Synthesis and in vitro antioxidant evaluation of new bis(α-aminoalkyl)phosphinic acid derivatives

Article abstract of DOI:10.1080/10426507.2016.1192620

Diamines were added to arylaldehydes in ethanol, which resulted in corresponding diimines. Novel bis-1-aminophosphinic acid compounds were synthesized through the interaction of diimines and hypophosphorous acid. The new compounds were characterized by elemental analyses, FT-IR and¹H,¹³C and³¹P NMR techniques. The in vitro antioxidant activity of the newly synthesized compounds were measured and found to exhibit significantly higher antioxidant activity than the standard.

Full text of DOI:10.1080/10426507.2016.1192620

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis and in vitro antioxidant evaluation of
new bis(α-aminoalkyl)phosphinic acid derivatives
Kamiran Sarac, Cahit Orek, Ahmet Cetin, Taner Dastan, Pelin Koparir, Sevgi
Durna Dastan & Metin Koparir
To cite this article: Kamiran Sarac, Cahit Orek, Ahmet Cetin, Taner Dastan, Pelin Koparir, Sevgi
Durna Dastan & Metin Koparir (2016): Synthesis and in vitro antioxidant evaluation of new
bis(α-aminoalkyl)phosphinic acid derivatives, Phosphorus, Sulfur, and Silicon and the Related
Elements, DOI: 10.1080/10426507.2016.1192620
To link to this article: http://dx.doi.org/10.1080/10426507.2016.1192620
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May 2016.
Published online: 23 May 2016.
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Synthesis and in vitro antioxidant evaluation of new bis(α-aminoalkyl)phosphinic acid
derivatives
Kamiran Saraca, Cahit Orekb, Ahmet Cetinc, Taner Dastanc, Pelin Koparird*, Sevgi Durna
Dastane and Metin Koparirb
a
Bitlis Eren University, Faculty of Architecture Engineering, Department of Metallurgy and
Material Engineering, 43400, Bitlis, Turkey
b Firat University, Faculty of Science, Department of Chemistry, 23119 Elazığ, Turkey
c
Department of Chemistry, Faculty of Arts and Science, Bingol University, 12000, Bingol,
Turkey
d Department of Chemistry, Forensic Medicine Institute, TR-4400 Malatya, Turkey
e
Department of Zootechnical and Animal Nutrition, Faculty of Veterinary, Cumhuriyet
University, 58140, Sivas, Turkey

Address correspondence to Pelin Koparir, Department of Chemistry, Forensic Medicine
Institute, TR-44000, Malatya, Turkey. E-mail: mpelin23@hotmail.com
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Abstract
Diamines were added to arylaldehydes in ethanol, which resulted in corresponding diimines.
Novel bis-1-aminophosphinic acid compounds were synthesized through the interaction of
diimines and hypophosphorous acid. The new compounds were characterized by elemental
1
13
31
analyses, FT-IR and H, C and P NMR techniques. The in vitro antioxidant activity of the
newly synthesized compounds were measured and found to exhibit significantly higher
antioxidant activity than the standard.
Keywords
Aldehydes; Amines; 1-Aminophosphinic acids; Antioxidant activity
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INTRODUCTION
It is well known that amino acids are the main components of various proteins and that they
generally play an important physiological role in life process. 1-aminophosphinic acids are
phosphorus analogues of natural amino acids and are selective inhibitors of various proteolytic
enzymes, particularly metallo-proteases.1--3 For this reason, aminophosphinic acids have been
researched and developed as potential antibacterial, antitumor and antivirotic materials in recent
years.4--6 Much consideration has been given to aminophosphinic acid ligands and their
complexes because of their novel structures and properties.7--13 Aminophosphonic acids are also
found as constituents of natural products.14 In contrast to the widely studied 1-aminophosphonic
acid derivatives,15--18 relatively few papers have reported the chemistry of α-aminophosphinic
acid derivatives.

