Enantioselective synthesis of new chiral 2-aziridinyl phosphonates and studies of their biological activities

Article abstract of DOI:10.1016/j.tetasy.2017.01.003

A new series of chiral aziridinyl phosphonates has been synthesized and evaluated for antibacterial and antifungal activities. For the synthesis, a Gabriel-Cromwell reaction was used to form aziridinyl phosphonates in 52–83% yield. In order to evaluate antibacterial and antifungal activities, MIC values were measured. Although most of the compounds showed insignificant activity, two of them provided low to moderate antifungal activity.

Full text of DOI:10.1016/j.tetasy.2017.01.003

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of new chiral 2-aziridinyl phosphonates
and studies of their biological activities
b
a
c
c
Özdemir Dogan a, , Sıdıka Polat Çakır , Nurzhan Beksultanova , Nurten Altanlar , Duygu Sßimßsek ,
⇑
Hasan Karabıyık d
a Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
b Department of Chemical Engineering, Çanakkale Onsekiz Mart University, 17100 Çanakkale, Turkey
c Department of Pharmaceutical Microbiology, Ankara University, 06100 Ankara, Turkey
d Dokuz Eylül University, Department of Physics, 35160 Izmir, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of chiral aziridinyl phosphonates has been synthesized and evaluated for antibacterial and
antifungal activities. For the synthesis, a Gabriel-Cromwell reaction was used to form aziridinyl phospho-
nates in 52–83% yield. In order to evaluate antibacterial and antifungal activities, MIC values were mea-
sured. Although most of the compounds showed insignificant activity, two of them provided low to
moderate antifungal activity.
Received 17 November 2016
Revised 11 December 2016
Accepted 3 January 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
and biological activity results of newly synthesized chiral aziridi-
nyl phosphonates.
Aziridines are one of the most valuable three membered hetero-
cyclic ring systems in synthetic organic chemistry and medicinal
chemistry.1 They are the valuable building blocks for the synthesis
of many organic compounds such as amino acids, amino alcohols,
pyrrolidines, pyrroles, b-lactams, and oxazoles. The aziridine skele-
ton can also be found in several natural products.2 Research con-
cerning mechanistic studies,3 ring opening reactions with
different Lewis acids and nucleophiles,4 and also conversion of
aziridines to structurally interesting compounds5 are well docu-
mented in the literature. Aziridinyl phosphonates have attracted
increasing attention in recent years.6 They are the precursors of
2. Results and discussion
The synthesis of new chiral aziridinyl phosphonates was easily
accomplished by following our previously reported synthetic strat-
egy.6f This strategy starts with acetyl phosphonate, which was
easily obtained from triethylphosphite and acetyl chloride using
the Michaelis-Arbuzov reaction. The second step of the synthesis
was the conversion of acetyl phosphonate to
a-tosylated
vinylphosphonate 2. This conversion was easily achieved by
treatment of acetyl phosphonate with DBU and tosyl chloride. In
the final step, the reaction of tosylate 2 with chiral amine by
Gabriel-Cromwell reaction provided aziridinyl phosphonates as a
mixture of diastereomers as shown in Table 1.
a
-amino phosphonates that can be used as enzyme inhibitors,7
as haptens for catalytic antibodies,8 as antibacterial agents,9 and
herbicides.10 For the synthesis of these compounds, especially
asymmetric ones, several methods have been reported in the liter-
ature.11 Generally asymmetric aziridination reactions involve the
addition of nitrenes to alkenes, Gabriel–Cromwell reactions, and
carbene additions to imines. In these methods, either chiral sub-
strates or chiral catalysts have been used to induce chirality. In
continuation of our work on the synthesis of new aziridinyl com-
pounds as potential chiral ligands12 and organocatalysts13 for the
asymmetric synthesis of organic compounds, we have prepared a
new series of chiral aziridinyl phosphonates and studied their bio-
logical activities. Herein we report the synthesis, characterization,
The absolute configuration of compound 4b was determined by
opening the aziridine ring with HCl, which yielded aminophospho-
nate salt 15 as shown in Scheme 1. The relative stereochemistry
within aminophosphonate salt 15 was determined by single crystal
X-ray analysis (Fig. 1) and the absolute configuration was assigned
from the known configuration of the a
-methylbenzyl centre.14 The
configurational assignments of the other stereoisomers were made
by analogy.15
After the synthesis of new chiral aziridinyl phosphonates, we
decided to determine their antibacterial and antifungal activity. In
our previous study, which was mainly on the racemic aziridinyl
phosphonates, it was seen that some of the aziridinyl phosphonates
showed better antibacterial activity than the drug ampicillin.6f It
⇑
Corresponding author.
