Intramolecular hydrogen bonding (P=O-H) stabilizes the chair conformation of six-membered ring phosphates

Article abstract of DOI:10.1021/jo050753+

Six-membered cyclic phosphates (2-phenoxy-2-oxo-1,3,2-dioxaphosphorinanes) bearing an internal protected or unprotected hydroxyl group were designed, synthesized, and studied by NMR and computational methods. Selective opening of O-isopropylidene-protecte

Full text of DOI:10.1021/jo050753+

Intramolecular Hydrogen Bonding (PdO--H) Stabilizes the Chair
Conformation of Six-Membered Ring Phosphates
Silvano Cruz-Gregorio,† Mario Sanchez,‡ Angel Clara-Sosa,† Sylvain Be`rnes,†
Leticia Quintero,*,† and Fernando Sartillo-Piscil*,†
Centro de Investigacio´n de la Facultad de Ciencias Qu´ımicas y Cento de Qu´ımica, Beneme´rita
Universidad Auto´noma de Puebla, 14 Sur Esq. San Claudio, Col. San Manuel, 72570 Puebla, Mexico,
and Departamento de Polimeros y Materiales, Universidad de Sonora, Rosales y Transversal s/n,
Edif. 3G, Col. Centro, 83000 Hermosillo Sonora, Mexico
fsarpis@siu.buap.mx
Received April 14, 2005
Six-membered cyclic phosphates (2-phenoxy-2-oxo-1,3,2-dioxaphosphorinanes) bearing an internal
protected or unprotected hydroxyl group were designed, synthesized, and studied by NMR and
computational methods. Selective opening of O-isopropylidene-protected 1,2-diols at the primary
site was achieved with either triethylsilane or trimethylallylsilane in the presence of BF3‚OEt2.
Applied to 5,6-O-isopropylidenepentofuranosides, this reaction gave rise to the formation of the
corresponding 1,3-diol precursors for the six-membered ring phosphates containing an O-isopropyl
or O-1,1-dimethyl-3-butenyl functional group at C-6. The O-1,1-dimethyl-3-butenyl protecting group
was efficiently removed after the phosphorylation with BF3‚OEt2, and the six-membered cyclic
phosphates containing free hydroxyl groups were obtained. A cyclic phosphate with a free hydroxyl
3
group oriented cis to the phosphoryl group shows a vicinal coupling constant JHP that is in
accordance with the chair conformation. This is due to the formation of a seven-membered
intramolecular hydrogen-bonded ring structure that stabilizes the chair conformation. Thus, the
strong tendency of the phenoxy group to be in an axial position is diminished by the internal
hydrogen bonding interaction. Computational studies provided strong support for the experimental
observation.
Introduction
phates) are of interest principally due to the importance
of the cyclic adenosine 3′,5′-monophosphate (cAMP) in
enzymatic processes.1 It has been demonstrated that the
biological activity of analogous six-membered cyclic phos-
phates depends on the configuration at the phosphorus
center.2 Studies in both solution and the solid state have
shown that the six-membered cyclic phosphates can exist
Conformational and configurational studies of 1,3,2-
dioxaphosphorinanes (or neutral six-membered ring phos-
* To whom correspondence should be addressed. Tel: +52 2222
2955500 ext 7387. Fax: +52 2222 454293.
† University of Puebla.
‡ University of Sonora.
10.1021/jo050753+ CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/05/2005
J. Org. Chem. 2005, 70, 7107-7113
7107

Cruz-Gregorio et al.
FIGURE 1. Conformational forms for neutral six-membered cyclic phosphates cis- and trans-fused to ribo- and xylofuranose
rings.
in a spontaneous chair/twist equilibrium;3 however, it has
been suggested that there is a preferential population of
the twist conformation in cellular media.4 Apparently,
the energy necessary to convert the chair form into the
twist form can be gained from the interactions between
enzymatic hydroxyl groups and the oxygen atoms of the
cyclic phosphate.4 This suggestion is based on conforma-
tional studies of neutral six-membered cyclic phosphates
trans-fused to a ribose ring. Due to the strain imposed
by the trans-fusion, only one twist and one chair form
have been observed for these bicyclic compounds (Figure
1), although in phosphates trans-fused to cyclohexane
derivatives,5 a further boat-twist conformation should be
considered.
