Enantioselective synthesis of (S)-2-amino-3-phosphonopropionic acid, (S)-AP-3, and (R)-2-amino-4-phosphonobutanoic acid, (R)-AP-4, via diastereoselective azidation of (4R,5R)-trans-N-[(diethoxyphosphoryl)propionyl]- and (4R,5R)-trans-N-[(diethoxyphosphoryl)butanoyl]hexahydrobenzoxazolidin-2-one

Article abstract of DOI:10.1016/j.tet.2006.06.018

N-Acylation of readily available, enantiopure oxazolidinone (4R,5R)-1b with (diethoxyphosphoryl)propionyl chloride and (diethoxyphosphoryl)butanoyl chloride affords de title substrates (4R,5R)-2 and (4R,5R)-7, respectively, which are azidated with high diastereoselectivity by means of the reaction between their sodium enolates (4R,5R)-2-Na and (4R,5R)-7-Na with trisyl azide. Removal of the chiral auxiliary from azidated products (4R,5R,2′S)-3 and (4R,5R,2′R)-8 followed by hydrogenation and hydrolysis of the resulting carboxylic acids (S)-4 and (R)-9 gave the pharmacologically relevant aminophosphonic acids (S)-AP-3 and (R)-AP-4 in good yield.

Full text of DOI:10.1016/j.tet.2006.06.018

Tetrahedron 62 (2006) 8404–8409
Enantioselective synthesis of (S)-2-amino-3-phosphonopropionic
acid, (S)-AP-3, and (R)-2-amino-4-phosphonobutanoic acid,
(
R)-AP-4, via diastereoselective azidation of (4R,5R)-trans-N-
(diethoxyphosphoryl)propionyl]- and (4R,5R)-trans-N-
(diethoxyphosphoryl)butanoyl]hexahydrobenzoxazolidin-2-one
[
[
a
a
a
b
Gloria Reyes-Rangel, Virginia Mara n˜ ꢀo n, C. Gabriela Avila-Ortiz, Cecilia Anaya de Parrodi,
c
Leticia Quintero and Eusebio Juaristi
a,
*
a
Depto. de Quı ´m ica, Centro de Investigaci oꢀ n y de Estudios Avanzados del Instituto Polite´cnico Nacional,
Apdo. Postal 14-740, 07000 Me´xico D.F., Me´xico
b
Depto. de Quı ´m ica y Biologı ´a , Universidad de las Ame´ricas-Puebla, Santa Catarina M aꢀ rtir, 72820 Cholula, Me´xico
Centro de Investigaci oꢀ n de la Fac. de Ciencias Quı´micas, Universidad Aut oꢀ noma de Puebla, 72570 Puebla, Me´xico
c
Received 9 April 2005; revised 4 June 2006; accepted 6 June 2006
Available online 7 July 2006
Abstract—N-Acylation of readily available, enantiopure oxazolidinone (4R,5R)-1b with (diethoxyphosphoryl)propionyl chloride and (dieth-
oxyphosphoryl)butanoyl chloride affords de title substrates (4R,5R)-2 and (4R,5R)-7, respectively, which are azidated with high diastereo-
selectivity by means of the reaction between their sodium enolates (4R,5R)-2-Na and (4R,5R)-7-Na with trisyl azide. Removal of the
0
0
chiral auxiliary from azidated products (4R,5R,2 S)-3 and (4R,5R,2 R)-8 followed by hydrogenation and hydrolysis of the resulting carboxylic
acids (S)-4 and (R)-9 gave the pharmacologically relevant aminophosphonic acids (S)-AP-3 and (R)-AP-4 in good yield.
Ó 2006 Elsevier Ltd. All rights reserved.
HO
1
. Introduction
HO
HO
O
O
HO
O
O
H2N
O
H2N
Excitatory amino acids (EAA) are the most common neuro-
transmitters in the mammalian central nervous system
CNS). Thus, EAA receptors offer an opportunity to develop
H2N
H2N
O
1
(
P(OH)2
P(OH)2
O
P(OH)2
therapeutic compounds for the treatment of several patholog-
ical conditions affecting the brain, such as Parkinson’s and
O
P(OH)2
2
,3
Alzheimer’s diseases.
In this context, several studies
(S) AP-3
(R) AP-4
(R) AP-5
(R) AP-6
have shown that phosphonic analogues of the aminodicar-
boxylic acids, glutamic acid, and their higher homologues,
are modulators for the N-methyl-D-aspartate (NMDA) recep-
tor site. Indeed, aminophosphonic acids AP-3, AP-4, AP-5,
and AP-6 (Fig. 1) have demonstrated to be particularly
potent.
Figure 1.
(
R)-enantiomer in the suppression of glutamate-mediated
4
neurotransmission. As a consequence, the asymmetric syn-
thesis of aminophosphonic acids has been intensely pursued
in recent years.
5
The biological activity of these compounds has been shown
to depend markedly on their stereochemical configuration.
