Regio- and stereoselectivity of the addition of O-, S-, N-, and C-nucleophiles to the β vinyl oxirane derived from D-glucal

Article abstract of DOI:10.1021/jo048981b

6-O-Trityl- (1a) and 6-(O-benzyl)-substituted epoxide (1b) derived from D-glucal were examined in their addition reactions with O-, C-, N-, and S-nucleophiles. A 1,4-regio- and β-stereoselective or an anti 1,2-addition pathway is commonly observed dependi

Full text of DOI:10.1021/jo048981b

Regio- and Stereoselectivity of the Addition of O-, S-, N-, and
C-Nucleophiles to the â Vinyl Oxirane Derived from D-Glucal
Valeria Di Bussolo, Micaela Caselli, Maria Rosaria Romano, Mauro Pineschi, and
Paolo Crotti*
Dipartimento di Chimica Bioorganica e Biofarmacia, Universita` di Pisa,
Via Bonanno 33, 56126 Pisa, Italy
crotti@farm.unipi.it
Received June 17, 2004
6-O-Trityl- (1a) and 6-(O-benzyl)-substituted epoxide (1b) derived from D-glucal were examined in
their addition reactions with O-, C-, N-, and S-nucleophiles. A 1,4-regio- and â-stereoselective or
an anti 1,2-addition pathway is commonly observed depending on the ability of the nucleophile to
coordinate with the oxirane oxygen. When TMSN3 or LiN3 are used as azide-based nucleophiles, a
1,2-syn-addition pathway is also observed.
SCHEME 1
Introduction
2-Unsaturated glycosides (pseudoglycals) are valuable
synthetic intermediates, since the unsaturation can be
further functionalized for the preparation of structural
units present in many natural, biologically active com-
pounds.1
In an attempt to devise a new method for the synthesis
of substituted pseudoglycals, epoxides 1a and 1b, differ-
ing only for the type of the 6-O-protecting group (trityl
or benzyl), appeared to be particularly interesting. Ep-
oxides 1a,b are at the same time glycals and vinyl
oxiranes. As vinyl oxiranes, they are characterized by a
double reactivity when subjected to a nucleophilic addi-
tion reaction: the nucleophile can attack (i) at the C(1)
vinyl terminus of the “conjugate system” through a
typical 1,4-addition pathway (conjugate addition or SN2′
process, route a) to yield R- and/or â-2-unsaturated
glycosides (pseudoglycals), hereafter generically called R-
and â-1,4-adducts, and (ii) at the allylic C(3) oxirane
carbon to give substituted glycals through a direct,
commonly completely anti 1,2-addition process (SN2
process, route b) to give substituted glycals, hereafter
generically called anti-1,2-adducts (Scheme 1).2 The C(1)
of the vinyl oxirane system also corresponds to the classic
reactive site of any glycal system, such as epoxides 1a,b
are. The regio- and stereochemical behavior of 1a with
O-nucleophiles (alcohols, phenol, and diacetone-D-glucose)3a
and of 1b with C-nucleophiles (Grignard reagents, di-
alkyllithium cuprates, and lithium alkyls)3b has been
previously described. Further results obtained with O-
and C-nucleophiles and new results obtained with S- and
SCHEME 2
N-nucleophiles together with a comprehensive examina-
tion of the behavior of these vinyl oxiranes in nucleophilic
addition reactions are now reported.
Results and Discussion
The synthesis of epoxides 1a,b starts from the com-
mercially available tri-O-acetyl-D-glucal (2) and proceeds
through a simple protection-deprotection protocol, as
shown in Scheme 2.3
Epoxides 1a and 1b are not sufficiently stable to be
isolated, but they can be only prepared in situ by
cyclization of the corresponding ultimate precursor, the
hydroxy mesylate 7a and 7b, respectively, under alkaline
conditions (t-BuOK) and then left to react immediately
with a nucleophile (O-, C-, N-, and S-nucleophiles).
O-Nucleophiles. The addition reaction of alcohols
(MeOH, EtOH, i-PrOH, t-BuOH) to epoxide 1a (alcohol
* To whom correspondence should be addressed. Tel: +39 050
2219690, Fax: +39 050 2219660.
