High-performance liquid chromatographic enantioseparation of N-aryl-thioureidoalkylphosphonates and thiourylenedi(alkylphosphonates) on polysaccharide-based chiral stationary phases

Article abstract of DOI:10.1002/chir.22794

The first successful enantioseparation of representative O,O-diphenyl-N-arylthioureidoalkylphosphonates, (±)-Ptc-Val^P(OPh)₂ & (±)-Ptc-Leu^P(OPh)₂ and thiourylenedi(isobutyl phosphonate), Tcm[Val^P(OPh)₂]₂ on analytical and semipreparative scale was achieved by high-performance liquid chromatography using polysaccharide-based chiral stationary phases (CPs). Atc-AA^P(OPh)₂ was obtained using modified tricomponent condensations of the corresponding aldehydes, N-arylthiourea and triphenyl phosphite whereas Tcm[Val^P(OPh)₂]₂ by the condensations of aldehydes, thiourea, and triphenyl phosphite. The prepared, racemic (±)-Atc-AA^P(OPh)₂ [(±)-Ptc-Val^P(OPh)₂, (±)-Ptc-Leu^P(OPh)₂, (±)-Ptc-Pgly^P(OPh)₂ and (±)-Ntc-Pgly^P(OPh)₂] and racemic (±)-Tcm[AA^P(OPh)₂]₂ [(±)-Tcm[Nva^P(OPh)₂]₂ & (±)-Tcm[Val^P(OPh)₂]₂] were adequately characterized and used for chromatographic separations on high-performance liquid chromatography–chiral stationary phases. The best results were obtained for (±)-Ptc-Val^P(OPh)₂, (±)-Ptc-Leu^P(OPh)₂ and (±)-Tcm[Val^P(OPh)₂]₂.

Full text of DOI:10.1002/chir.22794

Received: 5 October 2017
DOI: 10.1002/chir.22794
Accepted: 25 October 2017
S P E C I A L I S S U E A R T I C L E
High‐performance liquid chromatographic
enantioseparation of N‐aryl‐thioureidoalkylphosphonates
and thiourylenedi(alkylphosphonates) on polysaccharide‐
based chiral stationary phases
Józef Drabowicz1,2
| Marcin H. Kudzin3
| Zbigniew H. Kudzin4
| Patrycja Pokora‐Sobczak1
1 Centre of Molecular and Macromolecular
Studies, Polish Academy of Sciences,
Warsaw, Poland
2 Department of Chemistry and
Environment Protection, Jan Dlugosz
University, Czestochowa, Poland
3 Textile Research Institute, Lodz, Poland
4 Faculty of Chemistry, University of Lodz,
Lodz, Poland
Abstract
The first successful enantioseparation of representative O,O‐diphenyl‐N‐
arylthioureidoalkylphosphonates, ( )‐Ptc‐ValP(OPh)2 & ( )‐Ptc‐LeuP(OPh)2
and thiourylenedi(isobutyl phosphonate), Tcm[ValP(OPh)2]2 on analytical and
semipreparative scale was achieved by high‐performance liquid chromatogra-
phy using polysaccharide‐based chiral stationary phases (CPs). Atc‐AAP(OPh)2
was obtained using modified tricomponent condensations of the corresponding
aldehydes, N‐arylthiourea and triphenyl phosphite whereas Tcm[ValP(OPh)2]2
by the condensations of aldehydes, thiourea, and triphenyl phosphite. The pre-
pared, racemic ( )‐Atc‐AAP(OPh)2 [( )‐Ptc‐ValP(OPh)2, ( )‐Ptc‐LeuP(OPh)2,
Correspondence
Józef Drabowicz, Jan Dlugosz University,
Department of Chemistry and
Environment Protection, Armii Krajowej
13/15, Czestochowa, Poland.
Email: draj@cbmm.lodz.pl
( )‐Ptc‐PglyP(OPh)2
and
( )‐Ntc‐PglyP(OPh)2]
and
racemic
( )‐
Tcm[AAP(OPh)2]2 [( )‐Tcm[NvaP(OPh)2]2 & ( )‐Tcm[ValP(OPh)2]2] were ade-
quately characterized and used for chromatographic separations on high‐per-
formance liquid chromatography–chiral stationary phases. The best results
were obtained for ( )‐Ptc‐ValP(OPh)2, ( )‐Ptc‐LeuP(OPh)2 and ( )‐
Tcm[ValP(OPh)2]2.
