Do glycosyl sulfonium ions engage in neighbouring-group participation? A Study of oxathiane glycosyl donors and the basis for their stereoselectivity

Article abstract of DOI:10.1002/chem.201101889

Neighbouring-group participation has long been used to control the synthesis of 1,2-trans-glycosides. More recently there has been a growing interest in the development of similar strategies for the synthesis of 1,2-cis-glycosides, in particular the use of auxiliary groups that generate sulfonium ion intermediates. However, there has been some debate over the role of sulfonium ion intermediates in these reactions: do sulfonium ions actually engage in neighbouring-group participation, or are they a resting state of the system prior to reaction through an oxacarbenium ion intermediate? Herein, we describe the reactivities and stereoselectivities of a family of bicyclic thioglycosides in which an oxathiane ring is fused to the sugar to form a trans-decalin-like structure. A methyl sulfonium ion derived from one such glycosyl donor is so stable that it can be crystallised from ethanol, yet it reacts with complete stereoselectivity at high temperature. The importance of a ketal group in the oxathiane ring for maintaining this high stereoselectivity is investigated using a combination of experiment and ab initio calculations. The data are discussed in terms of S_N1 and S_N2 type mechanisms. Trends in stereoselectivity across a series of compounds are more consistent with selective addition to oxacarbenium ions rather than a shift between S_N1 and S_N2 mechanisms. Copyright

Full text of DOI:10.1002/chem.201101889

FULL PAPER
DOI: 10.1002/chem.201101889
Do Glycosyl Sulfonium Ions Engage in Neighbouring-Group Participation?
A Study of Oxathiane Glycosyl Donors and the Basis for their
StereoACHTNUTRGNEsNUG electivity
Martin A. Fascione,[a] Colin A. Kilner,[a] Andrew G. Leach,[b] and W. Bruce Turnbull*[a]
Abstract: Neighbouring-group partici-
pation has long been used to control
the synthesis of 1,2-trans-glycosides.
More recently there has been a grow-
ing interest in the development of simi-
lar strategies for the synthesis of
1,2-cis-glycosides, in particular the use
of auxiliary groups that generate sulfo-
nium ion intermediates. However,
there has been some debate over the
role of sulfonium ion intermediates in
these reactions: do sulfonium ions ac-
tually engage in neighbouring-group
participation, or are they a resting state
of the system prior to reaction through
an oxacarbenium ion intermediate?
Herein, we describe the reactivities
and stereoselectivities of a family of bi-
cyclic thioglycosides in which an oxa-
thiane ring is fused to the sugar to
form a trans-decalin-like structure. A
methyl sulfonium ion derived from one
such glycosyl donor is so stable that it
can be crystallised from ethanol, yet it
reacts with complete stereoselectivity
at high temperature. The importance of
a ketal group in the oxathiane ring for
maintaining this high stereoselectivity
is investigated using a combination of
experiment and ab initio calculations.
The data are discussed in terms of SN1
and SN2 type mechanisms. Trends in
stereoselectivity across a series of com-
pounds are more consistent with selec-
tive addition to oxacarbenium ions
rather than a shift between SN1 and
SN2 mechanisms.
Keywords: carbohydrates · density
functional calculations · neighbour-
ing-group effects · oxathiane · reac-
tion mechanisms
Introduction
reactions, in practice variable quantities of 1,2-trans-b-glyco-
sides also form and separation of the resulting mixtures is
often very difficult, or sometimes impossible. The stereose-
lective preparation of 1,2-cis-a-glycosides remains a funda-
mental challenge for oligosaccharide synthesis.[8] To combat
this problem, attention has become focused on the underly-
ing mechanistic theory of the glycosylation reaction.[9,10] Tra-
ditionally, stereoselectivity in the presence of non-participat-
ing protecting groups has been attributed to the kinetic
anomeric effect.[11] However, this principle has been chal-
lenged;[12] an alternative theory has emerged in the form of
the two-conformer hypothesis,[13,14] in which stereoselectivity
is determined by the selective addition of nucleophiles to
different conformations of an oxacarbenium ion intermedi-
ate. The identification of glycosyl triflate intermediates (or
contact/solvent separated ion pairs) has also provided sub-
stantial insight into the stereoselectivity of glycosyla-
tion.[15–17]
Recently, Boons and co-workers introduced a participat-
ing group that could provide 1,2-cis-a-glycosides
(Scheme 1a).[18] A glycosyl donor 1 bearing a modified
benzyl ether on O2 generates a bicyclic sulfonium ion 2
upon activation of the imidate leaving group. Subsequent re-
action with alcohols leads to 1,2-cis-a-glycosides with im-
pressive stereoselectivity.[18,19] Glycosyl sulfonium intermedi-
ates have often been observed, or inferred, in stereoselective
glycosylation reactions[18,20–23] and it is generally presumed
that the alcohol will directly displace the sulfonium group in
an SN2-like reaction. However, subsequent studies[21–23] have
Neighbouring-group participation provides a general strat-
egy for controlling the stereochemical outcome of chemical
reactions.[1] Typically, a nucleophilic group appended to one
face of a molecule will either displace a leaving group or in-
tercept a cationic intermediate to generate a quasi-stable
species. By blocking one face of the electrophile, the partici-
pating group will compel an external nucleophile to ap-
proach from the opposite face of the molecule, thus leading
to a stereospecific SN2-like reaction.[2] This strategy has been
widely used in carbohydrate chemistry for the synthesis of
1,2-trans-glycosides.[3] In this context, the participating group
is most commonly an ester[4] or cyclic imide group,[5] but
other nucleophilic groups have also been employed.[6]
In contrast, the synthesis of 1,2-cis-a-glycosides has tradi-
tionally relied upon the innate stereoselectivity of glycosyl
donors bearing non-participating protecting groups.[7] Al-
though a-glycosides may often be the major product of such
[a] Dr. M. A. Fascione, C. A. Kilner, Dr. W. B. Turnbull
School of Chemistry, University of Leeds
Leeds, LS2 9JT (UK)
Fax : (+44)1133436565
E-mail: w.b.turnbull@leeds.ac.uk
[b] Dr. A. G. Leach
AstraZeneca, Alderley Park, Macclesfield
Cheshire, SK10 4TF (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101889.
