Understanding the unusual regioselectivity in the nucleophilic ring-opening reactions of gem-disubstituted cyclic sulfates. Experimental and theoretical studies

Article abstract of DOI:10.1021/jo034178q

The regioselectivity of the nucleophilic ring-opening reactions of three gem-disubstituted cyclic sulfates with sodium azide has been studied from both experimental and theoretical viewpoints. It is found that, depending on the substituent present in the cyclic sulfate, the reaction displays reversed regioselectivity, which allows one or another regioisomer to be obtained with selectivities greater than 4:1. The theoretical calculations show that, contrary to previous understanding, the intrinsic preference in all cases is azide attack at the less-substituted C_β position, a consequence of similar stereoelectronic effects in the three sulfates considered. The observed preference for C_α attack in the case of the ester sulfate is explained in terms of differential solvent effects, which are in turn due to subtle differences in the charge transfer in the different transition structures.

Full text of DOI:10.1021/jo034178q

Un d er sta n d in g th e Un u su a l Regioselectivity in th e Nu cleop h ilic
Rin g-Op en in g Rea ction s of gem -Disu bstitu ted Cyclic Su lfa tes.
Exp er im en ta l a n d Th eor etica l Stu d ies
Alberto Avenoza,*,† J esu´s H. Busto,† Francisco Corzana,† J ose´ I. Garc´ıa,*,‡ and
J esu´s M. Peregrina†
Departamento de Quı´mica, Universidad de La Rioja, Grupo de S´ıntesis Quı´mica de La Rioja,
U.A.-C.S.I.C., E-26006 Logron˜o, Spain, and Departamento de Quı´mica Orga´nica, Instituto de Ciencia de
Materiales de Arago´n, C.S.I.C.-Universidad de Zaragoza, E-50009 Zaragoza, Spain
alberto.avenoza@dq.unirioja.es; jig@posta.unizar.es
Received February 7, 2003
The regioselectivity of the nucleophilic ring-opening reactions of three gem-disubstituted cyclic
sulfates with sodium azide has been studied from both experimental and theoretical viewpoints. It
is found that, depending on the substituent present in the cyclic sulfate, the reaction displays
reversed regioselectivity, which allows one or another regioisomer to be obtained with selectivities
greater than 4:1. The theoretical calculations show that, contrary to previous understanding, the
intrinsic preference in all cases is azide attack at the less-substituted Câ position, a consequence
of similar stereoelectronic effects in the three sulfates considered. The observed preference for CR
attack in the case of the ester sulfate is explained in terms of differential solvent effects, which are
in turn due to subtle differences in the charge transfer in the different transition structures.
In tr od u ction
amino alcohols. However, one of the best methods in-
volves the use of 1,2-azido alcohols, which are often
obtained by opening of cyclic sulfates with the azide ion
followed by hydrolysis, since these compounds have
several advantages (good nucleophile, mild reaction
conditions, and easy conversion into amine group).1,2
The important role of cyclic sulfates in organic syn-
thesis has been described in two recent reviews.1,2 In
particular, five-membered cyclic sulfates compete with
epoxides in terms of reactivity and selectivity, and in
many cases they are found to be superior to epoxides in
opening reactions with nucleophiles.
The development of both the catalytic asymmetric
dihydroxylation (AD) reaction3 (a tool to obtain chiral 1,2-
diols) and efficient methods for the preparation of cyclic
sulfates from 1,2-diols1,2,4 have contributed to the expan-
sion of the chemistry of these cyclic compounds.
On the other hand, 1,2-amino alcohols play important
roles in medicinal chemistry,5 coordination chemistry,
and asymmetric catalysis.6 There are a number of reac-
tions, including asymmetric aminohydroxylation (AA),7
that can be used in the synthesis of enantiopure 1,2-
Taking into account the observations outlined above,
and the fact that most intermolecular ring-opening
reactions between cyclic sulfates and nucleophiles pro-
ceed by the SN2 pathway with total inversion at the
reacting stereogenic center,1,2 we focused our attention
on the ring opening of cyclic sulfates with the azide ion.
A number of general features concerning the regioselec-
tivity of this reaction are well-established and are covered
in the aforementioned reviews. The regioselectivity is
controlled simultaneously by the steric interaction be-
tween the substrates and nucleophiles and by the elec-
tronic distribution of the substrates. For example, in
monosubstituted R,â-cyclic sulfates in which the sub-
stituent is a bulky alkyl group, the nucleophile attacks
almost exclusively at the Câ position (sulfate 1a gives
compound 3a , Scheme 1).5d,8 Nevertheless, the situation
is reversed when the substituent is an electron-with-
drawing group, since in this case it is the electronic
distribution of the substrate or the transition state rather
than the steric hindrance that seems to be the predomi-
† Universidad de La Rioja.
‡ CSIC-Universidad de Zaragoza.
(1) Lohray, B. B. Synthesis 1992, 1035-1052.
(2) Bittman, R.; Byun, H.-S.; He, L. Tetrahedron 2000, 56, 7051-
7091.
(3) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483-2547.
(4) Lohray, B. B.; Bhushan, V. Adv. Heterocycl. Chem. 1997, 68, 89-
180.
(5) (a) Hannun, Y. Science 1996, 274, 1855-1859. (b) Byun, H.-S.;
Bittman, R. In Phospholipids Handbook; Cevc, G., Ed.; Marcel Dek-
ker: New York, 1993; pp 97-140. (c) Lister, M. D.; Ruan, Z.-S.;
Bittman, R. Biochim. Biophys. Acta 1995, 1256, 25-30. (d) Byun, H.-
S.; Sadlofsky, J . A.; Bittman, R. J . Org. Chem. 1998, 63, 2560-2563.
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R. Chem. Soc. Rev. 1989, 18, 187-208. (c) Noyori, R.; Kitamura, M.
Angew. Chem., Int. Ed. Engl. 1991, 30, 49-69. (d) Itsuno, S.; Ito, K.;
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E. J . Pure Appl. Chem. 1990, 62, 1209-1216.
