The impact of oxacarbenium ion conformers on the stereochemical outcome of glycosylations

Article abstract of DOI:10.1016/j.carres.2010.02.027

The search for stereoselective glycosylation reactions has occupied synthetic carbohydrate chemists for decades. Traditionally, most attention has been focused on controlling the S_N2-like substitution of anomeric leaving groups as highlighted by Lemieux's in situ anomerization protocol and by the discovery of anomeric triflates as reactive intermediates in the stereoselective formation of β-mannosides. Recently, it has become clear that also S_N1-like reaction pathways can lead to highly selective glycosylation reactions. This review describes some recent examples of stereoselective glycosylations in which oxacarbenium ions are believed to be at the basis of the selectivity. Special attention is paid to the tereodirecting effect of substituents on a pyranosyl ring with an emphasis on the role of the C-5 carboxylate ester in the condensations of mannuronate ester donors.

Full text of DOI:10.1016/j.carres.2010.02.027

Carbohydrate Research 345 (2010) 1252–1263
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Review
The impact of oxacarbenium ion conformers on the stereochemical outcome
of glycosylations
Marthe T. C. Walvoort, Jasper Dinkelaar, Leendert J. van den Bos, Gerrit Lodder, Herman S. Overkleeft,
*
*
Jeroen D. C. Codée , Gijsbert A. van der Marel
Leiden Institute of Chemistry, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
The search for stereoselective glycosylation reactions has occupied synthetic carbohydrate chemists for
decades. Traditionally, most attention has been focused on controlling the SN2-like substitution of ano-
meric leaving groups as highlighted by Lemieux’s in situ anomerization protocol and by the discovery
of anomeric triflates as reactive intermediates in the stereoselective formation of b-mannosides. Recently,
it has become clear that also SN1-like reaction pathways can lead to highly selective glycosylation reac-
tions. This review describes some recent examples of stereoselective glycosylations in which oxacarbeni-
um ions are believed to be at the basis of the selectivity. Special attention is paid to the stereodirecting
effect of substituents on a pyranosyl ring with an emphasis on the role of the C-5 carboxylate ester in the
condensations of mannuronate ester donors.
Received 18 January 2010
Received in revised form 23 February 2010
Accepted 25 February 2010
Available online 4 March 2010
Keywords:
Oxacarbenium ion
Glycosylation
1,2-cis Linkage
Stereoselectivity
Uronic acid
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
nors preferentially form 1,2-cis products, although the formation
of 1,2-cis mannosidic linkages is disfavored on steric and electronic
The stereoselective construction of glycosidic linkages has long
been, and continues to be, one of the main challenges in synthetic
carbohydrate chemistry.1 Whereas 1,2-trans glycosidic linkages
can be obtained reliably by taking advantage of neighboring group
participation of an acyl protective group at the C-2 position in the
donor glycoside,2 a general method for the formation of 1,2-cis gly-
cosidic bonds has not been identified.3,4 As steering of the C-2
function is generally lacking, over the years attention has been fo-
cused on tuning other reaction parameters, such as the nature of
the anomeric leaving group in the donor glycoside and the corre-
sponding activator system,5 solvent systems6 and reaction temper-
atures.7 It is becoming increasingly clear that protecting groups or
functionalities at positions different from C-2 not only influence
the reactivity of the donor8,9 but can also have a profound effect
on the stereochemical outcome of a glycosylation reaction.10 For
example, the anchimeric assistance via a six- or seven-membered
ring by acyl protecting groups at O-311 and O-411b,12 in the donor
glycoside is subject of current research.13 The most striking exam-
ple of the influence of a non-participating protecting group on the
stereochemical outcome is probably the cis-directing effect of a
4,6-O-acetal function in mannosylation reactions.14 The group of
Crich has shown that 4,6-O-benzylidene-protected mannosyl do-
grounds (vide infra).15
In the development of efficient procedures for oligosaccharide
synthesis the outcome of a glycosylation reaction is usually inter-
preted with the aid of a generally accepted nucleophilic displace-
ment mechanism (Scheme 1).1 Typically, condensation of
a
suitably protected glycosyl donor and acceptor starts with the acti-
vation of the leaving group attached to the C-1 of the donor I by a
suitable electrophile (E+). Activated species II can then undergo an
SN2-type substitution by an appropriate nucleophile, such as the
acceptor. Alternatively, expulsion of the activated leaving group
in II can produce the oxacarbenium ion III. This oxacarbenium
ion can be intercepted by the counterion of the activator species
(XÀ) to give the reactive intermediate V, in which the group X is
covalently attached to the anomeric center of the glycosyl donor.
