Syntheses, characterizations, and crystal structures of phosphonopeptides

Article abstract of DOI:10.1002/hc.20227

α-Aminophosphonic acids and their derivatives, as phosphorus analogs of amino acids, have attracted much attention as they show a range of biological activities. In this paper, dialkyl phenyl(4-pyridylcarbonylamino)methylphosphonates were synthesized via

Full text of DOI:10.1002/hc.20227

Heteroatom Chemistry
Volume 18, Number 1, 2007
Syntheses, Characterizations, and Crystal
Structures of Phosphonopeptides
Fang Hua,1 Fang Meijuan,1 Liu Xiaoxia,1 Tang Guo,1
and Zhao Yufen1,2
1The Key Laboratory for Chemical Biology of Fujian Province, Department of Chemistry,
Xiamen University, Xiamen 361005, People’s Republic of China
2The Key Laboratory for Bioorganic Phosphorus Chemistry and Chemical Biology,
Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084,
People’s Republic of China
Received 12 September 2005; revised 6 December 2005
ety of pesticide and therapeutic areas [4]. The study
ABSTRACT: ꢀ-Aminophosphonic acids and their
is focused on the linkage of ꢀ-aminophosphonic
derivatives, as phosphorus analogs of amino acids,
acids and bioactive structure units in order to
have attracted much attention as they show a range
find novel phosphonopeptides and their derivatives
of biological activities. In this paper, dialkyl phenyl(4-
with higher bioactivity and low toxicity. Numer-
pyridylcarbonylamino)methylphosphonates were syn-
ous methods have been reported for the prepara-
thesized via the Mannich reaction (Yuan et al., Synthe-
tion of amides. The most typical procedures are the
sis 1990, 3, 256) and peptide coupling. Their structures
Yasutsugu Shimonishi method, the N-carboxyl an-
1
were confirmed by elemental analysis, IR, H NMR,
hydride (NCA) method, and the DCC-HOSu method
13C NMR, and MS. X-ray diffraction data of com-
[5–8]. Organic phosphorus coupling reagents [9–11]
pounds (2a, 2b, 2c) were reported respectively.
also have been applied for the synthesis of amides,
The antibacterial and antitumor activities of
such as the Appel [12] coupling reagents (triph-
these compounds are first reported in this paper.
enylphosphine and hexachloroethane). Hence, it is
ꢀ
C
2007 Wiley Periodicals, Inc. Heteroatom Chem
18:9–15, 2007; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20227
an easy, facile synthetic route for the coupling of
amides. X-ray diffraction structures of compounds
2a, 2b, 2c were determined. In the solid state,
for each 2a, 2b, 2c there is an intermolecular hy-
˚
INTRODUCTION
drogen bond (N 2· · ·O 2) with lengths 2.949(3) A,
˚
˚
2.891(3) A, and 2.919(5) A, respectively [13]. Bioas-
say showed that most of them are bioactive. For ex-
ample, 2a, 2b, 2c exhibited moderate cytotoxicity
toward the KB cell line (IC50 values are 114.1 ꢁg/mL,
68.5 ꢁg/mL, and 51.8 ꢁg/mL, respectively). Bioactiv-
ities increased with the bulk of the alkyl group.
The importance of ꢀ-aminophosphonic acids and
their derivatives is due to their diverse bioactivities
including herbicide [1], antibacterial [2], antiviral
and antitumor [3], and their utilizations in a vari-
Correspondence to: Zhao Yufen; E-mail: yfzhao@xmu.edu.csn.
Contract grant sponsor: Fujian Key Foundation of Science and
Technology.
EXPERIMENTAL
Contract grant number: 2002H011.
Contract grant sponsor: Fujian Foundation of Science and
Technology.
Contract grant number: 2001F008.
2007 Wiley Periodicals, Inc.
Materials and Methods
Triphenylphosphine, hexachloroethane, isonicotic
acid, and phosphorus trichloride were commercially
c
ꢀ
9

10 Hua et al.
available (they were obtained from Aldrich and
were used without further purification). The melt-
ing points were obtained with Yanaco micromelt-
ing point apparatus and are uncorrected. Infrared-
spectra were recorded on a Nicolet AVATAR 360
(10 mL) to afford the hydrochloride of dialkyl ꢀ-
aminobenzylphosphonate (1a–1c) as a white crys-
talline material [14–16].