(1) (a) Takhi, M.; Abdel-Rahman, A. A.-H.; Schmidt, R. R. Synlett
2001, 427 and references therein. (b) Linde, R. G., II; Egbertson, M.;
Coleman, R. S.; Jones, A. B.; Danishefsky, S. J. J. Org. Chem. 1990,
55, 2771.
(2) Yamamoto, Y. In Stereoselective Synthesis (Houben-Weyl); Helm-
chem, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme
Verlag: Stuttgart, 1996; Vol. 4, pp 2029-2040.
(3) (a) Di Bussolo, V.; Caselli, M.; Pineschi, M.; Crotti, P. Org. Lett.
2002, 4, 3695. (b) Di Bussolo, V.; Caselli, M.; Pineschi, M.; Crotti, P.
Org. Lett. 2003, 5, 2173, and references therein.
10.1021/jo048981b CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/13/2004
8702
J. Org. Chem. 2004, 69, 8702-8708

Addition of O-, S-, N-, and C-Nucleophiles to the â Vinyl Oxirane
TABLE 1. Regio- and Stereoselectivity of the Addition Reaction of O-Nucleophiles to the in Situ Prepared Epoxides 1a
and 1b
entry
epoxide
glycosyl acceptor (R2OX) (protocol)a
solvent
time (h)
product(s)
yield (%)
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1a
1b
1a
1a
1b
1a
1b
MeOH (A)
MeOH
0.5
0.5
0.5
0.5
0.5
2
8aâ (50%)/8aR (50%)
90b
83b
93b
92c
85c
91c
78c
91c
89c
76c
69c
64c
75c
63c
64c
93c
54c
49c
97b
92b
EtOH (A)
EtOH
9aâ (75%)/9aR (25%)
3
i-PrOH (A)
i-PrOH
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
THF
10aâ (95%)/ 10aR (5%)
4
MeOH (B)
8aâ
5
EtOH (B)
9aâ
6
i-PrOH (B)
10aâ
7
t-BuOH (B)
2
11aâ
8
BnOH (B)
3
12aâ
9
PhOH (B)
3
13aâ
10
11
12
13
14
15
16
17
18
19
20
diacetone D-glucose (B)
MeOH (B)
2
14aâ
18
1
8bâ
i-PrOH (B)
10bâ
diacetone D-glucose (B)
MeONa (B)
18
18
18
3
14bâ
8aâ
MeONa (B)
i-PrONa (B)
8bâ
10aâ
10aâ (60%)/16a (40%)
8bâ (60%)/15b (40%)
15a
i-PrONa/15-Crown-5 (B)
MeONa/15-Crown-5 (B)
MeO- Bu4N+ (B)
MeO- Bu4N+ (B)
18
18
1
THF
THF
1
15b
a A ) protocol A: R2OX as the solvent/nucleophile; B ) protocol B: benzene or THF as the solvent, R2OX,) 3-4 equiv. b Crude product.
c After purification by flash chromatography.
used as the solvent/nucleophile, protocol A)4 afforded the
corresponding O-glycosides (1,4-adducts) in a completely
1,4-regioselective way, but with a stereoselectivity de-
pending on the type of alcohol used.3a In fact, if in the
reaction carried out in MeOH an almost 1:1 mixture of
anomeric 2-unsaturated methyl R- and â-glycosides 8aR
and 8aâ was obtained, the use of more hindered alcohols
such as EtOH and i-PrOH led to an increased C(1)-â-
selectivity with a R/â ratio 25:75 and 5:95, respectively
(entries 1-3, Table 1). Only when a reduced amount of
alcohol (3 equiv) is added to the epoxide preformed in a
benzene solution (protocol B)4 is a completely 1,4-regio-
and â-stereoselective process obtained with the exclusive
formation of corresponding â-O-glycosides 8a-11aâ.
