Regiochemical control of the ring opening of 1,2-epoxides by means of chelating processes. Part 15: Regioselectivity of the opening reactions with MeOH of remote O-substituted regio- and diastereoisomeric pyranosidic epoxides under condensed- and gas-phase operating conditions

Article abstract of DOI:10.1016/S0040-4020(03)00078-4

The regiochemical behavior of pairs of regio- and diastereoisomeric epoxides derived from the 3,4,5,6-tetrahydro-2H-pyrane system, bearing an acetal group as the remote functionality, was determined in the acid methanolysis in the condensed phase (cd-phase) and in the reaction with MeOH in the gas-phase using a gaseous acid (D₃⁺), as the promoting agent. With only one exception, the results obtained in the opening process of these epoxides indicate the incursion in the gas-phase of D⁺-mediated chelated bidentate species able to modify the regiochemical result found in the methanolysis in the cd-phase.

Full text of DOI:10.1016/S0040-4020(03)00078-4

Tetrahedron 59 (2003) 1453–1467
Regiochemical control of the ring opening of 1,2-epoxides by
means of chelating processes. Part 15: Regioselectivity of
the opening reactions with MeOH of remote O-substituted
regio- and diastereoisomeric pyranosidic epoxides under
condensed- and gas-phase operating conditions
b
a
b
a
Paolo Crotti,a Gabriele Renzi, Lucilla Favero, Graziella Roselli, Valeria Di Bussolo
,
,
*
*
and Micaela Casellia
a
`
Dipartimento di Chimica Bioorganica e Biofarmacia, Universita di Pisa, Via Bonanno 33, 56126 Pisa, Italy
`
Dipartimento di Scienze Chimiche, Universita di Camerino, Via S.Agostino 1, 62032 Camerino, Italy
b
Received 1 October 2002; revised 13 December 2002; accepted 9 January 2003
Abstract—The regiochemical behavior of pairs of regio- and diastereoisomeric epoxides derived from the 3,4,5,6-tetrahydro-2H-pyrane
system, bearing an acetal group as the remote functionality, was determined in the acid methanolysis in the condensed phase (cd-phase) and
in the reaction with MeOH in the gas-phase using a gaseous acid (Dþ3 ), as the promoting agent. With only one exception, the results obtained
in the opening process of these epoxides indicate the incursion in the gas-phase of Dþ-mediated chelated bidentate species able to modify the
regiochemical result found in the methanolysis in the cd-phase. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
In order to verify the potential of the gas-phase operating
procedures and the associated chelating ability of a proton,
we have extended our examination, in the reaction with
MeOH, to epoxides cis 5 and 7 and trans 6 and 8,2b,c which
are structurally related to the previously studied epoxides
1–2a,b, but in which the remote heterofunctionality, due to
the insertion of the endocyclic oxygen close to the exocyclic
–OBn group, is now a typical acetal group. The pairs of
diastereoisomeric epoxides 5–8 are regioisomers, differing
The regiochemical outcome of remote OBn-substituted
cycloaliphatic oxiranes, such as epoxides 1–4a,b, can be
controlled, in the condensed phase (cd-phase) and in the
presence of a cis relationship between the oxirane and the
–OBn functionality (epoxides 1–4a) by the use of standard
opening reaction conditions or chelating conditions,1 to
give nice regioalternating processes, in some cases.2 In the
cd-phase, the proton did not give evidence of possessing a
chelating ability in any of the opening reactions of epoxides
examined.2,3 The situation is different when gas-phase
operating conditions are used. It was recently demonstrated
that the use of gaseous reaction conditions are particularly
effective in promoting, in the reaction of cis epoxides 1–4a
with MeOH, the intrinsic chelating ability of the proton
with regioselectivity levels similar to the ones obtained in
the cd-phase under chelating conditions.3 By means of this
procedure, it was possible, in the case of epoxide 2a, to
obtain the corresponding regioisomeric C-2 product,4
never obtained in the cd-phase under any conditions
(Scheme 1).2c,3
Keywords: epoxides; regioselectivity; gas phase reactions; chelation.
*
Corresponding authors. Tel.: þ39-50-44074; fax: þ39-50-43321;
e-mail: crotti@farm.unipi.it; gabriele.renzi@unicam.it
Scheme 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00078-4

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P. Crotti et al. / Tetrahedron 59 (2003) 1453–1467
Table 1. Distribution of products in the gas-phase acid-induced ring-opening with MeOH and in the methanolysis (condensed phase) of epoxide 9
Gas phase
System composition (Torr)a
Product distributionb
Epoxide
Bulk gas
MeOH
G %
G %
(0.09) 5
(0.11) 9
G %
G %
Total abs. yield (%)c
(0.53)
(0.61)
(0.59)
D2 (100)
D2 (760)
D2 (760)
(1.69)
(1.84)
(1.81)d
(0.44) 23
(0.40) 28
(0.19) 35
(0.82) 43
(0.52) 37
(0.15) 28
(0.54) 28
(0.38) 27
(0.13) 24
63
47
18
(0.07) 13
Condensed phase
0.2N H2SO4/MeOHe
74
98
95
26
2
5
10 M LiClO4/MeOHf
5 M LiClO4/MeCN/MeOH (10 equiv.)e
a
O2: 4 Torr, radiation dose 1.5£104 Gy (dose rate 1£104 Gy h21).
Total absolute yields (%) estimated from the percentage ratio of the combined G(M) values of products and the literature G(GAþ) values.13
3 Torr of NMe3 added to the gaseous mixture.
Ref. 5.
This work.
b
c
d
e
f
G values expressed as the number of molecules produced per 100 eV absorbed energy.
only in the relative position of the acetal group with respect
to the oxirane moiety. While, on one hand, the presence of
the exocyclic –OBn group is of fundamental importance
for the incursion of chelating processes in the cis
distereoisomers, as previously observed,2d the presence of
the endocyclic oxygen could also make the trans dia-
stereoisomers, commonly not sensitive to different opera-
ting conditions (standard or chelating), susceptible to
chelating processes and, as a consequence, to regioalter-
nating procedures.2b,c For a better insight into the
importance of the endocyclic oxygen in determining the
regiochemical outcome of the ring opening process of these
oxirane systems, the reaction in the gas-phase was carried
out also on the simplest reference oxirane 9,5 which is
devoid of the exocyclic OBn group. Epoxides 9 (Table 1)
and 5–8 were previously examined by the present authors in
opening reactions in the cd-phase with various nucleophiles
both under standard and chelating conditions, but, in the
case of 5–8, with the exclusion of MeOH.2b,c,5–7 As a
consequence, a preliminary examination of the regio-
chemical behavior of epoxides 5–8 also in the reaction
with MeOH in the cd-phase, under different conditions,
appeared to be necessary to rationalize the behavior of the
same epoxides in the gas-phase.
Scheme 2.

