Amino acids as suitable N-nucleophiles for the aza-Michael reaction of vinylphosphoryl compounds in water

Article abstract of DOI:10.1016/j.tetlet.2011.09.111

Application of water as a sole solvent promotes the aza-Michael reaction of diethyl vinylphosphonate and diphenylvinylphosphine oxide with α-substituted amino acid sodium salts generated in situ to afford the corresponding β-aminophosphonates and β-aminop

Full text of DOI:10.1016/j.tetlet.2011.09.111

Tetrahedron Letters 52 (2011) 6562–6565
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Tetrahedron Letters
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Amino acids as suitable N-nucleophiles for the aza-Michael reaction of
vinylphosphoryl compounds in water
⇑
Ekaterina V. Matveeva, Anatoly E. Shipov, Pavel V. Petrovskii, Irina L. Odinets
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov Str. 28, 119991 Moscow GSP-1, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2011
Revised 13 September 2011
Accepted 23 September 2011
Available online 2 October 2011
Application of water as a sole solvent promotes the aza-Michael reaction of diethyl vinylphosphonate and
diphenylvinylphosphine oxide with a-substituted amino acid sodium salts generated in situ to afford the
corresponding b-aminophosphonates and b-aminophosphine oxides in excellent yields and of high pur-
ity. The approach is equally suitable for the synthesis of both racemic and optically active compounds. In
the case of glycine, the mono and bis(phosphonoethyl)-substituted products are formed in 6:4 ratio and
when using a stoichiometric amount of the reactants, N,N-bis[2-(diethoxyphosphoryl)ethyl]glycine was
Keywords:
Green chemistry
Water
Aza-Michael addition
Vinylphosphoryl compounds
the only product. In contrast, to perform the double phosphonoethylation of
ing of the reaction mixture was required.
D,L-alanine, prolonged heat-
Ó 2011 Elsevier Ltd. All rights reserved.
a-Amino acids
b-Aminophosphonates
b-Aminophosphine oxides
Both natural and synthetic aminophosphonic acid derivatives,
being analogues of amino acids and competing with them for the
active sites of enzymes, possess diverse biological activity which
depends on the length of the alkyl chain between the phosphorus
and nitrogen atoms and their substituents.1 N-substituted amino
acids and peptides bearing a terminal phosphorus moiety are also
of interest in medicinal chemistry due to their valuable bioactivi-
ties. Thus, Phosphoramidon (isolated from Actynomyces) is effective
as a metalloprotease inhibitor2 and N-nucleoside phosphorami-
dates possess antitumor3 or antiviral4 properties. Among hydroly-
tically stable N-phosphonomethyl amino acids and peptides,
N-(phosphonomethyl)glycine,5 used worldwide as a herbicide, is a
well known example. Furthermore, a number of compounds of this
type demonstrate collagenase inhibiting properties,1 antibacterial
by correct juxtaposition of the key NH2, COOH, and P(O)(OH)2
functions.
