Novel C-4 heteroaromatic kainoid analogues: A parallel synthesis approach

Article abstract of DOI:10.1016/S0960-894X(99)00690-3

New C-4 thiazole 4, 5 and aminothiazole 6, 7 kainoid analogues were efficiently synthesised in five steps from commercially available (-)-α-kainic acid 1 and exhibited strong binding to the kainate receptors. A reactive α-bromoketone 10 was generated and

Full text of DOI:10.1016/S0960-894X(99)00690-3

Bioorganic & Medicinal Chemistry Letters 10 (2000) 309±311
Novel C-4 Heteroaromatic Kainoid Analogues: A Parallel
Synthesis Approach
Jack E. Baldwin,* Andrew M. Fryer and Gareth J. Pritchard
The Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, UK
Received 28 October 1999; accepted 9 December 1999
AbstractÐNew C-4 thiazole 4, 5 and aminothiazole 6, 7 kainoid analogues were eciently synthesised in ®ve steps from commer-
cially available ( )-a-kainic acid 1 and exhibited strong binding to the kainate receptors. A reactive a-bromoketone 10 was gener-
ated and reacted with thioamides and thioureas to form thiazole and aminothiazole heterocycles 11±14. Deprotection gave the new
kainoid amino acids 4±7 in excellent yield. # 2000 Elsevier Science Ltd. All rights reserved.
The kainoids are a unique family of non-proteinogenic
amino acids, isolated from several marine algal and
fungal sources.1 In addition to their complex structure,
the kainoids also possess interesting biological proper-
ties. In particular, they display potent neuroexcitatory
activity in the mammalian central nervous system
(CNS) and act at the kainate subclass of ionotropic
glutamate receptors.2 Ligands that show selective ago-
nist or antagonist activity at these speci®c receptors are
in high demand for use as tools in experimental neuro-
pharmacology.3,4 ( )-a-Kainic acid (1) is the parent
member of the kainoid family and was ®rst isolated
from the Japanese marine red alga Digenea simplex in
1953.5 Acromelic acid A 2 is the most potent naturally
occurring kainoid and was isolated along with several
other related acromelic acids from a toxic Japanese
mushroom Clitocybe acromelalga.6±8 Since then, a
number of unnatural C-4 aryl analogues of the acro-
melic acids have been synthesised and their neuro-
excitatory activity evaluated.1,9,10 The o-anisyl analogue
3 was shown to be the most highly neuroexcitatory kai-
noid known to date (Fig. 1).11
material here due to its availability and because all of
the required stereochemistry around the pyrrolidine ring
is in place.
Our aim was to convert the C-4 isopropylidene sub-
stituent into a reactive unit that could be readily trans-
formed by simple cyclisation reactions into a variety of
aromatic heterocycles. A related approach was used by
Shirahama and co-workers in the ®rst syntheses of
acromelic acid A (2) and acromelic acid B.6 They func-
tionalised the C-4 substituent of 1 for constructing the
pyridone rings of the acromelic acids. For the present
study, an a-bromoketone was chosen as the reactive
unit since a-bromoketones can react with thioamides
and thioureas to form thiazoles (Hantzsch synthesis)
and aminothiazoles, respectively.14 After initial inves-
tigations into di€erent protective group strategies, it
was found that tert-butyl esters for the carboxylic acids
and a benzoyl group for the secondary amine were the
most robust protecting groups for the subsequent
chemistry. Protection of 1 was therefore carried out by
treatment with isobutylene and concentrated sulfuric
acid in 1,4-dioxane followed by Schotten Baumann
acylation of nitrogen using aqueous sodium hydroxide
and benzoyl chloride to give the diester 8 in good yield
(Scheme 1).
Herein, we report a rapid and ecient, parallel synthesis
of new C-4 thiazole 4, 5 and aminothiazole 6, 7 ana-
logues of the acromelic acids starting from commercially
available ( )-a-kainic acid (1). Although we have recently
developed concise and versatile syntheses of both
natural12,13 and unnatural9,10 kainoids from trans-4-
hydroxy-l-proline, we have chosen 1 as our starting
Ozonolysis of 8 in a mixture of MeOH and DCM at
78 ꢀC followed by a reductive work up with tri-
phenylphosphine gave methyl ketone 9 in essentially
quantitative yield. A regiospeci®c bromination was
accomplished by the in situ generation of a silyl enol
ether from 9 using LiHMDS and TMSCl in THF at
78 ꢀC followed by treatment of the silyl enol ether
with phenyltrimethylammonium perbromide at 0 ꢀC.15
Keywords: alkaloids; amino acids and derivatives; natural products;
neurologically active compounds.
*Corresponding author. Tel.: +44-1865-275671; fax: +44-1865-
275632; e-mail: jack.baldwin@chem.ox.ac.uk
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(99)00690-3

