Mechanism of Phosphorus-Carbon Bond Formation in the Amidoalkylation of Phosphonous Carboxylic Acids

Article abstract of DOI:10.1021/acs.joc.0c02259

An unusual greater reactivity of phosphonous propionic acids was found in comparison with phosphonous propionic esters in carbamate version of Kabachnik-Fields reaction. Compounds of tricoordinated phosphorus generated in situ during the amidoalkylation o

Full text of DOI:10.1021/acs.joc.0c02259

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Mechanism of Phosphorus−Carbon Bond Formation in the
Amidoalkylation of Phosphonous Carboxylic Acids
Maxim E. Dmitriev, Sofia R. Golovash, Alexei V. Borodachev, and Valery V. Ragulin*
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ABSTRACT: An unusual greater reactivity of phosphonous propionic acids was found in comparison with phosphonous propionic
esters in carbamate version of Kabachnik−Fields reaction. Compounds of tricoordinated phosphorus generated in situ during the
amidoalkylation of hydrophosphorylic compounds in acetyl chloride/acetic anhydride mixture were found by 31P NMR analysis. A
hypothesis is proposed about the generation of spirophosphoranes in situ to explain the mechanism for the formation of the
phosphorus−carbon bond in the reaction under study.
The milder amidoalkylation conditions of hydrophosphor-
ylic compounds 4 in acetic anhydride at room temperature
compared to acetyl chloride made it possible to detect greater
reactivity of alkyl carbamates in comparison with amides.2
Under these conditions, for the first time, it was possible to
isolate N,N′-alkylidenebiscarbamates 5 (Scheme 2) as stable
intermediate reaction products.2 Previously, related com-
pounds, bisamides,7 and amidoalkylacetates8 have been
proposed as intermediates in the Oleksyszyn reaction.
INTRODUCTION
■
Studies of the carbamate version of the Kabachnik−Fields
reaction in recent years indicate its growing preference over
the amide and classical versions of this method for
construction of the α-aminophosphorylic function.1−3
The amide version of the reaction for trivalent phosphorus
chlorides 1 in acetic acid (Oleksyszyn reaction) was initially
proposed with the aim for synthesis of α-aminoalkylphosphor-
ylic compounds 2 (usually without isolation of N-protected
amino acids 3) (Scheme 1).4
Scheme 2. Formation of Phosphorus−Carbon Bond by
Arbuzov-Type Reaction
Scheme 1. Amide Version of the Kabachnik−Fields
Reaction
The reaction was further modified into the amidoalkylation
of dialkyl phosphites 1 in acetyl chloride or in a mixture of
acetic acid and thionyl chloride with the participation of
carbonyl compounds, amides (R′ = Alk), or carbamates (R′ =
OAlk, Scheme 1).5 Acetyl chloride and acetic anhydride are
effective solvents for carrying out the three-component amide
version of the Kabachnik−Fields reaction.5−7
Received: September 19, 2020
https://dx.doi.org/10.1021/acs.joc.0c02259
© XXXX American Chemical Society
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Biscarbamates 5 are a source of acyliminium cations 6,
charged Schiff bases which are formed under conditions of acid
catalysis and are highly reactive electrophilic component of the
reaction (Scheme 2).2,9 Intermediate 7, containing a PIII−OAc
anhydride fragment (Scheme 2), was proposed as nucleophilic
component directly involved in the formation of a
phosphorus−carbon bond.2,9 It was confirmed by experiments
with using presynthesized acetyldiethylphosphite and also
tetraethylpyrophosphite for generation in situ of acetyldiethyl-
phosphite.10
Thus, a phosphorus−carbon bond formation mechanism
was proposed in accordance with the Arbuzov reaction
resulting from a nucleophilic attack of acetyloxyderivative 7
on a positively charged carbon atom of iminium cation 6
(Scheme 2) which are generated in situ in AcCl/Ac2O, from
hydrophosphorylic compound 4 and N,N′-alkylidenebis-
(alkylcarbamate) 5, respectively.2,9 The transformation of
formed phosphonium ion 8 with the subsequent formation
of α-aminoalkylphosphorylic compound 9 proceeds in
accordance with the second stage of the Arbuzov reaction
(Scheme 2).
The amidoalkylation of hydrophosphorylic compounds,
containing an isoster of amino acid, is a convenient approach
to the synthesis of phosphinic pseudopeptides, which are
structural analogues of natural peptides, in the molecule of
which two amino acid components are linked by methyl-
enephosphorylic CH2P(O)(OH) fragment that mimics the
peptide NHC(O)−bond in the transition state of peptide
hydrolysis with a tetra-coordinated carbon atom.11 Therefore,
phosphinic peptides are potent inhibitors of matrix metal-
loproteinases (MMPs), which are a family of zinc-containing
endoproteases involved in diverse biological processes.12
The currently prevailing NP+C strategy for the synthesis of
phosphinic dipeptides11,12 is based on studies by Ciba-Geigy13
devoted to methods for the synthesis of N,P-protected building
blocks, which are phosphonous isosteres of natural amino acid.
The Michael−Pudovik addition of the latter to the
corresponding α-substituted acrylates leads to the formation
of target phosphinic dipeptides.11,12 We are developing a
promising shorter N+PC strategy for the synthesis of
phosphinic peptides with reverse order of construction of
desired molecule,2,9,14 which includes the step of amidoalky-
lation of phosphonous acids (PC-component), containing
isostere of the corresponding amino acid, for example, glutamic
acid 10 and 11 (Scheme 3). The using of corresponding
aldehydes and carbamates or presynthesized N,N′-alkylidene-
biscarbamates, for example, N,N′-methylthiopropylidene-bis-
(benzylcarbamate) 12 leads to the formation of N-protected
aminophosphinic acids, for example, pseudomethionylgluta-
mates 13 and 14 (Scheme 3).15a In accordance with this
synthetic strategy, bis(acetyl)phosphonite 15 (Scheme 3),
generated in situ from phosphonous PC-component 10, is
proposed as a nucleophilic component directly involved in the
formation of a phosphorus−carbon bond by the Arbuzov-type
reaction.2,15 However, attempts for amidoalkylation of
phosphonous acids 10 containing two ester functions using
benzyl carbamate and methylthiopropionic aldehyde in
accordance with the three-component carbamate version of
the Kabachnik−Fields reaction unexpectedly proved to be less
effective.15a Nonetheless, the use of presynthesized biscarba-
mate 12 allowed us to carry out the synthesis of
pseudomethionylglutamate 14 by amidoalkylation of phospho-
nous dicarboxylic acid 11.15a On the contrary, the use of
phosphonous acid 10 containing ester groups showed lower
results. The study for the synthesis of pseudoprolylglutamate
by cyclic amidoalkylation of phosphonous acids 10 and 11 also
showed the higher reactivity of diacid 11 compared to that of
diester 10.15b,c
We suggested that phosphonous dicarboxylic acid 11 is
capable of generating three possible PIII−OAc intermediates,
16a,c, in situ in AcCl/Ac2O medium (Scheme 3).15 In turn,
diethyl ether 11 under these conditions can generate in situ
only one intermediate, 15, the nucleophilicity of which should
be close to the nucleophilicity of intermediate 16a. Therefore,
the contribution to the reactivity of the PC-component is
probably due to intermediates 16b or 16c. Previously, we
assumed15 that in situ generated intermediate 16c containing a
glutaric anhydride ring is source for a noticeable increase in the
reactivity of PC-component 11. In this regard, it is of interest
to study the amidoalkylation of PC-component containing
only one carboxylic function.
