Preparation of dimethyl (R)- and (S)-2-(2-aminophenyl)-2- hydroxyethylphosphonate from anthranilic acid

Article abstract of DOI:10.1016/j.tetasy.2003.11.038

An efficient synthesis of both enantiomers of dimethyl δ-amino- β-hydroxyethylphosphonate 6 has been achieved starting from anthranilic acid, through the resolution of dimethyl (±)-2-(2-N,N- dibenzylaminophenyl)-2-hydroxyethylphosphonate 9 with (S)-O-meth

Full text of DOI:10.1016/j.tetasy.2003.11.038

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 457–463
Preparation of dimethyl (R)- and (S)-2-(2-aminophenyl)-2-
hydroxyethylphosphonate from anthranilic acid
a
Angelina Gonzalez-Morales, Daniel Dıaz-Coutino, Mario Fernandez-Zertuche,
a
a
ꢀ
ꢀ
Oscar Garcıa-Barradas and Mario Ordonez
~
ꢀ
b
a,
*
ꢀ
ꢀ~
a
ꢀ
ꢀ
Centro de Investigaciones Quımicas, Universidad Autonoma del Estado de Morelos, Av. Universidad No. 1001, 62210 Cuernavaca,
Mor., Mexico
bUnidad de Servicios de Apoyo en Resoluciꢀon Analꢀıtica, Universidad Veracruzana, Av. Dr. Luis Castelazo Ayala s/n. 91190 Xalapa,
Ver., Mexico
Received 20 October 2003; accepted 12 November 2003
Abstract—An efficient synthesis of both enantiomers of dimethyl d-amino-b-hydroxyethylphosphonate 6 has been achieved starting
from anthranilic acid, through the resolution of dimethyl ( )-2-(2-N,N-dibenzylaminophenyl)-2-hydroxyethylphosphonate 9 with
(S)-O-methylmandelic acid. The absolute configuration of the enantiomers 9 was assigned by the Dale and Mosher approach using
the extended Newman projections and molecular mechanics.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
O
P
O
OH
OH
+
OH
O-
R
R3N
P(OMe)2
Phosphonic acids and phosphonates containing amino
and hydroxy groups have attracted considerable atten-
tion in recent years for their role in biologically relevant
processes.1 In particular c-amino-b-hydroxyphospho-
nates (phosphostatine derivatives) 1 have resulted in
excellent Leu10–Val11 replacements (LVRs) in angio-
tensin II, providing a more potent inhibitory activity for
rennin over porcine pepsin and bovine cathepsin D.2;3
Phosphocarnitine4 2 and c-amino-b-hydroxypropyl-
phosphonic acid (GABOBP)5 3, have been recognized in
recent years as attractive analogues of 3-hydroxy-4-
trimethylaminobutyric acid (carnitine) and c-amino-b-
hydroxybutyric acid (GABOB), respectively. On the
other hand, racemic b-hydroxy- and c-hydroxy phos-
phonic acids 4 and 5 containing either a C- or N-linked
triazole via a three carbon chain to a phosphonic group,
have shown inhibition of the enzyme imidazole glycerol
phosphate dehydratase;6 an enzyme involved in the
biosynthesis of the essential plant amino acidÕs histi-
dine.7
NH2
2; R = Me
3; R = H
1
H
N
N
N
OH
O
N
O
N
P(OH)2
P(OH)2
N
OH
5
4
However, the literature records only one report on the
preparation of ( )-6.8 As a part of our program aimed
at the elaboration of efficient and versatile syntheses of
biologically active aminophosphonic acids and phos-
phonates containing amino and hydroxy groups,3;5 we
herein report the details of our approach for the
NH2 OH
NH2 OH
O
O
P(OMe)2
P(OMe)2
(R)-6
(S)-6
* Corresponding author. E-mail: palacios@buzon.uaem.mx
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.11.038

458
A. Gonzꢀalez-Morales et al. / Tetrahedron: Asymmetry 15 (2004) 457–463
preparation of unnatural dimethyl (R)- and (S)-d-amino-
b-hydroxyethylphosphonate 6 from antranilic acid,
which can be used for the preparation of short peptides.8
O
OH
P(OMe)2
NBn2
( )-9
2. Results and discussion
Ph
MeO
DCC, DMAP
CH Cl
2
2
A total synthesis of ( )-9 starting from the readily
available anthranilic acid is shown in Scheme 1. In the
first step, anthranilic acid was treated with K2CO3 and
an excess amount of benzyl bromide under reflux in a
mixture of MeOH:H2O, to give the corresponding benzyl
N,N-dibenzylanthranilate 7 in 96% yield. The benzyl-
anthranilate 7 was then treated with 2equiv of the
lithium salt of dimethyl methylphosphonate at )78 ꢁC in
THF to afford the b-ketophosphonate 8 in 93% yield.
