Synthesis of phosphinic acid pseudodipeptides of C2-symmetry

Article abstract of DOI:10.1080/10426507.2010.526677

Treatment of aromatic aldehydes with ammonia and hypophosphorus acid gave C2- symmetric 1-aminoarylmethylphosphinic acids. The latter compounds, activated in the presence of hexamethyldisilazane (HMDS) or trimethylsilyl chloride (TMSCl), successfully reacted with methyl acrylate to afford symmetric pseudodipeptides. The applied synthetic approach is briefly outlined here. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.526677

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Phosphorus, Sulfur, and Silicon and the
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Synthesis of Phosphinic Acid
Pseudodipeptides of C2 -Symmetry
Babak Kaboudin a , Fariba Saadati a & Tsutumo Yokomatsu b
a Department of Chemistry, Institute for Advanced Studies in Basic
Sciences, Gava Zang, Zanjan, Iran
b School of Pharmacy, Tokyo University of Pharmacy and Life
Sciences, Tokyo, Japan
Published online: 25 Apr 2011.
To cite this article: Babak Kaboudin , Fariba Saadati & Tsutumo Yokomatsu (2011) Synthesis of
Phosphinic Acid Pseudodipeptides of C2 -Symmetry, Phosphorus, Sulfur, and Silicon and the Related
Elements, 186:4, 804-805, DOI: 10.1080/10426507.2010.526677
To link to this article: http://dx.doi.org/10.1080/10426507.2010.526677
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Phosphorus, Sulfur, and Silicon, 186:804–805, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.526677
SYNTHESIS OF PHOSPHINIC ACID PSEUDODIPEPTIDES
OF C2-SYMMETRY
Babak Kaboudin,1 Fariba Saadati,1 and Tsutumo Yokomatsu2
1Department of Chemistry, Institute for Advanced Studies in Basic Sciences,
Gava Zang, Zanjan, Iran
2School of Pharmacy, Tokyo University of Pharmacy and Life Sciences,
Tokyo, Japan
Abstract Treatment of aromatic aldehydes with ammonia and hypophosphorus acid gave C2-
symmetric 1-aminoarylmethylphosphinic acids. The latter compounds, activated in the presence
of hexamethyldisilazane (HMDS) or trimethylsilyl chloride (TMSCl), successfully reacted with
methyl acrylate to afford symmetric pseudodipeptides. The applied synthetic approach is briefly
outlined here.
Keywords 1-Aminoalkylphosphinic acids; C2-symmetry; diastereoisomers; hypophosphorus
acid; pseudodipeptides
INTRODUCTION
Aminoalkylphosphinic acids are the phosphorus analogues of natural amino acids
that have potential biological activity and strong coordination ability. Because of the tetra-
hedral structure of the phosphinic acids R2PO2H (R = alkyl, aryl), they are considered
to mimic the transition states in hydrolysis of carboxylic esters, amides, and peptides.1
The incorporation of the phosphinic moiety into the peptide structure has been studied as
efficient approach for developing highly potent and selective inhibitors of various prote-
olytic enzymes, particularly metalloproteases. Aminophosphinic acid derivatives, built on
a C2-symmetry axis homodimer structural motif, are also attractive drugs that target the
protease of the human immunodeficiency virus, HIV-1 aspartic protease.2
RESULTS AND DISCUSSION
As a part of our effort to introduce novel methods for the synthesis of organophos-
phorus compounds, we have reported a convenient and simple method for the synthesis of
novel 1-aminophosphinic acids containing two phosphinic moieties with a C2-symmetry
axis (Scheme 1). The aminobisphosphinic acids 2 were synthesized in the reaction of
Received 16 September 2010; accepted 20 September 2010.
The authors gratefully acknowledge support by the Institute for Advanced Studies in Basic Sciences (IASBS)
Research Council under grant No. G2009IASBS120.
Address correspondence to Babak Kaboudin, Department of Chemistry, Institute for Advanced Studies in
Basic Sciences, Gava Zang, Zanjan 45195-1159, Iran. E-mail: kaboudin@iasbs.ac.ir
804

PHOSPHINIC ACID PSEUDODIPEPTIDES OF C2-SYMMETRY
805
HO O
O OH
HO O
P
O OH
P
H
H
(c or d), e
a, b
P
N
P
MeO
N
OMe
2 ArCHO
H
H
Ar
Ar
O
Ar Ar
O
1
2
3
Entry
Ar
Yield (%)
HMDS (conditions c) TMSCl (conditions d)
3a
3b
3c
3d
3e
3f
Ph
50
60
40
58
54
57
40
52
35
50
45
48
p-ClC6H4
p-FC6H4
p-MeOC6H4
p-MeC6H4
β-Naphthyl
Scheme 1 Reagents and conditions: (a) NH4OHaq, reflux, 5h; (b) H3PO2 (5 equiv.), reflux (ethanol), 10 h, then
washing with ethanol/water (9:1); (c) HMDS, 110◦C; (d) TMSCl, NEt3, CH2Cl2, 0◦C, stirred under Ar, 3h; (e)
methyl acrylate, 50◦C, stirred 12 h, then MeOH. The yield of isolated products 3, obtained by two activation
methods from 2, are compared.
aromatic adehydes 1 with ammonia, followed by treatment with anhydrous hypophospho-
rus acid.3 The difference in solubility allowed us to readily separate the obtained mixture
of diastereoisomers by simple washing.
C2-Symmetric phosphinic acid dipeptides 3 were obtained by the Michael addition
of 2 to methyl acrylate. Both applied activation/silylation agents: hexamethyldisilazane
(procedure c, Scheme 1) and trimethylsilyl choride (procedure d) gave target compounds
in moderate yields.
REFERENCES
1. Kukhar, V. P.; Hudson, H. R. In Aminophosphonic and Aminophosphinic Acids; John Wiley &
Sons: Chichester, UK, 2000.
2. Collinsova, M.; Jiracek, J. Curr. Med. Chem. 2000, 7, 629–647.
3. Kaboudin, B.; Saadati, F. Tetrahedron Lett. 2009, 50, 1450–1452.