Conformational analysis of cyclic phosphates derived from 5-C′ substituted 1,2-O-isopropylidene-α-D-xylofuranose derivatives

Article abstract of DOI:10.1016/S0040-4020(03)00582-9

Twelve 2-phenoxy-2-oxo-1,3,2-dioxaphosphorinanes fused with a 1,2-O-isopropylidene-α-D-xylofuranose moiety in cis orientation and substituted at the C′5 position were prepared in two steps from commercially available diacetone-α-D-glucose. Their conformations, and configurations were determined by ¹H and ³¹P NMR and X-ray crystallographic techniques. Both, chair-twisted-chair and chair-boat equilibria were observed in solution. We observed that the strong anisotropic shielding effect of the benzene ring in the phenoxy group generates an upfield shift of the H¹ hydrogen atom, when the cyclic phosphates adopt a boat conformation. This is due to a relative cis-orientation of the P-phenoxy group and the H¹ proton of the 1,2-O-isopropylidene-α-D-xylofuranose moiety. Therefore, the configuration of the phosphorus center (S_P or R_P) can be determined by ¹H NMR spectroscopy. Interestingly, the crystal structure of one of the cyclic phosphates exhibits two independent molecules in the asymmetric unit, one with a chair and the other one with a boat conformation.

Full text of DOI:10.1016/S0040-4020(03)00582-9

Tetrahedron 59 (2003) 4077–4083
Conformational analysis of cyclic phosphates derived from 5-C0
substituted 1,2-O-isopropylidene-a-D-xylofuranose derivatives
a
b
b
Fernando Sartillo-Piscil,a Silvano Cruz, Mario Sanchez, Herbert Hopfl,
,
*
´
¨
Cecilia Anaya de Parrodic and Leticia Quinteroa,
*
a
´ ´ ´
Centro de Investigacion de la Facultad de Ciencias Quımicas, Universidad Autonoma de Puebla, 14 sur esq san claudio, San Manuel,
72570 Puebla, Mexico
´ ´
Centro de Investigaciones Quımicas, Universidad Autonoma del Estado de Morelos, Av. Universidad 1001, C.P. 62210,
b
Cuernavaca, Mexico
Departamento de Quımica y Biologıa, Universidad de las Americas-Puebla, 72820, Santa Maria Catarina Martir, Puebla, Mexico
c
´
´
´
Received 26 February 2003; revised 9 April 2003; accepted 9 April 2003
Abstract—Twelve 2-phenoxy-2-oxo-1,3,2-dioxaphosphorinanes fused with a 1,2-O-isopropylidene-a-D-xylofuranose moiety in cis
orientation and substituted at the C05 position were prepared in two steps from commercially available diacetone-a-D-glucose. Their
conformations, and configurations were determined by 1H and 31P NMR and X-ray crystallographic techniques. Both, chair–twisted–chair
and chair–boat equilibria were observed in solution. We observed that the strong anisotropic shielding effect of the benzene ring in the
phenoxy group generates an upfield shift of the H1 hydrogen atom, when the cyclic phosphates adopt a boat conformation. This is due to a
relative cis-orientation of the P-phenoxy group and the H1 proton of the 1,2-O-isopropylidene-a-D-xylofuranose moiety. Therefore, the
configuration of the phosphorus center (SP or RP) can be determined by 1H NMR spectroscopy. Interestingly, the crystal structure of one of
the cyclic phosphates exhibits two independent molecules in the asymmetric unit, one with a chair and the other one with a boat
conformation. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussions
During the last three decades, the conformational analysis of
2-phenoxy-2-oxo-1,3,2-dioxaphosphorinanes and similar
compounds has been a field of intense research.1 Cyclic
nucleoside 30,50-monophosphates such as cAMP and cGMP
play an important role in the cell metabolism, for which the
conformational analysis of similar cyclic phosphates is
relevant, since the interaction with the enzyme active site
occurs probably through the pseudoaxial phosphoryl
oxygen of the twist conformer.2,3 In this regard Bentrude
et al., have extensively studied the conformation of different
cis and trans fused cyclic phosphates by NMR and
crystallographic techniques.1
The cyclic phosphates 4a–c, 4a0 –c0, 5a–c and 5a0 –c0 were
synthesized in two steps with acceptable overall yields of
40–70% (Scheme 1), whereby the 1,3-diol precursors 2a–c
and 3a–c were obtained in yields between 42 and 73%,
when applying a sequential hydrolysis–oxidation and
Grignard reagent addition protocol (in one pot) to
commercially available 1,2,5,6-O-diisopropylidene-a-D-
xylofuranose (Table 1). In these reactions the lowest yield
was obtained with the vinyl and the highest one with the
methyl Grignard reagent (entries 1 and 3, Table 1). The
diastereomeric pairs of the 1,3-diols could be separated
efficiently by column chromatography.
Herein, we report the synthesis, configurational, and
conformational analyses of various novel0model compounds
for the above mentioned nucleoside 30,5 -monophosphates,
in which a considerable strain is imposed by the presence of
a cisoid-like fused bicyclic structure bearing methyl, phenyl
and vinyl groups attached at the C05 position of the 1,2-O-
isopropylidene-a-D-xylofuranose moiety.