Funding information
the National Science Center (Poland),
Grant/Award Number: the OPUS Grant‐
UMO 2014/15/B/ST5/05329
KEYWORDS
chiral HPLC, enantiomers, meso compounds, N‐arylthioureidoalkylphosphonates, thioureas,
thiourylenedi(alkylphosphonates)
1 | INTRODUCTION
also in analytical and material chemistry.2 Since several
years, they have very often been used as
Thioureas are the subject of significant interest because of
their usefulness in industry,1,2 agriculture (eg, insect and
plant growth regulators, rodenticide agents, and due to
antifungal and herbicidal activity), pharmacy (as enzyme
inhibitors and antioxidants; antibacterials and
antiallergens; anti‐inflammatory agents and also antiepi-
leptic, antihypertensive and anticancer drugs, etc),1,2 and
organocatalysts.3-5 It should be noted here that, among
biological active thioureas, some contain the amino acid
motif (eg, Walpole et al,6 Vankatachalan and Uckun,7
Vardhan et al,8 and Korkmaz et al9). Moreover, thiourea
derivatives are valuable building blocks for the synthesis
of many types of compounds (amides, guanidines, and
heterocycles).10 The special type of thioureas‐N‐aryl‐
thioureido‐alkylphosphonates (Atc‐AAP(OPh)2) are key
compounds in the synthesis of 1‐amino‐alkylphosphonic
acids11-15—compounds of well documented biological
One of us (JD) thanks the National Science Center (Poland) for support
under the OPUS grant UMO 2014/15/B/ST5/05329.
Chirality. 2017;1–10.
wileyonlinelibrary.com/journal/chir
© 2017 Wiley Periodicals, Inc.
1

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DRABOWICZ ET AL.
activity16 and also interesting models for the structural
investigations.17-20 The presence in the N‐aryl‐
thioureidoalkylphosphonates Atc‐AAP(OPh)2 and/or
Tcm[AAP(OPh)2]2 of the alkylphosphonic functional group
in addition to the arylthiourea scaffolds results in the
appearance of the chelating and biological properties of
these compounds. Actually, a few thioreidoalkylphospho-
nates have been prepared and tested as antiviral21,22 and
antitumor compounds23 (Table 1).
this protocol has been successfully used to isolate samples
of several optically active nonprotein amino acids
with stereogenic carbon atoms (eg, Ilisz et al27 and
López‐Ram‐de‐Víu et al28).
In our research, we used, as stereochemical models, 2
types of ( )‐Atc‐AAP(OPh)2, namely, ( )‐Ptc‐AAP(OPh)2
(Ar = Ph, Nph; R = iPr, Bu, Ph)— derivatives of PTU2
and ( )‐Ntc‐AAP(OPh)2 derivatives of ANTU.2 For the
series of ( )‐Tcm[AAP(OPh)2]2, as representative model,
we chose the derivative of ValP (R = iPr).
Because Atc‐AAP(OPh)2 (R ≠ H) contains only 1
stereogenic carbon atom, they exist, respectively, as
enantiomers, R and S. On the other hand, compounds
Tcm[AAP(OPh)2]2 (R≠H) having 2stereogenic carbon
atoms may exist as 3 stereoisomers: 2 optical active
enantiomeric pairs R,R and S,S, and optical inactive meso
R,S form (Table 2).
2 | MATERIALS AND METHODS
2.1 | Chemicals and reagents
Because no paper on optically active Atc‐AAP(OPh)2
and/or Tcm[AAP(OPh)2]2 has been published, except for
the aminophosphonate, Btc‐AlaP(OPh)2, derived from
optically pure (+)‐1‐phenylethylthiourea11,15, we have
attempted to isolate them by the chiral chromatographic
resolution of the corresponding racemic mixtures.
