1.3 equiv.), THF, −78°C, 2 h; (ii) DMPU (6 equiv.), −78°C, 16 h, 88%; (iii) NH4Cl, H2O;
(iv) CF3CO2H, H2O, D, 3 h, 87% 12a; (v) 1 M HCl, THF, 2 h, 85% 12b.
Scheme 4. Synthesis of 4. (i) Boc2O, Et3N, DMAP, 44% (44% 12, 12% 20); (ii) Boc2O, DMAP (cat.), MeCN, 80% (15% 12); (iii)
RuCl3, NaIO4, H2O, EtOAc, MeCN, 4 h (iv) CH2N2, 52% from 13; (v) mCPBA, 16 h, 52%; (vi) NaOMe, MeOH, 0°C, 85%; (vii)
NaBH(OMe)3, THF; (viii) BF3·OEt, Et3SiH, CH2Cl2, 25% (two steps); (ix) 6 M HCl, 1 h, D, quant.

A. Ahmed et al. / Tetrahedron Letters 42 (2001) 3407–3410
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Scheme 5. Synthesis of trans-4. (i) LiOH, H2O, THF, 20°C, 86%; (ii) CH2N2, Et2O, 55% (5:1 cis:trans); (iii) NaBH(OMe)3, THF,
52% (single diastereoisomer); (iv) BF3·OEt, Et3SiH, CH2Cl2, −78 to 20°C, 70%; (ix) 6 M HCl, 1 h, D, 99%.
Oxidation of the p-methoxyphenyl group has to be the
next step, because the subsequent Baeyer–Villiger reac-
tion increases the electron density in the second aro-
(to A.A. and R.A.B.), to the Leverhulme Trust for a
grant, to Merck, Sharp and Dohme and to Oxford
Asymmetry International for support, and to Drs. M.
Rowley and O. Ichihara for many helpful and illumi-
nating discussions.
matic ring and would otherwise lead to
a
chemoselectivity problem (Scheme 4). Few nitrogen
protecting groups are compatible with the ruthenium-
catalysed oxidation,16,20,21 and we chose N-t-butyloxy-
carbonyl as the one most likely to yield good results.
Boc-protection of the unusually enolisable amide 12a
was initially problematic, and under standard
conditions22 (Boc2O, Et3N, DMAP or Boc2O, NaOH,
CH2Cl2) a significant quantity of the O-Boc enol car-
bonate 20 was formed. However, by using only a
catalytic quantity of DMAP in MeCN,23 we were able
to isolate a respectable 80% yield of 13 from this step.
The protected amide 13 was oxidised to the acid 14
using catalytic RuCl3 with NaIO4 as the stoichiometric
reoxidant,16 and a diazomethane work-up allowed us to
isolate the ester 15.24
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Furthermore, we were able to obtain the inactive trans
stereoisomer of 46 by carrying out the hydrolysis of the
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tion at C-4. Hydrolysis of 16 with LiOH, H2O, THF at
20°C gave a 5:1 mixture of trans-17 and 17 in 86% yield
which was converted to trans-4 by the same sequence of
reactions as that used to make 4 (Scheme 5).28
The synthesis of 4 and trans-4 demonstrates further the
potential of the dearomatising anionic cyclisation of
amides for use in the synthesis of kainoids. In the
accompanying paper we present the first example of an
asymmetric dearomatising anionic cyclisation, and we
show how it can be used to make a kainoid-like pyrog-
lutamate, as well as the key intermediate 12a in the
synthesis of 4 in enantiomerically enriched form, consti-
tuting a formal asymmetric synthesis of 4.
Acknowledgements
The authors are grateful to the EPSRC for studentships
.

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A. Ahmed et al. / Tetrahedron Letters 42 (2001) 3407–3410
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1
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compounds whose structures have been determined by
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paper. All new compounds described in this paper are
racemic.
very broad signals, probably due to slow rotation about
the ArꢀC bond.
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28. The stereochemistry of trans-19 was confirmed by NOE
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.