•
Reactive oxygen species (ROS) such as O2 , H2O2 and OH are generated in cells through
aerobic metabolic processes or as a result of interaction with exogenous agents. Low ROS levels
are essential for proper cell function, but excess levels lead to ‘oxidative stress’, which has been
linked to the progression of ageing and many human diseases, e.g. neurogenerative,
cardiovascular and cancer. Superoxide dismutases (SODs), catalase (CAT) and glutathione
peroxidase (GPx) are enzymes which act as a primary cellular defence system against oxidative
damage in living organisms. Organophosphorus compounds and P-heterocycles, in particular,
have been recognized as antioxidant drugs.19,20 Their mechanism and structure activity
relationships (SAR) have been extensively studied.21 Depending on their structure and
scavenging properties, phosphites and phosphonates may act as both primary and secondary
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antioxidants. In general, phosphites are considered to be hydroperoxide decomposing (secondary
antioxidants), but certain aryl phosphites should also be capable of acting as radical chain-
terminating (primary antioxidants) by trapping peroxyl radicals to produce aroxyl radicals.
Recent studies have elucidated reaction modes and the relationship between structure, reaction
mechanism and antioxidant activity.20,21
Over the past several years, our laboratories have reported the synthesis of 1-amino-H-
phosphinic acids.22,23 We have reported the synthesis and in vitro antimicrobial activity of novel
aminophosphinic acids containing cyclobutane and 1.3-thiazole. Building on previous studies,
we have prepared a series of derivatives of new α-aminophosphinic acids (Figure 1). In view of
the importance of phosphinic acid derivatives, this study’s goal was to find new biologically
active molecules. Here we report a new series of bis-1-amino-H-phosphinic acids and a
preliminary biological study of their antioxidative activity.
RESULTS AND DISCUSSION
Chemistry
Diimines are good precursors for synthesizing numerous organic compounds, especially
heterocyclic compounds.24,25 These easily accessible precursors can be produced by reacting
aromatic aldehydes in ammonia.
Schiff bases 3a--i were prepared following the published procedure22,23 by condensing the
corresponding diamines (1) with arylaldehyde (2) in ethanol at room temperature. The
corresponding imines were obtained in quantitative yields. The preparation of bis-
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aminophosphinic acids 4a--h was performed following Baylis et al.26 Reactions were carried out
in boiling ethanol for 24 h, after which mixtures were left overnight to stir at room temperature
(Figure 1).
Because two stereogenic carbons bonded to a phosphorus atom, and due to the prototopic
transfer of the acidic proton between the phosphoryl (P = O) and acidic (P--OH) sites, these
compounds exist as two diastereomeric forms: one meso-compound (R*, S*-4) and one racemic
pair (S*, S* or R*, R*-4), as shown in Figure 2.
The structures of 4a--h were determined by spectroscopy (1H, 13C and 31P NMR and FT-IR)
and by comparison to data in the literature of similar compounds.26--28
1
The H NMR spectra of 4a--h showed characteristic doublets at δ 6.5--7.0 ppm with
31
JP−H≈520 Hz constants, responsible for the P-H coupling. The P NMR spectrum exhibited two
major peaks at δ 28.6 and 24.4 due to the 4g diastereoisomers. In the infrared (IR) spectrum, the
most characteristic absorptions were at 3461--3533 cm−1 (OH), 3270--3309 cm−1 (NH), 1163--
1182 cm−1 (P = O), 1010--1080 cm−1 (P-O) and 2307--2390 cm−1 (P-H).
The proposed mechanism of formation of 4a-h is illustrated in Figure 3. The addition of
hypophosphorous acid to the azomethine bond of Schiff bases 3a--i led to the formation of meso-
compounds and racemic pairs.
Antioxidant Activity
All phosphinic acid derivatives 4a--h and standards were prepared at a range of
concentrations from 50 to 500 µg/mL. Table S 1 (Supplemental Materials) shows the results of
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antioxidant activity. Various methods were used to compare the antioxidant activity of the new
compounds against the standards. Experimental details are given in the supplemental materials
available online.