On the other hand, six-membered cyclic phosphates cis-
fused to a xylofuranose offer more conformational forms
than the corresponding trans-fused phosphates.3b,6 At
least two chair forms6 (C1 and C2), one twist form T,7
and two boat conformations are possible (B16 and B27)
(Figure 1). The two chair forms C1 and C2, the twist form
T, and the boat form B1 were proposed on the basis of
conformational studies of 3′,5′-xylo-cyclic adenosine mono-
phosphates in solution and in the solid state,6a of six-
membered cyclic phosphates cis-fused to cyclopentanes,6a
and of 1,2-O-isopropylidene-xylo-furanose derivatives.6c,7
We recently found for 5-substituted 1,2-O-isopropylidene-
3,5-O-phenoxyphosphoryl-R-D-xylofuranose derivatives7
that the boat conformation B2 and the chair conformation
C2 exist in approximately equal amounts in solution and
the solid state rather than in the C1 T B1 equilibrium
previously proposed.6a The existence of this conforma-
tional equilibrium was unambiguosuly demonstrated by
NMR and X-ray crystallography. Notably, in the boat
conformation the phenoxy group is placed in close prox-
imity to H-1, causing a shielding effect.7
On this basis, a novel method for the determination of
the absolute configuration at the phosphorus in this,7 and
other types,8 of six-membered bicyclic phosphates was
proposed. Additionally, VT-NMR studies of a compound,
which crystallized in two conformations (chair and boat)
within the same asymmetric unit, showed a marked
temperature dependence of the chemical shift for H-1.
On lowering the temperature, an upfield shift of H-1 was
observed. The gradual displacement of H-1 from 5.60 ppm
at 303 K to 5.31 ppm at 203 K indicates that the
population of the boat conformation is increased because
H-1 spends more time in proximity to the phenoxy group.
In other words, the mole fraction of the boat conformer
is increased at lower temperatures. Hermans and Buck
previously arrived at a similar conclusion based on the
(1) (a) Taylor, S. S.; Buechler, J. A.; Yonemoto, W. Annu. Rev.
Biochem. 1990, 59, 971-1005. (b) Revenkar, G. R.; Robin, R. K. In
Handbook of Experimental Pharmacology; Nelson, J. A., Kebabain, J.
W., Eds.; Springer-Verlag: Berlin and Heidelberg, West Germany,
1982; Vol. 58/I, Chapter 2 and references therein.
H-P vicinal coupling constants (3JHP 6a for the 3′,5′-xylo-
)
cAMP. This increased population of the boat conforma-
tion at lower temperatures is at odds with controversial
arguments regarding the well-established nO T σ*P-OR
interactions, which indicate that in the ground state the
phenoxy group should be axial.5,9
(2) (a) van Haastert, P. J. M.; van Driel, R.; Jastorff, B.; Baraniak,
J.; Stec, W. J.; de Wit, R. J. W. J. Biol. Chem. 1984, 259, 10020-10024.
(b) de Wit, R. J. W.; Hekstra, D.; Jastorff, B.; Stec, W. J.; Baraniak, J.;
van Driel, R.; van Haastert, P. J. M. Eur. J. Biochem. 1984, 142, 255-
260. (c) Erneux, C.; van Sande, J.; Jastorff B.; Dumont, J. E. Biochem.
J. 1986, 234, 193-197. (d) van Ool, P. J. J. M.; Buck, H. M. Eur. J.
Biochem. 1981, 121, 329-334.
With the above in mind, we designed and synthesized
a series of six-membered cyclic phosphates containing a
strategically internal hydroxyl group with the expectation
of stabilizing of the chair conformation by a seven-
membered intramolecular hydrogen bond (Figure 2).