Finally, the reduction of the b-ketophosphonate 8 was
achieved with NaBH4 in methanol at room temperature
affording the racemic mixture of dimethyl 2-(2-N,N-
dibenzylaminophenyl)-2-hydroxyethylphosphonate ( )-
9 in 90% yield.
O
OH
86.5%
MeO
O
Ph
O
MeO
Ph
O
O
O
O
P(OMe)2
P(OMe)2
+
NBn2
NBn2
(S,S)-10
(R,S)-11
Scheme 2.
derivatives. Thus, according to the Trost model,9 the
different orientation of the phenyl ring of mandelic
functionality in the extended Newman projection (Fig.
1), leads to selective shielding or deshielding of
CH2P(O)(OMe)2 and 2-(N,N-dibenzylaminophenyl)
groups at the stereogenic center. Thus, the spatial rela-
tionship between the CH2P(O)(OMe)2/2-(N,N-dibenzyl-
aminophenyl) groups and the phenyl ring were corre-
lated with the observed chemical shift change, thus
giving us the absolute configuration.11
Having efficiently prepared racemic 2-hydroxyphos-
phonate ( )-9, we turned our attention to the prime goal of
this work, that is, the preparation of enantiomers 9. We
first focused on the resolution of racemic 2-hydroxy-
phosphonate 9 via O-methylmandelate derivatives,9
which should, in principle, allow us to obtain both
enantiomers of 9. Thus, the reaction of racemic mixture
( )-9 with (S)-O-methylmandelic acid in presence of
DCC and DMAP in dichloromethane at room temper-
ature afforded the respective mandelates in good yield.
The mixture of diastereomers was cleanly separated on
column chromatography affording the less polar dia-
stereomer (S,S)-10 in 44.5% yield and the more polar
diastereomer (R,S)-11 in 42% yield (Scheme 2).
1
The analysis of H NMR spectroscopic data revealed
some significant differences between the (S,S)-10 and
(R,S)-11 diastereomers (Table 1).
From the spectral data of the diastereomeric derivatives
summarized in the Table 1, we observed that the less
polar diastereomer showed the two methyl signals for
(CH3O)2P at 3.45 and 3.51 ppm, entries 3 and 4, while
the more polar diastereomer showed two signals at 3.69
and 3.76 ppm, giving differences of 0.24 and 0.25 ppm,
respectively. These, differences can be explained as a
result of the shielding of methyl signals by the phenyl
ring of mandelic acid derivative in the less polar dia-
stereomer. On the other hand, the less polar diastereo-
With diastereomerically pure (S,S)-10 and (R,S)-11 in
hand, the next step was to assign the absolute configu-
ration of the stereogenic center at C2of the diastereo-
mers (S,S)-10 and (R,S)-11. To this purpose, we initially
used the classical approach developed by Dale and
Mosher,10 based on the analysis of chemical shift
changes in 1H and 31P NMR data of diastereomeric
O
O
O
H
BnBr/K CO
OBn
NBn2
OH
NH2
Anthranilic acid
2
3
O
H
OMe
CH2P(OMe)2
MeOH:H 0
2
NBn2
MeO
Ph
∆
O
H
d
c
96%
Ph
(MeO)2PCH2
7
H
Bn2N
H
Ha
H
O
O
(S,S)-10
o
Hb
THF, -78
C
MeP(OMe)
n-BuLi
2
93%
Bn2N
H
OMe
O
H
OH
O
O
O
O
MeO
Ph
H
a
O
P(OMe)2
P(OMe)2
CH P(OMe)
CH2P(OMe)2
O
Ph
H
H
b
2
2
NaBH
MeOH
90%
4
H
NBn2
NBn2
Hc
(R,S)-11
NBn2
( )-9
8
Hd
Scheme 1.
Figure 1. Extended Newman projections for (S,S)-10 and (R,S)-11.

A. Gonzꢀalez-Morales et al. / Tetrahedron: Asymmetry 15 (2004) 457–463
459
Table 1. 1H and 31P NMR chemical shifts of the mandelates (S,S)-10
and (R,S)-11
sult of the shielding by the phenyl ring of mandelic acid
derivative in the less polar diastereomer.12
Entry
Less polar
mandelate
More polar
mandelate
Dd (ppm)
In order to have more evidence on the absolute config-
uration of the diastereomers (S,S)-10 and (R,S)-11, we
resorted to a conformational search by Molecular
Mechanics (MM) using an MMX force field for geo-
metry minimization and energy assessment on the
mandelates.13 Uniform synchronized scanning at 5ꢁ
increments was carried out for dihedral angles D1 (C5–
C6–O17–C18) and D2 (O17–C18–C20–O32), allowing
for complete relaxation of the rest of the molecular
coordinates.14 (Fig. 2).