Hydroxyl radical (•OH) scavenging activity.
All compounds, BHT and ascorbic acid standards showed similar hydroxyl radical
scavenging activity. Nonetheless, compounds 4c and 4f exhibited the highest values. The
hydroxyl radical (•OH) scavenging activity of test compounds were in the following order:
ascorbic acid > BHT > 4c > 4f > 4h > 4g > 4d > 4a > 4e > 4b (Table 1).
Superoxide radical scavenging activity
Superoxide anions are oxygen-centred radicals and indicators of active free radicals with the
potential of reacting with biological macromolecules and thus causing tissue damage.29 All
compounds showed nearly equal activity levels. Compounds 4c, 4e and 4f exhibited the greatest
values, which were higher than α-tocopherol. Compound 4b exhibited the lowest activity. The
superoxide radical scavenging activity of the standards and test compounds were in the following
order: BHT > ascorbic acid > 4c > 4e > 4f > α-tocopherol > 4d > 4a > 4h > 4g > 4b (Table 1).
Diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity
The power of an antioxidant to transfer one electron to reduce a compound may be a
significant indicator of potential antioxidant activity.30 The ability to scavenge stable DPPH
radicals is a widely preferred and important method of evaluating antioxidant activity.31 In this
study, scavenging DPPH radicals was variable. Compound 4a exhibited the lowest activity,
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while compounds 4e and 4g had the greatest values. Scavenging efficiency on DPPH radicals
was in following order: ascorbic acid > 4e > 4g > 4h > 4b > BHT > 4c > 4f > 4d > 4a (Table 1).
Metal chelating activity
Chelating reactives are useful as secondary antioxidants as they reduce redox potential and
thus stabilize a metal ion’s oxidized form. Ferrozine can form complexes with Fe2+. This process
is obstructed when chelating agents are present, which decreases the red colour of the complex.
Thus, measuring the reduction of colour makes it possible to calculate chelating activity.32 The
production of these radicals may cause lipid peroxidation, protein modification and DNA
damage. Chelating agents may not trigger metal ions and possibly prevent metal-dependent
processes.33 In this study, 4c demonstrated the most activity while other compounds showed a
low ion chelating activity. In terms of chelating activity, they were in the following order: α-
tocopherol > 4c > BHT > 4f > 4d > 4h > 4g > 4a > 4b > 4e (Table S 1).
Hydrogen peroxide scavenging activity
Hydrogen peroxide exhibits powerful oxidizing effects and can be generated in vivo by
various oxidizing enzymes, including superoxide dismutase. The activity of hydrogen peroxide
scavenging was in the following order: ascorbic acid > 4f > 4c > BHT > 4h > 4g > 4d > 4e > 4a
> 4b. Compound 4f (IC50: 60.07µg/ml) and 4c (IC50: 60.87µg/ml) scavenged hydrogen
peroxide much more than other compounds and the BHT standard. It appears that levels of
hydrogen peroxide at or below around 20--50 mg have restricted cytotoxicity for many cell
types. Hence the elimination of hydrogen peroxide is crucial for the protection of pharmaceutical
and food systems (Table S 1). 34
EXPERIMENTS
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All solvents and reagents were purchased from commercial sources and used without further
purification. Melting points were determined on an Electrothermal 9100 melting point apparatus
and uncorrected, but checked with a differential scanning calorimeter (DSC). The IR spectra
1
13
were measured with a Perkin--Emler Spectrum One FT-IR spectrophotometer. The H, C and
1
31P spectra were taken on a Bruker AC-400 NMR spectrometer operating at 400 MHz for H,
100 MHz for 13C and 162 MHz for 31P. Compounds were dissolved in NaOD/D2O and chemical
shifts were referenced to TMS (1H and 13C NMR) and 85% H3PO4 (31P NMR). Elemental
1
13
analyses were performed on a LECO-CHNS-938. The Supplemental Material contains H, C
and 31P NMR spectra for compounds 4a--h (Figures S 1 -- S 21)
General procedure for the synthesis of 3a--h
A solution of diamine (20 mmol) in absolute ethanol (30 mL) was slowly added to a solution
of aldehyde (40 mmol) in absolute ethanol (20 mL). The stirred reaction mixture was refluxed
for 4 h. After cooling, a precipitate was formed which was collected by filtration, washed with
cold ethanol and recrystallized from a 9:1 mixture of ethanol and water.