RESULTS AND DISCUSSION
■
This work is devoted to the study of the amidoalkylation of
phosphonous PC-component 17 containing a glycine isoster
and one carboxylic function in the form of esters and acid form
(Scheme 4).
Two- and three-component reaction versions involving
benzylcarbamate and isobutyric and isovaleric aldehydes or
presynthesized N,N′-i-butylidene-bis(benzylcarbamate) 18 and
N,N′-i-amylidene-bis(benzylcarbamate) 19 with the formation
of phosphinic N-Cbz-pseudovalylglycines 20 and N-Cbz-
Scheme 3. Synthesis of Phosphinic Met−Glu−Peptide
Scheme 4. Two- and Three-Component Carbamate
Versions of the Kabachnik−Fields Reaction
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pseudoleucylglycines 21 were studied, and pseudopeptides 22
and 23 in free form were obtained (Scheme 4). Also, a two-
component cyclic version of the reaction using 4-N-Cbz-
aminobutyraldehyde 24 with the formation of phosphinic N-
Cbz-pseudoprolylglycine 25 was studied, and free pseudopro-
lylglycine 26 was obtained (Scheme 5).
version of amidoalkylation was also noted (entries 13 and 14,
also entries 15 and 16 in Table 1).
In addition, at the initial stage of the reaction, we were able
to fix the formation of bisacetylphosphonites 27−29 with
characteristic peaks for derivatives of trivalent phosphorus in
the region of 193−196 ppm (Scheme 6 and Supporting
Information part 1).
Scheme 5. Two-Component Cyclic Version of the
Kabachnik−Fields Reaction
Scheme 6. In Situ Generated POAc Derivatives of
Phosphonous Carboxylic Acid 17a and Its Esters 17b,c
We found that amidoalkylation in AcCl and in a AcCl/Ac2O
mixture (1:1−3) at room temperature proceeds extremely
rapidly; the formation of target phosphinic acids and the
disappearance of starting phosphonous PC-component 17
occur within a few minutes. However, carrying out the reaction
under milder conditions, in a mixture AcCl/Ac2O (1:4−7),
revealed higher reactivity of the PC-component containing an
acidic carboxylic function as compared to the phosphonous
component with an ester function (Supporting Information
part 1).
This regularity was observed in the three-component version
of amidoalkylation (compare entry 1 with entries 2 and 3 and
entry 6 with entries 7 and 8 in Table 1) and in the two-
component reaction of biscarbamates 18 and 19 with
phosphonous acid 17a and its esters 17b,c (entries 4 and 5,
as well as 9/10 and 11/12 in Table 1). A difference of
reactivity of carboxylic acid 17a and ester 17b in the cyclic
Moreover, we found that phosphonous propionic acid 17a,
in contrast to esters 17b,c, is capable of generating two
derivatives of three-coordinated phosphorus (Scheme 6). We
assume that diacetylphosphonite 27 is in situ converted into
cyclic phospholactone 30 with liberation of Ac2O. The possible
formation of lactone 30 from esters 17b,c and then from
phosphonites 28 and 29 with liberation of AcOR seems less
likely that confirmed by the absence of significant quantity of
dealkylated reaction products.
The nucleophilicity of diacetylphosphonite 27 generated
from 17a should not noticeably differ from the nucleophilicity
of diacetylphosphonites 28 and 29, which generated from ester
PC-component, regardless of the ester radical (R). This can be
explained by the close structure of these intermediates, which
differ only the ester function at the periphery of the PIII-
containing molecule, which can indirectly confirm by close
chemical shifts of diacetylphosphonites 27−29 (δP 193−196
ppm).
It is very likely that phospholactone 30 (δP 182 ppm) may
be responsible for increasing the reactivity of phosphonous
propionic acid 17a in comparison with phosphonous acids
17b,c containing ester functions. Nevertheless, it seems
difficult to explain the greater reactivity of lactone 30
compared to noncyclic acetylphosphonites 27−29, based on
the structural features of intermediates and their proposed
nucleophilicity.
We propose a hypothesis of spirophosphorane formation to
explain the results of this study. N-Protected phosphinic
pseudopeptides are unique compounds containing both β-
carboxylic function and β-carbamide fragments, which as
shown earlier by Yiotakis and colleagues,16,17 can facilitate the
successful reaction at the phosphorylic center by in situ
generating unstable phosphoranes18 containing the corre-
sponding five-membered cycles with participation of oxygen
atoms of propionic16 or carbamide functions.17
Table 1. Study of Amidoalkylation of Phosphonous
Propionic Acid 17a and Its Esters 17b,c
PC-
component/
product
AcCl/
entry Ac2O (v)
electrophilic
component
time
d
conversion
e
(h)
(%)
a
1
2
3
4
5
6
7
8
1:4
1:4
1:7
1:7
1:7
1:6
1:6
1:6
1:4
1:4
1:7
1:7
1:4
1:4
1:6
1:6
i-Pr
17a/20a
17b/20b
17b/20b
17a/20a
17b/20b
17a/21a
17b/21b
17c/21c
17a/21a
17c/21c
17a/21a
17c/21c
17a/25a
17b/25b
17a/25a
17b/25b
1.0
2.0
2.0
2.0
2.0
3.0
3.0
3.0
0.7
0.7
3.0
3.0
1.5
1.5
3.0
3.0
77
46
7
a
i-Pr
a
i-Pr
b
18
18
85
16
70
26
14
98
75
90
55
98
76
94
59
b
a
i-Bu
i-Bu
i-Bu
b
a
a
9
19
19
19
b
10
11
12
13
14
15
16
b
b
19
24
24
24
c
c
c
c
24
a
b
Three-component reaction version. Two-component reaction
c
d
The apical-equatorial orientation of two five-membered
rings in the trigonal-bipyramidal structure will be facilitated to
the formation of spirophosphoranes 31 (Scheme 7). This
corresponds to the rules of electronegativity of radicals,19 as
well as the rigidity of cycles20 for compounds of five-
version. Cyclic reaction version. The duration of the reaction,
from the mixing of all reagents to the analysis of the mixture by 13P
e
NMR. The content of reaction products in the reaction mixture was
determined by using of integrating for signals in the range of 50−70
ppm of 13P NMR spectrum (Supporting Information part 1).