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321

Results and Discussion
The synthesis of the oxathiane donors has been reported
previously and is summarised in Scheme 2.[25,26] Thioglyco-
side 8 was synthesised in a one-pot reaction from the pen-
Scheme 1. Two complementary sulfonium ion-based participating group
strategies: a) Boonsꢂ chiral auxiliary-based approach to 1,2-cis-a-glyco-
sides through trans-decalin sulfonium ion 2. b) A modified approach to
bicyclic oxathiane sulfonium ions 6, through activation of oxathiane ketal
4 and oxathiane ether 5.
Scheme 2. Synthesis of protected oxathiane donors. Reagents and condi-
tions: a) SCACTHNUGTRNE(UGN NH2)2, BF3·OEt2, MeCN, reflux then Et3N, 2-bromoaceto-
phenone (64%); b) i) NaOMe, MeOH; ii) p-TSA, MeOH (60% over 2
steps); c) TMSOTf, Et3SiH, ClCH2CH2Cl (89%); d) 11 Ac2O, pyr
(76%); e) 12 NaH, BnBr, DMF (87%); f) 13 BzCl, DMAP, pyr (71%);
g) 14 Ac2O, pyr (72%); h) 15 NaH, BnBr, DMF (83%).
cast doubt on this assumption because the observation of
sulfonium ions in a reaction mixture does not necessarily
mean that they are intermediates on the reaction pathway.
An alternative explanation would be that the sulfonium ion
is a “resting state” for the system, which goes on to react
taacetate 7, then subsequently deacetylated under Zemplꢁn
conditions and subjected to acidic methanol to afford the
unprotected oxathiane ketal 9. Triol 9 was then either pro-
tected under standard conditions to afford oxathiane ketal
donors 11–13, or reduced using a combination of trimethyl-
silyl trifluoromethanesulfonate (TMSOTf) and Et3SiH,
before protection to afford oxathiane ether donors 14 and
15.[26]
through
a high-energy oxacarbenium ion intermediate
giving rise to a Curtin–Hammett kinetic scenario.[24] In
which case, the stereoselectivity of the reaction would be de-
pendent on the conformation of the oxacarbenium ion.[13,14]
In this paper, we explore the factors influencing the ste-
reoselectivity of glycosylation reactions involving bicyclic
glycosyl sulfonium ions. Recently, we described the synthesis
of oxathiane glycosyl donors 4 and 5[25,26] (Scheme 1b) that
are pre-organised to form bicyclic trans-decalin sulfonium
ions 6, which are similar to the Boons intermediate 2. We
evaluate changes in reactivity and stereoselectivity arising
from different substituents on the oxathiane glycosyl donors.
These include 1) methylation and arylation of the sulfur ap-
pendage; 2) the presence and absence of an axial methoxy
group substituent on the oxathiane ring; and finally, 3) the
effect of other protecting groups attached to the sugar ring.
Ab initio calculations are used to rationalise the results of
these comparative experiments in the context of putative
SN1 and SN2 mechanisms.
Activation as methyl sulfonium salts: In a first set of experi-
ments we prepared the S-methyl sulfonium ions for compar-
ison to the S-phenyl sulfonium species reported by Boons
et al.[18] Woerpel and co-workers had previously noted a sig-
nificant reactivity difference between ethyl and phenyl sul-
fonium ions, while studying a model system for neighbour-
ing-group participation by sulfide groups.[21] Although their
phenyl sulfonium ion reacted with nucleophiles at ꢀ458C,
the ethyl sulfonium ion was stable up to 08C. This difference
can partially be attributed to inductive stabilisation by the
alkyl group,[27] so we expected to see a similar reduction in
reactivity upon methylation of the oxathiane donors. Never-
theless, we were surprised to find that the sulfonium salts
16–18 were all stable enough to be isolated following silica
gel chromatography (Scheme 3). Thus, methylation of oxa-
thiane donors 11–13 using methyl triflate, or trimethyloxoni-
322
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Oxathiane Glycosyl Donors and the Basis for their Stereoselectivity
FULL PAPER
Comparison of the structures of sulfonium ion 17-(R) and
an analogous equatorial sulfoxide 19[25] provides an insight
to why the methyl sulfonium ion 17-(R) is unusually stable.
In both structures the sulfur atom and anomeric carbon are
sp3 hybridised and the anomeric carbon–sulfur bond lengths
are very similar (1.853 ꢃ for sulfonium salt 17-(R) vs.
1.838 ꢃ for sulfoxide 19). Thus, there is little stretching of
the anomeric bond following S-activation, and the positive
charge is not delocalised onto the anomeric carbon/ring
oxygen atoms. Instead, the charge on the sulfonium ion is
stabilised by an electrostatic interaction with the methoxy
substituent on the oxathiane ring.[30] The distance separating
the methoxy oxygen atom and the sulfur in sulfoxide 19 is
3.206 ꢃ, which is approximately the sum of the van der
Waals radii for oxygen and sulfur. However, in the case of
sulfonium ion 17-(R), this distance is reduced to 3.031 ꢃ.
Therefore, the reduced reactivity of the oxathiane ketal gly-
cosyl donors could be partially attributed to a stabilising
effect of the methoxy group on the sulfonium ion.[30]
Scheme 3. Methylation of oxathiane ketal donors. The eq/ax ratio refers
to the configuration of the methyl sulfonium ion. Reagents and condi-
tions: a) MeOTf, DTBMP, CH2Cl2 (95%, d.r. 2:1); b) Me3O·BF4, MeCN,
4 ꢃ MS (85%, d.r. 2:1); c) MeOTf, DTBMP, MeCN (18·OTf 86%, d.r.
2:1); d) Me3O·BF4, MeCN, 4 ꢃ MS (18·BF4 83%, d.r. 5:4).
Despite the high stability of methyl sulfonium salt 17, it
was possible for glycosylation to take place under more
forcing conditions. Following heating to 1508C with the pri-
mary acceptor 20 in a microwave reactor, glycoside product
21 was isolated following acid-catalyzed cleavage of the O2
ketal protecting group (Scheme 4a). This two-step procedure
allowed easier purification, and afforded higher yields of the
um tetrafluoroborate, afforded the corresponding sulfonium
salts 16–18 in 83–95% yield.[28] Benzylated glycosyl donors
are usually very reactive because the electron-donating pro-
tecting groups can stabilise the formation of an oxacarbeni-
um ion intermediate.[29] However, the benzyl-protected sul-
fonium salt 17 was so unreactive that it could even be crys-
tallised from hot ethanol. X-ray analysis revealed that the
major product was the equatorial methyl sulfonium salt
(Figure 1a). To the best of our knowledge, the X-ray crystal
structure of stable glycosyl sulfonium salt 17-R is the first of
its kind.