For example, the (S)-enantiomer of 2-amino-4-phosphono-
butanoic acid AP-4 is 40 times more active than the
Some years ago, we reported a convenient procedure for the
preparation of both pairs of enantiomeric hexahydrobenzox-
azolidin-2-ones 1a–d from inexpensive cyclohexene oxide
and (S)-a-phenylethylamine (Fig. 2). We have also de-
scribed the use of 1a–d as effective chiral auxiliaries for
6,7
the stereoselective alkylation, acylation, and aldol condensa-
tion of propionic and hydrocinnamic acids. More recently,
Keywords: Chiral oxazolidinones; Aminophosphonic acids; Diastereoselec-
tive electrophilic amination; Enantioselective synthesis.
8
the application of oxazolidinones 1a–d as chiral sulfinyl
transfer reagents was also reported.
*
Corresponding author. Tel.: +52 55 5061 3722; fax: +52 55 5061 3389;
e-mail: juaristi@relaq.mx
9
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.018

G. Reyes-Rangel et al. / Tetrahedron 62 (2006) 8404–8409
8405
O
O
O
O
O
N
Na
N
O
O
O
O
O
O
E+
N
H
N
H
N
H
N
H
NaHMDS, -78 °C
O
O
1a
1b
1c
1d
O
P(OEt)2
O
E
Figure 2.
O
P(OEt)2
+
(4R,5R)-2
We would like to communicate the use of trans-oxazolidi-
none (4R,5R)-1b for the enantioselective synthesis of (S)-
AP-3 and (R)-AP-4.
1
0
(trisyl-N3), -78 °C
30 min
2
. Results and discussion
O
N
O
O
2
.1. Preparation of (4R,5R)-trans-N-[(diethoxyphos-
phoryl)propionyl]hexahydrobenzoxazolidin-2-one,
4R,5R)-2
N3
O
(
P(OEt)2
trans-Hexahydrobenzoxazolidinone 1b was N-acylated fol-
lowing the established protocol, by treatment with n-butyl-
1
1
(4R,5R,2'S)-3, ds > 98%
ꢁ
ꢁ
lithium at ꢀ78 C, followed by addition (ꢀ78 C) of
Scheme 2.
1
2
(diethoxyphosphoryl)propionyl chloride to generate the
N-propionyl derivative 2 (82% yield) (Scheme 1).
oxygens and the electrophile is incorporated from the less
sterically hindered face of the enolate (Scheme 2).
O
O
O
O
1
2
) n-BuLi, -78 °C
N
2.3. Removal of the chiral auxiliary and hydrogenation/
hydrolysis to give (S)-AP-3
O
N
H
)
O
Cl
P(OEt)2
O
82% yield)
1
b
O
P(OEt)2
Isolation of the desired aminophosphonic acid (S)-AP-3 was
accomplished in three steps, as outlined in Scheme 3. Thus,
removal of the oxazolidinone chiral auxiliary was achieved
(
(4R,5R)-2
0
Scheme 1.
by treatment of azide (4R,5R,2 S)-3 with lithium hydroper-
1
4,15
oxide, as suggested by Evans and co-workers.
tion proceeded with 72% yield and the resulting azide-acid
S)-4 was reduced by catalytic hydrogenation to afford
This reac-
2
.2. Diastereoselective azidation of (4R,5R)-2
(
From the various reagents available for the electrophilic ami-
a-amino acid (S)-5 in 48% yield. Finally, hydrolysis of the
diethyl phosphonate group was carried out with 6 N HCl
under reflux for 7 h to give the expected aminophosphonic
acid (S)-AP-3 [(S)-6, 51% yield], whose physical properties
and optical rotation coincided with those reported in the lit-
1
3
nation of carbanionic substrates, we chose to effect direct
azide transfer to the sodium enolate of phosphorylated pro-
pionyl substrate (4R,5R)-2. Thus, the sodium enolate derived
from oxazolidinone (4R,5R)-2, generated with sodium hexa-
1
0,16
methyldisilazide (NaHMDS), was treated with 1.1 equiv of
2
erature. The overall yield of the preparation of (S)-AP-3
from phosphorylated oxazolidinone (4R,5R)-2 was 11.6%.
ꢁ
,4,6-triisopropylbenzylsulfonyl azide (trisyl-N ) at ꢀ78 C
3
1
4
1
for 30 min (Scheme 2). Most gratifyingly, H NMR analy-
sis of the crude azidated product 3 showed a single set of
signals, indicating a diastereomeric purityꢂ98%.
2.4. Enantioselective synthesis of (R)-2-amino-4-phos-
phonobutanoic acid, (R)-AP-4
The absolute configuration of the newly created stereogenic
0
In a further application of hexahydrobenzoxazolidinone 1b
in the enantioselective preparation of a-amino-u-phospho-
nocarboxylic acids, (R)-2-amino-4-phosphonobutanoic acid,
(R)-AP-4, was synthesized via N-acylation of 1b with (di-
ethoxyphosphoryl)butanoic acid chloride to give derivative
(4R,5R)-7, which was then azidated, hydrogenated, and
center at C(2 ) in product 3 was established to be (S) by
means of chemical correlation with 2-amino-3-phosphono-
propionic acid (AP-3) as discussed in Section 2.3. This result
is consistent with the intermediacy of a (Z)-configured eno-
1
5
late, where the sodium cation is chelated by both carbonyl
O
O
O
HO
HO
HO
1
) H2O2, LiOH
2) Na2SO3
72% yield)
H2, Pd/C 10%
6N HCl
N
O
O
O
N3
O
MeOH, 1 atm H2N
∆, 7 h
H2N
O
N3
O
(
(48% yield)
O
(51% yield)
P(OEt)2
S)-4
P(OEt)2
P(OH)2
P(OEt)2
(
(S)-5
(S)-6, (S)-AP-3
(
4R,5R,2'S)-3
Scheme 3.