E-mail address: dogano@metu.edu.tr (Ö. Dogan).
http://dx.doi.org/10.1016/j.tetasy.2017.01.003
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Dogan, Ö;. et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.003

2
Ö. Dogan et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Table 1
Synthesis of chiral aziridinyl phosphonates
R*
N
O
P
R*
N
O
O
P
O
P
OEt
OEt
2
OEt
R*-N H2
DBU
TsCl
OEt
OEt
OEt
OEt
P
+
OEt
DBU
CH3CN, RT
H
H
OTs
O
Entry
1
Chiral amine (R⁄-NH2)
Aziridinyl phosphonatesa
de (%)
20
Me
Ph
NH2
Me
Ph
Me
Ph
O
O
P
H
OEt
OEt
OEt
OEt
N
N
3
+
P
H
4a,
49%
4b, 33%
Me
NH2
Me
O
P
Me
O
OEt
OEt
OEt
OEt
2
3
+
8
8
5
N
N
P
H
H
6a, 30%
6b, 35%
Me
NH2
Me
O
Me
O
+
+
OEt
OEt
OEt
N
N
P
P
OEt
H
H
7
8a
8b,
, 31%
Ph
36%
N
Ph
NH2
Ph
O
P
H
O
P
H
OEt
OEt
OEt
OEt
N
9
4
5
6
10a , 29%
Me
10b , 33%
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
O
O
+
OEt
OEt
OEt
OEt
11
NH2
N
N
28
P
P
H
H
12a , 20%
12b , 35%
Me
NH2
Me
O
P
Me
O
OEt
OEt
OEt
OEt
6
12
N
N
13
+
P
H
H
14a
14b
, 29%
, 23%
a
Isolated yields.
Cl
P
have showed low antibacterial activity against Escherichia coli and
Bacillus subtilis. None of the compounds showed any significant
activity against Staphylococcus aureus. Only compounds 4a, 4b
and 6a showed low antibacterial activity against Pseudomonas
aeruginosa and no other compounds showed any antibacterial
activity. Aziridinyl phosphonate 6b and 12b showed moderate to
low antifungal activity against Candida albicans with MIC values
Me
N
Ph
Ph
H
N
H
O
P
H
HCl (g)
ether
O
OEt
OEt
Me
Cl
OEt
OEt
4b
15
Scheme 1. Ring opening of aziridine by HCl.
of 12.5
lg/ml and 50 lg/ml, respectively.
3. Conclusion
was also found that the activity of aziridinyl phosphonates showed
some dependence on the group on the nitrogen. We decided to
study the antibacterial and antifungal activity of newly
synthesized compounds with different stereochemistries and
different substituents on the nitrogen. Accordingly the newly
synthesized compounds were tested against some bacteria and a
fungus to determine their minimum inhibitory concentration
(MIC) values. The MIC values obtained for aziridinyl
phosphonates (diastereomers of 4, 6, 8, 12, and 14) are listed in
Table 2 along with the reference antibiotics. All of the compounds
In conclusion, we have synthesized new chiral aziridinyl phos-
phonates in various yields from 40 to 82% and evaluated their
antibacterial and antifungal activities against S. aureus, E. coli,
B. subtilis, P. aeruginosa, and C. albicans. All of the tested aziridinyl
phosphonates exhibited low antibacterial activity against E. coli
and B. subtilis. In terms of antifungal activities, phosphonates 6b
and 12b displayed moderate to low activity against C. albicans,
respectively.
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Ö. Dogan et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
4.2. General procedure for the synthesis of aziridinyl
phosphonates
To a solution of 1-(diethoxyphosphoryl)vinyl 4-methylbenzene-
sulfonate 2 (1 equiv) in dry acetonitrile (around 1.9 M) was added
DBU (1.2 equiv) and chiral amine (1.2 equiv) at room temperature.
The resulting reaction mixture was stirred at this temperature for
approximately 3 days. After evaporation of acetonitrile under vac-
uum, the crude product was purified by column chromatography
on silica gel using a mixture of hexane and ethyl acetate as the
eluent.
4.2.1. Diethyl ((R)-1-((S)-1-phenylethyl)aziridin-2-yl)phospho-
nate 4a
Data are identical with those reported in the literature for ent-
4a.6f Colorless oil, [
a
]
D
20 = À45 (c 0.33, CH2Cl2). 1H NMR (CDCl3,
400 MHz): d 7.38–7.26 (m, 5H), 4.25–4.17 (m, 4H, AOCH2CH3),
2.47 (q, J = 6.5 Hz, 1H, ACHPh), 2.08 (dd, J = 8.9, 3.4 Hz, 1H), 1.67
(ddd, J = 19.4, 6.8, 3.6 Hz, 1H), 1.57 (t, J = 7.1 Hz, 1H), 1.47 (d,
J = 6.5 Hz, 3H, ACH3), 1.37 (t, J = 7.1 Hz, AOCH2CH3, 6H).