Scheme 4. Glycosylation reactions employing methylated oxathianes. Re-
agents and conditions: a) i) 4 ꢃ MS, proton sponge (6 equiv), CH2Cl2, mi-
crowave reactor 1508C, 15 min, ii) CSA, CH2Cl2 (83% over 2 steps, a/b>
98:2); b) i) MeOTf, CH2Cl2, RT, 4 h; ii) 4 ꢃ MS, 20, DTBMP, RT, 18 h
(30%, a/b 76:24). The low yield of disaccharide 23 was a result of com-
peting S-methyl transfer from the donor salt to the newly formed
S-methyl sulfide attached to O2 in product. See Ref. [25].
Figure 1. a) X-ray crystal structure of equatorial sulfonium salt 17-(R)
(ORTEP view, ellipsoid probability: 50%; CCDC accession number
805131). b) Comparison of inter-atomic distances in sulfonium salt
17-(R) and sulfoxide 19 (CCDC accession number 733122).
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323

W. B. Turnbull et al.
product. The significant temperature increase necessary to
facilitate glycosylation of the methyl sulfonium salt 17, com-
pared with the Boons sulfonium ion 1, is a testament to the
extra stability garnered from the introduction of both the
axial methoxy group and the S-Me appendage. However,
even at this high temperature, no b-glycoside was detected
in 1H NMR spectrum of the crude product mixture.
We anticipated that removal of the axial methoxy sub-
stituent from the oxathiane ring should increase the reactivi-
ty of the glycosyl donors. Therefore, benzyl-protected donor
15[26] was treated with methyl triflate to form the sulfonium
salt 22 (Scheme 4b). As expected, this sulfonium salt was
less stable that compound 17 and so the glycosyl acceptor
was added directly to the reaction mixture without first at-
tempting to isolate the activated glycosyl donor. The glyco-
sylation reaction proceeded overnight at room temperature,
thus demonstrating that this glycosyl donor was much more
reactive. However, disaccharide 23 was formed with lower
anomeric selectivity (a/b 76:24). Therefore, a direct compar-
ison between sulfonium ions 17 and 22 reveals that the axial
methoxy group has a significant effect on the stereoselectiv-
ity of glycosylation, as well as on the reactivity of the parent
sulfonium species.
Activation as aryl sulfonium salts: To further probe and cor-
roborate the effect of the axial methoxy group on stereose-
lectivity, we also studied the donors as aryl sulfonium salts.
Previously, we have reported an umpolung arylation strategy
for activating oxathiane ketal-S-oxides, which exploits the
unique reactivity of the oxathiane scaffold.[25] Activation of
glycosyl sulfoxides with triflic anhydride usually results in
rapid formation of oxacarbenium ions, which then proceed
to form glycoside products.[31] However, when oxathiane
ketal-S-oxides 24 were activated with triflic anhydride
(Table 1), the resulting triflyloxy sulfonium ions 25 remained
unreactive to acceptor alcohols until after the addition of an
electron-rich aromatic compound, for example, trimethoxy-
benzene (TMB). The TMB reacts selectively at the activated
sulfur atom, rather than at the anomeric carbon, to form
aryl sulfonium ions 26.[25] This low reactivity at the anomeric
Table 1. A comparative study of reactivity and a selectivity in glycosylation reactions employing a) oxathiane ketal-S-oxides 24 and b) oxathiane ether-
S-oxides 28.
Entry[a]
ROH[b]
Oxathiane
Ketal[c]
Yield
[%][d]
a/b[e]
Oxathiane
Ether[f]
Yield
[%][d]
a/b
1
20
35
20
35
19
19
32
32
85[g]
>98:2
33
33
34
34
61
71
67
62
88:12
2
3
4
44
>98:2
>98:2
>98:2
94:6
88
82:18
83:17
72
[a] All reactions were performed at a final donor concentration of 0.26m, and left for 18–24 h following acceptor addition. [b] 2.5 equiv [c] Results from
reference [25]. Unless otherwise stated, glycosylations were performed in C2H4Cl2 with Tf2O (1.1 equiv), 1,3,5-trimethoxybenzene (2.2 equiv) and
DIPEA (1.2 equiv) at ꢀ308C. The temperature was raised to ꢀ108C and a further 6 equiv of DIPEA and ROH were added, followed by heating at
508C. [d] Isolated product yields. [e] No b isomers were detected by NMR spectroscopy of crude glycosylation mixture. [f] Unless otherwise stated, glyco-
sylations were performed in CH2Cl2 with of Tf2O (1.1 equiv), 1,3,5-trimethoxybenzene (2.2 equiv) and DTBMP (2.5 equiv) at ꢀ608C. The temperature
was raised to ꢀ108C and ROH was added, followed by warming to RT. [g] 7.2 equiv DTBMP was used in place of DIPEA.
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Oxathiane Glycosyl Donors and the Basis for their Stereoselectivity
FULL PAPER
centre is consistent with the preceding observations on the
stability of “activated” oxathiane glycosyl donors.[32] Where-
as glycosylation reactions with the oxathiane ketal donors
19 and 32 were all completely stereoselective (a/b>98:2),[25]
the analogous reactions with the oxathiane ether donors 33
and 34 proceeded with a significant reduction in stereoselec-
tivity. When individual isomers of the products were re-ex-
posed to the reaction conditions, no anomerisation occurred;
therefore, we conclude that the reactions were under kinetic
control. Glycosylation of galactose acceptor 20 with acety-
lated donor 33 afforded glycoside products with an anomeric
ratio of a/b 88:12 (Table 1, entry 1), and a/b 94:6 with ben-
zylated acceptor 35 (Table 1, entry 2). Although the anome-
ric selectivity was slightly reduced in the latter example,
compared with the oxathiane ketal donor,[25] a much im-
proved yield of 71% was achieved.[33] The anomeric selectiv-
ities were even lower when using benzylated donor 34 with
the same glycosyl acceptors. The a/b anomeric ratio of the
products decreased to 82:18 for the reaction with galactose
acceptor 20 (Table 1, entry 3), and 83:17 with benzylated ac-
ceptor 35 (Table 1, entry 4). The observed loss of stereocon-
trol in glycosylation reactions with the oxathiane ether
donors 33 and 34 compared with the oxathiane ketal donors
19 and 32 is clear from Table 1, thus reiterating that the
axial methoxy group is essential for complete stereoselectiv-
ity in our glycosylation system. So why does the axial me-
thoxy group impart such an effect on the anomeric stereose-
lectivity?