Under these conditions, PhOH and BnOH could also be
added in the same regio- and stereoselective fashion to
afford â-O-glycosides 12aâ and 13aâ, respectively. In this
way, a new â-stereoselective glycosylation procedure was
found, which turned out to be useful also for the synthesis
of a disaccharide (14aâ) when diacetone-D-glucose was
used as the glycosyl acceptor (entries 4-10, Table 1).3a
Control experiments now carried out, under protocol
B, on epoxide 1b in the reaction with MeOH, i-PrOH,
and diacetone-D-glucose, as the glycosyl acceptors, af-
forded the corresponding â-O-glycosides 8bâ, 10bâ, and
14bâ in a completely regio- and stereoselective way,
SCHEME 3
indicating that the behavior of epoxide 1b is practically
identical to that of epoxide 1a (entries 11-13, Table 1).5
The regio- and stereochemical behavior of epoxides
1a,b with O-nucleophiles was examined also with an
alcoholate such as MeONa (1a and 1b) and i-PrONa (1a)
(protocol B).4 Contrary to our expectations, according to
which a complete 1,2-addition process appeared likely
under these typical alkaline SN2 conditions in the pres-
ence of a strong nucleophile, a complete 1,4-regio- and
â-stereoselective process was observed, as in the case of
alcohols (entries 14-16, Table 1).
The complete regio- and stereoselective result obtained
in the addition reaction of O-nucleophiles (alcohols and
alcoholates) to epoxides 1a and 1b can be rationalized
by a coordination between the oxirane oxygen and the
nucleophile through a hydrogen bond (alcohols) or the
metal (alcoholates) as shown in structures 17 and 18,
respectively (Scheme 3). In this way, the nucleophile is
efficiently transported on the â-face of the vinyl oxirane
system and appropriately arranged for an entropically
(4) In the reactions carried out under protocol A, hydroxy mesylate
7a (or 7b) was treated with t-BuOK in the alcohol (MeOH, EtOH,
i-PrOH, and t-BuOH) as the solvent. In the reactions carried out under
protocol B, hydroxy mesylate 7a (or 7b) was treated with t-BuOK in
anhydrous solvent (benzene, MeCN, Et2O, THF); the nucleophile (3-4
equiv) was then added. In the reactions carried out under protocol C,
hydroxy mesylate 7b was treated with R2MgBr (R2 ) Me, Ph, 3 equiv)
in anhydrous Et2O.
(5) For this reason, epoxides 1a and 1b were indifferently used in
this work in order to study the behavior of this particular vinyl oxirane
system in addition reactions with nucleophiles.
J. Org. Chem, Vol. 69, No. 25, 2004 8703

Di Bussolo et al.
SCHEME 4
favored â-directed conjugate addition, as experimentally
found. Confirmation of this rationalization was obtained
in the reaction of epoxides 1b and 1a with MeONa and
i-PrONa, respectively, in the presence of 15-crown-5, the
crown ether specific for Na+. In these modified reaction
conditions, the corresponding â-1,4-adduct 8bâ and 10aâ
was still present in the crude reaction mixture (nearly
60%), but a substantial amount of the corresponding anti
1,2-adduct, the hydroxy ether (HE) 15b and 16a, respec-
tively, was also obtained (nearly 40%) (entries 17 and
18, Table 1 and Scheme 4). Evidently, as a consequence
of the sequestering ability of the crown ether, under these
conditions, the epoxide is not entirely coordinated with
the nucleophile and an equilibrium exists between coor-
dinated and noncoordinated epoxide molecules (struc-
tures 18 and 19, respectively, Scheme 4). While in the
former, the nucleophilic attack can effectively occur from
the coordinated nucleophile to give the â-1,4-adduct
(route a), as stated above, the latter can react only with
the free, noncoordinated nucleophile. In this case, the
nucleophilic attack occurs necessarily at the C(3) allylic
oxirane carbon (route b), which, in the absence of any
other factors, is the most reactive position in these vinyl
oxirane systems,6 and the corresponding 1,2-adduct (15b
and 16a) was obtained in a completely anti fashion in
accordance with a classic SN2-type oxirane ring-opening
mechanism under the basic reaction conditions. These
results indicate that in order to have a complete 1,2-
addition pathway with O-nucleophiles, and probably also
with other types of nucleophiles, in oxirane systems such
as 1a and 1b, it is necessary to use a nucleophile which
is not able to coordinate with the oxirane oxygen through
a hydrogen bond or a counterion with a Lewis acid (LA)
character. In this framework, we thought that tetrabu-
tylammonium methoxide (Bu4N+OMe-), a reagent not
able to give a hydrogen bond and bearing a counterion
(Bu4N+) with no LA properties, might be the appropriate
reagent in order to have a complete 1,2-addition by the
MeO- species.7
The reaction of epoxides 1a and 1b with Bu4N+OMe-
(3 equiv, protocol B) in anhydrous THF resulted in a very
clean reaction affording the corresponding, practically
pure, anti 1,2-adduct, HE 15a and 15b, respectively, in
a completely 1,2-regio- and anti stereoselective fashion
(Scheme 4 and entries 19 and 20, Table 1). To date, this
is the only protocol available in order to obtain this class
of compounds.