Depending on the stability of the glycosyl oxacarbenium ion and
the nucleofugality of the leaving group XÀ an equilibrium will be
established between the covalent intermediate V, the contact ion
pair IV and the solvent-separated ion pair III. Nucleophilic attack
on the reactive intermediate V and contact ion pair IV proceeds
via an SN2-like mechanism, whereas attack of the solvent-sepa-
rated ion pair III occurs in an SN1-like fashion. Depending on the
many variables operating in a glycosylation reaction, the mecha-
nism can best be regarded as a continuum between SN2-like and
SN1-like substitution.16
* Corresponding authors.
E-mail addresses: jcodee@chem.leidenuniv.nl (J.D.C. Codée), marel_g@chem.lei
denuniv.nl (G.A. van der Marel).
In the pursuit of stereoselectivity, most attention has been fo-
cused on steering the reaction mechanism to the SN2-side of the
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.02.027

M. T. C. Walvoort et al. / Carbohydrate Research 345 (2010) 1252–1263
1253
O
E
X
O
O
O
O
LG
X
LG
E
X
X
X
I
II
III
IV
V
SN2-like
SN1-like
SN2-like
SN2-like
Scheme 1. General glycosylation mechanism.
continuum.17 In Lemieux’s groundbreaking in situ anomerization
protocol, for example, the higher reactivity of the b-oriented halide
C-3 when going from the covalent triflate to the oxacarbenium
ion intermediate is less than in the case of the 2,3-di-O-benzyl ben-
zylidene mannoside. Formation of the oxacarbenium ion is there-
fore more feasible causing the observed erosion in b-selectivity.23
Detailed studies on the stereoselectivity of 4,6-O-benzylidene
mannosides indicate the delicate balance between the reactive
intermediates III–V and the corresponding SN1-like and SN2-like
pathways.
toward direct nucleophilic displacement as compared to the
a-
anomer is exploited to provide 1,2-cis glycosides.18 It is now well
established that the reactivity of a donor glycoside critically de-
pends on the nature and configuration of the substituents on the
core of the pyranosyl ring.8 Electron-withdrawing or conformation
restricting groups disfavor the formation of the flattened (solvent-
separated) oxacarbenium ion and therefore shift the equilibrium
between the ion pair III and the covalent intermediate V to the side
of the latter species. For example, in their seminal work on the syn-
thesis of b-mannosides, Crich and co-workers have shown that
activation of a O-4–O-6 benzylidene acetal-containing mannopyr-
anosyl sulfoxide donor 1 with triflic anhydride leads to selective
2. Stereoselective SN1-like mechanisms
The intermediate oxacarbenium ion III (Scheme 1) has tradi-
tionally been considered to have little stereochemical preference,
because it can be attacked from both the a- and b-side. Oxacarbe-
formation of an anomeric
a
-triflate 3 (see Scheme 2).14 This reac-
nium ions have been the subject of detailed studies in the fields of
computational24 and analytical25 chemistry. Recently, several re-
search groups have described highly stereoselective glycosylations,
which were postulated to originate from the stereoselective substi-
tution of intermediate oxacarbenium ions. For example, Boons
et al. have shown that arabinofuranosyl donors, equipped with a
3,5-silylidene ketal function give rise to highly selective 1,2-cis gly-
cosylations. They argued that this selectivity originates from the
oxacarbenium ion adopting an E3 conformation (Scheme 3).26
Addition of an alcohol nucleophile (ROH) to this oxacarbenium
ion (6) occurs from the b-face via a staggered transition state, to
avoid an eclipsed interaction with the H-2 in 6.27
tive intermediate is attacked by the incoming nucleophile in an
SN2-like fashion to provide the b-linked products 4. The equilib-
rium between the (solvent-separated) oxacarbenium ion 2 and
covalent triflate 3 is shifted to the side of the anomeric triflate be-
cause the benzylidene function prevents formation of the flattened
mannosyl oxacarbenium ion.19 In a series of subsequent studies,
the groups of Crich and others20 investigated the mechanistic de-
tails behind this remarkable transformation. It is now clear that
the stereoselectivity of this type of mannosylation is uniformly
high and does not depend on the type of donor mannoside or acti-
vation protocol used. Although anomeric triflates have convinc-
ingly been demonstrated to be intermediates in this type of
Shuto et al. have shown that conformationally restricted pyr-
anosides can be used to effect the stereoselective formation of C-
glycosidic bonds.28 When xylosyl fluoride 8, protected with a
butanedimethylacetal (BDA), was treated with BF3ÁOEt2 and allyl-
mannosylation,
a-secondary H/D-kinetic isotope effects revealed
that a significant amount of oxacarbenium ion character developed
during the SN2-like displacement of the anomeric leaving group by
the incoming nucleophile.21 The reaction proved to be sensitive to
steric effects in the donor mannoside as bulky groups at C-3 and C-
2 caused erosion of the b-selectivity.22 Replacement of the C-2 or
C-3 alkoxy function by small groups such as a fluorine or a hydro-
gen atom also led to diminished selectivities. In this case, the in-
crease in steric interactions between the substituents at C-2 and
trimethylsilane the
a-linked C-allylxyloside 10 was obtained as
the sole product (Scheme 4). This selectivity can be explained with
conformationally restrained oxacarbenium ion 9 as product form-
ing intermediate. Because of the cyclic BDA acetal, flattening of the
pyranosyl ring can only lead to the formation of the 4H3 half chair
oxacarbenium ion. Nucleophilic attack on this oxacarbenium ion
Nuc
Tf2O
OBn
O
OBn
O
OBn
O
Ph
O
Ph
O
Ph
O
DCM, -78ºC
O
O
O
BnO
BnO
BnO
OTf
SPh
1
2
3
4
O
OTf
Nuc
OBn
O
Ph
O
O
Nuc
BnO
Scheme 2. b-Mannosylation via anomeric triflates.