The phosphorylation of the diols was carried out using
phenyldichlorophosphate and triethylamine in CH2Cl2,
affording, 4a–c, 4a0 –c0, 5a–c, 5a0 –c0 with high yield
(90–94%, see the Scheme 1). After the successful
separation of all diastereomeric pairs by column
chromatography, conformational and configurational
analyses were performed using standard NMR
methods together with X-ray structure determinations in
the case of 4a and 5b0. The specific 1H and 31P NMR
chemical shifts as well as the 3JHH, 3JHP and 4JHP coupling
constants of the cyclic phosphates are summarized in
Tables 2 and 3.
Keywords: conformation; cyclic phosphates; anisotropic shielding effect of
the benzene ring; conformational analysis.
*
Corresponding author. Tel.: þ52-2222-295500x7387; fax: þ52-2222-
454293; e-mail: fsarpis@siu.buap.mx, lquinter@siu.buap.mx.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00582-9

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F. Sartillo-Piscil et al. / Tetrahedron 59 (2003) 4077–4083
Scheme 1. Two step syntheses of the cyclic phosphates 4a–c, 4a0 –c0, 5a–c and 5a0 –c0.
4a in Fig. 1). Thus, a chair–twist equilibrium in solution and
Table 1. Preparation of the 1,3-diol precursors 2a–c and 3a–c
a permanent chair conformation in solid-state for 4a can be
proposed, as shown in Scheme 2. In contrast to the
corresponding unsubstituted cyclic phosphates derived
Entry
RMgX
Products
Yielda
Reference
1b
2b
3c
CH3–
Ph–
CH2vCH–
2a and 3a (2:1)
2b and 3b (1:4)
2c and 3c (1:1)
73
70
42
5
6
7
3
3
4
Table 3. JHH, JHP and JHP coupling constants of the cyclic phosphates
4a–c, 4a0 –c0, 5a–c and 5a0 –c0
a
Yields correspond to the mixture of diastereomers.
RMgBr.
RMgCl.
b
c
Compound
4JHP
3JH5aP
3JH5eP
3JH5aH4
3JH5eH4
4a
4a0
5a
16.0
15.0
2.2
2.5
Examination of the 31P NMR data reveals that the signal of
the cyclic phosphate 4a is centered at higher field than the
one of its diastereomer congener 4a0 (216.2 and
215.0 ppm, respectively). This suggests that the phenoxy
a
c
2.9
2.5
2.2
c
b
5a0
4b
4b0
5b
5b0
4c
4c0
5c
5c0
10.2
11.4
3.6
4.0
group of 4a is axially oriented (SP). The 3JH5P values for 4a
a
a
1.6
2.3
0
and 4a (3JH5P¼16.0 Hz for 4a and JH5P¼15.0 Hz for 4a0,
3
Table 3) suggest that the methyl group at C05 is oriented
pseudo-axially in the phosphorinane heterocyclic ring
(indicating a non chair conformation in solution). However,
a crystallographic study for 4a showed an almost perfect
chair conformation in the solid-state (see X-ray structure of
18.3
15.2
2.2
2.9
a
a
1.8
1.8
2.2
2.2
1H spectra were recorded at 400 MHz in CDCl3.
a
Peak broadened by JHP (,1.0 Hz).
Recorded in C6D6 to get overlapping signals separated.
No coupling constants observed, JHP (,0.5 Hz).
b
c
Table 2. Chemical 1H and 31P NMR shifts of the cyclic phosphates 4a–c,
4a0 –c0, 5a–c and 5a0 –c0
Compound
H1
H2
H3
H4
H5
31P
4a
4a0
5a
6.03
5.69
6.02
5.56
6.01
6.15
6.02
5.60
6.08
5.79
6.03
5.62
4.72
4.64
4.68
4.16
4.78
4.83
4.73
4.61
4.75
4.69
4.66
4.57
4.90
4.99
4.82
4.65
4.95
4.92
5.01
5.12
4.92
4.97
4.89
5.00
4.09
4.18
4.10
3.56
4.53
4.63
4.40
4.42
4.25
4.32
4.24
4.24
4.91
4.75
4.86
4.43
5.63
5.68
5.75
5.84
5.25
5.15
5.17
5.27
216.2
215.0
215.5
212.6
213.8
213.0
215.2
212.9
216.4
215.7
215.6
213.1
a
5a0
4b
4b0
5b
5b0
4c
4c0
5c
5c0
All spectra were recorded at frequencies of 400 and 161.8 MHz for proton
and phosphorus, respectively. Chemical shifts (d) are given in ppm.
Recorded in C6D6 to get overlapping signals separated.
Figure 1. Perspective view of the molecular structure of 4a in the solid-
state, showing a chair conformation for the 1,3,2-dioxaphosphorinane
heterocycle.
a

F. Sartillo-Piscil et al. / Tetrahedron 59 (2003) 4077–4083
4079
Scheme 2. Chair–twist conformational equilibrium of 4a in solution.
from 1,2-O-isopropylidene-a-D-ribo and xylofuranoses (i.e.
des-methyl, phenyl and vinyl 4a–c) in which the vicinal
coupling constants JH5P and crystallographic studies
proved a chair form both in solution and the solid-state.4
Figure 2. Perspective view of the molecular structure of 5b0 in the chair
conformation.