8406
G. Reyes-Rangel et al. / Tetrahedron 62 (2006) 8404–8409
Xc
Xc
O
1
2
) n-BuLi, -78 °C
O
Diastereoselective
azidation
O
O
O
N3
N
H
)
O
O
P(OEt)2
(64% yield)
1
b (Xc)
Cl
(
EtO)2P
O
(EtO)2P
(73% yield)
(
4R,5R)-7
(4R,5R,2'R)-8
Removal of
chiral auxiliary
(63% yield)
HO
H2N
HO
HO
O
O
O
O
hydrolysis
Catalytic
hydrogenation
H2N
N3
(69% yield)
(
60% yield)
(EtO)2P
(EtO)2P
R)-10
O
(EtO)2P
(R)-9
O
(R)-11
(
Scheme 4.
0
hydrolyzed as described above in the case of (4R,5R)-2. (R)-
-Amino-4-phosphonobutanoic acid, (R)-AP-4, was isolated
in 12.2% overall yield (Scheme 4).
4.2. (4R,5R)-trans-N-[3 -(Diethoxyphosphoryl)pro-
pionyl]hexahydrobenzoxazolidin-2-one, (4R,5R)-2
2
A dry 250-mL two-necked flask provided with a magnetic
stirrer, a dropping funnel, and a low-temperature thermo-
meter was charged with a mixture of (4R,5R)-1b (1.8 g,
3. Summary
1
2.75 mmol) in dry THF (130 mL) under nitrogen. The solu-
ꢁ
The potential of hexahydrobenzoxazolidinones 1a–d as ef-
fective chiral auxiliaries in the enantioselective synthesis
of a-amino-u-phosphonocarboxylic acids is demonstrated
by the use of phosphoryl derivatives (4R,5R)-2 and
tion was cooled to ꢀ78 C in dry ice/acetone bath before the
dropwise addition of a precooled solution of n-BuLi
(5.31 mL, 2.4 M in hexane, 12.75 mmol). Stirring was con-
ꢁ
tinued for 2 h at ꢀ78 C and then a precooled solution of
(
4R,5R)-7, which were prepared by N-acylation of 1b, for
(diethoxyphosphoryl)propionyl chloride (3.8 g, 16.57 mmol)
in THF (50 mmol) was added dropwise. The reaction
the highly stereoselective preparation of (2S)-amino-3-phos-
phonopropanoic acid, (S)-AP-3, and (2R)-amino-4-phos-
phonobutanoic acid, (R)-AP-4.
ꢁ
mixture was stirred at ꢀ78 C for 1 h, and allowed to warm
ꢁ
then quenched with saturated aqueous solution of NH Cl
up to ꢀ30 C with continued stirring during 3 h, and
4
(
30 mL). Water (120 mL) was added and the organic mate-
4. Experimental
rial was extracted with EtOAc (3ꢃ100 mL), dried with anhy-
drous Na SO , filtered, and evaporated. The crude product
4
2
4
.1. General
was purified by silica gel column chromatography (hexane/
EtOAc, 80:20 to 50:50) to give 3.49 g (82% yield) of
2
5
1
Flasks, stirring bars, and hypodermic needles used for the
generation and reactions of organometallic compounds
were dried for ca. 12 h at 120 C and allowed to cool in a des-
iccator over anhydrous CaSO . Anhydrous solvents were
4
obtained by distillation from benzophenone/ketyl radical.
n-Butyllithium was titrated according to the method of Juar-
isti and co-workers. TLC: Merck DC-F254 plates, detection
UV light, iodine vapor or ninhydrin spray. Flash chromato-
graphy: Merck silica gel (0.040–0.063 mm). Melting
points: Melt Temp apparatus, not corrected. H NMR spec-
tra: Jeol Eclipse-400 (400 MHz), Bruker Ultra Shield
(4R,5R)-2 as a colorless oil, [a]D ꢀ47.0 (c 1, CHCl ). H
3
NMR (CDCl , 400 MHz) d 1.25 (t, J¼7.0 Hz, 6H), 1.35
3
ꢁ
(m, 3H), 1.58 (m, 1H), 1.79 (m, 1H), 1.86 (m, 1H), 2.03
(m, 2H), 2.17 (m, 1H), 2.74 (m, 1H), 2.97 (m, 1H), 3.22
1
8
1
2
3
(m, 1H), 3.48 (ddd, J zJ ¼10.8 Hz, J ¼3.3 Hz, 1H), 3.81
1
2
3
13
(ddd, J zJ ¼11.5 Hz, J ¼3.6 Hz, 1H), 4.02 (m, 4H).