To answer this question one must first consider the mech-
anism of the glycosylation reaction. As the reactions em-
ploying oxathiane ether donors 33 and 34 yield some b-gly-
cosides, then in all probability a SN1-like (DN +AN)[34] mech-
anism is at least partially responsible for the products. The
reaction could proceed solely through an SN1 mechanism, or
it could involve a combination of SN1 and SN2 (ANDN) pro-
cesses.[35] For example, an SN2-like mechanism could be
mostly responsible for the a stereoselectivity observed, with
the alcohol displacing the sulfur atom in a concerted, stereo-
specific inversion process. The minor b anomer would prob-
ably be formed in an SN1-like dissociative mechanism, in
which the approach to the oxacarbenium ion could also be
stereoselective and afford mostly the a anomer, but also
produce the b anomer.
Density functional theory calculations: To gain further in-
sight, density functional theory (DFT) calculations were per-
formed to assess how small changes in the structure of the
auxiliary groups affect the energy gap between SN1 and SN2
barriers (Figure 2). For computational convenience, calcula-
tions were performed on simplified oxathiane ketal and oxa-
Figure 2. SN1 and SN2 transition states for oxathiane ketal and oxathiane ether sulfonium salts 37 and 40a and 40b determined using density functional
theory calculations at the B3LYP/6-31G* level of theory. Possible reaction pathways for a) oxathiane ketal sulfonium ion 37 and c) oxathiane ether sulfo-
nium ions 40a and 40b are depicted with ammonia employed as a model nucleophile. In energy profiles b), d) and e), DG° values are quoted in kcal
molꢀ1 relative to the lowest energy conformation of the parent sulfonium ions 37, 40a and 40b. All energy values have been corrected for the effects of
solvation according to the integral equation formalism polarisable continuum model (IEFPCM) with united atom Kohn–Sham (UAKS) radii based upon
a B3LYP/6-31+G* electronic structure.
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325

W. B. Turnbull et al.
thiane ether TMP sulfonium ions, in which the substituents
at O3 and O4 were replaced by methyl groups and the C6
and phenyl substituents were also truncated to methyl
groups. Ammonia was used as a model nucleophile because
it has higher symmetry and basicity than an alcohol,[22]
therefore eliminating considerations regarding the direction-
ure 2b and d). This result could be consistent with a shift in
favour of an SN1 mechanism for the oxathiane ether 40a,
which could account for the reduced stereoselectivity of the
glycosylation reactions.
Figure 2e depicts the calculated energy profile for the cor-
responding phenyl sulfonium ion 40b.[22] Removing the me-
thoxy groups from the aromatic ring reduces both the SN1
and SN2 transition state energies. This observation is consis-
tent with the higher reactivity of sulfonium ions bearing a
phenyl group rather than a trimethoxyphenyl (TMP) group.
However, the difference between the energies of the SN1
and SN2 transition states is also reduced (TMP DDG° vs.
phenyl DDG° =ꢀ4.4 vs. ꢀ0.3 kcalmolꢀ1, Figure 2d and e).
Therefore, the calculations indicate that the phenyl sulfoni-
um ion 40b is more likely to undergo an SN1-like mecha-
nism than TMP sulfonium ion 40a, and should thus be the
least stereoselective of the three glycosyl donors. This obser-
vation is consistent with a recent report by Boons and co-
workers that a benzyl-protected glycosyl donor bearing their
chiral auxiliary group is poorly stereoselective.[42] However,
Boons has previously reported[18] significantly higher a ste-
reoselectivities for his acetylated glycosyl donors than those
reported here using analogous TMP sulfonium ions. For ex-
ample, glycosylation of acceptor 35 with phenyl sulfonium
ion 42b is reported to give only a-configured product 43ba
(Scheme 5),[18] whereas TMP sulfonium ion 42a yields ap-
preciable quantities of the b-configured product 43ab
(Table 1).
ꢀ
ality of the O H bond vector as it approaches the sulfonium
ion, and the point at which the alcoholic proton is removed
during glycosylation mechanism.[13] Crich and Sharma have
demonstrated that hydrogen bonding between glycosyl
donors and acceptors is not an important factor in determin-
ing the stereoselectivity of glycosylation reactions.[36] Geo-
metries were optimised using B3LYP/6-31G*[37] in Gaussi-
an 03.[38] Additional single-point calculations using M06/6-
31+G**[39] were performed in Gaussian 09[40] and gave re-
sults that correlated well with the original B3LYP/6-31G*
calculations (see the Supporting Information). Energies
were corrected to free energies at 298 K with B3LYP/6-
31G* vibrational corrections and the effects of solvation
were modelled with free energies obtained using the integral
equation
formalism
polarisable
continuum
model
(IEFPCM) method with united atom Kohn–Sham (UAKS)
radii.[41]
Although the reactions modelled in silico are not identical
to the reactions performed in vitro, the DFT studies provide
a fair comparison of the balance that exists between SN1-
like or SN2-like mechanisms (DDG°) for two different
donors. In other words, is the oxathiane ether donor more
or less likely to react by an SN1 mechanism than the oxa-
thiane ketal donor?
The DFT models indicate that the presence or absence of
a methoxy group has no effect on the structures of sulfoni-
um ions 37 and 40a or SN2 transition states 36 and 39a (see
the Supporting Information). Therefore, the approach of the
nucleophile to the sulfonium ion is essentially unaffected by
the introduction of the methoxy substituent. The SN2 activa-
tion barrier is 0.5 kcalmolꢀ1 higher for ketal 37 over the
ether 40a once solvation effects are included (Figure 2b and
d; 19.5 vs. 20.0 kcalmolꢀ1). The structures for the SN1 transi-
tion states 38 and 41a are also very similar, which differ
only slightly in the angle of the trimethoxyphenyl group as
the auxiliary group rotates away from the anomeric carbon.
Again, removal of the methoxy group from the oxathiane
ring has a modest effect on the SN1 transition-state barriers
with ketal 38 being 0.9 kcalmolꢀ1 higher in energy than
ether 41a when the effect of solvation is included. This
value could be representative of the electrostatic stabilisa-
tion imparted by the ketal oxygen atom (see above).
Although these calculations suggest that the SN2 pathway
is the lowest in energy for both donors, this observation
should be treated with caution because the structures are
not identical to the compounds studied in vitro. However, a
fair comparison can be made between DDG° (SN2°–SN1°)
for both ketal and ether donors 37 and 40a, respectively.