C
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freshly distilled. Reactions described in this paper were controlled
using 31P NMR spectroscopy and (or) thin layer chromatography
(TLC). All of the compounds for which spectral and analytical data
are given were gomogenous by TLC. Analytical TLC was carried out
on silica-coated aluminum plates (silica gel Silufol-254, starch
cohesive) using a UV light as visualizing agent (254 nm) and flame
heat for control visualization. Chromatograms were visualized in
iodine vapor; the analysis and visualization of the free amino
phosphinic acids was carried out using ninhydrin solution. Column
chromatography was performed on silica gel L100/160 (Chemapol)
or silica gel 60 (Alfa Aesar) or silica gel 60 (Merck). All other reagents
and solvents (acetic anhydride, acetyl chloride, dichloromethane,
toluene, and others) were used dry. All reactions were performed
under an atmosphere of argon with magnetic stirring. Melting points
were determined on a Boetius PHMK apparatus or in open glass
capillaries and are uncorrected.
Scheme 7. Spirophosphorane Hypothesis in the Mechanism
of Phosphorus−Carbon Bond Formation
1H, 31P, and 13C NMR spectra were recorded on a Bruker DPX-200
Fourier spectrometer 31P and 13C NMR spectra are fully proton
decoupled; an DEPT 13C NMR experiment was carried out if
necessary. 31P NMR chemical shifts are reported on a δ scale (parts
per million, ppm) downfield from 85% H3PO4. Tetramethylsilane
(TMS) was used as an internal standard (1H NMR: TMS at 0.00
ppm, CHCl3 at 7.25 ppm, DMSO at 2.49 ppm, CH3OD at 3.30 ppm,
H2O at 4.75 ppm; 13C NMR: CDCl3 at 77.00 ppm, DMSO-d6 at
39.50 ppm, CD3OD at 49.0 ppm).
Negative-mode high-resolution mass spectra (HRMS) were
acquired using an Orbitrap Exactive (Thermofisher Scientific,
Bremen) mass spectrometer. A custom-built electrospray ion source
with the etched silica emitter was used,23 the electrospray voltage was
applied to the metal union connecting the plastic capillary with the
silica emitter. The sample was injected via syringe pump with the flow
rate of 1 μL/min. The samples were dissolved in acetonitrile at
concentration ∼1 mg/mL, with 0.5% formic acid, and then they were
diluted in acetonitrile again 50-fold for the analysis. Mass spectra of all
samples in the negative mode contained the (M − H) ion peaks; the
measured m/z and the isotopic patterns were compared with the
theoretical ones. The experimental m/z values for (M − H) peaks
correspond to the theoretical calculated values; the discrepancies are
<0.001 Da.
coordinated phosphorus. We suggest that the formation of
spirophosphoranes 31 is possible as result of nucleophilic
attack of phospholactone 30 on charged Schiff cation 6
followed by the formation of phosphonium ion 32, which can
be converted to spirophosphorane 31.
The formation of spirophosphoranes 31 can also occur as
result of 1,4-cycloaddition of lactone 30 to the nitrogen
analogue of α,β-unsaturated carbonyl compound, imine 33,
which in turn can be formed from Schiff cation 6 under the
conditions of reaction (Scheme 7). It is known that cyclic
esters of trivalent phosphorus acids react easily with α,β-
unsaturated carbonyl compounds to form spirophosphor-
anes.21
It is likely that phospholactone 30 with a three-coordinated
phosphorus atom may be more reactive in the 1,4-cyclo-
addition to N-alkyloxycarbonyl-imine 33 (Scheme 7) with the
formation of spirophosphorane 31 compared to diacetylphos-
phonites 27−29. Further transformation of spirophosphorane
31 can take place with the formation of phosphonium ions 32
or 34 or others related intermediates.
The general picture of possible transformations of unstable
intermediates of the spirophosphorane structure can probably
be more complicated by the existence of a spirophosphorane−
bipolar structure equilibrium, formed during the reversible
disclosure of the phospholene or phospholane cycles,21,22
which are not shown in the scheme. Apparently, subsequent
final breakdown of phosphorus−oxygen apical bonds of the
spirophosphorane leads to formation of N-protected α-
aminophosphinic propionic acids 35 (Scheme 7).
Synthesis of Starting Materials. Phosphonous acids (17a−c)
were synthesized in according to the procedures reported earlier14
with minor modifications.
2-Ethyloxycarbonyl-ethylphosphonous Acid 17b. Ammonium
hypophosphite (24.9 g, 0.3 mol) and hexamethydisilazane (96.8 g,
0.6 mol) under argon atmosphere were stirred for 2 h at 130−140 °C
on oil bath. Ethylacrylate (10.9 mL, 10.0 g, 0.1 mol) at 30−40 °C
during 1−1.5 h was added slowly dropwise to the in situ formed
bis(trimethylsilyl)hypophosphite. The reaction mixture was stirred at
25−40 °C for 5 h and then was cooled at 5−10 °C. A water−dioxane
solution (25 mL, 1.4 mol of H2O/10 mL of dioxane) was slowly
added dropwise to the formed solution, and reaction mixture was
evaporated in vacuo. The residue was partitioned between ethyl
acetate (100 mL) and water solutions (50 mL, pH ∼3). The water
phase was additionally twice extracted with ethyl acetate (100 mL).
Organic extracts were combined, dried over sodium sulfate, and
evaporated in vacuo. A residue representing ester 17b was isolated as
CONCLUSIONS
■
An unusually greater reactivity of phosphonous propionic acids
was found in comparison with that of phosphonous propionic
esters. Compounds of tricoordinated phosphorus generated in
situ during the amidoalkylation of hydrophosphorylic com-
pounds in a mixture of acetyl chloride and acetic anhydride
were found. A hypothesis is proposed concerning the
generation of unstable spirophosphoranes in situ to explain
the mechanism for the formation of phosphorus−carbon
bonds in the reaction under study.
1
colorless oil (23.7 g, 0.164 mol, 47% yield). H NMR (200 MHz,
1
CDCl3) δ = 12.02 (s, 1H), 7.15 (d, JPH = 561.2 Hz, 1H), 4.11 (q,
2H), 2.45−2.70 (m, 2H), 1.90−2.15 (m, 2H), 1.22 (t, 3JHH = 7.0 Hz,
3H). 31P{1H} NMR (81 MHz, CDCl3) δ = 35.87. Anal. Calcd for
C5H11O4P;%: C, 36.15; H, 6.67; P, 18.65. Found: C, 35.84; H, 6.98;
P, 18.37.