This study requires the phenoxy group to be located
cis to H-1 in the boat conformation. Conversely, if the
chair conformation is stabilized, then the phenoxy group
should spend more time in an equatorial position (equi-
librium A) and H-1 should be less affected by the phenoxy
group than anticipated at higher populations of the boat
conformer (equilibrium B). This can be monitored by the
chemical shift of H-1, which should be in accordance with
(3) (a) Bentrude, W. G.; Setzer, W. N. Stereospecificity in 31P-
Element Coupling: Proton-Phosphorus Coupling. In Phosphorus-31
NMR Spectroscopy in Stereochemical Analysis; Verkade, J. G., Quin,
L. D., Eds.; VCH: Weinheim, 1987. (b) Bentrude, W. G. Steric and
Stereoelectronic Effects in 1,3,2-Dioxaphosphorinanes. In Methods in
Stereochemical Analysis; Juaristi, E., Ed.; VCH: New York, 1995.
(4) Nelson, K. A.; Bentrude, W. G.; Setzer, W. N.; Hutchinson, J. P.
J. Am. Chem. Soc. 1987, 109, 4058-4064.
(5) Gorenstein, D. G.; Rowell, R.; Findlay, J. J. Am. Chem. Soc. 1980,
102, 5077-5081.
(6) (a) Hermans, R. J. M.; Buck, H. M. J. Org. Chem. 1988, 53,
2077-2084. (b) MacCoss, M.; Ezra, F. S.; Robins, M. J.; Danyluk, S.
S. Carbohydr. Res. 1978, 62, 203-212. (c) Neeser, J.-T.; Tronchet, J.
M. J.; Charollais, E. J. Can. J. Chem. 1983, 61, 1387-1396. (d)
Nifant’ev, E. E.; Elepina, L. T.; Borisenko, A. A.; Koroteev, M. P.;
Aslanov, L. A.; Ionov, V. M.; Sotman, S. S. Zh. Obshch. Khim. 1978,
48, 2453-2465. (e) Morr, M.; Ernst, L.; Mengel, R. Liebigs Ann. Chem.
1982, 651-665.
(8) Sartillo-Piscil, F.; Cruz-Gregorio, S.; Sa´nchez, M.; Quintero, L.
Tetrahedron 2004, 60, 3001-3008.
(9) Gorenstein, D. G. Chem Rev. 1987, 87, 1047-1077.
(7) Sartillo-Piscil, F.; Cruz-Gregorio, S.; Sa´nchez, M.; Ho¨pfl, H.;
Anaya de Parrodi, C.; Quintero, L. Tetrahedron 2003, 59, 4077-4083.
7108 J. Org. Chem., Vol. 70, No. 18, 2005

Intramolecular Hydrogen Bonding of PdO--H
SCHEME 1. Synthesis of 1,3-Diol Precursors 2 and
3 by Selective Opening of the 5,6-O-Isopropylidene
Group of 1
followed by selective protection of the primary hydroxyl
group, we explored a one-step nucleophilic opening of the
terminal O-isopropylidene group of 1 by silanes and BF3‚
OEt2.14 Thus, treatment of 1 with trimethylallylsilane or
triethylsilane in the presence of BF3‚OEt2 produced the
1,3-diol precursors 2 and 3 in yields of 70-72%, respec-
tively (Scheme 1).
FIGURE 2. Hypothetic chair and boat conformations.
the vicinal H-P coupling constant (3JHP). On the other
hand, if stabilization of the chair conformation is achieved
by intramolecular hydrogen bonding, the nonchair con-
formation will be diminished by the same interaction that
has been suggested to destabilize the chair and favor the
nonchair conformation in cyclic adenosine 3′,5′-mono-
phosphate derivatives.4
These reactions were highly regioselective, and the
isomeric 1,4-diols (not shown) were not observed. How-
ever, a BF3‚OEt2-catalyzed rearrangement of the isopro-
pylidene group from O-5:6 to O-3:5 did take place in low
yield (4, 10-12%).15 Other Lewis acids were tested in
order to increase the yields of 2 and 3; however, the best
results were obtained when 2 equiv of BF3‚OEt2 and 4
equiv of silane were employed. Mechanistic studies of this
selective nucleophilic ring opening are beyond the scope
of this work; however, our observations indicate that the
selectivity in the ring opening of the O-5,6 isopropylidene
group depends on the orientation and position of the free
hydroxyl group. This was confirmed when 1:2,5:6-O-
diisopropylidene-R-D-ribofuranose 5 and solketal 6 were
treated under the same conditions (BF3‚OEt2/Et3SiH).