Dimethyl ꢀ-Aminobenzylphosphonate Hydrochlo-
ride 1a: White crystals, yield 37.4%, mp 220.6–
223.5◦C; 1H NMR (D2O) δ: The NH2 signal dis-
appeared with D2O exchange, 7.44–7.64 (m, 5H,
ArH), 5.08 (d, 1H, JP-CH = 18 Hz, CH), 3.78 (s, 6H,
2OCH3); IR (KBr) ν: 3425 (N-H), 1245 (P O), 1033
(P O C), 1604, 1521, 1494, 1456 (aromatic vibra-
tions) (cm−1); MS m/z (%): 106.1 (10.64), 215.9
([M + H]+, 21.6), 430.7 ([2M + H]+, 100). Anal. Calcd
for C9H14NO3P·HCl: C 42.96, H 6.01, N 5.57; Found
C 42.81, H 6.05, N 5.48.
1
FT-IR spectrophotometer using KBr disks. H, 13C,
and 31P NMR spectra were recorded on a Var-
ian 500 MHz spectrometer operating on 500, 125,
202 MHz, respectively. The chemical shifts were
reported in ppm with respect to the references and
were stated relative to external tetramethylsilane
(TMS) for 1H and 13C NMR, and to 85% phos-
phoric acid for 31P NMR. Elemental analyses were
performed with a Flash EA 1112. All mass spectra
were acquired with a Bruker ESQUIRE-3000 plus
ion trap spectrometer equipped with a gas nebulizer
probe in the positive ion mode, microplate reader
(M-3550, Bio-Rad) at 595 to 655 nm as reference. A
Bruker SMART CCD X-ray diffractometer was used.
Diethyl ꢀ-Aminobenzylphosphonate Hydrochlo-
ride 1b: White crystals, yield 36.8%, mp 176.3–
1
177.6◦C; H NMR (D2O) δ: The NH2 signal disap-
peared with D2O exchange, 7.44–7.56 (m, 5H, ArH),
4.96 (d, 1H, J(P-CH) = 18 Hz, CH), 4.16 (d, J(CH -CH
=
)
3
2
8 Hz, 4H, 2CH2CH3), 1.26 (d, J(CH -CH ) = 8 Hz, 6H,
2CH2CH3); IR (KBr) ν: 3438 (N-H2 ),3 1239 (P O),
1024 (P O C), 1605, 1520, 1498, 1455 (aromatic vi-
brations) (cm−1); MS m/z (%): 106.1 (44.21), 243.9
([M + H]+ 95.44), 486.7 ([2M + H]+, 100). Anal. Calcd
for C11H18NO3P·HCl: C 47.24, H 6.85, N 5.01; found
C 47.10, H 6.77, N 4.76.
Syntheses
General Procedure for the Preparation of the
Hydrochloride of Dialkyl ꢀ-Aminobenzylphosphonate
(1a–1c). To the EtOH solution of ammonium ac-
etate (7.70 g, 0.10 mol) was added actively molec-
Diisopropyl ꢀ-Aminobenzylphosphonate Hydro-
chloride 1c: White crystals, yield 33.7%, mp
171.7–173.2◦C 1H NMR (D2O) δ: The NH2 sig-
nal disappeared with D2O exchange, 7.44–7.64
(m, 5H, ArH), 4.92 (d, 1H, J(P-CH) = 18 Hz, CH),
˚
ular sieves (4 A) (2.0 g), benzaldehyde (10.61 g,
0.10 mol), and dialkyl phosphite (0.10 mol) at room
temperature. The reaction mixture was stirred at
60◦C for 44 h and cooled to room temperature. The
reaction mixture was acidified to pH 1 with HCl, and
the solution was washed with Et2O to remove neu-
tral materials. The aqueous phase was then adjusted
to pH 11 with aq. NaOH, and the product was ex-
tracted with CH2Cl2. The solvent was removed to give
the crude product as pale yellow oil, which was fur-
ther treated with HCl (gas) in EtOH (10 mL)–Et2O
4.68 (d, JCH-CH = 6 Hz, 2H, 2CH(CH3)2), 1.26 (d,
3
J(CH-CH ) = 6 Hz, 12H, 2CH(CH3)2); IR (KBr) ν: 3431
3
(N-H), 1246 (P O), 1019 (P O C), 1595, 1562, 1516,
1457 (aromatic vibrations) (cm−1); MS m/z (%): 106.1
(17.16), 271.9 ([M + H]+, 66.53), 544.5 ([2M + H]+,
100). Anal. Calcd for C13H22NO3P·HCl: C 50.74, H
7.53, N 4.55; found C 50.51, H 7.56, N 4.39.
