A facile synthesis of optically active β-amino-β- arylethylphosphonates by mitsunobu reaction

Article abstract of DOI:10.1002/ejoc.200400420

We describe a convenient and simple synthesis of optically active β-amino-β-arylethylphosphonates based on Mitsunobu reactions of chiral β-aryl-β-hydroxyethylphosphonates, prepared in turn by Candida rugosa lipase catalyzed kinetic resolution of the corresponding racemates. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400420

FULL PAPER
A Facile Synthesis of Optically Active β-Amino-β-arylethylphosphonates by
Mitsunobu Reaction[‡]
Chengfu Xu[a] and Chengye Yuan*[a]
Keywords: β-Amino-β-arylethylphosphonates / Mitsunobu reaction / SN2 mechanism
We describe a convenient and simple synthesis of optically
active β-amino-β-arylethylphosphonates based on Mitsu-
nobu reactions of chiral β-aryl-β-hydroxyethylphosphonates,
prepared in turn by Candida rugosa lipase catalyzed kinetic
resolution of the corresponding racemates.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
with nitriles,[2a] β-oxophosphonates have been subjected to
reductive amination,[2b,3b,3c,5] etc. As to the preparation of
As phosphorus analogues of amino acids, aminophos- optically active β-amino-β-arylethylphosphonic acids and
phonic acids have attracted particular interest and have at- their esters, only Mikolajczyk et al. have reported asymmet-
tained a position of prominence in fields of research di- ric additions of α-phosphonate carbanions to enantiopure
rected towards the discovery, understanding, and modifi- sulfinimines.[6] The Mitsunobu reaction[7] is one of the most
cation of physiological processes in living organisms.[1,2] In effective reactions that can convert a hydroxy function into
the literature,[3] some racemic α-amino-β-arylethylphos- an amino group in organic molecules. To the best of our
phonic acids and β-amino-β-arylethylphosphonic acids are knowledge there are no reports dealing with the synthetic
reported to be strong inhibitors of PAL and anthocyanin application of this method to the preparation of β-amino-
synthesis and are also quite active botryticides. Some com- β-arylethylphosphonic acids and their esters.[7]
pounds, such as IϪIV, even gave full protection against
botrytis cinerea (on apples) at levels down to 60 ppm. An-
other important use of β-amino-β-arylethylphosphonic ac-
ids is as potential GABAB receptor antagonists;[4] examples
include compounds I and V.[4a]
In this paper we describe a convenient and simple pro-
cedure for the synthesis of optically active β-amino-β-aryle-
thylphosphonates based on subjection of chiral β-aryl-β-
hydroxyethylphosphonates[8a,8b] Ϫ conveniently prepared
by enzymatic catalysis[8] Ϫ to Mitsunobu reaction con-
ditions.
Result and Discussion
Because of their potential utilization and biological ac-
tivities, the chiral synthesis of β-amino-β-arylethylphos-
phonic acids and their esters is of interest to organic and
biological chemists.
There are a few reports on the synthesis of racemic β-
amino-β-arylethylphosphonic acids and their esters. As ex-
amples, lithiated methylphosphonates have been treated
A number of (2S)-β-aryl-β-hydroxyethylphosphonates
(1aϪj) and (2R)-β-aryl-β-butyryloxyethylphosphonates
were obtained by Candia rugosa lipase catalyzed (CRL-cat-
alyzed) hydrolysis in diisopropyl ether pre-equilibrated with
1.2  aqueous MgCl2.[8a,8b] The (2R)-β-aryl-β-butyryloxye-
thylphosphonates were then transformed into the corre-
sponding (2R)-β-aryl-β-hydroxyethylphosphonates (2aϪj)
by hydrolysis with use of a NaOH/H2O/MeOH system
rather than a K2CO3/MeOH system, since longer reaction
times were required in the latter case, even with no hydro-
lytic reaction sometimes being observed. As we have shown,
[‡]
Studies on Organophosphorus Compounds, 134. Part 133:
C. Xu, C. Yuan, Synthesis, in press.
[a]
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences
345 Lingling Lu, Shanghai, 200032, China
Fax: (internat.) ϩ 86-21-64166128
E-mail: yuancy@mail.sioc.ac.cn
4410
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400420
Eur. J. Org. Chem. 2004, 4410Ϫ4415

A Facile Synthesis of Optically Active β-Amino-β-arylethylphosphonates by Mitsunobu Reaction
FULL PAPER
this enzyme-catalyzed process gave good chemical yields
and excellent enantiomeric excesses[8a,8b] (Scheme 1).
Table 1. Synthesis of title compounds 3 and 4
Entry
R
Ar
Yield (%)
ee (%)
3
4
5
6
3[a]
4[b]
a
b
c
d
e
f
g
h
i
Me C6H5
80 79 95 93 95.0
82 84 96 96 95.2
83 82 94 95 58.9
94.8
96.7
60.5
50.9
7.5
96.7
98.8
95.8
99.4
98.7
Et
Et
Et
Et
Et
Et
Et
Et
Et
C6H5
4-MeC6H4
4-MeOC6H4 85 88 92 97 40.5
2-furyl
2-BrC6H4
4-FC6H4
4-ClC6H4
2,4-Cl2C6H3
4-O2NC6H4
89 91 95 95
7.8
72 69 93 94 95.5
93 91 96 92 97.1
91 91 90 91 95.1
70 71 89 91 99.8
55 50 85 88 97.6
j
[a] The ee values were determined by chiral HPLC of their derivative
5. [b] The ee values were determined by chiral HPLC of their deriva-
tive 6.
Scheme 1
The optically active β-aryl-β-hydroxyethylphosphonates
(1aϪj and 2aϪj) were converted into the corresponding chi-
ral β-amino-β-arylethylphosphonates with inversion of con-
figuration by an SN2 mechanism under Mitsunobu reaction
conditions (Scheme 2 and Table 1).
In order to evaluate this SN2 inversion process in the Mit-
sunobu reaction, the ee values of the title compounds 3aϪj
and 4aϪj required confirmation. Since the enantiomers of
the compounds 3aϪj or 4aϪj could not be resolved by chi-
ral HPLC, enantiomeric excess values could not be ob-
tained directly; thus, derivatization of those compounds was
conducted. The conversion of amines into their correspond-
ing benzyloxycarbonyl (Cbz) derivatives in 1  NaHCO3
was a good choice, since some literature examples[7b,9] have
utilized this method to determine the ee values of amines
(Scheme 3 and Table 1).
Scheme 3
From Table 1, we see that the results of the SN2 inversion
process in the Mitsunobu reaction are dependent on the
nature of the aryl substituents. If there are no substituent
groups (C6H5) or electron-withdrawing groups (F, Cl, Br,
or NO2) in the benzene ring, chiral β-aryl-β-hydroxyethyl-
phosphonates (1aϪj and 2aϪj) are converted into optically
active β-aryl-β-azidoethylphosphonates with almost com-
plete SN2 inversion of configuration under Mitsunobu reac-
tion conditions (ee values above 95%, even up to 99.8%).
