Stereochemistry of cycloaddition of (S)-N-(1-phenylethyl)-C-diethoxyphosphorylated nitrone with vinyl acetate. Studies on mutarotation of 3-(O,O-diethylphosphoryl)-5-hydroxyisoxazolidines

Article abstract of DOI:10.1016/j.tetasy.2008.01.009

Three enantiomerically pure diethyl 5-acetoxy-2-[(S)-1-phenylethyl]isoxazolidinyl-3-phosphonates were obtained by 1,3-dipolar cycloaddition of the title nitrone and vinyl acetate. Each of them was subsequently transformed into the respective 5-hydroxy derivatives, which exist as equilibrium mixtures of C5-anomers. Detailed mutarotation studies on a 3-(O,O-diethylphosphoryl)-5-hydroxyisoxazolidine system showed that trans-isomer (3S,5R) is favoured in the solid state, whereas after 48 h in chloroform-d solution it epimerises at C5 to an (89:11) equilibrium mixture of (3S,5S)- and (3S,5R)-isomer. The major (3S,5S)-anomer adopts a single E₃ conformation, which is stabilised by the C3-P(O)...HO-C5 hydrogen bond. Absolute configurations of the cycloadducts were established based on conformational analysis employing ¹H, ¹³C and ³¹P NMR data and confirmed by the transformation of the (3S,5R)-isomer into the known (S)-(+)-phosphohomoserine.

Full text of DOI:10.1016/j.tetasy.2008.01.009

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 279–287
Stereochemistry of cycloaddition of (S)-N-(1-phenylethyl)-
C-diethoxyphosphorylated nitrone with vinyl acetate. Studies on
mutarotation of 3-(O,O-diethylphosphoryl)-5-hydroxyisoxazolidines
Dorota G. Piotrowska*
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Ło´dz´, 90-151 Ło´dz´, Muszyn´skiego 1, Poland
Received 16 October 2007; accepted 9 January 2008
This paper is respectfully dedicated to Professor Maria Michalska
Abstract—Three enantiomerically pure diethyl 5-acetoxy-2-[(S)-1-phenylethyl]isoxazolidinyl-3-phosphonates were obtained by
1,3-dipolar cycloaddition of the title nitrone and vinyl acetate. Each of them was subsequently transformed into the respective 5-hydroxy
derivatives, which exist as equilibrium mixtures of C5-anomers. Detailed mutarotation studies on a 3-(O,O-diethylphosphoryl)-5-hydroxy-
isoxazolidine system showed that trans-isomer (3S,5R) is favoured in the solid state, whereas after 48 h in chloroform-d solution it
epimerises at C5 to an (89:11) equilibrium mixture of (3S,5S)- and (3S,5R)-isomer. The major (3S,5S)-anomer adopts a single E3
conformation, which is stabilised by the C3–P(O)ꢀ ꢀ ꢀHO–C5 hydrogen bond. Absolute configurations of the cycloadducts were
established based on conformational analysis employing 1H, 13C and 31P NMR data and confirmed by the transformation of the
(3S,5R)-isomer into the known (S)-(+)-phosphohomoserine.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
HO
O1
O
R'
N
5 OAc
OAc
2
The 1,3-dipolar cycloaddition of nitrones with various
alkenes has received considerable attention, since substi-
tuted isoxazolidines found applications as useful precursors
for the construction of important and potentially bioactive
compounds, including b-amino acids, b-lactams, amino
sugars as well as isoxazolidine nucleosides.1–4 In most cases
the regio- and stereochemistry of the cycloaddition is
predictable, although subtle structural differences of the
reagents can influence the ratio of the isomers.1,5 So far,
a vast number of the reactions of structurally diversified
nitrones and alkenes have been studied, the majority of
which were focused on asymmetric transformations.5,6
3
4
OH
R
1
2
Figure 1. Structural resemblance of 5-acetoxyisoxazolidines 1 and 1-O-
acetyl-2-deoxyfuranose 2.
Since 5-acetoxyisoxazolidines could be used as starting
materials in the Vorbruggen reaction,23 the synthesis of
¨
isoxazolidine analogues of nucleosides became apparent.
Following this reasoning, various modified nucleosides
have been obtained with some of them, for example, 3
and 4 (Fig. 2),24,25 revealing interesting biological activity.
Among various dipolarophiles reacted with nitrones, vinyl
acetate is of special interest, since 5-acetoxyisoxazolidine
cycloadducts 1 are formed, which can be considered as
O
F
structural analogues of 1-O-acetyl-2-deoxyfuranose
2
NH
(Fig. 1). Several achiral as well as chiral nitrones have been
examined in the reaction with vinyl acetate including syn-
thetic,7–21 as well as theoretical studies.15,22
Base
N
O
O
O
HN
N
3
4
*
Tel.: +48 42 677 92 35; fax: +48 42 678 83 98; e-mail: dorota@
ich.pharm.am.lodz.pl
Figure 2. Isoxazolidinyl nucleoside analogues 3 and 4.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.01.009

280
D. G. Piotrowska / Tetrahedron: Asymmetry 19 (2008) 279–287
O
P
O
P
EtO
EtO
EtO
EtO
n
Base
n
n
(EtO)2(O)P
Me
OAc
N
N
Me
O
N
Me
O
O
6
7
5
n=1, 2
Scheme 1. Chiacchio’s approach to isoxazolidine nucleoside analogues 5.
For example, Chiacchio et al. have reported the synthesis
of phosphonate analogues of isoxazolidinyl nucleosides 5,
which were obtained from nitrones 7 (n = 1 or 2) and vinyl
acetate following the subsequent coupling with selected
nucleobases (Scheme 1).7,10,11
As reported earlier, the reaction of the racemic C-phos-
phorylated nitrone with vinyl acetate led to a 90:10 mixture
of the corresponding trans- and cis-isoxazolidines.26 Based
on this observation, trans-isoxazolidines (3S,5R)-9a and
(3R,5S)-9b are also expected to be formed as the major
products in the cycloaddition of (S)-8 to vinyl acetate. To
confirm this assumption, detailed conformational analyses
of pure isoxazolidines 9 were undertaken based on the vic-
inal coupling constants (Table 1).29–35 It appeared that a
preferred conformation could only be unambiguously
established for the (3R,5S)-9b diastereoisomer only. The
isoxazolidine ring in (3R,5S)-9b adopts an 4E conformation
having the P(O)(OEt)2 and OAc groups in pseudoequato-
rial and axial positions, respectively (Fig. 3). The most
diagnostic vicinal couplings include: J(H–C3C4–Hb) =
10.8 Hz, which suggests almost perfect antiperiplanar
arrangement of the respective protons, J(H–C3C4–
Ha) = 0 Hz (the respective dihedral angle ꢁ80°) and J(P–
C3C4–C5) = 9.2 Hz (the respective dihedral angle ꢁ150°).