S-Nucleophiles. Thiols such as PhSH and EtSH and
a thiolate such as MeSNa were considered as typical
S-nucleophiles. If compared with the corresponding reac-
tion with alcohols, the addition reaction of PhSH and
EtSH to epoxide 1a (protocol B)4 led to the obtainment
of the corresponding anti-1,2-adduct (hydroxy thioethers
20a and 21a, respectively, Scheme 5) as largely the main
(in the case of PhSH) or the sole reaction product (in the
case of EtSH). Only in the case of PhSH, a slight, even if
significant, amount (15%) of the corresponding â-1,4-
adduct, the â-phenyl thioglycoside 25aâ, was observed.
In the framework of the rationalization previously used
for the corresponding reaction with alcohols, the reduced
ability of thiols, with respect to alcohols, to coordinate
with the oxirane oxygen considerably reduces the amount,
in the reaction medium, of a coordinated species such as
24, the only one which can lead to the â-1,4-adduct 25-
26aâ (route a, Scheme 5), to the point that this type of
addition is not experimentally observed with the less
acidic EtSH (pKa ) 10.78) or observed only at a slight
extent with the more acidic PhSH (pKa ) 6.61). As a
consequence, under these conditions most of the epoxide
is not coordinated with the nucleophile, and the reaction
with the free thiol can occur only at the C(3) allylic
oxirane carbon (route b, Scheme 5), to yield the anti-1,2-
adduct, as observed. Also with MeSNa a complete 1,2-
anti addition pathway is observed with exclusive obtain-
ment of the methylthio alcohol 22a3a to indicate that the
free, noncoordinated corresponding nucleophile should be
involved under these reaction conditions.8
N-Nucleophiles. Azide ion and diethylamine were
taken as examples of N-nucleophiles. The reaction of
epoxides 1a with NaN3 in MeCN led only to the recovery
of the unreacted starting epoxide, due to the scarce
solubility of the salt in the solvent. In the search for a
source of azide ion soluble in an organic solvent, but
(6) Jaime, C.; Ortun˜o, R. M.; Font, J. J. Org. Chem. 1988, 53, 139.
(7) This new reagent (Bu4N+OMe-) consists of the oily residue
derived from the complete solvent evaporation of the commercially
available 1 M Bu4N+OH- in MeOH: 1H NMR δ 3.26 (s, 3H), 3.12-
3.24 (m, 8H), 1.42-1.63 (m, 8H), 1.33 (sextet, 8H, J ) 7.2 Hz), 0.87 (t,
12H, J ) 7.2 Hz).
8704 J. Org. Chem., Vol. 69, No. 25, 2004

Addition of O-, S-, N-, and C-Nucleophiles to the â Vinyl Oxirane
SCHEME 5
SCHEME 6
epoxide 1a with TMSN3 in anhydrous benzene (protocol
B) turned out to be neither regio- nor stereoselective, and
yielded a reaction mixture containing three addition
products, the trans azido alcohol 28a (anti 1,2-adduct),
the 4-O-TMS derived â-azido glycoside 30aâ (â-1,4-
adduct), and, surprisingly, the cis azido alcohol 29a
(syn 1,2-adduct) in a 16:45:39 ratio (1H NMR) (Scheme
7).10 The diastereoisomeric relationship between azido
alcohols 28a and 29a was clearly established by ap-
propriate decoupling and NOE experiments (1H NMR)
and was confirmed by their oxidation (PCC/CH2Cl2) to
azido ketones 31a and 32a, respectively, whose diaste-
reoisomeric relationship was determined as well (1H
NMR).