Phosphonous Propionic Acid, 2-Hydroxycarbonyl-ethylphosph-
onous Acid 17a. Hydrolysis of ethyl ester 17b (10.0 g, 60.2 mmol)
with 60 mL of 3 N HCl after 4 h reflux gave free phosphonous
carboxylic acid 17a as a very viscous, almost glassy substance in 95%
yield (7.9 g). The spectral data of 17a did not differ significantly from
those previously published.24 1H NMR (200 MHz, D2O) δ = 6.95 (d,
1JPH = 558.6 Hz, 1H), 2.35−2.60 (m, 2H), 1.75−2.00 (m, 2H).
EXPERIMENTAL SECTION
■
Materials and Methods. All reagents used in the reactions
described in this manuscript are commercial, were purchased from
Acros Organics Ltd., Aldrich Chemical Co. Ltd., and Alfa Aesar
companies, and were used without additional purification. The
exception is isobutyric and isovaleric aldehydes, which were used as
D
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31P{1H} NMR (81 MHz, D2O) δ = 36.49. Anal. Calcd for C3H7O4P,
%: C, 26.10; H, 5.11; P, 22.43. Found: C, 25.86; H 5.35; P, 22.17.
2-(Benzyloxycarbonyl)ethylphosphonous Acid 17c. Synthesis of
2-(benzyloxycarbonyl)ethylphosphonous acid 17c was carried out by
the addition of in situ generated ammonium or potassium
hypophosphite (0.3 mol) bis(trimethylsilyl)hypophosphite to a benzyl
ester of acrylic acid (0.1 mol) in accordance with the above procedure
for the synthesis of ethyl ester 17b.14
General Procedure C (Cyclic Two-Component Reaction Version).
Phosphonous propionic acid (17a) (1.5 mmol) or the ethyl ester of
phosphonous propionic acid (17b) (1.5 mmol) in one portion and
immediately then acetyl chloride (1−4 mL) were added to the stirred
solution of 4-(N-benzyloxycarbonyl)-aminobutyraldehyde 24 (1.5
mmol) in 4−7 mL acetic anhydride.
The resulting mixture was stirred for 1−2 h (in the case of acid
17a) or for ∼20 h (in the case of ester 17b), and the progress of the
reaction was monitored by 31P NMR spectroscopy. After completion
of the reaction, 10 mL of water was added to the reaction mass, the
resulting mixture was stirred for an hour and extracted with ethyl
acetate (3 × 10 mL). The organic phase was dried over sodium sulfate
and evaporated in vacuo. The residue was purified by chromatography
on silica gel (eluent: chloroform−methanol (or i-propanol) (2−7%).
Characterization of N-Protected Pseudopeptides 20, 21,
and 25. N-Protected pseudodipeptides are a mixture of conformers.
This is probably due to (a) the presence of a chiral carbon center of
the aminophosphorylic fragment and (b) the presence of an amide
nitrogen atom and the inhibition of free rotation of the N-Cbz
fragment relative to the time scale of NMR. This manifests itself to
varying degrees in the NMR spectra under various conditions. The
presence of a five-membered pyrrolidine ring in the form of a
nonplanar cycle introduces additional elements of asymmetry,
manifested in the NMR spectra of proline-containing compounds.
In this regard, the 1H, 31P, and 13C spectra of N-Cbz-protected
pseudopeptides were recorded in various solvents. Hereafter, signals
marked with an asterisk refer to minor conformer forms.
Yield for 17c: 17.3 g, 76%. Low-melting crystals, off-white. Mp 36−
1
37 °C. H NMR (200 MHz, CDCl3) δ = 11.71 (s, 1H), 7.30−7.40
(m, 5H), 7.17 (d, 1JPH = 561.8 Hz, 1H), 5.12 (s, 2H), 2.55−2.80 (m,
2H), 1.90−2.20 (m, 2H). 31P{1H} NMR (81 MHz, CDCl3) δ =
3
35.70. 13C{1H} NMR (50 MHz, CDCl3) δ = 171.5 (d, JPC = 13.3
2
Hz), 135.3, 128.3, 128.1, 128.0, 66.5, 25.83 (d, JPC = 2.2 Hz), 24.12
(d, 1JPC = 95.5 Hz). Anal. Calcd for C10H13O4P, %: C, 52.64; H, 5.74;
P, 13.57. Found: C, 52.32; H, 5.96; P, 13.30.
General Synthesis of N,N′-Alkylidenebiscarbamates 18 and 19.
Synthesis of the title compounds was carried out in accordance with
the procedure previously described,9 with minor modification and
simplification.
TFA (0.05 mmol) and the corresponding aldehyde (2.5 mmol)
were then slowly added dropwise under stirring to a solution of benzyl
carbamate (5.0 mmol) in acetic anhydride (5 mL) at room
temperature. The stirring was continued for 10 h. Precipitated
crystals were filtered off and were flushed with acetic anhydride (1−2
mL) and then petroleum ether (1−2 mL). Biscarbamates 18 and 19
were recrystallized from diethyl ether−ethanol mixture.
The yields and constants, as well as 1H, 13C, and 31P NMR spectral
data, of biscarbamates 18 and 19 did not differ significantly from
those previously published.9b
1-(Benzyloxycarbonylamino)-2-methyl-propyl-2′-(hydroxycar-
bonyl)-ethylphosphinic Acid (20a). Yield: 0.23 g, 44% (procedure
A); 0.32 g, 63% (procedure B). White solid; mp 164−167 °C. Rf =
0.10−0.15 (CHCl3/EtOH ∼ 95:5). 1H NMR (200 MHz, DMSO-d6)
δ 7.48 (d, J = 10.2 Hz, 1H), 7.20−7.50 (m, 5H), 5.06 (AB − system,
2H), 3.45−3.70 (m, 1H), 2.25−2.50 (m, 2H), 2.0−2.25 (m, 1H),
1.65−1.95 (m, 2H), 0.85−1.00 (2d, J = 4.4 Hz, 6H). 31P{1H} NMR
(81 MHz, DMSO-d6) δ 47.26, 46.90*, 46.64*. 13C{1H} NMR (50
MHz, DMSO-d6) δ 173.6 (d, J = 16.1 Hz), 156.7 (d, J = 5.5 Hz),
137.2, 128.4, 127.7, 127.4, 65.5, 55.0 (d, J = 104.7 Hz), 27.5, 26.4,
4-(N-Benzyloxycarbonyl) aminobutyraldehyde 24. The title
compound was synthesized from 4-amino-butyraldehyde dimethyl
acetal according to the acylation procedure previously described.25
Amidoalkylation of Phosphonous Acid 17a and Its Esters 17b,c.