Consequently, the second major cycloadduct (3S,5R)-9a
also has trans-configuration. Additional evidence in sup-
port of the trans-relative configurations of (3S,5R)-9a and
(3R,5S)-9b will be given later. Based on this reasoning
the trans/cis diastereoselectivity of the cycloaddition of
(S)-8 and vinyl acetate is 92:8, very close to that observed
for the achiral nitrone 7 (n = 0).26 It would be tempting
to take advantage of the proximity of an E/Z ratio (7:93)
of the nitrone (S)-8 and the cis/trans diastereoselectivity
of the cycloaddition (8:92) in rationalising the stereochem-
ical outcome of the reaction. However, the possibility of an
E/Z equilibration under the reaction conditions (in our
case 60 °C) has recently been raised as a major argument
in difficulty in correlating E/Z ratio of a dipole with ratios
of cycloadducts.6
Recently, we succeeded in the synthesis of achiral C-phos-
phorylated nitrone 7 (n = 0) and its usefulness in 1,3-dipo-
lar cycloaddition with vinyl acetate was also studied.26,27 In
continuation of these efforts, N-chiral nitrone (S)-8 was re-
acted with vinyl acetate to obtain enantiomerically pure
isoxazolidine cycloadducts 9 (Scheme 2) and to possibly
investigate the mutarotation of the respective 5-hydroxyis-
oxazolidines. Furthermore, isoxazolidines 9 could be con-
sidered as useful precursors in the syntheses of
isoxazolidine nucleoside analogues 5 (n = 0).
O
OAc
OAc
O
Ph
N
Ph
N
+
(EtO)2(O)P
(EtO)2(O)P
9
(S)-8
Scheme 2. Retrosynthesis of 5-acetoxyisoxazolidine 9.
2. Results and discussion
Nitrone (S)-(+)-8 was obtained from diethyl form-
ylphosphonate and (S)-N-(1-phenylethyl)hydroxylamine
according to a known procedure and was found to exist
in a chloroform-d solution as a 7:93 mixture of E/Z iso-
mers.28 The reaction of (S)-8 and vinyl acetate gave a
58:34:2:6 mixture of cycloadducts (3S,5R)-9a, (3R,5S)-9b,
(3S,5S)-9c and (3R,5R)-9d (Scheme 3). Three pure diastereo-
isomers (3S,5R)-9a, (3R,5S)-9b and (3R,5R)-9d were
separated from this mixture by column chromatography
on silica gel in 48%, 18% and 4% yields, respectively.
The structure of isoxazolidines 9 resembles the 1-O-acetyl-
2-deoxyfuranose framework, in which the C4 of the fura-
nose ring is replaced with a nitrogen atom. Removal of
the acetyl group in 9 would lead to 5-hydroxyisoxazolidine
O
O
OAc
OAc
Ph
(EtO)2(O)P
(3
N
Ph
(EtO)2(O)P
(3 ,5
N
+
OAc
S
,5R
)-9a
R
S
)-9b
O
a
Ph
N
+
(EtO)2(O)P
OAc
O
O
OAc
(
S
)-8
Ph
(EtO)2(O)P
(3 ,5
N
Ph
(EtO)2(O)P
(3 ,5
N
+
S
S
)-9c
R
R
)-9d
Scheme 3. Reagents and conditions: (a) toluene, 60 °C, 24 h.

D. G. Piotrowska / Tetrahedron: Asymmetry 19 (2008) 279–287
281
Table 1. Stereochemically relevant vicinal couplings and chemical shifts for compounds 9a, 9b and 10a–10d and their conformations
Vicinal coupling constants (Hz)
and chemical shifts (ppm)
Compounds
(3S,5R)-9a
(3R,5S)-9b
(3S,5R)-10a
(3R,5S)-10b
(3S,5S)-10c
(3R,5R)-10d
J(P–C3C4–C5)
J(P–C3N–C)
J(H–C3C4–Ha)
J(H–C3C4–Hb)
J(H–C5C4–Ha)
J(H–C5C4–Hb)
J(P–C3C4–Ha)
J(P–C3C4–Hb)
d(H–C3)
d(Ha–C4)
d(Hb–C4)
d(H–C5)
d(H3C–C(O))
Conformation
3.1
14.3
4.8
8.7
6.6
9.2
6.0
6.3
10.8
0
5.1
2.6
16.0
3.9
9.0
6.3
6.9
9.7
7.5
9.0
0.9
2.0
17.2
0
9.9
0
1.4
14.3
1.5
10.8
0
2.4
2.7
5.1
9.0
5.4
5.4
18.9
20.4
3.64
2.90
2.69
6.51
2.12
5.7
18.6
23.4
3.65
2.79
2.61
5.80
—
13.5
33.9
3.45
2.25
2.42
5.61
—
15.0
32.7
3.44
2.18
1.80
5.35
—
17.1
3.51
2.43
2.70
6.16
1.77
4E
19.2
3.68
2.48
2.62
5.44
—
a
a
a
—
—
—
E3
3E
a A preferred conformation cannot be established unambiguously.
ion, the mixture of (3R,5S)-10b and (3R,5R)-10d was
obtained (Scheme 5). These experiments prove that the
absolute configurations at C3 in the diastereoisomeric pairs
(3R,5S)-9b and (3R,5R)-9d, and in (3S,5R)-9a and (3S,5S)-
9c are the same.
Hb
4
H
Ha
5
O
P(O)(OEt)2
Ph
N
Ac
3
O
H
1
The H NMR spectrum of the chloroform-d solution of
Figure 3. Preferred conformation of (3R,5S)-9b.
(3S,5R)-10a recorded immediately after dissolving crystals,
exhibited resonance characteristics of the trans-isomer
(3S,5R)-10a only. In the spectrum of the same solution ta-
ken 1 h later, a new set of signals attributed to the cis-iso-
mer (3S,5S)-10c (4%) appeared, in addition to resonances
of (3S,5R)-10a (96%). After 3 h, an 88:12 mixture of
(3S,5R)-10a and (3S,5S)-10c was observed, which changed
to 25:75 after 24 h. Finally, an equilibrium mixture (11:89)
of two anomers (3S,5R)-10a and (3S,5S)-10c was formed
after 48 h at room temperature. When this solution was
concentrated to dryness in vacuo at room temperature
derivative 10 for which mutarotation is expected, as no-
ticed earlier for structurally similar isoxazolidines,14,36–41
isoxazolines42 as well as other compounds possessing cyclic
hemiacetal or hemiketal moiety (e.g., hydroxylated oxasila-
cyclopentane derivatives).43–47 To this end, the acetyl
groups in the enantiomerically pure isoxazolidines 9 were
subjected to ammonolysis.
The treatment of (3S,5R)-9a with aqueous ammonia
cleanly produced a mixture of 5-hydroxyisoxazolidines
(C5-anomers), (3S,5R)-10a and (3S,5S)-10c (d31P NMR:
23.76 and 26.68 ppm, respectively) (Scheme 4). Chromato-
graphic removal of acetamide followed by crystallisation of
the appropriate fractions gave pure (3S,5R)-10a in 59%
yield. Similarly, ammonolysis of (3R,5S)-9b led to a mix-
ture of isoxazolidines (3R,5S)-10b and (3R,5R)-10d (d31P
NMR: 23.19 and 26.63 ppm, respectively) (Scheme 5). Fur-
thermore, when (3R,5R)-9d was treated in a similar fash-
1
and the solid obtained was re-dissolved in CDCl3, the H
NMR spectrum showed the presence of (3S,5R)-10a and
(3S,5S)-10c in a 80:20 ratio.