High‐performance liquid chromatography (HPLC)
using chiral stationary phases24-26 is a powerful tool for
the direct analysis of enantiomers. At the same time, this
chromatography is considered to be one of the most
effective methods for obtaining a small amount of pure
enantiomeric compounds within a reasonable time when
is carried out on semipreparative scale.24 For example,
All reagents and solvents were reagent grade and were
used without further purification, unless otherwise
specified. The mobile phases for liquid chromatography
were prepared from HPLC grade solvents: n‐Hexane
(Hx), methanol (MeOH), ethanol (EtOH), isopropanol
(2‐PrOH), acetonitrile (MeCN), and diethyl ether (Et2O),
purchased from Sigma‐Aldrich (Poland). Reactions
were monitored using 31P NMR and by thin‐layer chro-
matography on 0.25‐mm silica gel plates. Ultraviolet light
and phosphomolybdic acid sprays were applied for
visualization.
2.2 | Instrumentation
TABLE 1 Biologically active thioureidoalkylphosphonates
High‐performance liquid chromatography separations were
carried out on a Varian ProStar 210 (analytical enantiomer
separations) and using Recycling Preparative HPLC
instrument LC‐9101 (preparative enantiomer resolution),
manufactured by Japan Analytical Industry Co, Ltd.
Different solvents and binary and ternary mixtures of
solvents were used as eluents. Injections and collections
were made manually. The flow rate was 0.4 to 1 mL/
min. The analyte concentration in injected solutions was
5 mg/mL, and the injection volume was 2 to 20 μL.
Detection was performed at 254‐nm wavelengths.
Chen et al21
Liu et al22; Fan et al23
TABLE 2 Optically active thioureidoalkylphosphonates and
thiourylene dialkyl diphosphonate
The HPLC analytical assays were carried out operat-
ing under isocratic conditions at room temperature on
Chirobiotic V (250 mm × 4.6 mm, 5 μm particles [Astec,
11024 AST]) and Astec Chirobiotic T (250 mm × 4.6 mm,
5 μm particles [Astec, 12024 AST]) and Chiralcel OD
(250 nm × 4.6 mm, 10 μm particles [Daicel, 571‐001‐
50331]) columns. The HPLC semipreparative resolution
of compounds Atc‐AAP(OPh)2 and TC[ValP(OPh)2]2 was
carried out operating under isocratic conditions at room
temperature on a Astec Chirobiotic V2 (250 mm × 21.2 mm,
5 μm particles [Astec, 15044AST]) column.
[α]20D: +2.5 (CHCl3).11

DRABOWICZ ET AL.
3
The wavelength for UV detection was 254 nm.
Chromatograms are presented in the form A(U) = f
[time(min.)].
Optical rotations were measured with a Perkin‐Elmer
241 MC photo‐polarymeter, at a wavelength of 589 nm
(20 °C) using a glass cuvette with path length 9.999 cm.
[α]589 values are given in units of 10−1 deg cm g−1, and
concentrations are given in g/100 mL.
All melting points were determined using a Boetius
melting point apparatus and are uncorrected. NMR
spectra were recorded on a Brucker AC 200 spectrometer
1
operating at 200 MHz for H NMR and at 81.01 MHz for
2.3 | General procedure for the synthesis
of thiocarbamoil derivatives of
1‐aminoalkylphosphonates
Thioureidoalkylphosphonates Ptc‐AAP(OPh)2, 5 were
31P NMR, using deuterochloroform as a solvent. Chemical
ionization mass spectra were obtained on a Finnigan
MAT 95 mass spectrometer using isobutane as a reagent
gas. Elemental analyses (C, H, and N) were recorded on
an Elemental Analyzer Euro EA (Eurovector, Italy).