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Int. Ed. Engl. 1997, 36, 1483-1486. (b) Sharpless, K. B.; Tao, B.;
Schlingloff, G. Tetrahedron Lett. 1998, 39, 2507-2510. (c) Song, C. E.;
Oh, C. R.; Roh, E. J .; Lee, S.; Choi, J . H. Tetrahedron: Asymmetry 1999,
10, 671-674. (d) O’Brien, P. Angew. Chem., Int. Ed. 1999, 38, 326-
329. (e) Bodkin, J . A.; McLeod, M. D. J . Chem. Soc., Perkin Trans. 1
2002, 2733-2746.
10.1021/jo034178q CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/07/2003
4506
J . Org. Chem. 2003, 68, 4506-4513

Ring-Opening Reactions of gem-Disubstituted Cyclic Sulfates
the Gaussian 98 package.14 BSSE corrections have not been
considered in this work.
SCHEME 1. Regioselectivity of Rin g-Op en in g
Rea ction s of Cyclic Su lfa tes a n d Ep oxid es
Analytical frequencies were calculated at the B3LYP/6-
31+G(d) level and the nature of the stationary points was
determined in each case according to the appropriate number
of negative eigenvalues for the Hessian matrix. Scaled fre-
quencies were not considered since significant errors on the
calculated thermodynamical properties are not found at this
theoretical level.15
In all cases single-point energy calculations at the B3LYP/
6-311++G(2d,p) level were carried out on the B3LYP/6-31+G-
(d) geometries. Furthermore, solvent effects were taken into
account through single-point energy calculations with the
Isodensity Polarized Surface Continuum Model (IPCM)
method,16 as implemented in Gaussian 98, at the B3LYP/6-
31+G(d) level, using the dielectric permittivity of dimethyl-
formamide (38.25), which was the solvent used in most
experiments. The IPCM method only accounts for the electro-
static part of the solvation energy, and not for dispersion and
cavitation terms. However, as we are concerned only with
relative energies, it is foreseeable that the differential solvation
energy between two transition structures will be dominated
by the electrostatic term, given the differences in electric
moments (dipole and higher multipoles). On the other hand,
dispersion and cavitation solvation energies (which have
furthermore opposed signs) will tend to cancel out in these
conditions. This behavior has been previously observed, for
instance, in the case of Diels-Alder reactions.17 Some single-
point energy calculations were also carried out at the PCM/
B3LYP/6-31+G(d) level, using nitromethane as the solvent,
because of its close dielectric permittivity to dimethylforma-
mide (38.2), to test the possible influence of cavitation and
dispersion terms of the solvation energy, showing that our
hypothesis about the cancellation of these terms is correct.
Similarly, some single-point energy calculations were also
carried out at the IPCM/B3LYP/6-311++G(2d,p) level, show-
ing that the possible influence of the basis set size on the
solvation energies is almost nil, therefore we decided to use
the computationally more economical IPCM/B3LYP/6-31+G-
(d) level.
nant factor controlling the regioselectivity of the reaction
(sulfate 1b gives compound 2b, Scheme 1).9
Moreover, a comparative study of regioselectivity in
R,â-disubstituted cyclic sulfates and epoxides with vari-
ous nucleophiles has shown that, when the ring-opening
reaction is controlled by the electronic distribution of the
substrates, the nucleophilic attack at the CR position is
again almost exclusive in the cyclic sulfates (sulfate 1c
gives compound 2c, Scheme 1). On the other hand, with
R,â-epoxyesters the attack occurs at either the CR or Câ
position depending on the reaction conditions used (ep-
oxide 4c gives compounds 2c or 3c, Scheme 1).9b,c,10
In contrast with these cases, little is known about the
regioselectivity and stereoselectivity of gem-disubstituted
R,â-cyclic sulfates. To the best of our knowledge, only two
cases of reactions involving cyclic sulfates in which the
gem-disubstituted carbon center is activated for nucleo-
philic attack have been reported. Goodman and co-
workers11 synthesized R,â-dimethyl-R-amino acids using
as key steps the asymmetric dihydroxylation reaction of
benzyl tiglate, followed by cyclic sulfate formation and a
further stereoselective and regioselective ring-opening
reaction with the azide ion at the CR position of the cyclic
sulfate. Avenoza and co-workers12 used a similar protocol
to achieve an enantioselective synthesis of both (R)- and
(S)-R-methylserines.
Natural Bonding Orbital (NBO)18 analyses were carried out
with use of the NBO 3.1 program, as implemented in Gaussian
98.
To understand the behavior of this kind of cyclic sulfate
in the ring-opening reaction with the azide ion and to
shed light on the reaction mechanism and synthetic
implications involved, we performed both experimental
and theoretical studies. The results of this investigation
are presented in this paper.
Unless otherwise stated, only Gibbs free energies are used
for the discussion on the relative stabilities of the transition
structures considered. These energies were obtained by using
the following correction formula:
∆∆Gq ) ∆∆Ebasis + ∆∆G298 + ∆∆Gsolv
(1)
where ∆∆Ebasis is the relative energy at the B3LYP/6-311++G-
Com p u ta tion a l Deta ils
All calculations were carried out by means of the B3LYP
hybrid functional.13 Full optimizations and transition structure
searches, using the 6-31+G(d) basis set, were carried out with
(13) (a) Lee, C.; Yang, W.; Parr, R. Phys. Rev. B 1988, 37, 785-789.
(b) Becke, A. D. J . Chem. Phys. 1993, 98, 5648-5652.
(14) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millan, 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.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaroni, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonza´lez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B.; Chen, W.;
Replogle, E. S.; Pople, J . A. Gaussian98, Revisions A.7 and A.11;
Gaussian, Inc.: Pittsburgh, PA, 1998.
(8) (a) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655-
658. (b) He, L.; Byun, H.-S.; Bittman, R. J . Org. Chem. 1998, 63, 5696-
5699. (c) Parkes, K. E. B.; Bushnell, D. J .; Crackett, P. H.; Dunsdon,
S. J .; Freeman, A. C.; Gunn, M. P.; Hopkins, R. A.; Lambert, R. W.;
Martin, J . A.; Merrett, J . H.; Redshaw, S.; Spurden, W. C.; Thomas,
G. J . J . Org. Chem. 1994, 59, 3656-3664. (d) Yokumatsu, T.; Suemune,
K.; Shibuya, S. Heterocycles 1993, 35, 577-580. (e) Hoffmann, R. W.;
Stiasny, H. C. Tetrahedron Lett. 1995, 36, 4595-4598. (f) Hoye, T. R.;
Crawford, K. B. J . Org. Chem. 1994, 59, 520-522.