2-Aminoethylphosphonic acid (AEP) was the first identified
natural phosphonate isolated from celiate protozoa by Horiguchi
and Kandatsu10 in 1959 and found also in numerous marine ani-
mals, coelenterates, flagellates, fungi, and even in the human body
(in particular, in the human brain, heart, kidney, liver, intestine,
spleen, adrenal glands, and aorta),11 where it is primarily present
in lipids (phosphonolipids), proteins, and polysaccharides, and its
various derivatives possess diverse biochemical properties.1b,11
Therefore, it can be suggested that N-phosphonoethyl modified
amino acids or the corresponding peptidylphosphonates may be
interesting as potential drug candidates. However, in contrast to
the rather well developed area of N-phosphonomethyl substituted
amino acids, publications on this topic are few in number. Thus, as
early as 1979 the desired compounds were obtained in 43–65%
estimated and 13–16% isolated yields via the aza-Michael addition
of amino acid esters to diethyl vinylphosphonate in the presence of
sodium ethanolate in EtOH by Issleib et al.12 According to Bigge’s
report,9 the reaction of glycine methyl ester hydrochloride and
diethyl 2-bromoethylphosphonate in the presence of triethylamine
provided the mixed ethyl–methyl ester of phosphonoethylated
glycine (the yield was not given) which was transformed via an
acidic hydrolysis into the corresponding tris-acid hydrochloride
being a perspective NMDA antagonist. Later on, a similar strategy
but using potassium carbonate (4 equiv) and an excess of glycine
(4 equiv) in water (80 °C, 3 h) provided N-[2-(diethoxyphospho-
(alafosphalin or
L
-alanine-
L
-1-aminoethylphosphonic acid)6 or anti-
-aminophospho-
hypertensive7 properties (CGS 24592). Recently,
a
nates obtained from cognitive function enhancing oligopeptides as
the amine component were suggested as potential ‘twin-drugs’.8
Moreover, in view of the growing interest in new antagonists of
excitatory amino acids which are involved in the pathology of a
number of neurodegenerative disorders and epilepsy, a series of
N-phosphonoalkyl-, -alkenyl,- and -arylglycines was tested on an
NMDA (N-methyl-D-aspartate) competitive antagonist pharmaco-
phore model.9 In this case, the high receptor affinity was dictated
⇑
Corresponding author. Fax: +7 499 135 5085.
E-mail address: odinets@ineos.ac.ru (I.L. Odinets).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.111

E. V. Matveeva et al. / Tetrahedron Letters 52 (2011) 6562–6565
6563
Table 1
ryl)ethyl]glycine isolated via low-pressure reverse-phase chroma-
tography in quantitative yield.13 This compound was used as an
intermediate in the synthesis of a new type of tetranucleotide III,
containing alternating achiral phosphonate (negatively charged)
and N-ethyleneglycosyl amide (neutral) backbone linkages in di-
mer units. An alternative approach based on desulfurization of
(thiocarbamoylmethyl)phosphonates by nickel boride allowed
the corresponding N-(phosphonoethyl)-substituted glycine, ala-
nine, and phenylalanine to be obtained in 40–50% yields.14 In addi-
tion, a series of dipeptidyl b-aminophosphoryl compounds, useful
as human calpain I inhibitors, was synthesized via a multistep pro-
Aza-Michael reactions of diethyl vinylphosphonate 1 and D,L-alanine in water
H
O
N
COOH
CH3
EtO
EtO
P
O
P
H2O
2a
COOH
NH2
CH3
EtO
EtO
+
O
+
EtO
EtO
COOH
CH3
1
P
N
OEt
OEt
P
O
3a
cedure, but these compounds possess an
a-keto function, mimick-
ing peptide -ketoesters and
a
a
-ketoacids.15
Entry
Base/Amount
Temperature (°C)
Time (h)
Yielda (%)
Relevant challenges of modern organic chemistry such as ‘atom
economy’ and the application of ‘environmentally friendly condi-
tions’ prompted us to improve the synthesis of b-aminophosphoryl
compounds via the aza-Michael reaction of vinylphosphoryl com-
pounds.16,17 It was shown that the application of water as a sole
solvent (without any catalyst or co-solvent) significantly acceler-
ated the reaction and provided excellent yields, independently of
the water-solubility of the starting substrate (in water or on-water
reactions18), both of b-aminophosphonates possessing diverse bio-
chemical properties such as antibacterial, anti-HIV, and protease-
inhibiting activities,19 and useful as synthetic nonviral vector-med-
iated gene transfer agents,20 and the related b-aminophosphine
oxides, exhibiting coordination properties towards a variety of
metals.21 These compounds also found applications as ligands for
ruthenium-assisted enantioselective transfer hydrogenation of ke-
tones22 or building-blocks in the synthesis of P,N-ligands bearing
phosphine donor moieties.23
These key points stimulated us to use amino acid derivatives as
N-nucleophiles in aqueous aza-Michael reactions with vinylphos-
phoryl compounds and, in this Letter, we report on an efficient
general approach to N-(phosphorylethyl)amino acids opening up
the possibility of the facile, rapid, and cheap synthesis of these po-
tential drug candidates.