It should be noted that dried 2-hydroxycarbonyl-ethylphosphonous
acid 17a is a very viscous, almost glassy substance; it could not quickly
dissolve in acetic anhydride. Only a mixture of acetic anhydride and
acetyl chloride allowed 17a to dissolve very fast.
1
22.9 (d, J = 90.4 Hz), 20.8 (d, J = 8.1 Hz), 18.7 (d, J = 5.1 Hz). H
NMR (200 MHz, CDCl3 + drop of TFA) δ 7.25−7.50 (m, 5 H),
6.61*(∼30%) (d, J = 9.8 Hz, 1H), 5.77 (∼70%) (d, J = 10.3 Hz, 1H),
5.21* (s, 2H), 5.16 (s, 2H), 3.90−4.25 (m, 1H), 2.50−2.90 (m, 2H),
1.90−2.45 (m, 3H), 1.03 (d, J = 6.4 Hz, 3H), 1.00 (d, J = 5.9 Hz,
3H). 31P{1H} NMR (81 MHz, CDCl3 + drop of TFA) δ 59.03
(∼70%), 58.15* (∼30%). 13C{1H} NMR (50 MHz, CDCl3 + drop of
TFA) δ 177.8 (d, J = 7.7 Hz), 158.3* (d, J = 2.4 Hz), 157.7 (d, J = 2.9
Hz), 135.2, 134.6*, 129.0, 128.8, 128.6, 128.5, 127.9, 69.1*, 68.4,
55.6* (d, J = 103.2 Hz), 54.5 (d, J = 105.4 Hz), 27.9*, 27.8, 26.1,
25.9*, 22.0 (d, J = 89.3 Hz), 21.8* (d, J = 89.7 Hz), 20.5* (d, J = 10.1
Hz), 20.4 (d, J = 10.3 Hz), 17.5 (d, J = 2.2 Hz), 17.3* (d, J = 1.9 Hz).
Anal. Calcd for C15H22NO6P;%: C, 52.48; H, 6.46; P, 9.02. Found: C,
52.18; H, 6.58; P, 8.70.
Procedures for the Synthesis of Phosphinic Pseudopep-
tides. General Procedure A (Three-Component Reaction Version).
The corresponding aldehyde (1.7 mmol, ∼1.1 equiv) in one portion
and then immediately acetyl chloride (1−4 mL) were added to a
stirred mixture of phosphonous propionic acid (17a), the ethyl ester
(17b) (1.5 mmol), or the benzyl ester (17c) (1.5 mmol)
phosphonous propionic acid and benzylcarbamate (1.5 mmol) in
acetic anhydride (4−7 mL).
The resulting mixture was stirred for 1−2 h (in the case of acid
17a) or for ∼20 h (in the case of esters 17b and 17c), and the
progress of the reaction was monitored by 31P NMR spectroscopy.
After completion of the reaction, 10 mL of water was added to the
reaction mass; the resulting mixture was stirred for 1 h and extracted
with ethyl acetate (3 × 10 mL). The organic phase was dried over
sodium sulfate and evaporated in vacuo. The residue was purified by
chromatography on silica gel (eluent: chloroform−methanol (or i-
propanol) (from 2 to 10%).
1-(Benzyloxycarbonylamino)-2-methyl-propyl-2′-(ethyloxycar-
bonyl)-ethylphosphinic Acid (20b). Yield 0.30 g, 54% (procedure A);
0.41 g, 73% (procedure B). White solid; mp 86−88°C. Rf = 0.15
1
(CHCl3/CO(CH3)2 4:1). H NMR (200 MHz, CD3OD) δ 7.20−
7.45 (m, 5H), 5.12 (AB − system, 2H), 4.12 (q, 2H), 3.79 (dd, J =
5.1 Hz, 1H), 2.45−2.65 (m, 2H), 2.15−2.35 (m, 1H), 1.85−2.10 (m,
2H), 1.24 (t, J = 7.0 Hz, 3H) 1.02 (d, J = 4.2 Hz, 3H), 1.00 (d, J = 4.7
Hz, 3H). 31P{1H} NMR (81 MHz, CD3OD) δ 49.22, 48.43*.
13C{1H} NMR (50 MHz, CD3OD) δ 173.9 (d, J = 15.7 Hz), 159.0
(d, J = 5.5 Hz), 138.2, 129.5, 129.0, 128.8, 67.9, 62.0, 56.1 (d, J =
106.1 Hz), 29.2 (d, J = 1.5 Hz), 27.6 (d, J = 2.6 Hz), 23.9 (d, J = 91.5
General Procedure B (Two-Component Reaction Version). The
corresponding N,N′-alkylidene-bis(benzylcarbamate) 18 or 19 (1.5
mmol) in one portion and then immediately 1−4 mL of acetyl
chloride were added to a stirred mixture of phosphonous propionic
acid (17a) (1.5 mmol), a solution of ethyl ester (17b) (1.5 mmol), or
a solution of the benzyl ester (17c) (1.5 mmol) in 4−7 mL of acetic
anhydride at room temperature. The resulting mixture was stirred for
1−2 h (in the case of acid 17a) or for ∼20 h (in the case of esters 17b
and 17c); the progress of the reaction was monitored by 31P NMR
spectroscopy. After completion of the reaction, 10 mL of water was
added to the reaction mass; the resulting mixture was stirred for 1 h
and extracted with ethyl acetate (3 × 10 mL). The organic phase was
dried over sodium sulfate and evaporated in vacuo. The residue was
purified by chromatography on silica gel (eluent: chloroform−
methanol (or i-propanol) (from 2 to 10%).
1
Hz), 21.2 (d, J = 9.1 Hz), 18.8 (d, J = 5.1 Hz), 14.5. H NMR (200
MHz, CDCl3 + drop TFA) δ 7.25−7.45 (m, 5H, Ph), 6.59* (∼35%)
(d, J = 10.0 Hz, 1H, NH), 5.89 (∼65%) (d, J = 10.6 Hz, 1H), 5.21*
(s, 2H), 5.15 (s, 2H), 3.90−4.30 (m, 3H), 2.55−2.90 (m, 2H), 2.00−
2.50 (m, 3H), 1.95−2.45 (m, 3H), 1.28 (t, J = 7.0 Hz, 3H), 1.03 (d, J
= 4.1 Hz, 3H), 1.00 (d, J = 5.3 Hz, 3H). 31P{1H} NMR δ (81 MHz,
CDCl3 + drop TFA) δ 57.32 (∼65%), 56.96* (∼35%). 13C{1H}
NMR (50 MHz, CDCl3 + drop TFA) δ 175.0 (d, J = 9.2 Hz), 174.5*
E
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(35%) (d, J = 9.9 Hz), 158.4* (d, J = 5.2 Hz), 157.8 (d, J = 5.9 Hz),
135.1, 134.6*, 128.9, 128.8, 128.6, 128.5, 127.9, 69.2*, 68.4, 62.6,
62.5*, 55.5* (d, J = 104.7 Hz), 54.4 (d, J = 105.8 Hz), 27.9* (d, J =
1.4 Hz), 27.8 (d, J = 1.5 Hz), 26.4 (d, J = 5.5 Hz), 26.3* (d, J = 5.5
Hz), 22.0 (d, J = 87.7 Hz), 21.7* (d, J = 88.5 Hz), 20.5* (d, J = 11.1
Hz), 20.4 (d, J = 10.7 Hz), 17.5 (d, J = 4.1 Hz), 17.3* (d, J = 4.1 Hz),
13.7. Anal. Calcd for C17H26NO6P, %: C, 54.98; H, 7.06; P, 8.34.
Found: C, 54.80; H 7.23; P, 8.17.