1
CH2P(O)
CH2P(O)
(CH3O)2P
(CH3O)2P
NCH2Ph
NCH2Ph
CH(OH)
Ha
1.71
2.15
3.45
3.51
3.98
4.16
6.85
7.45
7.04
7.15
7.45
28.93
1.67
2.07
0.04
0.08
0.24
0.25
2
3
3.69
3.76
4
5
3.920.06
4.13
6.87
6
0.03
0.02
0.37
0.25
0.04
7
8
7.08
6.79
9
10
Hb
Hc
7.11
6.620.83
29.39
11
12(CH
Hd
Examination of the only conformation showed that for
(S,S)-10 diastereomer (Fig. 2), the phenyl ring of man-
delic acid derivative was close to the OMe groups on
P(OMe)2, which could produce the shielding effect in 1H
NMR. Additionally, analysis of the conformation for
the (S,S)-10 diastereomer (Fig. 2c), shows that proton
Hx in C2is anti to proton Hb and gauche to proton Ha in
C1; furthermore, the proton Ha is close to aromatic ring,
which could lead to selective shielding. Thus, the dihe-
dral angles calculated for Hb/Hx and Hb/Hx are 175.2ꢁ
and 67.3ꢁ, which correspond to Janti and Jgauche, respec-
tively. These values are also in line with the experimental
data JH =H ¼ 10 and JH =H ¼ 3:6 Hz, respectively.
3O)2P
0.46
mer showed signals for Ha, Hb, Hc, and Hd of the phenyl
ring of the anthranilic acid derivative at 7.43, 7.04, 7.15,
and 7.45 ppm, respectively, while the more polar dia-
stereomer showed these signals at 7.08, 6.79, 7.11, and
6.62, with differences of 0.37, 0.25, 0.04, and 0.83 ppm,
respectively. These, differences were initially explained
as a result of shielding to proton signals by the phenyl
ring in the more polar diastereomer. However, after
analysis of spectroscopic data, we found that the
chemical shift for aromatic protons Ha–d in the more
polar diastereomer were identical to compound 6;
therefore, the shielding of proton signals does not arise
from the influence of the phenyl ring of the mandelic
functionality.
x
x
a
b
Additionally, the chemical shifts for the proton Ha is
1.71 ppm, while for Hb is 2.15 ppm, which is consistent
with the preferential conformation found by Molecular
Mechanics for (S,S)-10 diastereomer.
Furthermore, the 31P NMR chemical shift for the less
polar diastereomer was 28.93 ppm while for the more
polar diastereomer it was 29.39 ppm, giving a difference
of 0.46 ppm. This difference could be explained as a re-
On the other hand, a similar conformational search on
the (R,S)-11 diastereomer showed three different con-
formations on the conformational population surface
(Fig. 3).
Figure 2. Conformational population surface for (S,S)-10 diastereomer.

460
A. Gonzꢀalez-Morales et al. / Tetrahedron: Asymmetry 15 (2004) 457–463
Figure 3. Conformational population surface and conformers for (R,S)-11 diastereomer.
In conformation C (the least populated, Fig. 3), the
effect of the phenyl ring of the mandelic functionality
would be more important on the methylene of the
benzyl group; however this effect is less significant on the
1H NMR spectrum. On the other hand, conformations
A and B (Fig. 3), show that the aromatic protons of the
anthranilic acid derivative are far away from the phenyl
rings of the mandelic functionality and benzyl groups:
Therefore the shielding effect in 1H NMR should not be
observed. These results are consistent with the experi-
mental 1H NMR data obtained, where the chemical
shifts for the aromatic protons of anthranilic fragment
in (R,S)-11 diastereomer were identical to those in
compound 6. Additional analysis of conformation A for
(R,S)-11 diastereomer (the more stable, Fig. 3), showed
that proton Hx in C2was anti to proton Hb and gauche
to proton Ha in C1; furthermore, proton Ha was close to
the aromatic ring, leading to selective shielding. Thus,
the dihedral angles calculated for Hb/Hx and Hb/Hx were
diastereomer with LiOH in a mixture of MeOH:H2O
(8:2) at room temperature followed by separation of the
(S)-O-methylmandelic acid by column chromatography
gave (S)-9 in 93% yield. The X-ray crystal structure of
(S)-9 is shown in Figure 4. In a similar way starting from
the (R,S)-11 diastereomer, (R)-9 was obtained in 89%
yield. Finally, the b-hydroxyethylphosphonates (S)-9
and (R)-9 were treated with palladium on carbon in
methanol under hydrogen gas at room temperature to
obtain dimethyl (S)- and (R)-2-(2-aminophenyl)-2-hy-
droxyethylphosphonate 6 in 82% and 83.8% yield,
respectively.
171.3ꢁ and 71.1ꢁ, which corresponding to Janti and Jgauche
respectively. These values correspond with the experi-
,
mental data JH =H ¼ 10 and JH =H ¼ 2:4 Hz. Further-
x
x
a
b
more, the chemical shift for proton Ha is 1.67 ppm, while
for Hb it is 2.07 ppm, which confirms the preferential
conformation found by Molecular Mechanics for the
(R,S)-11 diastereomer (Fig. 3).