1254
M. T. C. Walvoort et al. / Carbohydrate Research 345 (2010) 1252–1263
E3
ROH
NIS, AgOTf
DCM, -30 C
OTf
º
O
Si
O
Si
O
O
Si
O
O
tBu
O
SPh
tBu
O
tBu
O
OBn
OBn
BnO
tBu
tBu
tBu
OR
5
6
7
H
H
H
BnO
C1
O
O
O
Si
tBu
tBu
6
ROH
Scheme 3. 1,2-cis Glycosylation of conformationally locked arabinofuranoside 5.
4H3
OMe
OMe
O
BF3.OEt2
AllylTMS
X
OP
O
O
O
O
O
O
BnO
PO
F
BnO
10
only α
BnO
9
OMe
OMe
8
AllylTMS
OMe
O
OMe
OBn
O
TMSOTf
Et3Si-H
OBn
O
O
O
R
R
O
BnO
BnO
OH
OMe
OMe
H
11a
11b
11c
12a
12b
12c
β
R = Me (93%, )
R = Me
R = Ph
R = Ph (90%, β)
R = allyl (92%, β)
R = allyl
Scheme 4. Stereoselective nucleophilic addition on conformationally restricted pyranosyl oxacarbenium ions.
conformer occurs selectively on that diastereotopic face that leads
to the chair product as opposed to the twist boat conformer that
arises from attack on the other side.29 Following an analogous ap-
proach, the Shuto laboratory showed that ketoglycosides 11a–c are
stereoselectively reduced to provide the b-C-glycosidic products
12a–c.
anomeric charge the six-membered ring oxacarbenium ions adopt
either a 3H4 or a 4H3 half chair conformation. In these conforma-
tions, the methyl substituent preferentially takes up a pseudo-
equatorial position at C-3 or C-4 for steric reasons. The benzyloxy
groups on the other hand favor a pseudo-axial orientation at these
positions to allow stabilization of the electron-depleted anomeric
center and reduction of the electron-withdrawing effect.32 When
the C-4 methylated pyran is considered, the 4H3 oxacarbenium
ion 20 will be more stable than its 3H4 counterpart 19. Nucleophilic
attack on 20 occurs along a pseudo-axial trajectory on the b-face
leading to the chair product having a 1,4-cis-relationship.29 The
C-4 benzyloxy pyran on the other hand prefers the 4H3 half chair
In a series of elegant studies30,31 Woerpel and co-workers have
investigated the stereodirecting effect of ring substituents on the
nucleophilic attack of various C-nucleophiles on pyranosyl oxa-
carbenium ions. Mono-substituted pyranosyl acetates were acti-
vated with BF3ÁOEt2 in the presence of allyltrimethylsilane to
provide the allylated pyranosides as summarized in Scheme 5.
The stereochemical outcome of the allylations proved to be highly
dependent on the nature of the ring substituent at C-3 and C-4. For
example, C-4 methyl tetrahydropyran 13 mainly provided the 1,4-
cis product 16, whereas the C-4 benzyl ether 14 almost exclusively
gave the 1,4-trans adduct 17. Allylation of the C-3 methyl (21) and
C-3 benzyloxy pyrans (22) led to the formation of the 1,3-trans (23)
and 1,3-cis (24) products, respectively. The C-2 methylated pyran
27 did not show a significant preference for any of the isomers,
where allylation of the C-2 benzyloxy pyran 28 displayed a prefer-
ence for the formation of the 1,2-cis product 30. The C-6 benzyl-
oxymethyl pyran 33 provided the 1,5-trans and 1,5-cis products
34 in a 97:3 ratio. These results were explained by assuming an
equilibrium of oxacarbenium ion half chair conformers as product
forming intermediates. To best accommodate the positive
oxacarbenium ion 19, which is substituted from the
a-face. For
the C-3 substituted tetrahydropyrans 21 and 22 similar prefer-
ences can explain the observed selectivities in 23 and 24. The ben-
zyloxy substituent at C-2 and the benzyloxymethyl group at C-5
prefer to adopt a pseudo-equatorial orientation because of stabiliz-
ing hyperconjugative effects of the H-2 in 32 and the minimization
of steric interactions in 35/36.