(9) (a) Otsubo, K.; Inanaga, J .; Yamaguchi, M. Tetrahedron Lett.
1987, 28, 4435-4436. (b) Saito, S.; Takahashi, N.; Ishikawa, T.;
Moriwaka, T. Tetrahedron Lett. 1991, 32, 667-670. (c) Righi, G.;
Rumboldt, G.; Bonini, C. J . Org. Chem. 1996, 61, 3557-3560.
(10) Xiong, C.; Wang, W.; Hruby, V. J . J . Org. Chem. 2002, 67,
3514-3517.
(15) Bauschlicher, C. W., J r. Chem. Phys. Lett. 1995, 246, 40-44.
(16) Foresman, J . B.; Keith, T. A.; Wiberg, K. B.; Snoonian, J .;
Frisch, M. J . J . Phys. Chem. 1996, 100, 16098-16104.
(17) Ruiz-Lo´pez, M. F.; Assfeld, X.; Garc´ıa, J . I.; Mayoral, J . A.;
Salvatella L. J . Am. Chem. Soc. 1993, 115, 8780-8787.
(18) (a) Foster, J . P.; Weinhold, F. J . Am. Chem. Soc. 1980, 102,
7211-7218. (b) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev.
1988, 88, 899-926. (c) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J .
Chem. Phys. 1985, 83, 735-746.
(11) Shao, H.; Rueter, J . K.; Goodman, M. J . Org. Chem. 1998, 63,
5240-5244.
(12) Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J . M.;
Sucunza, D.; Zurbano, M. M. Tetrahedron: Asymmetry 2001, 12, 949-
957.
J . Org. Chem, Vol. 68, No. 11, 2003 4507

Avenoza et al.
SCHEME 2. Syn th esis of Cyclic Su lfa tes 8a -ca
TABLE 1. Rela tive En er gies, F r ee En er gies (in k ca l
m ol-1), a n d En tr op ies (in ca l K-1 m ol-1) for th e
Tr a n sition Str u ctu r es Descr ibed in Th is Wor k
a
a
b
c
TS
∆E0
∆Sa
∆∆G298 ∆∆Gsolv ∆∆Ebasis ∆∆Gq d
13a -sf
13a -sh
13a -a f
13a -a h 2.98 138.5
13b-sf 0.00 127.8
13b-sh 0.83 127.7
13b-a f 3.06 121.8
13b-a h 2.23 128.3
0.00 142.0
0.76 138.0
3.76 139.4
0.00
1.43
0.82
1.25
0.00
2.28
3.23
0.30
0.00
0.36
3.74
2.83
0.00
4.07
7.79
4.38
0.00
0.18
1.18
0.00
-0.18
1.51
0.00
0.42
2.92
1.90
1.64
2.06
7.25
0.00
-0.06
-3.48
13c-sf
13c-sh
13c-a f
0.00 134.6
2.88 133.6
6.23 135.7
0.00
0.46
-0.44
0.54
0.00
1.10
-4.30
-4.70
0.00
2.64
6.10
5.39
0.00
4.20
1.36
1.23
13c-a h 5.43 133.3
a
t
a
b
Reagents and conditions: (a) AD-mix â, MeSO2NH2, BuOH/
Calculated at the B3LYP/6-31+G(d) level. Calculated at the
c
H2O (1:1), 0 °C, 12 h, 81%, ee 93%. (b) OsO4, NMO, acetone/H2O
(4:1), rt, 24 h, 70%. (c) (i) LiOH‚H2O, H2O/MeOH (1:3), rt, 2 h; (ii)
AcCl, MeOH, reflux, 12 h, 85%. (d) SOCl2, CCl4, reflux, 4 h, 90%
of 7a from 6a , 92% of 7b from 6b, 91% of 7c from 6c. (e) NaIO4,
RuCl3, H2O/MeCN/CCl4 (3:2:2), 40 °C, 7 h, 92% of 8a from 7a , 86%
of 8b from 7b, 77% of 8c from 7c.
IPCM/B3LYP/6-31+G(d) level. Calculated at the B3LYP/6-
d
311++G(2d,p)//B3LYP/6-31+G(d) level. Calculated with eq 1 (see
Computational Details).
(2d,p)//B3LYP/6-31+G(d) level, ∆∆G298 represents the thermal
and entropic corrections at 298 K, calculated at the B3LYP/
6-31+G(d) level, and ∆∆Gsolv is the solvation correction (rela-
tive solvation free energies), calculated at the IPCM/B3LYP/
6-31+G(d) level.
SCHEME 3. Rin g-Op en in g Rea ction s of Cyclic
Su lfa tes 8a -c w ith th e Azid e Ion a
The relative energies and free energies of the structures
considered in this work are shown in Table 1. Hard data on
Cartesian coordinates, electronic energies, as well as entropies,
enthalpies, Gibbs free energies, and lowest frequencies of the
different conformations of all structures considered, are avail-
able as Supporting Information.
Resu lts a n d Discu ssion
1. Exp er im en ta l Stu d ies. Three different reactions
were investigated: the ring-opening of cyclic sulfates
8a -c with sodium azide under various conditions, which
generate mixtures of compounds 9a -c and 10a -c.
Subsequent acid hydrolyses gave the corresponding azido
alcohols 11a -c and 12a -c.
a
Reagents and conditions: (a) Method A: NaN3, DMF, 50 °C,
Syn th esis of Cyclic Su lfa tes. Olefins 5a and 5c were
obtained from commercially available 2-methyl-2-prope-
noic acid, which was transformed into the corresponding
2-methyl-2-propionyl chloride by the action of PCl5.