NMR (CDCl , 100 MHz) d 16.4 (d, J ¼6.2 Hz), 20.2 (d,
C
1
9
3
C/P
JC/P¼144.5 Hz), 23.5, 23.7, 28.4, 28.8, 30.0 (d, J
31
¼
C/P
2
0
2.3 Hz), 61.8 (d, J ¼6.9 Hz), 63.2, 81.6, 154.6, 173.5 (d,
C/P
1
JC/P¼17.7 Hz). P NMR (CDCl , 162 MHz) d 31.7. MS
3
+
(20 eV) m/z 334 (M +1, 24), 236 (16), 193 (99), 165 (100),
137 (89), 96 (45), 81 (17), 55 (9). HRMS (FAB) calcd for
C H NO P: 334.1420; found: 334.1425.
(
300 MHz), and Jeol GSX-270 (270 MHz) spectrometers;
C NMR spectra: Jeol Eclipse-400 (100 MHz) and Bruker
1
3
1
4
25
6
3
1
Ultra Shield (75 MHz); P NMR spectra: Jeol Eclipse-400
162 MHz) and Bruker Ultra Shield (121 MHz) spectro-
meters; Chemical shifts d are given in parts per million rel-
0
(
4.3. (4R,5R)-trans-N-[4 -(Diethoxyphosphoryl)buta-
noyl]hexahydrobenzoxazolidin-2-one, (4R,5R)-7
ative to Me Si as an internal reference, coupling constants
4
are given in J (hertz). Mass spectra were obtained in a
Hewlett–Packard HP-5986 instrument. High-resolution
mass spectra (HRMS) were obtained at the Instituto de Qu ´ı -
mica, UNAM, M ꢀe xico on an HPLC 1100 coupled to MSD
TOF Agilent Technologies mod. 1969A.
The same procedure described for the preparation of
(4R,5R)-2 was followed, with 2.0 g (14.2 mmol) of oxazoli-
dinone 1b, 5.1 mL of n-butyllithium (2.77 M in hexane,
14.2 mmol), and 4.12 g (17 mmol) of (diethoxyphosphoryl)-
butanoic acid chloride to give 3.6 g (73% yield) of (4R,5R)-7

G. Reyes-Rangel et al. / Tetrahedron 62 (2006) 8404–8409
8407
ꢁ
that was crystallized from CH Cl –AcOEt, mp 70–71 C,
2
(t, J¼7.1 Hz, 6H), 1.42 (m, 3H), 1.65 (m, 1H), 1.80–
2
2
5
1
[
a] ꢀ52.8 (c 1.04, CHCl ). H NMR (CDCl , 300 MHz)
2.05 (m, 5H), 2.20 (m, 2H), 2.80 (m, 1H), 3.57
(ddd, J zJ ¼11.0 Hz, J ¼3.3 Hz, 1H), 3.94 (ddd,
D
3
3
1
2
3
d 1.26 (t, J¼7.0 Hz, 6H), 1.30 (m, 3H), 1.60 (m, 1H),
1
2
3
1
.70–2.00 (m, 6H), 2.17 (m, 1H), 2.70–2.90 (m, 2H), 3.05
J zJ ¼11.5 Hz, J ¼3.6 Hz, 1H), 4.08 (m, 4H), 4.79 (dd,
1
2
3
1
2
13
(
(
m, 1H), 3.48 (ddd, J zJ ¼10.8 Hz, J ¼3.2 Hz, 1H), 3.82
J ¼8.5 Hz, J ¼7.7 Hz, 1H). C NMR (CDCl , 100 MHz)
3
1
2
3
ddd, J zJ ¼11.5 Hz, J ¼3.5 Hz, 1H), 4.03 (m, 4H).
d 16.4, 16.5, 22.2 (d, J ¼142.2 Hz), 23.5, 23.7, 24.1 (d,
C/P
1
3
C NMR (CDCl , 75 MHz) d 16.5, 16.5, 17.5 (d,
3
JC/P¼3.1 Hz), 28.4, 28.6, 60.9 (d, J ¼17.6 Hz), 61.9 (m),
C/P
3
1
JC/P¼4.6 Hz), 23.5, 23.7, 24.9 (d, J ¼141.3 Hz), 28.4,
63.5, 82.2, 154.2, 171.6. P NMR (CDCl , 162 MHz)
3
C/P
+
2
1
8.9, 36.6 (d, J ¼16.3 Hz), 61.5, 61.6, 63.1, 81.4, 154.7,
d 31.1. MS (20 eV) m/z 389 (M +1, 2.1), 220 (6.1), 192
(62.2), 164 (46.2), 136 (100), 109 (16.1). HR-ESI-TOF
m/z [2a$Na] calcd for C H N O PNa: 411.1404; found:
1
C/P
3
1
74.3. P NMR (CDCl , 121.5 MHz) d 32.4. MS (20 eV)
3
+
+
+
+
m/z 349 (M +2, 1), 348 (M +1, 6), 347 (M , 4), 302 (3),
5 25 4 6
2
1
50 (7), 207 (100), 179 (82), 165 (82), 152 (57), 151 (53),
25 (26), 123 (17), 96 (20). Elem. Anal. Calcd for
411.1411 (1.73 ppm).