The difference between SN1 and SN2 transition states de-
creases by 1.4 kcalmolꢀ1 upon removing the methoxy group
(ketal DDG° vs. ether DDG° =ꢀ5.8 vs. ꢀ4.4 kcalmolꢀ1, Fig-
Scheme 5. Comparison of TMP and phenyl sulfonium ions.
The calculations were repeated with acetyl protecting
groups on O3 and O4 to assess the impact of the protecting
groups on the balance between SN1 and SN2 reactions.
Figure 3 summarises experimental and theoretical results for
a set of comparable ester and ether-protected sulfonium
ions. Acetylated model glycosyl donors A1–C1 were predict-
ed to be more likely to undergo an SN2-type reaction than
the methylated model structures A2–C2. At first sight, these
results correlate with the increased experimental stereose-
lectivity for acetylated sulfonium ions B1 and C1 relative to
the analogous benzyl-protected compounds.
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Oxathiane Glycosyl Donors and the Basis for their Stereoselectivity
FULL PAPER
The two-conformer hypothesis: An alternative explanation
for the differing stereoselectivities observed could be that
all of these sulfonium ions react through an SN1-like mecha-
nism that generates oxacarbenium ion intermediates.[21,23] If
so, then could the “participating group” still exert an influ-
ence over the stereoselectivity of the glycosylation reaction?
To address this question the structures of a wide range of
oxacarbenium ion conformations were calculated for each
donor. Oxacarbenium ions can exist in either 3H4 or 4H3
half-chair
conformations
((3H4)-44
and
(4H3)-44,
Scheme 6),[43] each of which could react with a nucleophile
Figure 3. Correlation between the experimental stereoselectivity and pre-
dicted balance between SN2 and SN1 reaction mechanisms for a series of
comparable sulfonium ions. Where the range of reported experimental
stereoselectivities is wider than the bounds of the symbol, the range is in-
dicated by error bars. Experimental stereoselectivity values for sulfonium
ions A1, A2, B1 and B2 are based on data in Table 1; data for sulfonium
ions C1 and C2 are taken from references [18] and [42]. Although the
same set of donors has not been used for all six glycosyl donors, there
are sufficient pair-wise comparisons to allow a fair assessment. Single-
point calculations using M06/6-31+G** correlated well with the original
B3LYP/6-31G* results (see the Supporting Information).
Scheme 6. The two-conformer hypothesis.
to form a glycoside product 45; it is now broadly accepted
that the facial selectivity of nucleophile addition is different
4
for each conformer.[13,14] The H3 conformer will react pref-
3
erentially on the a face, and the H4 conformer reacts pref-
erentially on the b face, as these processes will return the
ion to a chair conformation rather than a more strained
twist-boat intermediate.[44] If the rates of these two addition
steps are equal, then the stereoselectivity is governed by the
3
4
relative abundance of the H4 and H3 conformers; however,
different steric interactions in the transition states may
render the addition steps inequivalent.[10]
A comparison of the acetylated structures, on the other
hand, does not support the hypothesis that stereoselectivity
is governed by the balance between SN1 and SN2 pathways.
The DFT calculations indicate that model sulfonium ion B1
should be almost as likely to undergo an SN2-type reaction
as model sulfonium ion A1, and much more likely to under-
go an SN2-type reaction than model sulfonium ion C1,
whereas experimentally, sulfonium ion B1 (i.e., 42a,
Scheme 5) is the least stereoselective of the acetylated com-
pounds. In summary, some trends in the experimental data
can be explained by the hypothesis that stereoselectivity re-
flects the balance between SN1 and SN2 mechanisms; howev-
er, this hypothesis is not consistent with a global view of all
the experimental data.
A Monte Carlo search was used to generate a broad
range of conformations for the substituents attached to H4
3
and 4H3 oxacarbenium ions 46–48. The geometry of each
conformer was optimised using DFT calculations (B3LYP/6-
31G*). Identical conformations were removed before per-
forming additional single-point calculations using M06/6-
31+G**. In some cases the oxacarbenium ions reacted
spontaneously with the sulfur atom to form oxathiane sulfo-
nium ions with various conformations. In many other cases,
3
the (b selective) H4 conformations of oxacarbenium ion 46
closed onto the ketal methoxy group to form dioxolanium
ion 49. Although this intermediate could be expected to
Chem. Eur. J. 2012, 18, 321 – 333
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327

W. B. Turnbull et al.
lead to intramolecular aglycone delivery (IAD), we have
noted previously that there is no evidence for IAD occur-
ring with our oxathiane ketal donors.[25] When one considers
that the energies of the dioxolanium ions are only 1–2 kcal
molꢀ1 lower than the most stable oxacarbenium ions (see
the Supporting Information), it is likely that formation of di-
oxolanium ions would not be irreversible; rather, all inter-
mediates would be expected to interconvert under the reac-
tion conditions, with the equilibrium lying in favour of the
bicyclic sulfonium ion.
4
Figure 4. Percentage abundance of H3 oxacarbenium ion conformers pre-
dicted from a Boltzmann distribution analysis of oxacarbenium ion ener-
gies at 298 K. TMP=2,4,6-trimethoxyphenyl. Energies are free energies
at the B3LYP/6-31G* or M06/6-31+G** levels based on B3LYP/6-31G*
optimised structures. The energy values were corrected for CH2Cl2 solva-
tion using the IEFPCM method with UAKS radii. The two-conformer hy-
pothesis predicts that systems favouring the 4H3 conformer will be more
selective for the formation of a-glycosides.
The structures that persisted as oxacarbenium ions were
then inspected by eye. Ions in which the auxiliary group par-
tially or completely obscured the more reactive face of the
bearing a trimethoxyphenylsulfide auxiliary group was pre-
dicted to be more a selective than ions 47b and 48, which is
in line with experimental results. However, ion 46 with the
ketal-linked auxiliary was predicted to be less a selective
than 47a, which differs from experiment (Table 1).