General Procedure for the Preparation of Dialkyl
Phenyl(4-pyridylcarbonylamino)methylphosphonate
(2a–2c). Triphenylphosphine (3.93 g, 15 mmol)
and hexachloroethane (3.58 g, 15 mmol) were
dissolved in 1,2-dichloroethane (20 mL) under
nitrogen atmosphere for 1 h. The reacted solution
was added dropwise to a mixture of the dialkyl
ꢀ-aminobenzylphosphonate hydrochloride (2.79 g,
10 mmol) and isonicotinic acid (1.23 g, 10 mmol)
in 1,2-dichloroethane (90 mL) and 4 mL of triethy-
lamine. After 24 h the reaction was completed. The
reaction mixture was acidified to pH 1 with HCl,
and the solution was washed with Et2O to remove
neutral materials. The aqueous phase was then
adjusted to pH 11 with aq. NaOH, and the product
was extracted with CH2Cl2; the solvent was removed
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

Syntheses, Characterizations, and Crystal Structures of Phosphonopeptides 11
J(CH-CH ) = 6 Hz, 12H, 2CH(CH3)2); 13C NMR (CDCl3)
to give the crude product, which was purified by
recrystallization [17,18].
3
δ: 150.26, 121.42, 141.15 (Py), 135.13, 128.61,
128.15, 128.65 (Ar), 165.39 (C O), 51.27 (CH),
72.48, 71.96 (2CH(CH3)2), 24.12, 24.01, 23.86, 23.81
(2CH(CH3)2); IR (KBr) ν: 3448 (N-H), 1676 (C O),
1231 (P O), 1009 (P O C), 1661, 1600, 1537, 1491
(aromatic vibrations) (cm−1); MS m/z (%): 211.0
(40.38), 377.0 ([M + H]+, 100), 752.8 ([2M + H]+,
22.63); 31P (CDCl3) δ: 19.9 ppm. Anal. Calcd for
C19H25N2O4P: C 60.63, H 6.69, N 7.44; found C 60.49,
H 6.74, N 7.33.
Dimethyl Phenyl(4-pyridylcarbonylamino)methyl-
phosphonate 2a: It was recrystallized from hot
ethanol to give white crystals, yield 76.5%, mp 134.1–
135.5◦C 1H NMR (CDCl3) δ: 9.72 (dd, J(NH-CH) = 9 Hz,
NH,), 8.38–8.68 (m, 4H, Py), 7.20–7.60 (m, 5H, ArH),
5.42 (dd, 1H, J(P-CH) = 21 Hz, J(NH-CH) = 9 Hz, CH), 4.02
(s, 6H, 2OCH3); 13C NMR (CDCl3) δ: 149.44, 123.94,
145.22 (Py), 133.69, 128.90, 127.25, 128.73 (Ar),
168.28 (C O), 52.39 (CH), 55.55, 53.93 (2OCH3); IR
(KBr) ν: 3402 (N-H), 1662 (C O), 1225 (P O), 1074
(P O C), 1557, 1511, 1495, 1453 (the vibration of
aromatic) (cm−1); MS m/z (%): 210.9 (19.48), 321
([M + H]+, 100), 641.0 ([2M + H]+, 1.01); 31P (CDCl3)
δ: 12.8 ppm. Anal. Calcd for C15H17N2O4P·H2O: C
53.26, H 5.66, N 8.28; found C 53.55, H 5.54, N 8.09.
Diethyl Phenyl(4-pyridylcarbonylamino)methyl-
phosphonate 2b: It was recrystallized from a 1:1
mixture of hexane and dichloroethane to give
RESULTS AND DISUSSION
Mass Spectroscopy
The main mass spectrometric data of compounds
in Table 1 showed [M + H]+ and [2M + H]+ signals.
Mass spectrometry of the 2a, 2b, 2c produced two
kinds of fragment ions at m/z 211 and 106. Scheme 2
shows fragmentation pathways of diethyl phenyl(4-
pyridylcarbonylamino)methylphosphonate (2b).
