Stereochemistry of cycloaddition of (S)-N-(1-phenylethyl)-C-phosphorylated nitrone with cyclopentene and 2,3-dihydrofuran

Article abstract of DOI:10.1016/j.tetasy.2008.09.027

Cycloaddition of (S)-N-(1-phenylethyl)-C-(diethoxyphosphoryl)nitrone to cyclopentene gave a mixture of diethyl (3S,3aR,6aS)- and (3R,3aS,6aR)-hexahydro-2-[(S)-1-phenylethyl]-2H-cyclopenta[d]isoxazol-3- yl-3-phosphonates with moderate (68:32) diastereoselectivity, while the reaction with 2,3-dihydrofuran led regiospecifically to the formation of an easily separable mixture of diethyl (3S,3aR,6aR)- and (3R,3aS,6aS)-hexahydro-2-[(S)-1-phenylethyl]furo[3,2-d]isoxazol-3-yl-3-p hosphonates in a 65:35 ratio. Absolute configurations of cycloadducts were established based on conformational analyses employing ¹H and ¹³C NMR data and confirmed by 2D NOE experiments. Diastereoisomeric diethyl (3S,3aR,6aS)- and (3R,3aS,6aR)-hexahydro-2-[(S)-1-phenylethyl]-2H-cyclopenta[d]isoxazol-3- yl-3-phosphonates were transformed into both enantiomers of tert-butyl (2S,3S,3aR,6aS)- and (2R,3R,3aS,6aR)-2-ethoxy-2-oxo-cyclopenta[d](1,2-oxaphospholan-3-yl)carb amates in good yields.

Full text of DOI:10.1016/j.tetasy.2008.09.027

Tetrahedron: Asymmetry 19 (2008) 2323–2329
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Stereochemistry of cycloaddition of (S)-N-(1-phenylethyl)-C-phosphorylated
nitrone with cyclopentene and 2,3-dihydrofuran
*
Dorota G. Piotrowska
´
´
´
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łódz, 90-151 Łódz, Muszynskiego 1, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Cycloaddition of (S)-N-(1-phenylethyl)-C-(diethoxyphosphoryl)nitrone to cyclopentene gave a mixture of
diethyl (3S,3aR,6aS)- and (3R,3aS,6aR)-hexahydro-2-[(S)-1-phenylethyl]-2H-cyclopenta[d]isoxazol-3-yl-
3-phosphonates with moderate (68:32) diastereoselectivity, while the reaction with 2,3-dihydrofuran
led regiospecifically to the formation of an easily separable mixture of diethyl (3S,3aR,6aR)- and
(3R,3aS,6aS)-hexahydro-2-[(S)-1-phenylethyl]furo[3,2-d]isoxazol-3-yl-3-phosphonates in a 65:35 ratio.
Absolute configurations of cycloadducts were established based on conformational analyses employing
1H and 13C NMR data and confirmed by 2D NOE experiments. Diastereoisomeric diethyl (3S,3aR,6aS)-
and (3R,3aS,6aR)-hexahydro-2-[(S)-1-phenylethyl]-2H-cyclopenta[d]isoxazol-3-yl-3-phosphonates were
transformed into both enantiomers of tert-butyl (2S,3S,3aR,6aS)- and (2R,3R,3aS,6aR)-2-ethoxy-2-oxo-
cyclopenta[d](1,2-oxaphospholan-3-yl)carbamates in good yields.
Received 5 September 2008
Accepted 26 September 2008
Available online 22 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
cycloaddition reactions with various alkenes have been de-
scribed.12,13 It was reasoned that 3-phosphorylated isoxazolidine
An
a-amino-c-hydroxy acid moiety is present in many natural
cycloadducts would have been appropriate substrates for the syn-
and synthetic products. Examples of such compounds containing
this moiety and showing important biological activity are collected
in Figure 1. Homoserine 1, the simplest representative of this
group, is involved in the biosynthesis of methionine and (S)-ade-
thesis of the phosphonate mimetics of
a
-amino-
c
-hydroxyacids. In
NH2
O
NH2
nosylomethionine. The lactone of L-threo-4-hydroxynorvaline 2
HO
COOH
H3C
O
(AL 719Y) was found to possess antimicrobial activity against Pseu-
domonas aeruginosa.1 Monatin 3 revealed properties such as being
an intense sweetener,2 whereas desihedrine 4, another naturally
occurring amino acid, is an agonist of non-NMDA Glu-receptor.3
Studies towards the design of glutamate analogues led to the syn-
thesis of conformationally rigid frameworks containing, among
others, isoxazoline or isoxazole rings incorporated to the 2-ami-
no-4-hydroxy acid unit.4 Compounds (R)-AMAA 5 and 4-HPCA 9
are known as NMDA receptor agonists,5,6 while (R)-ATAA 6 has
been recognised as an AMPA agonist.7 The presence of a lipophilic
side chain at C-4 in 8 increased its activity as a group I antagonist,
compared to (S)-HIBO 7.8,9 Bicyclic analogue ( )-11 showed a
noticeable affinity for NMDA receptors, and at the same time ap-
peared to be an anticonvulsant agent.10
(S)-1
2
Me
NH
H2N
CO2H
R
H
HO
CO2H
O
OH NH2
CO2H
HN
O
CO2H
H
3
4
HOOC
HO
HOOC
HO
HO
COOH
NH2
NH2
N
NH2
O
N
N
O
O
R=H
R=Bu (S)-8
(S)-7
5
6
(R)-
(R)-
Replacement of the carboxyl group with the phosphonate resi-
due has resulted in obtaining isosteric or bioisosteric analogues of
a vast number of natural products.11 Recently, syntheses of N-
substituted C-phosphorylated nitrones and their utilisation in
HOOC
HO
COOH
NH
H
O
H
HO
HOOC
NH
NH2
COOH
N
N
N
O
O
H
10
H
9
11
( )-
* Tel.: +48 42 677 92 35; fax: +48 42 678 83 98.