Compound 5, with a different orientation of the free
hydroxyl group, afforded the hydrolysis of both 5,6-O- and
1,2-O-isopropylidene groups (7). On the other hand,
opening of solketal 6, which contains the hydroxyl group
at a different position, was not selective (8 and 9 in a
ratio of 1:1, see Scheme 2).
Diols 2 and 3 were converted to the cyclic phosphates
10-13 by treatment with phenyldichlorophosphate in the
presence of triethylamine. Thee two pairs of diastereoi-
someric six-membered cyclic phosphates were separated
by chromatography over silica gel in good yields, and in
a 1:1 ratio (Scheme 3).
We next proceeded to establish a protocol for the
removal of the functional groups at C-6. Interestingly,
we found that the 1,1-dimethyl-3-buetenyl group is
quantitatively removed without hydrolysis of the 1,2-O-
isopropylidene group using 5 equiv of BF3‚OEt2 (Scheme
4). With this efficient cleavage of the 1,1-dimethyl-3-
butenyl group, the six-membered cyclic phosphates 14
Results and Discussion
Computational Methods. The geometry of each
stationary point was fully optimized with the Gaussian
98 software package10 implementing the 6-31G(d,p) basis
set using density functional theory (the Becke3LYP
functional).11 All points were characterized as minima by
calculating the harmonic vibrational frequencies, using
analytical second derivatives. The NMR shielding tensors
were calculated and visualized with GaussView 3.0 at a
higher level of theory (B3LYP/6 31+G(d,p)) using the
same stationary points with the GIAO12 (gauge-indepen-
dent atomic orbital) method.
Synthesis of 1,3-Diol Precursors and Six-Mem-
bered Cyclic Phosphates. Synthesis of sterochemically
defined model compounds began with 1,3-diol precursors
2 and 3 from 1:2,5:6-O-diisopropylidene-R-D-xylofuranose
1. Instead of a two-step procedure involving two steps,13
aqueous hydrolysis of the 5,6-O-isopropylidene group
(10) Gaussian 98, Revision A.9. Frisch, M. J.; Trucks, G. W.;
Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Zakrzewski, V. G.; Montgomery, J. A., Jr.,; Stratmann, R. E.; Burant,
J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain,
M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz,
J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez,
C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian, Inc.,
Pittsburgh, PA, 1998.
(11) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Lee,
C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785-789.
(12) Wolinski, K.; Hilton, J. F.; Pulay, P. J. Am. Chem. Soc. 1990,
112, 8251-8260.
(13) (a) Estevez, J. C.; Fairbank, A. J.; Fleet, G. W. J. Tetrahedron
1998, 54, 13591-13620. (b) Markovic, D.; Vogel, P. Org. Lett. 2004, 6,
2693-2696. (c) Bols, M. Carbohydrate Building Block; Wiley & Sons:
New York, 1996.
(14) Selective nucleophilic opening in anomeric O-isopropylidene
groups has been reported: (a) Ewing, G. J.; Robins, M. J. Org. Lett.
1999, 1, 635-636. (b) Kakefuda, A.; Shuto, S.; Nagahata, T.; Seki, J.-
I., Sasaki, T.; Matsuda, A. Tetrahedron 1994, 50, 10167-10182.
(15) Just, G.; Wang, Z. Y.; Chan, L. J. Org. Chem. 1988, 53, 1030-
1033.
J. Org. Chem, Vol. 70, No. 18, 2005 7109

Cruz-Gregorio et al.