3
instead, a slight downfield shift was noted for the H1
hydrogen of 4b0 (6.15 ppm). The configuration of the
phosphorus atoms was determined on the basis of the 31P
NMR spectra, using the criterion that signals, which are up-
field shifted, can be attributed to phosphorinanes having
their phenoxy group axially oriented (compare: d¼213.8
for 4b and 213.0 for 4b0).10 For the other diasteromeric
phosphate pair 5b and 5b0, 5b0 did show again the shielding
It appears that the 1,3-syn diaxial orientation of the methyl
and phenoxy groups does not affect significantly the chair
conformation, at least in the solid-state. In this regard, a
similar conformation has been previously reported in
solution for cis-4-methyl-2-oxo-2-phenoxy-1,3,2-dioxa-
phosphorinane8a and cis-4-benzyl-2-oxo-2-phenoxy-1,3,2-
dioxaphosphorinane.8b As already mentioned, the vicinal
3JH5P coupling constants of 15 Hz suggest a non chair
conformation also for 4a0 in solution. A detailed analysis of
the chemical shift displacements of the protons in the
furanose ring of this compound reveals that H1 is exposed to
a shielding effect (6.03 ppm for 4a and 5.69 ppm for 4a0).
From the inspection of Dreiding models and anomeric effect
considerations,9 it might be suggested that 4a0 adopts a boat
conformation with the pseudoaxial phenoxy group in
proximity to H1 (see Scheme 3).
effect for H1 (5.60 ppm and JHP ,1 Hz for 5b0 (RP);
3
3
6.02 ppm and JHP ,1 Hz for 5b (SP)). Thus, based on the
above arguments, the cyclic phosphate 5b should present a
chair–twist equilibrium and 5b0 a chair–boat equilibrium.
In contrast, for both 4b and 4b0 a chair–twist equilibrium
can be deduced.
Although, in similar compounds the existence of a boat
conformation has been established,1b,11 these conformations
differ from the one shown in Scheme 3.
The above discussion can be applied also to the other pair of
diastereomeric cyclic phosphates 5a and 5a0 with the methyl
group at C05 in equatorial position. The w-long range
Fortunately, a crystallographic study of 5b0 showed that our
prediction for the dynamic behaviour in solution was
correct. Nevertheless, this compound crystallised with two
independent molecules per asymmetric unit, of which one
has a chair conformation (Fig. 2) and the other one a boat
conformation (Fig. 3).
4
coupling constants JMeP with values of 2.9 and 2.5 Hz for
5a and 5a0, respectively, and the small vicinal coupling
constants, JHP ,1 and JHP ,0.5 for 5a and 5a0,
respectively, do confirm the absolute stereochemistry at
C05(S).5 As for 4a0, in the case of 5a0 having the phenoxy
group in equatorial or pseudoaxial orientation (RP), a
shielding effect is observed for H1 (6.08 ppm for 5a and
5.58 ppm for 5a0).
3
3
It should be mentioned that this is the first case, in which the
chair and boat conformations of a 2-phenoxy-2-oxo-1,3,2-
dioxaphosphorinane involved in a dynamic equilibrium in
solution, have been trapped simultaneously the solid-state.
1
At this stage, we realized that a simple H NMR spectrum
analysis might be sufficient to determine which confor-
mational equilibrium is present in solution for these model
compounds. In order to confirm our assumption, we
synthesized and analysed compounds 4b, 4b0, 5b and 5b0
1
(R¼Ph). The H NMR data of the diastereomeric pair of
cyclic phosphates 4b and 4b0, which were derived from the
minor diol 2b, did not show any shielding effect for H1, but
Figure 3. Perspective view of the molecular structure of 5b0 in the boat
conformation.
Scheme 3. Chair–boat equilibrium of 4a0 in solution.

4080
F. Sartillo-Piscil et al. / Tetrahedron 59 (2003) 4077–4083
Two further related structures with two independent
molecules in the asymmetric unit have been reported: in
the first case two 1,3,2-dioxaphosphorinane molecules are
present in the asymmetric unit, however, both have a boat
conformation.12a In the second case reported for a 2-thio-
1,3,2-dioxaphosphorinane, one had a half-chair confor-
mation and the other one a twisted-boat conformation.12b
which were derived from diols 2c and 3c. The 0shielding
effects observed for the H1 hydrogen atoms of 4c (RP) and
5c0 (RP) and the values of the vicinal coupling constants
0
3
3
(5.79 ppm, JHP ,1 Hz for 4c and 5.62 ppm, JHP ,1 Hz
for 5c0) are in agreement with a chair–boat conformation. In
the case of 4c (SP) and 5c (SP), their spectroscopic data are
consistent with a chair–twist equilibrium, with a high
population of the chair conformation for 4c (3JHP¼18.3 Hz),
see Tables 2 and 3.