The presence of electron-donating groups (entries c, d, e)
on the benzene ring produces a decrease in the ee values
due to partial SN2 reaction (ee values below 60%, even less
than 10%).
Scheme 2
In this reaction, instead of extraction with n-hexane[7aϪ7c]
to obtain the β-aryl-β-azidoethylphosphonates, the solvents
were evaporated under reduced pressure, and the residue
Thompson et al. reported the use of (PhO)2P(O)N3
was treated directly with Ph3P in benzene. The chiral title (DPPA)/DBU/THF to convert activated alcohols into az-
compounds 3aϪj and 4aϪj were finally synthesized in high ides.[10] We tried the this system to transform chiral β-aryl-
yields and with good enantiomeric excesses (Table 1).
β-hydroxyethylphosphonates (1j) into optically active β-am-
Eur. J. Org. Chem. 2004, 4410Ϫ4415
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4411

C. Xu, C. Yuan
FULL PAPER
1.2 mmol) in CH2Cl2 (2 mL) was added dropwise with stirring and
external cooling, at Ϫ15 to Ϫ10 °C, to a solution of DEAD (2.1 g,
1.2 mmol) in CH2Cl2 (0.5 mL). After 10 min, a solution of chiral β-
aryl-β-hydroxyethylphosphonates (2aϪj and 1aϪj) (1.0 mmol) was
added at the same temperature. HN3 in CHCl3 (5 mL)[11] was then
added dropwise. The mixture was kept at Ϫ15 to Ϫ10 °C for about
2 h and then at room temperature for another 3Ϫ6 h. After the
reaction mixture had been concentrated in vacuo, the residue was
dissolved in benzene (5 mL), and Ph3P (0.28 g, 1.1 mmol) was ad-
ded in one portion to the solution. After this mixture had been
stirred at room temperature for 2 h, water (0.2 mL) was added, and
the mixture was heated at 50Ϫ55 °C for 4 h. The reaction mixture
was allowed to cool to room temperature and extracted with aque-
ous HCl (3ϫ5 mL). The combined acid extracts were washed with
ethyl acetate (3 ϫ 10 mL), and the acid phase was neutralized to
pH ϭ 8Ϫ9 with Na2CO3 and was then extracted with ethyl acetate
(3 ϫ 10 mL). The combined organic extracts were washed with
brine (1 ϫ 15 mL) and dried with Na2SO4, and the solvents were
evaporated in vacuo to furnish the optically active products (3aϪj
and 4aϪj).
ino-β-arylethylphosphonates (3j), but the results were worse
than those of the Mitsunobu reaction (Scheme 4).
Scheme 4
We finally evaluated the Mitsunobu reaction SN2 inver-
sion process by comparison of the optical rotations of the
optically active dimethyl β-amino-β-arylethylphosphonate
(3a). The absolute configuration of dimethyl (2R)-β-amino-
β-arylethylphosphonate was determined by X-ray analysis
of its phosphonic acid, and its optical rotation is [α]D22
ϭ
Dimethyl (2R)-β-Amino-β-phenylethylphosphonate (3a): Colorless
oil. [α]2D0 ϭ Ϫ15.3 (c ϭ 1.0, CHCl3). IR (liquid film): ν˜max ϭ 3420,
Ϫ18.18 (c ϭ 1.2, CHCl3),[6] while the optical rotation of the
title compound (3a) is [α]2D0 ϭ Ϫ15.3 (c ϭ 1.0, CHCl3).
From the above data, the absolute configuration of di-
methyl β-amino-β-arylethylphosphonate (3a) was deduced
to be (2R), while the absolute configuration of dimethyl β-
aryl-β-hydroxyethylphosphonate (1a) is (2S). Consequently,
the Mitsunobu reaction here is also an SN2 process, as ex-
pected.
2955, 2852, 1455, 1241, 1056, 1032 cmϪ1 1H NMR (300 MHz,
.
CDCl3): δ ϭ 7.41Ϫ7.27 (m, 5 H, ArH), 4.45Ϫ4.38 (m, 1 H, ArCH),
3.76Ϫ3.66 (m, 6 H, OCH3), 2.27 (s, 2 H, NH2), 2.26Ϫ2.13 (m, 2
H, CHCH2P) ppm. 31P NMR (120 MHz, CDCl3): δ ϭ 32.3 ppm.
EI-MS: m/z (%) ϭ 229 (4) [Mϩ], 214 (7), 132 (9), 124 (18), 120
(28), 106 (100), 94 (54), 79 (72), 77 (24), 47 (18). C10H16NO3P
(229.21): calcd. C 52.40, H 7.04, N 6.11; found C 52.65, H 7.24,
N 5.99.
Dimethyl (2S)-β-Amino-β-phenylethylphosphonate (4a): Colorless
oil. [α]2D0 ϭ ϩ15.0 (c ϭ 1.0, CHCl3). Compound 4a is the enanti-
omer of 3a; its spectroscopic data are identical to those of 3a.
C10H16NO3P (229.21): calcd. C 52.40, H 7.04, N 6.11; found C
52.69, H 7.31, N 5.89.
Conclusion
In summary, we describe a convenient and simple method
for the synthesis of optically active β-amino-β-arylethylpho-
sphonates in high yields and with good enantiomeric excess
through the use of a Mitsunobu reaction SN2 inversion pro-
cess.
Diethyl (2R)-β-Amino-β-phenylethylphosphonate (3b): Colorless oil.
[α]2D0 ϭ ϩ8.2 (c ϭ 1.1, CHCl3). IR (liquid film): ν˜max ϭ 3473, 3373,
2983, 2903, 1494, 1455, 1392, 1238, 1054, 1028, 968, 701 cmϪ1. 1H
NMR (300 MHz, CDCl3): δ ϭ 7.41Ϫ7.27 (m, 5 H, ArH),
4.48Ϫ4.38 (m, 1 H, ArCH), 4.13Ϫ4.02 (m, 4 H, OCH2CH3), 2.39
(s, 2 H, NH2), 2.23Ϫ2.13 (m, 2 H, CHCH2P), 1.30 (t, J ϭ 7.2 Hz,
6 H, OCH2CH3) ppm. 31P NMR (120 MHz, CDCl3): δ ϭ
28.7 ppm. EI-MS: m/z (%) ϭ 257 (5) [Mϩ], 228 (5), 152 (4), 125
(11), 119 (30), 106 (100), 97 (9), 79 (11), 77 (8), 65 (3). C12H20NO3P
(257.27): calcd. C 56.02, H 7.84, N 5.44; found C 56.30, H 8.09,
N 5.16.