SCHEME 2. Influence of the Orientation and
Position of the Hydroxyl Group upon the Ring
Opening of the O-Isopropylidene Group
SCHEME 4. Protecting Group Cleavage in
Phosphates 10-13
SCHEME 3. Synthesis of the Six-Membered Cyclic
Phosphates 10-13
TABLE 1. Relevant 1H and 31P NMR Shifts for
Phosphates 10-15a,b
phosphate
H1
H2
H3
H4
H5
31P
and 15 were synthesized in only three steps from the
commercially available 1:2,5:6-O-diisopropylidene-R-D-
xylofuranose 1. Thus, with this selective nucleophilic
opening of the terminal O-isopropylidene group followed
by phosphorylation of the resulting 1,3-diol, and an
efficient deprotecting method, a promising protocol for
the selective transformation of acetonides has been
introduced, which has efficiency comparable to that of
the well-known cleavage of benzylidene acetals.16
Conformational and Configurational Analysis of
the Six-Membered Ring Phosphates. Since the ab-
solute stereochemistry of the carbohydrate framework
present in these phosphates is known, only the confor-
mation and configuration of the 1,3,2-dioxaphosphori-
nane ring remained to be determined. The relevant NMR
data are depicted in Tables 1 and 2. To assign the
absolute configuration at the phosphorus atom, we fol-
lowed our recent criterion,7,8 which is based on the
shielding effect of the diamagnetic current induced by
the aromatic ring of the phenoxy group on the chemical
shift of H-1 when both are cis oriented. Accordingly, the
six-membered cyclic phosphates 11, 13, and 15 (δ: 5.70,
5.73, and 5.52 ppm, respectively) are assigned the RP
configuration, and phosphates 10, 12, and 15 (all appear
at δ: 6.05 ppm) have the SP configuration.
10
11
12
13
14
15
6.05
5.70
6.05
5.73
6.05
5.52
4.73
4.64
4.72
4.65
4.75
4.57
4.96
5.06
4.93
5.08
4.96
5.21
4.38
4.38
4.38
4.39
4.44
4.32
4.87
4.73
4.86
4.75
4.82
4.75
-16.6
-15.6
-16.4
-15.8
-15.4
-12.2
a All spectra were recorded at 400 and 161 MHz for 1H and 31
P
NMR, respectively. b Chemical shifts (δ) are given in ppm.
TABLE 2. Relevant Vicinal Coupling Constants (3J) for
10-15a,b
phosphate
H5-P
H3-P
H5-H4
C2-P
10
11
12
13
14
15
16.5
13.2
16.4
13.2
14.8
18.1
2.4
6.0
2.1
2.4
10.6
7.9
11.1
6.8
11.3
10.8
1.6
1.6
4.2
2.4
2.0
<1.0
2.0
<1.0
a All spectra were recorded at frequencies of 400 and 161 MHz
for 1H and 31P NMR, respectively. b Coupling constants are given
in Hz.
uration at phosphorus.17 From Figure 3 it can be seen
that the 1,3,2-dioxaphosphorinane ring has a flattened
chair conformation (to minimize steric repulsions), simi-
lar to that found in related structures.18
Although phosphate 10 adopted a chair conformation
in the solid state, it did not exhibit the same behavior in
solution. On the basis of the vicinal coupling constant
3JH5-P of 16.5 Hz, a chair/twist conformation is suggested
X-ray crystallographic analysis of phosphate 10 con-
firmed the molecular structure and the absolute config-
(16) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999; Chapter 2.
7110 J. Org. Chem., Vol. 70, No. 18, 2005

Intramolecular Hydrogen Bonding of PdO--H
SCHEME 5. Hydrogen Bonding Interaction
Favoring the Chair Conformation
FIGURE 3. X-ray structure of phosphate 10 showing the
This is due to a high population of the chair conformation
in solution, which obviously is caused by the presence of
the free hydroxyl group. Comparing phosphate 15 to its
analogues 11 and 13, with the phenoxy group in equato-
rial or pseudoequatorial positions, a considerably higher
population of the boat conformation for 11 and 13 is
evident (3JH5-P ) 13.2 Hz for both phosphates 11 and 13).
Furthermore, if the 3JH5-P coupling constant of phosphate
flattened chair conformation of the 1,3,2-dioxaphosphorinane.
3
FIGURE 4. Newman projections showing the orientation
between the phosphorus atom and carbon C-2 for each of the
chair conformations.