In contrast to primary and secondary alkylamines, free amino
acids do not react with vinylphosphoryl compounds in water in
the absence of a catalyst even at elevated temperature, as was
1
2a
3a
1
2
3
4
5
6
7
8
9
None
None
20
100
20
20
20
20
100
20
20
20
24
3
100
100
70
67
69
0
–
–
–
–
–
–
–
4
15
–
–
–
–
6
Et3N/10 mol %
72
72
72
24
3
24
24
5
30
33
31
96
85
–
38
67
95
94
iPr2NEt/10 mol %
DMAP/5 mol %
Et3N/1 equiv
Et3N/1 equiv
0
NaHCO3/1 equiv
K2CO3/1 equiv
NaOH/1 equiv
NaOH/1 equiv
NaOH/1 equiv
100
62
33
5
10
11
12
20
20
20
48
0
Estimated yield according to 31P NMR spectroscopic data.
a
ture of the corresponding zwitterion and the salt with the starting
amino acid, in a 3:1 ratio along with contamination due to com-
pound 3a. Isolation of the pure product via column chromatogra-
phy (SiO2, EtOH–NH4OH = 70:30) proceeded with substantial loss
of the product that was isolated as the ammonium salt.
Searching for a more convenient procedure to provide high con-
version rates and easy isolation of the desired products we tested
inorganic bases in this reaction. The screening revealed that the
addition of the amino acid to vinylphosphonate 1 did not proceed
in the presence of NaHCO3 (1 equiv) and the reaction rate was
much lower compared with that in the presence of Et3N when
K2CO3 was used as the base (38% conversion over 24 h at rt). At
demonstrated in a model reaction of D,L-alanine and the water-sol-
uble vinylphosphonate 1 (Table 1, entries 1,2). Such reduced reac-
tivity of the free acid is connected with the formation of
zwitterionic species. Using tertiary amines in catalytic amounts
the same time, addition to vinylphosphonate 1 of the D,L-alanine
sodium salt generated in situ under the action of NaOH proceeded
readily under ambient conditions with a reaction rate comparable
with that in the presence of Et3N and provided an excellent yield of
the N-[2-(diethoxyphosphoryl)ethyl]alanine 2a sodium salt iso-
lated via simple lyophilization of the reaction mixture (94% purity
according to the 1H and 31P NMR spectroscopic data, 6% of 3a–Na
was present as the only impurity).
After optimization of the procedure, other substituted racemic
and optically active L- or D-amino acids were used in reaction with
1 in the presence of NaOH to afford the corresponding sodium salts
in excellent yields (Scheme 1). The above-mentioned side-reaction
i
(10 mol % Et3N, Pr2NEt, or 5 mol % DMAP) triggers the reaction,
however, it stopped at a conversion level of ꢀ30%, apparently
due to the establishment of the equilibrium with participation of
free D,L-alanine and 2a, and their zwitterionic species formed in
the presence of the tertiary amine. In these cases, the 31P NMR
spectra of the reaction mixtures demonstrated singlets at ca. d
29 ppm and d 33 ppm (approximately in 20:8 ratio) corresponding
to the zwitterionic form of 2a and its ammonium salt, along with
the signal of the starting compound 1 at d 17.2 ppm (Table 1, en-
tries 3–5).