Experimental
General: IR spectra were recorded with a Shimadzu IR-440 spec-
trometer. EI mass spectra (MS) were run with an HP-5989A mass
spectrometer. 1H NMR spectra were recorded with a Bruker AMX
330 (300 MHz) spectrometer in CDCl3, and chemical shifts are re-
ported in ppm downfield relative to TMS (internal standard). 31P
NMR spectra were taken with the same spectrometer with 80%
phosphoric acid as external standard. CRL (901 units/mg) was pur-
chased from Sigma Chemical Co. Chiral liquid chromatography
system: Waters 515 HPLC pump; UV Waters 2487 Dual λ Ab-
sorbance Detector, 254 nm; Penelson Network chromatography in-
terface NCI 900, Turbochrom Navigator data station software;
CHIRALPAK AD column and dimensions: 0.46 cm ϫ 25 cm; flow
rate: 0.7 mL/min; eluent: hexane/2-propanol ϭ 9:1 to 8:2 (v/v).
Diethyl (2S)-β-Amino-β-phenylethylphosphonate (4b): Colorless oil.
[α]2D0 ϭ Ϫ8.5 (c ϭ 1.0, CHCl3). Compound 4b is the enantiomer of
3b; its spectroscopic data are identical to those of 3b. C12H20NO3P
(257.27): calcd. C 56.02, H 7.84, N 5.44; found C 56.32, H 8.01,
N 5.22.
Diethyl (2R)-β-Amino-β-(p-methylphenyl)ethylphosphonate (3c):
Colorless oil. [α]2D0 ϭ Ϫ3.5 (c ϭ 0.7, CHCl3). IR (liquid film):
ν˜max ϭ 3373, 2983, 2908, 1515, 1240, 1054, 1029, 966, 821 cmϪ1
.
1H NMR (300 MHz, CDCl3): δ ϭ 7.28 (d, J ϭ 7.8 Hz, 2 H, ArH),
7.15 (d, J ϭ 7.8 Hz, 2 H, ArH), 4.42Ϫ4.36 (m, 1 H, ArCH),
4.13Ϫ4.03 (m, 4 H, OCH2CH3), 2.33 (s, 3 H, ArCH3), 2.17 (s, 2
H, NH2), 2.19Ϫ2.04 (m, 2 H, CHCH2P), 1.31 (t, J ϭ 7.2 Hz, 6 H,
OCH2CH3) ppm. 31P NMR (120 MHz, CDCl3): δ ϭ 29.8 ppm. EI-
MS: m/z (%) ϭ 271 (4) [Mϩ], 242 (2), 152 (2), 133 (34), 120 (100),
General Procedure for the Preparation of Chiral β-Aryl-β-hydroxy-
ethylphosphonates 1a؊j and 2a؊j: This was based on the litera-
ture method.[8]
General Procedure for the Preparation of Chiral β-Amino-β-aryl-
ethylphosphonates 3a؊j and 4a؊j: A solution of Ph3P (0.31 g,
4412
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4410Ϫ4415

A Facile Synthesis of Optically Active β-Amino-β-arylethylphosphonates by Mitsunobu Reaction
FULL PAPER
118 (15), 97 (6), 91 (12), 80 (6), 65 (5). C13H22NO3P (271.30): calcd.
C 57.55, H 8.17, N 5.16; found C 57.80, H 8.19, N 5.16.
1 H, ArCH), 4.13Ϫ4.03 (m, 4 H, OCH2CH3), 2.22 (s, 2 H, NH2),
2.16Ϫ2.07 (m, 2 H, CHCH2P), 1.31 (t, J ϭ 7.2 Hz, 6 H,
OCH2CH3) ppm. 31P NMR (120 MHz, CDCl3): δ ϭ 24.4 ppm. EI-
MS: m/z (%) ϭ 275 (5) [Mϩ], 246 (5), 152 (8), 137 (36), 125 (28),
124 (100), 122 (20), 108 (9), 97 (21), 80 (12). C12H19FNO3P
(275.26): calcd. C 52.36, H 6.96, N 5.09; found C 52.49, H 6.90,
N 5.08.
Diethyl (2S)-β-Amino-β-(p-methylphenyl)ethylphosphonate (4c):
Colorless oil. [α]2D0 ϭ ϩ3.5 (c ϭ 1.0, CHCl3). Compound 4c is the
enantiomer of 3c; its spectroscopic data are identical to those of
3c. C13H22NO3P (271.30): calcd. C 57.55, H 8.17, N 5.16; found C
57.82, H 8.29, N, 5.36.
Diethyl (2S)-β-Amino-β-(p-fluorophenyl)ethylphosphonate (4g): Col-
orless oil. [α]2D0 ϭ ϩ15.4 (c ϭ 1.8, CHCl3). Compound 4g is the
enantiomer of 3g; its spectroscopic data are identical to those of
3g. C12H19FNO3P (275.26): calcd. C 52.36, H 6.96, N 5.09; found
C 52.17, H 6.96, N, 5.28.
Diethyl (2R)-β-Amino-β-(p-methoxyphenyl)ethylphosphonate (3d):
Colorless oil. [α]2D0 ϭ Ϫ3.2 (c ϭ 1.0, CHCl3). IR (liquid film):
ν˜max ϭ 3370, 2983, 2909, 1612, 1513, 1249, 1052, 1030, 967, 833
cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ 7.31 (d, J ϭ 6.9 Hz, 2 H,
ArH), 6.88 (d, J ϭ 6.6 Hz, 2 H, ArH), 4.43Ϫ4.39 (m, 1 H, ArCH),
4.13Ϫ4.02 (m, 4 H, OCH2CH3), 3.80 (s, 3 H, OCH3), 2.26 (s, 2 H,
NH2), 2.18Ϫ2.04 (m, 2 H, CHCH2P), 1.31 (t, J ϭ 6.9 Hz, 6 H,
OCH2CH3) ppm. 31P NMR (120 MHz, CDCl3): δ ϭ 27.3 ppm. EI-
MS: m/z (%) ϭ 287 (8) [Mϩ], 271 (10), 149 (44), 136 (100), 134
(29), 109 (10), 93 (5), 79 (5), 77 (6), 65 (5). C13H22NO4P (287.29):
calcd. C 54.35, H 7.72, N 4.88; found C 54.11, H 7.77, N 4.78.
Diethyl (2R)-β-Amino-β-(p-chlorophenyl)ethylphosphonate (3h):
Colorless oil. [α]2D0 ϭ Ϫ8.2 (c ϭ 1.3, CHCl3). IR (liquid film):
ν˜max ϭ 3373, 3299, 2984, 2908, 1491, 1238, 1090, 1054, 1028, 967,
828 cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ 7.33 (dd, J ϭ 8.7 Hz,
4 H, ArH), 4.08 (dt, J ϭ 4.2, 9.9 Hz, 1 H, ArCH), 4.12Ϫ4.02 (m,
O4 H, CH2CH3), 2.77 (s, 2 H, NH2), 2.22Ϫ2.05 (m, 2 H,
CHCH2P), 1.30 (t, J ϭ 7.2 Hz, 6 H, OCH2CH3) ppm. 31P NMR
(120 MHz, CDCl3): δ ϭ 28.3 ppm. EI-MS: m/z (%) ϭ 291 (10)
[Mϩ], 262 (9), 153 (44), 140 (100), 125 (29), 108 (10), 97 (14), 80
(10), 77 (8). C12H19ClNO3P (291.71): calcd. C 49.41, H 6.56, N
4.80; found C 49.09, H 6.52, N 4.86.