15 is compared to the JH5-P coupling constant of its
diastereoisomeric congener 14, which also contains a free
hydroxyl group in the same position, the small value of
3JH5-P (14.8 Hz) suggests a chair/nonchair equilibrium.
It was recently demonstrated that in this case the
nonchair conformation corresponds to a twist conforma-
instead of the chair/chair equilibrium (C1 T C2 equilib-
rium depicted in Figure 1). The value of the vicinal
coupling constant between carbon C-2 and the phospho-
rus atom (3JC2-P) is 10.6 Hz, suggesting an anti orienta-
tion. For the C1 conformation, the gauche orientation
between carbon C-2 and the phosphorus atom should lead
to a smaller value of 3JC2-P (<5.0 Hz). Additionally, H-3
3
tion.7 So, according to the JH5-P coupling constant for
phosphates 10 and 12, a marked chair T twist equilib-
rium is proposed (Scheme 5).
A reasonable explanation for the increase of the chair
conformation in phosphate 15 postulates stabilization of
the chair 15c by internal hydrogen bonding (PdO--H-
O) at the expense of the boat conformation 15b. Absent
the hydroxyl group, a high population of the boat
conformation for phosphate 15 should be expected as this
allows the phenoxy group to be axially located and take
3
should be oriented equatorially and the value of JH3-P
should be larger than 14 Hz (Figure 4).19
In the case of phosphate 11, values of 13.2 and 7.9 Hz
3
3
were found for JH5-P and JC2-P, respectively, and an
3
increment in the JH3-P (6.0 Hz) coupling constant
occurred. This is in accordance with a chair/boat equi-
librium (C2/B2, Figure 1), caused by the tendency of the
phenoxy group to adopt the axial position, which is a
consequence of the anomeric effect.
For the remaining pairs of diastereomeric phosphates
(12 and 13; 14 and 15), the conformational behavior was
quite similar. However, the large value of the 3JH5-P (18.1
Hz) coupling constant for phosphate 15 is noteworthy.
advantage of stabilizing hyperconjugation (nO T σ*P-OP
)
with the ring oxygens (Scheme 5).5,7,8,9 In the hydrogen
3
bond accepting solvent DMSO-d6, the JH5-P had a
smaller value (from 18.1 Hz in CDCl3 to 13.6 Hz in
DMSO-d6), and the chemical shift for H-1 was downfield
shifted (5.52 ppm in CDCl3 to 5.80 ppm in DMSO-d6),
indicating restoration of the chair conformation with the
nO T σ*P-OP hyperconjugation, thereby providing further
support for the hydrogen-bonding hypothesis.
(17) The X-ray crystallographic studies were done by using a Bruker
P4 diffractometer (λMoKR ) 0.71073 Å, monochromator: graphite, T )
296 K, ω-2θ scan). Direct methods (SHELXS-97) were used for
structure solution, and a riding model software package (SHELXL-
97) was used for refinement and data output. Hydrogen atoms were
refined with isotropic U tied to their respective heavy atom. Crystal-
lographic data for the structure reported in this paper has been
deposited with the Cambridge Crystallographic Data Centre as
supplementary. CCDC No. 266689. Copies of the material can be
obtained, free of charge, on application to the Director, CCDC, 12 Union
Road, Cambridge, CB2 1EZ, U.K. (fax: (+44)1223-336-033, e-mail:
deposit@ccdc.cam.ac.uk, www: http://www.ccdc.cam.ac.uk).
(18) (a) Day, R. O.; Gorenstein, D. G.; Holmes, R. R. Inorg. Chem.
1983, 22, 2192-2195. (b) Magomedova, N. S.; Sobolev, A. N.; Koroteev,
M. P.; Pugashova, N. M.; Bel’skii, V. K.; Nifant’ev, EÄ . E. Zh. Strukt.
Khim. 1991, 32, 67-73.
To further demonstrate the existence of this unusual
conformational behavior for 15, in which the anomeric
effect is opposed by an internal hydrogen bonding inter-
action (seven-membered intramolecular hydrogen bond
structure), we performed DFT calculations (B3LYP/6-
31G(d,p))11 and found an intramolecular hydrogen bond
(PdO- -HO) with a distance of 2.17 Å (Figure 5).
