Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9237–9240
A novel oxidative side-chain transformation of a-amino acids
and peptides by methyltrioxorhenium/H2O2 system
Francesco Lazzaro,a Marcello Crucianelli,a,* Francesco De Angelis,a
Veronica Nerib and Raffaele Saladinob,*
a
`
Dipartimento di Chimica, Ingegneria Chimica e Materiali, Universita dell’Aquila, via Vetoio, I-67010-Coppito (AQ), Italy
b
`
INFM, Dipartimento A.B.A.C., Universita della Tuscia, via S.Camillo De Lellis, I-01100 Viterbo, Italy
Received 1 October 2004; accepted 13 October 2004
Available online 28 October 2004
Abstract—N-Boc derivatives of Met, Cys, and Trp, the properties of which resemble those of the respective amino acid residues
present in proteins, are efficiently oxidized by methyltrioxorhenium and H2O2. A high regioselectivity for the oxidation of these resi-
dues when embedded into peptides was also found.
Ó 2004 Elsevier Ltd. All rights reserved.
The synthesis of unnatural amino acids and peptides of-
fers great flexibility for the designing of novel bio-active
protein analogues.1 Several methods have been devel-
oped in recent years to overcome some drawbacks, such
as the poor stability and the lack of oral absorption,
which can reduce the use of peptide analogues as thera-
peutic agents. Two main synthetic strategies based on
amino acid side-chain transformations and backbone
modifications were proposed. Backbone modifications
include changes at any one of the three characteristic
repeating NH, CO, and a-CH elements.2 Side-chain
modifications are mainly obtained by oxidation of low
redox potential residues.3–8 Selective C–H hydroxyl-
ations of high redox potential leucine derivatives have
been also described.9a Despite extensive work on stoichio-
metric procedures for amino acid side-chain modifica-
tions,9b only a few examples concerning the use of
catalytic procedures are reported. In the last decade
methyltrioxorhenium (MTO, MeReO3) has been used
in several organic transformations.10 The reactive inter-
mediates for these oxidations are a monoperoxo [MeRe-
(O)2O2] and a bis-peroxo [MeReO(O2)2] g2-rhenium
complexes.11 To the best of our knowledge there are
no reports in the literature dealing with the oxidation
of amino acids and peptides with MTO. Herein we
describe that N-Boc derivatives of methionine (Met),
cysteine (Cys), and triptophane (Trp), the properties of
which resemble those of respective amino acid residues
in proteins, are efficiently oxidized by MTO and envi-
ronmental friendly H2O2. Noteworthy, a high chemo-
selectivity was observed in the oxidation of these
amino acids when embedded into peptides.
Initially, we tried to study the oxidation of N-Boc deriva-
tives of Val, Leu, Ile, Pro, Ser, Tyr, Thr, Met, Cys, His,
and Trp as representative model compounds. Briefly,
1.0mmol of substrate dissolved in 5mL of solvent (EtOH
or AcOH), was added portionwise with MTO (5% in
weight) and H2O2 (30% aqueous solution; 2.0equiv of
H2O2 except where otherwise specified) at room temper-
ature. At the end of reaction a small amount of MnO2
was added and the solvent evaporated after filtration.
The reaction products were characterized by the usual
NMR and MS analyses and by comparison with authen-
tic samples.1c Under these experimental conditions MTO
showed a high chemoselectivity, Boc-Met-OMe 1, Boc-
Cys-OMe 2, and Boc-Trp-OMe 3 being the only reactive
substrates. Treatment of 1 with MTO/H2O2 system in
EtOH afforded after 2h the corresponding sulfone 4 as
the only recovered product, in quantitative conversion
of substrate and 80% isolated yield (Scheme 1). A better
result was obtained in acetic acid, in which case 4 was
recovered in 90% yield after 10min.
Keywords: Amino acid side-chain oxidation; Homogeneous catalysis;
Hydrogen peroxide; Methyltrioxorhenium.
*
Corresponding authors. Tel.: +39 0761 357284; fax: +39 0761 357242
(R.S.); tel.: +39 0862 433780; fax: +39 0862 433753 (M.C.); e-mail
The oxidation of 2 in EtOH was performed with differ-
ent amounts of H2O2. In the presence of 2.0equiv of
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.074