Diethyl (2S)-β-Amino-β-(p-methoxyphenyl)ethylphosphonate (4d):
Colorless oil. [α]2D0 ϭ ϩ3.5 (c ϭ 1.0, CHCl3). Compound 4d is the
enantiomer of 3d; its spectroscopic data are identical to those of
3d. C13H22NO4P (287.29): calcd. C 54.35, H 7.72, N 4.88; found C
54.09, H 7.72, N, 4.79.
Diethyl (2S)-β-Amino-β-(p-chlorophenyl)ethylphosphonate (4h): Col-
orless oil. [α]2D0 ϭ ϩ8.5 (c ϭ 1.0, CHCl3). Compound 4h is the
enantiomer of 3h; its spectroscopic data are identical to those of
3h. C12H19ClNO3P (291.71): calcd. C 49.41, H 6.56, N 4.80; found
C 49.27, H 6.81, N 4.71.
Diethyl (2R)-β-Amino-β-(2-furyl)ethylphosphonate (3e): Colorless
oil. [α]2D0 ϭ Ϫ0.5 (c ϭ 0.8, CHCl3). IR (liquid film): ν˜max ϭ 3459,
3379, 2985, 2910, 1232, 1054, 1027, 969 cmϪ1. 1H NMR (300 MHz,
CDCl3): δ ϭ 7.36Ϫ7.35 (1 H, m, C4H3O), 6.33Ϫ6.22 (m, 2 H,
C4H3O), 4.48Ϫ4.40 (m,
1 H, ArCH), 4.16Ϫ4.05 (m, 4 H,
Diethyl (2R)-β-Amino-β-(o,p-dichlorophenyl)ethylphosphonate (3i):
Colorless oil. [α]2D0 ϭ Ϫ33.8 (c ϭ 0.8, CHCl3). IR (liquid film):
OCH2CH3), 2.54 (s, 2 H, NH2), 2.42Ϫ2.05 (m, 2 H, CHCH2P),
1.35Ϫ1.26 (m, 6 H, OCH2CH3) ppm. 31P NMR (120 MHz,
CDCl3): δ ϭ 31.2 ppm. EI-MS: m/z (%) ϭ 247 (13) [Mϩ], 218 (11),
172 (5), 125 (12), 109 (75), 96 (100), 80 (16), 69 (9). HR-MS calcd.
for C10H18NO4P [Mϩ]: 247.0973; found 247.1014.
ν˜max ϭ 3377, 3306, 2984, 2908, 1471, 1237, 1053, 1028, 968 cmϪ1
.
1H NMR (300 MHz, CDCl3): δ ϭ 7.64 (d, J ϭ 8.4 Hz, 1 H, ArH),
7.37Ϫ7.26 (m, 3 H, ArH), 4.80 (dt, J ϭ 3.3, 11.4 Hz, 1 H, ArCH),
4.19Ϫ4.03 (m, 4 H, OCH2CH3), 2.66 (s, 2 H, NH2), 2.27Ϫ2.01 (m,
2 H, CHCH2P), 137Ϫ1.27 (m, 6 H, OCH2CH3) ppm. 31P NMR
(120 MHz, CDCl3): δ ϭ 27.7 ppm. EI-MS: m/z (%) ϭ 326 (3) [Mϩ
ϩ 1], 290 (22), 187 (25), 174 (100), 152 (24), 125 (45), 108 (17), 97
(24), 80 (19). C12H18Cl2NO3P (326.16): calcd. C 44.19, H 5.56, N
4.29; found C 44.17, H 5.86, N 4.00.
Diethyl (2S)-β-Amino-β-(2-furyl)ethylphosphonate (4e): Colorless
oil. [α]2D0 ϭ ϩ1.0 (c ϭ 0.9, CHCl3). Compound 4e is the enantiomer
of 3e; its spectroscopic data are identical to those of 3e. HR-MS
calcd. for C10H18NO4P [Mϩ]: 247.0973. Found: 247.1001.
Diethyl (2R)-β-Amino-β-(o-bromophenyl)ethylphosphonate (3f): Col-
orless oil. [α]2D0 ϭ Ϫ31.7 (c ϭ 0.7, CHCl3). IR (liquid film): ν˜max ϭ
3376, 2983, 2908, 1467, 1441, 1236, 1054, 1027, 969, 758 cmϪ1. 1H
NMR (300 MHz, CDCl3): δ ϭ 7.66 (d, J ϭ 7.8 Hz, 1 H, ArH),
7.52 (d, J ϭ 7.8 Hz, 1 H, ArH), 7.34 (t, J ϭ 7.5 Hz, 1 H, ArH),
7.12 (d, J ϭ 7.5 Hz, 1 H, ArH), 4.79 (dt, J ϭ 2.7, 11.4 Hz, 1 H,
ArCH), 4.20Ϫ4.04 (m, 4 H, OCH2CH3), 2.33 (s, 2 H, NH2),
2.30Ϫ1.98 (m, 2 H, CHCH2P), 1.38Ϫ1.27 (m, 6 H, OCH2CH3)
ppm. 31P NMR (120 MHz, CDCl3): δ ϭ 26.5 ppm. EI-MS: m/z
(%) ϭ 336 (1) [Mϩ], 256 (62), 199 (20), 186 (91), 184 (100), 152
(15), 125 (36), 104 (14), 97 (21), 80 (15). C12H19BrNO3P (336.16):
calcd. C 42.88, H 5.70, N 4.17; found C 42.81, H 5.90, N, 4.01.
Diethyl (2S)-β-Amino-β-(o,p-dichlorophenyl)ethylphosphonate (4i):
Colorless oil. [α]2D0 ϭ ϩ33.8 (c ϭ 1.0, CHCl3). Compound 4i is the
enantiomer of 3i; its spectroscopic data are identical to those of 3i.
C12H18Cl2N2O3P (326.16): calcd. C 44.19, H 5.56, N 4.29; found
C 44.11, H 5.85, N 4.07.