Having well established the geometry of the preferen-
tial conformer for phosphate 15, we were surprised to
find that the chemical shift of H-1 appears at higher field
than in any of the analogous phosphates 13 and 11, even
though they possess the same configuration at the
phosphorus atom (H-1 and PhO are oriented cis). This
result is in apparent contradiction with the previous
assumption that the benzene ring current should shield
(19) Quin, L. D. Stereospecificity in 31P-Element Coupling: Phos-
phorus-Carbon Coupling. In Phosphorus-31 NMR Spectroscopy in
Stereochemical Analysis; Verkade, J. G., Quin, L. D., Eds.; VCH:
Weinheim, 1987.
J. Org. Chem, Vol. 70, No. 18, 2005 7111

Cruz-Gregorio et al.
ers of phosphate 16 that crystallized independently
within the same asymmetric unit of the crystal lattice.20
When the same computational treatment was applied to
phosphate 16, we found that both optimized structures,
16c and 16b, match in geometry to the molecules present
in the solid state (Figure 7). It can be also seen that H-1
resides within the shielding region when the phosphate
exists in the chair conformation (perpendicular) and out
of it (parallel), in the boat conformation (Figure 7),
enabling the previous discussion to be continued.21 On
the basis of the chemical shift of H-17 or the vicinal H-P
coupling constants,6a it was assumed that the molar
fraction of the boat conformer (or nonchair conformation)
is increased upon lowering the temperature because H-1
was shifted upfield at lower temperatures (and the value
3
of JH-P is increased). Now, it is clear that H-1 is more
shielded by the diamagnetic current induced by the
aromatic ring, when the phosphate ring has a chair
conformation, not when it is in a boat conformation
(Figure 7).
FIGURE 5. Optimized structure for 15 calculated at the
B3LYP/6-31G(d,p) level.
Empirical approximations to estimate the population
and the ∆G° for the chair/nonchair equilibria in solution
are known, but most are method dependent.4,6a,22 Based
on the very good matching between the X-ray structures
and the calculated structures of phosphate 16, we can
establish the relative energies and free energies for
conformer pairs 16c/16b and 15c/15b (G ) H - TS, as
the “sums of the electronic and thermal free energies”,
obtained at T ) 298.15 K).23 For the equilibrium 16c/
16b, ∆E°rel ) +0.78 kcal/mol and the G ) +1.27 kcal/
mol, leading to an approximate population of 56% and
44% for the chair and boat conformations, respectively,
and for the equilibrium 15c/15b, ∆E°rel ) +1.21 kcal/
mol, G ) +0.69 kcal/mol, 79% and 21% of 15c and 15b,
respectively. Thus, it can be established that intramo-
lecular hydrogen bonding stabilizes the chair conforma-
tion of cyclic phosphate 15 in the chair conformation with
respect to those cyclic phosphates lacking the intramo-
lecular hydrogen bond. To the best of our knowledge, this
is the first example in which a chair conformation of a
neutral six-membered cyclic phosphate is stabilized by
an intramolecular hydrogen bonding interaction (PdO- -
HO). For charged six-membered cyclic phosphates (analo-
gous to cAMP), it has been suggested that in cellular
media intermolecular interactions with the hydroxyl
groups provide the driving force to change a chair
conformation into a twist conformation. It is now appar-
ent that such interactions can equally favor any confor-
mation (chair, twist, or boat) and that the driving force
that converts one form to another one comes from the
natural nO T σ*P-OP hyperconjugations, which are fa-
vored in highly polar environments (water). A previous
theoretical work invoked intramolecular hydrogen bond-
ing in cAMP and cGMP but suggested that these occurred
FIGURE 6. Shielding density for 15 in a chair conformation
as seen by H-1 in the ZZ direction mapped between the values
of -0.02 and 0.02 on the current density ) Z (isosurface at a
value of 0.00008).
the hydrogen atom H-1 more in the boat conformation
than in the chair conformation. However, although the
phenoxy group may be closer to H-1 in a boat than in a
chair conformation, it is not necessary for H-1 to reside
within the shielding region of the diamagnetic current
induced by the aromatic ring. Two different orientations
of the benzene ring with respect to H-1 are possible: one
perpendicular (H-1 resides in the shielding region) and
another one parallel (with H-1 away from the shielding
region). NMR shielding tensors for phosphate 15 were
calculated at the B3LYP/6-31+G(d,p) level using the
same stationary point. The shielding density was mapped
and is shown in Figure 6.