E-mail address: dorota@ich.pharm.am.lodz.pl
Figure 1.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.027

2324
D. G. Piotrowska / Tetrahedron: Asymmetry 19 (2008) 2323–2329
HO
RHN
O
O
X
X
Ph
N
X
Ph
N
+
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
13 X=CH2
14 X=O
11
12
9
8
(S)-
10
Scheme 1. Synthetic strategy for phosphonates 13 (X = CH2) and 14 (X = O).
this report, the synthesis of isoxazolidines 11 (X = CH2) and 12
(X = O) via cycloaddition of (S)-N-(1-phenylethyl)-C-phosphory-
lated nitrone (S)-8 to cyclopentene 9 and 2,3-dihydrofuran 10,
respectively, is presented (Scheme 1). Subsequent transformation
of cycloadducts 11 (X = CH2) and 12 (X = O) into enantiomerically
can be explained by the initial removal of the 1-phenylethyl moi-
ety with the simultaneous introduction of t-butoxycarbonyl group
at nitrogen atom. This makes cleavage of the N–O bond in isoxazol-
idine (3S,3aR,6aS)-17 difficult. After extending the reaction time of
the hydrogenolysis to 48 h, 13% of (3S,3aR,6aS)-17 were again
found in the reaction mixture, whereas the amount of
(2S,3S,3aR,6aS)-16 increased to 22% at the expense of (1S,2R,10S)-
15 (65%).
pure
a-amino-c-hydroxyphosphonates 13 or 14 is expected if
hydrogenolytic removal of the 1-phenylethyl group and simulta-
neous cleavage of the N–O bond in 11 or 12 were to have occurred
in good yields.
Since attempts at separating pure (1S,2R,10S)-15 proved
unsuccessful, the crude reaction mixture obtained after hydrogen-
olysis of (3S,3aR,6aS,10S)-11a was treated with DBU (1 equiv). This
resulted in a transformation of (1S,2R,10S)-15 into a mixture of
(2S,3S,3aR,6aS)-16 and its P-epimer (2R,3S,3aR,6aS)-18, whereas
2. Results and discussion
Thermal cycloaddition of nitrone (S)-814 to cyclopentene pro-
duced a 65:35 mixture of isoxazolidines (3S,3aR,6aS,10S)-11a and
(3R,3aS,6aR,10S)-11b (Scheme 2). Both diastereoisomers were sep-
arated on a silica gel column, to give (3S,3aR,6aS,10S)-11a in 54%
and (3R,3aS,6aR,10S)-11b in 17% yield, respectively. Similarly, the
reaction of (S)-8 with 2,3-dihydrofuran 10 led to the formation of
a 68:32 mixture of diastereoisomeric isoxazolidines (3S,3aR,6a-
R,10S)-12a and (3R,3aS,6aS,10S)-12b, which were again isolated by
column chromatography in 27% and 29% yield, respectively.
To synthesise an N-Boc-aminohydroxyphosphonate (1S,2R,10S)-
15, isoxazolidine (3S,3aR,6aS,10S)-11a was subjected to catalytic
hydrogenolysis in the presence of Boc2O. In addition to
(1S,2R,10S)-15 (83%), the crude product contained an 1,2-oxaphos-
pholane (2S,3S,3aR,6aS)-16 (4%) and isoxazolidine (3S,3aR,6aS)-17
(13%) (Scheme 3). Unfortunately, attempts to purify (1S,2R,10S)-
15 failed. Instead, when the crude mixture was subjected to chro-
(3S,3aR,6aS)-17 remained untouched. When
a crude reaction
mixture containing (2S,3S,3aR,6aS)-16, (2R,3S,3aR,6aS)-18 and
(3S,3aR,6aS)-17 in a 63:11:26 ratio was chromatographed on a
silica gel column, pure (2S,3S,3aR,6aS)-16 was separated in 57%
yield followed by fractions of impure 1,2-oxaphospholane
(2R,3S,3aR,6aS)-18 (8%) and N-Boc-isoxazolidine (3S,3aR,6aS)-17
(7%).
EtO
O
P
O
BocHN
(2R,3S,3aR,6aS)-18
Similarly, isoxazolidine (3R,3aS,6aR,10S)-11b was hydrogenated
and then treated with DBU (1 equiv) to give 1,2-oxaphospholane
(2R,3R,3aS,6aR)-16 in 54% yield after purification on a silica gel col-
umn (Scheme 4).
Unfortunately, attempts at transforming isoxazolidines 12 into
phosphonates 19 by catalytic hydrogenolysis in the presence of
Boc2O (Scheme 5) led to the formation of complex mixtures of
unidentified products.
matography on
a silica gel column the 1,2-oxaphospholane
(2S,3S,3aR,6aS)-16 was isolated in 38% yield followed by fractions
containing impure (1S,2R,10S)-15 (10%) and (3S,3aR,6aS)-17 (4%).
This indicates that the transformation of (1S,2R,10S)-15 into
(2S,3S,3aR,6aS)-16 takes place on silica gel, since (2S,3S,3aR,6aS)-
16 was isolated as a major product, whereas only traces of
(1S,2R,10S)-15 were recovered. The formation of (3S,3aR,6aS)-17
O
6a
O
O
X
Ph
N
X
Ph
N
X
Ph
N
a
3
+
+
3a
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(S)-8
9
X=CH2
(3S,3aR,6aS,1'S)-11a
(3S,3aR,6aR,1'S)-12a
(3R,3aS,6aR,1'S)-11b
(3R,3aS,6aS,1'S)-12b
10 X=O
Scheme 2. Reagents and conditions: (a) toluene, 60 °C, 48 h.
EtO
O
NH
Boc
OH
O
O
6a
O
Boc
6a
Ph
N
N
P
2
a
3
1'
1
3
+
+
(EtO)2(O)P
3a
3a
BocHN
(EtO)2(O)P
(3S,3aR,6aS,1'S)-11a
(EtO)2(O)P
(1S,2R,1'S)-15
(2S,3S,3aR,6aS)-16
(3S,3aR,6aS)-17
b
Scheme 3. Reagents and conditions: (a) Boc2O, H2, Pd–C and Pd(OH)2, EtOH, 20 h; (b) DBU, CDCl3, 24 h.

D. G. Piotrowska / Tetrahedron: Asymmetry 19 (2008) 2323–2329
2325
NH
EtO
O
Boc
OH
O
O
Boc
O
N
Ph
N
P
2
a
1
1'
(EtO)2(O)P
+
+
BocHN
(EtO)2(O)P
(3R,3aS,6aR)-17
(EtO)2(O)P
(3R,3aS,6aR,1'S)-11b
(1R,2S,1'R)-15
(2R,3R,3aS,6aR)-16
b
Scheme 4. Reagents and conditions: (a) Boc2O, H2, Pd–C and Pd(OH)2, EtOH, 20 h; (b) DBU, CDCl3, 24 h.
was found for the minor isomer (3R,3aS,6aS,10S)-12b (Table 1). This
observation allows us to attribute the analogous E3/E4 conforma-
tion of fused isoxazolidine and tetrahydrofuran rings in 12b, in
which again the diethoxyphosphoryl group at C3 as well as both
H–C3a and H–C6a bridgehead hydrogens are forced to occupy the
same side of the molecule (Fig. 2). On the other hand, analysis of
vicinal couplings found for the major isomer (3S,3aR,6aR,10S)-12a
revealed that this compound prefers to adopt E6a/E6 (isoxazoli-
dine/tetrahydrofuran) conformation, in which the diethoxyphos-
phoryl group and a fused tetrahydrofuran fragment once again
are situated on the opposite sides of the ring junction to minimise
their steric interactions. It is worth noting that this conformation
was also stabilised by the anomeric effect of the O6–C6a–O1 sub-
unit. In this conformation, the N-(1-phenylethyl) residue in 12a is
oriented pseudoaxially, and thus avoids serious repulsion with the
diethoxyphosphoryl group.
