A convenient one-pot synthesis of phosphino-dipeptide analogs

Article abstract of DOI:10.1080/10426500212259

A general "one-pot" synthetic method is described for the preparation of phosphinodipeptides of type 1, in 60-80% overall yield, allowing the variation of the substituents in α and/or β position to the phosphorus atom and also in α position to the nitrogen atom.

Full text of DOI:10.1080/10426500212259

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Phosphorus, Sulfur, and Silicon and the Related
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A Convenient One-Pot Synthesis of Phosphino-
Dipeptide Analogs
Jean-Luc Pirat a , Agnes Coulombeau a , Arielle Genevois-Borella b & Henri-Jean Cristau a
a Laboratoire de Chimie Organique , C.N.R.S, E.N.S.C.M. , Montpellier Cedex, France
b Centre de Recherche de Vitry-Alfortville , Aventis , Vitry-Sur-Seine, France
Published online: 27 Oct 2010.
To cite this article: Jean-Luc Pirat , Agnes Coulombeau , Arielle Genevois-Borella & Henri-Jean Cristau (2002) A Convenient
One-Pot Synthesis of Phosphino-Dipeptide Analogs, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:6-7,
1793-1796, DOI: 10.1080/10426500212259
To link to this article: http://dx.doi.org/10.1080/10426500212259
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:1793–1796
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290092866
A CONVENIENT ONE-POT SYNTHESIS OF
PHOSPHINO-DIPEPTIDE ANALOGS
Jean-Luc Pirat,a Agnes Coulombeau,a Arielle Genevois-Borella,b
and Henri-Jean Cristaua
Laboratoire de Chimie Organique, C.N.R.S, E.N.S.C.M.,
Montpellier Cedex, Francea and Aventis, Centre de Recherche de
Vitry-Alfortville, Vitry-Sur-Seine, Franceb
(Received February 28, 2001; accepted December 25, 2001)
A general “one-pot” synthetic method is described for the preparation
of phosphinodipeptides of type 1, in 60–80% overall yield, allowing the
variation of the substituents in and/or position to the phosphorus
atom and also in position to the nitrogen atom.
Keywords: Alkyl hypophosphite; aminoalkylphosphinic acids;
Kabachnik–Fields reaction; Michael addition; phosphinopeptides
Analogous to -amino-carboxylic acids and their derived peptides, 1-
aminoalkylphosphonic acids, and the corresponding peptides (phos-
phonopeptides) interfere with biological mechanisms through their
hydroxyphosphonyl function.1 The phosphinopeptides 1, P–C analogs
of phosphonopeptides, are better candidates for the elaboration of more
stable biologically active compounds. Construction of such compounds
requires the synthesis of the phosphinodipeptides analogs of type 1 as
building blocks.
Compounds 1 are generally prepared in a multistep synthesis from
the corresponding adequately protected 1-aminoalkylphosphonous
acids.2
We developed a general “one-pot” three-step synthesis for the prepa-
ration of phosphinodipeptides of type 1 affording the possibility of vari-
ation of R1 and R2 groups (Figure 1). Each step of this reaction was
improved separately until the yield was more than 90%; then all the
steps were carried out without purification, for combinatorial or parallel
synthesis.
Address correspondence to Jean-Luc Pirat, Laboratoire de Chimie Organique, UMR
´
5076 du C.N.R.S., E.N.S.C.M., 8 rue de l’Ecole Normale, 34296 Montpellier, Cedex, France.
1793

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J.-L. Pirat et al.
FIGURE 1 Synthesis of phosphino-dipeptide analogs.
RESULTS AND DISCUSSION
Synthesis of Alkyl Hypophosphites 2
Alkyl hypophosphites, unstable but more reactive than the hypophos-
phorous acid, were preferred to the bis(trimethysilyl) phosphonite,
which is highly pyrophoric (Step 1, Figure 2).
In spite of many changes in the reaction conditions, the poor yield
obtained in pure ethyl hypophosphite 2a does not permit one to pro-
ceed with the synthesis using ethyl hypophosphite as starting material.
However, methyl hypophosphite 2b could be generated in situ3 in very
good yield and at good purity (95 to 99%). Therefore we decided to use
methyl hypophosphite 2b for the next step.
Synthesis of Methyl Phosphinate 3
Improving on the Baylis method,4 the intermediate 1-amino-
alkylphosphonous acids 3 were prepared by a dropwise addition of an
excess (1.6 equivalents) of several imines (or triazine), to methyl hy-
pophosphite 2b, in refluxing dry methanol (Figure 3). Thus, the methyl
phosphinates 3 were obtained in good yield (79–89%), and the pu-
rity could be increased up to 85–95% by simple precipitating out of
by-products.
Products 3b were then used directly, without additional purification,
in Step 3 of the synthesis.
FIGURE 2 Preparation of alkyl hypophosphite 2 (Step 1).

Phosphino-Dipeptide Analogs
1795
FIGURE 3 Preparation of methyl phosphinates 3 (Step 2).
Synthesis of Phosphinodipeptide Analogs 1
The last step of the synthesis (Step 3), a Michael addition of the phos-
phinates 3b to various -substituted acrylates was performed accord-
ing to the method developed by Parsons et al., but by using t-BuOK in
tetrahydrofuran (THF), an overcrowded base in catalytic amount, in-
stead of MeONa in MeOH, as basic activating agent in order to reduce
the demethylation of the phosphinate as side reaction. Compounds 1b,
from differently substituted acrylates, are obtained in 78–87% yields
(Figure 4) as a mixture of diastereoisomers that can be partially sepa-
rated by chromatography.
Selective and Total Deprotection of Phosphinodipeptide
Analogs 1
In order to show the value of phosphinodipeptide analogs 1 as build-
ing blocks, examples of selective deprotection of the various functional
groups were performed, by acid (47% HBr) or basic hydrolysis (NaOH),
by hydrogenolysis (H2/Pd C), or by methanolysis (BrSiMe3; MeOH) in
almost quantitative yields.
CONCLUSION
A general three-step synthesis has been developed for the “one-pot”
preparation of phosphinodipeptides 1, as a mixture of diastereoisomers,
FIGURE 4 Preparation of phosphinopeptides analogs 1 (Step 3).

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J.-L. Pirat et al.
in 60–80% overall yield, which allows variation of the substituents on
the carbon in positions and/or to the phosphorus.
Selective or complete cleavages of the various protective groups were
performed, in usual ways, in almost quantitative yields.
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Berlin, 1984), vol. 21, pp. 1–110.
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