On the basis of the experience gained in the studies
carried out on the stereoselectivity of the acid solvolysis
of 2-aryloxiranes, an oxirane system in which substantial
amounts of the corresponding syn adduct are commonly
observed,11 the results obtained in the reaction of 1a with
TMSN3 can be rationalized by admitting the incursion
in the reaction medium, after “protonation” of the oxirane
oxygen by the TMS- group of the reagent, of two
equilibrating intermediate species, 33 and 34 (Scheme
7). In the intimate ion/dipole pair 33, in which the allylic
C(3)-O oxirane bond is not yet broken, but only consid-
erably extended, the nucleophilic attack can reasonably
occur (i) at C(1) by the azido group coordinated to the
oxirane oxygen through the TMS- group to give the
â-1,4-adduct 30aâ (route a) or (ii) at the allylic oxirane
C(3) by a noncoordinated azido nucleophile to give the
anti 1,2-adduct 28a (route b). Internal rearrangement of
33 with further loosening of the dipole (O-TMS-) from
the allylic carbenium ion leads to the nucleophile sepa-
rated ion/dipole pair 34, in which the allylic oxirane bond
is now completely broken and an extended coordination
between the carbocationic center and the coordinated
azido group is present. In 34, the attack by the internal
nucleophile with retention of configuration to give the
cis azido alcohol 29a (the syn 1,2-adduct, route c) rather
than by an external one with inversion of configuration
(route d), appears to be favored by entropic factors.11 The
different from the common trimethylsilyl azide (TMSN3,
vide infra), tetramethylguanidinium azide (TMGA)9 was
thought to be appropriate and interesting to evaluate.
TMGA is soluble in an organic solvent such as MeCN
and, interestingly, is characterized by the presence of a
counterion (tetramethylguanidinium, TMG+) with no LA
properties. The reaction of 1a and 1b with TMGA in
MeCN (protocol B) proceeds in a completely 1,2-regio- and
anti stereoselective way, affording the trans azido alcohol
28a and 28b (anti 1,2-adduct), respectively, as the only
reaction product (Scheme 6).
As confirmation of previous considerations, the non-
coordinating nature of the counterion (TMG+) makes the
epoxide react with the nucleophile (N3-) in a noncoordi-
nated fashion, necessarily at the C(3) oxirane carbon, as
shown in 27 (Scheme 6), affording the completely 1,2-
regio- and anti stereoselective result.
The behavior of the more common organic source of
N3-, TMSN3, is decidedly different: the reaction of
(8) It is interesting to note how the behavior of MeSNa (exclusive
anti-1,2-addition) is different from the behavior of MeONa (exclusive
â-1,4-addition) in the same reaction conditions. Probably, the different
basicity of the corresponding nucleophilic species (MeS- and MeO-)
and, as a consequence, the different nature of the associated ion/pair
(MeS-Na+ and MeO-Na+) is responsible of the incursion (in the case
of MeONa) or the absence (in the case of MeSNa) of the corresponding
epoxide-nucleophile coordination through the metal to justify the
opposite regiochemical behavior so far observed.
(10) Control experiments carried out on azido derivatives 28a, 29a,
and 30aâ showed that they are stable under the reaction conditions
(TMSN3/benzene, rt).
(11) Crotti, P.; Dell’Omodarme, G.; Ferretti, M.; Macchia, F. J. Am.
Chem. Soc. 1987, 109, 1463 and pertinent references therein.
(9) (a) Crotti, P.; Di Bussolo, V.; Favero, L.; Macchia, F.; Pineschi,
M. Tetrahedron Lett. 1996, 37, 1675. For the preparation of TMGA,
see: Papa, A. J. J. Org. Chem. 1966, 31, 1426.
J. Org. Chem, Vol. 69, No. 25, 2004 8705

Di Bussolo et al.
SCHEME 7
SCHEME 8
different nature of the “counterion” of the nucleophile
(azido group) present in TMGA and TMSN3 is clearly
responsible for the completely different regio- and ste-
reoselectivity obtained in the reaction of epoxide 1a with
these two N3--based nucleophiles.