Diethyl (2R)-β-Amino-β-(p-nitrophenyl)ethylphosphonate (3j): Col-
orless oil. [α]2D0 ϭ ϩ13.3 (c ϭ 0.6, CHCl3). IR (liquid film): ν˜max ϭ
3377, 2985, 2909, 1608, 1521, 1348, 1239, 1053, 1028, 967, 857
cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ 8.20 (d, J ϭ 7.2 Hz, 2 H,
ArH), 7.61 (d, J ϭ 6.9 Hz, 2 H, ArH), 4.59Ϫ4.51 (m, 1 H, ArCH),
4.16Ϫ4.06 (m, 4 H, OCH2CH3), 2.48 (s, 2 H, NH2), 2.19Ϫ2.05 (m,
2 H, CHCH2P), 1.32 (dt, J ϭ 3.3, 6.9 Hz, 6 H, OCH2CH3) ppm.
31P NMR (120 MHz, CDCl3): δ ϭ 25.5 ppm. EI-MS: m/z (%) ϭ
302 (1) [Mϩ], 285 (32), 258 (6), 273 (19), 164 (46), 152 (100), 125
(92), 105 (30), 97 (42), 80 (25). C12H19N2O5P (302.27): calcd. C
47.68, H 6.78, N 9.27; found C 47.48, H 6.73, N 8.99.
Diethyl (2S)-β-Amino-β-(o-bromophenyl)ethylphosphonate (4f): Col-
orless oil. [α]2D0 ϭ ϩ31.9 (c ϭ 1.0, CHCl3). Compound 4f is the
enantiomer of 3f; its spectroscopic data are identical to those of 3f.
C12H19BrNO3P (336.16): calcd. C 42.88, H 5.70, N 4.17; found C
42.58, H 5.96, N 4.00.
Diethyl (2R)-β-Amino-β-(p-fluorophenyl)ethylphosphonate (3g): Col-
orless oil. [α]2D0 ϭ Ϫ15.1 (c ϭ 2.3, CHCl3). IR (liquid film): ν˜max ϭ
Diethyl (2S)-β-Amino-β-(p-nitrophenyl)ethylphosphonate (4j): Col-
orless oil. [α]2D0 ϭ Ϫ13.8 (c ϭ 1.0, CHCl3). Compound 4i is the
3468, 3373, 3299, 2985, 2909, 1604, 1510, 1228, 1054, 1029, 967, enantiomer of 3i; its spectroscopic data are identical to those of 3i.
840 cmϪ1 1H NMR (300 MHz, CDCl3): δ ϭ 7.39Ϫ7.35 (t, J ϭ C12H19N2O5P (302.27): calcd. C 47.68, H 6.78, N, 9.27; found C
7.5 Hz, 2 H, ArH), 7.02 (t, J ϭ 7.8 Hz, 2 H, ArH), 4.46Ϫ4.38 (m, 47.57, H 6.67, N 9.01.
.
Eur. J. Org. Chem. 2004, 4410Ϫ4415
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4413

C. Xu, C. Yuan
FULL PAPER
General Procedure for the Preparation of Chiral β-Aryl-β-(benzyl-
Diethyl (2R)-β-Benzyloxycarbonylamino-β-(p-methoxyphenyl)ethyl-
oxycarbonylamino)ethylphosphonates 5a؊j and 6a؊j: Substrates phosphonate (5d): Colorless oil. [α]2D0 ϭ ϩ17.8 (c ϭ 0.5, CHCl3). IR
3aϪj and 4aϪj (50 mg), CbzCl (0.3 mL), and NaHCO3 (1 , 1 mL)
were placed in a flask, and after the mixture had been stirred at
room temperature for 1 h, ethyl acetate (5 mL) and brine (5 mL)
were added. The aqueous layer was extracted with ethyl acetate (3
(liquid film): ν˜max ϭ 3267, 2983, 1720, 1515, 1249, 1028, 969, 835,
1
699 cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 7.33 (s, 5 H, ArH),
7.26 (d, J ϭ 8.4 Hz, 2 H, ArH), 6.87 (d, J ϭ 6.6 Hz, 2 H, ArH),
6.07 (s, 1 H, NH), 5.14Ϫ5.02 (m, 3 H, OCH2Ph, ArCH), 4.04Ϫ3.81
ϫ5 mL); the combined extracts were dried with anhydrous sodium (m, 4 H, OCH2CH3), 3.80 (s, 3 H, OCH3), 2.41Ϫ2.20 (m, 2 H,
sulfate, the solvent was removed under reduced pressure, and the
residue was subjected to flash chromatography to furnish the chiral
CHCH2P), 1.25 (t, J ϭ 7.2 Hz, 3 H, OCH2CH3), 1.15 (t, J ϭ
7.2 Hz, 3 H, OCH2CH3) ppm. EI-MS: m/z (%) ϭ 421 (5) [Mϩ],
products 5aϪj and 6aϪj. The eluting solvents were ethyl acetate 300 (7), 286 (100), 258 (11), 230 (8), 212 (6), 192 (9), 134 (15), 91
and n-hexane (1:1 to 3:1) and the yields are listed in Table 1.
(60), 77 (5). C21H28NO6P (421.43): calcd. C 59.85, H 6.70, N 3.32;
found C 59.57, H 6.54, N 3.14.
Dimethyl (2R)-β-Benzyloxycarbonylamino-β-phenylethylphosphon-
ate (5a): Colorless oil. [α]2D0 ϭ Ϫ23.7 (c ϭ 1.0, CHCl3). IR (liquid
film): ν˜max ϭ 3271, 3064, 2955, 1720, 1536, 1253, 1061, 1033, 818,
699 cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ 7.37Ϫ7.24 (m, 10 H,
ArH), 6.09 (s, 1 H, NH), 5.18Ϫ5.04 (m, 3 H, OCH2Ph, ArCH),
3.63 (d, J ϭ 11.1 Hz, 3 H, OCH3), 3.43 (d, J ϭ 10.5 Hz, 3 H,
OCH3), 2.50Ϫ2.28 (m, 2 H, CHCH2P) ppm. EI-MS: m/z (%) ϭ
363 (5) [Mϩ], 255 (7), 242 (12), 228 (36), 214 (30), 146 (25), 132
(30), 124 (48), 110 (39), 91 (100), 77 (18). C18H22NO5P (363.35):
calcd. C 59.50, H 6.10, N 3.85; found C 59.37, H 6.17, N 3.74.
Diethyl (2S)-β-Benzyloxycarbonylamino-β-(p-methoxyphenyl)ethyl-
phosphonate (6d): Colorless oil. [α]2D0 ϭ Ϫ18.2 (c ϭ 0.8, CHCl3).
Compound 6d is the enantiomer of 5d; its spectroscopic data are
identical to those of 5d. C21H28NO6P (421.43): calcd. C 59.85, H
6.70, N 3.32; found C 59.87, H 6.73, N 3.09.