Boc NH
OH
O
Ph
N
O
3
a
2
1'
(EtO)2(O)P
O
1
(EtO)2(O)P
(3S,3aR,6aR,1'S)-12a
(2R/S,3R,1'S)-19
Scheme 5. Reagents and conditions: (a) Boc2O, H2, Pd–C and Pd(OH)2, EtOH, 20 h.
In structural studies on phosphonates (3S,3aR,6aS,10S)-11a,
(3R,3aS,6aR,10S)-11b, (3S,3aR,6aR,10S)-12a and (3R,3aS,6aS,10S)-
12b, we first focused attention on establishing preferred conforma-
tion of the fused isoxazolidine and tetrahydrofuran or cyclopen-
tane rings. Thus, the relative configurations of the substituents in
the isoxazolidine ring would become available.
Our previous observations on N-methyl isoxazolidine 20 turned
out to be useful.13 Based on analysis of the available vicinal cou-
pling constants (Table 1), it was established that 20 exists in an
E3/E4 (isoxazolidine/tetrahydrofuran) conformation (Fig. 2),13 in
which bulky diethoxyphosphoryl and tetrahydrofuran rings adopt
pseudoequatorial positions regarding the isoxazolidine ring to
minimise their steric repulsions. A similar set of vicinal couplings
The assignment of the relative configurations in diastereoiso-
meric cycloadducts (3S,3aR,6aS,10S)-11a and (3R,3aS,6aR,10S)-11b
seemed to be more difficult since at C6, in a bicyclic skeleton,
two additional hydrogen atoms are present, when compared to
compounds (3S,3aR,6aR,10S)-12a and (3R,3aS,6aS,10S)-12b. Based
on analysis of the vicinal couplings found in the 1H and 13C NMR
Table 1
Stereochemically relevant vicinal couplings for compounds 11a, 11b, 12a, 12b, 20 and 21 and their conformations
Vicinal coupling constants (Hz)
Compounds
(3S,3aR,6aR,10S)-12a
(3S,3aR,6aS,10S)-11a
(3R,3aS,6aR,10S)-11b
21
(3R,3aS,6aS,10S)-12b
20
J(P–C3C4–C6a)
J(P–C3C3a–C4)
J(P–C3N–C)
J(H–C3C3a–H)
J(H–C3C3a–H)
J(H–C3aC6a–H)
8.3
5.3
2.0
17.7
6.9
5.7
3.6
6.4
0
5.7
0
4.8
Overlap
Overlap
Overlap
Overlap
1T2/6T6a
9.2
4.9
0
18.0
7.5
7.5
0
7.5
0
4.0
0
9.8
3.4
0
16.2
8.0
8.0
0
8.0
0
3.7
0
6.0
Overlap
Overlap
Overlap
Overlap
E3/E5
3.5
10.3
10.6
17.1
4.2
5.4
2.4
9.9
—
8.6
4.9
3.4
17.4
7.8
5.7
0
7.8
—
—
10.0
3.8
0
17.1
8.4
5.4
0.9
8.4
—
J(H–C3aC4–H
J(H–C3aC4–Hb)
J(H–C6aC6–H
J(H–C6aC6–Hb)
a
)
a
)
—
—
—
—
—
—
J(H
J(H
a
a
–C6C5–Hb)
–C6C5–H
—
—
a
)
)
6.0
12.1
6.4
8.0
0
J(Hb–C4C5–H
J(H –C4C5–H
J(Hb–C4C5–Hb)
a
9.0
6.9
8.1
3.6
11.7
5.4
7.8
0.6
E3/E4
11.4
5.4
8.4
0
a
a)
J(Ha–C4C5–Hb)
Conformationa
E3/4T5
E
6a/E6
E3/E4
a
Isoxazolidine ring/fused ring.
Hβ
H
H
H
H
H
H
H
Hβ
H
H
H
H
6
P
H
P
H
O
O
3
O
O
Me
H
H
5
Hα
Me
H
O
N
N
H
N
O
N
O
H
5
Me
H
Me
H
6a
6a
P
P
N
P
4
P
4
H
Hα
3
3
H3
H3
H
N
Hβ
O
O
H
H
Hα
H
Me
H
Me
20
12b
12a
21
11b
11a
Figure 2. The preferred conformation of 20,13 12a and 12b; P = P(O)(OEt)2.
Figure 3. The preferred conformation of 21,13 11a and 11b; P = P(O)(OEt)2.

2326
D. G. Piotrowska / Tetrahedron: Asymmetry 19 (2008) 2323–2329
Table 2
Stereochemically relevant chemical shifts (ppm) for compounds 12a, 12b and 20
Compounds
Chemical shifts (ppm)
d(H
a
–C4)
d(Hb–C4)
d(H
a
–C5)
d(Hb–C5)
d(H–C3)
d(H–C3a)
d(H–C6a)
(3R,3aS,6aS,10S)-12b
(3S,3aR,6aR,10S)-12a
20
1.60
2.01
1.89
1.87
2.22
2.02
3.24
4.22
3.97
3.76
4.05
4.04
2.74
3.34
2.66
3.34
3.50
3.42
5.66
5.80
5.71
Table 3
Stereochemically relevant chemical shifts (ppm) for compounds 11a, 11b and 21
Compounds
Chemical shifts (ppm)
d(H
a
–C4)
d(Hb–C4)
d(H
a
–C5)
d(Hb–C5)
d(H
a
–C6)
d(Hb–C6)
d(H–C3)
d(H–C3a)
d(H–C6a)
(3R,3aS,6aR,10S)-11b
(3S,3aR,6aS,10S)-11a
21
1.28
1.70
Overlap
1.44
1.70
Overlap
1.04
1.70
Overlap
1.35
1.60
Overlap
1.80
1.88
1.85
1.35
1.46
Overlap
2.42
3.06
2.38
3.12
3.21
3.23
4.44
4.44
4.47
spectra (Table 1) of the minor isomer (3R,3aS,6aR,10S)-11b, it was
concluded that this compound exists in a E3/4T5 (isoxazolidine/
cyclopentane) conformation (Fig. 3), which closely resembles the
conformation previously established for isoxazolidine 21, obtained
from N-methyl nitrone and cyclopentene.13 A set of vicinal cou-
plings (Table 1) extracted from the spectra of the major isomer
(3S,3aR,6aS,10S)-11a indicates that this molecule prefers 1T2/6T6a
(isoxazolidine/cyclopentane) conformation (Fig. 3), in which spa-
tial interactions of bulky substituents, namely, the diethoxyphos-
phoryl group and the N-(1-phenylethyl) residue are completely
avoided.