P. Crotti et al. / Tetrahedron 59 (2003) 1453–1467
1455
Table 2. Distribution of products in the gas-phase acid-induced ring-opening with MeOH and in the methanolysis (condensed phase) of epoxides cis 5 and
trans 6
Gas phase
System composition (Torr)a
Product distributionb
Epoxide
Bulk gas
MeOH
G %
G %
G %
G %
(0.28) 13
(0.19) 10
Total abs. yield (%)c
(0.62)
(0.58)
(0.57)
D2 (100)
D2 (760)
D2 (760)
(1.79)
(1.73)
(1.72)d
(0.82) 37
(0.60) 33
(0.20) 23
(0.69) 31
(0.79) 43
(0.45) 52
(0.43) 19
(0.25) 14
(0.12) 14
74
61
29
(0.10) 11
Condensed phase
0.2N H2SO4/MeOH
MeONa/MeOH
10 M LiClO4/MeOH
87
94
22
13
6
78
Gas phase
System composition (Torr)a
Product distributionb
Epoxide
(0.60)
(0.71)
(0.62)
Bulk gas
D2 (100)
D2 (760)
MeOH
(1.77)
(1.93)
(1.80)d
G %
G %
G %
(0.44) 22
(0.38) 20
(0.12) 19
G %
Total abs. yield (%)c
67
64
21
(0.35) 17
(0.47) 24
(0.17) 27
(0.90) 45
(0.76) 40
(0.25) 40
(0.32) 16
(0.31) 16
(0.09) 14
D2 (760)
Condensed phase
0.001N H2SO4/MeOH
MeONa/MeOH
10 M LiClO4/MeOH
22
20
98
78
80
2
a
O2: 4 Torr, radiation dose 1.5£104 Gy (dose rate 1£104 Gy h21).
Total absolute yields (%) estimated from the percentage ratio of the combined G(M) values of products and the literature G(GAþ) values.13
3 Torr of NMe3 added to the gaseous mixture.
b
c
d
G values expressed as the number of molecules produced per 100 eV absorbed energy.
2. Results
MeOH) to give the results shown in Tables 2 and 3. Whereas
epoxides 7 and 8 turned out to be completely insensitive to
different operating conditions, showing a complete C-1
regioselectivity as under standard conditions, epoxides 5
and 6 showed an interesting inversion of regioselectivity
and the corresponding C-2 (HE 11, from 5) and C-1
products (HE 12, from 6) were the ring-opened products
largely (in the case of HE 11) or exclusively present (in the
case of HE 12) in the corresponding crude reaction product
(Table 2). From all these results (Tables 2 and 3), it
appeared that the C-2 products from both epoxides 7 and 8
(HEs 15 and 17 from 7 and 8, respectively), because not
present in the methanolysis reaction of the corresponding
epoxides, had to be prepared by alternative unequivocal
synthetic procedures (Scheme 3). The alkaline hydrolysis of
cis and trans epoxides 7 and 8 afforded the trans diols 20
and 22, respectively, as the only reaction product (see
Section 4). Monomethylation of diols 20 and 22 by means of
Epoxides 5–9 were prepared as previously described.2b,c,5
The reference compounds, the pairs of regioisomeric
hydroxy ethers (HEs, C-1 and C-2 products)4 from each
epoxide (HEs 10 and 11 from 5, 12 and 13 from 6, 14 and 15
from 7, 16 and 17 from 8) were prepared as follows. The
direct acid methanolysis (0.2N H2SO4/MeOH) of epoxides
5 and 68 afforded corresponding mixtures of HEs 10 (C-
product) and 11 (C-2 product) (87:13 from 5) and HEs 12
(C-1 product) and 13 (C-2 product) (22:78 from 6) which
were separated by preparative TLC. The same reaction
carried out on the regioisomeric epoxides cis 7 and trans 8
afforded only the corresponding C-1 product (HEs 14 and
16 from 7 and 8, respectively) (Scheme 2 and Tables 2 and 3).
The methanolysis reactions in the cd-phase of epoxides 5–8
were repeated under chelating conditions (10N LiClO4/

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P. Crotti et al. / Tetrahedron 59 (2003) 1453–1467
Table 3. Distribution of products in the gas-phase acid-induced ring-opening with MeOH and in the methanolysis (condensed phase) of epoxides cis 7 and
trans 8
Gas phase
System composition (Torr)a
Product distributionb
Epoxide
Bulk gas
MeOH
G %
G %
G %
G %
Total abs. yield (%)c
(0.58)
(0.51)
(0.61)
D2 (100)
D2 (760)
D2 (760)
(1.72)
(1.58)
(1.81)d
(0.76) 38
(0.50) 35
(0.14) 25
(0.59) 29
(0.57) 40
(0.30) 53
(0.41) 20
(0.22) 15
(0.08) 14
(0.25) 12
(0.15) 10
(0.05) 9
67
48
19
Condensed phase
0.2N H2SO4/MeOH
MeONa/MeOH
10 M LiClO4/MeOH
.99
.99
.99
,1
,1
,1
Gas phase
System composition (Torr)a
Product distributionb
Epoxide
(0.64)
(0.53)
(0.53)
Bulk gas
D2 (100)
D2 (760)
MeOH
(1.84)
(1.60)
(1.62)d
G %
(1.24) 59
(0.93) 66
(0.46) 73
G %
(0.10) 5
(0.06) 4
(0.01) 2
G %
G %
Total abs. yield (%)c
70
47
21
(0.46) 22
(0.25) 18
(0.10) 16
(0.30) 14
(0.17) 12
(0.06) 9
D2 (760)
Condensed phase
0.2N H2SO4/MeOH
MeONa/MeOH
10 M LiClO4/MeOH
.99
.99
.99
,1
,1
,1
a
O2: 4 Torr, radiation dose 1.5£104 Gy (dose rate 1£104 Gy h21).
Total absolute yields (%) estimated from the percentage ratio of the combined G(M) values of products and the literature G(GAþ) values.13
3 Torr of NMe3 added to the gaseous mixture.
b
c
d
G values expressed as the number of molecules produced per 100 eV absorbed energy.
the MeI/NaH protocol (1 equiv.) afforded the corresponding
crude reaction products consisting of a 65:5:30 mixture of
HEs 17 and 14, and dimethoxy derivative 21 from 20, and of
a 60:10:30 mixture of HEs 15 and 16, and dimethoxy
derivative 23 from 22 (1H NMR), from which HEs 17 and
15 were separated pure by preparative TLC.
compounds could be significant (ketones 24 and 25 from
epoxides 5 and 6, ketones 25 and 26 from epoxides 7 and 8,
and ketones 27 and 28 from epoxide 9) (Scheme 4).
Hydroboration–oxidation of olefin 292b afforded a crude
reaction product reasonably consisting of an uninvestigated
mixture of regio- and stereoisomeric alcohols of types 30
and 31, which were oxidized by PCC to give an almost 1:1
mixture of the corresponding ketones 24 and 25, which were
separated by preparative TLC. The LiAlH4 reduction of
epoxides 8 and 9 afforded, in an almost exclusive way,
alcohols 32 and 33, respectively,2c,5 which were oxidized
(PCC) to pure ketones 269a and 27.9b Ketone 28 is
commercially available (Scheme 5).
As for epoxide 9, the corresponding reference compounds,
the HEs 18 and 19, were prepared as previously described
(Scheme 2).5
Ketones 24–28 were also prepared as possible reference
non-addition products, whose formation could be particu-
larly favored in the reactions carried out under gas-phase
operating conditions. In fact, in these conditions, as a
consequence of the low amount of the nucleophilic
molecules (MeOH) present in the reaction mixture, the
rearrangement pathway of the intermediate protonated
epoxide (34a in Scheme 6, vide infra) to carbonyl
Epoxides 5–9 were subjected to opening reactions with
MeOH in the cd-phase under standard (acid methanolysis by
0.2N H2SO4/MeOH)8 and chelating conditions (10 M
LiClO4 in MeOH)6 and in the gas-phase under the catalysis

P. Crotti et al. / Tetrahedron 59 (2003) 1453–1467
1457
Scheme 3.
Scheme 4.
þ
þ
1H NMR and GC–MS examination of the crude reaction
mixtures from the cd- and gas-phase methanolysis reactions
of epoxides 5–9 indicated the presence of addition products,
the corresponding HEs 10–19 and non-addition products,
the corresponding ketones 24–28 (Tables 1–3).
¨
of a gaseous Bronsted acid [GA ¼D3 ] obtained by
g-radiolysis of the corresponding neutral bulk gas precursor
(G¼D2) (Scheme 6).10 The primary ionic product from
g-radiolysis of D2 is D2þ, which rapidly reacts with D2 to
give Dþ3 and a D atom. The D3þ ion is stable in pure D2,
while the D atom can be efficiently trapped by O2,
appropriately added to the reaction mixture, to give the
stable DO2 species.11 In this way, it is possible to exclude
the incursion of radical processes under our protocol. The
results obtained are shown in Tables 1–3. In the gas-phase,
the bulk gas pressure was varied, and different operating
conditions were used: low- (100 Torr) and high-pressure
bulk gas (760 Torr). In this last case, the opening reactions
were repeated also in the presence of NMe3 (3 Torr).
Low-pressure bulk gas conditions correspond to long-lived
excited-ion conditions, because of the reduced collapse of
the ionic species with the molecules of the bulk gas, while
the use of a high pressure and the contemporary presence of
NMe3 correspond to a low ion lifetime.12 The sharp yield
decrease when NMe3 is introduced demonstrates the ionic
origin of the reaction products, independently ensured by
the presence of O2, an effective radical scavenger (see
above).
As a different product distribution is obtained in D2 as a
function of the experimental conditions (low or high bulk
gas pressure) and the presence or absence of NMe3, the
reactions carried out in the gas-phase in conditions of low
ion lifetime, that is under high pressure and in the presence
of NMe3 (see above), appear to be more similar to the
cd-phase operating conditions and, as a consequence, more
appropriate for an effective comparison between the results
obtained in the cd- and gas-phase (Tables 1–3, results in
bold), as previously stated.3
3. Discussion
The behavior of epoxide 9 in methanolysis reactions in the
cd-phase5,6 shows an almost complete regioselectivity (up
to 98%) towards the C-1 product, the ‘chelation product’