The discrepancies between the different functionals is
best illustrated by comparison of two conformers of ion 47a
(Figure 5). The B3LYP/6-31G* calculations indicate that the
lowest energy 3H4 and 4H3 conformers are isoenergetic
(DG8= +17.3 vs. +17.4 kcalmolꢀ1 relative to sulfonium ion
4
oxacarbenium ion (i.e., the a face for the H3 conformer and
3
the b face for the H4 conformer) were excluded from fur-
ther analysis. A Boltzmann distribution was applied to the
remaining oxacarbenium ions to estimate the relative abun-
3
4
dance of reactive H4 and H3 conformers that would be pre-
dicted to lead to b- and a-glycosides, respectively. The
weighting introduced in this analysis effectively excludes
structures that are more than approximately 2 kcalmolꢀ1
above the lowest energy species in each set. Figure 4 shows
4
the percentage of ions that are predicted to have a H3 con-
formation (i.e., the conformation that should lead to a-gly-
coside products). A higher percentage of ions in the 4H3
conformation is predicted to correlate with greater a selec-
tivity.[45]
The initial B3LYP-derived energies predict that oxacarbe-
nium ions 46 and 47b should be more a selective than ions
47a and the more simple 2O-methyl ion 48 (Figure 4) This
result does not correlate well with experimental stereoselec-
tivities for the ether-protected glycosyl donors (I–III;
Figure 3). However, the B3LYP functional may not be opti-
mal for systems in which dispersion-dependent interactions
are important.[46] Therefore, additional single-point energy
calculations were performed using the M06 functional[39]
with 6-31G* and 6-31+G** basis sets and also B3LYP/6-
31+G**. Changing the basis set did not have a significant
impact on the Boltzmann distributions. However, switching
to the M06 functional gave a different overall profile for
ions 46–48 (Figure 4). In this case the oxacarbenium ion 47a
Figure 5. a) 3H4 and b) 4H3 conformations of oxacarbenium ion 47a that
have equal energies in the B3LYP calculations, but differ significantly in
M06 calculations. The DG8 values are quoted relative to the lowest
energy sulfonium ion.
328
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Oxathiane Glycosyl Donors and the Basis for their Stereoselectivity
FULL PAPER
Table 2. Stereoselectivity in oxathiane ether-S-oxide glycosylation reac-
tions.
40a). Both ions are stabilised by electrostatic interactions
with a methoxy group on the aromatic ring; in the H3 con-
4
former the oxygen atom interacts directly with C1 and the
plane of the aromatic ring faces the cationic centre, but in
3
ꢀ
the H4 conformer, the interaction involves a CH O hydro-
gen bond to the anomeric centre and the aromatic plane is
away from the remainder of the molecule. The M06/6-31+
3
ꢀ
G** calculations disfavour the H4 conformer with the CH
O interaction (DG8= +19.9 kcalmolꢀ1), but favour the H3
4
ꢀ
conformer with the C O interaction (DG8= +15.4 kcal
molꢀ1). The overall effect is an increase in the predicted a
selectivity for ion 47a. Additional calculations contrasting
SCF and MP2 energies (see the Supporting Information)
highlighted that dispersion-based interactions which depend
upon electron correlation were important in these systems
and so we conclude that the M06 calculations are more reli-
able in this case.[47] Although the DFT calculations are able
to make a prediction of the likely outcome if the two-con-
former hypothesis were to be applicable, the fact that they
do not reveal a consistent correlation with the experimental
data across all compounds studied suggests that the stereo-
selectivity of the reactions is not solely based on the relative
Entry[a]
Donor
ROH
Yield
[%][b]
a/b
93:7
95:5
>98:2[d]
97:3
1
2
33
33
33
33
50
51
52
53
70
69
82
67
3[c]
4
[a] Unless otherwise stated, all reactions were performed at a final donor
concentration of 0.11m, and left for 18–24 h following acceptor addition.
Glycosylations were performed in CH2Cl2 with 4 ꢃ MS, Tf2O (1.1 equiv),
ArH (2.2 equiv) and DTBMP (2.5 equiv) at ꢀ608C. The temperature was
raised to ꢀ108C and ROH (1.2 equiv) was added, followed by warming
to RT. [b] Isolated product yields. [c] 2.5 equiv [d] No b isomers were de-
tected by NMR spectroscopic analysis of the crude glycosylation mixture.
4
energies of the 3H4 and H3 conformers.
It is clear from the experimental results that a variety of
factors can affect the stereoselectivity of these glycosylation
reactions, for example, the structure of the acceptor alcohol,
the protecting groups on the glycosyl donor and the sub-
stituents on the oxathiane ring. So do these modifications in-
fluence stereoselectivity by changing the balance between
SN1 and SN2 pathways, or, by modulating the stereoselectiv-
ity of the SN1 contribution to the reaction mechanism?
1C4 conformation in which there are unfavourable 1,3-diaxial
interactions. Therefore, less reactive/more bulky nucleo-
philes should be less inclined to react with oxacarbenium
3
ions in the H4 conformation, and may display greater ste-
Steric factors also influence stereoselectivity: Glycosylation
reactions with the oxathiane ether-S-oxide 33 were extended
to include more hindered secondary and tertiary alcohols
(Table 2). Reaction with hindered acceptor 52 was com-
pletely a stereoselective (Table 2, entry 3, a/b> 98:2), and
reaction with tertiary alcohol 53 formed very little
b-anomer (Table 2, entry 4, a/b 97:3). Glycosylation of ben-
zylated mannoside 50 was less stereoselective (Table 3,
entry 1; a/b 93:7), but when the analogous less reactive diac-
etylated mannoside 51 was used as an acceptor, the stereo-
selectivity rose slightly to a/b 95:5 (Table 2, entry 2). These
examples illustrate that the stereoselectivity does vary de-
pending on the reactivity of the nucleophile, with more hin-
dered alcohols leading to higher stereoselectivity.
An SN2 mechanism should become more likely as nucleo-
philicity increases. Conversely, if nucleophilicity decreases as
a consequence of steric hindrance or electronic deactivation,
an SN2 mechanism should become less likely. The results
presented here do not thus appear to be consistent with a
shift between SN1 and SN2 pathways. On the other hand,
they could be consistent with stereoselective addition to an
oxacarbenium ion. The steric bulk of the nucleophile should
have no effect on the conformational equilibrium of an oxa-
carbenium ion.[48] However, the two-conformer hypothesis
(Scheme 6) assumes that the b-glycoside initially forms in a
reoselectivity than would be predicted by simply calculating
3
4
the relative abundance of H4 and H3 conformers. In other
words, the relative transition-state barriers are also impor-
tant in influencing stereoselectivity.
The effect of protecting groups on stereoselectivity: As
noted above, the nature of the protecting groups on the
sugar ring can also influence the stereoselectivity of the oxa-
thiane ether glycosyl donors. For example, reactions of ace-
tylated donor 33 (Table 1, entries 1 and 2) were more stereo-
selective than those using the benzylated donor 34 (Table 1,
entries 3 and 4). Similarly, when benzylated oxathiane 15
and the analogous acetylated compound were activated
using benzyne,[26] the benzylated donor displayed lower a se-
lectivity. Boons and co-workers have noted a similar effect
when using glycosyl donors bearing chiral auxiliaries.[42,49]
Specifically, if an ester or carbonate protecting group was
used at the O3 position, then stereoselectivities were much
higher than when using an ether protecting group at O3.