In a similar way, after 24 h at room temperature an equilib-
rium mixture of (3R,5S)-10b and (3R,5R)-10d (10:90) was
produced.
The relative configurations in the diastereoisomers (3S,5R)-
10a and (3S,5S)-10c, as well as in (3R,5S)-10b and (3R,5R)-
10d were established based on 1H, 13C and 31P NMR
spectroscopic data. Comparison of the respective vicinal
couplings in (3S,5R)-10a and (3S,5R)-9a strongly suggests
that they both exist in the same conformation or similar
conformational equilibrium (Table 1). On the other hand,
analysis of vicinal coupling constants for (3S,5S)-10c (Ta-
ble 1) shows that the isoxazolidine ring exists in a single
OH
O
O
O
OAc
OH
a
Ph
(EtO)2(O)P
(3 ,5
N
Ph
(EtO)2(O)P
(3 ,5
N
Ph
N
+
(EtO)2(O)P
S
R
)-9a
S
R
)-10a
(3S,5S)-10c
Scheme 4. Reagents and conditions: (a) NH4OH, EtOH, rt, 2 h.
O
O
O
O
OAc
OH
OH
OAc
a
a
Ph
(EtO)2(O)P
(3
N
Ph
(EtO)2(O)P
(3
N
Ph
(EtO)2(O)P
(3
N
Ph
(EtO)2(O)P
(3R,5R)-9d
N
+
R
,5
S
)-9b
R
,5S
)-10b
R
,5R
)-10d
Scheme 5. Reagents and conditions: (a) NH4OH, EtOH, rt, 2 h.

282
D. G. Piotrowska / Tetrahedron: Asymmetry 19 (2008) 279–287
E3 conformation, in which the P(O)(OEt)2 and hydroxy
groups are cis-oriented (Fig. 4). The unexpected diaxial ori-
entation of two bulky groups P(O)(OEt)2 and Ph(CH3)CH
can be rationalised by the stabilisation of this conforma-
tion by a very strong intramolecular P(O)ꢀ ꢀ ꢀH–O hydrogen
bond (Fig. 4). Furthermore, a very similar set of couplings
has also been found for (3R,5R)-10d, which supports the
Ph
OH
N O
O
OH
O
H
Ph
N
Ph
N
O
P
(EtO)2(O)P
(EtO)2(O)P
EtO
EtO
H
O
trans-10
11
cis-10
3
Scheme 6. Mutarotation of 5-hydroxyisoxazolidine 10.
existence of a single E conformation of the isoxazolidine
ring again stabilised by the P(O)ꢀ ꢀ ꢀH–O hydrogen bond
(Table 1, Fig. 4), thereby indicating a cis-relationship of
the substituents at C3 and C5 in (3R,5R)-10d. As in
(3S,5S)-10c, so in (3R,5R)-10d three antiperiplanar
arrangements of atoms exist in H–C3C4–Hb, P–C3C4–
Hb and P–C3N–C moieties as concluded from the respec-
tive vicinal couplings: J(P–C3C4–Hb) = 33.9 and 32.7 Hz,
J(H–C3C4–Hb) = 9.9 and 10.8 Hz and J(P–C3N–
C) = 17.2 and 14.3 Hz. Close to 90° H–C5C4–Ha dihedral
angles reflect a lack of the respective couplings. These con-
figurational assignments are additionally supported by
comparison of the 31P NMR shifts of the hydrogen-bonded
cis-isomers (3S,5S)-10c (d 26.68 ppm) and (3R,5R)-10d (d
26.63 ppm) with non-bonded trans-isomers (3S,5R)-10a
and (3R,5S)-10b (d 23.76 and 23.19 ppm, respectively).
Furthermore, significantly downfield shifted signals of
OH protons in hydrogen-bonded cis-phosphonates
(3S,5S)-10c and (3R,5R)-10d (d 6.17 and 6.05 ppm) were
observed, when compared to the corresponding signals of
OH group in trans-isomers (3S,5R)-10a and (3R,5S)-10b
(d 3.10 and 2.40 ppm).
(3S,5R)-9a and (3S,5S)-9c in the same 1:2 ratio. Unfortu-
nately, pure (3S,5S)-9c could not be efficiently separated
from these mixtures.
Although significant differences in chemical shifts were ob-
1
served in the H NMR spectra of diastereoisomeric cyclo-
adducts (3S,5R)-9a and (3R,5S)-9b, the assignment of
their absolute configurations was not possible, since the
available data did not allow us to unambiguously establish
the conformation of (3S,5R)-9a. However, detailed analy-
1
ses of H NMR chemical shifts of (3S,5S)-10c [obtained
from (3S,5R)-9a] and (3R,5R)-10d [obtained from
(3R,5S)-9b] showed that an already existing 1-phenylethyl
functionality produces indicative space-oriented aniso-
tropic effects. First of all, the C* carbon of 1-phenylethyl
group is antiperiplanar to the P atom in both compounds
[3JCNCP = 17.2 and 14.3 Hz for (3S,5S)-10c and (3R,5R)-
10d, respectively]. Significant upfield shifts of the Hb–C4
(d 1.80 ppm), Ha–C4 (d 2.16 ppm) and H–C5 (d
5.35 ppm) in (3R,5R)-10d, as compared to the chemical
shifts of the same protons in (3S,5S)-10c (d 2.25, 2.42
and 5.61 ppm, respectively) are best explained by the
shielding of the Ph group in (3R,5R)-10d, which is not pos-
sible in the diastereoisomer (3S,5S)-10c (Fig. 5).
EtO
O
P
EtO
CH3
Hb
H
O
3
H
O
H
H
5
Ha
N
N
O
5
4
4
H
H
3
H
CH3
H
b
O
Ha
O
CH3
H3C
P
O
H
EtO
O
H
N
H
EtO
N
H
O
EtO
O
H
H
H
5
(3
S
,5S
)-10c
(3
R
,5R
)-10d
H
OEt
O
O
P
H
H
P
EtO
Figure 4. The preferred conformations of (3S,5S)-10c and (3R,5R)-10d.
4
H
H
OEt
H
(3
S,5S)-10c
(3R,5R)-10d
At this stage it became clear that the relative configurations
at C3 and C5 are the same in the two diastereoisomeric
pairs of the cycloadducts: trans in (3S,5R)-9a as well as
(3R,5S)-9b and cis in (3S,5S)-9c as well as (3R,5R)-9d.
Figure 5. The preferred conformations of (3S,5S)-10c and (3R,5R)-10d.