1458
P. Crotti et al. / Tetrahedron 59 (2003) 1453–1467
conditions, the observed high C-1 regioselectivity (74%)
is driven by the electron-withdrawing inductive effect of the
endocyclic oxygen, which forces epoxide 9 to react through
the less stable conformation 9b, and the corresponding
protonated structure 36b, in order to allow, in accordance
with Fu¨rst–Plattner rule,15 trans diaxial attack of the
nucleophile on the less electronically unfavored C(1)
oxirane carbon. The same regioselectivity result (70%) is
also obtained in the gas-phase (Dþ/MeOH), indicating that
the proton is not able to chelate in this system (Scheme 7
and Table 1), in any, cd- or gas-phase, conditions.
The regioselectivity observed in the cd-phase with epoxides
cis 5 and trans 6 indicates that these epoxides are sensitive
to the variation of the reaction operating conditions. In fact,
under standard conditions (0.2 and 0.001N MeOH/H2SO4
for 5 and 6, respectively)8 a C-1 (87%) and a C-2 selectivity
(78%) is observed with 5 and 6, respectively, which
corresponds to a non-chelated process through the more
stable conformations 5a in the case of 5 and 6a in the case of
6, as previously discussed,2b with trans diaxial nucleophilic
attack on the C(1) and C(2) oxirane carbons of the
corresponding protonated structure 37a (from 5a) and 39a
(from 6a), respectively (Schemes 8 and 9). The use of
LiClO4, as the promoting agent, has a great influence on the
regiochemical outcome in the methanolysis of both
epoxides 5 and 6: in 5 and 6 an inversion of regioselectivity
with respect to standard conditions is observed and in the
case of 6 an almost complete C-1 selectivity is obtained
(Table 2).16 These results may be easily rationalized by
admitting the incursion in these chelating conditions of
chelated bidentate species such as 38 (M¼Liþ) (from 5) and
40 (M¼Liþ) (from 6) (Schemes 8 and 9) which are attacked
by the MeOH at the C(2) and C(1) oxirane carbon,
respectively, in accordance with the Fu¨rst–Plattner rule.15,17
Under gas-phase operating conditions, the regioselectivity
observed with epoxides 5 and 6 (Table 2) gives evidence of
the incursion of the chelating ability of the proton in these
conditions, even if with reasonable differences: with respect
to standard conditions, while on one hand a nice C-2
Scheme 5.
(HE 18, Table 1) in the methanolysis carried out in the
presence of LiClO4 (Table 1), confirming the extraordinary
ability of Liþ to chelate between the heterofunctionalities
present in 9, the endocyclic and the oxirane oxygens, as
shown in structure 35 (Scheme 7).14 Under standard
Scheme 6.

P. Crotti et al. / Tetrahedron 59 (2003) 1453–1467
1459
Scheme 7.
selectivity is observed in the case of 5, only a slight decrease
of the C-2/C-1 product ratio (from 78/22 to 60/40,
Scheme 9) is observed in the case of 6. These results may
be rationalized by reasonably admitting the incursion of
chelated structures 38 (M¼D, Scheme 8) from 5 and 40
(M¼D, Scheme 9) from 6. The partially disappointing
result obtained with epoxide 6 is to be correlated with
the poor ability of the proton to act as a chelating agent
between the oxirane and endocyclic oxygens, as previously
observed in the case of epoxide 9 (see above). On the
contrary, the regiochemical result obtained with epoxide 5
would indicate that the chelation of the proton between the
oxygens of the oxirane and the exocyclic OBn group (as
shown in 38, Scheme 8) appears to be particularly
favored.
methanolysis in the cd-phase with epoxides 7 and 8,
which turned out to be completely insensitive to the
variation of the reaction conditions (standard or chela-
ting).2c In fact in these epoxides, due to the closeness of the
oxirane ring to the acetal functionality, the regioselectivity
appears to be driven by the inductive electron-withdrawing
effect of the heterofunctionality. As a consequence, under
standard conditions, epoxides 7 and 8 react in that
conformation (less stable conformation 7b and 8b2c and
the corresponding protonated structure 41b and 45,
Schemes 10 and 11) which allows nucleophilic attack by
the MeOH on the corresponding C(1) oxirane carbon
furthest from the acetal group and related unfavorable
inductive effect, giving the complete C-1 selectivity
constantly observed in these conditions (Tables 2 and 3).
On passing to chelating conditions, no variation of the
regioselectivity is observed in the case of epoxide 8, simply
Decidedly less interesting results are obtained in the
Scheme 8.

1460
P. Crotti et al. / Tetrahedron 59 (2003) 1453–1467
Scheme 9.
because the only chelation process possible in this system
(chelated structure 46) occurs in conformation 8b which is
also reactive under standard conditions (protonated struc-
ture 45, see above) (Scheme 11). A similar situation is
present also in the case of epoxide 7: chelation can occur, as
shown in 42, in conformation 7b which is also reactive
under standard conditions (protonated structure 41b, see
above) (Scheme 10). Actually in the case of 7, an important
difference is present with respect to 8, but evidently not
influential on the final regioselective result. In 7, in fact,
there is also the possibility of a chelation process through
conformation 7a as shown in 44, which would afford, by
nucleophilic trans diaxial attack of MeOH on the C(2)
oxirane carbon, a C-2 selectivity actually not observed.
Evidently, as previously admitted,2c MeOH is too weak
nucleophile to attack the electronically unfavored C(2)
oxirane carbon of 44 (Scheme 10).18
The use of gas-phase operating conditions, while uneffec-
tive, as expected, in the case of trans epoxide 8, to modify
the result of complete C-1 regioselectivity observed in the
cd-phase (no chelation process can occur, but the one
depicted in 46, M¼D, Scheme 11, see discussion above),
really makes the difference in the case of the cis epoxide 7:
Scheme 10.

P. Crotti et al. / Tetrahedron 59 (2003) 1453–1467
1461
Scheme 11.
Table 4. Heats of formation (kcal mol21) for ketones 24–28
Data obtained by semiempirical calculation AM1 (HYPERCHEM).
1
Table 5. H NMR and IR data for HEs 10–17 and diols 20 and 22
HE
1H NMR d
IR (CCl4) (OH stretching), cm21
Ha (J, Hz)a
Hb (Jor W1/2, Hz)b
Hc (J or W1/2, Hz)c
1,2 OH· · ·Od
1,2 OH· · ·Oe
1,3 OH· · ·Of
h
h
10
11
12
13
14
15
16
17
20
22
4.88 (3.1, 2.3)g
4.83 (3.2)j
3605i
3601l
3605i
3605i
3601p
3597i
3603i
3601i
3599i
3605i
3.79 (W1/2¼11.4)k
3.12 (W1/2¼4.6)k
3537i
4.47 (8.3, 2.4)g
4.87 (3.6, 1.2)g
5.00 (3.0)o
3.57 (8.7, 4.8)m
h
3.91 (11.3, 8.6, 5.1)n
3.09 (10.5, 8.6, 5.0)n
3.67 (11.7, 5.5, 2.5)n
2.96 (7.0, 5.6)g
h
3582i
3574i
4.43 (5.6)o
3.64 (8.7, 7.0, 4.4)n
3539i
3539l
h
4.26 (7.3)o
3.25 (10.8, 8.8, 4.9)n
4.97 (3.4)o
3.96 (11.7, 9.4, 5.2)n
3.40 (9.2, 3.8)g
3.34 (8.2, 6.9)g
3.02 (9.4, 3.4)g
h
4.98 (3.8)o
4.31 (6.9)o
3.67 (11.5, 8.2, 5.1)n
a
CHOBn.
CHOH.
CHOMe, in the case of HEs 10–17; CHOH in the case of diols 20 and 22 (see Schemes 1, 2, and 12).
Trans 1,2-diequatorial interaction.
Cis 1,2-equatorial–axial interaction.
Cis 1,3-diaxial interaction.
Doublet of doublets.
The signal overlaps with other signals.
Strong band.
Unresolved triplet.
Multiplet.
Weak band.
b
c
d
e
f
g
h
i
j
k
l
m Triplet of doublets.
n
Doublet of doublets of doublets.
Doublet.
Shoulder.
o
p