1
white crystals, yield 82.0%, mp 107.0–108.1◦C; H
NMR (CDCl3) δ: 8.23 (dd, J(NH-CH) = 9 Hz, NH),
8.08–8.28 (m, 4H, Py), 7.23–7.62 (m, 5H, ArH),
5.76 (dd, 1H, J(P-CH) = 21 Hz, J(CH-NH) = 9 Hz CH),
3.98 (t, J(CH -CH = 8 Hz, 4H, 2CH2CH3), 1.22 (d,
)
J(CH -CH ) = 8 2Hz,36H, 2CH2CH3); 13C NMR (CDCl3) δ:
3
1502.51, 121.19, 140.84 (Py), 134.64, 128.47, 128.17,
128.78 (Ar), 165.09 (C O), 51.40 (CH), 63.72, 63.20
(2CH2CH3), 16.44, 16.10 (2CH2CH3); IR (KBr) ν:
3440 (N-H), 1664 (C O), 1244 (P O), 1032 (P O C),
1596, 1546, 1500, 1456 (aromatic vibrations) (cm−1);
MS m/z (%): 211.0 (17.77), 348.9 ([M + H]+, 100),
696.7 ([2M + H]+, 10.16); 31P (CDCl3) ꢂ: 19.5 ppm.
Anal. Calcd for C17H21N2O4P: C 58.62, H 6.08, N
8.04; found C 58.44, H 6.10, N 7.95.
Diisopropyl Phenyl(4-pyridylcarbonylamino)-
methylphosphonate 2c: It was recrystallized from a
1:2 mixture of acetic ether and petroleum ether to
give white crystals, yield 85.1%, mp 134.3–135.7◦C;
1H NMR (CDCl3) δ: 7.94 (dd, J(NH-CH) = 9 Hz, NH),
8.05–8.29 (m, 4H, Py), 7.18–7.72 (m, 5H, ArH),
5.72 (dd, 1H, J(P-CH) = 21 Hz, J(NH-CH) = 9Hz, CH),
4.50 (d, J(CH-CH ) = 6 Hz, 2H, 2CH(CH3)2), 1.20 (d,
SCHEME 2
3
TABLE 1 The Main Mass Spectra Data of 1a–1c, 2a–2c
Compounds
m/z (%)
1a
1b
1c
2a
2b
2c
106.1 (10.64)
106.1 (44.21)
106.1 (17.16)
210.9 (19.48)
211.0 (17.77)
211.0 (40.38)
215.9 (M + H+, 21.60)
243.9 (M + H+, 95.44)
271.9 (M + H+, 66.53)
321.0 (M + H+, 100)
348.9 (M + H+, 100)
377.0 (M + H+, 100)
430.7 (2M + H+,100)
486.7 (2M + H+,100 )
544.5 (2M + H+, 100)
641.0 (2M + H+, 1.01)
696.7 (2M + H+, 10.16)
752.8 (2M + H+, 22.63)
237.7 (87.23)
267.0 (90.47)
294.1 (98.25)
215.6 (30.48)
244.0 (44.57)
271.8 (27.83)
Heteroatom Chemistry DOI 10.1002/hc

12 Hua et al.
TABLE 2 Crystal data and Refinement Details for compounds 2a, 2b, and 2c
2a
2b
2c
CCDC number
Empirical formula
Formula weight
Temperature (K)
Crystal size
Crystal system
Space group
248275
C15H17N2O4P
320.28
248276
C17H21N2O4P
348.33
248277
C19H25N2O4P·H2O
394.38
293(2)
293(2)
293(2)
0.21 × 0.19 × 0.15
0.35 × 0.27 × 0.26
Monoclinic
C2/c
0.10 × 0.09 × 0.20
Monoclinic
Triclinic
P(2)1/n
P-1
Unit cell dimensions
˚
a (A)
10.748(3)
14.417(4)
10.920(3)
90.0
111.28(4)
90.0
1576.7(7)
4
23.714(5)
8.093(5)
20.019(5)
90.0
110.325(5)˚
90.0
3602(3)
8
10.438(2)
13.738(3)
16.398(3)
102.579(3)
105.028
93.650
2198.5(7)
2
1.185
˚
b (A)
˚
c (A)
ꢀ (◦)
ꢃ (◦)
ꢄ (◦)
3
˚
Volume (A )
Z
d (Mg/m3)
1.349
0.193
672
1.285
0.175
1472
μ(mm−1
F(000)
)
0.154
832
Diffractometor
Bruker APEX area-detector
Bruker APEX area-detector
Bruker APEX
area-detector
Monochromatize Mo Kꢀ
(0.7103p
Radiation
Monochromatize Mo Kꢀ (0.7103) Monochromatize Mo Kꢀ
(0.7103)
θ range (deg)
Limiting indices