General procedure for the synthesis of 4a--h
Hypophosphorous acid (50%, 2 mol equivalent) in ethanol was added to the imine in ethanol
(50 ml for 20 mmol). The mixture was refluxed for 24 h and then cooled. The solid product was
filtered off and washed with a solvent mixture of ethanol and water and air dried at room
temperature.
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(Ethane-1,2-diylbis{imino[(2-hydroxyphenyl)methanediyl]})bis(phosphinic
(4a)(C16H22N2O6P2)
acid)
White solid, yield 60%, m.p. 250-252°C. IR (KBr, υ, cm−1): 3400 (─OH), 3215 (─NH),
3041 (─Ar-H), 2825-2971 (─C-H), 2384 (─PH), 1597 (─C = C), 1182 (─P = O), 1017-1042
1
(─P-O) cm1. H-NMR (400 MHz, NaOD/D2O, δ, ppm): 6.92 (m, 4H, Ar-H), 6.60 (d, 2H, J =
13
514.8 Hz, PH), 6.40 (m, 4H, Ar-H), 3.99 (m, 2H, PCH), 2.71 (m, 4H, N-CH2). C-NMR (100
MHz, NaOD/D2O, δ, ppm): 163.3, 128.2, 127.7, 124.4, 118.6, 113.6, 55.9 46.1. Elem. Anal.:
Calculated: C, 48.01; H, 5.54; N, 7.00. Found: C, 48.50; H, 5.20; N, 6.85.
(Ethane-1,2-diylbis{imino[(4-methoxyphenyl)methanediyl]})bis(phosphinic
(4b)(C18H26N2O6P2)
acid)
White solid, yield 55%, m.p. 200-203°C. IR (KBr, υ, cm−1): 3411 (─OH), 3266 (─NH),
3078 (─Ar-H), 2836-2997 (─C-H), 2324 (─PH), 1612 (─C = C), 1165 (─P = O), 1046-1069
1
(─P-O) cm1. H-NMR (400 MHz, NaOD/D2O, δ, ppm): 6.88 (m, 4H, Ar-H), 6.57 (d, 2H, J =
516.4 Hz PH), 6.28 (m, 4H, Ar-H), 3.01 (m, 2H, PCH), 2.87 (s, 6H, O-CH3), 2.02 (m, 4H, N-
13
CH2). C-NMR (100 MHz, NaOD/D2O, δ, ppm): 158.1, 129.6, 127.9, 114.0, 63.1, 62.3, 55.3,
44.8. Elem. Anal.: Calculated: C, 50.47; H, 6.12; N, 6.54. Found: C, 50.05; H, 6.50; N, 6.93.
{Ethane-1,2-diylbis[imino(thiophen-2-ylmethanediyl)]}bis(phosphinic
(4c)(C12H18N2O4P2S2)
acid)
White solid, yield 43%, m.p. 220-222°C. IR (KBr, υ, cm−1): 3437 (─OH), 3241 (─NH),
3082-3095 (─Ar-H), 2940-2963 (─C-H), 2318 (─PH), 1617 (─C = C), 1180 (─P = O), 1066
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(─P-O) cm1. 1H-NMR (400 MHz, NaOD/D2O, δ, ppm): 7.10 (s, 2H, Ar-H), 6.75 (s, 2H, Ar-H),
6.71(d, 2H, J = 518.4 Hz PH), 6.68 (s, 2H, Ar-H), 3.67 (m, 2H, PCH), 2.22 (m, 4H, N-CH2). 13C-
NMR (100 MHz, NaOD/D2O, δ, ppm):138.5, 126.7, 125.5, 59.2, 58.2, 45.4, 42.5, 39.2. Elem.