Further in situ addition of methoxymethylamine or
dimethylamine gave olefins 5a or 5c, respectively, ac-
cording to the protocol described in the literature.19 Olefin
5a was subjected to the AD reaction in the presence of
AD-mix â, giving diol 6a with excellent enantiomeric
excess according to the results obtained by Sharpless et
al.20 The amide group of this diol was transformed into
the corresponding methyl ester group to obtain diol 6b
in two steps (basic hydrolysis with LiOH and subsequent
esterification with AcCl in refluxing MeOH), as described
in the literature.12 Diol 6c was obtained from olefin 5c
by dihydroxylation with OsO4 in the presence of N-
methylmorpholine N-oxide (NMO) (Scheme 2).
48 h. Method B: NaN3, acetone/H2O (9:1), rt, 96 h. (b) 20% H2SO4,
rt, 48 h.
generated in situ, gave sulfates 8a -c in good yields
(Scheme 2).
Rin g-Op en in g Rea ction of Cyclic Su lfa tes. Sul-
fates 8a -c were treated with sodium azide under various
conditions to give mixtures of the acyclic sulfates 9a -c
and 10a -c. These compounds could not be separated by
column chromatography and were therefore immediately
subjected to a further acid hydrolysis to give the corre-
sponding azido alcohols 11a -c and 12a -c (Scheme 3).
When sulfate 8b was treated with sodium azide in the
presence of N,N-dimethylformamide (DMF) at 50 °C, a
regioselectivity of 4.5:1 in favor of R-azido â-sulfate 10b
was obtained. This situation is in agreement with the
results described previously.12 Treatment of the reaction
mixture (9b + 10b) with 20% H2SO4 gave the corre-
sponding mixture of azido alcohols (11b + 12b), which
could be separated by column chromatography (Scheme
3).
Diols 6a -c were then transformed into the corre-
sponding R,â-cyclic sulfites 7a -c with thionyl chloride
and subsequent oxidation of these sulfites with RuO4,
(19) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818.
(20) Bennani, Y. L.; Sharpless, K. B. Tetrahedron Lett. 1993, 34,
2079-2082.
The regioselectivity of the reaction was measured from
the crude reaction mixtures by integration of the 1H NMR
signals corresponding to the R-methyl group.
4508 J . Org. Chem., Vol. 68, No. 11, 2003

Ring-Opening Reactions of gem-Disubstituted Cyclic Sulfates
F IGURE 2. Some geometrical features of the TS 13a ,
calculated at the B3LYP/6-31+G(d) level.
+ 12c) in 91% yield and with a regioselectivity of 11c/
12c ) 6:1, i.e. similar to that found for sulfate 8a and
opposite to that for sulfate 8b. At first glance, the
differences in electronic effects between the substituents
in sulfates 8a -c can hardly justify the almost complete
reversal of regioselectivity observed. For this reason, we
carried out a theoretical study of the reaction between
sodium azide and these sulfates. Despite the importance
of cyclic sulfates in organic synthesis there have not been
any previous reports concerning computational studies
on the ring-opening reaction with nucleophiles. Indeed,
it is only recently that ab initio and DFT theoretical
calculations regarding the solvent effects on the hydroly-
sis of simple model sulfates, including a cyclic structure,
have been reported.21 These reactions, however, follow a
different mechanism since the nucleophilic attack takes
place at the sulfur atom.
2. Th eor etica l Stu d ies. Rea cta n ts. First, we calcu-
lated the structures of the reactants, the azide anion, and
the three sulfates 8a -c. Simplification of the structures
of the sulfates was not considered to take into account
all the steric interactions relevant in the transition
structures. Some relevant features of the minimum
energy conformations of 8a -c are shown in Figure 1.
Tr a n sition Str u ctu r es. For each sulfate 8a -c, the
corresponding transition structures (TS) resulting from
nucleophilic attack of the azide anion on the CR (“hin-
dered”) and Câ (“free”) positions were located in the two
possible carbonyl conformations, namely syn or anti with
regard to the R-methyl group. This leads to four possible
TS for each sulfate and these are denoted as 13a -c-sh ,
13a -c-a h , 13a -c-sf, and 13a -c-a f, respectively.
Several geometrical features of these TS are shown in
Figures 2-4 and the energetic results are gathered in
Table 1.
F IGURE 1. B3LYP/6-31+G(d) geometries of the minimum
energy conformations of 8a-c.
However, to our surprise, when sulfate 8a was treated
with sodium azide in the presence of N,N-dimethylfor-
mamide (DMF) at 50 °C, a regioselectivity of 3:1 in favor
of â-azido R-sulfate 9a was obtained. This regioselectivity
was enhanced when the same reaction was carried out
at room temperature in acetone/H2O (9:1), although a
time of 96 h was needed to complete the reaction. In this
case the temperature could not be increased because at
1
50 °C we detected in the H NMR spectrum a product
arising from the nucleophilic attack of water. The regi-
oselectivity of the opening reaction was determined in
the final mixture of azido alcohols (11a + 12a ) prior to
separation, using the same protocol as described above
for the opening reaction of sulfate 8b (Scheme 3).
Alternatively, both azido alcohols were obtained by the
ring-opening reaction of cyclic sulfite 7a , under the same
conditions (Method A), with the product mixture (11a +
12a ) obtained in 85% yield and with a regioselectivity of
11a /12a ) 5.5:1. These azido alcohols could be separated
by column chromatography (Scheme 3).
In view of the results obtained on the regioselectivity
of the ring-opening reaction of sulfate 8a , it can be
concluded that the reaction is not controlled by the
electronic distribution of the substrate, a situation in
stark contrast to the previously accepted position. To
corroborate this feature, we carried out the ring-opening
reaction of another cyclic sulfate, namely amide 8c. In
this case, nucleophilic attack of the azide ion on the
sulfate 8c, followed by hydrolysis, gave the mixture (11c
A number of geometrical features can be established
for transition structures 13a (Figure 2). On one hand,
(21) (a) Lopez, X.; Dejaegere, A.; Karplus, M. J . Am. Chem. Soc.
2001, 123, 11755-11763. (b) Lopez, X.; Dejaegere, A.; Karplus, M. J .