C H NO P: C, 51.86; H, 7.55; N, 4.03; found: C, 52.00;
1
H, 7.28; N, 4.03.
4.6. (2S)-Azido-3-(diethoxyphosphoryl)propionic acid,
(S)-4
5
26
6
0
azidopropionyl]hexahydrobenzoxazolidin-2-one,
0
4
.4. (4R,5R)-trans-N-[3 -(Diethoxyphosphoryl)-(2 S)-
In a 100-mL flask providedwith magneticstirrer and nitrogen
atmosphere was placed 856 mg (2.28 mmol) of azide
0
0
resulting solution was cooled to 0 C before the addition
(
4R,5R,2 S)-3
(4R,5R,2 S)-3 in 35 mL of THF and 11.5 mL of water. The
ꢁ
of 1.04 mL (9.12 mmol) of 30% H O and 191.8 mg
A dry two-necked flask provided with magnetic stirrer, drop-
ping funnel, and low-temperature thermometer was charged
with a mixture of (4R,5R)-2 (300 mg, 0.9 mmol) in THF
2
2
(4.56 mmol) of LiOH$H O. The reaction mixture was stirred
2
ꢁ
6.0 mL of water was added. Immediately thereafter, 20 mL
at 0 C for 3 h and then 634 mg (5.02 mmol) of Na SO in
2
3
(
ꢀ
30 mL) under nitrogen. The solution was cooled to
78 C in dry ice/acetone bath before the dropwise addition
ꢁ
of a precooled solution of NaHMDS (0.9 mL, 1 M in hexane,
of 0.5 N solution of NaHCO was added and the aqueous
3
solution was extracted with EtOAc (2ꢃ50 mL) to remove the
oxazolidinone auxiliary. The aqueous phase was acidulated
to pH¼2.0 with 1 N HCl and extracted with CH Cl
ꢁ
0
.9 mmol). After 30 min at ꢀ78 C a precooled solution of
trisyl azide (306.5 mg, 0.99 mmol) in THF (5 mL) was
added dropwise. The reaction mixture was stirred for
2
2
(3ꢃ50 mL). The organic extracts were combined, dried
3
4
0 min before the addition of glacial acetic acid (0.24 mL,
.14 mmol). The reaction mixture was allowed to warm up
with anhydrous Na SO , and evaporated. The product (S)-4
2
4
was purified by silica gel column chromatography (i-PrOH/
MeOH/AcOH, 8:1:0.3) to give 417 mg (72% yield) of a
to room temperature and stirred for 3 h. Saturated aqueous
NH Cl (5 mL) was added and the organic material was ex-
2
5
1
colorless oil, [a]D +44.1 (c 1, CHCl ). H NMR (CDCl ,
3 3
4
tracted with EtOAc (3ꢃ30 mL), dried with anhydrous
400 MHz)
d
1.32 (t, J¼7.0 Hz, 6H), 2.19 (ddd,
1
2
3
1
Na SO , filtered, and concentrated in a rotary evaporator.
2
J zJ ¼16.5 Hz, J ¼9.2 Hz, 1H), 2.42 (ddd, J ¼19.1 Hz,
4
2
3
The crude product was purified by flash chromatography
J ¼15.4 Hz, J ¼4.4 Hz, 1H), 4.11–4.21 (m, 5H), 9.35 (s,
3 C/P
1
3
(
(
hexane/EtOAc, 1:1) to yield 222 mg (66% yield) of azide
4R,5R,2 S)-3 as a colorless oil, [a]D ꢀ42.0 (c 1, CHCl ).
1H). C NMR (CDCl , 100 MHz) d 16.3 (d, J
¼
0
25
H NMR (CDCl , 300 MHz) d 1.33 (m, 6H), 1.40 (m, 3H),
23.7 Hz), 27.9 (d, JC/P¼144.5 Hz), 57.0 (d, J ¼3.8 Hz),
3
C/P
1
63.0 (d, J ¼6.9 Hz), 63.1 (d, J ¼6.9 Hz), 171.1 (d, J
¼
3
C/P C/P C/P
3
1
1
2
.66 (m, 1H), 1.88 (m, 2H), 2.20 (m, 2H), 2.51 (m, 1H),
.60 (m, 1H), 3.59 (m, 1H), 3.98 (ddd, J zJ ¼11.3 Hz,
15.3 Hz). P NMR (CDCl , 162 MHz) d 27.8. MS (20 eV)
3
1
2
+
m/z 252 (M +1, 38), 180 (60), 152 (35), 134 (8), 122
(100), 97 (52), 80 (26), 70 (30), 58 (13), 43 (70). HRMS
(FAB) calcd for C H N O P: 252.0749; found: 252.0744.
