Synthesis of amino acid-derived imidazoles from enantiopure N-protected α-amino glyoxals

Article abstract of DOI:10.1016/S0040-4039(99)02267-4

A range of novel imidazoles, including three histidine derivatives, with chiral side chains derived from amino acids and dipeptides have been synthesised from N-Cbz-protected α-amino glyoxals. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02267-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1275–1278
Synthesis of amino acid-derived imidazoles from enantiopure
N-protected α-amino glyoxals
Michelle Groarke, M. Anthony McKervey ∗ and Mark Nieuwenhuyzen
School of Chemistry, The Queen’s University, Belfast BT9 5AG, Northern Ireland, UK
Received 25 October 1999; accepted 7 December 1999
Abstract
A range of novel imidazoles, including three histidine derivatives, with chiral side chains derived from amino
acids and dipeptides have been synthesised from N-Cbz-protected α-amino glyoxals. © 2000 Elsevier Science Ltd.
All rights reserved.
Keywords: amino acids; diazoketones; α-amino glyoxals; oxidation; imidazole synthesis.
The first synthesis of enantiopure N-protected α-amino glyoxals from α-amino acids and dipeptides
was recently reported from this laboratory.1,2 The key step of the synthesis was oxidation of N-protected
α-amino diazoketones using dimethyldioxirane (DMD) in acetone (Eq. (1)).
(1)
These glyoxals have considerable potential as chiral educts in the chemical elaboration of amino acids
and peptides and we have already shown how they can be employed in condensation reactions with
various amines to produce imino ketones,3 amino ketones,3 and six-membered nitrogen heterocycles
such as quinoxalines1,4 and azaquinoxalines.4 We have now explored further uses for these glyoxals
in heterocycle synthesis and report here the synthesis of several amino acid and dipeptide-derived
imidazoles. The presence of rigid, bifunctional structural elements such as imidazoles and other five-
membered heterocyclic rings in peptide-derived compounds is of particular interest because of their
ability to confer a wide range of biological properties.5
∗
Corresponding author. Tel: (+44) 01232 225588; fax: (+44) 01232 225544; e-mail: tmckervey@quchem.com (M. A.
McKervey)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02267-4
tetl 16195

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A well-tested route to imidazoles involves condensation of a 1,2-dicarbonyl compound with ammonia
in the presence of an aldehyde.6 We have found that N-protected α-amino glyoxals function very
effectively as the dicarbonyl component in this route to imidazoles (Eq. (2)). In practice, the diazoketone
was oxidised with DMD in acetone, after which the solvent was removed at reduced pressure and replaced
by methanol. Ammonium acetate and the aldehyde were then added and the mixture was stirred under
reflux overnight.
(2)
Application of this procedure to the glyoxals derived from N-Cbz-L-alanine, N-Cbz-L-valine, N-Cbz-
L-phenylalanine, N-Cbz-L-isoleucine and the glyoxal derived from the dipeptide Phe-Ala using benzal-
dehyde as the aldehydic component furnished disubstituted imidazoles 1, 2, 3, 4 and 5, respectively, in
60–70% yields. The product in each case was purified by flash chromatography on silica.
The 1H NMR spectra of imidazoles 1–5 were consistent with the assigned structures, the ring proton
on C-5 of the imidazole nucleus appearing at ca. δ 6.8. The molecular structure of imidazole 1 has been
confirmed by X-ray diffraction analysis (see Fig. 1).7 The NMR spectra of imidazoles 4 and 5 indicated
Fig. 1. Molecular structure of 2-phenyl-4-(1-(S)-benzyloxycarbonylamino-ethyl)-1H-imidazole 1 showing the atom-labelling
scheme for all non-hydrogen atoms. Thermal ellipsoids at 50% level