obtained by tricomponent condensation of the
FIGURE 1 Synthesis of Atc‐AAP(OPh)2 (5)
TABLE 3 Names, abbreviations, and structures of ( )‐Atc‐AAP(OPh)2 and ( )‐Tcm(AAP[OPh]2)2 discussed in this Worka
Abbreviations
Name
Ptc‐AAP(OPh)2
R
Diphenyl 1‐(3‐phenyl)thioureido]alkyl‐phosphonate
Ptc‐AlaP(OPh)2
Ptc‐NvaP(OPh)2
Ptc‐ValP(OPh)2
Ptc‐NleP(OPh)2
Ptc‐PglP(OPh)2
Me
n‐Pr
i‐Pr
n‐Bu
Ph
Diphenyl 1 ‐[(3‐phenyl)thioureido]ethyl‐ phosphonate
Diphenyl 1 ‐(3‐phenyl)thioureido]‐n‐butyl‐ phosphonate
Diphenyl 1‐[(3‐phenyl)thioureido]‐2‐methylpropyl‐phosphonate
Diphenyl 1 ‐(3‐phenyl)thioureido]‐n‐pentyl‐ phosphonate
Diphenyl 1 ‐(3‐phenyl)thioureido]benzyl‐ phosphonate
Abbreviations
Ntc‐AAP(OPh)2
Ntc‐AlaP(OPh)2
Ntc‐PglP(OPh)2
Name
R
Diphenyl 1‐(3‐napthyl)thioureido]alkyl‐phosphonate
Diphenyl 1 ‐(3‐napthyl)thioureido]ethyl‐ phosphonate
Diphenyl 1 ‐(3‐napthyl)thioureido]benzyl‐ phosphonate
Me
Ph
Abbreviations
Name
Tcm[AAP(OPh)2]2
Tcm[AAP(OPh)2]2
Tcm[AAP(OPh)2]2
R
Tetraphenyl (Thiourylenedialkyl)‐ diphosphonate
Tetraphenyl (Thiourylenedi‐n‐butyl)‐ diphosphonate
Tetraphenyl [Thiourylene‐ di(2‐methylpropyl)]diphosphonate
n‐Pr
i‐Pr
aApplied names were in accordance with the JUPAC rules, and the abbreviations were in agreement with the general rules elaborated by Kudzin et al.15,25

4
DRABOWICZ ET AL.
corresponding arylthioureas 2 (prepared from appropriate
isothiocyanate 1), aldehydes 3, and triphenyl phosphite
(4) according to modified procedure of Kudzin&Stec
(Figure 1).11,15
The yields and physical constants of all prepared Atc‐
AAP(OPh)2, listed in Table 3, are given in Supplementary
Information.
3 | RESULTS AND DISCUSSION
3.1 | Procedures for the resolution of
rac‐thiocarbamoil derivatives of
1‐aminoalkylphosphonates
3.1.1 | Chromatographic separations of
( )‐Atc‐AAP(OPh)2
Thiourylenebis(alkylphosphonates) Tcm[AAP(OPh)2]2
6 was obtained by the modified Birum procedure
(Figure 2).15,29 The yields and physical constants for all
prepared Tcm[AAP(OPh)2]2 are given in Supplementary
Information.
Names, abbreviations, and structures of ( )‐Atc‐
AAP(OPh)2 and ( )‐Tcm[AAP(OPh)2]2 discussed in this
work are presented in Table 3.
Analytical separations of ( )‐Atc‐AAP(OPh)2
Solutions of ( )‐Atc‐AAP(OPh)2 (20 mg) in chloroform‐
methanol solution [10:1; 1 mL) were analyzed by means
of enantio‐differentiating HPLC. The representative
chromatographic conditions, for Chiralcel OD and
Chirobiotic V columns, and eluents with increasing
polarity, from hexane‐ROH 95:5 (A1), through hexane‐
FIGURE 2 Synthesis of Tcm[AAP(OPh)2]2
TABLE 4 Chromatographic conditions applied for the analytical enantioseparation of ( )‐Atc‐AAP(OPh)2
Atc‐AAP(OPh)2
Ptc‐AlaP(OPh)2
Column
Eluent
Flow [mL/min]
Relat. Ret. α
Chiralcel OD (Ch‐OD)
A1
0.5
<1.05
Ptc‐NvaP(OPh)2
Ptc‐ValP(OPh)2
Ptc‐NleP(OPh)2
Chiralcel OD (Ch‐OD)
Chiralcel OD (Ch‐OD)
Chirobiotic V (Ch‐V)
A1
A1
0.5
0.5
<1.05
1.48
A1
A2
0.4
0.5
1.11
1.06
Ptc‐PglP(OPh)2
Ntc‐AlaP(OPh)2
Ntc‐PglP(OPh)2
Chiralcel OD (Ch‐OD)
Chiralcel OD (Ch‐OD)
Chiralcel OD (Ch‐OD)
A1
A3
0.5
0.4
<1.05
<1.05
A1
A3
0.4
0.4
1.05
<1.05
Injection volume 0.002 mL. Eluents: A1 [Hexane‐(iPrOH‐EtOH; 4:1) in the ratio 95:5 (v/v)]; A2 [Hexane‐(iPrOH‐EtOH; 4:1) in the ratio 70:30 (v/v)]; A3 [MeOH
(100%)].