Am. Chem. Soc. 1999, 121, 5548-5558.
J . Org. Chem, Vol. 68, No. 11, 2003 4509

Avenoza et al.
F IGURE 3. Some geometrical features of the TS 13b,
calculated at the B3LYP/6-31+G(d) level.
F IGUR E 4. Some geometrical features of the TS 13c,
calculated at the B3LYP/6-31+G(d) level.
the N-C distances of the forming bonds are shorter in
the case of nucleophilic attack at the less-hindered Câ
position (13a -sf and 13a -a f). This could be interpreted
in terms of these TS being later in the reaction coordi-
nate, although the distances of the C-O breaking bond
are also shorter for 13a -sf and 13a -a f, which would
indicate an earlier position in the reaction coordinate.
In fact, it can be concluded that both 13a -sf and 13a -a f
TS are more compressed than 13a -sh and 13a -a h . This
situation can be explained by steric effects, which must
be more important in the case of nucleophilic attack at
the most hindered position (13a -sh and 13a -a h ), result-
ing in a longer N-C distance in the TS. Natural popula-
tion analyses of the TS allow further clarification of this
point. Thus, the charge transfer from the azide anion to
the sulfate in the TS is 0.312 and 0.349 electrons
respectively for 13a -sf and 13a -a f, whereas it is 0.382
and 0.393 for 13a -sh and 13a -a h , respectively. This is
consistent with a later TS for nucleophilic attack at the
most hindered CR position. Therefore, if a single geo-
metrical feature is to be chosen as a rapid indication of
the earliness of the TS, the C-O breaking bond distance
seems to be more reliable.
As far as the relative energies of the four TS are
concerned (Table 1), it can be seen that 13a -sf is the
lowest energy TS both in the gas phase and in solution.
The basis set effect seems to be less important in
describing the relative energy of the TS, since the values
calculated at the B3LYP/6-31+G(d) level and those
calculated at the B3LYP/6-311++G(2d,p)//B3LYP/6-
31+G(d) level are very similar. Both the thermal and
solvation corrections follow the same trend in favoring
13a -sf over the rest of the TS. Thus, the energy differ-
ence between nucleophilic attack at the less and the more
hindered positions is calculated to be greater than 4 kcal
mol-1, which is in qualitative agreement with the high
regioselectivity observed in the reactions of 8a .
13b-sh and 13b-a h (0.345 and 0.342 for 13b-sf and
13b-a f, and 0.386 and 0.400 for 13b-sh and 13b-a h ,
respectively). On the other hand, and in a similar way
to that found for TS 13a , the N-C bond-forming distance
is longer in the case of 13b-sh and 13b-a h , which can
be attributed to greater steric interactions in these TS.
From the energy viewpoint, the gas-phase calculations
lead to conclusions similar to those found for TS 13a , i.e.,
13b-sf is the lowest energy TS, showing that the intrinsic
stereoelectronic effects are in the same sense for both
kinds of structures. However, the situation dramatically
changes when solvent effects are taken into account. The
TS 13b-a h is preferentially solvated in comparison to
13b-sf by ca. 3.5 kcal mol-1. This preferential solvation
leads to a reverse regioselectivity for this reaction, with
nucleophilic attack at the most hindered CR position now
being favored by ca. 1.6 kcal mol-1, which is again in
qualitative agreement with the experimental results.
As a referee noted, solvation effects may be sensitive
to the basis set size. Given that solvation is so critical in
determining the relative stability of these TS, we carried
out single-point energy calculations at the IPCM/B3LYP/
6-311++G(2d,p) level for 13b-a h and 13b-sf. The quali-
tative conclusions reached with the 6-31+G(d) basis set
do not change, and thus, the preferential solvation of
13b-a h is ca. 2.6 kcal mol-1, whereas this TS is lower in
energy than 13b-sf by ca. 0.8 kcal mol-1, when all the
energy corrections are taken into account.
Another possible source of error in correctly assigning
the role of the solvent in the regioselectivity is the neglect
of cavitation and dispersion terms of the solvation energy
by the IPCM method. To test this point, single-point
energy calculations were carried out at the PCM/B3LYP/
6-31+G(d) level for 13b-a h and 13b-sf. Unfortunately,
dimethylformamide is not parametrized in Gaussian 98,
so that these solvation terms cannot be calculated for this
solvent. We then considered nitromethane as a reason-
able substitute, because it is parametrized, and has the
same dielectric permittivity (38.2) as dimethylformamide,
so that the electrostatic component of the solvation
energy will be essentially the same. The results obtained
are shown in Table 2.
In transition structures 13b (Figure 3) the same
features as described for TS 13a are reproduced. Thus,
the C-O breaking bond distance is shorter for 13b-sf
and 13b-a f, indicating an earlier TS for the nucleophilic
attack at the less-hindered position. The natural popula-
tion analysis also agrees with this conclusion, since the
charge transfer is lower for these TS when compared with
4510 J . Org. Chem., Vol. 68, No. 11, 2003

Ring-Opening Reactions of gem-Disubstituted Cyclic Sulfates
TABLE 2. P CM/B3LYP /6-31+G(d ) Ca lcu la ted Solva tion
the reaction coordinate. Although we believe that this is
the case, we think that the reoptimization of the TS in
the presence of the reaction field will result in an
enhancement of solvent effects, as already demonstrated
in other cases,17,22 but will not cause changes in the
relative stability of the TS with regard to that observed
in the single-point energy calculations.