1 - (Be n z y l o x yc a r b o n yla mino)-2-methyl-bu tyl-2 ′-
(hydroxycarbonyl)ethylphosphinic Acid (21a). Yield 0.28 g, 53%
(procedure A); 0.38 g, 71% (procedure B). White solid; mp 183−185
°C. Rf = 0.15 (CHCl3/EtOH ∼ 95:5). 1H NMR (200 MHz, DMSO-
d6) δ 7.52 (d, J = 9.1 Hz, 1H, NH), 7.20−7.40 (m, 5H), 5.04 (AB −
system, 2H), 3.55−3.85 (m, 1H), 2.25−2.55 (m, 2H), 1.65−1.90 (m,
2H), 1.30−1.70 (m, 3H), 0.87 (d, J = 6.1 Hz, 3H), 0.80 (d, J = 6.1
Hz, 3H). 31P{1H} NMR (81 MHz, DMSO-d6) δ 47.40, 46.72*.
13C{1H} NMR (50 MHz, DMSO-d6) δ 173.6 (d, J = 15.7 Hz), 156.2
NMR (81 MHz, CDCl3 + drop of TFA) δ 59.91, 59.17*, 58.81*.
Anal. Calcd for C23H30NO6P, %: C, 61.74; H, 6.76; P 6.92. Found: C,
61.39; H, 6.91; P 6.98. HRMS (ESI) calcd for C23H29NO6P m/z: [M
− H]− 446.1727. Found 446.1706.
{1-(Benzyloxy)carbonyl)pyrrolidin-2-yl}-(2′-hydroxycarbonyl)-
ethylphosphinic Acid (25a). Yield: 0.28 g, 54% (procedure C); pale
1
yellow oil; Rf = 0.2 (CHCl3/EtOH ∼ 95:5). H NMR (200 MHz,
CDCl3) δ 8.80−9.30 (s, broad, 2H), 7.20−7.45 (m, 5H, Ph), 5.11
(AB − system, 2H), 4.05−4.25 (m, 1H), 3.25−3.75 (m, 2H), 1.45−
2.90 (m, 8H). 31P{1H} NMR (81 MHz, CDCl3) δ 55.08, 54.39*.
13C{1H} NMR (50 MHz, CDCl3) δ 176.2 (d, J = 12.3 Hz), 156.0,
155.0*, 136.1, 136.0*, 128.5, 128.2, 127.9, 67.7, 67.0*, 55.7 (d, J =
108.1 Hz), 55.6* (d, J = 107.7 Hz), 47.2, 26.4, 26.1*, 25.5, 24.6, 23.0
(d, J = 88.6 Hz), 22.7* (d, J = 92.4 Hz). Anal. Calcd for C15H20NO6P,
%: C, 52.79; H, 5.91; N, 4.10. Found: C, 52.54, 52,60; H, 6.12, 6.23;
N, 4.00, 3.78.
{1-(Benzyloxy)carbonyl)pyrrolidin-2-yl}-(2′-ethyloxycarbonyl)-
ethylphosphinic Acid (25b). Yield: 0.35 g, 63% (procedure C); pale
yellow oil. Physicochemical and spectral data of phosphinic N-Cbz-
Pro-Gly-OEt 25b did not differ significantly from those previously
published.15c
The acid hydrolysis of corresponding N-protected amino-
phosphinic acids 20, 21, and 25 (1 mmol) was carried out by
refluxing with 5 mL of 6 N HCl for 7−10 h. The subsequent
evaporation of reaction mixture and treatment of residue with
propylene oxide in aqueous ethanol made it possible to isolate
aminophosphinic acids−pseudodipeptides 22, 23, and 26 in the free
form.
(d, J = 4.0 Hz), 137.2, 128.4, 127.8, 127.5, 65.5, 48.2 (d, J = 106.5
Hz), 35.6, 26.4, 24.0 (d, J = 11.3 Hz), 23.3, 21.7 (d, J = 86.0 Hz),
20.8. 1H NMR (200 MHz, CD3OD) δ 7.20−7.45 (m, 5H), 5.10 (AB
− system, 2H), 3.90−4.10 (m, 1H), 2.45−2.70 (m, 2H), 1.85−2.10
(m, 2H), 1.45−1.80 (m, 3H), 0.95 (d, J = 6.1 Hz, 3H), 0.89 (d, J =
1
6.1 Hz, 3H). 31P{1H} NMR (81 MHz, CD3OD) δ 51.54, 50.54*. H
NMR (200 MHz, CDCl3 + drop of TFA) δ = 7.20−7.45 (m, 5 H),
6.47*(∼35%) (d, J = 9.8 Hz, 1H), 5.61 (∼65%) (d, J = 9.8 Hz, 1H),
5.23* (s, 2H), 5.15 (s, 2H), 4.10−4.35 (m, 1H), 2.60−2.90 (m, 2H),
2.00−2.35 (m, 2H), 1.40−1.85 (m, 3H), 0.96 (d, J = 6.1 Hz, 3H),
0.93* (d, J = 6.1 Hz, 3H), 0.88 (d, J = 6.1 Hz, 3H), 0.81* (d, J = 6.1
Hz, 3H). 31P{1H} NMR (81 MHz, CDCl3 + drop of TFA) δ 61.03,
60.47* (∼35%). 13C{1H} NMR (50 MHz, CDCl3 + drop of TFA) δ
178.8* (∼35%), 178.0, 158.1*, 157.4, 135.1, 134.4*, 129.1, 128.7,
128.0, 69.3*, 68.5, 49.2* (d, J = 105.8 Hz), 48.3 (d, J = 103.5 Hz),
36.0*, 35.7, 26.0, 25.85*, 24.3 (d, J = 10.6 Hz), 23.1, 23.0*, 20.8 (d, J
= 91.1 Hz), 20.5* (d, J = 90.0 Hz), 20.59, 20.47*. Anal. Calcd for
C16H24NO6P, %: C, 53.78; H, 6.77; P, 8.67. Found: C, 53.56; H 6.95;
P, 8.49. HRMS (ESI) calcd for C16H23NO6P m/z: [M − H]−
356.1258. Found 356.1248.
Characterization of Aminophosphinic Acids 22, 23, and 26.