Indeed, examination of the molecular models of both cis-
diastereoisomers (3S,5S)-10c and (3R,5R)-10d revealed
The analysis of stereochemical results described above indi-
cates that isomerisation of 5-hydroxyisoxazolidines 10 in-
volves a ring opening and subsequent re-cyclisation of the
corresponding acyclic isomers 11 (Scheme 6). The process
is reversible, since the ratio of isomers changed after con-
centration of an equilibrium mixture. In a solid state the
trans-diastereoisomer 10 is favoured, whereas the corre-
sponding hydrogen-bonded cis-isomer predominates in a
chloroform-d solution.
spatial
orientations
of
substituents
along
the
Ph(CH3)HC–N bond in (3S,5S)-10c and (3R,5R)-10d
(Fig. 6). To prove preferred conformations of both iso-
mers, 2D NOE experiments were performed. Positive sig-
nals between the HCPh–H–C5, HCPh–H–C4 and HCPh–
H–C3 in (3S,5S)-10c indicate spatial proximity of the H–
C5, H–C3, H–C4 and HC proton of the 1-phenylethyl
group. Moreover, a positive signal between the H–C3
and Ph was observed for this isomer. On the other hand,
positive signals for HCPh–H–C3 and HCPh–H–C3 pairs
in (3R,5R)-10d support the preferred conformation shown
in Figure 6. These observations unambiguously prove the
absolute configurations at C3 and C5 in the isoxazolidine
ring as (3S,5S) for isomer 10c and (3R,5R) for 10d.
When pure 5-hydroxyisoxazolidine (3S,5R)-10a was trea-
ted with acetic anhydride in the presence of triethylamine,
the O-acetates (3S,5R)-9a and (3S,5S)-9c were obtained in
a 1:2 ratio. Similarly, acetylation of an equilibrium mixture
of (3S,5R)-10a and (3S,5S)-10c (2:8) gave compounds

D. G. Piotrowska / Tetrahedron: Asymmetry 19 (2008) 279–287
283
P@Oꢀ ꢀ ꢀH–O hydrogen bond (Fig. 7) additionally stabilised
by the formation of a six-membered ring, which exists in a
chair conformation. The other argument supporting the
H-bonding in (2S,3S)-13 comes from the close resemblance
of the H-bonded fragment in (2S,3S)-13 with that in a
2-hydroxyalkyl phosphonate system 14, since the stabilis-
ing role of the intramolecular hydrogen bond in 2-hydroxy-
alkyl phosphonates has been well recognised.49–52 This
clearly demonstrates that the OH and P@O groups are
located on the same side of the 1,2-oxaphospholane ring
and thus proves the (S)-absolute configuration at the phos-
phorus in (2S,3S)-13.
..
..
CH3
O
H3C
O
H
H
H
(EtO)2(O)P
P(O)(OEt)2
H
H
H
H
H
H
OH
H
OH
(3S
,5
S
)-10c
(3
R
,5
R
)-10d
Figure 6. Preferred Newman projections for (3S,5S)-10c and (3R,5R)-10d
and major NOESY correlations used to establish the absolute
configurations.
To gather additional evidence for the already established
absolute configuration at C3 in isoxazolidine (3S,5R)-10a
as well as in (3S,5S)-10c their transformation into the
known (S)-phosphohomoserine (S)-12 was proposed
(Scheme 7).
X
H
CH3
EtO
H
H
Ph
O
N
O
OEt
H
EtO
P
P
O
O
O
H
H
NH2
O
OH
(2
S
,3
S
)-13
14
Ph
(EtO)2(O)P
(3 ,5
N
(HO)2(O)P
OH
Figure 7. The preferred 1T2 conformation of (2S,3S)-13 and H-bonding in
a 2-hydroxyalkyl phosphonate system 14.
(S)-12
S
R
)-10a
)-10c
(3S,5S
Finally, a hydroxylamine (2S,3S)-13 was subjected to
acetylation to give the stable acetate (2S,3S)-15. This
derivative was subsequently transformed into the known
phosphohomoserine (S)-(+)-1253–55 by hydrogenolytic
cleavage of the N–O bond and removal of the 1-phenyl-
ethyl residue followed by hydrolysis of the phosphonate
esters (Scheme 9). Furthermore, it was reasoned that
hydrogenolysis of (2S,3S)-15 in the presence of Boc2O
would lead to enantiomerically pure 1,2-oxaphospholane
(2S,3S)-16, which may be considered as potential QS
inhibitor. Indeed, transformation of (2S,3S)-15 into
(2S,3S)-16 was accomplished in 52% yield after column
chromatography. Hydrolysis of (2S,3S)-16 under acidic
conditions again gave (S)-(+)-12.
Scheme 7. Synthetic approach to phosphohomoserine (S)-12.
To this end, a crude mixture of 5-hydroxyisoxazolidines
(3S,5R)-10a and (3S,5S)-10c was subjected to NaBH4
reduction. The reaction was capricious and led to a com-
plex mixture, from which diastereoisomerically pure 3-
hydroxylamino-1,2-oxaphospholane (2S,3S)-13 could be
isolated in, at best, 66% yield by fast column chromatogra-
phy on silica gel (Scheme 8). When kept at room tempera-
ture, this compound appeared to be unstable undergoing
decomposition. The 31P NMR spectrum of the sample ta-
ken one month later showed the presence of signals at
1.01, 0.58 and ꢂ10.83 ppm in a 9:29:62 ratio.
Both samples of phosphohomoserine (S)-12 obtained from
(2S,3S)-13 (Scheme 9) were found to be dextrorotatory.
According to the literature data, the levorotatory enantio-
mer of 12 has the (R)-absolute configuration.53 This earlier
finding fully supports our configurational assignments for
isoxazolidines (3S,5S)-10c and (3R,5R)-10d, as well as
those for the enantiomers of diethyl 5-(hydroxymethyl)-2-
[(S)-1-phenylethyl]isoxazolidinyl-3-phosphonate and O,O-
OEt
O
O
OH
P
a
Ph
N
O
Ph
N
(EtO)2(O)P
OH
(3
S
,5
R
S
)-10a
)-10c
(2S,3S)-13
(3
S
,5
Scheme 8. Reagents and conditions: (a) NaBH4, EtOH, rt, 6 h.
The formation of the 1,2-oxaphospholane ring as well as
the configuration of the newly generated stereogenic centre
at phosphorus was established on the basis of the NMR
spectral data. First of all, the 31P NMR resonance for
(2S,3S)-13 appeared at 42.47 ppm, which is characteristic
of 1,2-oxaphospholanes.48 Analysis of vicinal couplings
Table 2. Stereochemically relevant vicinal couplings for (2S,3S)-13
Vicinal coupling constants (Hz)
(2S,3S)-13
J(P–C3N–C)
16.6
16.8
5.1
7.8
3.6
9.3
6.0
8.5
8.1
J(Hb–C5O–P)
J(Ha–C5O–P)
J(Hb–C5C4–Ha)
J(Hb–C5C4–Hb)
J(Ha–C5C4–Ha)
J(Ha–C5C4–Hb)
J(H–C3C4–Hb)
J(H–C3C4–Ha)
J(Ha–C4C3–P)
J(Hb–C4C3–P)
Conformation
1
extracted from the H and 13C NMR spectra showed that
1
this ring exists in a T2 conformation with 1-phenylethyl
substituent in the pseudoequatorial position (Table 2).
Furthermore, in the 1H NMR spectrum, a downfield
shifted signal of HO was observed (d1H = 6.07 ppm), and
examination of several NMR spectra of 13 proved that it
was practically ( 0.1 ppm) concentration independent.
This observation clearly proves the presence of a strong
7.0
22.2
1T2

284
D. G. Piotrowska / Tetrahedron: Asymmetry 19 (2008) 279–287
NH2
by the Microanalytical Laboratory of this Faculty on Per-
b, c, d
e
kin–Elmer PE 2400 CHNS analyser. Polarimetric measure-
ments were conducted on a Perkin–Elmer 241 MC
apparatus.