Diethyl (2R)-β-Benzyloxycarbonylamino-β-(2-furyl)ethylphosphon-
ate (5e): Colorless oil. [α]2D0 ϭ ϩ7.2 (c ϭ 0.6, CHCl3). IR (liquid
film): ν˜max ϭ 3245, 3036, 2984, 2933, 1722, 1540, 1507, 1257, 1027,
1
969, 739, 699 cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 7.36Ϫ7.30
(m, 6 H, ArH, C4H3O), 6.32Ϫ6.24 (m, 2 H, C4H3O), 5.96 (d, J ϭ
7.2 Hz, 1 H, NH), 5.29Ϫ5.12 (m, 3 H, OCH2Ph, ArCH), 4.07Ϫ3.86
(m, 4 H, OCH2CH3), 2.48Ϫ2.27 (m, 2 H, CHCH2P), 1.26 (t, J ϭ
7.2 Hz, 3 H, OCH2CH3), 1.18 (t, J ϭ 7.2 Hz, 3 H, OCH2CH3)
ppm. EI-MS: m/z (%) ϭ 381 (3) [Mϩ], 343 (65), 260 (35), 246 (100),
218 (29), 205 (34), 172 (44), 138 (39), 111 (55), 91 (53), 65 (24%).
C18H24NO6P (381.36): calcd. C 56.69, H 6.34, N 3.67; found C
56.58, H 6.09, N 3.63.
Dimethyl (2S)-β-Benzyloxycarbonylamino-β-phenylethylphosphonate
(6a): Colorless oil. [α]2D0 ϭ ϩ23.8 (c ϭ 1.0, CHCl3). Compound 6a
is the enantiomer of 5a; its spectroscopic data are identical to those
of 5a. C18H22NO5P (363.35): calcd. C 59.50, H 6.10, N 3.85; found
C 59.57, H 6.09, N 3.69.
Diethyl (2R)-β-Benzyloxycarbonylamino-β-phenylethylphosphonate
(5b): Colorless oil. [α]2D0 ϭ Ϫ22.5 (c ϭ 0.8, CHCl3). IR (liquid film):
ν˜max ϭ 3267, 3034, 2984, 2909, 1722, 1537, 1249, 1025, 968, 699
Diethyl (2S)-β-Benzyloxycarbonylamino-β-(2-furyl)ethylphosphonate
(6e): Colorless oil. [α]2D0 ϭ Ϫ7.5 (c ϭ 0.8, CHCl3). Compound 6e
is the enantiomer of 5e; its spectroscopic data are identical to those
of 5e. C18H24NO6P (381.36): calcd. C 56.69, H 6.34, N 3.67; found
C 56.41, H 6.39, N 3.56.
cmϪ1 1H NMR (300 MHz, CDCl3): δ ϭ 7.36Ϫ7.24 (m, 10 H,
.
ArH), 6.14 (s, 1 H, NH), 5.16Ϫ5.03 (m, 3 H, OCH2Ph, ArCH),
4.05Ϫ3.76 (m, 4 H, OCH2CH3), 2.39Ϫ2.24 (m, 2 H, CHCH2P),
1.24 (t, J ϭ 7.5 Hz, 3 H, OCH2CH3), 1.10 (t, J ϭ 7.2 Hz, 3 H,
OCH2CH3) ppm. EI-MS: m/z (%) ϭ 391 (11) [Mϩ], 256 (60), 242
(23), 228 (9), 196 (11), 182 (7), 138 (11), 125 (11), 104 (13), 91 (100),
77 (8). C20H26NO5P (391.40): calcd. C 61.37, H 6.70, N 3.58; found
C 61.53, H 6.69, N 3.54.
Diethyl
(2R)-β-Benzyloxycarbonylamino-β-(o-bromophenyl)ethyl-
phosphonate (5f): Colorless oil. [α]2D0 ϭ ϩ5.6 (c ϭ 1.0, CHCl3). IR
(liquid film): ν˜max ϭ 3262, 3065, 2984, 1724, 1562, 1254, 1055,
1025, 969, 755, 698 cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 7.53
1
Diethyl (2S)-β-Benzyloxycarbonylamino-β-phenylethylphosphonate
(6b): Colorless oil. [α]2D0 ϭ ϩ22.9 (c ϭ 1.0, CHCl3). Compound 6b
is the enantiomer of 5b; its spectroscopic data are identical to those
of 5b. C20H26NO5P (391.40): calcd. C 61.37, H 6.70, N 3.58; found
C 61.52, H 6.67, N 3.55.
(d, J ϭ 7.8 Hz, 1 H, ArH), 7.47 (d, J ϭ 7.2 Hz, 1 H, ArH),
7.34Ϫ7.27 (m, 6 H, ArH), 7.13 (d, J ϭ 7.2 Hz, 1 H, ArH), 6.10 (d,
J ϭ 3.3 Hz, 1 H, NH), 5.41 (dd, J ϭ 5.4, 23.1 Hz, 1 H, ArCH),
5.13Ϫ5.03 (m, 2 H, OCH2Ph), 4.16Ϫ3.84 (m, 4 H, OCH2CH3),
2.44Ϫ2.32 (m, 2 H, CHCH2P), 1.28 (t, J ϭ 6.9 Hz, 3 H,
OCH2CH3), 1.09 (t, J ϭ 6.3 Hz, 3 H, OCH2CH3) ppm. EI-MS:
m/z (%) ϭ 471 (2) [Mϩ], 469 (2) [Mϩ], 390 (76), 347 (9), 277 (8),
257 (32), 241 (13), 211 (14), 183 (17), 125 (11), 91 (100), 65 (8).
C20H25BrNO5P (470.30): calcd. C 51.08, H 5.36, N 2.98; found C
51.38, H 5.44, N 2.89.
Diethyl (2R)-β-Benzyloxycarbonylamino-β-(p-methylphenyl)ethyl-
phosphonate (5c): Colorless oil. [α]2D0 ϭ Ϫ3.2 (c ϭ 1.0, CHCl3). IR
(liquid film): ν˜max ϭ 3266, 3034, 2983, 2930, 1721, 1539, 1517,
1251, 1059, 1027, 967, 699 cmϪ1 1H NMR (300 MHz, CDCl3):
.
δ ϭ 7.32 (s, 5 H, ArH), 7.21 (d, J ϭ 7.5 Hz, 2 H, ArH), 7.13 (d,
J ϭ 7.2 Hz, 2 H, ArH), 6.13 (s, 1 H, NH), 5.13Ϫ5.02 (m, 3 H,
OCH2Ph, ArCH), 4.02Ϫ3.81 (m, 4 H, OCH2CH3), 2.32 (s, 3 H,
ArCH3), 2.36Ϫ2.18 (m, 2 H, CHCH2P), 1.35Ϫ1.11 (m, 6 H,
OCH2CH3) ppm. EI-MS: m/z (%) ϭ 405 (4) [Mϩ], 270 (85), 242
(10), 210 (10), 196 (7), 118 (13), 97 (7), 91 (100), 77 (6), 65 (10%).
C21H28NO5P (405.43): calcd. C 62.21, H 6.96, N 3.45; found C
62.22, H 6.97, N 3.52.