At this stage, it became evident that the relative configurations
of the diethoxyphosphoryl group at C3 and both bridgehead hydro-
gens at C3a and C6a in the isoxazolidine ring are the same (cis) in
both diastereoisomeric pairs of the cycloadducts (3S,3aR,6aS,10S)-
11a and (3R,3aS,6aR,10S)-11b, as well as in (3S,3aR,6aR,10S)-12a
and (3R,3aS,6aS,10S)-12b.
To gather further evidence for different spatial orientations of
the Ph(CH3)HC residues in relation to the isoxazolidine skeleton
in (3S,3aR,6aR,10S)-12a and (3R,3aS,6aS,10S)-12b, 2D NOE experi-
ments were performed; the relevant positive signals are depicted
in Figure 5. NOE signals between the ortho protons of the aromatic
ring in (3R,3aS,6aS,10S)-12b and H–C3 and H–C5 are of special sig-
nificance, and fully support our previous conclusions based on
analysis of the aromatic ring shieldings. On the other hand, NOE
signals between H–C5 and Me–C*, H–C* and H–C3 in (3S,3aR,6a-
R,10S)-12a clearly point out that the phenyl ring primarily resides
outside the molecule. These observations unambiguously prove
the absolute configurations at C3, C3a and C6a in the isoxazolidine
ring as (3S,3aR,6aR) for isomer 12a and (3R,3aS,6aS) for 12b.
H
H
H6a
H
P
H
O
H
Assignments of the absolute configurations in both diastereo-
isomeric cycloadducts (3S,3aR,6aR,10S)-12a and (3R,3aS,6aS,10S)-
12b could now be undertaken, since significant differences in the
chemical shifts were noticed in their 1H NMR spectra (Table 2),
which are caused by the space-oriented (S)-1-phenylethyl func-
O
Me
H
O
N
H
H
H
P
4
H
H3
H
H
5
N
H
H
O
H
H
Me
tionality.15 Large upfield shifts of H
a
–C4, Hb–C4, H
C5 in the minor isomer (3R,3aS,6aS,10S)-12b as compared to the
shifts of the same protons in (3S,3aR,6aR,10S)-12a (
d = 0.41,
a–C5 and Hb–
H
12a
12b
D
Figure 5. The most important NOESY correlations for (3S,3aR,6aR,10S)-12a and
(3R,3aS,6aS,10S)-12b.
0.35, 0.98 and 0.29 ppm, respectively) can only be explained by
the shielding of these protons by the phenyl group in
(3R,3aS,6aS,10S)-12b. This phenomenon was not observed in the
diastereoisomer (3S,3aR,6aR,10S)-12a as well as in a phenyl lacking
N-methyl isoxazolidine 20.13 The preferred positions of the phenyl
groups in (3S,3aR,6aR,10S)-12a and (3R,3aS,6aS,10S)-12b could be
illustrated as shown in Figure 4.
Similarly, significant differences in chemical shifts were also ob-
served in the 1H NMR spectra of (3S,3aR,6aS,10S)-11a and
(3R,3aS,6aR,10S)-11b (Table 3), and were used in establishing their
absolute configurations. Upfield shifts of Ha–C4, Hb–C4, Ha–C5
and Hb–C5 in the minor isomer (3R,3aS,6aR,10S)-11b as compared
to the shifts of the same protons in (3S,3aR,6aS,10S)-11a
..
(Dd = 0.42, 0.26, 0.66 and 0.25 ppm, respectively) undoubtedly
..
H3C
H
H
CH3
arise due to the shielding effect of the phenyl ring observed in
(3R,3aS,6aR,10S)-11b. The preferred locations of the phenyl groups
in both (3S,3aR,6aS,10S)-11a and (3R,3aS,6aR,10S)-11b were con-
firmed by 2D NOE experiments (Fig. 6), and thereby the absolute
configurations in diastereoisomeric isoxazolidines (3S,3aR,6a-
S,10S)-11a and (3R,3aS,6aR,10S)-11b were proved.
Although our observations of the stereochemistry of the cyclo-
addition between (S)-N-(1-phenylethyl)-C-(diethoxyphospho-
ryl)nitrone (S)-8 and alkenes are limited to cyclopentene and 2,3-
dihydrofuran, as well as to the earlier reported reactions with allyl
alcohol14 and vinyl acetate,16 the general tendency for the forma-
H
H
O
H
O
H
(EtO)2(O)P
P(O)(OEt)2
H
H
H
H
4
O
5
O
H
H
H
H
H
H
12a
12b
Figure 4. The preferred conformations of (3S,3aR,6aR,10S)-12a and (3R,3aS,6aS,10S)-
12b.

D. G. Piotrowska / Tetrahedron: Asymmetry 19 (2008) 2323–2329
2327
hexahydrofuro[3,2-d]isoxazole framework was formed regiospe-
cifically. The diastereoselectivity of this reaction was moderate
since isoxazolidines (3S,3aR,6aR,10S)-12a and (3R,3aS,6aS,10S)-12b
were obtained in a 68:32 ratio. Similarly, reaction of (S)-8 with
O
P
H
H
H
Hβ
O
H
H
6
H
H
O
3
O
Me
H
N
5
H
H
H
H
P
N
H
Hα
H
3
cyclopentene gave
a mixture of two isoxazolidines (3S,3aR,
H
Hα5
H
O
6aS,10S)-11a and (3R,3aS,6aR,10S)-11b with comparable diastereo-
selectivity (65:35). Separations of diastereoisomeric isoxazolidines
(3S,3aR,6aS,10S)-11a and (3R,3aS,6aR,10S)-11b, as well as (3S,3aR,
6aR,10S)-12a and (3R,3aS,6aS,10S)-12b were successfully achieved
with chromatography.
H
H
Me
11a
11b
Figure 6. The most important NOESY correlations for (3S,3aR,6aS,10S)-11a and
(3R,3aS,6aR,10S)-11b.