The combination of NMR and Molecular Mechanical
data suggests strongly that the less polar compound is
the (S,S)-diastereomer while the more polar compound
is the (R,S)-diastereomer.15
Figure 4. X-ray structure for (S)-9.16
With the absolute configuration assigned to the diaste-
reomerically pure mandelates (S,S)-10 and (R,S)-11,
the preparation of both enantiopure forms of dimethyl
c-amino-b-hydroxyethylphosphonates 9 could be com-
pleted (Scheme 3). Thus, the treatment of (S,S)-10
In conclusion, we have found a new methodology for
the preparation of enantiomerically pure dimethyl (R)-
and (S)-d-amino-b-hydroxyethylphosphonate 6 from
anthranilic acid, which could be incorporated in short

A. Gonzꢀalez-Morales et al. / Tetrahedron: Asymmetry 15 (2004) 457–463
461
OCH2Ph), 6.91 (d, J ¼ 8:0 Hz, 1H, Harom), 6.93 (ddd,
J ¼ 7:6, 7.6, 0.8 Hz, 1H, Harom), 7.16–7.38 (m, 14H,
Harom), 7.45 (dd, J ¼ 7:6, 1.6 Hz, 2H, Harom), 7.72(dd,
J ¼ 7:6, 1.8 Hz, 1H, Harom). 13C NMR (100 MHz,
CDCl3) d 57.1 (NCH2Ph), 67.1 (OCH2Ph), 121.0, 121.4,
124.9, 127.1, 128.3, 128.4, 128.5, 128.7, 128.7, 131.5,
132.0, 136.1, 138.0, 150.9, 168.3 C@O.
Ph
O
MeO
O
Ph
O
MeO
O
O
O
P(OMe)2
P(OMe)2
NBn2
NBn2
(S,S)-10
(R,S)-11
LiOH
LiOH
3.2. Synthesis of dimethyl 2-(2-N,N-dibenzylamino-
phenyl)-2-oxoethylphosphonate 8
93%
89%
MeOH:H O
2
MeOH:H O
2
O
O
OH
OH
A solution of dimethyl methylphosphonate (6.5 g,
52mmol) and anhydrous THF (80 mL) was cooled at
)78 ꢁC before of the slow addition (16.4 mL, 25.5 mmol)
of n-BuLi in hexane (2.4 M). The resulting solution was
stirred at )50 ꢁC for 1 h, after which the solution was
cooled to )78 ꢁC and then slowly added to a solution of
the (N,N-dibenzyl)anthranilate 7 (5.34 g, 13.1 mmol) in
THF (120 mL). The reaction mixture was stirred at
)78 ꢁC for 3 h before the addition of a saturated solution
of NH4Cl. The organic layer was separated and the
aqueous layer extracted with ethyl acetate (3 · 50 mL).
The combined organic extracts were dried over Na2SO4
and evaporated under reduced pressure. The crude
product was purified by column chromatography (ethyl
acetate–hexane 4:1) to afford 8 (5.1 g, 93%) as a yellow
oil. 1H NMR (400 MHz, CDCl3) d 3.65 (d, J ¼ 11:2Hz,
6H, (CH3O)2P), 4.03 (d, J ¼ 22:0 Hz, 2H, CH2P(O)),
P(OMe)2
P(OMe)2
NBn2
NBn2
(R)-9
(S)-9
H
Pd/C
H
Pd/C
2
2
83.8%
82%
(R)-6
(S)-6
Scheme 3.
peptides, as potential bioactive materials or used for the
preparation of non-ionic selective X-ray contrast
agents.8
3. Experimental
4.12(s, 4H, NCH Ph), 6.96 (d, J ¼ 8:0 Hz, 1H, Harom),
2
7.05–7.11 (m, 5H, Harom), 7.23–7.31 (m, 6H, Harom), 7.35
(ddd, J ¼ 8:0, 8.0, 1.6 Hz, 1H, Harom), 7.53 (dd, J ¼ 7:6,
1.6 Hz, 1H, Harom). 13C NMR (100 MHz, CDCl3) d 39.8
(d, J ¼ 129:1 Hz, CH2P(O)), 53.0 (d, J ¼ 6:1 Hz,
(CH3O)2P), 57.5 CH2Ph, 121.6, 122.5, 127.6, 128.5,
129.1, 129.1, 130.5, 132.2, 133.9, 136.6, 149.9 C@O. 31P
NMR (200 MHz, CDCl3) d 24.56.
Optical rotations were taken on a Perkin–Elmer 241
polarimeter in a 1 dm tube; concentrations are given in
g/100 mL. For flash chromatography, silica gel 60 (230–
1
400 mesh ASTM, Merck) was used. H NMR spectra
were registered on a Varian INOVA 400 (400 MHz), 13C
NMR (100 MHz), and 31P NMR on a Varian Mercury
200. The spectra were recorded in D2O or CDCl3 solu-
tion, using TMS as the internal reference. Microanalyses
were registered on an Elemental VARIO EL III.