Diethyl
(2S)-β-Benzyloxycarbonylamino-β-(o-bromophenyl)ethyl-
phosphonate (6f): Colorless oil. [α]2D0 ϭ Ϫ5.8 (c ϭ 1.0, CHCl3).
Compound 6f is the enantiomer of 5f; its spectroscopic data are
identical to those of 5f. C20H25BrNO5P (470.30): calcd. C 51.08, H
5.36, N 2.98; found C 51.31, H 5.28, N 2.81.
Diethyl (2R)-β-Benzyloxycarbonylamino-β-(p-fluorophenyl)ethylpho-
sphonate (5g): Colorless oil. [α]2D0 ϭ Ϫ4.6 (c ϭ 2.8, CHCl3). IR
Diethyl
(2S)-β-Benzyloxycarbonylamino-β-(p-methylphenyl)ethyl-
(liquid film): ν˜max ϭ 3264, 3036, 2984, 2910, 1719, 1540, 1512,
1
phosphonate (6c): Colorless oil. [α]2D0 ϭ ϩ3.5 (c ϭ 1.0, CHCl3). 1251, 1226, 1058, 1027, 969, 840, 699 cmϪ1. H NMR (300 MHz,
Compound 6c is the enantiomer of 5c; its spectroscopic data are
identical to those of 5c. C21H28NO5P (405.43): calcd. C 62.21, H
6.96, N 3.45; found C 62.14, H 6.96, N 3.56.
CDCl3): δ ϭ 7.37Ϫ7.27 (m, 7 H, ArH), 7.01 (t, J ϭ 8.4 Hz, 2 H,
ArH), 6.25 (s, 1 H, NH), 5.12Ϫ5.02 (m, 3 H, OCH2Ph, ArCH),
4.06Ϫ3.80 (m, 4 H, OCH2CH3), 2.34Ϫ2.22 (m, 2 H, CHCH2P),
4414
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4410Ϫ4415

A Facile Synthesis of Optically Active β-Amino-β-arylethylphosphonates by Mitsunobu Reaction
FULL PAPER
1.25 (t, J ϭ 7.2 Hz, 3 H, OCH2CH3), 1.13 (t, J ϭ 7.2 Hz, 3 H, 97 (42), 80 (25). C20H25N2O7P (436.40): calcd. C 55.05, H 5.77, N
OCH2CH3). 31P NMR (120 MHz, CDCl3): δ ϭ 24.4. EI-MS: m/z 6.42; found C 55.28, H 5.81, N 6.18.
(%) ϭ 409 (5) [Mϩ], 301 (14), 274 (44), 164 (13), 150 (55), 138
Diethyl (2S)-β-Benzyloxycarbonylamino-β-(p-nitrophenyl)ethylphos-
(48), 111 (75), 97 (80), 91 (85), 83 (83), 70 (66), 57 (100) ppm.
phonate (6j): Colorless oil. [α]2D0 ϭ ϩ20.1 (c ϭ 1.0, CHCl3). Com-
C20H25FNO5P (409.39): calcd. C 58.68, H 6.16, N 3.42; found C
pound 6i is the enantiomer of 5i; its spectroscopic data are identical
58.90, H 6.18, N 3.29.
to those of 5i. C20H25N2O7P (436.40): calcd. C 55.05, H 5.77, N
6.42; found C 55.35, H 5.75, N 6.48.
Diethyl
(2S)-β-Benzyloxycarbonylamino-β-(p-fluorophenyl)ethyl-
phosphonate (6g): Colorless oil. [α]2D0 ϭ ϩ5.0 (c ϭ 1.6, CHCl3).
Compound 6g is the enantiomer of 5g; its spectroscopic data are
identical to those of 5g. C20H25FNO5P (409.39): calcd. C 58.68, H
6.16, N 3.42; found C 58.88, H 6.19, N 3.30.
Acknowledgments
This project was supported by the National Natural Science Foun-
dations of China (Grant No. 20272075 and 20072052).
Diethyl
(2R)-β-Benzyloxycarbonylamino-β-(p-chlorophenyl)ethyl-
phosphonate (5h): Colorless oil. [α]2D0 ϭ Ϫ6.3 (c ϭ 0.8, CHCl3). IR
(liquid film): ν˜max ϭ 3263, 3035, 2984, 2932, 1719, 1539, 1494,
1249, 1025, 969, 834, 698 cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ
7.31Ϫ7.24 (m, 9 H, ArH), 6.29 (s, 1 H, NH), 5.12Ϫ5.01 (m, 3 H,
OCH2Ph, ArCH), 4.06Ϫ3.82 (m, 4 H, OCH2CH3), 2.32Ϫ2.20 (m,
2 H, CHCH2P), 1.24 (t, J ϭ 6.9 Hz, 3 H, OCH2CH3), 1.13 (t, J ϭ
6.9 Hz, 3 H, OCH2CH3). EI-MS: m/z (%) ϭ 425 (2) [Mϩ], 290 (44),
276 (8), 262 (5), 234 (7), 138 (18), 125 (13), 91 (100), 65 (10) ppm.
C20H25ClNO5P (425.85): calcd. C 56.41, H 5.92, N 3.29; found C
56.50, H 5.90, N 3.21.
[1]
V. P. Kukhar, H. R. Hudson, Aminophosphonic and Aminophos-
phinic Acids, Wiley, Chichester, New York, 2000.
[2] [2a]
[2b]
R. Engel, Chem. Rev. 1977, 77, 349Ϫ367.
J. M. Varlet,
[2c]
N. Collignon, Synth. Commun. 1978, 8, 335Ϫ343.
W. B.
Jang, W. S. Shin, K. Lee, D. Y. Oh, Synth. Commun. 1997,
27, 4101Ϫ4105.
[3] [3a]
[3b]
L. Maier, Phosphorus, Sulfur Silicon 1990, 53, 43Ϫ67.
L. Maier, P. J. Diel, Phosphorus, Sulfur Silicon 1995, 107,
[3c]
245Ϫ255.
L. Maier, P. J. Diel, Phosphorus, Sulfur Silicon
1996, 109Ϫ110, 341Ϫ344.
[4] [4a]
G. Abbenante, R. Hughes, R. H. Prager, Aust. J. Chem.
1997, 50, 523Ϫ527. [4b] G. Abbenante, R. Hughes, R. H. Prager,
Diethyl
(2S)-β-Benzyloxycarbonylamino-β-(p-chlorophenyl)ethyl-
[4c]
Aust. J. Chem. 1994, 47, 1441Ϫ1452.
N. Hara, Y. Hara, Y.
phosphonate (6h): Colorless oil. [α]2D0 ϭ ϩ6.5 (c ϭ 1.0, CHCl3).
Compound 6h is the enantiomer of 5h; its spectroscopic data are
identical to those of 5h. C20H25ClNO5P (425.85): calcd. C 56.41,
H 5.92, N 3.29; found C 56.56, H 5.98, N 3.15.