1462
P. Crotti et al. / Tetrahedron 59 (2003) 1453–1467
Scheme 12.
in these conditions, a 2.1:1 ratio is obtained between
regioisomeric C-2 and C-1 products (Table 3). This result
may reasonably be explained by the necessary incursion of
the chelated bidentate species 43 in which the epoxide
adopts its more stable conformation 7a: subsequent
nucleophilic attack on C(2) oxirane carbon of 43 leads to
the regioselectivity observed. However, it would be difficult
to explain why the same result is not observed under
chelating conditions in the cd-phase, through the corre-
sponding chelated species 44, without invoking some other
factors such as a synergic effect due to an increased
nucleophilicity of MeOH in the gas-phase,19 which makes
the weak nucleophile MeOH able to attack the electro-
nically unfavorable C(2) oxirane carbon of 43 (Scheme 10),
as only stronger nucleophiles (PhSH, NHEt2, and N23 ) are
able to do on the corresponding chelated species 44 in the
related opening reaction under chelating conditions in the
cd-phase (Scheme 10).2c
gas-phase operating conditions (about 9–28%). The relative
amounts of the components of the pairs of regioisomeric
ketones 24–29 from each epoxide (Tables 1–3 and Scheme
4) appear to reflect the corresponding calculated relative
stability shown in Table 4.3
4. Structures and configurations
The structure and relative configuration of HEs 10–17
obtained as regioisomeric pairs (C-1 and C-2 products) in
the above-mentioned opening reactions of epoxides 5–8
with MeOH was unequivocally determined by simple
considerations based on (i) their method of synthesis and
configuration of the starting epoxide, (ii) the anti stereo-
selectivity commonly observed in the opening reactions of
typically cycloaliphatic epoxides under the conditions
used,2 (iii) an examination of their 1H NMR spectra
(coupling constants and/or half-band-width (W1/2)) of the
signal of the protons a to OBn, OH and OMe groups (Ha, Hb
and Hc, respectively, Table 5),2,20a and the use of
appropriate double resonance experiments, and finally (iv)
As expected, non-addition products, the corresponding
ketones 24–28, completely absent in the opening reactions
carried out in the cd-phase, were constantly obtained under

P. Crotti et al. / Tetrahedron 59 (2003) 1453–1467
1463
by examination of their IR spectra in dilute CCl4 in the 3m
6. Experimental
range (OH stretching band, Table 5).2,20b Keeping in mind
that OH and OMe groups are necessarily in a 1,2-trans
relationship in all the HEs 10–17, the presence of a strong
intramolecular 1,3 OH· · ·O hydrogen bond in 11 (conformer
6.1. General
1H and 13C NMR spectra were determined with a Bruker AC
200 spectrometer on CDCl3 solution using tetramethylsilane
as the internal standard. IR spectra for comparison between
compounds were taken with a Mattson 3000 FTIR
spectrophotometer. All reactions were followed by TLC
on Alugram SIL G/UV254 silica gel sheets (Machery–
Nagel) with detection by UV. Preparative TLC were
performed on 2.0 or 0.5-mm Macherey–Nagel DC-Fertig-
platten UV254 silica gel plates. Silica gel 60 (Machery–
Nagel 230–400 mesh) was used for flash chromatography.
THF was distilled from sodium/benzophenone ketyl under
a nitrogen atmosphere immediately prior to use. Epoxides
5–92b,c,5 olefin 29,2b alcohols 32,2b 33,5 HEs 18 and 19,5
were prepared as previously described. Ketone 28 is
commercially available (Aldrich).
11a) and 15 (conformer 15a) (n 3537 and 3539 cm21
,
respectively) and of a strong equatorial-axial 1,2 OH· · ·O
interaction in 14 (n 3582 cm21) (Table 5), possible only
when a cis 1,3- and 1,2-relationship between the two
interacting groups (–OH and OBn) is, respectively,
present,20b confirms the structure of HEs 11, 14 and 15
(Scheme 12).21
The presence of a sole, intense trans diequatorial 1,2
OH· · ·O interaction (n 3601–3605 cm21 20b
in HEs 10, 12,
)
13, 16, and 17, indicates for these compounds the preference
for a conformation having more substituents in the
equatorial position. As a consequence, the axial (in 12 and
16) or equatorial nature (in 10, 13, and 17) of the Ha proton
makes the determination of the exact structures of HEs 10,
12, 13, 16 and 17 possible (Table 5). The structure and
relative configuration of diols 20 and 22, derived from
epoxides 7 and 8, respectively (Scheme 3), was reasonably
assigned on the basis of the regiochemical behavior
previously observed in the ring-opening reactions of the
same epoxides with other common nucleophiles under basic
conditions (NHEt2/EtOH, PhSH/NEt3, AlMe3),2c and on the
reasonable assumption that epoxides 7 and 8 should have a
similar regiochemical behavior also in a fairly similar
reaction like alkaline hydrolysis (KOH/DMSO). However,
the structure of 20 and 22 were confirmed by the presence in
6.1.1. Hydroboration–oxidation of olefin 29. Following a
previously described procedure,2b a solution of olefin 29
(0.25 g, 1.31 mmol) in anhydrous THF (3.0 mL) was treated
at 08C with 10 M BH3·Me2S (0.18 mL) in anhydrous THF
(2.0 mL) and the reaction mixture was stirred at rt for 18 h.
Aqueous 2N NaOH (0.56 mL) was carefully added, then the
reaction mixture was cooled at 08C and treated with 36%
H2O2 (0.56 mL). After 1 h refluxing under stirring, dilution
with water, extraction with ether and evaporation of the
washed (water) ether extracts afforded a crude liquid
product (0.23 g) which was filtered through a short silica
gel column. Elution with an 8:2 petroleum ether/AcOEt
afforded an oily product (0.14 g) consisting of a mixture of
alcohols of type 30 and 31 (1H NMR).2b
22 of a weak 1,3–OH· · ·O hydrogen bond (n 3539 cm21
)
possible only if the interacting OH and OBn groups are in a
cis relationship, as shown in the corresponding conformer
22a (Scheme 12), and by the presence in 20 of an
equatorial–axial 1,2–OH· · ·O interaction (n 3574 cm21
)
possible only if the central OH group is in a cis relationship
6.1.2. Synthesis of ketones 24 and 25. A solution of the
mixture of alcohols 30 and 31 (0.10 g, 0.48 mmol) in
CH2Cl2 (3.0 mL) was added at 08C to a mixture of PCC
(0.155 g, 0.72 mmol), AcONa (0.044 g, 0.54 mmol) and
molecular sieves (0.41 g) in CH2Cl2 (5.0 mL) and the
resulting reaction mixture was stirred 4 h at rt. Et2O was
added and the mixture was stirred overnight at the same
temperature. Evaporation of the washed (water) and filtered
(celite) organic solution afforded a liquid product (0.080 g)
mostly consisting of an almost 1:1 mixture of ketones 24
and 25 which was subjected to preparative TLC (a 7:3
hexane/AcOEt mixture was used as the eluant). Extraction
of the two most intense bands (the faster moving band
contained 24) afforded pure ketones 24 (0.025 g, 25% yield)
and 25 (0.030 g, 30% yield).
with the OBn group, as shown in Scheme 12 (Table 5).20b
5. Conclusion
In conclusion, we have verified that in the gas-phase
operating conditions, without the complicating interference
of the solvent and counterion effects, it is possible to
observe the incursion of intramolecular chelating processes
mediated by the proton (actually Dþ)10 in opening reactions
with MeOH in the presence of a gaseous acid (GAþ¼D3þ) of
a series of pyranosidic epoxides bearing a remote acetal
functionality.22 The regiochemical behavior towards the
chelation product is in all cases similar or decidedly superior
to that obtained in the cd-phase when the opening reactions
were carried out in the presence of a metal salt such as
LiClO4, indicating that the proton, which turns out to be
scarcely or not at all effective in the cd-phase as a chelating
agent, possesses chelating properties in the gas-phase even
superior to those of Liþ in the cd-phase. This is well-
demonstrated by the fact that the cis epoxide 7 afforded in
the gas-phase a high relative amount of HE 15 (the chelation
product, Scheme 10) which was completely absent in the
corresponding methanolysis reactions carried out with 7
under any conditions in the cd-phase.
2-(Benzyloxy)-3,4,5,6-tetrahydro-2H-pyran-5-one (24), a
colorless liquid (Found: C, 69.54; H, 7.12. C12H14O3
requires: C, 69.89; H, 6.84): IR n 1724 cm21 (CO); H
NMR d 7.25–7.46 (m, 5H), 5.09 (t, 1H, J¼4.2 Hz), 4.80 (d,
1H J¼12.0 Hz), 4.59 (d, 1H J¼12.0 Hz), 4.22 (d, 1H J¼
16.9 Hz), 3.95 (d, 1H J¼16.9 Hz), 2.39–2.70 (m, 2H),
2.20–2.37 (m, 1H), 1.98–2.14 (m, 1H). 13C NMR d 209.21,
137.97, 129.07, 128.44, 95.89, 70.02, 67.88, 34.30, 28.72.
MS (m/z) 65, 77, 85, 91, 104, 206 (Mþ).
1
2-(Benzyloxy)-3,4,5,6-tetrahydro-2H-pyran-4-one (25), a
colorless liquid (Found: C, 69.71; H, 7.06. C12H14O3