2.28–25.0
1.83–25.0
1.53–25
−11 = h = 12 −17 = k = 16
−28 = h = 28 −9 = k = 9
−12 = h = 12 −16 = k = 16
−19 =l = 19
15980
−12 =l = 12
−23 =l = 23
Reflections collections
Independent reflections
Data/restraints/
7844
12050
2757 [R(int) = 0.0234]
3162 [R(int) = 0.0240]
7695 [R(int) = 0.0269]
2757 / 0 / 199
3162/ 0 / 219
7985/ 0 / 478
parameters
Goodness-of-fit on F2
R indices [I > 2σ(I )]
1.182
1.05
1.070
R1 = 0.0627, wR2 = 0.1609
R1 = 0.0770, wR2 = 0.2403
R1 = 0.0900,
wR2 = 0.2429
R1 = 0.1079,
wR2 = 0.2593
Full-matrix least-squares
1.35/−0.52
R indices (all data)
R1 = 0.0581, wR2 = 0.1648
R1 = 0.0836, wR2 = 0.2478
Refinement methods
Full-matrix least-squares
Full-matrix least-squares
0.99/−0.36
Larg−e3st diff. Peak/hole 0.34/−0.22
˚
(e A
)
◦
˚
TABLE 3 Selected Bond Lengths (A) and Angles ( ) for C15H17N2O4P (2a)
Bond Lengths
Angles
( ◦)
˚
(A)
P(1)–O(2)
P(1)–O(3)
P(1)–O(4)
P(1)–C(13)
N(1)–C(8)
N(1)–C(9)
N(2)–C(12)
N(2)–C(13)
O(1)–C(12)
O(3)–C(14)
O(4)–C(15)
1.459(2)
1.568(2)
1.553(2)
1.814(3)
1.329(5)
1.320(5)
1.342(4)
1.458(3)
1.215(3)
1.434(4)
1.434(4)
O(2)–P(1)–O(4)
O(3)–P(1)–O(2)
O(4)–P(1)–O(3)
O(3)–P(1)–C(13)
O(4)–P(1)–C(13)
O(2)–P(1)–C(13)
C(9)–N(1)–C(8)
C(12)–N(2)–C(13)
C(14)–O(3)–P(1)
C(15)–O(4)–P(1)
117.18(14)
113.83(13)
102.78(13)
105.52(14)
102.32(13)
113.83(14)
115.6(3)
121.3(2)
123.1(2)
123.3(2)
Heteroatom Chemistry DOI 10.1002/hc

Syntheses, Characterizations, and Crystal Structures of Phosphonopeptides 13
◦
˚
TABLE 4 Selected Bond Lengths (A) and Angles ( ) for C17H21N2O4P (2b)
Bond Lengths
Angles
( ◦)
˚
(A)
P(1)–O(2)
P(1)–O(3)
P(1)–O(4)
P(1)–C(13)
N(1)–C(8)
N(1)–C(9)
N(2)–C(12)
N(2)–C(13)
O(1)–C(12)
O(3)–C(14)
O(4)-C(16)
1.449 (2)
1.560 (3)
1.568 (2)
1.822 (3)
1.305 (6)
1.316 (6)
1.334 (4)
1.443 (3)
1.206 (4)
1.433 (5)
1.415 (5)
O(3)–P(1)–O(4)
O(3)–P(1)–C(13)
O(4)–P(1)–C(13)
O(2)–P(1)–O(3)
O(2)–P(1)–O(4)
O(2)–P(1)–C(13)
C(16)–O(4)–P(1)
C(14)–O(3)–P(1)
C(8)–N(1)–C(9)
C(12)–N(2)–C(13)
107.27 (15)
102.96 (14)
108.49 (14)
116.08 (15)
108.49 (14)
113.15 (13)
125.0 (3)
126.3 (2)
116.0 (4)
121.4 (2)
◦
˚
TABLE 5 Selected Bond Lengths (A) and Angles ( ) for C19H25N2O4P (2c)
Bond Lengths
Angles
( ◦)
˚
(A)
P(1)–O(2)
P(1)–O(3)
P(1)–O(4)
P(1)–C(13)
N(1)–C(8)
N(1)–C(9)
N(2)–C(12)
N(2)–C(13)
O(1)–C(12)
O(3)–C(14)
O(4)-C(17)
1.453(3)
1.570(3)
1.553(3)
1.814(4)
1.318(6)
1.312(6)
1.334(5)
1.458(5)
1.215(5)
1.464(5)
1.477(6)
O(3)–P(1)–O(4)
O(2)–P(1)–O(3)
O(3)–P(1)–C(13)
O(2)–P(1)–O(4)
O(4)–P(1)–C(13)
O(2)–P(1)–C(13)
C(8)–N(1)–C(9)
C(12)–N(2)–C(13)
C(14)–O(3)–P(1)
C(17)–O(4)–P(1)
103.05(16)
114.34(16)
105.22(19)
117.11(17)
100.57(17)
114.78(18)
115.2(4)
120.1(3)
122.9(2)
123.7(3)
squares procedure based on F2 using the SHELXL-
97 program system.