FIGURE 3 Chromatogram for the enantioseparation of ( )‐Ptc‐NleP(OPh)2 on a Chirobiotic V column. Eluent: Hx–(iPrOH–EtOH; 4:1),
70:3 (v/v); flow 0,4 mL/min

DRABOWICZ ET AL.
5
ROH 70:30 (A2) and finally methanol (100%), are sum-
marized in Table 4.
The results of the analytical enantioseparations of the
representative Atc‐AAP(OPh)2 on Chirobiotic V column,
namely, ( )‐Ptc‐NleP(OPh)2, ( )‐Ptc‐ValP(OPh)2, and
( )‐Ntc‐PglP(OPh)2 are presented on Figures 3–6, respec-
tively. Chromatograms in Figures 3 and 4 exhibit strong
influence of solvent polarity on separation efficiency.
Thus, for the eluent, containing 4.1% (v/v) of alcohol in
hexane‐ROH system presents poor enantio‐separability,
FIGURE 4 Chromatogram for the enantioseparation of ( )‐Ptc‐NleP(OPh)2 on a Chirobiotic V column. Eluent: Hx–(iPrOH–EtOH, 4:1),
95:5 (v/v); flow 0,4 mL/min
FIGURE 5 Chromatogram for the enantio‐separation of ( )‐Ptc‐ValP(OPh)2 on a Chirolcel OD column [eluent: Hx–(iPrOH–EtOH, 4:1),
95:5 (v/v); flow 0,5 mL/min]
FIGURE 6 Chromatogram for the enantioseparation of ( )‐Ntc‐PglP(OPh)2 on a Chiracel OD column [eluent: Hx–(iPrOH–EtOH, 4:1),
95:5 (v/v); flow 0,5 mL/min]
TABLE 5 Separation parameters of ( )‐ Ptc‐NleP(OPh)2 enantio-
mers separated on Chirobiotic V column (Figure 1[2])
TABLE 6 Separation parameters of ( )‐ Ptc‐ValP(OPh)2 enantio-
mers separated on Chirolcel OD column (Figure 5)
Enantiomer
Signal Area
Retention Time, min
Enantiomer
Signal Area
Retention Time, min
1
49.5
42.7
1
49.2
14.6
2
50.5
47.6
2
49.4
21.6

6
DRABOWICZ ET AL.
FIGURE 7 Chromatogram of the first enantiomer (+)‐Ptc‐NleP(OPh)2 (RT 20.3 min). Chromatograms of the separated enantiomers of ( )‐
Ptc‐NleP(OPh)2 on a Chirobiotic V2 column [eluent: Hx–(iPrOH–EtOH, 4:1), 95:5 (v/v); flow 0,5 mL/min]
FIGURE 8 Chromatogram of the second enantiomer (‐)‐Ptc‐NleP(OPh)2 (RT 23.7 min). Chromatograms of the separated enantiomers of
( )‐Ptc‐NleP(OPh)2 on a Chirobiotic V2 column [eluent: Hx–(iPrOH–EtOH, 4:1), 95:5 (v/v); flow 0,5 mL/min]
namely, R.T., 12.935 and 13.734 minutes, respectively
(Figure 3). Similar, poor enantioseparability was
obserwed for ( )‐Ptc‐AlaP(OPh)2, ( )‐Ptc‐NvaP(OPh)2,
( )‐Ptc‐PglP(OPh)2, and ( )‐Ntc‐AlaP(OPh)2. This
enantioseparability improved greatly for the eluent con-
taining 4.5% of alcohol in a mixture with hexane
(Figure 4). Separation parameters of ( )‐ Ptc‐NleP(OPh)2
related to Figure 4 are listed in Table 5.
(Figure 4; Table 5) suggest the use of semipreparative
Chirobiotic V2 column for semipreparative separations
( )‐Ptc‐NleP(OPh)2 as a model derivative for the ( )‐
Atc‐AAP(OPh)2 family.
The separation was performed using Chirobiotic
V2 (Ch‐V2) column and Hexane‐(iPrOH‐EtOH; 4:1) in
ratio 95:5 (v/v) as a solvent. Injection volumes were
The eluent system Hx–(iPrOH–EtOH, 4:1), 95:5 (v/v)
with flow 0.4 mL/min, allowed separation of ( )‐Ptc‐
ValP(OPh)2 on the Chirolcel OD column. The chromato-
gram is presented on Figure 5. Separation parameters of
( )‐ Ptc‐ValP(OPh)2 are given in Table 6.