1464
P. Crotti et al. / Tetrahedron 59 (2003) 1453–1467
requires: C, 69.89; H, 6.84): IR n 1728 cm21 (CO); H
NMR d 7.14–7.37 (m, 5H), 5.14 (dd, 1H, J¼3.9, 2.8 Hz),
4.70 (d, 1H J¼12.1 Hz), 4.46 (d, 1H J¼12.1 Hz), 4.09 (td,
1H, J¼11.1, 3.9 Hz), 3.89 (ddd, 1H, J¼11.1, 6.8, 3.2 Hz),
2.27–2.69 (m, 4H). 13C NMR d 205.12, 137.65, 129.02,
128.41, 98.68, 69.54, 59.72, 47.77, 42.14. MS (m/z) 65, 71,
91, 99, 133, 206 (Mþ).
11.5, 4.7, 2.7 Hz), 3.47 (td, 1H, J¼11.5, 2.7 Hz), 1.96 (dtd,
1H, J¼13.3, 5.1, 2.7 Hz), 1.71 (dtd, 1H, J¼13.3, 11.5,
4.7 Hz), and see Table 5. 13C NMR d 137.68, 129.07,
128.73, 128.58, 102.56, 75.65. 71.36, 71.27, 61.69, 32.38.
1
6.1.5. Methylation of diols 20 and 22. Typical procedure.
A solution of diol 22 (0.14 g, 0.62 mmol) in anhydrous THF
(4 mL) was added at 08C to a suspension of NaH (0.15 g of a
60% dispersion in mineral oil, 0.62 mmol) in anhydrous
THF (2 mL) and the reaction mixture was stirred at 408C for
4 h. MeI (0.91 g, 6.30 mmol) was added and the resulting
reaction mixture was stirred at 508C for 18 h. After cooling,
dilution with Et2O and water, and evaporation of the
washed (water) organic extracts afforded a crude liquid
product (0.136 g) which was subjected to preparative TLC
(a 7:3 hexane/AcOEt mixture was used as the eluant).
Extraction of the three most intense bands (the fastest-
and slowest-moving bands contained 23 and 15, respec-
tively) afforded pure dimethoxy derivative 23 (0.037 g, 24%
yield), HE 16 (0.012 g, 8% yield) and HE 15 (0.050 g, 34%
yield).
6.1.3. Synthesis of ketones 26 and 27. Proceeding as
above described for the preparation of ketones 24 and 25, a
solution of alcohol 32 (0.065 g, 0.31 mmol) in CH2Cl2
(2 mL) was added at 08C to a mixture of PCC (0.101 g,
0.47 mmol), AcONa (0.284 g, 0.35 mmol), and molecular
sieves (0.27 g) in CH2Cl2 (4 mL) and the resulting reaction
mixture was stirred 4 h at rt. Usual work-up afforded a liquid
product (0.057 g) mostly consisting of ketone 26 which was
subjected to preparative TLC (a 7:3 hexane/Et2O mixture
was used as the eluant). Extraction of the most intense band
afforded pure 2-(benzyloxy)-3,4,5,6-tetrahydro-2H-pyran-
3-one (26) (0.033 g, 52% yield), as a colorless liquid
(Found: C, 69.53; H, 6.61. C12H14O3 requires: C, 69.89; H,
6.84): IR n 1724 cm21 (CO); 1H NMR d 7.17–7.34 (m, 5H),
4.74 (d, 1H, J¼11.7 Hz), 4.64 (s, 1H), 4.51 (d, 1H, J¼
11.7 Hz), 4.09 (dt, 1H, J¼11.3, 3.7 Hz), 3.64 (ddt, 1H, J¼
11.3, 4.4, 2.1 Hz), 2.73 (ddd, 1H, J¼14.8, 11.8, 7.5 Hz),
2.28–2.42 (m, 1H), 1.91–2.20 (m, 2H). 13C NMR d 203.14,
137.39, 129.07, 128.58, 99.62, 70.10, 59.59, 36.43, 28.12.
MS (m/z) 65, 71, 91, 99, 133, 206 (Mþ).
r-2-(Benzyloxy)-t-3,c-4-dimethoxy-3,4,5,6-tetrahydro-2H-
pyran (23), a colorless liquid (Found: C, 66.32; H, 7.74.
1
C14H20O4 requires: C, 66.65; H, 7.99); H NMR d 7.16–
7.36 (m, 5H), 4.83 (d, 1H, J¼12.0 Hz), 4.55 (d, 1H, J¼
12.0 Hz), 4.26 (d, 1H, J¼7.0 Hz), 3.91 (ddd, 1H, J¼11.8,
4.7, 2.7 Hz), 3.52 (s, 3H), 3.38 (s, 3H), 3.29 (td, 1H, J¼11.8,
2.7 Hz), 3.18 (ddd, 1H, J¼10.5, 8.2, 5.0 Hz), 2.96 (dd, 1H,
J¼8.2, 7.0 Hz), 1.96 (ddt, 1H, J¼13.2, 5.0, 2.7 Hz), 1.51
(dddd, 1H, J¼13.2, 11.8, 10.5, 4.7 Hz). 13C NMR d 138.20,
128.84, 128.19, 128.11, 103.10, 83.87, 80.10, 71.06, 61.37,
60.83, 57.82, 30.42.
Application of the same procedure to alcohol 33 (0.102 g,
1.0 mmol) afforded a crude product (0.075 g) which was
subjected to preparative TLC (a 7:3 hexane/Et2O mixture
was used as the eluant). Extraction of the most intense band
afforded pure ketone 27 (0.040 g, 40% yield).9a
c-2-(Benzyloxy)-t-3-methoxy-r-3,4,5,6-tetrahydro-2H-
pyran-4-ol (15), a colorless liquid (Found: C, 65.29; H, 7.37.
C13H18O4 requires: C, 65.53; H, 7.61): IR, see Table 5; 1H
NMR d 7.16–7.34 (m, 5H), 4.80 (d, 1H, J¼11.8 Hz), 4.51
(d, 1H, J¼11.8 Hz), 3.92 (ddd, 1H, J¼11.9, 5.3, 4.4 Hz),
3.48 (s, 3H), 3.34–3.48 (m, 2H), 1.86–2.02 (m, 1H), 1.59
(dtd, 1H, J¼13.2, 8.5, 4.4 Hz), and see Table 5. 13C NMR d
137.79, 129.04, 128.44, 101.64, 82.81, 70.91, 69.30, 60.46,
59.88, 31.35. MS (m/z) 45, 59, 91, 101, 135, 238 (Mþ).
6.1.4. Synthesis of diols 20 and 22. Typical procedure.
A solution of cis epoxide 7 (0.16 g, 0.78 mmol) in DMSO
(2.5 mL) and aqueous 2N KOH (2.5 mL) was stirred for
18 h at 708C. Dilution with water, extraction with Et2O and
evaporation of the washed (water) ether extracts afforded
a crude oily product (0.15 g) which was subjected to pre-
parative TLC (a 6:4 hexane/AcOEt mixture was used as the
eluant). Extraction of the most intense band afforded pure
c-2-(benzyloxy)-3,4,5,6-tetrahydro-2H-pyran-r-3,t-4-diol
(20) (0.11 g, 63% yield), as a solid, mp 101–1038C
(recrystallized from hexane) (Found: C, 64.55; H, 7.01.
C12H16O4 requires: C, 64.27; H, 7.19): IR, see Table 5; 1H
NMR d 7.29–7.41 (m, 5H), 4.78 (d, 1H, J¼11.6 Hz), 4.48
(d, 1H, J¼11.6 Hz), 3.62–3.94 (m, 3H), 1.97 (ddt, 1H, J¼
12.6, 4.0, 2.0 Hz), 1.69 (tdd, 1H, J¼12.6, 11.4, 5.3 Hz), and
see Table 5. 13C NMR d 137.83, 129.00, 128.51, 128.43,
98.79, 75.00, 69.86, 69.30, 59.09, 41.27, 33.09.
Application of the same procedure to diol 20 (0.106 g,
0.47 mmol) afforded a crude liquid product (0.13 g) which
was subjected to preparative TLC (a 7:3 hexane/Et2O
mixture was used as the eluant). Extraction of the three most
intense bands (the fastest- and slowest-moving bands
contained 21 and 17, respectively) afforded pure dimethoxy
derivative 21 (0.021 g, 18% yield), HE 14 (0.003 g, 3%
yield), and HE 17 (0.042 g, 37% yield).
Application of the same procedure to trans epoxide 8
(0.20 g, 0.97 mmol) afforded a crude oily product (0.17 g)
which was subjected to preparative TLC (a 7:3 hexane/Et2O
mixture was used as the eluant). Extraction of the most
intense band afforded pure t-2-(benzyloxy)-3,4,5,6-tetra-
hydro-2H-pyran-r-3,t-4-diol (22) (0.14 g, 64% yield), as a
solid, mp 77–798C (recrystallized from hexane) (Found: C,
64.39; H, 6.92. C12H16O4 requires: C, 64.27; H, 7.19): IR,
r-2-(Benzyloxy)-c-3,t-4-dimethoxy-3,4,5,6-tetrahydro-2H-
pyran (21), a colorless liquid (Found: C, 66.54; H, 7.68.
C14H20O4 requires: C, 66.65; H, 7.99); H NMR d 7.16–
7.36 (m, 5H), 4.92 (d, 1H, J¼3.4 Hz), 4.70 (d, 1H, J¼
12.2 Hz), 4.49 (d, 1H, J¼12.2 Hz), 3.70 (ddd, 1H, J¼11.8,
5.5, 2.4 Hz), 3.51–3.77 (m, 2H), 3.37 (s, 3H), 3.34 (s, 3H),
3.12 (dd, 1H, J¼9.0, 3.4 Hz), 2.00 (ddt, 1H, J¼12.6, 4.8,
2.4 Hz), 1.48 (dtd, 1H, J¼12.6, 10.8, 5.5 Hz). 13C NMR d
138.01, 128.89, 128.62, 128.25, 96.26, 82.49, 76.88, 76.94,
69.33, 58.70, 57.77, 30.97.
1
1
see Table 5; H NMR d 7.10–7.35 (m, 5H), 4.90 (d, 1H,
J¼11.5 Hz), 4.58 (d, 1H, J¼11.5 Hz), 4.00 (ddd, 1H, J¼