4.2.2. Diethyl ((S)-1-((S)-1-phenylethyl)aziridin-2-yl)phospho-
nate 4b
Data are identical with those reported in the literature ent-4b.6f
Colorless oil,
[
a
]
20 = À16 (c 0.66, CH2Cl2). 1H NMR (CDCl3,
D
Figure 1. X-ray structure of compound 15.
400 MHz): d 7.40–7.26, m, 5H), 3.96–3.70 (m, 4H, AOCH2CH3),
2.43 (q, J = 6.5 Hz, 1H, ACHPh), 2.31 (dd, J = 9.1, 2.8 Hz, 1H), 1.73
(t, J = 7.0 Hz, 1H), 1.57 (ddd, J = 19.1, 6.9, 3.6 Hz, 1H), 1.48 (d,
J = 6.6 Hz, 3H, ACH3), 1.19 (t, J = 7.0 Hz, AOCH2CH3, 3H), 1.10 (t,
J = 7.0 Hz, AOCH2CH3, 3H).
4. Experimental
4.1. General
4.2.3. Diethyl ((R)-1-((R)-1-cyclohexylethyl)aziridin-2-yl)phos-
phonate 6a
All chiral amines are commercially available and were used as
received from Sigma–Aldrich, unless otherwise stated. Column
chromatography was performed using 230–400-mesh silica gel.
1H, 13C, and 31P NMR spectra were reported on a Brucker Avance
DPX-400 instrument at 400, 100, and 162 MHz, respectively rela-
tive to TMS for 1H and 13C NMR and H3PO4 for 31P NMR. Optical
Colorless oil, [a]
21 = +38.1 (c 1.0, CHCl3), Rf = 0.35 (EtOAc). 1H
D
NMR (CDCl3, 400 MHz): d 4.19–4.09 (m, 4H, AOCH2CH3), 2.15
(dd, J = 3.5, 8.9 Hz, 1H), 1.82–1.65 (m, 5H), 1.61 (t, J = 6.9 Hz, 1H),
1.50–1.46 (m, 1H), 1.41 (ddd, J = 3.6, 6.7, 20.3 Hz, 1H), 1.33 (t,
J = 7.0 Hz, 6H, AOCH2CH3), 1.28–1.11 (m, 4H), 1.09 (d, J = 5.0 Hz,
3H, ACH3), 1.06–0.94 (m, 2H). 13C NMR (CDCl3, 100 MHz): d 71.3
(d, JC–P = 6.5 Hz, ACHCyclo), 62.6 (d, JC–P = 6.5 Hz, AOCH2CH3),
62.1 (d, JC–P = 6.4 Hz, AOCH2CH3), 43.8, 33.4 (d, JC–P = 5.5 Hz), 29.8
(d, JC–P = 219.3 Hz, ACHPO(OEt)2), 30.9, 30.1, 28.8, 26.5, 26.4,
17.1, 16.4 (t, JC–P = 5.9 Hz, AOCH2CH3, 2C). 31P NMR (CDCl3,
161 MHz): d 24.1. IR (cmÀ1): 2980, 2924, 2852, 1245, 1023, 964,
749. HRMS-EI (m/z): calculated for C14H28NO3P [M+H]: 290.1885
and found: 290.1885.
rotations were measured on
a Rudolph Research Analytical
Autopol III Polarimeter. An Agilent 6224 TOF-LC/MS instrument
was used for mass analyses. IR spectra were obtained by Bruker
Platinum ATR-IR instruments and are reported in cmÀ1. X-ray
diffraction data of aminophosphonate salt 15 were collected with
an Agilent XCalibur X-ray diffractometer with EOS CCD detector
using Mo-K
radiation (graphite crystal monochromator
a
k = 0.7107 Å) at the room temperature.
Table 2
Antibacterial activities of aziridinyl phosphonates
MIC values (lg/ml)
Compounds
S. aureus ATCC 25923
E. coli ATCC 25922
P. aeruginosa ATCC 27853
B. subtilis ATCC 6633
C. albicans ATCC 10231
4a
4b
6a
6b
8a
8b
12a
12b
14a
14b
Sultamicillin
Ampicillin
Fluconazole
Ciprofloxacin
P100
P100
P100
P100
P100
P100
P100
P100
P100
P100
0.78
100
100
100
100
100
100
100
100
100
100
—
100
100
100
100
100
100
100
100
100
100
100
100
100
0.78
50
100
100
100
12.5
100
100
100
50
100
100
—
—
0.78
—
P100
P100
P100
P100
P100
P100
P100
—
1.56
—
0.19
—
—
0.09
—
—
—
—
0.09
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4
Ö. Dogan et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
4.2.4. Diethyl ((S)-1-((R)-1-cyclohexylethyl)aziridin-2-yl)phos-
4.2.8. Diethyl ((S)-1-((R)-1-phenylbutyl)aziridin-2-yl)phospho-
phonate 6b
nate 10b
Colorless oil. [
a]
21 = À21.6 (c 1.0, CHCl3), Rf = 0.22 (EtOAc). 1H
Colorless oil, 33%. [a]
17 = +5.5 (c 1.0, CHCl3), Rf = 0.29 (EtOAc).