En er gy Ter m s (in k ca l m ol-1) for Tw o Selected TS
TS
EElec
∆EElec
ECav
∆ECav
EDisp
∆EDisp
13b-sf
13b-a h
-42.21
0.00 23.89
-43.73 -1.52 23.96
0.00
0.07
-22.74
-22.74
0.00
0.00
TABLE 3. Ch a r ge Tr a n sfer fr om th e Azid e An ion to th e
Su lfa te Rea cta n t in th e TS, Ca lcu la ted fr om Na tu r a l
P op u la tion An a lyses, a t th e B3LYP /6-31+G(d ) (ga s p h a se)
a n d IP CM/B3LYP /6-31+G(d ) (solu tion ) Levels
Experimental support would also help to clarify the
role of solvent effects on the regioselectivity of these
reactions. On one hand, the reaction of 8b in solvents
that are less polar than DMF should lead to lower or even
reverse regioselectivity as a result of a lower differential
solvation of 13b-a h . Several experiments were carried
out with acetone (ꢀ ) 20.70), but the solubility of the
sodium azide was too low in this solvent and the reaction
does not proceed at an appreciable rate. On the other
hand, reaction of 8c in solvents that are more polar than
DMF should also lead to lower regioselectivity, this time
due to a greater differential solvation of 13c-a h . A
reaction carried out in dimethyl sulfoxide (DMSO, ꢀ )
46.68) led to a regioselectivity of 5:1, somewhat lower
than the 6:1 observed in DMF. When the dielectric
permittivity of the solvent was further increased by using
N-methyl formamide (ꢀ ) 182.4), the regioselectivity
dropped to 3.6:1. The linear correlation between the
Kirkwood function23 (ꢀ - 1)/(2ꢀ + 1) and the ∆∆G
calculated at 298 K from the experimental regioselectivity
values is excellent (r ) 0.990). These results do support
the conclusions reached from the theoretical study.
Unfortunately, solubility of the reagents and low nucleo-
philicity of the solvent are two prerequisite conditions
and these limit the choice of solvents for an experimental
investigation into the key role of solvent effects on the
regioselectivity of these reactions.
TS
gas phase
solution
13a -sf
13a -a h
13b-sf
13b-a h
13c-sf
13c-a h
0.312
0.393
0.345
0.400
0.321
0.376
0.279
0.390
0.341
0.345
0.312
0.353
As can be seen, in agreement with our former hypoth-
esis, the cavitation and dispersion terms cancel out
almost perfectly, so that the differential solvation energy
between both TS is practically the same as the dif-
ferential electrostatic solvation energy, which is, in turn,
very similar to the value calculated at the IPCM/B3LYP/
6-31+G(d) level.
In transition structures 13c (Figure 4) the same
geometrical features as described for TS 13a and 13b are
reproduced. Therefore, in principle, it can be concluded
that the three sulfates have the same intrinsic behavior
from a mechanistic point of view.
In terms of energy, TS 13c shares some features of both
13a and 13b. Thus, the results of gas-phase calculations
show that 13c-sf is the lowest energy TS, which is
analogous to the situation found for TS 13a and 13b.
Furthermore, the differential solvation favors TS 13c-a h
over 13c-sf, again in an analogous way to 13b. However,
contrary to the latter TS, this differential solvation is not
sufficiently high to reverse the relative stability of the
two TS, and therefore 13c-sf continues to be the lowest
energy TS even when solvation effects are taken into
account.
It can be concluded that the intrinsic features of the
TS for the three sulfates are very similar, which indicates
similar stereoelectronic effects acting in all cases. How-
ever, there are important subtle changes due to the
different electronic effects of the sulfate substituents, and
these result in differential stabilization of one or another
TS because of solvent effects. The natural population
analysis of the TS, both in the gas phase and in solution,
sheds some light on this point. The most relevant results
are shown in Table 3.
Con clu sion s
The regioselectivity of the nucleophilic ring-opening
reactions of three gem-disubstituted cyclic sulfates with
sodium azide depends on the substituent present in the
cyclic sulfate. Amide substituents lead preferentially to
products arising from nucleophilic attack at the least-
substituted Câ position, whereas reverse regioselectivity
is obtained with ester substituents. This is advantageous
from a synthetic point of view, since it allows one or
another regioisomer to be obtained preferentially with
selectivities greater than 4:1.
Theoretical calculations show that, contrary to the
previously accepted situation, the intrinsic preference in
all cases is for azide attack at the least-substituted Câ
position on the basis of similar stereoelectronic effects
acting on the TS of the three sulfates considered. The
observed preference for CR attack in the case of the ester
sulfate is explained in terms of differential solvent effects,
which are in turn due to subtle differences in the charge
transfer of the different transition structures.
As can be seen, the behavior of the charge transfer
follows the observed solvation pattern. Thus, in the case
of 13a -a h , the charge transfer is almost the same in both
the gas phase and solution, whereas it is smaller for
13a -sf in solution than in the gas phase. This results in
a preferential solvation of the latter due to a greater
charge localization. The situation is reversed for TS 13b
and 13c. Here, TS 13b-a h and 13c-a h show smaller
charge-transfer values in solution than in the gas phase,
as compared with 13b-sf and 13c-sf, thus resulting in
preferential solvation of the former.
Exp er im en ta l Section
Gen er a l P r oced u r es. Unless otherwise stated, all starting
materials were obtained from commercial suppliers and used
without further purification. Melting points are uncorrected.
(22) Assfeld, X.; Ruiz-Lo´pez, M. F.; Garc´ıa, J . I.; Mayoral, J . A.;
Salvatella, L. J . Chem. Soc., Chem. Commun. 1995, 1371-1372.
(23) Kirkwood, J . G. J . Chem. Phys. 1934, 2, 351-361.
It can be argued that, under these conditions, solvent
effects must also be relevant for the position of the TS in
J . Org. Chem, Vol. 68, No. 11, 2003 4511

Avenoza et al.
All manipulations involving air-sensitive reagents were carried
out under a dry argon atmosphere with standard Schlenk
techniques. Solvents were purified according to standard
procedures. Analytical TLC was performed with use of pre-
coated plastic sheets of 40 × 80 mm2. Column chromatography
was performed with silica gel 60 (230-400 mesh). Organic
solutions were dried over anhydrous Na2SO4 and, when
necessary, concentrated under reduced pressure by using a
rotary evaporator. NMR spectra were recorded at 300 MHz
(1H) and at 75 MHz (13C) and are reported in ppm downfield
from TMS. Microanalyses were in good agreement with the
calculated values. Mass spectra were obtained by electrospray
ionization (ESI).
Anal. Calcd for C6H13NO3: C, 48.97; H, 8.90; N, 9.52. Found:
C, 48.79; H, 8.98; N, 9.60.