3
J ¼3.3 Hz, 1H), 4.11 (q, J¼7.2 Hz, 2H), 4.16 (q,
1
3
J¼7.1 Hz, 2H), 5.22 (m, 1H). C NMR (CDCl , 75 MHz)
3
7 15 3 5
d 16.5 (d, J ¼6.2 Hz), 23.5, 23.7, 27.2 (d, J
¼
¼
C/P
C/P
C/P
1
4
42.7 Hz), 28.5, 28.6, 56.2 (d, JC/P¼1.5 Hz), 62.3 (d, J
4.7. (2R)-Azido-4-(diethoxyphosphoryl)butanoic acid,
(R)-9
.1 Hz), 62.4 (d, J ¼4.1 Hz), 63.6, 82.1, 154.2, 171.0 (d,
C/P
3
1
JC/P¼13.8 Hz). P NMR (CDCl , 121 MHz) d 26.4. MS
3
+
(
(
(
20 eV) m/z 375 (M +1, 0.8), 346 (1.7), 249 (8.6), 205
2.3), 178 (61), 150 (62), 122 (100), 97 (22), 81 (17), 58
5.4). HRMS (FAB) calcd for C H N O P: 375.1433;
The same procedure described for the preparation of (S)-4
was followed with 1.12 g (2.9 mmol) of (4R,5R,2 R)-8,
0
1.31 mL (11.57 mmol) of H O , 243 mg (5.8 mmol) of
1
4
24
4
6
2 2
found: 375.1436.
LiOH$H O, and 802 mg (6.4 mmol) of Na SO to give
2 2 3
2
5
4
83 mg (63% yield) of (R)-9 as a pale yellow oil, [a]
D
0
azidobutanoyl]hexahydrobenzoxazolidin-2-one,
0
1
4
.5. (4R,5R)-trans-N-[4 -(Diethoxyphosphoryl)-(2 S)-
+32.4 (c 1.02, CHCl ). H NMR (CDCl , 300 MHz) d 1.30
3 3
(t, J¼7.0 Hz, 6H), 2.00 (m, 4H), 3.98 (br, 1H), 4.08 (q,
0
13
(
4R,5R,2 R)-8
J¼7.0 Hz, 2H), 4.10 (q, J¼7.0 Hz, 2H), 9.36 (br, 1H).
C
NMR (CDCl , 75 MHz) d 16.4, 16.5, 21.6 (d, J
3
¼
C/P
The same procedure described for the preparation of
0
141.2 Hz), 25.0, 62.3, 62.4, 63.2 (d, J ¼16.4 Hz), 174.5.
C/P
31
(
(
4R,5R,2 S)-3 was followed with 1.0 g (2.9 mmol) of
4R,5R)-7, 3.17 mL of LiHMDS (1 M in hexane,
P NMR (CDCl , 121 MHz) d 32.6. MS (20 eV) m/z 26.5
3
+
(M , 16.6), 236 (10.5), 219 (8.5), 192 (62.7), 164 (43.8),
136 (100), 128 (51.1), 109 (26.1), 100 (45.1), 82 (20.2), 72
(16.2), 54 (41.0), 44 (56.9). HR-ESI-TOF m/z [2a$Na]
calcd for C H N O PNa: 288.07198; found: 288.07231
(1.15 ppm).
3
.2 mmol), 0.98 g (3.2 mmol) of trisyl azide, and 0.76 mL
13.2 mmol) of glacial acetic acid to give 712 mg (63.7%
+
(
yield) of (4R,5R,2 R)-8 as a slightly yellow oil, [a]
ꢀ
0
39.0 (c 1, CHCl ). H NMR (CDCl , 400 MHz) d 1.29
25
D
8 16 3 5
1
3
3

8408
G. Reyes-Rangel et al. / Tetrahedron 62 (2006) 8404–8409
4
(
.8. (2S)-Amino-3-(diethoxyphosphoryl)propionic acid,
S)-5
5.1 mL of 6 N HCl to give 119 mg (69% yield) of amino
ꢁ
acid (R)-11 [(R)-AP-4] as a white solid, mp 206–208 C,
2
5
10c
25
[
HCl) for the (S)-enantiomer. H NMR (D O, 400 MHz)
a] ꢀ25.0 (c 1.0, 6 N HCl); lit. [a]D +27.6 (c 3.0, 6 N
D
1
In a hydrogenation flask were placed 370 mg (1.47 mmol) of
S)-4, 30 mL of methanol, and 37 mg of 10% Pd/C. The flask
2
1
2
(
d 1.71 (m, 2H), 2.13 (m, 2H), 4.03 (dd, J ¼J ¼5.7 Hz,
1
3
was pressurized with hydrogen (1 atm) and shaken at room
temperature for 1 h. The reaction mixture was filtered over
Celite and the filtrate was evaporated in a rotary evaporator.
The residue was purified by silica gel column chromato-
1H).
133.8 Hz), 24.5, 53.7 (d, JC/P¼16.0 Hz), 172.3. P NMR
C NMR (D O, 100 MHz) d 23.4 (d, J
2 C/P
¼
3
1
(D O, 162 MHz) d 25.4.
2
graphy i-PrOH/MeOH/NH Cl (6:1:0.5) to give 160 mg
4
ꢁ
(
[
48% yield) of (S)-5 as a waxy solid with mp 123–125 C,
a] +14.7 (c 1.02, CHCl ). H NMR (CDCl , 400 MHz)
Acknowledgements
2
5
1
D
3
3
d 1.29 (t, J¼7.0 Hz, 3H), 1.30 (t, J¼7.0 Hz, 3H), 2.42 (ddd,
We are grateful to Consejo Nacional de Ciencia y Tecnolog ´ı a
for financial support via grant 45157-Q.