D
D
NMR (CDCl3, 400 MHz): d 4.20–4.10 (m, 4H, AOCH2CH3), 2.10
(dd, J = 3.2, 9.0 Hz, 1H), 1.93–1.86 (m, 1H), 1.79–1.71 (m, 2H),
1.70–1.65 (m, 1H), 1.59–1.54 (m, 2H), 1.53–1.47 (m, 2H), 1.34 (t,
J = 7.1 Hz, 6H, AOCH2CH3), 1.28–1.07 (m, 6H), 1.05 (d, J = 6.3 Hz,
3H, ACH3). 13C NMR (CDCl3, 100 MHz): d 71.3 (d, JC–P = 7.0,
ACHCyclo), 62.0 (d, JC–P = 5.0 Hz, AOCH2CH3), 61.6 (d,
JC–P = 6.2 Hz, AOCH2CH3), 42.6, 31.9 (d, JC–P = 219.0 Hz, ACHPO
(OEt)2), 30.4, 29.8, 27.0, 26.5, 26.4, 26.2, 16.2 (d, JC–P = 6.1 Hz,
AOCH2CH3), 16.1 (d, JC–P = 6.4 Hz, AOCH2CH3), 15.5 (ACH3). 31P
NMR (CDCl3, 161 MHz): d 23.7. IR (cmÀ1): 2979, 2923, 2852,
1244, 1022, 960, 780. HRMS-EI (m/z): calculated for C14H28NO3P
[M+H]: 290.1885 and found: 290.1889.
1H NMR (CDCl3, 400 MHz): d 7.35–7.24 (m, 5H), 3.93–3.69 (m,
4H, AOCH2CH3), 2.32 (dd, J = 4.1, 9.1 Hz, 1H), 2.25 (t, J = 6.8 Hz,
1H), 1.90–1.84 (m, 2H), 1.76 (t, J = 6.8 Hz 1H), 1.51 (ddd, J = 3.7,
6.9, 19.3 Hz, 1H), 1.30–1.21 (m, 2H), 1.17 (t, J = 7.0 Hz, 3H, AOCH2-
CH3), 1.10 (t, J = 7.0 Hz, 3H, AOCH2CH3), 0.86 (t, J = 7.3 Hz, 3H,
ACH3). 13C NMR (CDCl3, 100 MHz): d 142.1, 128.2 (2ÂCH), 127.9
(2ÂCH), 127.4, 76.5 (d, J = 6.6 Hz, ACHPh), 62.4 (d, J = 6.3 Hz,
AOCH2CH3), 61.7 (d, J = 6.0 Hz, AOCH2CH3), 39.3, 33.0 (d,
J = 5.2 Hz), 30.3 (d, JC–P = 215.6 Hz, ACHPO(OEt)2), 29.7, 19.4, 16.2
(d, JC–P = 6.2 Hz, AOCH2CH3, 2C), 14.0. 31P NMR (CDCl3, 161 MHz):
d 23.0. IR (cmÀ1): 2958, 2931, 1246, 1022, 961, 735, 700. HRMS-
EI (m/z): calculated for C16H26NO3P [M+H]: 312.1728 and found:
312.1732.
4.2.5. Diethyl ((R)-1-((R)-1-(naphthalen-1-yl)ethyl)aziridin-2-yl)
phosphonate 8a
4.2.9. Diethyl ((R)-1-((R)-3,3-dimethylbutan-2-yl)aziridin-2-yl)
Colorless oil. [a]
21 = +70.0 (c 1.0, CHCl3), Rf = 0.51 (EtOAc). 1H
D
phosphonate 12a
Colorless oil, yield: 20%. [a]
34 = +29.5 (c 1.0, CHCl3), Rf = 0.41
D
NMR (CDCl3, 400 MHz): d 7.99 (d, J = 5.5 Hz, 1H), 7.91–7.85 (m,
2H), 7.76 (d, J = 8.2 Hz, 1H), 7.50–7.45 (m, 3H), 4.29–4.20 (m, 4H,
AOCH2CH3), 3.21 (q, J = 6.4 Hz, 1H), 2.15 (dd, J = 3.5, 9.0 Hz, 1H),
1.82 (ddd, J = 3.6, 6.8, 19.5 Hz, 1H), 1.62 (d, J = 6.5 Hz, 3H, ACH3),
1.54 (t, J = 7.1 Hz, 1H), 1.40 (t, J = 7.0 Hz, AOCH2CH3, 6H). 13C
NMR (CDCl3, 100 MHz): d 139.7, 133.6, 130.4, 128.8, 127.4, 125.7,
125.6, 125.2, 123.9, 122.9, 77.2 (ACHNaphthyl), 62.6 (d,
JC–P = 6.5 Hz, AOCH2CH3), 62.3 (d, JC–P = 6.2 Hz, AOCH2CH3), 32.8
(d, JC–P = 218.0 Hz, ACHPO(OEt)2), 31.7 (d, JC–P = 5.3 Hz, ACH2N),
22.9 (ACH3), 16.40 (d, JC–P = 5.9 Hz, AOCH2CH3), 16.36 (d,
JC–P = 5.9 Hz, AOCH2CH3). 31P NMR (CDCl3, 161 MHz): d 23.1. IR
(cmÀ1): 2983, 1242, 1022, 965, 747. HRMS-EI (m/z): calculated
for C18H24NO3P [M+H]: 334.1572 and found: 334.1572.