(HO)2(O)P
OH
(S)-12
OEt
OEt
O
O
a
P
P
O
O
c, d
O
Ph
N
Ph
N
OEt
O
OH
(2S,3S)-13
OAc
(2S,3S)-15
P
The following adsorbents were used: column chromatogra-
phy, Merck Silica Gel 60 (70–230 mesh); analytical TLC,
HNBoc
(2S,3S)-16
Merck TLC plastic sheets Silica Gel 60 F254
.
Scheme 9. Reactions and conditions: (a) Ac2O, NEt3, DMAP, rt, 3 h; (b)
H2/Pd(OH)2–C, EtOH, rt, 24 h; (c) 6 M HCl, reflux, 6 h; (d) propylene
oxide, EtOH; (e) Boc2O, H2/Pd(OH)2–C, EtOH, rt, 20 h.
4.1. Cycloaddition of the nitrone (S)-(+)-8 with vinyl acetate
Nitrone (S)-8 (0.784 g, 2.75 mmol) [prepared from (S)-N-
(1-phenylethyl)hydroxylamine and formylphosphonate]28
and vinyl acetate (0.51 mL, 5.5 mmol) were stirred in tolu-
ene (5 mL) at 60 °C for 24 h. After the disappearance of the
starting nitrone, the mixture was concentrated in vacuo to
give a crude product (0.9 g) which was purified by column
chromatography on silica gel with toluene–isopropanol
(50:1, v/v) to afford (3R,5R)-9d (0.041 g, 4%), (3R,5S)-9b
(0.185 g, 18%) and (3S,5R)-9a (0.492 g, 48%) all as colour-
less oils.
diethyl 4-hydroxypyrrolidinyl-2-phosphonate based on ad-
vanced conformational and configurational studies pre-
sented in this and former papers.28,55
3. Conclusions
The 1,3-dipolar cycloaddition of nitrone (S)-8 and vinyl
acetate led regiospecifically and with high (92:8) trans-
selectivity to a mixture of four diethyl 5-acetoxy-2-[(S)-1-
phenylethyl]isoxazolidinyl-3-phosphonates, from which
pure isomers (3S,5R)-9a, (3R,5S)-9b and (3R,5R)-9d were
isolated. Removal of the O-acetyl group from (3S,5R)-9a
produced a mixture of 5-hydroxy derivatives (3S,5R)-10a
and (3S,5S)-10c.
4.1.1. Diethyl (3S,5R)-5-acetoxy-2-[(S)-1-phenylethyl]isox-
azolidinyl-3-phosphonate (3S,5R)-9a. IR (film): m = 3472,
2983, 2934, 1751, 1454, 1374, 1233, 1051, 1027, 974 cmꢂ1
.
20
1
½aꢃD ¼ ꢂ128:1 (c 1.4, CHCl3). H NMR (CDCl3): d 7.40–
7.20 (m, 5H), 6.51 (dd, J = 6.6, 2.4 Hz, 1H, H–C5), 4.19
(dq, J = 6.6, 1.5 Hz, 1H, HC–CH3), 4.18–3.95 (m, 3H),
3.95–3.78 (m, 1H), 3.64 (ddd, J = 9.0, 8.7, 4.8 Hz, 1H,
H–C3), 2.90 (dddd, J = 18.9, 14.1, 6.6, 4.8 Hz, 1H, Ha–
C4), 2.69 (dddd, J = 20.4, 14.1, 8.7, 2.4 Hz, 1H, Hb–C4),
2.12 (s, 3H, CH3–C(O)), 1.46 (d, J = 6.6 Hz, 3H, CH3–
CH), 1.30 (t, J = 6.9 Hz, 3H), 1.22 (t, J = 6.9 Hz, 3H).
13C NMR (CDCl3): d 169.98 (C@O), 142.49, 128.73,
Mutarotation of 3-(O,O-diethylphosphoryl)-5-hydroxyis-
oxazolidines was studied in detail in (3S,5R)-10a revealing
the formation of an 11:89 equilibrium mixture of (3S,5R)-
10a and (3S,5S)-10c after 48 h at room temperatures in
chloroform-d solution. In a solid state, the trans-isomer
(3S,5R)-10a is favoured, whereas in solution, strong intra-
molecular hydrogen bonds stabilise the cis-isomer (3S,5S)-
10c in an E3 conformation with axially oriented P(O)(OEt)2
and OH groups.
3
128.05, 128.00, 98.63 (d, J(CCCP) = 3.1 Hz, C5), 67.25 (d,
3J(CNCP) = 14.3 Hz, CH–Ph), 63.15 (d, J = 6.9 Hz,
CH2OP), 63.06 (d, J = 5.7 Hz, CH2OP), 58.47 (d,
1J(CP) = 176.1 Hz, C3), 37.24 (s, C4), 21.61, 20.31, 16.81
(d, J = 7.2 Hz), 16.73 (d, J = 6.0 Hz). 31P NMR (CDCl3):
d 22.11. Anal. Calcd for C17H26NO6P: C, 54.98; H, 7.06;
N, 3.77. Found: C, 54.68; H, 7.36; N, 3.73.
The absolute configurations of the isoxazolidine cycload-
ducts have been established based on the conformational
analysis of (3S,5S)-10c [obtained from (3S,5R)-9a] and
(3R,5R)-10d [obtained from (3R,5S)-9b] taking advantage
of the anisotropic effects of aromatic ring present in the
(S)-1-phenylethyl auxiliary. In addition, by transformation
of a mixture of (3S,5R)-10a and (3S,5S)-10c into the
known (S)-(+)-phosphohomoserine, the absolute configu-
ration was unambiguously correlated with the literature
data.
4.1.2. Diethyl (3R,5S)-5-acetoxy-2-[(S)-1-phenylethyl]isox-
azolidinyl-3-phosphonate (3R,5S)-9b. IR (film): m = 3475,
2982, 1751, 1453, 1375, 1234, 1024, 981 cmꢂ1
.
20
1
½aꢃD ¼ ꢂ17:8 (c 1.2, CHCl3). H NMR (CDCl3): d 7.40–
7.20 (m, 5H), 6.16 (d, J = 5.1 Hz, 1H, H–C5), 4.40 (br q,
J = 6.9 Hz, 1H, HC–CH3), 4.35–4.15 (m, 4H), 3.51 (ddd,
J = 10.8, 6.3, 2.1 Hz, 1H, H–C3), 2.70 (dddd, J = 17.1,
12.9, 10.8, 5.1 Hz, 1H, Hb–C4), 2.43 (ddd, J = 12.9, 6.3,
5.7 Hz, 1H, Ha–C4), 1.77 (s, 3H, CH3–C(O)), 1.57 (d,
J = 6.9 Hz, 3H, CH3–CH), 1.39 (t, J = 7.2 Hz, 3H), 1.36
(t, J = 7.2 Hz, 3H). 13C NMR (CDCl3): d 169.71 (C@O),
4. Experimental
3
1H, 13C and 31P NMR were taken in CDCl3 or D2O on
Varian Mercury-300 spectrometer with TMS as an internal
standard at 300, 75.5 and 121.5 MHz, respectively. 1H{31P}
139.82, 129.29, 127.89, 127.41, 94.72 (d, J(CCCP) = 9.2 Hz,
3
C5), 65.70 (d, J(CNCP) = 6.0 Hz, CH–Ph), 63.96 (d,
J = 6.3 Hz, CH2OP), 62.55 (d, J = 6.9 Hz, CH2OP), 56.05
1
1
2
NMR and H–1H COSY experiments were applied, when
(d, J(CP) = 174.3 Hz, C3), 39.17 (d, J(CCP) = 2.6 Hz, C4),
21.38, 21.29, 16.75 (d, J = 5.4 Hz), 16.67 (d, J = 5.7 Hz).
