The synthesis of novel heterocyclic substituted α-amino acids; Further exploitation of α-amino acid alkynyl ketones

Article abstract of DOI:10.1039/a909720a

A range of novel heterocyclic substituted α-amino acids has been synthesised by cyclocondensations of (S)-2-tertbutoxycarbonylamino-4-oxohex-5-ynoic acid tert-butyl ester with enamines, phenylhydrazine, hydroxylamine and phenyl azide. The Royal Society of

Full text of DOI:10.1039/a909720a

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The synthesis of novel heterocyclic substituted ꢀ-amino acids;
further exploitation of ꢀ-amino acid alkynyl ketones
Robert M. Adlington, Jack E. Baldwin,* David Catterick, Gareth J. Pritchard and
Lam T. Tang
1
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford,
UK OX1 3QY. E-mail: jack.baldwin@chem.ox.ac.uk
Received (in Cambridge, UK) 9th December 1999, Accepted 21st December 1999
A range of novel heterocyclic substituted ꢀ-amino acids
has been synthesised by cyclocondensations of (S)-2-tert-
butoxycarbonylamino-4-oxohex-5-ynoic acid tert-butyl
ester with enamines, phenylhydrazine, hydroxylamine and
phenyl azide.
et al.,13 with the Z-geometry of the enamine double bond
expected due to the possibility of hydrogen bonding. Bohlmann
and Rahtz had however carried out their cyclocondensations
at elevated temperatures and it was subsequently found that
stirring an ethanolic solution of 1 with either enamine 2 or 3,
at reflux, then resulted in high conversion to the pyridin-6-yl
substituted, protected, β-alanines 6 and 7 (Scheme 2).
Interest in heterocyclic substituted non-proteinogenic α-amino
acids has arisen due to the diverse range of biological and
toxicological properties many of these compounds display,
for example lathyrine,1 azatyrosine,2 and mimosine.3 We have
therefore recently developed a versatile synthetic route towards
compounds of this type, which is applicable to a parallel–
combinatorial synthesis, to allow the formation of analogue
families.4,5 This was achieved by the formation of a range of
α-amino acid alkynyl ketones, by the introduction of alkynyl
ketone moieties into the side chains of -aspartic and -
glutamic acids. These reactive substrates were then shown to
undergo high yielding cyclocondensations with a range of
amidines to allow a diverse family of pyrimidin-4-yl substituted
α-amino acids to be generated. The alkynyl ketone moiety,
being an analogue of the β-dicarbonyl, is however a flexible
reactive building block capable of varied heterocyclic
construction.4–10 It was therefore decided to further exploit
this reactive group in the generation of a range of heterocyclic
substituted α-amino acids (Scheme 1).
Scheme 1
The reactive substrate (S)-2-tert-butoxycarbonylamino-
4-oxohex-5-ynoic acid tert-butyl ester 1 was selected as a
representative α-amino acid alkynyl ketone for exploring
cyclocondensation reactions. Selective protection of the α-
amino and α-carboxylic acid functionalities of -aspartic acid,
followed by conversion of the free side chain acid to the
‘Weinreb’ amide and reaction with ethynylmagnesium bromide
thus allowed 1 to be generated, as outlined previously.4,5
Scheme 2 Reagents and conditions: i, NMM, BuiOCOCl, THF,
Ϫ15 ЊC, HN(OMe)MeؒHCl, NEt3, DMF, 74%; ii, HCCMgBr (5 equiv.),
Et2O, Ϫ78 ЊC; iii, 2 or 3, EtOH, RT; iv, 2 or 3, EtOH, reflux.
Literature evidence also suggested that cyclocondensation of
1 with hydrazines and hydroxylamine should allow access to
both pyrazole and isoxazole substituted amino acids.7,8 Reac-
tion of (S)-2-tert-butoxycarbonylamino-4-oxohex-5-ynoic acid
tert-butyl ester 1 with hydrazines was therefore investigated
by stirring an ethanol solution of 1 and phenylhydrazine
hydrochloride with solid sodium carbonate. This allowed the
desired pyrazolyl substituted protected α-amino acids 8a/b to
be isolated in satisfactory yield, as an inseparable mixture of
regioisomers, in a 1:1 ratio by 1H NMR (Scheme 3).
Cyclocondensations of 1 with hydroxylamine were then
attempted to investigate a similar preparation of isoxazoles.
The expected products from our condensation reaction
appeared attractive targets, with interest in isoxazolyl α-amino
acids having arisen due to non-protein amino acids such as
ibotenic acid being regarded as conformationally restricted
glutamic acid analogues.14,15 Thus reaction of 1 with hydroxyl-
Bohlmann and Rahtz reported that cyclocondensations
between alkynyl ketones and suitable enamines allowed the
generation of functionalised pyridines in excellent yields.6 In
order to access pyridine substituted amino acids, which
would bear relation to the naturally occurring amino acid -
azatyrosine, condensation reactions between 1 and 3-amino-
but-2-enoic acid methyl ester 2 and 4-aminopent-3-en-2-one 3,
prepared by literature procedures,11,12 were therefore carried
out. Initial reactions between 1 and either 2 or 3, carried out in
ethanol at room temperature, led to almost quantitative conver-
1
sion to single products. H NMR analysis of these products
indicated that instead of a cyclocondensation to form the
desired pyridines, the disubstituted trans-alkenes 4 and 5 had
3
formed (olefinic J = 15.5 Hz compared to ca. 8.0 Hz for pyr-
idines). This observed trans addition to the triple bond of the
alkynyl ketone was consistent with that reported by Bromidge
J. Chem. Soc., Perkin Trans. 1, 2000, 303–305
This journal is © The Royal Society of Chemistry 2000
303