Thus, both molecules trapped into the asymmetric unit
exhibited a ready equilibrium between the chair and the boat
forms in solution. This very short gap in energy between
both conformations has been shown depends on the
temperature, and the mole fraction of the nonchair
conformer is increased upon lowering the temperature4,11b
Therefore, we selected compound 5b0 for a variable
temperature NMR experiment in the range of 213–303 K
(in CD2Cl2). During this experiment a gradual change of the
upfield shift of H1 from 5.60 ppm at 303 K to 5.31 ppm at
203 K was observed, indicating that the population of the
boat conformer is increased (H1 and the phenoxy group
spend more time closely). These results are in agreement
with the VT NMR experiments of Hermans et al., even
though these authors used different parameters for their
conformational analysis (vicinal and geminal coupling
3. Conclusion
In conclusion, the conformational analysis of cyclic
phosphates, which have substituents that may induce a
conformational restriction, revealed the existence of very
specific conformational equilibria. It could be shown that
for the 2-phenoxy-2-oxo-1,3,2-dioxaphosphorinanes
studied herein, the spectroscopic evidence for the dynamic
equilibria in solution can be obtained not only from the
3
well-studied vicinal coupling constant JHP and the 31P
NMR chemical shifts, but also from the simple chemical
shift of the axially oriented hydrogen atom in the furanose
ring.
3
2
constants, JHP and JHH, respectively).11b
The reason for the equimolar presence of the chair and boat
conformers in the solid-state of 5b0 may be attributed to
intermolecular interactions in the crystal lattice. Indeed,
there is an intermolecular hydrogen bonding interaction
between the phosphoryl oxygen atom of the molecule in the
boat conformation and the H5 hydrogen atom of the
molecule in the chair conformation (Fig. 4). The distance
4. Experimental
4.1. General
Instrumental. NMR studies were carried out on a JEOL
Eclipseþ400 instrument. Standards were TMS (1H, 13C)
and H3PO4 (31P). Chemical shifts are stated in parts per
million. COSY, HETCOR and NOESY experiments have
been carried out in order to assign the H and 13C spectra
completely. High resolution mass spectra (FABþ ion mode)
were obtained on a Jeol JMS-SX102A equipment (10 kV).
5
˚
of the P¼O–H interaction is 2.32 A, which is significantly
shorter than the sum of the van-der-Waals radii between
˚
oxygen and hydrogen (2.70 A).
1
It has been suggested, that for a strong enzyme-nucleoside
interaction with cyclic nucleoside 30,50-monophosphates to
occur, a pseudoaxial orientation of the phosphoryl oxygen
atom of the nucleoside is required, which is only possible in
a twist conformation.2 However, according to the results
presented herein, we consider that the boat conformation
should be considered as a further appropriate conformation
for such an intermolecular interaction.
X-Ray crystallography. X-ray diffraction studies of single
crystals were performed for 4a and 5b0 on a Bruker Apex
˚
diffractometer (lMo Ka¼0.71069 A, monochromator:
graphite, T¼293 K). Absorption corrections were applied.
(SADABS); corrections were also made for Lorentz and
polarization effects. Solution and refinement: direct
methods (SHELXS-86)13 for structure solution and the
SHELXTL14 and CRYSTALS15 software package for
refinement and data output. Non-hydrogen atoms were
refined anisotropically, and hydrogen atoms were calculated
in all cases, using a riding model during the Least-squares
refinement. The most important crystallographic data have
been summarised in Table 4. In the case of compound 5b0
there are two independent molecules in the asymmetric unit.
In an effort to generalize this conformational study, we
examined four additional diastereomeric cyclic phosphates,
Crystallographic data for the structures reported in this
paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication
numbers CCDC-200060-200061. Copies of the data can
be obtained free of charge on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK (fax: (þ44)
1223-336-033, e-mail: deposit@ccdc.cam.ac.uk, www:
http://www.ccdc.cam.ac.uk).
Figure 4. Intermolecular CH· · ·O interaction between the chair and boat
conformers of 5b0 in the solid-state.

F. Sartillo-Piscil et al. / Tetrahedron 59 (2003) 4077–4083
Table 4. Crystallographic data for compounds 4a and 5b0
4081
Crystal data
4a
5b0
Formula
Crystal size (mm3)
C15H19O7P
0.11£0.17£0.33
C20H21O7P
0.10£0.24£0.27
MW (g mol21
Space group
)
342.27
P21
404.34
P212121
Cell parameters
˚
a (A)
˚
5.7607(6)
10.1353(11)
14.5184(16)
100.919(2)
832.33(16)
2
11.0021(6)
14.8941(9)
23.9451(14)
90
3923.8(4)
8
0.180
b(A)
˚
c (A)
b (8)
3
˚
V (A )
Z
m (mm21
)
0.197
1.366
rcalcd (g cm23
)
1.369
Data collection
u limits (8)
hkl limits
2,u,25
26, 6;, 12; 212, 217, 17
2,u,25
213, 13; 217, 17; 228, 28
No. collected reflection
No. ind. refl. (Rint
8035
2910 (0.036)
2727
38,246
6905 (0.057)
4809
)
No. observed reflectiona
Refinement
Rb
Rw
0.058
0.122
212
1.285
20.05
20.24
0.26
0.037
0.087
510
0.961
20.08
20.16
0.14
c
No. of variables
GOOF
Flade parameter
Drmin (e A
˚
Drmax (e A
23
˚
)
)
23
a
Fo . 4sðFoÞ:
Rw ¼ ½ wðFo2 2 Fc2Þ = wðFo2Þ ꢀ
P
P
b
c
R ¼ ðF2 2 Fc2Þ= F2:
Po
o P
2
2 1=2
:
4.2. General protocol for the synthesis of diols 2a–c and
3a–c
4.2.3. (5R)-1,2-O-Isopropylidene-5-phenyl-a-D-xylofura-
nose 2b.6 1H NMR d: 1.24 (s, 3H), 1.45 (s, 3H), 2.87 (d, 1H,
J¼5.5 Hz), 3.20 (d, 1H, J¼4.7 Hz), 4.00 (m, 1H), 4.32 (m,
1H), 4.50 (d, 1H, J¼3.6 Hz), 5.0 (t, 1H, J¼4.7 Hz), 6.01 (d,
1H, J¼6.6 Hz) ppm; 13C NMR d: 26.1, 26.7, 73.6, 75.4,
82.1, 85.1, 105.0, 111.8, 126.0, 128.3, 128.8, 139.2 ppm.