(S)-4-Met h yl-2-oxo-2λ4-[1,3,2]d ioxa t h iola n e-4-ca r b ox-
ylic Acid N-Meth oxy-N-m eth yla m id e (7a ). Column chro-
matography on silica gel, eluting with hexane/ethyl acetate
(6:4), gave 6.19 g of sulfite 7a of S-configuration (90%). [R]25
D
+36.6 (c 1.04, MeOH). 1H NMR (CDCl3) δ 1.52 (s, 3H), 1.77 (s,
3H), 3.06-3.16 (m, 6H), 3.66 (s, 6H), 4.20 (d, 1H, J ) 9.0 Hz),
4.35 (d, 1H, J ) 9.0 Hz), 5.10 (d, 1H, J ) 3.6 Hz), 5.13 (d, 1H,
J ) 3.6 Hz). 13C NMR (CDCl3) δ 21.8, 22.3, 33.0, 61.1, 73.3,
73.9, 87.8, 89.1, 168.0. ESI+ (m/z) 210. Anal. Calcd for C6H11
-
NO5S: C, 34.44; H, 5.30; N, 6.69. Found: C, 34.37; H, 5.33;
N, 6.65. Duplication of some signals was observed in the 1H
and 13C NMR spectra, indicating the existence of two conform-
ers in solution.
Gen er a l P r oced u r e for t h e Gen er a t ion of Cyclic
Su lfites. The corresponding diol 6 (32.8 mmol) was dissolved
in CCl4 (60 mL) and SOCl2 (7.74 g, 42.6 mmol) was then added.
The resulting solution was heated under reflux for 4 h. The
solvent and excess SOCl2 were evaporated and the crude
product was purified by column chromatography to give the
corresponding sulfite 7 as a colorless liquid.
4-Met h yl-2-oxo-2λ4-[1,3,2]d ioxa t h iola n e-4-ca r b oxylic
Acid N,N-Dim eth yla m id e (7c). Column chromatography on
silica gel, eluting with hexane/ethyl acetate (1:1), gave 5.72 g
of sulfite 7c (91%). 1H NMR (CDCl3) δ 1.58 (s, 3H), 1.78 (s,
3H), 2.85-2.93 (m, 6H), 3.10-3.20 (m, 6H), 4.25 (d, 1H, J )
9.0 Hz), 4.37 (d, 1H, J ) 9.0 Hz), 5.20 (d, 1H, J ) 3.6 Hz),
5.34 (d, 1H, J ) 3.6 Hz). 13C NMR (CDCl3) δ 22.9, 23.3, 36.8,
37.2, 37.8, 37.9, 75.1, 75.2, 88.5, 89.4, 168.1, 168.6. Anal. Calcd
for C6H11NO4S: C, 37.30; H, 5.74; N, 7.25. Found: C, 37.47;
H, 5.73; N, 7.28. Duplication of some signals was observed in
the 1H and 13C NMR spectra, indicating the existence of two
conformers in solution.
Gen er a l P r oced u r e for th e Gen er a tion of Cyclic Su l-
fa tes. Compound 7 (2.78 mmol) was dissolved in a mixture of
water (15 mL), MeCN (10 mL), and CCl4 (10 mL). NaIO4 (1.16
g, 5.42 mmol) and RuCl3 hydrate (10 mg, 0.05 mmol) were
added and the solution was vigorously stirred for 7 h at 40
°C. Ethyl ether (75 mL) was added to the cooled mixture. The
organic layer was removed, dried (Na2SO4), and concentrated.
The crude product was chromatographed to give the corre-
sponding compound 8 as a colorless liquid.
(S)-4-Met h yl-2,2-d ioxo-2λ6-[1,3,2]d ioxa t h iola n e-4-ca r -
boxylic Acid N-Meth oxy-N-m eth yla m id e (8a ). Column
chromatography on silica gel, eluting with hexane/ethyl acetate
Gen er a l P r oced u r e for R in g-Op en in g R ea ct ion s of
Su lfites. To a solution of cyclic sulfite 7 (31.6 mmol) in DMF
(30 mL) was added NaN3 (2.72 g, 41.8 mmol). The mixture
was stirred at 50 °C for 48 h to give a mixture of azido alcohols
11 and 12. The solvent was removed and the residue parti-
tioned between H2O (30 mL) and ethyl acetate (70 mL). The
aqueous layer was successively washed with ethyl acetate (4
× 40 mL), the combined organic layers were dried (Na2SO4)
and concentrated, and the crude product was chromatographed
to give â-azido R-alcohol 11 and R-azido â-alcohol 12 as
colorless liquids.
(6:4), gave 576 mg of sulfate 8a of S-configuration (92%). [R]22
D
1
+8.1 (c 0.65, MeOH). H NMR (CDCl3) δ 1.83 (s, 3H), 3.25 (s,
3H), 3.78 (s, 3H), 4.41 (d, 1H, J ) 9.0 Hz), 5.31 (d, 1H, J ) 9.0
Hz). 13C NMR (CDCl3) δ 21.4, 32.9, 61.5, 75.3, 88.0, 166.6. ESI+
(m/z) 226. Anal. Calcd for C6H11NO6S: C, 32.00; H, 4.92; N,
6.22. Found: C, 31.87; H, 4.91; N, 6.19.
4-Met h yl-2,2-d ioxo-2λ6-[1,3,2]d ioxa t h iola n e-4-ca r b ox-
ylic Acid N,N-Dim eth yla m id e (8c). Column chromatogra-
phy on silica gel, eluting with hexane/ethyl acetate (1:1), gave
448 mg of sulfate 8c (77%). 1H NMR (CDCl3) δ 1.80 (s, 3H),
2.98 (s, 3H), 3.16 (s, 3H), 4.45 (d, 1H, J ) 9.3 Hz), 5.24 (d, 1H,
J ) 9.3 Hz). 13C NMR (CDCl3) δ 22.4, 37.1, 37.6, 76.7, 88.3,
166.5. Anal. Calcd for C6H11NO5S: C, 34.44; H, 5.30; N, 6.69.
Found: C, 34.41; H, 5.38; N, 6.63.