310
J. E. Baldwin et al. / Bioorg. Med. Chem. Lett. 10 (2000) 309±311
Figure 1.
Scheme 1. Reagents: (i) isobutylene, c. H2SO4 then NaOH, PhCOCl; (ii) O3, MeOH, CH2Cl2, 78 ꢀC then PPh3, to rt; (iii) LiHMDS, TMSCl,
78 ꢀC then PhNMe3Br3, to rt.
Bromoketone 10 was obtained in excellent yield as a
white, crystalline solid after puri®cation by silica gel
chromatography.
yielding steps from commercially available ( )-a-kainic
acid (1). This route should allow the preparation of a
number of C-4 heteroaromatic kainoid analogues by
parallel cyclisation reactions with bromoketone 10.
Such compounds will be extremely valuable for neuro-
pharmacologists as new tools for probing the kainate
receptors and their function in the CNS. New kainoids
4±7 are currently undergoing biological evaluation,
initial results have shown that compounds 4 and 6 are
the twice as active as 3 and are thus the most potent
neuroexcitatory kainoids known. The synthesis of dif-
ferent reactive units at the C-4 position and cyclisation
reactions giving other heteroaromatic kainoid ana-
logues are currently under investigation.
Cyclisation reactions were then performed with 10 using
a number of representative condensing reagents, namely
thioacetamide, thiobenzamide, thiourea and N-methyl-
thiourea (Scheme 2). The reactions proceeded cleanly,
giving the thiazole 11, 12 and aminothiazole derivatives
13, 14 in excellent yields (see Table 1). Deprotection of
11±14 was performed by treatment with 6 M hydro-
chloric acid under re¯ux. Puri®cation with Dowex1
50WX8 ion-exchange resin furnished the free amino
acids 4±7 in high yields.
Con®rmation of the correct 4S stereochemistry was
gained by 1H NMR NOE experiments with 4 and 5 and
by comparison of the spectral data of 4, 6 and 7 with
their C-4 epimers which were synthesised by an analo-
gous route. This work will be reported in detail in due
course. All new compounds gave satisfactory analytical
and spectroscopic data.
Table 1. Cyclisation and deprotection reactions
R
Cyclised
product
Yield (%)
Deprotected
kainoid
Yield (%)
Me
Ph
NH2
NHMe
11
12
13
14
99
91
100
100
4
5
6
7
100
100
97
In summary, C-4 thiazole and aminothiazole kainoid
amino acids 4±7 have been synthesised in ®ve high
100
Scheme 2. Reagents: (i) RCSNH2, NaHCO3, EtOH, Á; (ii) 6 M HCl (aq), Á then Dowex1 50WX8.

J. E. Baldwin et al. / Bioorg. Med. Chem. Lett. 10 (2000) 309±311
311
Acknowledgements
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We would like to thank the EPSRC for a studentship to
AMF and the EPSRC mass spectrometry service
(Swansea) for high resolution mass spectra. We also
thank L. Ho€mann-La Roche for biological evaluation
of compounds 4±7.
9. Baldwin, J. E.; Bamford, S. J.; Fryer, A. M.; Rudolph, M.
P. W.; Wood, M. E. Tetrahedron 1997, 53, 5233.
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