31P NMR (CDCl3): d 22.42. Anal. Calcd for C17H26NO6P:
C, 54.98; H, 7.06; N, 3.77. Found: C, 54.56; H, 7.23; N,
3.86.
necessary to support spectral assignments. IR spectra were
measured on an Infinity MI-60 FT-IR spectrometer. Melt-
ing points were determined on an electrothermal apparatus
and are uncorrected. Elemental analyses were performed

D. G. Piotrowska / Tetrahedron: Asymmetry 19 (2008) 279–287
285
4.1.3. Diethyl (3R,5R)-5-acetoxy-2-[(S)-1-phenylethyl]isox-
azolidinyl-3-phosphonate (3R,5R)-9d. IR (film): m = 2982,
3.45 (dd, J = 10.8, 9.9 Hz, 1H, H–C3), 2.42 (dddd,
J = 33.9, 13.5, 9.9, 5.4 Hz, 1H, Hb–C4), 2.25 (t, J = 13.5,
1H, Ha–C4), 1.50 (d, J = 6.6 Hz, 3H, HC–CH3), 1.36 (t,
J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR
(CDCl3): d 141.31, 128.59, 127.99, 127.84, 98.97 (d,
1746, 1454, 1375, 1234, 1052, 1023, 967 cmꢂ1
.
20
1
½aꢃD ¼ ꢂ107:5 (c 0.9, CHCl3). H NMR (CDCl3): d 7.45–
7.40 (m, 2H), 7.40–7.26 (m, 3H), 6.16 (dd, J = 3.0,
1.2 Hz, 1H, H–C5), 4.51 (br q, J = 6.9 Hz, 1H, HC–
CH3), 4.36–4.22 (m, 2H), 4.22–4.10 (m, 2H), 2.98 (dt,
J = 8.7, 2.1 Hz, 1H, H–C3), 2.57–2.48 (m, 2H, H2C4),
2.10 (s, 3H, CH3–C(O)), 1.65 (d, J = 6.9 Hz, 3H, CH3–
CH), 1.41 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H).
13C NMR (CDCl3): d 170.55 (C@O), 137.65, 130.44,
3
3J(CCCP) = 2.0 Hz, C5), 66.45 (d, J(CNCP) = 17.2 Hz,
CH-Ph), 64.88 (d, J = 6.9 Hz, CH2OP), 62.16 (d,
1
J = 7.2 Hz, CH2OP), 57.14 (d, J(CP) = 176.6 Hz, C3),
2
36.82 (d, J(CCP) = 2.9 Hz, C4), 20.36 (s, CH3), 16.72 (d,
J = 6.0 Hz), 16.52 (d, J = 5.7 Hz). 31P NMR (CDCl3): d
26.68.
3
128.02, 127.85, 93.97 (d, J(CCCP) = 8.3 Hz, C5), 63.77 (d,
J = 6.9 Hz), 63.70 (d, J = 3.1 Hz), 62.44 (d, J = 6.9 Hz),
56.75 (d, 1J(CP) = 167.7 Hz, C3), 39.60 (d, 2J(CCP) = 2.6 Hz,
C4), 21.65, 20.59, 16.77 (d, J = 6.0 Hz), 16.73 (d,
J = 5.7 Hz). 31P NMR (CDCl3): d 22.28. Anal. Calcd for
C17H26NO6P: C, 54.98; H, 7.06; N, 3.77. Found: C,
54.94; H, 7.29; N, 3.75.
4.2.2. Diethyl (3R,5S)- and (3R,5R)-5-hydroxy-2-((S)-1-
phenylethyl)isoxazolidinyl-3-phosphonates (3R,5S)-10b and
(3R,5R)-10d. As described in Section 4.2, from (3R,5S)-
9b (0.156 g, 0.420 mmol), a 4:6 mixture of anomers
(3R,5S)-10b and (3R,5R)-10d (0.103 g, 75%) was obtained
as a colourless oil.
4.2. Ammonolysis of isoxazolidines 9 (general procedure)
4.2.2.1. Compound (3R,5S)-10b. (NMR data were
extracted from the spectrum of a 40:60 mixture of
(3R,5S)-10b and (3R,5R)-10d): 1H NMR (CDCl3): d
7.40–7.26 (m, 5H), 5.44 (dd, J = 5.1, 0.9 Hz,1H, H–C5),
4.41 (q, J = 6.9 Hz, 1H, HC–CH3), 4.40–4.05 (m, 4H),
3.69 (ddd, J = 9.0, 7.5 Hz, 3.3 Hz, 1H, H–C3), 2.61 (dddd,
J = 19.2, 12.9, 9.0, 5.1 Hz, 1H, Hb–C4), 2.50 (dddd,
J = 12.9, 9.0, 7.5, 0.9 Hz, 1H, Ha–C4), 2.40 (s, 1H, OH),
1.48 (d, J = 6.9 Hz, 3H, HC–CH3), 1.36 (t, J = 7.2 Hz,
3H), 1.33 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3): d
To a solution of isoxazolidine 9 (1.0 mmol) in EtOH
(2 mL), concentrated ammonia (25%) was added (5 mL).
The reaction mixture was stirred for 2 h at room tempera-
ture and then all volatiles were removed under reduced
pressure to give a crude product, which was chromato-
graphed on silica gel column with chloroform–methanol
(100:1, v/v).
4.2.1. Diethyl (3S,5R)- and (3S,5S)-5-hydroxy-2-((S)-1-
phenylethyl)isoxazolidinyl-3-phosphonates (3S,5R)-10a and
(3S,5S)-10c. As described in Section 4.2, from (3S,5R)-9a
(0.215 g, 0.580 mmol), a 1:1 mixture of anomers (3S,5R)-
10a and (3S,5S)-10c (0.188 g, 99%) was obtained. Crystal-
lisation of this mixture from ether gave (3S,5R)-10a
(0.112 g, 59%) as colourless needles.
3
142.50, 128.47, 128.32, 128.23, 97.04 (d, J(CCCP) = 6.9 Hz,
3
C5), 67.78 (d, J(CNCP) = 9.7 Hz, CH–Ph), 63.65 (d,
J = 6.6 Hz, CH2OP), 62.84 (d, J = 7.2 Hz, CH2OP), 57.43
1
(d, J(CP) = 178.4 Hz, C3), 36.89 (C4), 20.70 (s, CH3),
16.90 (d, J = 5.7 Hz,), 16.65 (d, J = 5.7 Hz). 31P NMR
(CDCl3): d 23.19.