of double phosphonoethylation of D, L-alanine was observed also in
Complete conversion was observed over 24 h at rt when the
proportion of tertiary amine (Et3N) was increased up to 1 mol
equiv. At that point, the 31P NMR spectrum of the reaction mixture
revealed a separated singlet at ꢀd 29 ppm and two closely located
signals at ca. d 33.5 ppm in 18:78:4 ratio. These resonances were
assigned to the zwitterionic form of 2a and the corresponding
ammonium salts 2a and 3a, respectively. Note that an increase in
the reaction temperature up to 100 °C resulted in quantitative con-
version in 3 h, however, the proportion of the double phosphono-
ethylation product 3a also increased to 15% (Table 1, entry 7). A
multinuclear NMR analysis of the crude products obtained by
lyophilization of the reaction mixtures (entries 6 and 7) revealed
that the desired phosphorylated alanine 2a was present as a mix-
the reaction of 1 with aspartic acid and in that with glycine. In the
first case, the side product 3e was formed in a negligible amount
(5%, NMR-estimated yield) while in the case of glycine the propor-
tions of mono and diphosphonoethylated products 2g–Na and
3g–Na, respectively, were comparable to each other (6:4). In other
words, the nucleophilic properties of glycine sodium salt are close
to those of N-[2-(diethoxyphosphoryl)ethyl]glycine, 2g–Na. In-
deed, when the reactants were used in a stoichiometric ratio,
bis(phosphorylethyl)-substituted glycine sodium salt 3g–Na was
formed as the sole product (the 31P NMR spectrum demonstrated
a singlet at ca. d 33.4) and the corresponding free acid 3g was
isolated in high yield after acidification (see ESI for experimental
details). Alternatively, the presence of an
a-substituent in the

6564
E. V. Matveeva et al. / Tetrahedron Letters 52 (2011) 6562–6565
O
P
R1
L- or D-
COOH
NH2
R
R
COOH
R1
H
N
O
P
N
COOH
R
R
+
R
R
R1
P
O
P
1. H2O/NaOH
2. H+
R
R
2a-e,g, 5
O
H
3a,e,g
H
L-
1,4
COOH
N
N
COOH
H
P
R
O
R
2f, 6
R =OEt (1,2,3), Ph (4,5,6)
R1 = CH3 (2a,3a), CH2Ph (2b), iPr (2c), CH2CH2SCH3 (2d,5), CH2COOH (2e,3e), H (2g,3g)
Scheme 1. Aza-Michael addition of amino acids to vinylphosphoryl compounds.
amino acid inhibited the double phosphonoethylation. Thus, it re-
quired 2 days at 70 °C to achieve an 85% conversion in the reaction
R1
N
R1
N
O
P
O
P
1. Me3SiBr/CH3CN
2. aq. MeOH
COOH
COOH
of
D,L
-alanine and vinylphosphonate 1 used in a 1:2 ratio.
HO
HO
EtO
EtO
The reactivity of the amino acid sodium salts decreased along
R
R
7a,e,f
2a,e,f, 3g
the series proline > alanine ꢁ glycine > phenylalanine, that is, the
reactivities were similar to those found for the addition of amines
to vinylphosphoryl compounds in water, that is, secondary amines
were more reactive than primary ones and additional steric hin-
drance decreased the reaction rate.16,17 It should be noted that
the addition of amino acids can be performed in water also for
the water-insoluble diphenylvinylphosphine oxide 4, however, in
this case elevated temperatures were used to reduce the reaction
time.
O
HO
P
R1=CH2CH2P(O)(OEt)2, R=H (3g)
HO
O
P
N
COOH
1. Me3SiBr/CH3CN, 2. aq. MeOH
HO
HO
8
2a, 7a: R1= H, R=CH3; 2e, 7e: R1 = H, R = CH2COOH; 2f, 7f: R1, R = (CH2)3
Scheme 2. Synthesis of free N-(2-phosphonoethyl)amino acids.
The final products were isolated in high yields as the corre-
sponding sodium salts via lyophilization of the crude reaction mix-
tures. It should be emphasized that despite the fact that diethyl
phosphonates are inclined to partial hydrolysis to monoesters if
the reaction proceeds in the presence of sodium hydroxide, we
did not observe such a process under the reaction conditions em-
ployed and the singlet chemical shifts in the 31P NMR spectra
and integral intensities in the 1H NMR spectra of the crude prod-
ucts isolated via lyophilization, confirmed these observations.
Alternatively, these salts can be transformed into the corre-
sponding free acids 2a–g, 3a,g, 5, and 6 via acidification with
HCl, removal of the water in vacuo, and treatment of the residue
with ethanol to remove the precipitated sodium chloride.24 Natu-
rally, for such a transformation it is more convenient to use the
crude reaction mixtures rather than the isolated sodium salts.
However, under this work-up procedure, some product loss was
observed due to the limited solubility of the products in their zwit-
terionic form in EtOH and, in some cases, the corresponding free
acids were isolated as strong complexes with the residual NaCl
which could be removed by repeated recrystallization. Therefore,
the application of cation exchange chromatography (Dowex
50WX8) was found to be the most convenient procedure for the
isolation of the phosphorylated free amino acids as stable hydrates.