P. Crotti et al. / Tetrahedron 59 (2003) 1453–1467
1465
t-2-(Benzyloxy)-t-3-methoxy-r-3,4,5,6-tetrahydro-2H-
pyran-4-ol (17), a colorless liquid (Found: C, 65.40; H, 7.82.
C13H18O4 requires: C, 65.53; H, 7.61): IR, see Table 5; 1H
NMR d 7.16–7.36 (m, 5H), 4.69 (d, 1H, J¼12.2 Hz), 4.47
(d, 1H, J¼12.2 Hz), 3.73 (ddd, 1H, J¼12.7, 11.7, 2.5 Hz),
3.55 (ddd, 1H, J¼11.7, 5.4, 1.6 Hz), 3.27 (s, 3H), 1.90
(dddd, 1H, J¼12.7, 5.2, 2.5, 1.6 Hz), 1.63 (tdd, 1H, J¼12.7,
11.7, 5.4 Hz), and see Table 5. 13C NMR d 137.94, 128.96,
128.64, 128.35, 95.17, 83.97, 69.30, 67.30, 58.73, 57.89,
33.14. MS (m/z) 45, 59, 91, 101, 135, 238 (Mþ).
C13H18O4 requires: C, 65.53; H, 7.61): IR, see Table 5; 1H
NMR d 7.23–7.43 (m, 5H), 4.91 (d, 1H, J¼11.7 Hz), 4.61
(d, 1H, J¼11.7 Hz), 4.01 (ddd, 1H, J¼12.2, 5.0, 2.0 Hz),
3.43 (s, 3H), 3.47–3.88 (m, 2H), 2.04 (ddt, 1H, J¼12.8, 4.9,
2.0 Hz), 1.58 (tdd, 1H, J¼12.8, 10.8, 5.0 Hz), and see Table
5. 13C NMR d 137.72, 128.97, 128.60, 128.40, 102.89,
80.60, 75.03, 71.28, 62.25, 57.53, 30.18. MS (m/z) 71, 91,
92, 101, 160, 238 (Mþ).
Application of the same procedure to trans epoxide 6
(0.052 g, 0.25 mmol) afforded after 1 h a crude liquid
product (0.058 g), consisting of a complex mixture also
containing products deriving from –OBn/MeOH exchange
at the anomeric carbon (GC and 1H NMR). When the same
reaction was repeated using a 0.001N H2SO4–MeOH
solution (3 h, rt), a crude reaction product (0.052 g) was
obtained, consisting of a 78:22 mixture of HEs 13 and 12
(GC), which was subjected to preparative TLC (an 8:2
hexane/AcOEt mixture was used as the eluant). Extraction
of the two most intense bands (the faster-moving band
contained 13) afforded pure HEs 12 (0.010 g, 17% yield)
and 13 (0.037 g, 62% yield).
6.1.6. Acid methanolysis of epoxides 5–8. Typical pro-
cedure. A solution of cis epoxide 5 (0.052 g, 0.25 mmol) in
0.2N H2SO4 in MeOH (2 mL) was stirred 2 h at rt. Dilution
with ether and evaporation of the washed (saturated aqueous
NaHCO3) organic solution afforded a crude product
(0.059 g) consisting of a 13:87 mixture of HEs 11 and 10
(GC), which was subjected to preparative TLC (an 8:2
hexane/AcOEt mixture was used as the eluant). Extraction
of the two most intense bands (the faster-moving band
contained 11) afforded pure HEs 11 (0.006 g, 10% yield)
and 10 (0.041 g, 69% yield).
c-2-(Benzyloxy)-t-5-methoxy-r-3,4,5,6-tetrahydro-2H-
pyran-4-ol (11), a colorless liquid (Found: C, 65.21; H, 7.44.
C13H18O4 requires: C, 65.53; H, 7.61): IR, see Table 5; 1H
NMR d 7.20–7.36 (m, 5H), 4.72 (d, 1H J¼11.8 Hz), 4.44
(d, 1H J¼11.8 Hz), 4.04 (dd, 1H, J¼12.7, 2.1 Hz), 3.55 (dd,
1H, J¼12.7, 3.2 Hz), 3.38 (s, 3H), 2.14 (dt, 1H, J¼14.1,
3.5 Hz), 1.75 (ddd, 1H, J¼14.1, 4.3, 3.2 Hz), and see Table
5. 13C NMR d 137.69, 129.09, 128.51, 97.81, 78.49, 70.27,
66.21, 58.39, 57.85, 32.96. MS (m/z) 58, 91, 108, 131, 147,
238 (Mþ).
t-2-(Benzyloxy)-t-4-methoxy-r-3,4,5,6-tetrahydro-2H-
pyran-5-ol (12), a colorless liquid (Found: C, 65.69; H, 7.48.
C13H18O4 requires: C, 65.53; H, 7.61): IR, see Table 5;
1H NMR d 7.18–7.34 (m, 5H), 4.79 (d, 1H J¼11.9 Hz),
4.49 (d, 1H, J¼11.9 Hz), 4.00 (dd, 1H, J¼11.5, 4.8 Hz),
3.33 (s, 3H), 3.15 (dd, 1H, J¼11.5, 8.7 Hz), 3.07–3.20
(m, 1H), 2.24 (ddd, 1H, J¼12.9, 4.6, 2.4 Hz), 1.48 (ddd,
1H, J¼12.9, 10.3, 8.3 Hz), and see Table 5. 13C NMR d
138.00, 129.02, 128.52, 128.38, 99.36, 80.62, 70.77, 69.99,
65.46, 56.94, 34.35. MS (m/z) 65, 91, 99, 131, 147, 238
(Mþ).
c-2-(Benzyloxy)-t-4-methoxy-r-3,4,5,6-tetrahydro-2H-
pyran-5-ol (10), a colorless liquid (Found: C, 65.78; H, 7.39.
C13H18O4 requires: C, 65.53; H, 7.61): IR, see Table 5; 1H
NMR d 7.19–7.33 (m, 5H), 4.64 (d, 1H, J¼11.8 Hz), 4.36
(d, 1H, J¼11.8 Hz), 3.66–3.74 (m, 1H), 3.41–3.65 (m, 3H),
3.33 (s, 3H), 2.19 (ddd, 1H, J¼12.9, 4.4, 2.3 Hz), 1.45
(ddd, 1H, J¼12.9, 9.8, 3.1 Hz), and see Table 5. 13C NMR
d 138.17, 129.02, 128.52, 128.35, 97.54, 79.12, 70.51,
69.44, 63.00, 57.11. MS (m/z) 91, 99, 122, 131, 147, 238
(Mþ).
t-2-(Benzyloxy)-t-5-methoxy-r-3,4,5,6-tetrahydro-2H-
pyran-4-ol (13), a colorless liquid (Found: C, 65.82; H, 7.33.
C13H18O4 requires: C, 65.53; H, 7.61): IR, see Table 5; 1H
NMR d 7.14–7.36 (m, 5H), 4.61 (d, 1H, J¼11.9 Hz), 4.35
(d, 1H, J¼11.9 Hz), 3.77 (dd, 1H, J¼10.5, 5.0 Hz), 3.42
(unresolved t, 1H, J¼10.5 Hz), 3.38 (s, 3H), 2.09 (ddd, 1H,
J¼13.1, 5.1, 1.2 Hz), 1.59 (ddd, 1H, J¼13.1, 11.3, 3.6 Hz),
and see Table 5. 13C NMR d 138.23, 128.99, 128.31,
128.25, 97.28, 81.89, 69.32, 68.43, 60.14, 58.58, 37.39. MS
(m/z) 74, 91, 113, 131, 147, 238 (Mþ).
Application of the same procedure to cis epoxide 7 (0.052 g,
0.25 mmol) afforded after 1 h a crude liquid product
consisting of practically pure c-2-(benzyloxy)-t-4-methoxy-
r-3,4,5,6-tetrahydro-2H-pyran-3-ol (14) (0.058 g, 97%
yield), as a colorless liquid (Found: C, 65.60; H, 7.31.
C13H18O4 requires: C, 65.53; H, 7.61): IR, see Table 5; 1H
NMR d 7.27–7.39 (m, 5H), 4.77 (d, 1H, J¼11.8 Hz), 4.51
(d, 1H, J¼11.8 Hz), 3.78 (td, 1H, J¼11.7, 2.4 Hz), 3.10–
3.59 (m, 2H), 3.43 (s, 3H), 2.00–2.13 (m, 1H), 1.43–1.64
(m, 1H), and see Table 5. 13C NMR d 137.91, 129.04,
128.58, 128.44, 98.87, 78.28, 73.31, 70.02, 59.10, 57.40,
30.14. MS (m/z) 71, 91, 92, 101, 160, 238 (Mþ).
6.1.7. Alkaline methanolysis (MeONa/MeOH) of epox-
ides 5–8. General procedure. A solution of the epoxide
(0.052 g, 0.25 mmol) and MeONa (0.21 g, 4.0 mmol) in
anhydrous MeOH (4.0 mL) was stirred at 808C for 18 h.
Dilution with Et2O and evaporation of the washed (water)
organic solution afforded a crude reaction product which
was analyzed by GC to give the results shown in Tables 2
and 3.
6.1.8. Methanolysis of epoxides 5–9 in the presence of
LiClO4. General procedure. A solution of the epoxide
(0.052 g, 0.25 mmol) in anhydrous MeOH (2 mL), contain-
ing LiClO4 (2.13 g, 10 M solution), was stirred at 808C for
the time shown in Tables 2 and 3. Dilution with ether and
evaporation of the washed (water) organic solution afforded
a crude reaction product which was analyzed by GC to give
the results shown in Tables 1–3.
Application of the same procedure to trans epoxide 8
(0.052 g, 0.25 mmol) afforded after 1 h a crude liquid
product consisting of practically pure t-2-(benzyloxy)-t-4-
methoxy-r-3,4,5,6-tetrahydro-2H-pyran-3-ol (16) (0.058 g,
97% yield), as a colorless liquid (Found: C, 65.59; H, 7.36.