In the cycloadditions of (S)-N-(1-phenylethyl)-C-(diethoxy-
phosphoryl)nitrone (S)-8 with cyclopentene and 2,3-dihydrofuran
isoxazolidines having an (S)-configuration at C3 were formed as
the major products. These observations are in agreement with
the stereochemistry observed earlier for analogous reactions with
allyl alcohol14 and vinyl acetate.16
tion of the major isoxazolidines having an (S)-configuration at C3
was noticed.
In a two-step transformation of (3S,3aR,6aS,10S)-11a, two 1,2-
oxaphospholanes (2S,3S,3aR,6aS)-16 (d31P = 39.80 ppm) and (2R,
3S,3aR,6aS)-18 (d31P = 37.63 ppm) were formed (Scheme 3). By
analogy, from (3R,3aS,6aR,10S)-11b again two 1,2-oxaphospholanes
(2R,3R,3aS,6aR)-16 and (2S,3R,3aS,6aR)-18 were produced. This is
because a new stereogenic centre at the phosphorus atom is cre-
ated, whereas configurations at C3, C3a and C6 in a fused 1,2-oxa-
phospholane/cyclopentane system remained intact. The 31P NMR
chemical shifts of (2S,3S,3aR,6aS)-16 and (2R,3S,3aR,6aS)-18 could
be useful in assigning the absolute configurations at the phospho-
rus atom, since it was previously noticed that 31P NMR signals of
hydrogen-bonded isomers of 1,2-oxaphospholanes are shifted
downfield, when compared to non-bonded P-epimers.17–19
Furthermore, in the 1H NMR spectra of the enantiomers of 1,2-oxa-
phospholanes 16 signals of HN were shifted downfield
(d1H = 5.22 ppm), when compared to the same signals for 18
(d1H = 4.80 ppm). This observation clearly indicates the presence
of a strong P@Oꢀ ꢀ ꢀH–N hydrogen bond in isomers 16 which means
that P@O and NH groups are on the same side of the 1,2-oxaphos-
pholane ring, and thereby the (S)-absolute configuration of the
newly generated stereogenic centre at the phosphorus in
(2S,3S,3aR,6aS)-16 and (R) in (2R,3R,3aS,6aR)-16 was established.
Detailed analysis of 1H and 13C NMR spectra of 1,2-oxaphospho-
lane 16 allowed us to unequivocally establish the preferred confor-
mation of this compound. Based on the analysis of vicinal
couplings [J(H3a–H6a) = 5.4 Hz, J(H3a–H3) = 8.7 Hz, J(H3a–HP) =
Catalytic hydrogenolysis of isoxazolidines (3S,3aR,6aS,10S)-11a
or (3R,3aS,6aR,10S)-11b performed in the presence of Boc2O led to
the chromatographically unstable N-Boc-protected phosphonates
(1S,2R,10S)-15 or (1R,2S,10R)-15 contaminated with the products
of an intramolecular transesterification at phosphorus [(2S,3S,
3aR,6aS)-16 and (2R,3R,3aS,6aR)-16, respectively] and the N-Boc-
isoxazolidines (3S,3aR,6aS)-17 or (3R,3aS,6aR)-17 in which the
N–O bond was retained. Phosphonates (1S,2R,10S)-15 and
(1R,2S,10R)-15 were then transformed into mixtures of enantiome-
rically pure 1,2-oxaphospholanes (2S,3S,3aR,6aS)-16 and
(2R,3S,3aR,6aS)-18 or (2R,3R,3aS,6aR)-16 and (2S,3R,3aS,6aR)-18,
respectively, by treatment with DBU. Enantiomerically pure 1,2-
oxaphospholanes (2S,3S,3aR,6aS)-16 and (2R,3R,3aS,6aR)-16 were
separated by chromatography.
The preferred conformations for diastereoisomeric isoxazoli-
dines (3S,3aR,6aS,10S)-11a or (3R,3aS,6aR,10S)-11b, as well as for
(3S,3aR,6aR,10S)-12a and (3R,3aS,6aS,10S)-12b were established.
Shielding effects observed in the 1H NMR spectra of cycloadducts
were employed for assigning the absolute configurations of three
new stereogenic centres at C3, C3a and C6 in isoxazolidine rings,
which were then confirmed by 2D NOE experiments.
4. Experimental
1H NMR spectra were taken in CDCl3 on the following spectrom-
eters: Bruker Avance II Plus (700 MHz) and Varian Mercury-300
with TMS as an internal standard. 13C and 31P NMR spectra were
recorded for CDCl3 solutions on Bruker Avance II Plus spectrometer
at 176.2 and 283.5 MHz, or a Varian Mercury-300 machine at 75.5
and 121.5 MHz, respectively. 1H{31P} NMR, 1H–1H COSY and
NOESY experiments were applied, when necessary to support
spectroscopic assignments. IR spectra were measured on an Infin-
ity MI-60 FT-IR spectrometer. Melting points were determined on a
Boetius apparatus and are uncorrected. Elemental analyses were
performed by the Microanalytical Laboratory of this Faculty on Per-
kin–Elmer PE 2400 CHNS analyser. Polarimetric measurements
were conducted on a Optical Activity PolAAr 3001 apparatus.
The following adsorbents were used: column chromatography,
Merck Silica Gel 60 (70–230 mesh); analytical TLC, Merck TLC plas-
27.9 Hz, J(H3a–H4 ) = 8.7 Hz, J(H3a–H4b) = 8.7 Hz, J(H6a–H6 ) =
a
a
4.8 Hz, J(H6a–H6b) = 3.0 Hz and J(P–C4) = 0 Hz], the 3E conformation
is evident for the 1,2-oxaphospholane ring and a fused cyclopen-
tane ring adopts the 3aE conformation. In addition to H-bonding
(vide supra) the 3E conformation of the 1,2-oxaphospholane ring
is stabilised by the equatorially positioned N-Boc group and pseud-
oaxially oriented ethoxy substituent at phosphorus (Fig. 7).
H
H
H
O
O
H
H
H
H
P
N
EtO
Boc
H
H
3
H
(2S,3S,3aR,6aS)-16
tic sheets Silica Gel 60 F254
.
Figure 7. The preferred 3E/3aE conformation of hydrogen-bonded 1,2-oxaphospho-
lane (2S,3S,3aR,6aS)-16.
4.1. General procedure for the cycloaddition of the nitrone (S)-
(+)-8 with cyclopentene 9 or 2,3-dihydrofuran 10
Nitrone (S)-8 (1.0 mmol) and cycloalkene 9 or 10 (10 mmol)
were stirred in toluene (1–2 mL) at 60 °C, and the disappearance
of the starting nitrone was monitored by TLC. All volatiles were re-
moved in vacuo, and the crude product was purified by column
chromatography on a silica gel column.