3.3. Synthesis of dimethyl ( )-2-(2-N,N-dibenzylamino-
phenyl)-2-hydroxyethylphosphonate ( )-9
Flasks, stirrer bars and hypodermic needles used for the
generation of organometallic compounds were dried for
ca. 12h at 120 ꢁC and allowed to cool in a dessicator
over anhydrous calcium sulfate. Anhydrous solvents
(ethers) were obtained by distillation from benzophe-
none ketyl. The (S)-O-methylmandelic acid was pre-
pared according to literature procedure.17
A mixture of dimethyl 2-(2-N,N-dibenzylaminophenyl)-
2-oxoethylphosphonate 8 (5.34 g, 12.7 mmol), sodium
borohydride (3.84 g, 0.1 mol) and methanol (100 mL)
was stirred at room temperature for 10 h under a
nitrogen atmosphere. After the reaction mixture was
carefully treated with a saturated solution of NH4Cl, the
solvent was removed under reduced pressure, and the
residue dissolved in water and extracted with ethyl
acetate. The combined organic extracts were dried over
Na2SO4 and evaporated under reduced pressure. The
crude product was crystallized from ethyl acetate–hex-
ane 4:1 to afford ( )-9 (4.9 g, 90%) as a crystalline solid,
Mp 115–118 ꢁC. The NMR data is identical to (R)- and
(S)-9.
3.1. Synthesis of benzyl (N,N-dibenzyl)anthranilate 7
A solution of benzyl bromide (40 g, 0.23 mol) was slowly
added to a solution of the anthranilic acid (8 g, 0.06 mol)
and K2CO3 (32.3 g, 0.23 mol) in a 5:1 mixture of meth-
anol–water (300 mL). The reaction mixture was refluxed
for 2h and the solvent removed under reduced pressure.
Water was added to the residue and then extracted with
ethyl acetate (3 · 100 mL). The combined organic layers
were dried over Na2SO4 and evaporated under reduced
pressure. The crude product was purified by flash
chromatography (hexane–ethyl acetate 9:1) to afford 7
3.4. Esterification of ( )-9 with (S)-O-methylmandelic
acid
To a solution of ( )-9 (9.0 g, 21.2 mmol) and (S)-O-
methylmandelic acid (5.6 g, 33.9 mmol) in dichlorome-
thane (250 mL), 4-dimethylaminopyridine DMAP
1
(22.8 g, 96%) as a white solid, Mp 53–55 ꢁC. H NMR
(400 MHz, CDCl3) d 4.18 (s, 4H, NCH2Ph), 5.35 (s, 2H,

462
A. Gonzꢀalez-Morales et al. / Tetrahedron: Asymmetry 15 (2004) 457–463
(400 mg, 3.2mmol) and 1,3-dicyclohexylcarbodiimide
DCC (7.0 g, 42mmol) were added. The reaction mixture
was stirred at room temperature for 20 h. After 1,3-
dicyclohexylurea DCU was filtered off, the liquid layer
was evaporated under reduced pressure. The crude
product was purified by column chromatography (ethyl
acetate–hexane 6:4) to afford (S,S)-10 (5.4 g, 44.5%) as a
colorless oil (less polar) and (R,S)-11 (5.1 g, 42%) as a
colorless oil (more polar).
the volatiles were removed under reduced pressure. The
residue was dissolved in ethyl acetate and washed with
water. The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The crude product
was purified by crystallization from ethyl acetate–di-
chloromethane to give (S)-9 (1.4 g, 93%) as a white solid,
20
D
Mp 115–118 ꢁC. ½aŠ ¼ +5.9 (c ¼ 1:4, CHCl3). 1H NMR
(400 MHz, CDCl3) d 1.86 (ddd, J ¼ 18:4, 15.2, 2.8 Hz,
1H, CH2P(O)), 1.99 (ddd, J ¼ 15:2, 15.2, 10.0 Hz, 1H,
CH2P(O)), 3.70 (d, J ¼ 10:8 Hz, 3H, (CH3O)2P), 3.79
(d, J ¼ 10:8 Hz, 3H, (CH3O)2P), 3.94 (d, J ¼ 2:8 Hz,
1H, OH), 4.05 (s, 4H, CH2Ph), 5.67 (tt, J ¼ 10:0,
2.8 Hz, 1H, CH(OH)), 7.14–7.30 (m, 13H, Harom), 7.40
(d, J ¼ 7:6 Hz, 1H, Harom). 13C NMR (100 MHz, CDCl3)
d 34.4 (d, J ¼ 135:1 Hz, CH2P(O)), 52.4 (d, J ¼ 6:1 Hz,
(CH3O)2P), 52.6 (d, J ¼ 6:1 Hz, (CH3O)2P), 59.4
CH2Ph, 64.6 (d, J ¼ 3:8 Hz, CH(OH)), 124.2, 125.9,
126.8, 127.4, 128.2, 128.4, 128.4, 129.5, 137.9, 148.1. 31P
NMR (200 MHz, CDCl3) d 33.03. Anal. Calcd for
C24H28NO4P: C, 67.75; H, 6.63; N, 3.29. Found C,
67.73; H, 6.70; N, 3.33.