(EtOAc). 1H NMR (CDCl3, 400 MHz): d 4.11–4.05 (m, 4H, AOCH2-
CH3), 2.12 (dd, J = 3.5, 8.9 Hz, 1H), 1.57 (t, J = 6.8 Hz, 1H), 1.36
(ddd, J = 3.5, 6.5, 20.8 Hz 1H), 1.24 (t, J = 7.0 Hz, 6H, AOCH2CH3),
1.07 (t, J = 6.6 Hz, 1H), 0.99 (d, J = 6.4 Hz, 3H, ACH3), 0.87 (s, 9H,
AC(CH3)3). 13C NMR (CDCl3, 100 MHz): d 74.2 (d, JC–P = 6.3 Hz,
ACHt-butyl), 62.5 (d, JC–P = 6.5 Hz, AOCH2CH3), 62.2 (d,
JC–P = 6.2 Hz, AOCH2CH3), 35.6 (d, JC–P = 5.7 Hz, ACH2N), 35.1 (AC
(CH3)3), 28.6 (d, JC–P = 219.9 Hz, ACHPO(OEt)2), 26.8 (AC(CH3)3),
16.3 (t, JC–P = 5.6 Hz, 2C, AOCH2CH3), 15.5 (ACH3). 31P NMR (CDCl3,
161 MHz): d 24.1. IR (cmÀ1): 2976, 1245, 1032, 964, 751, 544.
HRMS-EI (m/z): calculated for C12H26NO3P [M+H]: 264.1728 and
found: 264.1736.
4.2.6. Diethyl ((S)-1-((R)-1-(naphthalen-1-yl)ethyl)aziridin-2-yl)
4.2.10. Diethyl ((S)-1-((R)-3,3-dimethylbutan-2-yl)aziridin-2-yl)
phosphonate 8b
phosphonate 12b
Colorless oil. [a]
21 = +15.0 (c 1.0, CHCl3), Rf = 0.29 (EtOAc). 1H
D
Colorless oil, yield: 35%. [
a]
34 = À132.8 (c 1.0, CHCl3), Rf = 0.35
D
NMR (CDCl3, 400 MHz): d 8.10 (br s, 1H), 7.87–7.85 (m, 2H), 7.76
(d, J = 8.1 Hz, 1H), 7.50–7.45 (m, 3H), 3.99–3.84 (m, 4H, OCH2CH3),
3.19 (bs, 1H), 2.41 (dd, J = 3.6, 9.1 Hz, 1H), 1.84 (t, J = 7.0 Hz, 1H),
1.62 (d, J = 6.5 Hz, ACH3, 3H), 1.55 (ddd, J = 3.6, 6.9, 19.3 Hz, 1H),
1.16 (t, J = 7.0 Hz, AOCH2CH3, 3H), 1.08 (t, J = 7.2 Hz, AOCH2CH3,
3H). 13C NMR (CDCl3, 100 MHz): d 139.1, 133.8, 130.7, 128.9,
127.7, 125.7, 125.5, 125.3, 124.8, 123.3, 77.2 (ACHNaphthyl),
62.3 (d, JC–P = 6.5 Hz, AOCH2CH3), 61.8 (d, JC–P = 6.1 Hz, AOCH2CH3),
31.6 (d, JC–P = 216.4 Hz, ACHPO(OEt)2), 32.3 (d, JC–P = 5.1 Hz, ACH2-
N), 22.8 (ACH3), 16.2 (d, JC–P = 6.4 Hz, 2C, AOCH2CH3). 31P NMR
(CDCl3, 161 MHz): d 22.9. IR (cmÀ1) 2981, 1243, 1023, 951, 777,
748. HRMS-EI (m/z): calculated for C18H24NO3P [M+H]: 334.1572
and found: 334.1578.