3. Conclusions
In the 1,3-dipolar cycloaddition of (S)-N-(1-phenylethyl)-C-
(diethoxyphosphoryl)nitrone (S)-8 with 2,3-dihydrofuran, the

2328
D. G. Piotrowska / Tetrahedron: Asymmetry 19 (2008) 2323–2329
4.1.1. Diethyl (3S,3aR,6aS)- and (3R,3aS,6aR)-hexahydro-2-[(S)-
1-phenylethyl]-2H-cyclopenta[d]isoxazol-3-yl-3-phosphonates
(3S,3aR,6aS,10S)-11a and (3R,3aS,6aR,10S)-11b
From nitrone (S)-8 (0.856 g, 3.00 mmol) and cyclopentene
(2.64 mL, 30.0 mmol), a mixture of phosphonates 11a and 11b
was obtained. Purification on silica gel column with methylene
chloride–MeOH (200:1, v/v) gave isoxazolidine 11a (0.524 g, 54%)
followed by 11b (0.18 g, 17%).
2.4 Hz, 1H, H
a–C4), 1.53 (d, J = 6.6 Hz, 1H, HC–CH3), 1.32 (t,
J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3,
176.2 MHz):
d 142.77, 128.44, 127.89, 127.52, 108.90 (d,
3J(CCCP) = 3.5 Hz, C6a), 67.70 (s, C5), 65.70 (d, J(CNCP) = 10.6 Hz,
3
1
CH–CH3), 64.59 (d, J(CP) = 166.3 Hz, C3), 62.95 (d, J = 6.3 Hz),
3
62.90 (d, J = 7.4 Hz), 50.33 (s, C3a), 32.08 (d, J(CCCP) = 10.3 Hz, C4),
19.54 (s, CH3–CH), 16.71 (d, J = 5.4 Hz), 16.64 (d, J = 5.2 Hz). 31P
NMR (CDCl3, 283.5 MHz): d 22.08. Anal. Calcd for C17H26NO5P: C,
57.46; H, 7.37; N, 3.94. Found: C, 57.52; H, 7.36; N, 3.98.
4.1.1.1. Diethyl (3S,3aR,6aS)-hexahydro-2-[(S)-1-phenylethyl]-
2H-cyclopenta[d]isoxazol-3-yl-3-phosphonate (3S,3aR,6aS,10S)-
4.1.2.2. Diethyl (3R,3aS,6aS)-hexahydro-2-[(S)-1-phenylethyl]-
furo[3,2-d]isoxazol-3-yl-3-phosphonate
11a.
IR (film):
ꢂ
m
= 2964, 1686, 1495, 1450, 1252, 1052, 1025,
(3R,3aS,6aS,10S)-12b.
966 cmꢁ1. ½a 2D0
¼ þ69:2 (c 0.9, CHCl3). 1H NMR (CDCl3, 700 MHz):
IR (film): m = 2978, 2936, 1638, 1453, 1247, 1098, 1050, 1023,
d 7.50–7.40 (m, 2H), 7.38–7.20 (m, 3H), 4.60 (q, J = 6.9 Hz, 1H,
HC–CH3), 4.44 (t, J = 5.7 Hz, 1H, H–C6a), 4.22–4.12 (m, 4H), 3.21
(dddd, J = 17.7, 6.9, 6.4, 3.6 Hz, 1H, H–C3a), 3.06 (dd, J = 6.9,
2.1 Hz, 1H, H–C3), 1.88 (dd, J = 14.7, 4.8 Hz, 1H), 1.75–1.67 (m,
3H), 1.65–1.60 (m, 1H), 1.52–1.42 (m, 1H), 1.46 (d, J = 6.9 Hz, 3H,
HC–CH3), 1.34 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR
(CDCl3, 176.2 MHz): d 143.68, 128.13, 127.57, 126.74, 82.65 (d,
969 cmꢁ1. ½a 2D0
ꢂ
¼ ꢁ91:5 (c 1.3, CHCl3). 1H NMR (CDCl3, 700 MHz):
d 7.50–7.45 (m, 2H), 7.38–7.26 (m, 3H), 5.66 (d, J = 5.7 Hz, 1H, H–
C6a), 4.46 (q, J = 6.9 Hz, 1H, HC–CH3), 4.31–4.11 (m, 4H), 3.76
(dd, J = 8.7, 7.8 Hz, 1H, Hb–C5), 3.34 (ddt, J = 17.4, 7.8, 5.7 Hz, 1H,
H–C3a), 3.24 (ddd, J = 11.7, 8.7, 5.4 Hz, 1H, H
a–C5), 2.74 (dd,
J = 7.8, 3.3 Hz, 1H, H–C3), 1.87 (ddt, J = 12.9, 11.7, 7.8 Hz, 1H, Hb–
C4), 1.60 (dd, J = 12.9, 5.4 Hz, 1H, Ha–C4), 1.59 (d, J = 6.9 Hz, 1H,
1
3J(CCCP) = 8.3 Hz, C6a), 65.63 (d, J(CP) = 163.5 Hz, C3), 63.41 (d,
HC–CH3), 1.39 (t, J = 7.2 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H). 13C NMR
(CDCl3, 176.2 MHz): d 138.71, 129.95, 127.84, 127.64, 105.79 (d,
J = 6.3 Hz), 62.18 (d, J = 6.9 Hz), 61.34 (d, J = 2.0 Hz, CH–CH3),
2
3
3
50.69 (d, J(CCP) = 2.6 Hz, C3a), 32.16 (d, J(CCCP) = 5.3 Hz, C4),
32.14, 24.06, 16.80 (d, J = 5.7 Hz), 16.76 (d, J = 6.0 Hz), 11.80 (s,
CH3–CH). 31P NMR (CDCl3, 283.5 MHz): d 23.93. Anal. Calcd for
C18H28NO4P: C, 61.18; H, 7.99; N, 3.96. Found: C, 61.45; H, 8.09;
N, 3.82.
3J(CCCP) = 8.6 Hz, C6a), 66.47 (s, C5), 63.88 (d, J(CNCP) = 3.4 Hz, CH–
1
CH3), 63.68 (d, J = 6.6 Hz), 62.70 (d, J(CP) = 165.2 Hz, C3), 62.52 (d,
2
3
J = 7.2 Hz), 50.56 (d, J(CCP) = 2.3 Hz, C3a), 31.40 (d, J(CCCP) = 4.9 Hz,
C4), 21.11 (s, CH3–CH), 16.82 (d, J = 5.7 Hz), 16.71 (d, J = 6.0 Hz). 31
P
NMR (CDCl3, 283.5 MHz): d 21.78. Anal. Calcd for C17H26NO5P: C,
57.46; H, 7.37; N, 3.94. Found: C, 57.70; H, 7.32; N, 3.85.