Anal.: Calculated: C, 37.89; H, 4.77; N, 7.36. Found: C, 37.50; H, 4.85; N, 7.08.
(Propane-1,3-diylbis{imino[(2-hydroxyphenyl)methanediyl]})bis(phosphinic
(4d)(C17H24N2O6P2)
acid)
White solid, yield 47%, m.p. 217-219°C. IR (KBr, υ, cm−1): 3403 (─OH), 3258 (─NH),
3050 (─Ar-H), 2935-2997 (─C-H), 2335 (─PH), 1605 (─C = C), 1179 (─P = O), 1049 (─P-O)
cm1. 1H-NMR (400 MHz, NaOD/D2O, δ, ppm): 6.84 (m, 4H, Ar-H), 6.62 (d, 2H, J = 514.4 Hz,
PH), 6.40 (m, 4H, Ar-H), 3.94 (d, 2H, J = 12.8 Hz, PCH), 2.07 (m, 4H, N-CH2), 1.23 (s, 2H, N-
CH2-CH2). 13C-NMR (100 MHz, NaOD/D2O, δ, ppm): 165.2, 128.1, 127.6, 124.3, 118.6, 113.5,
55.5, 44.6, 28.2. Elem. Anal.: Calculated: C, 49.28; H, 5.84; N, 6.76. Found: C, 49.04; H, 5.64;
N, 7.28.
(Propane-1,3-diylbis{imino[(4-methoxyphenyl)methanediyl]})bis(phosphinic
(4e)(C19H28N2O6P2)
acid)
White solid, yield 45%, m.p. 256-258°C. IR (KBr, υ, cm−1): 3414 (─OH), 3252 (─NH),
3043 (─Ar-H), 2912-2997 (─C-H), 2315 (─PH), 1613 (─C = C), 1181 (─P = O), 1070 (─P-O)
1
cm1. H-NMR (400 MHz, NaOD/D2O, δ, ppm): 7.30 (m, 4H, Ar-H), 7.05 (m, 4H, Ar-H), 6.95
(d, 2H, J = 520 Hz, PH), 3.77 (s, 6H, O-CH3), 3.70 (m, 2H, PCH), 2.15 (m, 4H, N-CH2), 1.24
(m, 2H, N-CH2-CH2). 13C-NMR (100 MHz, NaOD/D2O, δ, ppm): 158.1, 129.6, 127.9, 114.0,
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63.1, 62.3, 55.3, 44.8, 27.7. Elem. Anal.: Calculated: C, 51.59; H, 6.38; N, 6.33. Found: C,
51.24; H, 6.45; N, 6.83.
{Propane-1,3-diylbis[imino(thiophen-2-ylmethanediyl)]}bis(phosphinic
(4f)(C13H20N2O4P2S2)
acid)
White solid, yield 45%, m.p. 243-245°C. IR (KBr, υ, cm−1): 3400 (─OH), 3224 (─NH),
3072 (─Ar-H), 2914-2971 (─C-H), 2328 (─PH), 1613 (─C = C), 1198 (─P = O), 1054 (─P-O)
cm1. 1H-NMR (400 MHz, NaOD/D2O, δ, ppm): 7.55 (d, 2H, Ar-H), 7.21 (t, 2H, Ar-H), 7.13 (s,
2H, Ar-H), 6.99 (d, 2H, J = 524.4 Hz, PH), 4.06 (m, 2H, PCH), 2.39 (m, 4H, N-CH2), 1.65 (m,
13
2H, N-CH2-CH2). C-NMR (100 MHz, NaOD/D2O, δ, ppm): 138.6, 127.2, 127.0, 125.7, 59.5,
58.6, 45.0, 27.7. Elem. anal.: Calculated: C, 39.59; H, 5.11; N, 7.10. Found: C, 39.09; H, 5.45;
N, 7.43.