(EtOAc). 1H NMR (CDCl3, 400 MHz): 4.19–4.11 (m, 4H, AOCH2CH3),
2.01 (dd, J = 3.2, 9.5 Hz, 1H), 1.73 (ddd, J = 3.4, 6.8, 20.9 Hz, 1H),
1.44 (t, J = 7.1 Hz, 1H), 1.34 (t, J = 7.0 Hz, 3H, AOCH2CH3), 1.33 (t,
J = 7.0 Hz, 3H, AOCH2CH3), 1.17 (q, J = 6.3 Hz, 1H), 1.05 (d,
J = 6.5 Hz, 3H, ACH3), 0.99 (s, 9H, AC(CH3)3). 13C NMR (CDCl3,
100 MHz):
d
74.5 (d, JC–P = 7.1 Hz, ACHt-butyl), 62.2 (d,
JC–P = 6.3 Hz, AOCH2CH3), 62.1 (d, JC–P = 6.6 Hz, AOCH2CH3), 34.9
(d, JC–P = 217.0 Hz, CHPO(OEt)2), 34.8 (AC(CH3)3), 28.6 (d,
JC–P = 5.5 Hz, ACH2N), 26.9 (AC(CH3)3, 3C), 16.3 (t, JC–P = 5.8 Hz,
AOCH2CH3, 2C), 15.8 (ACH3). 31P NMR (CDCl3, 161 MHz): d 19.2.
IR (cmÀ1): 2976, 1243, 1022, 960, 772, 543. HRMS-EI (m/z): calcu-
lated for C12H26NO3P [M+H]: 264.1728 and found: 264.1732.
4.2.11. Diethyl ((R)-1-((R)-1-(naphthalen-2-yl)ethyl)aziridin-2-
4.2.7. Diethyl ((R)-1-((R)-1-phenylbutyl)aziridin-2-yl)phospho-
yl)phosphonate 14a
nate 10a
Colorless oil, 29%. [a]
34 = +51.2 (c 1.0, CHCl3), Rf = 0.38 (EtOAc).
D
Colorless oil, 29%. [a]
18 = +34.8 (c 1.0, CHCl3), Rf = 0.46 (EtOAc).
D
1H NMR (CDCl3, 400 MHz): d 7.83–7.05 (m, 4H), 7.50 (dd, J = 1.4,
8.6 Hz, 1H), 7.48–7.45 (m, 2H), 4.28–4.19 (m, 4H, AOCH2CH3),
2.61 (q, J = 6.4 Hz, 1H), 2.11 (dd, J = 3.5, 9.0 Hz, 1H), 1.74 (ddd,
J = 3.6, 6.8, 19.3 Hz, 1H), 1.62 (t, J = 7.2 Hz, 1H), 1.55 (d, J = 6.5 Hz,
ACH3, 3H), 1.39 (t, J = 7.1 Hz, 6H, AOCH2CH3). 13C NMR (CDCl3,
100 MHz): d 141.1, 133.1, 132.6, 127.8, 127.6, 127.4, 125.8, 125.5,
125.0, 124.9, 70.8 (d, JC–P = 7.0 Hz, ACHNaphthyl), 62.6 (d,
JC–P = 6.5 Hz, AOCH2CH3), 62.2 (d, JC–P = 6.3 Hz, AOCH2CH3), 32.4
(d, JC–P = 217.7 Hz, 2C, ACHPO(OEt)2), 31.4 (d, JC–P = 5.3 Hz, ACH2N),
23.2 (ACH3), 16.3 (d, JC–P = 6.0 Hz, AOCH2CH3). 31P NMR (CDCl3,
161 MHz): d 22.8. IR (cmÀ1): 2978, 1240, 1020, 964, 943, 748,
537, 478. HRMS-EI (m/z): calculated for C18H24NO3P [M+H]:
334.1572 and found: 334.1580.
1H NMR (CDCl3, 400 MHz): d 7.24–7.23 (m, 4H), 7.19–7.17 (m,
1H), 4.17–4.08 (m, 4H, AOCH2CH3), 2.21 (dd, J = 4.8, 8.1 Hz, 1H),
1.91 (dd, J = 3.4, 8.9 Hz, 1H), 1.85–1.69 (m, 2H), 1.63 (ddd, J = 3.6,
6.8, 19.8 Hz, 1H), 1.43 (t, J = 7.1 Hz, 1H), 1.29 (t, J = 7.0 Hz, 6H,
AOCH2CH3), 1.18–1.09 (m, 2H), 0.78 (t, J = 7.3 Hz, 3H, ACH3). 13C
NMR (CDCl3, 100 MHz): d 142.5, 128.1 (2xCH), 127.5 (2ÂCH),
127.2, 75.9 (d, J = 7.2 Hz, ACHPh), 62.6 (d, J = 6.6 Hz, AOCH2CH3),
62.4 (d, J = 6.2 Hz, AOCH2CH3), 39.5, 33.2 (d, JC–P = 217.7 Hz,
ACHPO(OEt)2), 30.9 (d, J = 5.5 Hz), 18.8, 16.44 (d, JC–P = 5.9 Hz,
AOCH2CH3), 16.40 (d, JC–P = 5.9 Hz, AOCH2CH3), 14.0. 31P NMR
(CDCl3, 161 MHz): d 23.1. IR (cmÀ1): 2958, 2931, 1244, 1021,
962, 735, 700. HRMS-EI (m/z): calculated for C16H26NO3P [M+H]:
312.1728 and found: 312.1732.