Having determined the preference of each substituent in the
pyranose oxacarbenium ion, Woerpel and co-workers investigated
the influence of a combination of multiple substituents on the
selectivity of the C-glycosylation reaction.33 The stereodirecting ef-
fects of the substituents appended to the pyranose core as revealed
in Scheme 5 cannot simply be added to account for the obtained
selectivities in 38 and 42 (Scheme 6). Steric interactions between

M. T. C. Walvoort et al. / Carbohydrate Research 345 (2010) 1252–1263
1255
O
OAc
O
BF3 OEt2
DCM, -78 C
º
TMS
R
R
3H4
4H3
cis / trans
R
O
OAc
O
R
O
O
16
: R = Me
94 / 6
17: R = OBn
1
/ 99
19
20
R
R
18
93 / 7
: R = CH2Bn
R
13:
R = Me
1,4 cis or trans
14: R = OBn
:
15
R = CH2Bn
R
O
O
OAc
cis / trans
R
O
O
23
: R = Me
<1 / >99
R
24: R = OBn
89 / 11
25
31
26
32
R
R
1,3 cis or trans
21:
R = Me
22:R = OBn
OAc
O
O
cis / trans
R
O
O
52 / 48
R
29:R = Me
30:
83 / 17
R = OBn
R
R
R
1,2 cis or trans
27:R = Me
28:
R = OBn
R
R
R
R
O
OAc
O
R
34: R = OBn
cis / trans
3 / 97
O
O
35
36
1,5 cis or trans
33:R = OBn
Scheme 5. Stereochemistry of substitutions of mono-substituted pyranosyl acetates.
O
OAc
O
BF3 OEt2
DCM, -78ºC to 0 ºC
TMS
n(R)
n(R)
4H3
3H4
Nuc
OBn
OBn
BnO
O
OAc
OBn
O
OBn
OBn
BnO
O
O
OBn
α / β = 8 / 92
BnO
BnO
BnO
BnO
OBn
OBn
37
Nuc
39
OBn
38
40
Nuc
OBn
O
OAc
OBn
O
O
O
BnO
BnO
α / β = 50 / 50
OBn
O
Bn
OBn
41
OBn
42
Nuc
43
OBn
44
Scheme 6. Stereochemistry of substitutions of tri-substituted pyranosyl acetates.
the substituents and the incoming nucleophile have an important
effect in both the ground state energies of the oxacarbenium ion
conformers and the transition states leading to the a- and b-prod-
ucts. Allylation of lyxose acetate 37, having the manno configura-
tion at C-2, C-3 and C-4, yielded mainly the 1,2-cis product 38,
corresponding to nucleophilic attack on ion 40 (Scheme 6). This
is in line with the results obtained for the mono-substituted tetra-
hydropyran acetals, even though the incoming nucleophile has a
disfavored steric interaction with the C-3 substituent. Xylose ace-
tate 41 reacts in a non-selective manner to afford a 1:1 mixture
of anomers (42). The favorable orientation of the C-3 and C-4 ben-
zyl ethers in ion 44 is offset by the destabilizing steric interaction
between the C-2 and C-4 substituents and the 1,3-diaxial interac-
tion of the incoming nucleophile with the group at C-3. These data
show that the stereochemical outcome of the glycosylation results
from both the stability of the oxacarbenium ion, which depends on

1256
M. T. C. Walvoort et al. / Carbohydrate Research 345 (2010) 1252–1263
a combination of steric and electronic substituent effects, and the
steric interactions of the incoming nucleophile with the oxacarbe-
nium ion.