(2,2-dimethylpropane-1,3-diylbis[imino(4-methoxyphenyl)methanediyl)]bis(phosphinic
acid) (4g)(C21H32N2O6P2)
White solid, yield 55%, m.p. 244-246°C. IR (KBr, υ, cm−1): 3417 (─OH), 3221 (─NH),
3041 (─Ar-H), 2933-2992 (─C-H), 2307 (─PH), 1609 (─C = C), 1163 (─P = O), 1054 (─P-O)
1
cm1. H-NMR (400 MHz, NaOD/D2O, δ, ppm): 7.50 (m, 4H, Ar-H), 7.25 (m, 4H, Ar-H), 6.53
(d, 2H, J = 517.6 Hz, PH), 3.42 (s, 6H, O-CH3), 3.19 (d, 2H, J = 12.4 Hz, PCH), 1.66 (s, 4H, N-
CH2), 0.38 (m, 6H, CH2-C-CH3). 13C-NMR (100 MHz, NaOD/D2O, δ, ppm): 157.7, 129.2,
31
128.1, 113.7, 64.5, 63.5, 57.4, 55.0, 33.7, 22.8. P-NMR (162 MHz, NaOD/D2O, δ, ppm): 28.6,
24.4. Elem. Anal.: Calculated: C, 53.62; H, 6.86; N, 5.95. Found: C, 53.41; H, 6.41; N, 5.64.
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{(2,2-dimethylpropane-1,3-diyl)bis[imino(thiophen-2-ylmethanediyl)]}bis(phosphinic
acid)(4h)(C15H24N2O4P2S2)
White solid, yield 49%, m.p. 217-219°C. IR (KBr, υ, cm−1): 3400 (─OH), 3215 (─NH),
3074 (─Ar-H), 2928-2973 (─C-H), 2351 (─PH), 1697 (─C = C), 1197 (─P = O), 1054 (─P-O)
1
cm1. H-NMR (400 MHz, NaOD/D2O, δ, ppm): 7.01 (m, 2H, Ar-H), 6.60 (m, 4H, Ar-H), 6.54
(d, 2H, J = 525.2 Hz, PH), 3.50 (d, 2H, J = 15.2 Hz, PCH), 1.76 (m, 4H, N-CH2), 0.40 (m, 6H,
CH2-C-CH3). 13C-NMR (100 MHz, NaOD/D2O, δ, ppm): 139.59, 127.0, 126.3, 125.2, 61.1, 60.2,
57.6, 33.7, 23.4, 22.8. 31P-NMR (162 MHz, NaOD/D2O, δ, ppm): 27.6, 24.3.Elem. Anal.:
Calculated: C, 48.43; H, 6.32; N, 6.27. Found: C, 48.61; H, 6.51; N, 6.04.
CONCLUSION
In this study, we synthesized a new series of bis-1-amino-H-phosphinic acid derivatives and
used different methods to compare their antioxidative activity. The novel phosphonous acids
were obtained in moderate yields varying from 40--60%, which was more than expected, since
several authors [40--42] reported much lower conversion rates for additions to two azomethine
groups. Among various bis-1-amino-H-phosphinic acids derivatives, compounds 4c and 4f
showed higher antioxidant activity than the other derivatives and the standard BHT compound.
The lowest activity values were generally from compounds 4a and 4b.
STATISTICAL EVALUATION
Data analyses were done using SPSS 22.0 (IBM Corp., Armonk, NY, USA). Linear
regression was conducted to provide mathematical models of determinism between dependency
(concentration) and independency (inhibition percentage). IC50 values were calculated with both
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linear and cubical models. Data were evaluated at 95% confidence intervals.
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REFERENCES
[1] Latajka, R.; Krezel, A.; Mucha, A.; Jewginski, M.; Kafarski, P. J. Mol. Struct. 2008, 877
64-71.