4.1.1.2. Diethyl (3R,3aS,6aR)-hexahydro-2-[(S)-1-phenylethyl]-
2H-cyclopenta[d]isoxazol-3-yl-3-phosphonate (3R,3aS,6aR,10S)-
4.2. Hydrogenation of isoxazolidine 11a and 11b (general
procedure)
11b.
IR (film): m = 2976, 1650, 1454, 1246, 1220, 1050, 1024,
964 cmꢁ1
.
½
a 2D0
ꢂ
¼ ꢁ106:8 (c 1.0, CHCl3). 1H NMR (CDCl3,
700 MHz): d 7.50–7.40 (m, 2H), 7.38–7.20 (m, 3H), 4.46 (q,
J = 6.9 Hz, 1H, HC–CH3), 4.44 (br dd, J = 7.5, 4.0 Hz, 1H, H–C6a),
4.32–4.10 (m, 4H), 3.12 (dq, J = 18.0, 7.5 Hz, 1H, H–C3a), 2.42 (dd,
J = 7.5, 1.8 Hz, 1H, H–C3), 1.80 (dd, J = 12.6, 6.0 Hz, 1H), 1.62 (d,
J = 6.9 Hz, 3H, HC–CH3), 1.45 (dddd, J = 13.2, 12.1, 8.0, 7.5 Hz, 1H),
1.39 (t, J = 7.2 Hz, 3H), 1.37–1.32 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H),
1.27 (dd, J = 13.2, 6.4 Hz, 1H), 1.09–0.98 (m, 1H). 13C NMR (CDCl3,
A solution of isoxazolidine 11a (0.060 g, 0.17 mmol) in ethanol
(1.5 mL) was kept under an atmospheric pressure of hydrogen over
the mixture of 20% Pd(OH)2–C (10 mg) and 10% Pd–C (10 mg) at
room temperature for 15 h. The suspension was filtered through
a layer of Celite, and the solution was concentrated to give crude
amino alcohol (1S,2R,10S)-15 (0.06 g). 31P NMR (CDCl3,
121.5 MHz): d 39.80 (16, 4%), 26.37 (15, 83%) and 21.49 (17,
13%). 1H NMR (CDCl3, 300 MHz): d 5.63 (br d, J = 10.5 Hz, 1H, NH,
15), 4.65–4.60 (m, 1H, 15), 4.40–4.38 (m, 1H, 15), 4.25–4.05 (m,
6H, 15), 2.20–2.00 (m, 1H, 15), 2.00–1.80 (m, 2H, 15), 1.80–1.60
(m, 4H, 15), 1.44 (s, 9H, 15), 1.35 (t, J = 7.0 Hz, 3H, 15), 1.32 (t,
J = 7.0 Hz, 3H, 15).
The crude product was purified on a silica gel column with
methylene chloride–methanol (100:1, v/v) to give 1,2-oxaphos-
pholane (2S,3S,3aR,6aS)-16 as a white solid (20 mg, 38%), followed
by fractions containing impure isoxazolidine (3S,3aR,6aS)-17
(0.003 g, 4%) and amino alcohol (1S,2R,10S)-15 (0.006 g, 10%).
176.2 MHz):
d
138.22, 130.63, 127.54, 127.48, 81.68 (d,
1
3J(CCCP) = 9.2 Hz, C6a), 65.18 (d, J(CP) = 162.6 Hz, C3), 63.28 (d,
J = 6.3 Hz), 62.18 (d, J = 6.9 Hz), 62.72 (s, CH–CH3), 50.72 (d,
3
2J(CCP) = 2.6 Hz, C3a), 31.90 (d, J(CCCP) = 4.9 Hz, C4), 32.10, 23.46,
20.82 (s, CH3–CH), 16.88 (d, J = 5.4 Hz), 16.77 (d, J = 6.0 Hz). 31P
NMR (CDCl3, 283.5 MHz): d 24.29. Anal. Calcd for C18H28NO4P: C,
61.18; H, 7.99; N, 3.96. Found: C, 61.19; H, 7.98; N, 4.04.
4.1.2. Diethyl (3S,3aR,6aR)- and (3R,3aS,6aS)-hexahydro-2-[(S)-
1-phenylethyl]furo[3,2-d]isoxazol-3-yl-3-phosphonates
(3S,3aR,6aR,10S)-12a and (3R,3aS,6aS,10S)-12b
From nitrone (S)-8 (0.856 g, 3.00 mmol) and a 2,3-dihydrofuran
(2.26 mL, 30.0 mmol), a mixture of phosphonates 12a and 12b was
obtained. Purification on silica gel column with toluene–isopropa-
nol (50:1, v/v) gave isoxazolidine 12b (0.29 g, 27%) followed by 12a
(0.306 g, 29%).
4.2.1. tert-Butyl (2S,3S,3aR,6aS)-2-ethoxy-2-oxo-cyclo-
penta[d](1,2-oxaphospholan-3-yl)carbamate (2S,3S,3aR,6aS)-16
Mp = 90–91 °C. IR (KBr):
m = 3258, 2977, 1706, 1536, 1364,
1280, 1235, 1174, 1054, 969, 895 cmꢁ1. ½a D20
¼ ꢁ98:4 (c 1.0, CHCl3).
ꢂ
1H NMR (CDCl3, 300 MHz): d 5.22 (br dd, J = 8.1, 5.7 Hz, 1H, HN),
4.66 (dddd, J = 5.4, 4.8, 3.0, 1.8 Hz, 1H, H–C6a), 4.21 (ddd, J = 16.8,
8.7, 8.1 Hz, 1H, H–C3), 4.21–4.11 (m, 2H, CH2OP), 3.00 (ddq,
J = 27.9, 8.7, 5.4 Hz, 1H, H–C3a), 2.10–1.85 (m, 3H), 1.84–1.63 (m,
3H), 1.45 (s, 9H), 1.34 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3,
75.5 MHz): d 155.63 (d, J = 13.7 Hz, C@O), 83.24 (d, J = 6.3 Hz,
C6a), 80.38 (s, C(CH3)3), 63.47 (d, J = 6.3 Hz, CH2OP), 46.48 (d,
J = 132.8 Hz, C3), 46.26 (d, J = 10.3 Hz, C3a), 34.26 (d, J = 5.2 Hz,
C6), 28.52 (s, C(CH3)3), 25.70, 23.87, 16.71 (d, J = 5.7 Hz,
CH3CH2OP). 31P NMR (CDCl3, 121.5 MHz): d 39.80. Anal. Calcd for
C13H24NO5P: C, 51.14; H, 7.92; N, 4.59. Found: C, 51.31; H, 8.12;
N, 4.76.