4.2.1.1. Compound (3S,5R)-10a. Mp 103–104 °C. IR
(KBr): m = 3427, 3293, 2987, 2931, 1455, 1211, 1055,
4.2.2.2. Compound (3R,5R)-10d. (NMR data were ex-
tracted from the spectrum of a 10:90 equilibrium mixture
of (3R,5S)-10b and (3R,5R)-10d): 1H NMR (CDCl3): d
7.40–7.26 (m, 5H), 6.05 (br s, 1H, OH), 5.36 (br d,
J = 5.4 Hz, 1H, H–C5), 4.45–4.05 (m, 4H), 3.85 (q,
J = 6.9 Hz, 1H, HC–CH3), 3.44 (ddd, J = 10.8, 7.5,
1.5 Hz, 1H, H–C3), 2.16 (ddd, J = 15, 13.5, 1.5 Hz, 1H,
Ha–C4), 1.80 (dddd, J = 32.7, 13.5, 10.8, 5.4 Hz, 1H,
Hb–C4), 1.58 (d, J = 6.9 Hz, 3H, HC–CH3), 1.40 (t,
J = 7.2 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR
(CDCl3): d 139.69, 128.75, 128.37, 127.93, 97.56 (d,
20
1035, 989 cmꢂ1. ½aꢃD ¼ ꢂ71:5 (c 1.4, CHCl3). H NMR
(CDCl3): d 7.40–7.20 (m, 5H), 5.80 (dd, J = 6.3, 2.7 Hz,
1H, H–C5), 4.37 (q, J = 6.6 Hz, 1H, HC–CH3), 4.19–15
(m, 2H), 4.15–3.95 (m, 1H), 3.92–3.80 (m, 1H), 3.65
(ddd, J = 10.8, 9.0, 3.9 Hz, 1H, H–C3), 3.10 (br s, 1H,
OH), 2.79 (dddd, J = 18.6, 13.8, 6.3, 3.9 Hz, 1H, Ha–C4),
2.61 (dddd, J = 23.4, 13.8, 9.0, 2.7 Hz, 1H, Hb–C4),
1.53 (d, J = 6.6, 3H, HC–CH3), 1.29 (t, J = 7.2 Hz, 3H),
1.22 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3): d 143.19,
1
3
128.47, 127.96, 127.58, 99.90 (d, J(CCCP) = 2.6 Hz, C5),
3
3J(CCCP) = 1.4 Hz, C5), 67.00 (d, J(CNCP) = 14.3 Hz, CH–
67.24 (d, 3J(CNCP) = 16.0 Hz, CH–Ph), 62.89 (d,
J = 7.2 Hz, CH2OP), 62.38 (d, J = 6.6 Hz, CH2OP), 59.01
Ph), 65.19 (d, J = 6.9 Hz, CH2OP), 62.38 (d, J = 7.4 Hz,
1
1
CH2OP), 57.43 (d, J(CP) = 178.4 Hz, C3), 38.20 (s, C4),
(d, J(CP) = 175.2 Hz, C3), 38.00 (s, C4), 21.20 (s, CH3),
16.72 (d, J = 6.0 Hz), 16.52 (d, J = 5.7 Hz). 31P NMR
(CDCl3): d 23.76. Anal. Calcd for C15H24NO5P: C, 54.71;
H, 7.35; N, 4.25. Found: C, 54.85; H, 7.45; N, 4.30.
20.70 (s, CH3), 16.90 (d, J = 5.7 Hz,), 16.65 (d,
J = 5.7 Hz). 31P NMR (CDCl3): d 26.63.
4.2.1.2. Compound (3S,5S)-10c. (NMR data were ex-
tracted from the spectrum of an 11:89 equilibrium mixture
of (3S,5R)-10a and (3S,5S)-10c): 1H NMR (CDCl3): d
7.40–7.20 (m, 5H), 6.17 (d, J = 12.5 Hz, 1H, OH), 5.61
(dd, J = 12.5, 5.4 Hz, 1H, H–C5), 4.40–4.22 (m, 2H),
4.15–3.93 (m, 2H), 3.87 (q, J = 6.6 Hz, 1H, HC–CH3),
4.2.3. Diethyl (3R,5S)- and (3R,5R)-5-hydroxy-2-((S)-1-
phenylethyl)isoxazolidinyl-3-phosphonates (3R,5S)-10b and
(3R,5R)-10d. As described in Section 4.2, from (3R,5R)-
9d (0.053 g, 0.153 mmol), a (2:8) mixture of 5-hydroxyisox-
azolidines (3R,5S)-10b and (3R,5R)-10d was obtained (34
mg, 68%) as a colourless oil.

286
D. G. Piotrowska / Tetrahedron: Asymmetry 19 (2008) 279–287
4.3. (2S,3S)-2-Ethoxy-2-oxo-3-{N-hydroxy-N-[(S)-1-phen-
ylethyl]amino}-1,2-oxaphospholane (2S,3S)-13
(1 mL) was hydrogenated under atmospheric pressure over
20% Pd(OH)2–C (10 mg) at room temperature for 20 h.
The suspension was filtrated through a layer of Celite.
The solution was concentrated and the residue was chro-
matographed on a silica gel column with chloroform–
methanol (100:1, v/v) to give (2S,3S)-16 (0.031 g, 52%) as
a colourless oil. IR (film): m = 3268, 2980, 2933, 1741,
To a solution of 5-hydroxyisoxazolidines (3S,5R)-10a and
(3S,5S)-10c (0.123 g, 0.330 mmol) in ethanol (2 mL),
sodium borohydride (0.037 g, 0.99 mmol) was added. The
reaction mixture was stirred at room temperature for 6 h
and ethanol was removed in vacuo. The residue was sus-
pended in CH2Cl2 (10 mL) and anhydrous MgSO4 (0.5 g)
was added. After filtration and concentration, the solution
was evaporated to give a crude product, which was purified
by column chromatography with chloroform–methanol
(100:1, v/v) to give (2S,3S)-13 as a colourless oil (0.059 g,
1708, 1530, 1455, 1367, 1256, 1167, 1044, 1006, 969,
20
830 cmꢂ1. ½aꢃD ¼ ꢂ33:8 (c 0.9, CHCl3). 1H NMR (CDCl3):
d 5.15 (br s, 1H, NH), 4.29 (dddd, J = 13.8, 9.6, 6.8, 4.5 Hz,
1H), 4.20 (dq, J = 8.7, 7.2 Hz, 2H), 4.07 (dddd, J = 9.6,
8.4, 7.5, 5.7 Hz, 1H), 3.98 (br q, J = 6.9 Hz, 1H), 2.58
(ddddd, J = 24.9, 13.2, 7.5, 5.7, 4.5 Hz, 1H), 2.22 (ddq,
J = 13.2, 8.4, 6.9 Hz, 1H), 1.45 (s, 9H), 1.37 (t,
J = 7.2 Hz, 3H). 13C NMR (CDCl3): d 155.65 (d, J =
11.8 Hz), 80.55, 65.11 (d, J = 7.8 Hz), 63.85 (d, J =
6.6 Hz), 42.81 (d, J = 136.9 Hz), 32.69 (d, J = 10.9 Hz),
28.53, 16.69 (d, J = 5.7 Hz). 13P NMR (CDCl3): d 41.01.