For the synthesis of 2a–c and 3a–c a sequential
hydrolysis–oxidation–Grignard-reagent-addition reaction
protocol has been carried out. A solution of 1 (0.8 mmol)
and periodic acid (0.9 mmol) in 50 mL of dry ethyl acetate
was stirred for 3 h, whereby a solid formed that was
separated by filtration. Evaporation under reduced
pressure afforded a colorless syrup, which was dissolved
in 10 mL of dry diethyl ether and cooled to 08C. Then,
immediately the corresponding alkyl magnesium bromide
(21 mmol) was added and the mixture was allowed to react
for 4 h. After addition of a saturated solution of NH4Cl, the
product was extracted with ethyl acetate and the solution
dried over Na2SO4. The residue obtained after evaporation
under reduced pressure was purified by column
chromatography.
4.2.4. (5S)-1,2-O-Isopropylidene-5-phenyl-a-D-xylofura-
nose 3b.6 1H NMR d: 1.24 (s, 3H), 1.48 (s, 3H), 3.05 (b,
1H), 4.14 (b, 1H), 4.20 (m, 1H), 4.50 (d, 1H, J¼3.7 Hz),
5.28 (d, 1H, J¼3.0 Hz), 6.01 (d, 1H, J¼3.7 Hz) ppm; 13C
NMR d: 26.1, 26.8, 73.7, 75.4, 82.1, 85.2, 105.1, 111.8,
126.0, 128.3, 128.8, 138.9 ppm.
4.2.5. (5R)-1,2-O-Isopropylidene-5-vinyl-a-D-xylofura-
nose 2c.7 1H NMR d: 1.31 (s, 3H), 1.48 (s, 3H), 4.09 (t,
1H, J¼3.3 Hz), 4.27 (d, 1H, J¼2.6 Hz), 4.52 (m, 1H), 5.43
(d, 1H, J¼10.6 Hz), 5.52 (d, 1H, J¼17.2 Hz), 5.99 (m, 2H)
ppm.
4.2.1. (5R)-1,2-O-Isopropylidene-5-methyl-a-D-xylofura-
nose 2a.5 1H NMR d: 1.31 (s, 3H), 1.38 (d, 3H, J¼6.6 Hz),
1.47 (s, 3H), 2.75 (b, 1H), 3.94 (t, 1H, J¼3.6 Hz), 4.25 (b,
1H), 4.33 (m, 2H), 4.51 (d, 1H, J¼3.7 Hz), 5.97 (d, 1H,
J¼3.7 Hz) ppm; 13C NMR d: 19.3, 26.1, 26.7, 66.5, 75.1,
82.4, 85.2, 104.8, 111.6 ppm.
4.2.6. (5S)-1,2-O-Isopropylidene-5-vinyl-a-D-xylofura-
nose 3c.7 1H NMR d: 1.31 (s, 3H), 1.48 (s, 3H), 4.04 (dd,
1H, J¼4.0, 2.5 Hz), 4.32 (d, 1H, J¼2.5), 4.51 (d, 1H,
J¼3.6 Hz), 4.68 (t, 1H, J¼5.2 Hz), 5.31 (dd, 1H, J¼10.6,
1.1 Hz), 5.48 (dd, 1H, J¼17.2, 1.1 Hz), 5.98 (m, 2H) ppm.
4.2.2. (5S)-1,2-O-Isopropylidene-5-methyl-a-D-xylofura-
nose 3a.5 1H NMR d: 1.29 (s, 3H), 1.33 (d, 3H, J¼6.6 Hz),
1.46 (s, 3H), 2.11 (b, 1H), 2.91 (b, 1H), 3.93 (t, 1H,
J¼3.3 Hz), 4.21 (m, 2H), 4.50 (d, 1H J¼3.7 Hz), 5.94 (d,
1H, J¼3.7) ppm; 13C NMR d: 20.7, 26.2, 26.8, 61.1, 76.5,
82.1, 85.6, 104.7, 111.8 ppm.