[4d]
Goto, Jpn. J. Pharmacol. 1990, 52, 345Ϫ354.
N. Hara, Y.
Natsui, Y. Goto, Eur. J. Pharmacol. 1990, 179, 17Ϫ25.
R. F. Borch, M. D. Bernstein, H. D. Durst, J. Am. Chem. Soc.
1971, 93, 2897Ϫ2904.
[5]
[6]
M. Mikolajczyk, P. Lyzwa, J. Drabowicz, M. W. Wieczorek, J.
Blaszcyk, Chem. Commun. 1996, 1503Ϫ1504.
Diethyl
(2R)-β-Benzyloxycarbonylamino-β-(o,p-dichlorophenyl)-
ethylphosphonate (5i): Colorless oil. [α]2D0 ϭ ϩ6.5 (c ϭ 1.1, CHCl3).
IR (liquid film): ν˜max ϭ 3262, 3066, 2984, 2909, 1724, 1540, 1253,
1057, 1028, 969, 865, 755, 699 cmϪ1. 1H NMR (300 MHz, CDCl3):
δ ϭ 7.42Ϫ7.21 (m, 8 H, ArH), 6.63 (d, J ϭ 6.6 Hz, 1 H, NH),
5.45Ϫ5.30 (m, 1 H, ArCH), 5.12Ϫ5.02 (m, 2 H, OCH2Ph),
4.10Ϫ3.86 (m, 4 H, OCH2CH3), 2.45Ϫ2.21 (m, 2 H, CHCH2P),
1.27 (t, J ϭ 7.2 Hz, 3 H, OCH2CH3), 1.10 (t, J ϭ 7.2 Hz, 3 H,
OCH2CH3). EI-MS: m/z (%) ϭ 459 (1) [Mϩ], 424 (9), 324 (7), 275
(9), 217 (4), 152 (7), 125 (12), 91 (100), 65 (10) ppm.
C20H24Cl2NO5P (460.29): calcd. C 52.19, H 5.26, N 3.04; found C
52.21, H 5.41, N 2.94.
[7] [7a]
T. Gajda, M. Matusiak, Synth. Commun. 1992, 22,
2193Ϫ2203. [7b] C. Y. Yuan, C. F. Xu, Y. H. Zhang, Tetrahedron
[7c]
2003, 59, 6095Ϫ6102.
T. Gajda, M. Nowalinska, S. Za-
wadzki, A. Zwierzak, Phosphorus, Sulfur Silicon 1995, 105,
[7d]
45Ϫ60.
C. P. Chen, K. Prasad, O. Repic, Tetrahedron Lett.
1991, 32; 7175Ϫ7178. [7e] U. Schmidt, K. Mundinger, R. Mang-
old, A. Lieberknecht, J. Chem. Soc., Chem. Commun. 1990,
[7f]
1216Ϫ1219.
U. Schmidt, K. Mundinger, B. Riedl, G. Haas,
R. Lau, Synthesis 1992, 1201Ϫ1202. [7g] T. Gajda, Tetrahedron:
Asymmetry 1994, 5, 1965Ϫ1972. [7h] T. Gajda, Phosphorus, Sul-
[7i]
fur Silicon 1993, 85, 59Ϫ68.
thesis 1992, 367Ϫ368.
T. Gajda, M. Matusiak, Syn-
[8] [8a]
Y. H. Zhang, Z. Y. Li, C. Y. Yuan, Tetradedron Lett. 2002,
43, 3247Ϫ3249. [8b] Y. H. Zhang, C. F. Xu, J. F. Li, C. Y. Yuan,
Chin. J. Chem. 2003, 21, 883Ϫ892. [8c] A. Woschek, W. Lindner,
F. Hammerschmidt, Adv. Synth. Catal. 2003, 345, 1287Ϫ1298.
Diethyl
(2S)-β-Benzyloxycarbonylamino-β-(o,p-dichlorophenyl)-
ethylphosphonate (6i): Colorless oil. [α]2D0 ϭ Ϫ6.8 (c ϭ 1.0, CHCl3).
Compound 6i is the enantiomer of 5i; its spectroscopic data are
identical to those of 5i. C20H24Cl2NO5P (460.29): calcd. C 52.19,
H 5.26, N 3.04; found C 52.33, H 5.43, N, 3.07.
[8d]
F. Hammerschmidt, W. Lindner, F. Wuggenig, E. Zarbl,
[8e]
Tetrahedron: Asymmetry 2000, 11, 2955Ϫ2964.
merschmidt, F. Wuggenig, Tetrahedron: Asymmetry 1999, 10,
1709Ϫ1721.
1997, 53, 4627Ϫ4636.
merschmidt, Tetrahedron 1995, 51, 4933Ϫ4946.
F. Ham-
[8f]
Diethyl (2R)-β-Benzyloxycarbonylamino-β-(p-nitrophenyl)ethylphos-
phonate (5j): Colorless oil. [α]2D0 ϭ Ϫ19.9 (c ϭ 0.9, CHCl3). IR
(liquid film): ν˜max ϭ 3377, 2985, 2909, 1608, 1521, 1348, 1239,
1053, 1028, 967, 857 cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ 8.20
(d, J ϭ 8.7 Hz, 2 H, ArH), 7.51 (d, J ϭ 8.1 Hz, 2 H, ArH), 7.33
(s, 5 H, C6H5), 6.44 (s, 1 H, NH), 5.20Ϫ5.03 (m, 3 H, OCH2Ph,
ArCH), 4.10Ϫ3.88 (m, 4 H, OCH2CH3), 2.32Ϫ2.25 (m, 2 H,
CHCH2P), 1.27 (t, J ϭ 6.9 Hz, 3 H, OCH2CH3), 1.12 (t, J ϭ
6.9 Hz, 3 H, OCH2CH3) ppm. EI-MS: m/z (%) ϭ 302 (1) [Mϩ],
285 (32), 258 (6), 273 (19), 164 (46), 152 (100), 125 (92), 105 (30),
M. Drescher, F. Hammerschmidt, Tetrahedron
[8g]
M. Drescher, Y. F. Li, F. Ham-
[9] [9a]
M. V Sanchez, F. Rebolledo, V. Gotor, Tetrahedron: Asym-
metry 1997, 8, 37Ϫ40. [9b] E. L Iglesias, F. Rebolledo, V. Gotor,
Tetrahedron: Asymmetry 2000, 11, 1047Ϫ1050.
[10]
[11]
A. S. Thompson, G. R. Humphrey, A. M. DeMarco, D. J.
Mathre, E. J. J. Grabowski, J. Org. Chem. 1993, 58, 5886Ϫ5888.
H. Wolef, in: Organic Reactions, J. Wily and Sons Inc., New
York, 1947, vol. 3, chapter 8, p. 327Ϫ329.
Received June 16, 2004
Eur. J. Org. Chem. 2004, 4410Ϫ4415
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4415