In good agreement with the above-described results
with TMGA and TMSN3, the reaction of epoxide 1a with
LiN3 in MeCN (protocol B) afforded a 7:3 mixture of cis
azido alcohol 29a (syn-1,2-adduct) and trans azido alcohol
28a (anti-1,2-adduct). Evidently, the marked LA property
of the counterion (Li+) is able to polarize the C(3)-O
oxirane bond and determine the incursion of a nucleo-
phile separated ion/dipole pair, structurally correspond-
ing to 34, which leads to the syn adduct, the azido alcohol
29a. Interestingly, when the more solvating THF is used,
a mixture with an almost inverted composition (cis azido
alcohol 29a/trans azido alcohol 28a ) 20:80) was ob-
tained.
The treatment of epoxide 1a with NHEt2 under pro-
tocol B did not afford any addition product. However,
when Yb(OTf)3, a previously described efficient catalyst
for the addition reaction of amines to epoxides,12 was
added to the reaction mixture, a rapid reaction occurred
with the exclusive formation of the corresponding anti
1,2-adduct, the trans amino alcohol 36a. The absence of
any coordination between the nucleophile (the amine)
and the epoxide determines, as usual, a nucleophilic
attack in a noncoordinated fashion on the allylic C(3)
oxirane carbon under the necessary activation by the
metal catalyst, as shown in structure 35 (Scheme 8).
C-Nucleophiles. As for the reaction of epoxide 1b with
C-nucleophiles, different results were obtained depending
on the type of reagent. Grignard reagents such as
MeMgBr and PhMgBr did not react with epoxide 1b
generated in situ from hydroxy mesylate 7b in the
presence of t-BuOK (protocol A).3b However, when MeMg-
Br or PhMgBr were added directly to hydroxy mesylate
7b (protocol C),4 a clean reaction occurred with the
formation of an almost 1:1 mixture of secondary alcohols
39b and 40b (R2 ) Me or Ph) (Scheme 9). Contrary to
our previous report,3b in alcohols 39b and 40b a relative
trans configuration is present between the two substit-
uents at C(4) and C(5), as demonstrated by NOE experi-
ments. This structural evidence would indicate that a
highly stereocontrolled Grob fragmentation process on
hydroxy mesylate 7b, as shown in 37, by the basic
Grignard reagent (R2MgBr) to the trans aldehyde 38,
then unstereoselectively attacked by the excess of R2-
MgBr, could more appropriately rationalize the result
(Scheme 9).13
(13) Initially,
a highly stereocontrolled isomerization by the
Grignard reagent (R2MgBr) of the in situ formed epoxide 1b to the
C(4) epimer of aldehyde 38 (Scheme 9), then attacked by the excess of
R2MgBr, was thought to be responsible of the result and a cis
configuration was consequently assigned to alcohols 39b and 40b.3b
See also footnote 19 of ref 3b.
(12) Crotti, P.; Favero, L.; Macchia, F.; Pineschi, M. Tetrahedron
Lett. 1994, 35, 7089.
8706 J. Org. Chem., Vol. 69, No. 25, 2004

Addition of O-, S-, N-, and C-Nucleophiles to the â Vinyl Oxirane
SCHEME 9
sponding â-C-glycosides 42bâ as the only reaction prod-
ucts. As previously, a coordination of the reagent (RLi)
with the oxirane oxygen through the metal, as shown in
43, was considered responsible for the observed regio- and
stereoselectivity (Scheme 9).3b
As a further C-nucleophile, the cyanide species was
examined. As in the case of NaN3, the use of NaCN as a
source of the cyanide ion was unsuccessful due to the
scarce solubility of the salt in the reaction solvent
(MeCN). On the contrary, the reaction of epoxide 1a with
TMSCN, a cyanide species soluble in an organic solvent
such as MeCN (protocol B), afforded the corresponding
â-C-glycoside, the nitrile 44aâ, as the only reaction
product. Also this result is consistent with a coordination
between the oxirane oxygen and the reagent through the
TMS- group, as shown in structure 45 (Scheme 10),
followed by a â-directed attack of the coordinated nu-
cleophile on the C(1) of the vinyl oxirane system (route
a).