1-Amino-2-methylpropyl-2′-(hydroxycarbonyl)-ethylphosphinic
Acid (22). Yield: 0.16 g, 76%; white solid; mp 184−186 °C. 1H NMR
(200 MHz, D2O) δ 2.80−3.20 (m, 1H), 2.40−2.65 (m, 2H), 2.10−
2.30 (m, 1H), 1.75−2.00 (m, 2H), 1.03 (d, J = 7.3 Hz, 3H), 0.99 (d, J
= 7.9 Hz, 3H). 31P{1H} NMR (81 MHz, D2O) δ 34.73. 13C{1H}
NMR (50 MHz, D2O) δ 177.5 (d, J = 15.0 Hz), 55.7 (d, J = 91.5 Hz),
26.9, 26.8, 24.4 (d, J = 95.9 Hz), 20.1 (d, J = 6.2 Hz), 17.9 (d, J = 5.1
Hz). Anal. Calcd for C7H16NO4P, %: C, 40.19; H, 7.71; N, 6.70.
Found: C, 39.84; H, 7.99; N, 6.55. HRMS (ESI) calcd for
C7H15NO4P m/z: [M − H]− 208.0733. Found 208.0730.
1-Amino-3-methylbutyl-2′-hydroxycarbonyl)-ethylphosphinic
Acid (23). Yield: 0.18 g, 81%, white solid; mp 179−181 °C. 1H NMR
(200 MHz, D2O) δ 3.05−3.25 (m, 1H), 2.40−2.60 (m, 2H), 1.70−
1.95 (m, 2H), 1.40−1.70 (m, 3H), 0.86 (d, J = 5.9 Hz, 3H), 0.81 (d, J
= 6.5 Hz, 3H). 31P{1H} NMR (81 MHz, D2O) δ 35.93. 13C{1H}
NMR (50 MHz, D2O) δ 177.2 (d, J = 14.4 Hz), 48.3 (d, J = 92.9 Hz),
36.1, 26.5 (d, J = 3.7 Hz), 24.0 (d, J = 8.9 Hz), 22.6 (d, J = 95.5 Hz),
22.3, 20.0. Anal. Calcd for C8H18NO4P, %: C, 43.05; H, 8.13; N, 6.28.
Found: C, 42. 90; H, 8.33; N, 6.14. HRMS (ESI) calcd for
C8H17NO4P m/z: [M − H]− 222.0890. Found 222.0886.
Pyrrolidin-2-yl)-2′-(hydroxycarbonyl)-ethylphosphinic Acid (26).
1-(Benzyloxycarbonylamino)-3-methyl-butyl-2′-(ethyloxycar-
bonyl)-ethylphosphinic Acid (21b). Yield: 0.32 g, 55% (procedure
A); 0.36 g, 63% (procedure B). White solid; mp 110−112 °C. Rf = 0.2
1
(CHCl3/CO(CH3)2 4:1). H NMR (200 MHz, CDCl3) δ 9.69 (s,
broad, 1H), 7.20−7.40 (m, 5H), 5.16 (d, J = 11.0 Hz, 1H), 5.10 (s,
2H), 4.12 (q, 2H), 3.95−4.20 (m, 1H), 2.45−2.70 (m, 2H), 1.90−
2.15 (m, 2H), 1.40−1.80 (m, 3H), 1.22 (t, 3H), 0.93 (d, J = 5.9 Hz,
3H), 0.90 (d, J = 5.9 Hz, 3H). 31P{1H} NMR (81 MHz, CDCl3) δ
55.68, 54.33*. 13C{1H} NMR (50 MHz, CDCl3) δ 172.2 (d, J = 15.4
Hz), 156.1 (d, J = 4.4 Hz), 136.2, 128.5, 128.2, 128.0, 67.3, 61.0, 47.7
(d, J = 106.5 Hz), 36.2, 26.3 (d, J = 2.6 Hz), 24.3 (d, J = 11.3 Hz),
23.4, 21.6 (d, J = 92.6 Hz), 21.04, 14.14. Anal. Calcd for
C18H28NO6P, %: C, 56.10; H, 7.32; P 8.04. Found: C, 55.83,
55.70; H, 7.54, 7.58; P 7.78, 7.74.
1
Yield: 0.13 g, 63%; white solid; mp 186−187 °C. H NMR (200
MHz, D2O) δ 3.35−3.60 (m, 1H), 3.10−3.35 (m, 2H), 2.35−2.65
(m, 2H), 1.60−2.30 (m, 6H). 31P{1H} NMR (81 MHz, D2O) δ
33.86, 32.32*. 13C{1H} NMR (50 MHz, D2O) δ 177.2 (d, J = 14.4
Hz), 56.5 (d, J = 92.9 Hz), 47.1 (d, J = 4.8 Hz), 26.7 (d, J = 3.3 Hz),
25.3, 24.1 (d, J = 96.9 Hz), 23.9 (d, J = 7.0 Hz). Anal. Calcd for
C7H14NO4P, %: C, 40.58; H, 6.81; N, 6.76. Found: C, 40.21; H, 6.98;
N, 6.51. HRMS (ESI) calcd for C7H13NO4P m/z: [M − H]−
206.0577. Found 206.0572.
1-(Benzyloxycarbonylamino)-3-methyl-butyl-2′-(benzyloxycar-
bonyl)-ethylphosphinic Acid (21c). Yield: 0.34 g, 51% (procedure
A); 0.45 g, 67% (procedure B). White solid; mp 105−107 °C. Rf = 0.2
1
(CHCl3/CO(CH3)2 4:1). H NMR (200 MHz, CDCl3) δ 10.19 (s,
broad, 1H), 7.20−7.40 (m, 10H), 5.00−5.15 (m, 5H, 2CH2), 3.85−
4.20 (m, 1H), 2.50−2.80 (m, 2H), 1.90−2.20 (m, 2H), 1.35−1.80
(m, 3H), 0.91 (d, J = 5.5 Hz, 3H), 0.89 (d, J = 6.1 Hz, 3H). 31P{1H}
NMR (81 MHz, CDCl3) δ = 55.91, 54.58*. 13C{1H} NMR (50 MHz,
CDCl3) δ 171.9 (d, J = 16.1 Hz), 156.1 (d, J = 4.6 Hz), 136.1, 135.6,
128.7, 128.5, 128.2, 128.0, 67.2, 66.7, 47.7 (d, J = 106.6 Hz), 36.1,
26.3 (d, J = 2.3 Hz), 24.3 (d, J = 11.1 Hz), 23.4, 21.5 (d, J = 92.8 Hz),
21.0. 13C NMR (50 MHz, CDCl3, DEPT) δ 129.2, 129.0, 128.7,
128.4, 67.7, 67.2, 48.1 (d, J = 106.5 Hz), 36.5, 26.8 (d, J = 2.7 Hz),
24.8 (d, J = 11.5 Hz), 23.9, 22.0 (d, J = 92.3 Hz), 21.5. 1H NMR (200
MHz, CDCl3 + drop TFA) δ 7.20−7.45 (m, 10H, Ph), 6.47* (∼30%)
(d, J = 9.8 Hz, 1H), 5.72 (∼70%) (d, J = 9.8 Hz, 1H), 5.05−5.25*
(m, 4H), 4.05−4.35 (m, 1H), 2.65−3.00 (m, 2H), 2.0−2.35 (m, 2H),
1.45−1.85 (m, 3H), 0.95 (d, J = 6.1 Hz, 3H), 0.93* (d, J = 5.7 Hz,
3H), 0.89 (d, J = 6.7 Hz, 3H), 0.80* (d, J = 6.7 Hz, 3H). 31P{1H}
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02259.