As part of a program directed toward the synthesis of fragments
of naturally occurring anionic polysaccharides, we became
interested in the construction of alginate oligomers.34 Alginates
are linear anionic polysaccharides build up from either repeating
stitution of an intermediate a-triflate, which is stabilized with re-
spect to the solvent-separated oxacarbenium ion-triflate ion pair
because of the electron-withdrawing effect of the C-5 carboxylate
ester (Scheme 8). Alternatively, it is hypothesized that the mannur-
onate oxacarbenium ion is at the basis of the observed stereoselec-
tivity (Scheme 9). In the most favorable 3H4 oxacarbenium ion 73,
the substituents at C-2, C-3 and C-4 take up their preferred orien-
tation (vide supra). In this constellation the C-5 ester is placed in
an axial position, thereby allowing the through-space stabilization
of the electron-depleted anomeric center while minimizing its
electron-withdrawing effect.36
To evaluate the conformational preference for the C-5 carboxyl-
ate ester, mono-substituted tetrahydropyran 75 and its benzyl-
oxymethyl counterpart 76 were investigated (Scheme 10). From
Table 3 it is clear that the C-5 carboxylate ester containing pyran
75 reacts in a highly 1,5-cis fashion when compared to benzyl-
oxymethyl pyran 76. With the aid of oxacarbenium ion half chair
conformers 77 and 78 the stereochemical trends revealed in Table
3 can be explained. The preferential formation of the 1,5-cis linked
products originates from nucleophilic attack on the 3H4 oxacarbe-
nium ion 77, in which the carboxylate ester occupies a pseudo-axial
orientation. When the steric requirements of the nucleophile in-
crease in going from methanol to isopropanol, tert-butanol and
adamantanol, the 1,5-cis preference decreases because of increased
1,3-diaxial interactions with the axial carboxylate ester.
(1?4)-linked b-D-mannuronic acid monomers, a-L-guluronic acid
monomers or (1?4)-linked mannuronic acid–guluronic acid
hetero-dimers. The synthesis of fragments of these polymers thus
required the repetitive installment of multiple cis-glycosidic link-
ages. At the onset of our synthetic efforts toward guluronic acid olig-
omers very little was known of glycosylations involving
L
-gulose and
L
-guluronic acid. Therefore we investigated the glycosylating prop-
erties of a set of
L
-gulosyl donors (e.g., 45, 50, 52 and 55).34b
-gulose donors have an unusually
It soon became apparent that
L
strong preference for the formation of 1,2-cis glycosidic linkages
(see Table 1). To exclude that double stereodifferentiation35 is
responsible for this selectivity, we also examined
48. The identical outcome in the condensations of the
-gulosides 45 and 48 refutes this possibility.37 It has previously
D-gulose donor
L
- and
D
been hypothesized that the anomeric effect can have an important
stereodirecting effect in the attack of a nucleophile to a ‘flat’
oxacarbenium ion, promoting the formation of the more stable
a-product.[1a,3a,19d] In gulose, however, the anomeric effect
should be largely offset by the 1,3-diaxial interaction of the agly-
con and the C-3 substituent.à We therefore dismissed the anomeric
effect to be at the basis of the observed selectivity. The sulfonium
chemistry used in our glycosylations can lead to the formation of
intermediate glycosyl triflates as convincingly demonstrated by
Crich and co-workers (vide supra).12b If a single anomeric triflate of
sufficient stability is generated, like in the benzylidene mannopyran-
oside case, stereoselective SN2-like displacements can be achieved.
To corroborate the conformational preference of the C-5 carbox-
ylate in 77/78 we calculated the relative energies of a series of
mono-substituted tetrahydropyran oxacarbenium ions having dif-
ferent substituents at C-5, as summarized in Figure 1.37 It can be
seen that the oxacarbenium ion that positions the carboxylate es-
ter in an axial position is indeed more stable than the half chair
oxacarbenium ion having this substituent in an equatorial orienta-
tion. For comparison, the trifluoromethyl tetrahydropyran was also
evaluated and the calculated energies reveal that for this pyran the
equatorial isomer is slightly more stable than its axial counterpart.
These results indicate that the preference for the C-5 carboxylate
ester to reside in an axial position stems from the through-space
stabilization of the positively charged anomeric center rather than
from an electron-withdrawing inductive effect.§ The small differ-
ence in stability between the equatorial and axial C-5 CF3 isomeric
oxacarbenium ions became apparent when 1-phenylsulfanyl-5-tri-
fluoromethyltetrahydropyran was coupled with benzyl alcohol to
provide an anomeric mixture of 1-benzyloxy-5-trifluoromethyltetra-
In the gulose case, it is conceivable that both
triflates exist. Also in this case the anomeric effect, which stabilizes
the axial -triflate, is counterbalanced by steric effects making the
- and b-triflate equally stable. It is thus unlikely that the -selectiv-
a- and b-anomeric
a
a
a
ity in the gulosylations arises from the SN2-like substitution of the
b-triflate. When the two likely gulosyl oxacarbenium ion intermedi-
ates, the 3H4 conformer 57 and its 4H3 counterpart 58, are considered
it becomes clear that all substituents are favorably positioned in the
former half chair and unfavorably in the latter (Scheme 7). The 3H4
conformer 57 will therefore be substantially more stable than its
4H3 congener 58. In line with the proposal of Woerpel and co-work-
ers, nucleophilic attack on the 3H4 oxacarbenium ion 57 occurs in a
hydropyran (
a
:b ꢀ 1:1).37
When the relative energies of the C-5 carboxylate esters are
translated to the mannuronate ester oxacarbenium ions, it be-
comes clear that the carboxylate ester can take up the most favor-
able axial orientation in the 3H4 oxacarbenium ion 73, in line with
the preferred orientation of the other ring substituents (Scheme 9).