These excellent separation parameters, summarized in
Table 5, suggest the use of semipreparative Chiracel OD col-
umn for semipreparative separations of ( )‐Ptc‐ValP(OPh)2.
However, the same chromatographic conditions lead
to very poor separation of ( )‐Ntc‐PglP(OPh)2 α = 1.06
(Figure 6).
TABLE 7 Separation parameters of ( )‐Tcm[ValP(OPh)2]2 iso-
mers separated on semi‐preparative Chirobiotic V column (Figure 6)
Signal Relative
Area
Retention
Time, min
Isomer
Meso
11.8
16.5
6.98
7.78
Enantiomer E1
Enantiomer E2
35.9
35.9
9.82
15.16
TABLE 8 Optical characterisation of optically active samples of
Ptc‐NleP(OPh)2]2 isolated from the appropriate fractions collected
during separation of racemic Ptc‐NleP(OPh)2]2
3.2 | Semipreparative separations of ( )‐
Atc‐AAP(OPh)2
Fraction
α589
ee, %
Fast
+
99.8
The excellent separation parameters of ( )‐Ptc‐
Slow
−
40.4
NleP(OPh)2 obtained on analytical Chirobiotic V column

DRABOWICZ ET AL.
7
0.02 mL and flow 0.5 mL/min at ambient temperature
(Figures 7 and 8, Table 7). Chromatograms of separated
enantiomers of ( )‐Ptc‐NleP(OPh)2 are presented on
Figures 7 and 8.
Chromatographically separated fractions of the (+)
enantiomer of Ptc‐NleP(OPh)2 and the (−)‐enantiomer of
Ptc‐NleP(OPh)2 contaminated with of the (+)‐enantiomer
were collected, evaporated in vacuo, and dried over P4O10
TABLE 9 Chromatographic conditions applied for the enantio‐separation of ( )‐Tcm[ValP(OPh)2]2 isomers
Analytical Mode Semipreparative Mode
Column
Eluent
Flow, mL/min
Inj. vol., mL
Column
Eluent
Flow, mL/min
Inj. vol., mL
Ch‐V
C
0.7
0.002
Ch‐V2
C
1.0
0.02
Columns: Chirobiotic V (Ch‐V) and Chirobiotic V2 (Ch‐V2). Developing system C: MeCN–Et2O [80:20 (v/v)].
FIGURE 9 Chromatogram for the analytical enantioseparation of ( )‐Tcm[ValP(OPh)2]2 on a Chirobiotic V column [eluent: MeCN–Et2O
(80:20; v/v), flow 0,7 mL/min]
FIGURE 10 Chromatograms for the enantio‐separation of ( )‐Tcm[ValP(OPh)2]2 on a Chirobiotic V2 column [eluent: MeCN–Et2O (80:20;
v/v), flow 0,7 mL/min]. Chromatogram of the sample with the predominance of the meso form of Tcm[ValP(OPh)2]2

8
DRABOWICZ ET AL.
FIGURE 11 Chromatograms for
the enantio‐separation of ( )‐
Tcm[ValP(OPh)2]2 on a Chirobiotic V2
column [eluent: MeCN–Et2O (80:20; v/v),
flow 0,7 mL/min]. Chromatogram of the
faster moving enantiomer
[(‐)‐Tcm[ValP(OPh)2]2]
FIGURE 12 Chromatograms for the enantio‐separation of ( )‐Tcm[ValP(OPh)2]2 on a Chirobiotic V2 column [eluent: MeCN–Et2O (80:20;
v/v), flow 0,7 mL/min]. Chromatogram of the second (slower) enantiomer (+)‐Tcm[ValP(OPh)2]2
The applied conditions were modified for
semipreparative resolution using Chirobiotic V2 column.
The chromatograms of resoluted isomers, namely, the meso
isomer, the first eluted isomer E2, and the second eluted iso-
mer E2, are presented in Figures 10, 11, and 12, respectively.
Optical characterisation of the separated isomers of
Tcm[ValP(OPh)2]2 is given in Table 10.