(20) Although,both molecules were reported in ref 7, no theoretic
study was carried out, nor was there detailed observation on the
orientation of the benzene ring over the xylo-furanose ring.
(21) Discussion regarding on the VT-NMR experiment.
(22) (a) Lambert, J. B.; Featherman, S. I. Chem. Rev. 1975, 75, 611-
626. (b) Eliel, E. L. J. Chem. Educ. 1975, 52, 762-767. (c) Lee, C. H.;
Sarma, R. H. J. Am. Chem. Soc. 1976, 98, 3541-3548. (d) Gerlt, J. A.;
Gutterson, N. I.; Drews, R. E.; Sokolow, J. A. J. Am. Chem. Soc. 1980,
102, 1665-1670.
(23) The energies (electronic + thermal energies) and the free
energies were corrected. All of these energies were extracted from the
frequency calculations. We thank a reviewer for raising this point.
As seen from Figure 6, H-1 (blue color) is placed
perpendicular to the shielding density (red color) when
phosphate 15 is in the chair conformation. In support of
this argument, we analyzed the chair and boat conform-
7112 J. Org. Chem., Vol. 70, No. 18, 2005

Intramolecular Hydrogen Bonding of PdO--H
FIGURE 7. Shielding density (red color) for the chair and boat conformations of phosphate 16.
between C2-OH and H4.24 We note that the conforma-
tional study presented here has similar conclusions to
one reported by Rebek,25 although with different in-
tramolecular interactions (CdO- -H-N), in which the
conformational equilibria of cavitands that flutter be-
tween C4v T C2v symmetries, is determined by seven-
membered intraannular hydrogen-bonded ring struc-
tures.
stereoelectronic factors (mainly the anomeric effect). To
synthesize the 1,3-diol precursors for the six-membered
cyclic phosphates cis-fused to a glucofuranose derivative,
a selective nucleophilic ring opening of 1,2-O-isopropy-
lidene group by a silane was introduced. A method for
the selective removal of a novel protecting hydroxyl group
was also reported. This method is the subject of ongoing
investigations and applications other synthetic proce-
dures, to be reported in due course.
Conclusions
Acknowledgment. We thank CONACyT for finan-
cial support, Project No. 35102, Grant No. 171952 (S.C.-
G.), and Beneme´rita Universidad Auto´noma de Puebla
(BUAP) for partial support (F.S.-P). We also thank
Professors David Crich (UIC) and Herbert Ho¨pfl (CIQ)
for helpful discussions.
By NMR and computational methods, it has been
demonstrated that intramolecular hydrogen bonds be-
tween the phosphoryl oxygen and a hydroxyl group
stabilize the chair conformation of a neutral six-mem-
bered cyclic phosphate. Although intramolecular and
intermolecular hydrogen-bonding interactions have dif-
ferent energies, our results demonstrate that intramo-
lecular hydrogen-bonding interactions stabilize a confor-
mation that is otherwise considered to be disfavored by
Supporting Information Available: Experimental pro-
cedures and characterization data for all obtained compounds,
copies of 1H and 13C NMR spectra for all new compounds, and
Cartesian coordinates for conformers 15c, 15b, 16c, and 16b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Topiol, S.; Morgan, T. K.; Sabio, M.; Lumma, W. C. J. Am.
Chem. Soc. 1990, 112, 1452-1459.
(25) Rudkevich, D. M.; Hilmersson, G.; Rebek, J., Jr. J. Am. Chem.
Soc. 1997, 119, 9911-9912.
JO050753+
J. Org. Chem, Vol. 70, No. 18, 2005 7113