[2] Cates, L. A.; Li, V. S. Pharm. Res. 1985, 2, 135-136.
[3] Ye, Y.; Liu, M.; Kao, J. L.-F.; Marshall, G.R. Biopolymer 2008, 89, 72-85.
[4] Gittens, S. A.; Bansal, G.; Zernicke, R. F.; Uludag, H. Adv. Drug. Deliv. Rev. 2005, 57,
1011–1036.
[5] Sanders, J. M.; Gómez, A. O.; Mao, J.; Meints, G.A.; Van Brussel, E.M.; Burzynska, A.;
Kafarski, P.; Gonzáles-Pacanowska, D.; Oldfield, E. J. Med. Chem. 2003, 46, 5171–5183.
[6] Collinsova, M.; Jiracek, J. Curr. Med. Chem. 2000,7, 629–647.
[7] Kafarski, P.; Lejczak, B.; Tyka, R.; Koba, L.; Pliszczak, E.; Wieczorek, P. J. Plant Growth
Reg. 1995, 14, 199-203.
[8] Luckman, S. P.; Coxon, F. P.; Ebetino, F. H.; Russell, G. G.; Rogers, M. J. J. Bone Miner.
Res. 1998, 13, 1668-1678.
[9] Katoh, M.; Hiratake, J.; Kato, H.; Oda, J.Bioorg. Med. Chem. Lett. 1996, 6, 1437-1442.
[10] Kaboudin, B.; As-Habei, N. Tetrahedron Lett. 2003, 44, 4243-4245.
[11] Kaboudin, B.; Haruki, T.; Yamaghishi, T.; Yokomatsu, T. Tetrahedron 2007, 63, 8199-
8205.
[12] Kaboudin, B.; Haruki, T.; Yamagishi, T.; Yokomatsu, T. Synthesis 2007, 20, 3226-3232.
[13] Kaboudin, B.; Jafari, J. Iran. Chem. Soc. 2008, 5, S97-S102.
[14] Kukhar, V. P.; Hudson, H. R. Aminophosphonic and Aminophosphinic Acids, Wiley:
Chichester, 2000.
14
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[15] Hyun-Joon, H.; Gong-Shil, N. Synth. Commun. 1992, 22, 1143.
[16] Gancarz, R.; Wieczorek, J. S. Synthesis 1978, 625.
[17] Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36, 1379-1386.
[18] Worms, K. H.; Schmidt-Dunker, M. In Organic Phosphorus Compounds, Vol. 7;
Kosolapoff, G. M.; Maier, L., Eds.; Wiley: New York, 1976, 1.
[19] Nurulain, S. M.; Szegi, P.; Tekes, K.; Naqvi S. N. 2013, 64, 169-177.
[20] Schwetlick, K.; Pionteck, J.; Habicher, T.W.D. J. Eur. Polym. 1987, 23, 383-388.
[21] Földes, E.; Maloschik, E.; Kriston, I.; Staniek, P.; Pukánszky, B. Polym. Degrad. Stabil.
2006, 91, 479–487.
[22] Koparir, P.; Karaarslan, M.; Orek, C.; Koparir, M. Phosphorus Sulfur Silicon Relat. Elem.
2011, 186, 2368-2376.
[23] Koparir, P.; Karaarslan, M.; Orek, C.; Koparir, M.Phosphorus Sulfur Silicon Relat. Elem.
2012, 187, 864-870.
[24] (a) Saigo, K.; Kubota, N.; Takebayashi, S.; Hasegawa, M. Bull. Chem. Soc. Jpn. 1986, 59,
931–932; (b) Corey, E. J.; Kuhnle, F. N. M. Tetrahedron Lett. 1997, 38, 8631–8634; (c)
Larter, M. L.; Phillips, M.; Ortega, F.; Aguirre, G.; Somanathan, R.; Walsh, P. J.