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acid 10, in almost quantitative yield, as a single regioisomer
1
(Scheme 3). H NMR (CD3OD) analysis indicated that pre-
sumably only the regioisomer 10 was formed owing to the high
ppm value (δH 9.11 ppm) of the C-5 aromatic proton (usually
ca. 8.5–9.0 ppm).8,16
The enantiomeric purity of this range of heterocyclic amino
acids was then determined by conversion of their N-depro-
tected forms (Boc deprotection was carried out by azeotropic
distillation with TsOHؒH2O–PhMe) to both their (R)- and
(S)-Mosher’s amides and shown, by 19F NMR analysis, to be
greater than 98% ee.18
Facile deprotection of the amino acids 7, 8a/b, 9a/b and 10
was carried out by their dissolution in TFA–anisole; full depro-
tection of 6 being carried out by refluxing in 1 M HCl. The free
amino acids 11 and 12 were then obtained, by ion-exchange
chromatography, as solids in high yields and the amino acids
13a/b, 14a/b and 15 were isolated as their TFA salts, after di-
ethyl ether trituration, due to their low solubilities (Scheme 4).
Scheme 3 Reagents and conditions: i, H2N–NHPhؒHCl, Na2CO3, H2O,
EtOH, reflux; ii, H2N–OHؒHCl, EtOH, pyridine, reflux; iii, H2N–
OHؒHCl, EtOH, reflux; iv, Ph–N3, Et2O, reflux.
amine hydrochloride in an ethanol solution with solid sodium
carbonate only allowed isolation of the isoxazole 9a in a poor
13% yield.7 Variation of the solvent and base employed, to
ethanol and 1.2 equivalents of pyridine, subsequently allowed
the regioisomeric isoxazoles 9a/b to be obtained in a 51% yield,
as a 3:1 separable mixture of regioisomers.16 Giacomelli et al.
however had reported a successful condensation of hydroxyl-
amine upon an enamino ketone, albeit in low yield, by a simple
reaction with the hydrochloride salt in refluxing methanol.17
We therefore investigated the possibility of cyclocondensations
that were not subject to the hydroxlamine being released by
the addition of base. Hydroxylamine hydrochloride was thus
refluxed in ethanol with 1 and the isoxazole 9a isolated
exclusively in a respectable 62% yield (Scheme 3).
It was next decided to attempt the formation of a 1,2,3-
triazolyl substituted α-amino acid by a cycloaddition with an
azide. It had been shown that reaction of azides with alkynyl
ketones had led to exclusive addition at the acetylene and there-
fore reaction of 1 with phenyl azide was carried out in refluxing
diethyl ether.8 This generated the triazol-4-yl, protected, amino
Scheme 4 Reagents and conditions: i, 1 M HCl, reflux; ii, Dowex 50X8-
100 ion exchange resin; iii, TFA, anisole, DCM.
304
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4 R. M. Adlington, J. E. Baldwin, D. Catterick and G. J. Pritchard,
In summary we have shown that our methodology can be
readily expanded to other novel heterocyclic systems. Further
exploitation of the alkynyl ketone reactive group has allowed
efficient construction of a range of representative heterocyclic
non-proteinogenic amino acids. This has further highlighted
the flexibility and power of our approach with pyridinyl, pyr-
azolyl, isoxazolyl and 1,2,3-triazolyl substituted β-alanines
being generated in approximately 15% yield from -aspartic
acid. Further routes to novel heterocyclic non-protein amino
acids will be reported in due course.
Chem. Commun., 1997, 1757; R. M. Adlington, J. E. Baldwin,
D. Catterick and G. J. Pritchard, J. Chem. Soc., Perkin Trans. 1,
1999, 855.
5 R. M. Adlington, J. E. Baldwin, D. Catterick and G. J. Pritchard,
J. Chem. Soc., Perkin Trans. 1, preceding paper.
6 F. Bohlmann and D. Rahtz, Chem. Ber., 1957, 90, 2265.
7 K. Bowden and E. R. H. Jones, J. Chem. Soc., 1946, 953.
8 K. M. Johnston and R. G. Shotter, J. Chem. Soc. (C), 1968, 1774.
9 D. Obrecht, C. Abrecht, A. Grieder and J. M. Villalgordo, Helv.
Chim. Acta, 1997, 80, 65.
10 L. I. Vereshchagin, L. G. Tikhenova, A. V. Maksikova, E. S.
Serebryakova, A. G. Proidakov and T. M. Filippora, Zh. Org. Khim.,
1980, 16, 730.
Acknowledgements
11 J. Decombe, Anal. Chem., 1952, 18, 115.
We thank the EPSRC for a studentship to D. C. and the EPSRC
mass spectrometry service (Swansea) for high resolution mass
spectra.
12 C. Mentzer, Bull. Soc. Chim. Fr., 1945, 12, 166.
13 S. M. Bromidge, D. A. Entwhistle, J. Goldstein and B. S. Orlek,
Synth. Commun., 1993, 23, 487.
14 U. Madsen, M. A. Dumpis, H. Brauner-Osborne and L. B.
Piotrovsky, Bioorg. Med. Chem. Lett., 1998, 8, 1563.
15 M. Falorni, G. Giacomelli and E. Spanu, Tetrahedron Lett., 1998,
39, 9241.
References
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16 Regioisomers were assigned by H and 13C NMR and comparison
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to literature compounds.8 Full details will be reported in due course.
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Communication a909720a
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