3.5. Less polar diastereomer (S,S)-10
20
D
½aŠ ¼ +23.8 (c ¼ 14, CHCl3). 1H NMR (400 MHz,
CDCl3) d 1.71 (ddd, J ¼ 19:6, 15.6, 3.6 Hz, 1H,
CH2P(O)), 2.15 (ddd, J ¼ 15:6, 15.6, 10.0 Hz, 1H,
CH2P(O)), 3.33 (s, 3H, CH3O), 3.45 (d, J ¼ 10:8 Hz, 3H,
(CH3O)2P), 3.51 (d, J ¼ 10:8 Hz, 3H, (CH3O)2P), 3.98
(d, J ¼ 13:6 Hz, 2H, NCH2Ph), 4.16 (d, J ¼ 13:6 Hz,
2H, NCH2Ph), 4.75 (s, 1H, CH(OCH3)), 6.85 (ddd,
J ¼ 10:0, 10.0, 3.6 Hz, 1H, CH(OH)), 7.04 (ddd,
J ¼ 6:8, 6.8, 0.8 Hz, 1H, Harom), 7.13–7.37 (m, 16H,
Harom), 7.45 (dd, J ¼ 7:6, 2.0 Hz, 2H, Harom). 13C NMR
(100 MHz, CDCl3) d 31.9 (d, J ¼ 138:2Hz, CH 2P(O)),
52.1 (d, J ¼ 6:1 Hz, (CH3O)2P), 52.3 (d, J ¼ 6:1 Hz,
(CH3O)2P), 57.4 (CH3OCH), 58.1 CH2Ph, 67.9 (d,
J ¼ 6:1 Hz, CHCH2P(O)), 82.8 CH(OCH3), 124.3,
125.3, 125.8, 127.0, 127.4, 128.1, 128.4, 128.5, 128.6,
129.4, 135.8, 137.1, 137.2, 148.3, 169.5 C@O. 31P NMR
In a similar way, (R,S)-11 (2.46 g, 4.3 mmol) afforded
(R)-9 (1.62g, 89%) as a white solid, Mp 115–118 ꢁC.
20
½aŠ ¼ )6.1 (c ¼ 1:14, CHCl3). Anal. Calcd for
D
C24H28NO4P: C, 67.75; H, 6.63; N, 3.29. Found C,
67.69; H, 6.78; N, 3.18.
(200 MHz, CDCl3)
d
28.93. Anal. Calcd for
3.8. Synthesis of dimethyl (S)-2-(2-aminophenyl)-2-
hydroxyethylphosphonate 618
C33H36NO6P: C, 69.10; H, 6.33; N, 2.44. Found C,
68.97; H, 6.45; N, 2.69.
Dimethyl (S)-2-(2-N,N-dibenzylaminophenyl)-2-hydroxy-
ethylphosphonate 9 (84 mg, 0.2mmol) was treated with
palladium on carbon (8.4 mg, 10% wt) in methanol
(12mL) and two drops of (20%) HCl/ iPrOH and then
stirred for 10 min under hydrogen gas at room tem-
perature. The mixture was filtered through a pad of
celite, and the solvents removed under reduced pressure.
The residue was dissolved in dichloromethane (5 mL),
washed with a saturated solution of NaHCO3 (1 mL),
dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by column chromatography
(dichloromethane–hexane–methanol 4:4:1) to afford the
3.6. More polar diastereomer (R,S)-11
20
D
½aŠ ¼ +35.1 (c ¼ 5:3, CHCl3). 1H NMR (400 MHz,
CDCl3) d 1.67 (ddd, J ¼ 18:4, 15.6, 2.4 Hz, 1H,
CH2P(O)), 2.07 (ddd, J ¼ 15:6, 15.6, 10.0 Hz, 1H,
CH2P(O)), 3.40 (s, 3H, CH3O), 3.69 (d, J ¼ 11:0 Hz, 3H,
(CH3O)2P), 3.76 (d, J ¼ 11:0 Hz, 3H, (CH3O)2P), 3.92
(d, J ¼ 13:6 Hz, 2H, NCH2Ph), 4.13 (d, J ¼ 13:6 Hz,
2H, NCH2Ph), 4.85 (s, 1H, CH(OCH3)), 6.64 (dd,
J ¼ 8:4, 1.2Hz, 1H, H arom), 6.79 (ddd, J ¼ 8:0, 8.0,
2.0 Hz, 1H, Harom), 6.87 (ddd, J ¼ 10:0, 10.0, 2.4 Hz, 1H,
CH(OH)), 7.07–7.36 (m, 17H, Harom). 13C NMR
(100 MHz, CDCl3) d 32.3 (d, J ¼ 138:1 Hz, CH2P(O)),
52.4 (d, J ¼ 6:1 Hz, (CH3O)2P), 52.8 (d, J ¼ 6:1 Hz,
(CH3O)2P), 57.5 (CH3OCH), 58.3 CH2Ph, 67.5 (d,
J ¼ 6:1 Hz, CHCH2P(O)), 82.4 CH(OCH3), 124.1,
125.2, 125.6, 127.1, 127.6, 128.2, 128.3, 128.6, 128.7,
129.5, 135.9, 136.9, 137.1, 148.1, 169.3 C@O. 31P NMR
enantiomer (S)-6 (39.8 mg, 82%), as a yellow oil.