4.3. General protocol for the synthesis of the cyclic
phosphates 4a–c, 4a0 –c0, 5a–c, 5a0 –c0
The synthetic protocol used for the preparation of 4a–c,
4a0 –c0, 5a–c, 5a0 –c0 is outlined in what follows for
compounds 4b and 4b0. To a solution of diol 2b (580 mg,

4082
F. Sartillo-Piscil et al. / Tetrahedron 59 (2003) 4077–4083
2.17 mmol) and NEt3 (1.52 mL, 10.89 mmol) in dry CH2Cl2
(20 mL) a solution of PhOP(O)Cl2 in 2 mL of dry CH2Cl2
was added dropwise (0.390 mL, 2.6 mmol). The reaction
mixture was allowed to stir for 4 h before it was quenched
with H2O. The separated organic phase was dried over
Na2SO4. After evaporation of the solvent under reduced
pressure, the products were separated by column chroma-
tography (3:1 mixture of hexane/ethyl acetate) affording 4b
and 4b0 in global yields of 50 and 45%, respectively.
1H, J¼5.5, 3.3 Hz), 4.82 (d, 1H, J¼3.6 Hz), 4.92 (apparent
t, 1H, J¼3.4 Hz), 5.68 (dd, 1H, J¼11.2, 5.5 Hz), 6.14
(d, 1H, J¼3.6 Hz), 7.0–7.5 (m, 10H) ppm; 13C NMR d:
26.3, 26.8, 79.1, 80.0, 81.9, 84.1, 105.3, 112.9, 119.8, 126.2,
129.0, 129.8, 136.1 ppm; 31P NMR d: 213.0 ppm;
FABS m/z 405.1103 [MþH]þ (calcd for C20H21O7P
405.1103).
4.3.7. (5S, SP)-1,2-O-Isopropylidene-5-phenyl-3,5-O-
phenoxyphosphoryl-a-D-xylofuranose 5b. Mp¼191–
1
4.3.1. (5R, SP)-1,2-O-Isopropylidene-5-methyl-3,5-O-
phenoxyphosphoryl-a-D-xylofuranose 4a. Mp¼126–
1938C; H NMR d: 1.30 (s, 3H), 1.43 (s, 3H), 4.40 (m,
1H,), 4.72 (d, 1H, J¼3.6 Hz), 5.0 (apparent d, J¼1.8 Hz),
5.75 (broad s), 6.02 (d, 1H, J¼3.6 Hz), 7.1–7.5 (m, 10H)
ppm; 13C NMR d: 26.2, 26.6, 74.8, 79.6, 82.8, 83.3, 104.8,
112.7, 119.4, 125.5, 126.6, 128.6, 129.0, 134.6 ppm; 31P
NMR d: 215.2 ppm; FABS m/z 405.1105 [MþH]þ (calcd
for C20H21O7P 405.1103).
1
1278C; H NMR d: 1.32 (s, 3H), 1.49 (s, 3H), 1.56 (d, 1H,
J¼7.3 Hz), 4.11 (dd, 1H, J¼2.2, 4.4 Hz), 4.72 (d,
J¼3.6 Hz), 4.91 (m, 1H), 4.92 (ddd, 1H, J¼16.0, 7.3,
2.2 Hz), 6.04 (d, 1H, J¼3.6 Hz), 7.1–7.4 (m, 5H) ppm; 13C
NMR d: 19.4, 26.1, 26.6, 73.6, 80.8, 93.9, 104.7, 112.7,
119.6, 125.4, 130.0 ppm; 31P NMR d: 216.2 ppm; FABS
m/z 343.0936 [MþH]þ (calcd for C15H19O7P 343.0947).
4.3.8. (5S, RP)-1,2-O-Isopropylidene-5-phenyl-3,5-O-
phenoxyphosphoryl-a-D-xylofuranose 5b0. Mp¼138–
1408C; 1H NMR d: 1.24 (s, 3H), 1.30 (s, 3H), 4.42
(dd, 1H, J¼3.0, 2.2 Hz), 4.60 (d, 1H, J¼3.6 Hz), 5.11
(dd, 1H, J¼4.5, 3.0 Hz), 5.61 (d, 1H, J¼3.6 Hz), 5.84
(broad s, 1H), 7.1–7.4 (m, 10H) ppm; 13C NMR d: 26.2,
26.8, 75.6, 78.3, 82.8, 83.81, 104.8, 112.8, 120.3, 125.8,
126.6, 128.6, 129.0, 129.8, 134.5 ppm; 31P NMR d:
212.9 ppm; FABS m/z 405.1089[MþH]þ (calcd for
C20H21O7P 405.1103).
4.3.2. (5R, RP)-1,2-O-Isopropylidene-5-methyl-3,5-O-
phenoxyphosphoryl-a-D-xylofuranose 4a0. 1H NMR d:
1.28 (s, 3H), 1.46 (s, 3H), 1.62 (d, 3H, J¼7.0 Hz), 4.18 (q,
1H, J¼2.6 Hz), 4.64 (d, 1H, J¼3.6 Hz), 4.74 (ddd, 1H,
J¼15.0, 7.0, 2.5 Hz), 4.99 (dd, 1H, J¼5.8, 2.9 Hz), 5.69 (d,
H, J¼3.6 Hz), 7.1–7.3 (m, 5H) ppm; 13C NMR d: 19.7,
26.2, 28.8, 77.3, 77.9, 81.2, 84.0, 104.9, 112.7, 120.2, 125.5,
129.7 ppm; 31P NMR d: 215.0 ppm; FABS m/z 343.0936
[MþH]þ (calcd for C15H19O7P 343.0947).