Gen er a l P r oced u r e for R in g-Op en in g R ea ct ion s of
Su lfa tes. Meth od A: To a stirred solution of cyclic sulfate 8
(31.6 mmol) in DMF (30 mL) was added NaN3 (2.72 g, 41.8
mmol). The mixture was stirred at 50 °C for 2 d to give a
mixture of acyclic azido sulfates 9 and 10. The reaction was
concentrated under reduced pressure, ethyl ether (30 mL) and
water (1 mL) were added, and the solution was chilled to 0
°C. Aqueous H2SO4 (20%; 3 mL) was added and the solution
was vigorously stirred at room temperature for 2 d. The
organic layer was collected and concentrated, and the crude
product was chromatographed to give â-azido R-alcohol 11 and
R-azido â-alcohol 12 as colorless liquids. Meth od B: To a
solution of cyclic sulfate 8 (2.14 mmol) in acetone (20 mL) and
water (2 mL) was added NaN3 (0.35 g, 5.38 mmol). The mixture
was stirred at room temperature for 96 h to give a mixture of
acyclic azido sulfates 9 and 10. Compounds 11 and 12 were
obtained following the same protocol as described above for
Method A.
(S)-3-Azid o-2-h yd r oxy-N-m eth oxy-2,N-d im eth ylp r op i-
on a m id e (11a ). Starting from sulfite 7a and after column
chromatography on silica gel, eluting with hexane/ethyl acetate
(3:7), 4.55 g of â-azido R-alcohol (S)-11a (76%) was obtained.
Compound (S)-11a : [R]24 -68.9 (c 1.97, MeOH). 1H NMR
D
(CDCl3) δ 1.41 (s, 3H), 3.28 (s, 3H), 3.45-3.50 (m, 2H), 3.70
(s, 3H). 13C NMR (CDCl3) δ 22.8, 33.5, 57.4, 60.9, 75.8, 173.6.
ESI+ (m/z) 188 + Na. Anal. Calcd for C6H12N4O3: C, 38.29; H,
6.43; N, 29.77. Found: C, 38.21; H, 6.41; N, 29.71.
(R)-2-Azid o-3-h yd r oxy-N-m eth oxy-2,N-d im eth ylp r op i-
on a m id e (12a ). Starting from sulfite 7a and after column
chromatography on silica gel, eluting with hexane/ethyl acetate
(3:7), 803 mg of R-azido â-alcohol (R)-12a (13%) was obtained.
1
[R]22 +61.6 (c 0.96, MeOH). H NMR (CDCl3) δ 1.50 (s, 3H),
D
3.22 (s, 3H), 3.55-3.85 (m, 5H). 13C NMR (CDCl3) δ 17.6, 33.2,
60.9, 66.6, 68.6, 171.6. ESI+ (m/z) 188 + Na. Anal. Calcd for
C6H12N4O3: C, 38.29; H, 6.43; N, 29.77. Found: C, 38.20; H,
6.42; N, 29.74.
2,3-Dih yd r oxy-2,N,N-tr im eth ylp r op ion a m id e (6c). To
a solution of 5c (0.95 g, 8.41 mmol) in acetone/H2O (4:1) (68
mL) at 0 °C were added NMO (4.90 g, 42.05 mmol) and OsO4
(9 mL, 0.84 mmol, 2.5% w). The mixture was stirred at room
temperature for 24 h. The acetone was evaporated and the
residue partitioned between H2O (30 mL) and ethyl acetate
(70 mL). The aqueous layer was washed with ethyl acetate (4
× 40 mL), the combined organic extracts were dried (Na2SO4)
and concentrated, and the crude product was chromatographed
with methanol/ethyl acetate (5:95) to give diol 6c as an oil
(70%). 1H NMR (CDCl3) δ 1.33 (s, 3H), 2.93 (br s, 3H), 3.20
(br s, 3H), 3.39 (d, 1H, J ) 12.0 Hz), 3.94 (d, 1H, J ) 12.0 Hz),
4.36 (br s, 2H). 13C NMR (CDCl3) δ 14.0, 21.4, 60.3, 69.2, 174.0.
3-Azido-2-h ydr oxy-2,N,N-tr im eth ylpr opion am ide (11c).
Starting from sulfate 8c and after column chromatography on
silica gel, eluting with hexane/ethyl acetate (1:1), 291 mg of
â-azido R-alcohol 11c (79%) was obtained. Compound 11c: 1H
NMR (CDCl3) δ 1.44 (s, 3H), 2.90-3.19 (m, 6H), 3.40 (d, 1H,
J ) 12.6 Hz), 3.64 (d, 1H, J ) 12.6 Hz). 13C NMR (CDCl3) δ
23.2, 38.0, 58.8, 75.4, 172.9. Anal. Calcd for C6H12N4O2: C,
41.85; H, 7.02; N, 32.54. Found: C, 41.79; H, 7.04; N, 32.59.
2-Azido-3-h ydr oxy-2,N,N-tr im eth ylpr opion am ide (12c).
Starting from sulfate 8c and after column chromatography on
4512 J . Org. Chem., Vol. 68, No. 11, 2003

Ring-Opening Reactions of gem-Disubstituted Cyclic Sulfates
silica gel, eluting with hexane/ethyl acetate (1:1), R-azido
â-alcohol 12c was obtained as a mixture with 11c. Compound
12c: 1H NMR (CDCl3) δ 1.35 (s, 3H), 2.95-3.26 (m, 6H), 3.77
(d, 1H, J ) 12.3 Hz), 3.98 (d, 1H, J ) 12.3 Hz).
B02) for financial support.
Su p p or tin g In for m a tion Ava ila ble: Tables of electronic
energies, as well as entropies, Gibbs free energies (the last
three data series at 25 °C), lowest frequencies, and Cartesian
coordinates for the different conformations of the structures
considered in this work. This material is available free of
charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We thank the Ministerio de
Ciencia y Tecnolog´ıa (projects PPQ2001-1305 and
PPQ2002-04012), Gobierno de La Rioja (project ANGI-
2001/30), and Universidad de La Rioja (project API-01/
J O034178Q
J . Org. Chem, Vol. 68, No. 11, 2003 4513