Tetrahedron Lett. 1998, 39, 4785–4788; (d) Lozinskaya, N. A.; Tsybezova, V. V.;
Proskurnina, M. V.; Zefirov, N. S. Russ. Chem. Bull. 2003, 52, 674–678; (e) Nishiyama,
K.; Saito, M.; Oba, M. Bull. Chem. Soc. Jpn. 1988, 61, 609–611; (f) Uchida, H.; Shimizu,
T.; Reddy, P. Y.; Nakamura, S.; Toru, T. Synthesis 2003, 8, 1236–1240; (g) Uchida, H.;
Tanikoshi, H.; Nakamura, S.; Reddy, P. Y.; Toru, T. Synlett. 2003, 1117–1120; (h)
Kaboudin, B.; Saadati, F. Heterocycles 2005, 65, 353–357.
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[25] (a) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157–160; (b) Isobe, T.; Fukuda, K.;
Araki, Y.; Ishikawa, T. Chem. Commun. 2001, 3, 243–244; (c) Anastassiadou, M.;
Baziard-Mouysset, G.; Payard, M. Synthesis 2000, 13, 1814–1816; (d) Corey, E. J.; Huang,
H. C. Tetrahedron Lett. 1989, 30, 5235; (e) Corey, E. J.; Imwinkelried, R.; Pikul, S. B. J.
Am. Chem. Soc. 1989, 111, 5493–5495; (f) Corey, E. J.; Kim, S. S. J. Am. Chem. Soc.
1990, 112, 4976–4977.
[26] Lewkowski, J.; Rybarczyk, M. Heteroatom Chem. 2008, 19, 283-287.
[27] Boyd, E. A.; Chan, W. C.; Loh Jr., V. M.; Tetrahedron Lett., 1996, 37, 1647-1650.
[28] Schmidt, H. Chem. Ber., 1948, 81,477-483.
[29] Halliwell, B.; Gutteridge, J. M. C.; Aruoma,O. I. Anal. Biochem. 1987,165, 215-219.
[30] Wright, J. S.; Johnson, E. R.; Dilabio, G. A. J. Am. Chem. Soc. 2001,123, 1173-1183.
[31] Orhani, I.;Ozcelik, B.; Sener, B. Turk. J. Biol. 2011,35, 251-258.
[32] Yamaguchi, F.; Ariga, T.; Yoshimura, Y.; Nakazawa, H. J. Agric. Food Chem. 2000,
48,180-185.
[33] Finefrock, A. E.; Bush, A. I.; Doraiswamy, P. M. J. Am. Geriatr. Soc. 2003, 51, 1143-
1148.
[34] Kilic, I.; Yeşiloglu, Y.; Bayrak, Y. Spectrochim. Acta A. 2014, 130, 447-452.
[35] Liu, F.; Ooi, V. E. C.; Chang, S. T.Life Sci. 1997,60, 763-771.
[36] Nguyen, M. A. T.;Mungara, A. K.; Kim, J. A.; Lee, K. D.; Park, S. Phosphorus Sulfur
Sikicon Relat. Elem. 2015, 190, 191–199,
[37] Cuendet, M.; Hostettmann, K.;Potterat, O. H. Helv. Chim. Acta. 1997,80, 1144-1152.
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[38] Dinis, T. C. P.; Madeira, V. C.; Almeida, L. M. Arch. Biochem. Biophys. 1994, 315,161-
169.
[39] Ruch, R. J.; Cheng, S. J.; Klaunig, J. F. Carcinogenesis, 1989, 10, 1003-1008.
[40] Failla, S.; Finocchiaro, P. Phosphorus Sulfur. 1993, 85, 65–72.
[41] Failla, S.; Finocchiaro, P.; Hagele, G.; Rapisardi, R. Phosphorus Sulfur. 1993, 82, 79–90.
[42] Failla, S.; Finocchiaro, P. Phosphorus Sulfur. 1995, 107, 79–86.
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Figure 1. Synthesis of compound 4a–h.
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Figure 2. Preparation of racemic and meso 4a–h.
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Figure 3. Mechanism of formation of 4a–h.
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