4.3.9. (5R, SP)-1,2-O-Isopropylidene-5-vinyl-3,5-O-phen-
1
oxyphosphoryl-a-D-xylofuranose 4c. H NMR d: 1.34 (s,
4.3.3. (5S, SP)-1,2-O-Isopropylidene-5-methyl-3,5-O-
phenoxyphosphoryl-a-D-xylofuranose 5a. 1H NMR d:
1.31 (s, 3H), 1.48 (s, 3H), 1.55 (dd, 3H, J¼6.4, 2.9 Hz), 4.10
(m, 1H), 4.69 (d, 1H, J¼3.6 Hz), 4.82 (apparent d, 1H,
J¼1.8 Hz), 4.86 (broad dd, 1H, J¼6.6, 1.5 Hz), 6.01 (d, 1H,
J¼3.6 Hz), 7.1–7.4 (m, 5H) ppm; 13C NMR d: 18.4, 26.1,
26.6, 74.4, 75.6, 82.5, 83.6, 104.6, 112.6, 119.3, 125.3,
130.1, 150.2 ppm; 31P NMR d: 215.5 ppm; FABS m/z
343.0939 [MþH]þ (calcd for C15H19O7P 343.0947).
3H), 1.5 (s, 3H), 4.25 (broad d, 1H, J¼2.2 Hz), 4.74 (d, 1H,
J¼3.6 Hz), 4.92 (apparent t, 1H, J¼2.5 Hz), 5.25 (dd, 1H,
J¼18.3, 7.3 Hz), 5.42 (broad d, 1H, J¼10.6 Hz), 5.53 (d,
1H, J¼17.2 Hz), 6.08 (ddd, J¼17.2, 10.6, 7.3 Hz), 6.09 (d,
1H, J¼3.6 Hz), 7.1–7.4 (m, 5H) ppm; 13C NMR d: 26.2,
26.6, 75.7, 80.9, 81.4, 83.8, 104.6, 112.8, 119.7, 121.4,
125.5, 129.9, 131.7 ppm; 31P NMR d: 216.4 ppm; FABS
m/z 355.0932 [MþH]þ (calcd for C16H19O7P 355.0947).
4.3.4. (5S, RP)-1,2-O-Isopropylidene-5-methyl-3,5-O-
phenoxyphosphoryl-a-D-xylofuranose 5a0. 1H NMR d:
0.93 (s, 3H), 1.45 (s, 3H), 1.14 (dd, 3H, J¼6.6, 2.5 Hz), 3.56
(dd, 1H, J¼4.2, 2.2 Hz), 4.16 (d, 1H, J¼3.6 Hz), 4.45 (q,
1H, J¼6.6 Hz), 4.65 (dd, 1H, J¼4.1, 2.9 Hz), 5.57 (d, 1H,
J¼3.6 Hz) ppm; 13C NMR d: 18.6, 26.2, 26.7, 74.3, 75.2,
82.3, 84.1, 104.6, 112.7, 120.2, 125.6, 129.7 ppm; 31P NMR
d: 212.6 ppm; FABS m/z 343.0938 [MþH]þ (calcd for
C15H19O7P 343.0947).
4.3.10. (5R, RP)-1,2-O-Isopropylidene-5-vinyl-3,5-O-
phenoxyphosphoryl-a-D-xylofuranose 4c0. 1H NMR d:
1.32 (s, 3H), 1.48 (s, 3H), 4.33 (dd, 1H, J¼5.3, 2.6 Hz), 4.70
(d, 1H, J¼3.6 Hz), 4.98 (dd, 1H, J¼7.7, 2.9 Hz), 5.17 (d,
1H, J¼15.2 Hz), 5.47 (dd, 1H, J¼10.6, 1.4 Hz), 5.67 (dd,
1H, J¼17.0, 1.8 Hz), 5.80 (d, 1H, J¼3.6 Hz), 6.04 (ddd, 1H,
J¼17.0, 10.6, 6.2, 5.5 Hz), 7.1–7.4 (m, 5H) ppm; 13C NMR
d: 26.2, 26.8, 75.8, 80.8, 81.6, 84.1, 105.1, 112.8, 120.2,
120.3, 125.5, 129.8, 131.5 ppm; 31P NMR d: 215.7 ppm;
FABS m/z 355.0939 [MþH]þ (calcd for C16H19O7P
355.0947).