They proposed that an SN2-like mechanism could be fav-
oured by either 1) the use of protecting groups that would
destabilise an oxacarbenium ion intermediate or by 2) modi-
fying the auxiliary to increase the stability of the sulfonium
ion.[42]
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329

W. B. Turnbull et al.
If hypothesis (1) is correct, then destabilising the oxacar-
benium ion by exploiting the torsional and electronic con-
straints of a benzylidene acetal protecting group[50] should
also favour an SN2-like reaction. Oxathiane 10 was protected
with a benzylidene acetal before acetylation of O3 and oxi-
dation with mCPBA to give sulfoxide 55 (Scheme 7). Acti-
tivities of ester-protected glycosyl sulfonium ions displayed
poor correlation with the calculated balance between SN1
and SN2 transition-state energies across the set of three dif-
ferent sulfonium ions studied. Thus, enhancements in stereo-
selectivity attained by changing the protecting groups may
not solely represent a shift in the balance between SN1 and
SN2 mechanisms.
The two-conformer hypothesis offers an alternative ex-
planation for the enhanced stereoselectivity observed when
ester protecting groups are employed. Woerpel and co-
workers have proposed that benzyl ether substituents at O3
3
and O4 both favour the H4 conformer of an oxacarbenium
ion in which they can provide trans-annular electrostatic sta-
bilisation.[52] Therefore, benzyl ether protecting groups at
these positions should favour formation of the b anomer.
Woerpel,[52] and Bols[53] have also shown that this effect is
reduced if the ethers are replaced by electron-withdrawing
3
ester groups that are less able to stabilise the H4 conforma-
tion. In other words, even if the reaction proceeds in part
via an oxacarbenium ion intermediate, then ester protecting
groups at O3 and O4 should favour a selectivity.
Phenyl vs. trimethoxyphenyl auxiliary groups: It has been
suggested that increasing the stability of the sulfonium ion
should favour an SN2-like mechanism.[42] As demonstrated
above, an axial methoxy group on the oxathiane ring can
stabilise a methyl sulfonium ion to the point at which it can
be crystallised from ethanol (Figure 1). This glycosyl donor
is completely stereoselective when subjected to reactions at
high temperatures (Scheme 4). Athough these observations
appear to support the hypothesis, the presence of a ketal
group in the oxathiane ring is not sufficient to ensure com-
plete stereoselectivity.[54] Furthermore, the reactions of sul-
fonium ions 42a and 42b do not support the hypothesis
(Scheme 5). Our DFT calculations indicate that the trime-
thoxyphenyl group in compound 42a stabilises the sulfoni-
um ion through a favourable interaction between a methoxy
group and the sulfur atom (Figure 6).[30] The corresponding
phenylsulfonium ion 42b lacks this interaction and is thus
less stable/more reactive.[55] If the hypothesis is correct, one
would expect sulfonium ion 42a to be more likely to under-
go an SN2 mechanism and thus be more stereoselective.
However, the converse is true: intermediate 42b is reported
Scheme 7. A benzylidene acetal-protected oxathiane. Reagents and con-
ditions: a) i) PhCHACHTUNGTRENNUNG(OMe)2, pTSA, CH3CN; ii) Ac2O, pyr (61% over 2
steps); b) mCPBA, CH2Cl2, ꢀ788C (84%, d.r. 57:43); c) 4 ꢃ MS, 1,3,5-tri-
methoxybenzene, DTBMP, Tf2O, CH2Cl2, ꢀ608C to ꢀ108C; d) 20,
ꢀ108C to RT, 12 d (69%, a/b 93:7).
vation with triflic anhydride in the presence of TMB gave
the trimethoxyphenyl (TMP) sulfonium salt 56 which react-
ed very slowly at RT with diacetone galactose 20, taking
12 days to approach complete reaction. The glycoside prod-
uct 57 was isolated in 69% yield as a 93:7 a/b mixture. Al-
though the stereoselectivity was higher than observed previ-
ously for oxathiane ether donors 33 and 34 (Table 1, en-
tries 1 and 3), the formation of the b-product indicated that
an SN1 pathway was still in operation. In this case, the b-gly-
3
coside could not result from a H4 intermediate as the con-
formation of the sugar ring is locked by the benzylidene
acetal; therefore, it probably arises from a change in mecha-
nism to involve an a-triflate intermediate.[15,48] Nevertheless,
such an intermediate would presumably also be the product
of an SN1-like opening of the oxathiane ring.
Destabilising the oxacarbenium ion intermediate appears
to have a greater impact on the reactivity of the donor,
rather than its stereoselectivity. This observation is perhaps
not surprising when one considers that models of the SN2
transition states have considerable oxacarbenium ion char-
acter.[16,22,51] Factors that destabilise an oxacarbenium ion in-
termediate would thus also destabilise the SN2 transition
state. The modelling results summarised in Figure 3 do indi-
cate that ester protecting groups should increase the proba-
bility of an SN2-like mechanism. However, the stereoselec-
Figure 6. Model of sulfonium ion 58 and structure of analogous sulfonium
ion 42a showing the interatomic distance between the sulfur atom and
nearest methoxy group. The stabilisation resulting from this through
space interaction renders the trimethoxyphenyl sulfonium ion less reac-
tive than the corresponding phenyl sulfonium ion 42b.
330
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Chem. Eur. J. 2012, 18, 321 – 333

Oxathiane Glycosyl Donors and the Basis for their Stereoselectivity
FULL PAPER
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
to glycosylate acceptor 35 with complete a stereoselectiv-
ity,[18] whereas the trimethoxyphenyl analogue 42a yields a
94:6 mixture of a- and b anomers (Table 1). Therefore, al-
though there are some apparent correlations between sulfo-
nium ion stability and stereoselectivity, increasing the stabil-
ity of the sulfonium ion does not necessarily lead to greater
flux through the SN2 pathway or higher stereoselectivity.