20
D
½aŠ ¼ +13.3 (c ¼ 1:2, CHCl3). 1H NMR (400 MHz,
D2O) d 2.19 (ddd, J ¼ 18:8, 15.2, 3.2 Hz, 1H, CH2P(O)),
2.68 (ddd, J ¼ 15:2, 10.4 Hz, 1H, CH2P(O)), 3.71
(d ¼ 10:8 Hz, 3H, (CH3O)2P), 3.75 (d ¼ 10:8 Hz, 3H,
(CH3O)2P), 5.13 (ddd, J ¼ 10:4, 3.2Hz, 1H, CHOH),
6.65 (d, J ¼ 8:0 Hz, 1H, Harom), 6.71 (ddd, J ¼ 8:0,
1.2Hz, 1H, H arom), 7.06 (d, J ¼ 8:4 Hz, 1H, Harom), 7.08
(ddd, J ¼ 8:4, 1.6 Hz, 1H, Harom). 13C NMR (100 MHz,
D2O) d 30.8 (d, J ¼ 135:8 Hz, CH2P(O)), 52.6 (d,
J ¼ 6:1 Hz, (CH3O)2P), 52.8 (d, J ¼ 6:1 Hz, (CH3O)2P),
69.0 (CHCH2P(O)), 117.1, 118.4, 126.6 (d, J ¼ 16 Hz),
127.3, 129.0, 145.6. 31P NMR (200 MHz, D2O) d 33.70.
(200 MHz, CDCl3)
d
29.39. Anal. Calcd for
C33H36NO6P: C, 69.10; H, 6.33; N, 2.44. Found C,
69.23; H, 6.38; N, 2.37.
3.7. Dimethyl (S)-2-(2-N,N-dibenzylaminophenyl)-2-
hydroxyethylphosphonate 9
The procedure described above for the (S)-enantiomer,
was followed using the dimethyl (R)-2-(2-N,N-dibenz-
ylaminophenyl)-2-hydroxyethylphosphonate 9 (77 mg,
0.18 mmol) and treated with palladium on carbon 8 mg
(10% wt) in methanol (12mL) and two drops of (20%)
The diastereomer (S,S)-10 (2.03 g, 3.54 mmol) was dis-
solved in MeOH/H2O 8:2(100 mL) and stirred at room
temperature with LiOH (206 mg, 8.46 mmol). After 15 h,

A. Gonzꢀalez-Morales et al. / Tetrahedron: Asymmetry 15 (2004) 457–463
463
10. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512.
11. For the assignment of the absolute configuration of the
secondary alcohols by NMR see: (a) Porto, S.; Duran, J.;
HCl/iPrOH and stirred for 10 min under hydrogen gas
at room temperature, obtaining (37 mg, 83.8%) dimethyl
(R)-2-(2-aminophenyl)-2-hydroxyethylphosphonate 6, as
20
a viscous oil. ½aŠ ¼ )13.7 (c ¼ 1:4, CHCl3). The NMR
D
data are identical to (S)-6.
~
Seco, J. M.; Quinoa, E.; Riguera, R. Org. Lett. 2003, 5,
2979; Seco, J. M.; Tseng, L.-H.; Godejohann, M.;
~
Quinoa, E.; Riguera, R. Tetrahedron: Asymmetry 2002,
13, 2149; (b) Seco, J. M.; Quinoa, E.; Riguera, R.
~
Tetrahedron: Asymmetry 2001, 12, 2915; (c) Ohtani, I.;
Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1973, 95, 512.
Acknowledgements
12. For the assignment of absolute configuration of hydroxy-
phosphonates by 31P NMR see: (a) Reference 4a; (b)
Reference 5; (c) Maly, A.; Lejczak, B.; Kafarski, P.
Tetrahedron: Asymmetry 2003, 14, 1019; (d) Wroblewsky,
A. E.; Piotrowska, D. G. Tetrahedron: Asymmetry 2000,
11, 2615; (e) Kozlowski, J. M.; Rath, N. P.; Spilling, C. D.
Tetrahedron 1995, 51, 6385.
We gratefully acknowledge Conacyt, Mexico, for
financial support via grant 41657-Q, and graduate fel-
lowship by A.G.M. We are also grateful to UQUIFA-
MEXICO for the donation of anthranilic acid, and
a graduate fellowship by D.D.C. We also thanks
~
M. Munoz for their valuable technical help for the
obtention of the X-ray structures.