The 3H4 conformer should thus be significantly more stable than its
4H3 counterpart.**,– When a nucleophile attacks the mannuronate
ester 3H4 oxacarbenium ion 73 on the b-face, unfavorable 1,3-diaxial
interactions will develop with both the C-3 and the C-5 substituent
on the pyranose core. Woerpel and co-workers have previously
hypothesized that the mannopyranosyl oxacarbenium ion provides
pseudo-axial fashion on the a-face to provide the 1,2-cis chair prod-
uct. It should be noted that in the two possible transition states from
either the 3H4 or the 4H3 half chair, the incoming nucleophile will
experience one 1,3-diaxial interaction, making both transitions
states comparably favorable on steric grounds.
As outlined in Table 1, the nature of the protecting groups only
has a marginal effect on the stereoselectivity of the gulosyl donors.
Also the nature of the C-5 substituent does not influence the stere-
oselectivity significantly. This stands in contrast to the results we
obtained in the mannopyranosyl series. Mannopyranosyl donors
are generally considered to provide
a
-selective condensations15
and the stereoselective construction of the b-mannosidic linkage
has indeed been a long-standing challenge. During our synthetic
studies toward alginate oligomers we discovered that glycosyla-
tions with mannuronate ester donors proceed with excellent selec-
tivity to provide the b-mannuronate products (see e.g., Table 2).
This stereochemical outcome can be explained by the SN2-like sub-
§
The CF3-group has a rp-value of 0.54 and an F-value of 0.38. The CO2Me group has
p-value of 0.45 and an F-value of 0.34. See: Ref. 45.
In the L-gulopyranosyl and D-mannupyranosyluronate ester oxacarbenium ion all
a
r
**
substituents contribute positively to the stability of one of the two half chair
conformers (i.e., the 3H4 half chair), leading to stereoselective glycosylations.
Glycosylations of pyranoses with conflicting substituent preferences are in majority
less stereoselective. See Ref. 37.
–
The mannosyl 3H4 oxacarbenium ion has been calculated to be 6.8 kcal molÀ1
more stable than its 4H3 counterpart (see Ref. 33). Combining this value with the
energies presented in Figure 1, it can be calculated that the mannuronate oxacarbe-
à
The proportion of the
a-anomer of gulose in aqueous solution is 17%, where
glucose exists for 36% and mannose for 66% in the
a
-form. See: Ref. 44.
nium ion 3H4 73 is favored over the 4H3 conformer 74 by ꢀ9 kcal mol-1
.

M. T. C. Walvoort et al. / Carbohydrate Research 345 (2010) 1252–1263
1257
Table 1
Condensations of gulose and guluronic acid donorsa
Entry
Donor
Acceptor
Product
OBn
O
HO
BnO
BnO
O
SPh
OBn
BnO
BnO
OBn
O
BnO
BnO
O
OBn
OMe
46
45
1
OBn
O
BnO
BnO
BnO
47
OMe
71%
cis : trans = 13:1
BnO
BnO
HO
BnO
BnO
OBn
OBn
O
O
O
BnO
SPh
BnO
OMe
BnO
BnO
46
BnO
O
2
48
O
BnO
BnO
BnO
49
OMe
76%
cis : trans = 10:1
OBn
HO
CO2Me
BnO
O
SPh
OBn
MeO2C
O
BnO
BnO
OBn
O
O
BnO
BnO
OMe
50
46
OBn
3
O
BnO
BnO
BnO
51
OMe
73%
cis : trans = 3:1
OBn
O
O(CH2)3N3
OBn
O(CH2)3N3
OBn
OBn
O
OBn
SPh
OBn
O
TBSO
TBSO
O
TBSO
OLev
OH
OBn
52
53
4
O
OBn
TBSO
OLev
54
48%
cis : trans = 6:1
OH
O(CH2)3N3
OBn
O(CH2)3N3
OBn
OBn
O
OBn
O
OBn
O
OBn
O
TBSO
O
tBu
TBSO
OH
Si
O
OBn
O
tBu
5
53
55
OBn
O
56
tBu
O
Si
tBu
cis : trans = 10:1
84%
a
Reagents: Ph2SO, Tf2O, TTBP, DCM.