Please cite this article in press as: Dogan, Ö;. et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.003

Ö. Dogan et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
4.2.12. Diethyl ((S)-1-((R)-1-(naphthalen-2-yl)ethyl)aziridin-2-
The cultures were obtained from Mueller-Hinton Broth (Difco)
for all the bacterial strains after 24 h of incubation at 37 °C. Candida
albicans was maintained in Sabouraud Dextrose Broth (Difco) after
incubation for 24 h at 25 °C. Testing was carried out in Mueller-
Hinton broth and Sabouraud Dextrose Broth (Difco) and the 2-fold
serial dilution technique was applied.
Isolated colonies from fresh overnight cultures were inoculated
into MHB and SDB media to turbidity comparable to that of 0.5
McFarland standards. Then, 0.1 ml of these bacterial suspensions
were transferred into tubes containing 15 mL of MHB and SDB.
These suspensions were used in experiments. A set of tubes con-
taining only inoculated broth was used as controls. After incuba-
tion for 24 h at 37 °C for the antibacterial assay and for 48 h at
25 °C for the antifungal assay, the last tube with no growth of
microorganism and/or yeast was recorded to represent the MIC
yl)phosphonate 14b
Yellow oil, 39%. [a]
34 = +55.5 (c 1.0, CHCl3), Rf = 0.23 (EtOAc). 1H
D
NMR (CDCl3, 400 MHz): d 7.68–7.65 (m, 4H), 7.42 (d, J = 8.6 Hz,
1H), 7.33–7.27 (m, 2H), 3.81–3.62 (m, 3H, AOCH2CH3), 3.58–3.48
(m, 1H, AOCH2CH3), 2.38 (q, J = 6.2 Hz, 1H), 2.20 (dd, J = 2.6,
9.1 Hz, 1H), 1.60 (t, J = 7.0 Hz, 1H), 1.45 (ddd, J = 3.6, 6.8, 19.1 Hz,
1H), 1.39 (d, J = 6.5 Hz, ACH3, 3H), 0.96 (t, J = 7.1 Hz, 3H, AOCH2-
CH3), 0.77 (t, J = 7.0 Hz, 3H, AOCH2CH3). 13C NMR (CDCl3,
100 MHz): d 140.3, 132.7, 132.4, 127.4, 127.2, 127.0, 125.4, 125.4,
125.1, 124.8, 70.7 (d, JC–P = 6.9 Hz, ACHNaphthyl), 61.7 (d,
JC–P = 6.3 Hz, AOCH2CH3), 61.1 (d, JC–P = 6.1 Hz, AOCH2CH3), 31.5
(d, JC–P = 5.1 Hz, ACH2N), 30.7 (d, JC–P = 215.5 Hz, ACHPO(OEt)2),
22.3 (ACH3), 15.6 (d, JC–P = 6.3 Hz, AOCH2CH3), 15.4 (d,
JC–P = 6.2 Hz, AOCH2CH3). 31P NMR (CDCl3, 161 MHz): d 22.8. IR
(cmÀ1): 2980, 1244, 1023, 962, 789, 745, 531, 478. HRMS-EI
(m/z): calculated for C18H24NO3P [M+H]: 334.1572 and found:
334.1582.
(lg/ml). All tests were carried out in duplicate as a control. Tests
were carried out according to CLSI recommendations.16
4.4. X-ray crystallographic study
4.2.13. (S)-Diethyl 1-((S)-1-phenylethylamino)-2-chloroethyl-
phosphonate HCl 15
A
suitable
sample
of
aminophosphonate
salt
15
(0.375 Â 0.322 Â 0.264 mm3) was chosen for the crystallographic
study and then mounted on a glass fiber for collection of X-ray
data. The systematic absences and intensity symmetries indicated
that the salt 15, (C14H24NO3PCl)+ÁClÀ, crystallizes in orthorhombic
chiral space group P212121. The data collection, cell refinement
and data reduction was performed using CrysAlisPro.17 Cell param-
eters were determined with the aid of 1538 reflections in the range
of [4.117° 6 h 6 25.01°]. A total of 4084 reflections within the h
range of [3.595° 6 h 6 25.678°] was collected in the rotation mode.