Anal. Calcd for C10H20NO5P: C, 45.28; H, 7.60; N, 5.28.
Found: C, 45.38; H, 7.82; N, 5.19.
66%). IR (film): m = 3293, 2982, 2932, 1453, 1368, 1247,
20
1047, 1010, 950, 830, 772, 704 cmꢂ1. ½aꢃD ¼ ꢂ18:1 (c 1.3
1
CHCl3). H NMR (CDCl3): d 7.40–7.25 (m, 5H), 6.07 (s,
1H, N–OH), 4.32 (dddd, J = 16.8, 9.0, 7.8, 3.6 Hz, 1H,
Hb–C5), 4.17–4.02 (m, 2H, CH2OP), 3.88 (dddd, J = 9.3,
9.0, 6.0, 5.1 Hz, 1H, Ha–C5), 3.86 (q, J = 6.6 Hz, 1H,
CH–CH3), 3.17 (ddd, J = 12.3, 8.5, 8.1 Hz, 1H, H–C3),
2.64 (ddddd, J = 13.0, 9.3, 8.1, 7.8, 7.0 Hz, 1H, Ha–C4),
2.07 (ddddd, J = 22.2, 13.0, 8.5, 6.0, 3.6 Hz, 1H, Hb–C4),
1.54 (d, J = 6.6 Hz, 3H, CH–CH3), 1.25 (t, J = 6.7 Hz,
4.6. (S)-1-Amino-3-hydroxypropylphosphonic acid (S)-12
3H, CH3–CH2–OP). 13C NMR (CDCl3):
d 141.17,
4.6.1. Transformation of (2S,3S)-15 into (S)-12. A solu-
tion of oxaphospholane (2S,3S)-15 (0.070 g, 0.21 mmol)
in ethanol (1 mL) was hydrogenated under atmospheric
pressure over 20% Pd(OH)2–C (10 mg) at room tempera-
ture for 24 h. The suspension was filtrated through a layer
of Celite. The solution was concentrated, the residue dis-
solved in 6 M HCl (1 mL) and refluxed for 5 h. After that
the solution was removed and the residue dissolved in eth-
anol (0.5 mL) and neutralised with propylene oxide. The
solvent was withdrawn, and solid washed with ethanol
128.68, 128.28, 127.88, 64.93 (d, J = 16.6 Hz, CH–Ph),
64.90 (d, J = 9.0 Hz, C5), 62.94 (d, J = 6.3 Hz, CH2OP),
57.23 (d, J = 149.2 Hz, C3), 25.39 (very br s, C4), 20.70
(s, CH3–CH), 16.67 (d, J = 5.4 Hz, CH3CH2OP). 31P
NMR (CDCl3): d 42.47. Anal. Calcd for C13H20NO4P: C,
54.73; H, 7.07; N, 4.91. Found: C, 54.53; H, 7.34; N, 4.79.
4.4. (2S,3S)-2-Ethoxy-2-oxo-3-{N-acetoxy-N-[(S)-1-phenyl-
ethyl]amino}-1,2-oxaphospholane (2S,3S)-15
and dried to afford (S)-12 (0.030 g, 90%) as a white amor-
A
mixture of oxaphospholane (2S,3S)-13 (0.08 g,
20
phous solid; mp 214–216 °C (lit.54 mp 214 °C). ½aꢃD ¼ þ6:3
0.28 mmol), acetic anhydride (0.08 mL, 0.84 mmol) and tri-
ethylamine (0.13 mL, 0.92 mmol) containing DMAP (a few
crystals) in methylene chloride (2 mL) was stirred at room
temperature for 3 h. Afterwards, the reaction mixture was
concentrated in vacuo and the residue was chromato-
graphed on silica gel with chloroform–methanol (50:1,
v/v) to give (2S,3S)-15 (0.074 g, 81%) as a colourless oil.
(c 1.1, H2O) {lit.54 [a]D = +7.3 (c 1, H2O)}. 1H NMR
(D2O): d 3.82 (t, J = 6.6 Hz, 2H), 3.40 (ddd, J = 13.8,
8.7, 4.2 Hz, 1H), 2.24–2.07 (m, 1H), 2.05–1.85 (m, 1H).
31P NMR (D2O): d 14.09. Anal. Calcd for C3H10NO4P:
C, 23.23; H, 6.50; N, 9.03. Found: C, 23.04; H, 6.65; N,
8.88.
IR (film): m = 2983, 1770, 1454, 1364, 1265, 1198, 1042,
20
1008, 828 cmꢂ1. ½aꢃD ¼ ꢂ5:2 (c 0.9, CHCl3). 1H NMR
4.6.2. Hydrolysis of (2S,3S)-16. A solution of (2S,3S)-16
(0.031 g, 0.12 mmol) in 6 M HCl (1 mL) was refluxed for
6 h. The solution was removed under reduced pressure,
and the residue was dissolved in ethanol (0.5 mL) and neu-
tralised with propylene oxide. The solvent was withdrawn,
the solid washed with anhydrous ethanol and dried to give
(S)-12 (0.018 g, 95%), which was identical in all respects to
the compound described in Section 4.6.1.
(CDCl3): d 7.43–7.25 (m, 5H), 4.40 (br s, 1H), 4.32 (br s,
1H), 4.20–4.11 (m, 2H, CH2OP), 3.40–3.87 (m, 1H),
3.60–3.40 (br m, 1H), 2.50 (br s, 1H), 2.30 (br s, 1H),
1.98 (s, 3H, CH3C(O)), 1.50 (d, J = 6.6 Hz, 3H, CH–
CH3), 1.32 (t, J = 6.7 Hz, 3H, CH3–CH2–OP). 13C NMR
(CDCl3): d 170.14 (C@O), 140.60, 128.63, 128.13, 128.06,
62.21 (d, J = 10.3 Hz, CH–Ph), 64.39 (d, J = 7.4 Hz,
CH2OP), 62.87 (d, J = 6.3 Hz, C5), 55.88 (d,
J = 138.1 Hz, C3), 21.03, 19.57, 19.27 (very br s), 16.76
(d, J = 5.5 Hz, CH3CH2OP). 31P NMR (CDCl3): d 37.23.
Anal. Calcd for C15H22NO5P: C, 55.04; H, 6.77; N, 4.28.
Found: C, 55.07; H, 7.05; N, 4.26.
Acknowledgements
´
The author is grateful to Professor Andrzej E. Wroblewski
4.5. tert-Butyl (2S,3S)-2-ethoxy-2-oxo-1,2-oxaphospholan-
3-ylcarbamate (2S,3S)-16
for support and stimulating discussions during preparation
of this manuscript. Mrs. Jolanta Płocka is acknowledged
for her excellent technical assistance. This work was sup-
´ ´
A
solution of oxaphospholane (2S,3S)-15 (0.074 g,
ported by the Medical University of Łodz internal funds
0.23 mmol) and Boc2O (0.060 g, 0.28 mmol) in ethanol
(502-13-332 and 503-3014-1).

D. G. Piotrowska / Tetrahedron: Asymmetry 19 (2008) 279–287
287
25. Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.;
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