1277
that these products were formed as single diastereoisomers from which we concluded that epimerisation
did not occur in the course of the condensation reactions.
One of the attractions of this route to imidazoles is the scope for variation in the reaction components.
For example, the reaction of the glyoxals derived from N-Cbz-L-phenylalanine, N-Cbz-L-valine and N-
Cbz-L-leucine with formaldehyde as the aldehyde source led to the formation of three monosubstituted
imidazoles 6, 7 and 8, in (80%), (76%) and (78%) yield, respectively.
Three further variations in the aldehyde component are represented by methyl glyoxylate 9, N-Cbz-
L-alaninal 10 and the Phe-Ala derived aldehyde 11, which on reaction with the glyoxal derived from
N-Cbz-L-valine and ammonium acetate furnished imidazoles 12, 13 and 14, respectively. Yet another
variation in imidazole synthesis is the use of a primary amine as the source of one of the ring nitrogen
atoms. We have already shown that N-protected α-amino glyoxals form aldimines with amines such as
1-aminobutane (Scheme 1).3
Scheme 1.
The aldimines 15 and 16 derived from the glyoxals of N-Cbz-L-alanine and N-Cbz-L-phenylalanine
and 1-aminobutane, respectively, were combined with benzaldehyde and ammonium acetate to form N-
alkyl imidazoles 17 and 18 in unoptimised yields of 31 and 28%, respectively.
We have also applied aspects of this methodology to a glyoxal synthesised from L-aspartic acid. This
application is of particular interest in that it offers the possibility of synthesising histidine derivatives
from aspartic acid. The known doubly protected aspartic acid derivative8 19 was readily transformed, via
diazoketone 20, into glyoxal 21. Three separate condensation combinations of 21 and ammonium acetate
with benzaldehyde, methyl glyoxalate and aldehyde 11 were examined and found to yield histidine
derivatives 22, 23 and 24, respectively, in moderate yields.

1278
In conclusion, these studies further demonstrate the versatility of N-protected α-amino glyoxals in the
synthesis of novel polyfunctional heterocycles.
1. Typical experimental procedure for 2-phenyl-4-(1-(S)-benzyloxycarbonyl amino-ethyl)-1H-imi-
dazole (1)
N-Cbz-L-alanine diazoketone (100 mg, 0.4 mmol) was oxidised using DMD (8.6 mL, 0.07 M) in
acetone at room temperature. After 10 min the solvent was removed in vacuo and replaced by methanol
(20 mL). NH4OAc (308 mg, 4 mmol) and benzaldehyde (0.12 mL, 1.2 mmol) were added. The mixture
was stirred at reflux overnight then cooled to room temperature after which the solvent was evaporated.
The crude reaction mixture was then taken up in CH2Cl2, washed with saturated NaHCO3, H2O and
brine, dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure to yield the crude
imidazole. Purification was carried out by flash chromatography on silica using EtOAc:hexane (50:50)
as eluant to give imidazole 1 as a white solid (91 mg, 71%); mp 152–154°C. Found: C, 70.8; H, 5.9; N,
12.9%. C19H19N3O2 requires C, 71.0; H, 5.9; N, 13.1%. [α]D20 –31.7 (c 1.04, CHCl3); νmax (KBr)/cm−1
3316, 1716, 1699, 1653; 1H NMR (500 MHz, CDCl3) 1.55 (3H, d, J=6.8 Hz, CH3CH(NH)), 4.88 (1H,
m, CH3CH(NH)), 5.09, 5.15 (2H, 2×d, J=12.2 Hz, PhCH2OCO), 5.36 (1H, br s CH(NH)), 6.88 (1H, s,
C_CHNH), 7.35 (8H, m, ArH), 7.76 (2H, d, J=7.3 Hz, ArH); 13C NMR (75 MHz, CDCl3) 14.21, 44.27,
66.93, 125.29, 128.05, 128.16, 128.56, 128.67, 128.86, 130.29, 136.51, 146.73, 156.52, 171.14; m/z 321
(M+), 91(PhCH2 100).
References
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