13. PC Model: Gilbert, K. E., Serena Sofware, Bloomintong,
1991.
14. The conformational energy maps originating from each
minimum energy conformation and population surfaces
were drawn by means of a Surfer program. (Surfer version
8.0, Golden Sofware, 809 14th St. Golden, CO, 80401-
1866). The corresponding conformational population
surface was calculated from the potential energy surface
by means of the relationship
References and notes
1. Aminophosphonic and Aminophosphinic Acids: Chemistry
and Biological Activity; Kukhar, V. P., Hudson, H. R.,
Eds.; John Wiley: New York, 2000, and references cited
therein.
eÀEi=RT
2. Dellaria, J. F., Jr.; Maki, R. G.; Stein, H. H.; Cohen, J.;
Whittern, D.; Marsh, K.; Hoffman, D. J.; Plattner, J. J.;
Perum, T. J. J. Med. Chem. 1990, 33, 534.
P
Pi ¼
n
ÀEi=RT
e
i¼1
ꢀ~
ꢀ
3. Ordonez, M.; De la Cruz, R.; Fernandez-Zertuche, M.;
Munoz-Hernandez, M.-A. Tetrahedron: Asymmetry 2002,
where Ei is the intramolecular conformational energy of
the ith state.
~
ꢀ
13, 559.
15. For the assignment of the absolute configuration of
secondary alcohols using molecular mechanics and
4. (a) Wroblewsky, A. E.; Halajewska-Wosik, A. Tetrahe-
dron: Asymmetry 2000, 11, 2053; (b) Wroblewsky, A. E.;
Halajewska-Wosik, A. Eur. J. Org. Chem. 2002, 2758; (c)
Mikolajczyk, M.; Luczak, J.; Kielbasinski, P. J. Org.
Chem. 2002, 67, 7872.
~
NMR data see: Latypov, Sh. K.; Seco, J. M.; Quinoa,
E.; Riguera, R. J. Org. Chem. 1996, 61, 8569.
16. X-ray crystal data of (S)-9 was collected at 298 K using a
Bruker APEX instrument (MoKa radiation, k ¼
ꢀ~
5. Ordonez, M.; Gonzalez-Morales, A.; Ruız, C.; De la Cruz,
R.; Fernandez-Zertuche, M. Tetrahedron: Asymmetry
ꢀ
ꢀ
ꢁ
0:71073 A). The SHELXTL v. 6.1 program package was
ꢀ
used for structure solution and refinement. The structure
was solved by direct methods and refined by full-matrix
least squares procedures. All non-hydrogen atoms were
refined anisotropically. (S)-6: C24H27NO4P, M ¼ 424:44,
monoclinic space group P21, a ¼ 10:981ð12Þ, b ¼ 10:662
2003, 14, 1775.
6. Mori, I.; Iwasaki, G.; Kimura, Y.; Matsunaga, S.-I.;
Ogawa, A.; Nakano, T.; Buser, H.-P.; Hatano, M.;
Tada, S.; Hayakawa, K. J. Am. Chem. Soc. 1995, 117,
4411.
7. Histidine biosynthesis: (a) Martin, R. G.; Berbereich, M.
A.; Ames, B. N.; Davis, W. W.; Goldberger, R. F.;
Yourno, J. D. In Methods in Enzymology; Tabor, H.,
Tabor, C.W., Eds.; Academic: New York, 1971; Vol. 17B,
pp 3–44; (b) Miflin, B. J. In The Biochemistry of Plants;
Miflin, B.J., Ed.; Academic: New York, 1980; Vol. 5, pp
533–539.
8. (a) Shalem, H.; Shatzmiller, S.; Feit, B.-A. J. Chem. Soc.,
Perkin Trans. 1 2000, 2831; (b) Shalem, H.; Shatzmiller, S.;
Feit, B.-A. Liebigs Ann 1995, 433.
9. Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P.
G.; Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.;
Ponticello, G. S.; Varga, S. L.; Springer, J. P. J. Org.
Chem. 1986, 51, 2370.
ꢁ
ð12Þ, c ¼ 11:325ð13Þ A, b ¼ 117:001ð2Þꢁ, V ¼ 1181:3 ð2Þ
3
A , Z ¼ 2, Dc ¼ 1:193 g cmÀ1, 11,418 reflections measured,
ꢁ
4166 unique ðRint ¼ 0:0223Þ, which were used in all
calculations, final R values were 0.0602 ½F > 4rðF ފ and
0.0619 (all data). Crystallographic data for the structures
in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 227064. Copies of the data can be
obtained free of charge, on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
17. (a) Bonner, W. A. J. Am. Chem. Soc. 1951, 73, 3126; (b)
McKenzie, A. J. Chem. Soc. 1899, 75, 753.
18. For the synthesis of ( )-6, see Ref. 8.