The crystal data and the final refinement de-
tails of 2a, 2b, and 2c are given in Table 2, selected
bond distances and angles are shown in Tables 3–5,
respectively [19,20]. The crystal structures and
X-Ray Crystallography
Data were collected at 298 K on a Bruker SMART
CCD X-ray diffractometer fitted with Mo Kꢀ radia-
˚
tion (λ = 0.7013 A). The structures were solved by
direct methods yielding the positions of all non-
hydrogen atoms, and refined with a full-matrix least
FIGURE 2 ORTEP drawing of the unit cell packing 2a. Dis-
placement ellipsoids are at 50% probability level. Hydrogen
atoms are omitted for clarity.
FIGURE 1 ORTEP drawing of the molecular structure 2a.
Displacement ellipsoids are at 50% probability level.
Heteroatom Chemistry DOI 10.1002/hc

14 Hua et al.
FIGURE 3 ORTEP drawing of the molecular structure 2b.
Displacement ellipsoids are at 50% probability level.
FIGURE 5 ORTEP drawing of the molecular structure 2c.
Displacement ellipsoids are at 50% probability level.
gles are 166.9(3)◦, 169.1(3)◦, and 171.2(5)◦, respec-
tively. C(12), O(1), and N(2) are coplanar with the
pyridine.
unit cells packing figures are shown in Figs. 1–6
[21,22].
The adjacent bonds O(4) P(1) O(3) (mean,
˚
˚
˚
1.561(2) A for 2a; 1.564(3) A for 2b; 1.562(4) A for
2c) are similar to ammonium dimethylphosphate
˚
Biological Activities
(1.559(7) A) and methylethylenephosphate (1.57(1)
A) [23,26]. The phenyl and pyridine groups are pla-
˚
Antibacterial and antitumor activities were also
determined [27]. Five microbes (Aspergillus sp.,
Cadida albicans, Escherchia coli, Staphylococcus
allreus, and Bacillus stubtilis) were used as indicator
organisms to determine the antimicrobial activity of
1a, 1b, 1c, 2a, and 2b. These compounds displayed
weak antibacterial activity against Staphylococ-
cus allreus (inhibition zone = 7 mm); however, 1c
displayed high antibacterial activity against Bzcillus
subtilis (inhibition zone = 12 mm). The cytotoxicty
nar well within the experimental error. The packing
of the molecules assumed to be dictated by van der
Waal interactions and by intermolecular hydrogen
bonds. Two hydrogen bond donors formed hydro-
gen bonds in the crystal, as depicted in Figs. 2, 4,
and 6 (unit-cell packing diagram viewed). In 2a,
2b, and 2c, the length of the intermolecular hydro-
˚
˚
gen bonds (N-2· · ·O-2) are 2.949(3) A, 2.891(3) A,
˚
and 2.919(5) A, respectively; and N-2 H· · ·O-2 an-
FIGURE 4 OR TEP drawing of the unit cell packing 2b. Dis-
placement ellipsoids are at 50% probability level. Hydrogen
atoms are omitted for clarity.
FIGURE 6 ORTEP drawing of the unit cell packing 2c. Dis-
placement ellipsoids are at 50% probability level. Hydrogen
atoms are omitted for clarity.
Heteroatom Chemistry DOI 10.1002/hc

Syntheses, Characterizations, and Crystal Structures of Phosphonopeptides 15
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of 10 ꢁg/mL by MTT assay according to the pro-
cedure described in the literature [28]. The cell
line used was a human cancer cell line, KB cells.
2a, 2b, and 2c all displayed antimicrobial activity
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charge from the Director, CCDC, 12 Union Road,
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