4.3.5. (5R, SP)-1,2-O-Isopropylidene-5-phenyl-3,5-O-
phenoxyphosphoryl-a-D-xylofuranose 4b. Mp¼108–
1
1098C; H NMR d: 1.31 (s, 3H), 1.44 (s, 3H), 4.52 (dd,
4.3.11. (5S, SP)-1,2-O-Isopropylidene-5-vinyl-3,5-O-
phenoxyphosphoryl-a-D-xylofuranose 5c. 1H NMR d:
1.30 (s, 3H), 1.51 (s, 3H), 4.23 (dd, 1H, J¼4.4, 2.2 Hz), 4.69
(d, 1H, J¼3.6 Hz), 4.89 (apparent d, 1H, J¼1.8 Hz), 5.17
(broad d, 1H, J¼6.2 Hz), 5.40 (d, 1H, J¼10.6 Hz), 5.50 (d,
1H, J¼17.2 Hz), 6.02 (d, 1H, J¼3.6 Hz), 6.04 (dddd, 1H,
J¼17.2, 10.6, 6.2, 1.8 Hz), 7.2–7.4 (m, 5H) ppm; 13C NMR
d: 26.2, 26.6, 74.1, 79.2, 82.5, 83.6, 104.8, 112.8, 119.3,
119.5, 125.5, 130.15, 131.7 ppm; 31P NMR d: 215.6 ppm;
FABS m/z 355.0958 [MþH]þ (calcd for C16H19O7P
355.0947).
1H, J¼3.6, 2.9 Hz), 4.78 (d, 1H, J¼3.6 Hz), 4.95 (dd, 1H,
J¼7.3, 2.9 Hz), 5.63 (dd, 1H, J¼10.2, 3.6 Hz), 6.01 (d, 1H,
J¼3.6 Hz), 7.2–7.6 (m, 10H) ppm; 13C NMR d: 26.3, 26.8,
79.9, 81.9, 82.1, 84.0, 105.2, 112.9, 120.0, 125.6, 129.1,
129.8, 136.3 ppm; 31P NMR d: 213.8 ppm; FABS m/z
405.1104 [MþH]þ (calcd for C20H21O7P 405.1103).
4.3.6. (5R, RP)-1,2-O-Isopropylidene-5-phenyl-3,5-O-
phenoxyphosphoryl-a-D-xylofuranose 4b0. Mp¼110–
1
1128C; H NMR d: 1.33 (s, 3H), 1.46 (s, 3H), 4.63 (dd,

F. Sartillo-Piscil et al. / Tetrahedron 59 (2003) 4077–4083
4083
5. Valverde, S.; Hernandez, A.; Herradon, B.; Rabanal, R. M.;
Martin-Lomas, M. Tetrahedron 1987, 43, 3499.
4.3.12. (5S, RP)-1,2-O-Isopropylidene-5-vinyl-3,5-O-
phenoxyphosphoryl-a-D-xylofuranose 5c0. 1H NMR d:
1.28 (s, 3H), 1.45 (s, 3H), 4.24 (dd, 1H, J¼4.4, 2.2 Hz), 4.57
(d, 1H, J¼3.6 Hz), 5.0 (dd, 1H, J¼4.4, 2.5 Hz), 5.28 (broad
d, 1H, J¼6.2 Hz), 5.40 (d, 1H, J¼10.6 Hz), 5.48 (d, 1H,
J¼16.1 Hz), 5.60 (d, 1H, J¼3.6 Hz), 6.00 (dddd, 1H,
J¼16.1, 10.6, 6.2, 1.8 Hz), 7.1–7.4 (m, 5H) ppm; 13C NMR
d: 26.2, 26.8, 74.9, 77.8, 82.3, 83.8, 104.8, 112.8, 119.7,
120.2, 125.7, 129.7, 131.7 ppm; 31P NMR d: 213.2 ppm;
FABS m/z 355.0951 [MþH]þ (calcd for C16H19O7P
355.0947).
6. Mereyala, H. B.; Joe, M.; Gadikota, R. R. Tetrahedron:
Asymmetry 2000, 11, 4071.
7. Horton, D.; Tsai, H. Carbohydr. Res. 1977, 58, 89.
8. (a) Majoral, J. P.; Navech, J. Bull. Soc. Chim. Fr. 1971, 96.
(b) Crich, D.; Sartillo-Piscil, F.; Quintero, L.; Wink, D. J.
J. Org. Chem. 2002, 67, 3360.
9. Juaristi, E.; Cuevas, G. Tetrahedron 1992, 48, 5019.
10. (a) Gorenstein, D. G.; Rowell, R. J. Am. Chem. Soc. 1979, 101,
4925. (b) Gorenstein, D. G.; Rowell, R.; Findlay, J. J. Am.
Chem. Soc. 1980, 102, 5077.
11. (a) Morr, M.; Ernst, L.; Mengel, R. Liebigs Ann. Chem. 1982,
651. (b) Hermans, R. J. M.; Buck, H. M. J. Org. Chem. 1988,
53, 2077.
Acknowledgements
We thank CONACyT for financial support, Project No.
35102 and Grants 121996, 127042 to F. S.-P. and M. S.,
respectively. We thank Professor Dr Jean L. Fourrey for
helpful comments.
12. Both 1,3,2-dioxaphosphorinane molecules present in the
asymmetric unit have a boat conformation (a) Day, R. O.;
Bentrude, W. G.; Yee, K. C.; Setzer, W. N.; Deiters, J. A.;
Holmes, R. R. J. Am. Chem. Soc. 1984, 106, 103. (b) one of the
2-thio-1,3,2-dioxaphosphorinane has a half-chair confor-
mation and the other one a twist-boat conformation Dom-
inguez, Z. J.; Cortez, M. T.; Gordillo, B. Tetrahedron 2001,
57, 9799.
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