Nuc
PO
OP
PO
OP
PO
O
O
OP
1,2-trans
1,2-cis
OP
OP
Nuc
3H4
57
58 4
: H3
:
Scheme 7. Nucleophilic attack on the gulopyranosyl oxacarbenium ion.

1258
M. T. C. Walvoort et al. / Carbohydrate Research 345 (2010) 1252–1263
Table 2
b-Mannosylations using various mannosyl uronate donors and acceptors
Entry
Donor
Acceptor
Product
MeO2C OBn
HO
OBn
O
MeO2C
AcO
BnO
O
O
AcO
BnO
59
BnO
SPh
O
BnO
1a
O
BnO
BnO
BnO
(94%, only β)
OMe
46
BnO
60
OMe
MeO2C OBn
O
BnO
Ph
Ph
BnO
O
O
O
O
2a
MeO2C OBn
O
BnO
61
SPh
O
O
BnO
OpMP
SPh
OpMP
SPh
O
HO
62
MeO2C OBn
BnO
BnO
63 (69%, only β)
MeO2C OBn
O
OBn
O
MeO2CH2
MeO2C OBn
O
BnO
O
LevO
HO
LevO
3b
OCB
CF3
O
BnO
BnO
BnO
65
64
66
β
(65%, only )
MeO2C OBn
TMS
MeO2C OBn
O
O
BnO
BnO
BnO
BnO
4c
67
O
68
(74%, only β)
NPh
a
b
c
Reagents: Ph2SO, Tf2O, TTBP.
Conditions: Ph2SO, Tf2O, DTBMP.
TMSOTf (cat).
MeO2C OBn
MeO2C OBn
O
BnO
MeO2C OBn
MeO2C OBn
O
BnO
Ph2SO, Tf2O
DCM, -50ºC
O
O
BnO
BnO
BnO
BnO
BnO
BnO
Ph
69
OTf
SPh
S
OTf
S
Ph
61
70
OTf
71
TfO Ph
Nuc SN1-like
SN2-like Nuc
MeO2C OBn
O
BnO
Nuc
BnO
72
Scheme 8. Mechanism behind the b-selectivity in condensations of mannuronate ester donors.
Nuc
OP
OP
PO
CO2Me
OP
PO
CO2Me
O
O
1,2-trans
1,2-cis
OP
Nuc
73: 3H4
74: 4H3
Scheme 9. Nucleophilic attack on the mannuronate ester oxacarbenium ion.
a
-selective condensations because these steric interactions are large
to the benzyloxymethylene group leads to less steric hindrance of
the former group with the incoming nucleophile.||
enough to prevent nucleophilic attack on the b-face of the 3H4 oxa-
carbenium ion.33 A Curtin–Hammett kinetic scenario, in which prod-
uct formation arising from the higher ground state energy 4H3
oxacarbenium ion was forwarded to account for the formation of
With the objective to exclude the formation of the 3H4 oxacarbe-
nium ion and thereby induce nucleophilic attack on the other half
the a-product. The extra stabilization by the axial C-5 ester in oxa-
carbenium ion 73 can prevent such a Curtin–Hammett scheme to oc-
cur. Furthermore, the reduced size of the methyl ester as compared
||
The A-values for the methyl ester and CH2OH are 1.2 kcal molÀ1 and
1.8 kcal molÀ1, respectively. See: Ref. 46.

M. T. C. Walvoort et al. / Carbohydrate Research 345 (2010) 1252–1263
1259
Nuc
O
O
R
O
SPh
O
Nuc
Nuc
3
77
MeO
BnO
: H4
MeO
O
O
Ph2SO, Tf2O
TTBP, DCM
-78 C, 5 min.
Nucleophile
-78 oC, 15 min.
75
79
º
O
SPh
O
R
BnO
4
78
: H3
76
80
Nuc
Scheme 10. Substitutions on mono-functionalized tetrahydropyrans 75 and 76.
activationof 81 wastentativelyassigned to be the
a
-triflate82. Upon
Table 3
Condensations of 75 and 76
treatment of this species with a variety of glycosyl acceptors the
disaccharides 90–92 were predominantly formed (see Table 4).