4.1.2.1. Diethyl (3S,3aR,6aR)-hexahydro-2-[(S)-1-phenylethyl]-
furo[3,2-d]isoxazol-3-yl-3-phosphonate
(3S,3aR,6aR,10S)-12a.
IR (film):
m
ꢂ
= 2980, 2934, 1678, 1453, 1247, 1054, 1025,
967 cmꢁ1. ½a 2D0
¼ ꢁ17:1 (c 1.2 CHCl3). 1H NMR (CDCl3, 700 MHz):
d 7.40–7.22 (m, 5H), 5.80 (d, J = 5.4 Hz, 1H, H–C6a), 4.42 (q,
J = 6.6 Hz, 1H, HC–CH3), 4.22 (dt, J = 9.0, 6.9 Hz, 1H, Ha–C5), 4.20–
4.13 (m, 2H), 4.13–4.02 (m, 1H), 4.05 (ddd, J = 9.0, 8.1, 3.6 Hz, 1H,
Hb–C5), 4.00–3.88 (m, 1H), 3.50 (ddddd, J = 17.1, 9.9, 5.4, 4.2,
2.4 Hz, 1H, H–C3a), 3.34 (dd, J = 7.2, 4.2 Hz, 1H, H–C3), 2.24 (dddd,
J = 12.9, 9.9, 9.0, 8.1 Hz, 1H, Hb–C4), 2.01 (dddd, J = 12.9, 6.9, 3.6,

D. G. Piotrowska / Tetrahedron: Asymmetry 19 (2008) 2323–2329
2329
4.3. Transformation of (3S,3aR,6aS,10S)-11a and (3R,3aS,
6aR,10S)-11b into (2S,3S,3aR,6aS)-16 and (2R,3R,3aS,6aR)-16
(general procedure)
(0.086 g, 54%) followed by impure 1,2-oxaphospholane (2S,3R,3a-
S,6aR)-18 (0.006 g, 4%) and isoxazolidine (3R,3aS,6aR)-17
(0.004 g, 3%).
The crude product obtained after hydrogenation of 11a or 11b
(0.06 g, 0.17 mmol) was dissolved in CDCl3 (2 mL), and DBU
(0.025 mL, 0.17 mmol) was added. After 24 h, the reaction mixture
was concentrated and residue was purified on silica gel column
with chloroform–methanol (100:1, v/v), and than appropriate frac-
tions were collected and crystallised from ether/hexanes.
4.3.2.1. tert-Butyl (2R,3R,3aS,6aR)-2-ethoxy-2-oxo-cyclopenta[d]-
(1,2-oxaphospholan-3-yl)carbamate
(2R,3R,3aS,6aR)-16.
Mp = 90–91 °C.
½
a 2D0
ꢂ
¼ þ98:8 (c 1.0, CHCl3). Anal. Calcd for
C13H24NO5P: C, 51.14; H, 7.92; N, 4.59. Found: C, 51.23; H, 8.22;
N, 4.57.
Acknowledgements
4.3.1. Transformation of (3S,3aR,6aS,10S)-11a into
(2S,3S,3aR,6aS)-16
Mrs. Jolanta Płocka is acknowledged for her excellent technical
assistance. This work was supported by the Medical University of
From isoxazolidine (3S,3aR,6aS,10S)-11a (0.184 g, 0.521 mmol),
oxaphospholane (2S,3S,3aR,6aS)-16 was obtained as a white solid
(0.09 g, 57%) identical in all respects to the compound described
in Section 4.2.1, followed by impure 1,2-oxaphospholane
(2R,3S,3aR,6aS)-18 (0.012 g, 8%) and isoxazolidine (3S,3aR,6aS)-17
(0.01 g, 7%).
´
Łódz internal funds (502-13-773 and 503-3014-1).
References
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4.3.1.1. tert-Butyl (2R,3S,3aR,6aS)-2-ethoxy-2-oxo-cyclopenta[d]-
(1,2-oxaphospholan-3-yl)carbamate (2R,3S,3aR,6aS)-18.
1H
NMR (CDCl3, 300 MHz): d 4.82–4.75 (m, 2H, NH and H–C6a), 4.42
(dt, J = 19.2, 8.7 Hz, 1H, H–C3), 4.30–4.15 (m, 2H), 3.15–2.90 (m,
1H, H–C3a), 2.09–1.90 (m, 2H), 1.90–1.78 (m, 1H), 1.75–1.60 (m,
3H), 1.46 (s, 9H), 1.39 (t, J = 7.0 Hz, 3H). 31P NMR (CDCl3,
121.5 MHz): d 37.63.
4.3.1.2. tert-Butyl (3S,3aR,6aS)-hexahydro-3-diethoxyphospho-
ryl-cyclopenta[d]isoxazolidine-2-carboxylate (3S,3aR,6aS)-17.
1H NMR (CDCl3, 300 MHz): d 4.82 (dt, J = 7.2, 2.7 Hz, 1H, H–C6),
4.33 (dd, J = 9.0, 1.8 Hz, 1H, H–C3), 4.23–4.11 (m, 4H), 3.41–3.28
(m, 1H, H–C3a), 2.00–1.75 (m, 3H), 1.75–1.50 (m, 3H), 1.51 (s,
9H), 1.34 (t, J = 7.0 Hz, 3H), 1.33 (t, J = 7.0 Hz, 3H). 13C NMR (CDCl3,
75.5 MHz): d 165.93 (d, J = 13.5 HZ, C@O), 87.51, 82.69 (C6a), 63.46
(d, J = 7.2 Hz), 62.98 (d, J = 6.6 Hz), 62.02 (d, J = 170.6 Hz, C3), 48.80
(d, J = 2.0 Hz, C3a), 33.24, 28.71, 28.41, 24.93, 16.75 (d, J = 5.7 Hz),
16.70 (d, J = 6.0 Hz). 31P NMR (CDCl3, 121.5 MHz): d 21.49.
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4.3.2. Transformation of (3R,3aS,6aR,10S)-11b into
(2R,3R,3aS,6aR)-16
From isoxazolidine (3R,3aS,6aR,10S)-11b (0.184 g, 0.521 mmol),
oxaphospholane (2R,3R,3aS,6aR)-16 was obtained as a white solid