1
2
3
J zJ ¼15.4 Hz, J ¼10.6 Hz, 1H), 2.58 (m, 1H), 3.86 (m,
1
H), 4.08 (q, J¼7.0 Hz, 2H), 4.12 (q, J¼7.0 Hz, 2H), 7.01
1
3
(
br, 1H). C NMR (CDCl , 100 MHz) d 16.4, 26.4 (d,
3
3
1
JC/P¼139.2 Hz), 49.8, 62.7, 172.2 (d, J ¼15.3 Hz). P
NMR (CDCl , 162 MHz) d 29.9. MS (20 eV) m/z 226
References and notes
C/P
3
+
(
M +1, 3), 180 (100), 152 (45), 138 (7), 124 (55), 106 (35),
7 (8), 83 (6), 57 (7), 45 (74). HRMS (FAB) calcd for
C H NO P: 226.0844; found: 226.0841.
1. Ferkany, J. W.; Willetts, J.; Borosky, S. A.; Clissold, D. B.;
Karbon, E. W.; Hamilton, G. S. Bioorg. Med. Chem. Lett.
1993, 3, 33.
9
7
17
5
2
. (a) Young, A. B.; Greenamyre, J. T.; Hollingsworth, Z.; Albin,
R.; D’Amato, C.; Shoulson, I.; Penny, J. B. Science 1988, 241,
4
(
.9. (2R)-Amino-4-(diethoxyphosphoryl)butanoic acid,
R)-10
981; (b) Collingridge, G. L.; Singer, W. Trends Pharmacol. Sci.
1990, 11, 290; (c) Klockgether, T.; Turski, L. Ann. Neurol.
1990, 28, 539; (d) Zivin, J. A.; Choi, D. W. Sci. Am. 1991,
265, 56.
The same procedure described for the preparation of (S)-5
was followed with 483 mg (1.8 mmol) of (R)-9, 25 mL of
methanol, and 48.3 mg of 10% Pd/C to give 262 mg (60%
3
. (a) Rosowsky, A.; Forsch, R. A.; Moran, R. G.; Kohler, W.;
Freisheim, J. H. J. Med. Chem. 1988, 31, 1326; (b) Schoepp,
D. D.; Johnson, B. G. J. Neurochem. 1989, 53, 1865.
ꢁ
25
yield) of (R)-10 as a white solid, mp 152–154 C, [a]
ꢀ
D
1
0c
25
8.24 (c 3.64, H O); lit. [a]D +9.22 (c 5.0, H O) for the
2 2
1
(
S)-enantiomer. H NMR (D O, 300 MHz) d 1.30 (t,
2
4. Koerner, J. F.; Cotman, C. W. Brain Res. 1981, 216, 192.
. See, for example: (a) Ornstein, P. L. J. Org. Chem. 1989, 54,
251; (b) Muller, M.; Mann, A.; Taddei, M. Tetrahedron Lett.
1
2
J¼7.0 Hz, 6H), 1.80–2.20 (m, 4H), 3.78 (dd, J ¼J ¼5.4 Hz,
5
1
3
1
NMR (D O, 75 MHz) d 15.8, 15.9, 20.3 (d, J
H), 4.12 (q, J¼7.2 Hz, 2H), 4.14 (q, J¼7.2 Hz, 2H).
C
¼
2
2
C/P
1993, 34, 3289; (c) Garc ´ı a-Barradas, O.; Juaristi, E.
Tetrahedron 1995, 51, 3423; (d) Garc ´ı a-Barradas, O.; Juaristi,
E. Tetrahedron: Asymmetry 1997, 8, 1511.
1
6
40.0 Hz), 23.7 (d, JC/P¼3.8 Hz), 54.7 (d, J ¼19.1 Hz),
C/P
3
1
3.8 (d, JC/P¼1.3 Hz), 63.9 (d, J ¼1.3 Hz), 173.6.
C/P
P
NMR (D O, 121 MHz) d 34.4.
2
6. (a) Anaya de Parrodi, C.; Juaristi, E.; Quintero, L.; Clara-Sosa,
A. Tetrahedron: Asymmetry 1997, 8, 1075; (b) For a review,
see: Anaya de Parrodi, C.; Juaristi, E. Synlett 2006, in press.
4
.10. (2S)-Amino-3-phosphonopropionic acid, (S)-6
7
. For recent reviews on the use of (R)- and (S)-a-phenylethyl-
amine in the preparation of enantiopure compounds, see: (a)
Juaristi, E.; Escalante, J.; Le ꢀo n-Romo, J. L.; Reyes, A.
Tetrahedron: Asymmetry 1998, 9, 715; (b) Juaristi, E.;
Le ꢀo n-Romo, J. L.; Reyes, A.; Escalante, J. Tetrahedron:
Asymmetry 1999, 10, 2441.
In a 25-mL flask provided with magnetic stirrer were placed
74 mg (0.77 mmol) of (S)-5 and 4.0 mL of 6 N HCl. The re-
1
action mixture was heated to reflux for 7 h, allowed to cool to
room temperature, and concentrated in a rotary evaporator.