It is interesting to note the decidedly different behavior
of the two silylated reagents utilized in the present study,
TMSN3 and TMSCN, in their reaction with epoxide 1a.
In the case of TMSN3 a mixture of syn 1,2-, anti 1,2-,
and â-1,4-adducts was obtained (Scheme 7), whereas with
TMSCN the corresponding â-1,4-adduct was the only
reaction product (Scheme 10). The different behavior of
these two reagents should be ascribed to their different
polarizability and, practically, to their different “acidity”.
In fact, as HN3 (pKa ) 4.74) is more acidic than HCN
(pKa ) 9.3), also TMSN3 should reasonably be more
“acidic” than TMSCN, and the -Si-N3 bond more polar-
ized than the corresponding -Si-CN bond. As a conse-
quence, TMSN3 is able to polarize the allylic oxirane
C(3)-O bond until its rupture and to determine the
formation of the allylic carbocation species 34 (Scheme
7), whose incursion is responsible, in particular, for
the formation of the corresponding syn 1,2-adduct, oth-
erwise difficult to be justified. With TMSCN, the coor-
dination epoxide-nucleophilic reagent is not followed
by a polarization of the allylic oxirane C(3)-O bond,
and only the product, the â-1,4-adduct, deriving from
the coordination process, is correctly observed (Scheme
10).
SCHEME 10
On their own, cuprates such as Me2CuLi and EtMgBr
in the presence of stoichiometric CuCN afforded only the
corresponding 1,2-addition product, the alcohol 41b, R2
) Me, Et (Scheme 9).3b Only lithium alkyls such as MeLi,
BuLi, i-PrLi, t-BuLi, and PhLi gave a completely 1,4-
regio- and â-stereoselective result affording the corre-
SCHEME 11
J. Org. Chem, Vol. 69, No. 25, 2004 8707

Di Bussolo et al.
Conclusions
rupture (structure 48, Scheme 11), the formation of a syn
1,2-adduct, the “retention product”, can be observed.
Taken as a whole, the results obtained in the addition
reaction of O-, N-, S-, and C-nucleophiles to D-glucal
derived epoxides 1a and 1b, allow us to make some
general considerations about the behavior of these simple
and interesting vinyl oxirane systems. In particular:
(i) When the nucleophile is able to coordinate with the
oxirane oxygen of 1a,b14 through a hydrogen bond (ROH),
a “protonation” process (TMSCN, TMSN3) or a metal
having LA properties (RONa, RLi), a nucleophilic attack
by the coordinated nucleophile is highly favored and
necessarily occurs, for structural reasons, only at the C(1)
oxirane bond in a â direction (structures 46 and 47,
Scheme 11). The reaction is completely 1,4-regio- and
â-stereoselective, affording the corresponding â-1,4-
adduct, the “chelation product”, as the only reaction
product.
(iii) If the nucleophile is not able to coordinate with
the oxirane oxygen of 1a,b, the opening reaction pathway
necessarily involves the free, noncoordinated epoxide
with the free nucleophile. In this framework, the nucleo-
philic attack can occur only at the C(3) oxirane carbon
which, in the absence of any other factors such as
coordination, is the most reactive position in these glycal-
derived oxirane systems (structure 49, Scheme 11). The
anti 1,2-adduct, the “nonchelation product”, is, in this
way, selectively and exclusively obtained.
Acknowledgment. This work was supported by the
Universita` di Pisa and MIUR. P.C. gratefully acknowl-
edges Merck Research Laboratories for the generous
financial support derived from the 2002 ADP Chemistry
Award.
(ii) If the nucleophile coordinated with the oxirane
oxygen is able, as in the case of TMSN3 and LiN3, to
polarize the C(3)-O bond to the point of its complete
Supporting Information Available: General information
and experimental details; spectral and analytical data of all
compounds prepared in this study. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) Obviously, the involvement in the coordination process of both
the endocyclic and exocyclic oxygens present in 1a and 1b cannot be
excluded.
JO048981B
8708 J. Org. Chem., Vol. 69, No. 25, 2004