■
sı
Supporting Information part 1: General experimental
procedures; synthesis of the starting compounds;
amidoalkylation of phosphonous propionic acid 17a
and its carboxylic esters 17b,c; general procedures for
the synthesis of phosphinic pseudopeptides 20, 21, and
F
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25; NMR 31P spectral study for the amidoalkylation of
phosphonous acids 17a−c, including 31P NMR spectra
of reaction mixtures (PDF)
Chem. 1982, 113, 59−71. (e) Oleksyszyn, J. An Amidoalkylation of
Trivalent Phosphorus Compounds with P (O) H Functions Including
Acetic Acid Solutions of PCl3, RPCl2 or R2PCl, Diesters of
Phosphorus Acid and Phosphorus III Acids. J. Prakt. Chem. 1987,
329, 19−28.
1
Supporting Information part 2: H, 13C, and 31P NMR
spectra of starting compounds and pseudopeptides 20−
23, 25, and 26; HRMS spectral data and also (PDF)
FAIR data, including the primary NMR FID files, for
compounds 20a, 20b, 21a, 21b, 21c, 22, 23, 25a, 26
(ZIP)
(5) (a) Yuan, C.; Wang, G.; Chen, S. Dialkyl or Diphenyl α-
(Benzyloxycarbonylamino)benzylphosphonates. Synthesis 1990, 1990,
522−524. (b) Yuan, C.; Chen, S.; Wang, G. Studies on Organo-
phosphorus Compounds; XLVI. A Facile and Direct Route to Dialkyl
1-(Benzyloxycarbonylamino)alkylphosphonates and dies on phospho-
rus Compounds XLVII: Acetyl Chloride - A Versatile Reagent for the
Synthesis of 1-Aminoalkyl- and Amino(aryl)methylphosphonic Acid
Derivatives. Synthesis 1991, 1991, 490−493. (c) Yuan, C.; Chen, S.
Studies on Organophosphorus Compounds; LXIII. A New and Facile
Synthetic Route to Protected Phosphonodipeptides: A Backbone for
the Formation of Oligophosphonopeptides. Synthesis 1992, 1992,
1124−1128. (d) Chen, S.; Cowark, J. K. A general method for the
synthesis of N-protected α-aminoalkylphosphinic acids. Tetrahedron
Lett. 1996, 37, 4335−4338. (e) Chung, S.-K.; Kang, D.-H.
Asymmetric synthesis of α-aminophosphonates via diastereoselective
addition of phosphite to chiral imine derivatives. Tetrahedron:
Asymmetry 1996, 7, 21−24.
(6) (a) Nasopoulou, M.; Georgiadis, D.; Matziari, M.; Dive, V.;
Yiotakis, A. A Versatile Annulation Protocol toward Novel Con-
strained Phosphinic Peptidomimetics. J. Org. Chem. 2007, 72, 7222−
7228. (b) Matziari, M.; Yiotakis, A. Shortcut to Fmoc-Protected
Phosphinic Psedodipeptidic Blocks. Org. Lett. 2005, 7, 4049−4052.
(7) Oleksyszyn, J.; Gruszecka, E. Amidoalkylation of phosphorous
acid. Tetrahedron Lett. 1981, 22, 3537−3540.
AUTHOR INFORMATION
Corresponding Author
Valery V. Ragulin − Institute of Physiologically Active
Substances of the Russian Academy of Sciences, Chernoglovka,
Moscow Region 142432, Russia; orcid.org/0000-0002-
3967-1034; Email: rvalery@dio.ru
■
Authors
Maxim E. Dmitriev − Institute of Physiologically Active
Substances of the Russian Academy of Sciences,
Chernoglovka, Moscow Region 142432, Russia
Sofia R. Golovash − Institute of Physiologically Active
Substances of the Russian Academy of Sciences,
Chernoglovka, Moscow Region 142432, Russia
Alexei V. Borodachev − Institute of Physiologically Active
Substances of the Russian Academy of Sciences,
Chernoglovka, Moscow Region 142432, Russia
(8) Soroka, M. The synthesis of 1-aminoalkylphosphonic acids. A
revised mechanism of the reaction of phosphorus trichloride, amides
and aldehydes or ketones in acetic acid (Oleksyszyn reaction). Liebigs
Ann. Chem. 1990, 1990, 331−334.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02259
(9) (a) Dmitriev, M. E.; Ragulin, V. V. Arbuzov-type reaction of
acylphosphonites and N-alkoxycarbonylimine cations generated in
situ with trifluoroacetic anhydride. Tetrahedron Lett. 2012, 53, 1634−
1636. (b) Dmitriev, M. E.; Rossinets, E. A.; Ragulin, V. V.
Amidoalkylation of Hydrophosphorylic Compounds. Russ. J. Gen.
Chem. 2011, 81, 1092−1104.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Part of this work was supported by the budget of the IPAC
RAS State Targets 2019 (topic no. 0090-2019-0008) and
partially was supported by a grant from the Russian
Foundation for Basic Research 18-03-00959. The authors
would like to thank V. I. Kozlovski for HRMS data and
analyses.
(10) Dmitriev, M. E.; Ragulin, V. V. Acyloxy Derivatives of Trivalent
Phosphorus in Amidoalkylation of Hydrophosphorylic Compounds.
Russ. J. Gen. Chem. 2013, 83, 1888−1894.
(11) Mucha, A. Synthesis and Modifications of Phosphinic
Dipeptide Analogues. Molecules 2012, 17, 13530−13568.
(12) Georgiadis, D.; Dive, V. Phosphinic Peptides as Potent
Inhibitorsof Zinc-Metalloproteases. Top. Curr. Chem. 2014, 360, 1−
38.
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