The residue was redissolved in 6.0 mL of ethanol and treated
with 2.0 mL of propylene oxide. The resulting suspension
ꢁ
8. Anaya de Parrodi, C.; Clara-Sosa, A.; P ꢀe rez, L.; Quintero, L.;
Mara n˜ ꢀo n, V.; Toscano, R. A.; Avi n˜ a, J. A.; Rojas-Lima, S.;
Juaristi, E. Tetrahedron: Asymmetry 2001, 12, 69.
was heated to 50 C for 2 h, and concentrated in a rotary
evaporator to give a white solid, which was redissolved in
1.0 mL of water and crystallized upon addition of 3.0 mL
of ethanol to give 67 mg (51% yield) of amino acid (S)-6
9
. Clara-Sosa, A.; P ꢀe rez, L.; S ꢀa nchez, M.; Melgar-Fern ꢀa ndez, R.;
Juaristi, E.; Quintero, L.; Anaya de Parrodi, C. Tetrahedron
2004, 60, 12147.
ꢁ
NaOH); lit. [a]D +12.6 (c 0.75, 1 N NaOH) for the (R)-
25
[
(S)-AP-3], mp 224–226 C, [a] ꢀ12.0 (c 1.0, 1 N
D
1
0d
25
1
6
25
Hg
10d
10. For previous asymmetric syntheses of (R)- and/or (S)-AP-3 and
(R)- or (S)-AP-4, see: (a) Villanueva, J. M.; Collignon, N.; Guy,
A.; Savignac, P. Tetrahedron 1983, 39, 1299; (b) Smith,
E. C. R.; McQuaid, L. A.; Paschal, J. W.; DeHoniesto, J.
J. Org. Chem. 1990, 55, 4472; (c) Soloshonok, V. A.;
Belokon, Y. N.; Kuzmina, N. A.; Maleev, V. I.; Svistunova,
N. Y.; Solodenko, V. A.; Kukhar, V. P. J. Chem. Soc., Perkin
Trans. 1 1992, 1525; (d) Yokomatsu, T.; Sato, M.; Shibuya,
S. Tetrahedron: Asymmetry 1996, 7, 2743; (e) Lohse, P. A.;
Felber, R. Tetrahedron Lett. 1998, 39, 2067; (f) Minowa, N.;
Hirayama, M.; Fukatsu, S. Tetrahedron Lett. 1984, 25, 1147;
(g) Zeiss, H.-J. Tetrahedron 1992, 48, 8263.
enantiomer. [a]
ꢀ54.0 (c 1.0, 1 N NaOH); lit.
25
Hg
16
[
a] +58.9 (c 1.0, 1 N NaOH) for the (R)-enantiomer.
1
1
H NMR (D O, 270 MHz) d 2.09 (m, 1H), 2.30 (ddd, J z
2
2
3
1
J ¼16.5 Hz, J ¼3.9 Hz, 1H), 4.14 (ddd, J ¼15.1 Hz,
2
3
13
J ¼9.8 Hz, J ¼3.9 Hz, 1H). C NMR (D O, 67 MHz)
2
d 28.1 (d, J ¼130.9 Hz), 49.7 (d, J ¼4.2 Hz), 171.9 (d,
C/P
C/P
3
1
JC/P¼12.5 Hz). P NMR (D O, 109 MHz) d 18.6.
2
4
.11. (2R)-Amino-4-phosphonopropionic acid, (R)-11
The same procedure described for the preparation of (S)-6
was followed with 224 mg (0.94 mmol) of (R)-10 and

G. Reyes-Rangel et al. / Tetrahedron 62 (2006) 8404–8409
8409
1
1
1
1
1. Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83.
2. Janecki, T.; Bodalski, R. Synthesis 1989, 506.
3. Erdik, E.; Ay, M. Chem. Rev. 1989, 89, 1947.
4. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am.
Chem. Soc. 1990, 112, 4011.
consideration that the CH P(O)(OH) group has higher priority
2
2
1
7
2
than the carboxylic CO H group in the CIP rules shows that
dextrorotatory AP-3 corresponds to the (R)-enantiomer.
17. See, for example: (a) Juaristi, E. Introduction to Stereo-
chemistry and Conformational Analysis; Wiley: New York,
NY, 1991; (b) Eliel, E. L.; Wilen, S. H. Stereochemistry of
Organic Compounds; Wiley: New York, NY, 1994.
18. Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M.
Organic Synthesis via Boranes; Wiley: New York, NY, 1975;
pp 12–15.
1
5. (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
1
981, 103, 2127; (b) Evans, D. A.; Takacs, J. M.; McGee,
L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J. Pure Appl.
Chem. 1981, 53, 1109; (c) Evans, D. A. Aldrichimica Acta
1982, 15, 23; (d) Evans, D. A.; Nelson, J. V.; Taber, T. R.
Top. Stereochem. 1982, 13, 1.
6. The configuration assigned to the dextrorotatory enantiomer
19. Juaristi, E.; Mart ´ı nez-Richa, A.; Garc ´ı a-Rivera, A.; Cruz-
S ꢀa nchez, J. S. J. Org. Chem. 1983, 48, 2603.
20. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
1
1
of AP-3 was mistakenly reported as (S). Nevertheless,
0