1466
P. Crotti et al. / Tetrahedron 59 (2003) 1453–1467
6.2. Reactions in the gas-phase
Acknowledgements
6.2.1. Materials. Oxygen and trimethylamine were high-
purity gases from Matheson Gas Products Inc., deuterium
(99.98%) was purchased from Aldrich and all were used
without further purification. The chemical purity of starting
pyranosidic oxirane substrates was verified by analytical gas
chromatography on the same columns used for the analysis
of their gas-phase products.
This work was supported by the University of Pisa and
`
tifica e Tecnologica), Roma. P. C. gratefully acknowledges
Merck Research Laboratories for the generous financial
support derived from the 2002 ADP Chemistry Award.
MURST (Ministero dell’Universita e della Ricerca Scien-
6.2.2. Procedure. The gaseous mixtures were prepared by
conventional procedures23 with the use of a greaseless
vacuum line. The selected pyranosidic oxirane, the
methanol, the thermal radical scavenger O2, and the tri-
methylamine were introduced into carefully outgassed
250-mL Pyrex bulbs, each equipped with a break-seal
arm. The bulbs were filled with D2 (100 or 760 Torr), and
then allowed to come to room temperature; the fragile
ampoules were broken, and the gaseous components were
allowed to mix before being subjected to irradiation.
The gaseous mixtures were submitted to irradiation at a
constant temperature (37.58C) in a 60Co 220 Gammacell
from Nuclear Canada Ltd (dose: 1.5£104 Gy; dose rate:
1£104 Gy h21, determined with a Fricke dosimeter). The
total absolute yields of the radiolytic products are given as
the percentage ratio of their G(M) values, i.e. the number of
molecules of product M formed per 100 eV of energy
absorbed by the gaseous mixture, in relation to the G vþalue
References
1. Standard reaction conditions: epoxide opening reactions
carried out with the nucleophile (MeOH in the methanolysis)
under protic acid catalysis, or without any catalysis in an
appropriate solvent (MeOH/H2SO4 and MeONa/MeOH, in the
case of methanolysis). Chelating reaction conditions: epoxide
opening reactions carried out with the nucleophile in the
presence of a metal salt (MeOH/LiClO4, in the case of
methanolysis).
2. (a) Crotti, P.; Di Bussolo, V.; Favero, L.; Macchia, F.;
Pineschi, M. Tetrahedron 2002, 58, 6069–6091, and refer-
ences therein. (b) Chini, M.; Crotti, P.; Gardelli, C.; Macchia,
F. J. Org. Chem. 1994, 59, 4131–4137. (c) Calvani, F.; Crotti,
P.; Gardelli, C.; Pineschi, M. Tetrahedron 1994, 50,
12999–13021. (d) Chini, M.; Crotti, P.; Flippin, L. A.;
Macchia, F. J. Org. Chem. 1990, 55, 4265–4272.
3. Crotti, P.; Di Bussolo, V.; Favero, L.; Pineschi, M.;
Marianucci, F.; Renzi, G.; Amici, G.; Roselli, G. Tetrahedron
2000, 56, 7513–7524.
¨
for the formation of the Bronsted acid precursor, G(D3 )¼
3.11. Control experiments, carried out at doses ranging from
1£104 to 1£105 Gy, showed that the relative yields of
products are largely independent of the dose. The constancy
of the G(M) value for a given product M by varying the
radiation dose indicates that products arise from a single
radiolytic reaction.13,23
4. The C-1 and C-2 product nomenclature refers to the attacking
site of the nucleophile, i.e. at the C(1) or C(2) oxirane carbon
of epoxides 1–9, in accordance with the numbering scheme
shown in Schemes 1 and 2.
5. Chini, M.; Crotti, P.; Gardelli, C.; Macchia, F. Tetrahedron
1994, 50, 1261–1274.
6.2.3. Product analysis. The radiolytic products were
analyzed by injecting measured portions of the homo-
geneous reaction mixture into a Hewlett–Packard 5890
series II gas chromatograph, equipped with a flame
ionization detector. In order to prevent selective loss of
the reaction products by adsorption on the glass of the
reaction bulb (and to obtain reproducible and meaningful
reaction yields), the analysis was repeated after careful
washing of the bulb walls with anhydrous ether. Satisfactory
agreement between the results of the gaseous mixture and
the ether solution analysis was found in all runs. The
products were identified by comparison of their retention
volumes with those of authentic reference compounds on the
following columns: (i) a 50 m long, 0.31 mm i.d. Ultra1e
crosslinked methyl silicone fused silica capillary column,
operating at temperatures ranging from 80 to 2208C,
58C min21; (ii) a 25 m long, 0.32 mm i.d. Carbowax 20e
Ultra performance capillary column, operating at tempera-
tures ranging from 60 to 1808C, 48C min21. The identity of
the products was further confirmed by GLC–MS, using a
Hewlett–Packard 5890A gas chromatograph in line with a
HP 5971A quadrupole mass spectrometer. The yields were
determined from the areas of the corresponding eluted peaks,
using the internal standard method and individual calibration
factors to correct for the detector response. The results given
in Tables 1–3 are the average of at least three measurements
taken on at least two different runs for each point.
6. In the case of epoxide 9, the methanolysis in the cd-phase
under chelating conditions has been previously conducted with
5 M LiClO4 in MeCN in the presence of MeOH (10 equiv.),5
that is in conditions slightly different from the ones used in the
present paper with epoxides 5–8 (10 M LiClO4 in MeOH). As
a consequence, for the sake of an appropriate comparison of
the results, the methanolysis of 9 under chelating conditions
was repeated using the conditions adopted for epoxides 5–8.
For the reactions in the cd-phase under standard conditions,
the acid solution (0.2N H2SO4 in MeOH) presently utilized
with epoxides 5–8 is the same previously utilized with
epoxide 9.5
7. For other studies on the regioselectivity of the opening
reactions of oxirane systems structurally related to epoxides 7
and 8, see: (a) Schulz, M.; Kluge, R.; Liebsch, S.; Lessig, J.;
Halik, M.; Gadissa, F. Tetrahedron 1996, 52, 13151–13166.
(b) Carret, G.; Grouiller, A.; Pacheco, H. Carbohydr. Res.
1982, 111, 59–66. (c) Picq, D.; Anker, D.; Pacheco, H.
Tetrahedron Lett. 1981, 22, 4517–4520.
8. The acid methanolysis of trans epoxide 6 conducted with the
commonly used 0.2N H2SO4/MeOH solution, afforded a
complex reaction mixture containing, in addition to HEs 12
and 13, also large amounts of products, not further
investigated, deriving from exchange between the acetalic
–OBn group and MeOH, with consequent epimerization at the
anomeric C(1)-carbon. On the contrary, the use of a more
diluted acid condition (0.001N H2SO4/MeOH) afforded a