General: All solvents were dried prior to use, according to standard
methods.[56] Methyl trifluoromethanesulfonate (MeOTf), trifloromethane-
sulfonic anhydride (Tf2O) and trimethylsilyl trifluoromethanesulfonate
(TMSOTf) were distilled under a N2(g) atmosphere. Boron trifluoride di-
ethyl etherate (BF3·OEt2) was distilled over calcium hydride, and all
other commercially available reagents were used as received. Where ap-
propriate anhydrous quality material was purchased. All solvents used
for flash chromatography were GPR grade, except hexane and ethyl ace-
tate, when HPLC grade was used. All concentrations were performed in
vacuo, unless otherwise stated. All reactions were performed in oven
dried glassware under a N2(g) atmosphere, unless otherwise stated.
Conclusion
At the time of designing the oxathiane glycosyl donors, we
assumed that stereoselectivity would arise from an SN2-like
displacement of the equatorial sulfonium ion by an acceptor
alcohol. However, variation of the oxathiane structure re-
vealed that some of the sulfonium ions were not completely
stereoselective, and probably follow an SN1-type mechanism
(at least in part). A ketal group on the oxathiane ring signif-
icantly reduced the reactivity of the glycosyl donors, to the
point at which a methyl glycosyl sulfonium ion was suffi-
ciently stable to isolate and crystallise from an alcoholic sol-
vent. Despite this low reactivity, the ketal group was able to
preserve the stereoselectivity of the glycosylation reaction
under forcing conditions. Activation of the glycosyl donors
as trimethoxyphenyl (TMP) sulfonium ions reinforced the
observation that the ketal group is important for stereose-
lectivity in these glycosylation reactions. DFT studies on the
TMP sulfonium ions indicated that converting the ketal
group to an ether could potentially lead to a shift towards
an SN1-type mechanism. However, extrapolating this argu-
ment to include acetylated glycosyl sulfonium ions led to
conclusions that were not in line with experimental observa-
tions (Scheme 5).
General procedure for glycosylation reactions with oxathiane ether-S-
oxides: Tf2O (1.1 equiv) was added to a solution of oxathiane ether-S-
oxide 33 or 34 (1 equiv), 1,3,5-trimethoxybenzene (2.2 equiv), DTBMP
(2.5 equiv) and 4 ꢃ molecular sieves in CH2Cl2 (initial donor concentra-
tion 0.26m), cooled to ꢀ608C. The reaction mixture was warmed to
ꢀ108C over 10 min. A solution of the glycosyl acceptor (2.5 equiv for pri-
mary alcohol acceptors; 1.2 equiv for secondary and tertiary alcohol ac-
ceptors) in CH2Cl2 (final donor concentration 0.21m for primary alcohol
acceptors; 0.11m for secondary and tertiary alcohol acceptors) was then
added and the reaction mixture was stirred for 18–24 h at RT. The reac-
tion mixture was then diluted with CH2Cl2 (5 mL), washed with 1m HCl
(2ꢄ5 mL), aq. NaHCO3 (2ꢄ5 mL) and aq. NaCl (2ꢄ5 mL), dried
(MgSO4) and concentrated to afford a crude syrup. The crude syrup was
purified by size exclusion chromatography (Sephadex LH-20 resin;
eluted with methanol (50 mLhꢀ1)) to afford the desired disaccharide.
Density functional theory calculations: All quantum mechanical calcula-
tions were performed in Gaussian 03 and Gaussian 09.[38,40] Geometries
were optimised with B3LYP/6–31G* and were characterised with fre-
quency calculations.[37] Transition states were identified by redundant co-
ordinate scans from the lowest energy conformations of reactant cyclic
sulfoniums; SN1 transition states correspond to an internal rotation link-
ing conformations of open-chain oxacarbenium ions and the cyclised
structure. Conformation ensembles were expanded in Maestro using the
MacroModel module (Schrçdinger, LLC);[57] the oxacarbenium ions were
modelled by transforming to the neutral cyclic imines (O was exchanged
with N). Two low energy conformations of this ring were identified that
placed the substituents all equatorial or all axial. The ring and atoms at-
tached directly to it were then fixed and the remainder of the molecule
expanded using the Monte-Carlo sampling option and the OPLS force-
field and a chloroform solvent model, as implemented in Maestro. The
resulting conformations were reduced using the conformer elimination
protocol and employing an RMSD cut off based on heavy atoms of
1.5 ꢃ. Subsequent optimisation of the conformations with B3LYP/6–
31G* occasionally caused these conformations to converge; such occur-
rences were removed upon manual inspection. Additional single-point
calculations were performed with M06/6–31+G**. Solvation calculations
employed the IEFPCM method based on B3LYP/6–31+G* and used the
parameters for dichloromethane and the UAKS radii.[58] Boltzmann dis-
tributions for the fractional number of “open” oxacarbenium ions Ni/N
having conformation i, were calculated using the following formula (Eq.
1):
DFT models of oxacarbenium ions did not support an al-
ternative hypothesis that the stereoselectivity is based on
3
4
the relative abundance of H4 and H3 conformers. However,
the trends in stereoselectivity that arise upon changing sub-
stituents on the oxathiane ring, protecting groups on the gly-
cosyl donor, or the structure of the nucleophile, appear to
be more consistent with changes in the stereoselectivity of
addition to an oxacarbenium ion, rather than a shift be-
tween SN1 and SN2 pathways.
So, do glycosyl sulfonium ions engage in neighbouring
group participation? In part, they may do, but much of their
chemistry is at odds with the SN2 mechanism that formed
the basis for designing these glycosyl donors. Nevertheless,
we note that sulfide-based auxiliary groups undoubtedly
offer an effective strategy for the highly stereoselective syn-
thesis of a-glycosides.
Ni
N
eꢀDG =RT
i
P
ð1Þ
¼
i eꢀDG =RT
i
In which, DGi is the difference in energy (in kcalmolꢀ1) between confor-
mation i and the lowest energy “open” oxacarbenium ion, R is the gas
constant and T is the absolute temperature (298 K).
Experimental Section
Full experimental details and analytical data for compounds prepared,
coordinates for compounds modelled using DFT calculations are includ-
ed in the Supporting Information. CCDC-733122(19),[25] CCDC-733123
(33) and CCDC-805131 (17-(R)) contains the supplementary crystallo-
Chem. Eur. J. 2012, 18, 321 – 333
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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331

W. B. Turnbull et al.
Org. Chem. 2009, 74, 4982–4991; f) M. T. Yang, K. A. Woerpel, J.
Org. Chem. 2009, 74, 545–553.
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Chem. Eur. J. 2012, 18, 321 – 333

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Received: June 20, 2011
Published online: December 2, 2011
Chem. Eur. J. 2012, 18, 321 – 333
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www.chemeurj.org
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