The products were white hygroscopic solids. Their rather high
melting points as well as the presence in their IR spectra of absorp-
tion bands at 1609–1626 cmꢂ1 which are characteristic25 for an
ammonium species >NHþ2 are indicative of the zwitterionic struc-
tures of 2a–g, 5, and 6. Since the chiral carbon atom of the amino
acid is not affected during the reaction, using optically active start-
ing materials, the sodium salts and the corresponding N-[2-(dieth-
oxyphosphoryl)ethyl]-amino acids were obtained in optically pure
form. The pattern of CD spectra of the products 2a–f is similar to
those observed for the corresponding amino acids and their optical
rotation values (see ESI) confirm this supposition.
Finally, b-aminophosphonates 2a–g could be easily converted
into free phosphonic acids via treatment with Me3SiBr in acetoni-
trile followed by methanolysis of the intermediate silyl esters
(Scheme 2) as was exemplified by the synthesis of the mono(phos-
phonoethylated) amino acids 7a,e,f, and the bis(phosphonoethy-
lated) glycine 8. This procedure is convenient, as a typical acidic
hydrolysis resulted either in partial decomposition of the product
via a retro-addition affording the parent amino acid in the case
of concentrated HCl or proceeded very slowly (3 equiv 6 N HCl,
24 h, 75%).
In conclusion, using water to accelerate the aza-Michael reac-
tion for vinylphosphoryl compounds, even for those that are insol-
uble in water, we have developed an effective procedure for the
synthesis of N-(2-diethoxyphosphonoethyl)-amino acids and their
analogues with phosphine oxide moieties using racemic or opti-
cally active amino acids as the N-nucleophiles. Excluding the reac-
tion with glycine, where the products of mono and double
phosphonoethylations were formed in similar amounts, the so-
dium salts of a-substituted amino acids were formed in near quan-
titative yields. The sodium salts could be further used either in
solution in water or in a pure form after removal of the water for
further synthetic procedures, or transformed into the correspon-
ding free acids. This cheap and green approach represents a
straightforward procedure to a range of biologically active drug
candidates or complexing agents.
Acknowledgments
This work was supported by the Program of Chemistry and
Material Science Division of the RAS and the program of President
of Russian Federation ‘For Young PhD scientists’ (No. MK-
425.2010.3).

E. V. Matveeva et al. / Tetrahedron Letters 52 (2011) 6562–6565
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Supplementary data
Supplementary data (detailed experimental procedures inclu-
ding the syntheses, physicochemical data, and full NMR assign-
ments for all new compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.09.111.
18. Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302.
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24. N-[2-(Diethoxyphosphoryl)ethyl]-
amino acids (2a–f, 5,6) (general procedure): (a) Sodium salts: a mixture of
diethyl vinylphosphonate (0.41 g, 2.5 mmol) or diphenylvinylphosphine
and
N-[2-(diphenylphosphoryl)ethyl]-
1
oxide 4 (0.57 g, 2.5 mmol), the corresponding amino acid (2.5 mmol), and
NaOH (0.10 g, 2.5 mmol) in H2O (5 ml) was stirred either under ambient
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L-
methionine and 4), 72 h for the reaction of 1 and -phenylalanine and 48 h for
L
the reaction of vinylphosphonate 1 with other amino acids. The corresponding
sodium salts were isolated as white hygroscopic powders by lyophilization of
the crude reaction mixture. (b) Free acids: After completion of the reaction, the
mixture was acidified with 5.4 N HCl (0.46 ml, 2.5 mmol) in H2O (2 ml) and
then concentrated to dryness under reduced pressure. The residue was
dissolved in EtOH (10 ml), precipitated NaCl was filtered, and the filtrate was
concentrated in vacuo and dried over P2O5 to give the crude final products. If
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a Dowex
50WX8-H+column and eluted with EtOH–NH4OH = 7:3. The fraction from the
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and the final acid precipitated with Et2O.
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