TABLE 10 Optical characterisation of the separated isomers of
Tcm[ValP(OPh)2]2
Fractions
α589
ee, %
Meso form
0
0
Faster isomer
Slower isomer
−
90.8
99.4
+
in an evacuated dessicator. Their physicochemical
characterization is given in Table 8.
4 | CONCLUSION
Racemic ( )‐Atc‐AAP(OPh)2 and ( )‐Tcm[AAP(OPh)2]2
were analyzed by HPLC with chiral columns. The best ana-
lytical separations were obtained for ( )‐Ptc‐ValP(OPh)2,
( )‐Ptc‐LeuP(OPh)2, and ( )‐Tcm[ValP(OPh)2]2.
3.3 | Chromatographic separations of ( )‐
Tcm[AAP(OPh)2]2
Compounds
( )‐Ptc‐LeuP(OPh)2
and
( )‐
The optical resolution of compounds having the general
structure ( )‐Tcm[AAP(OPh)2]2was demonstrated using
( )‐Tcm[ValP(OPh)22, as a model derivative. Thus,
solutions of ( )‐Tcm[ValP(OPh)2]2 (20 mg) in chloro-
form‐methanol solution [10:1; 1 mL) were subjected for
the optical resolutions under chromatographic conditions,
summarized in Table 9. Chromatogram for the analytical
mode enantioseparation of ( )‐Tcm[ValP(OPh)2]2 is
presented in Figure 9.
Tcm[ValP(OPh)2]2 were subjected for enantioseparation on
semipreparative columns affording the corresponding enan-
tiomers, subsequently analyzed using chiralo‐optical method.
For the first time, efficient HPLC methods for the
analytical and semipreparative optical resolution of repre-
sentative N‐arylthiocarboylaminophosphonate derivatives
have been developed. The use of ternary mixtures of n‐
hexane/ethanol/chloroform as eluent and polysaccharide‐
based chiral stationary phases allowed good baseline

DRABOWICZ ET AL.
9
12. Kudzin ZH. Investigations in the domain of 1‐
aminoalkylphosphonic acids (Badania w dziedzinie kwasów 1‐
aminoalkanofosfonowych). WUŁ, Łódź. 1996;1‐110.
enantioseparations to be achieved at the analytical scale.
The analytical method was successfully scaled up to
semipreparative loadings, and about 60 to 70 mg of race-
mates, Atc‐AAP(OPh)2, was resolved per hour.
13. Kudzin ZH. Aminoalkanephosphonates. Six decades of explora-
tions. Prace Naukowe Akademii Częstochowskiej im.
Długosza; Chemia i Ochrona Środowiska. 2005;IX:29‐76.
J
ACKNOWLEDGMENTS
14. Kudzin ZH, Kudzin MH, Drabowicz J, Stevens C.
Aminophosphonic acids‐phosphorus analogues of natural
amino acids. 1: syntheses of α‐aminophosphonic acids. Curr
Org Chem. 2011;15:2015‐2071.
The authors sincerely thank the late Dr Jerzy Łuczak and
Łukasz Majtczak, MSc, for helping with chromatographic
experiments.
15. Kudzin ZH, Kudzin MH, Drabowicz J. Thioureidoal-
kylphosphonates in the synthesis of 1‐aminoalkylphosphonic
acids. The Ptc‐aminophosphonate method. ARKIVOC. 2011;
VI:227‐269.
CONFLICTS OF INTEREST
The authors declare no conflict of interest
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Aminophosphinic Acids. Chemistry and Biological Activity.
Chichester, New York, Weinheim, Brisbane, Singapore, Toronto:
John Wiley & Sons, Ltd.; 2000.
ORCID
Józef Drabowicz http://orcid.org/0000-0002-4899-5970
Marcin H. Kudzin http://orcid.org/0000-0003-1161-8343
Zbigniew H. Kudzin http://orcid.org/0000-0002-1497-7416
17. Chęcińska L, Małecka M, Olszak T, Kudzin ZH. O,O‐diphenyl 2‐
methyl‐1‐(3‐phenyl‐thioureido)‐propanephosphonate.
Crystallogr E. 2001;57:1213‐1218.
Acta
18. Chęcińska L, Sieroń L, Bukowska‐Strzyżewska M, Kudzin ZH,
Fabian L. Two derivatives of (N‐phenylthioureidoalkyl)
phosphonates. Acta Crystallogr C. 2003;59:046‐050.
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