P. Crotti et al. / Tetrahedron 59 (2003) 1453–1467
1467
crude reaction product only containing the addition products,
the HEs 12 and 13 (Table 2).
17. The regioalternating process obtained with epoxide 6 would
also indicate, besides the particular ability of Liþ to be a
bidentate ligand between the oxirane oxygen and the
endocyclic oxygen (structure 40, M¼Liþ, Scheme 9), as
previously observed also in the case of the reference oxirane 9,
that when a chelating process leads to nucleophilic attack on
the electronically more favored oxirane carbon (like the C(1)
oxirane carbon of 40, M¼Liþ, Scheme 9, and of the previously
examined 35,5 Scheme 7), decidedly high regioselectivities
are obtained.
18. Stronger nucleophiles than MeOH, such as N23 , Et2NH, and
PhSH gave, in the case of epoxide 7 under chelating conditions
in the cd-phase, significative amount (23–25%) of C-2
product.2c On the contrary, epoxide 8 constantly gave, as in
the case of the presently examined methanolysis, a complete
C-1 regioselectivity with all the nucleophiles (N23 , Et2NH,
PhSH) and conditions (standard and chelating) tried.2c
19. Hunter, E. P.; Lias, S. G. J. Phys. Chem. Ref. Data 1998, 27,
413–656.
9. (a) Descours, D.; Anker, D.; Pacheco, H.; Chareire, M.; Carret,
G. Eur. J. Med. Chem. Chim. Ther. 1977, 12, 313–316.
(b) Hirsch, J. A.; Jarmas, A. A. J. Org. Chem. 1978, 43,
4106–4110.
10. In the gas-phase, Dþ (actually Dþ3 ) was used instead of Hþ
(actually Hþ3 ) simply for practical reasons (necessary purity of
the corresponding bulk gas, D2 and H2, respectively).
However, in the opening reactions of epoxides 5–9 with
MeOH, Dþ3 and Hþ3 obviously behave in the same way, except
for the hydron transfer kinetic isotopic effect (KIE). However,
in the gas-phase Dþ3 -protonation of organic molecules is
normally a very fast, highly exothermic process and, therefore,
the hydron transfer KIE is usually invisibly small. As a
consequence, no difference is made in the discussion between
Dþ3 and Hþ3 .
11. Spinks, J. W. T.; Woods, R. J. Introduction to Radiation
Chemistry; Wiley: New York, 1990; pp 213–214.
12. (a) Crotti, P.; Di Bussolo, V.; Favero, L.; Pineschi, M.;
Sergiampietri, D.; Renzi, G.; Ricciutelli, M.; Roselli, G.
Tetrahedron 1997, 53, 5515–5536. (b) Chini, M.; Crotti, P.;
Minutolo, F.; Dezi, E.; Lombardozzi, A.; Pizzabiocca, A.;
Renzi, G. Tetrahedron 1993, 49, 5845–5858. (c) Cecchi, P.;
Chini, M.; Crotti, P.; Pizzabiocca, A.; Renzi, G.; Speranza, M.
Tetrahedron 1991, 47, 4683–4692.
20. (a) Jackman, L. M.; Sternhell, S. Applications of Nuclear
Magnetic Resonance Spectroscopy in Organic Chemistry; 2nd
ed. Pergamon: London, 1969; p 286. (b) Macchia, B.;
Macchia, F.; Monti, L. Gazz. Chim. Ital. 1970, 100, 35–63.
21. The confirmed structure of HE 11 makes it possible to assign
the regioisomeric structure to HE 10.
22. Obviously, the different regiochemical results obtained on
passing from the cd-phase to the gas phase operating
conditions could be explained by admitting that the confor-
mational equilibrium inside epoxides 5–9, and therefore the
results, could be simply affected by the change from solution
to gas phase conditions and not by the incursion of chelating
processes mediated by the proton. However, the perfect
correspondence of the regioselectivity observed in the reaction
with MeOH, both under cd-phase and gas-phase conditions, of
the trans epoxides 1–4b,3 in which, for purely structural
reasons, no type of chelating process is possible, suggests that
any regioselectivity difference observed with epoxides 5–9 (as
in the case of cis epoxides 1–4a) between cd-phase and gas-
phase conditions should be reasonably ascribed to the
incursion, in these last conditions, of proton-mediated
chelating processes, as previously adequately stated.3
23. Speranza, M. In Fundamentals and Applications of Gas Phase
Ion Chemistry: Ion Molecule Reactions and Radiation
Chemistry; Jennings, K. R., Ed.; Kluwer Academic: The
Netherlands, 1999; pp 335–380.
13. (a) Ausloos, P.; Lias, S. G.; Gorden, Jr. R. J. Chem. Phys.
1963, 39, 3341–3348. (b) Ausloos, P. In Ion-Molecule
Reactions; Franklin, J. L., Ed.; Plenum: New York, 1970.
(c) Ausloos, P.; Lias, S. G. J. Chem. Phys. 1962, 36,
3163–3170. (d) Freeman, G. R. Radiat. Res. Rev. 1968, 1,
1–74. (e) Sandoval, L. B.; Ausloos, P. J. Chem. Phys. 1963,
38, 2454–2460. (f) Speranza, M.; Pepe, N.; Cipollini, R.
J. Chem. Soc., Perkin Trans. 2 1979, 1179–1186.
14. Structure 35 is the only chelated structure possible from
epoxide 9, with the epoxide forced in the less stable
conformation 9b. In accordance with Fu¨rst–Plattner’s rule,15
nucleophilic attack on 35 can occur only at the C(1) oxirane
carbon.
15. (a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley: New York, 1994; p 730. (b) Fu¨rst, A;
Plattner, P. A. Abstract of Papers. 12th International Congress
of Pure and Applied Chemistry 1951; p 409.
16. Under chelating conditions, epoxides 5 and 6 gave signifi-
cative inversion of regioselectivity with respect to standard
conditions also with other nucleophiles (Cl2, N32, Et2NH).2b