The structure was solved by direct methods (SHELXS-97)18 and
refined (on F2) by full matrix least-squares (SHELXL-2016/4).19
All non-H atoms were refined anisotropically. Disorder refinement
models were applied to one of ethyl group (C1 and C2) and atom
C3 in the other ethyl group of diethyl phosphonate fragment with
the aid of SUMP instruction in order to assign independently site
occupancy factors (s.o.f.s) to the disordered atoms. After final
refinement cycle, s.o.f.s for C1A/C1B and C2A/C2B were obtained
as 0.60(1)/0.40(1), while respective s.o.f.s for C3A/C3B were
obtained as 0.730(9)/0.270(8). All H atoms except for those linked
to the asymmetric C atoms (C6 and C8) and atom C4 were placed in
their calculated positions (CAH = 0.93 Å for aromatic CH, 0.96 Å for
methyl CH, 0.97 Å for methylene CH and NAH = 0.89 Å for NH2)
and were refined by the riding model with Uiso(H) set to 1.2–
1.5 Ueq(C or N). H atoms of stereogenic C atoms were located to dif-
ference Fourier map. SADI restraints were used to model wholly
disordered ethyl fragment. Similar Uij (SIMU) restraint was also
applied to the atom pairs of C4/C3A and C4/C3B. Equal Uij con-
straints (EADP) were used for C1B and C2B. Using 3018 indepen-
dent reflections (Rint = 0.018), final refinement cycle was
converged to R1 = 0.0442 for 232 parameters (2518 observed
reflections), to wR2 = 0.0911 (all independent reflections) and
GooF(S) = 1.056.
Compound 4b was dissolved in dry diethyl ether (6 ml) at room
temperature. HCl gas [generated by the dropwise addition of HCl
(37%, 2 ml) over sulfuric acid (98%, 2 ml)] was passed through the
solution for 15 minutes where an oily layer was formed. The reac-
tion flask was then dipped into an ice bath and scratched with a glass
rod to obtain compound 15 as a white solid. The solvent was then
evaporated and the white solid was recrystallized from hexane–
ethyl acetate (1:1) for X-ray analysis. White crystals (84% yield),
mp:119.4 °C. [
a
]
D
22 = À16 (c 1.0, CHCl3), Rf = 0.67 (EtOAc). 1H NMR
(CDCl3, 400 MHz): d 7.67 (d, J = 6.9 Hz, 2H), 7.56–7.33 (m, 3H),
4.87 (q, J = 6.8 Hz, 1H, ACHPh), 4.47 (td, J = 6.7, 12.2 Hz, 1H, ACH2Cl),
4.43–4.13 (m, 4H, AOCH2CH3), 3.98 (td, J = 6.4, 12.4 Hz, 1H, ACH2Cl),
3.62 (dt, J = 5.9, 17.5 Hz, 1H, ACHP(OEt)2), 1.96 (d, J = 6.8 Hz, 3H,
ACH3), 1.38 (t, J = 7.0 Hz, 3H, AOCH2CH3), 1.36 (t, J = 7.0 Hz, 3H,
AOCH2CH3). 13C NMR (CDCl3, 100 MHz): d 136.0, 129.7, 129.3
(2ÂCH), 128.6 (2ÂCH), 64.7 (d, JC–P = 6.8 Hz, AOCH2CH3), 64.3
(d, JC–P = 6.9 Hz, AOCH2CH3), 60.3 (d, JC–P = 4.4 Hz, ACH2Cl), 54.4
(d, JC–P = 149.9 Hz, ACHPO(OEt)2), 39.4 ACHPh), 20.3 (ACH3), 16.4
(d, JC–P = 5.7 Hz, AOCH2CH3), 16.3 (d, JC–P = 5.7 Hz, AOCH2CH3). 31P
NMR (CDCl3, 161 MHz): d 16.7. IR (cmÀ1): 3064, 2981, 2187, 2125,
2013, 1248, 1224, 993, 703. HRMS-EI (m/z): calculated for
C
14H24Cl2NO3P [M+]: 355.0871 and found: 355.0866.
4.3. Antibacterial and antifungal assays
In antibacterial and antifungal assays, the compounds and the
standards were dissolved in 12.5% DMSO at concentrations of
200
in the test medium were prepared at the required quantities of
200, 100, 50, 25, 12.5, 6.25, 3.12, 1.56 and 0.78 g/ml concentra-
lg/ml. Further dilutions of the compounds and standard drugs
l
tions with Mueller-Hinton Broth and Sabouraud Dextrose Broth.
The minimum inhibitory concentrations (MIC) were determined
using the 2-fold serial dilution technique.
Acknowledgments
A control test was also performed containing inoculated broth
supplemented with only DMSO at the same dilutions as those used
in our experiments and this was found to be inactive in the culture
medium. All the compounds were tested for their in vitro growth
inhibitory activity against Escherichia coli ATCC 25922, Staphylococ-
cus aureus ATCC 25923, Pseudomonas aeruginosa ATCC 27853,
Bacillus subtilis ATCC 6633 and Candida albicans ATCC 10231
strains. The microorganisms used in this study were obtained from
the culture collection of the Ankara University Faculty of Pharmacy
Pharmaceutical Microbiology Department. Sultamicillin, ampi-
cillin, fluconazole and ciprofloxacin were used as control drugs.
We thank the Scientific and Technological Research Council of
Turkey (TUBITAK, Grant No. 114Z161) and Middle East Technical
University (METU) for the financial support.
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