Obviously the -linked disaccharide products can not arise from di-
rect SN2-like displacement of the observed anomeric -triflate 82.
a-
Entry
Nucleophile
Product,
a
:b (yield)
a
a
OH
1
79a, 1: 7.7 (67%)
80a, 1: 1.4 (82%)
They can however arise from the oxacarbenium ion intermediate
83 which can only access the 4H3 half chair conformation because
of the conformational restriction imposed by the BDA acetal. In the
condensation of mannuronate 81 and primary alcohol 46 a substan-
tial amount of b-linked disaccharide was also formed. Formation of
this product can be explained by the direct SN2-like displacement
of anomeric triflate 82, because of the relatively high nucleophilicity
of theacceptor alcoholinvolved. Crich and co-workers previously re-
portedthatthecondensationof thisacceptorwiththe‘non-oxidized’
2
3
79b, 1: 3.8 (48%)
79c, 1: 2.9 (52%)
80b, 1: 0.60 (61%)
80c, 1: 0.38 (60%)
OH
OH
OH
4
79d, 1: 1.2 (52%)
80d, 1: 0.33 (74%)
BDA-protected mannopyranosyl donor provided only the a-linked
disaccharide,11c indicating that the C-5 carboxylate provides some
extra stabilization to the anomeric triflate. For less reactive glycosyl
acceptors 83 and 84 the conformational restriction of the BDA ace-
tal8a,39in combination with the electron-withdrawing effect of the
C-5 carboxylic ester in 81 apparently can not prevent the anomeric
triflate from dissociating into the oxacarbenium ion. Glycosylation
takes place through the latter species.
MeO
O
O
OMe
COOMe
O
O
O
To gain further insight into the factors underlying the selectivity
of the mannuronate ester donors the glycosylation behavior of
mannosaziduronic acid ester 93 was studied.40 We have previously
noted that the substitution of the C-2 O-benzyl group in 2,3-di-O-
0 kcal/mol
MeO
+3.4 kcal/mol
+3.4 kcal/mol
O
0 kcal/mol
O
O
OMe
benzyl-4,6-benzylidene mannopyranosyl thiodonors for
a C-2
azide functionality led to a decreased b-selectivity for this type of
donor.41 In the case of the mannuronate donor 93, introduction
of the C-2 azide did not have an adverse effect on the selectivity
and disaccharides 94, 96, and 98 were obtained in high yield from
93 and acceptors 46, 95 and 97, respectively (see Table 5).
+1.1 kcal/mol
Me
Me
O
In studying the activation process of donor 93, low-temperature
NMR measurements revealed that treatment of b-thiodonor 93 with
Ph2SO and Tf2O in CD2Cl2 led to a mixture of two anomeric triflates
(see Fig. 2). These two mannuronate triflates were in dynamic equi-
librium because the two resonance sets observed at À80 °C coa-
lesced upon warming of the NMR probe to À40 °C. When cooled
back to À80 °C the two distinct sets of peaks reappeared. Similar
NMR spectra were obtained when the activation of N-(phenyl)triflu-
oroacetimidate donor 99 with a stoichiometric amount of TfOH was
studied. The two anomeric triflates observed at À80 °C were deter-
0 kcal/mol
O
-0.9 kcal/mol
CF3
CF3
O
0 kcal/mol
-0.3 kcal/mol
Figure 1. Calculated relative energies (MP3) of C-5 substituted pyranosyl oxa-
carbenium ions.
mined to be
a
-mannosyl triflate 100, having a 4C1 conformation
and its 1C4 counterpart 101. Interestingly the 1C4 conformer 101,
having the anomeric triflate in the equatorial position, prevailed in
the reaction mixture (1C4:4C1 = 3:1). It is of interest that we obtained
a similar result in the activation of mannuronate 59 under identical
conditions, and noted that methyl (4-acetyl-2,3-O-benzyl-1-trifluo-
chair conformer, the glycosylation behavior of conformationally re-
stricted mannuronate donor 81 was investigated (Scheme 11).38
Glycosylations with BDA-protected mannopyranosyl donors were
previously reported to occur with high a
-selectivity.11c Using low-
temperature NMR spectroscopy the activation of thiomannuronate
81 was followed and the single intermediate that was formed upon
romethylsulfonyl-a-mannopyranosyluronate) exists as a 1.4:1 mix-
ture of 1C4:4C1 chairs at À80 °C.

1260
M. T. C. Walvoort et al. / Carbohydrate Research 345 (2010) 1252–1263
Nuc
OP
CO2Me
MeO
MeO
OBn
O
OBn
O
MeO2C
MeO2C
Ph2SO, Tf2O
DCM, -50 oC
O
BnO
PO
O
O
O
SPh
O
OTf
OMe
OMe
OTf
Nuc
81
82
83
SN1-like
SN2-like
MeO
MeO
OBn
O
OBn
MeO2C
MeO2C
O
O
O
O
Nuc
O
OMe
OMe
Nuc
84b
84a
Scheme 11. Mechanism of glycosylation of conformationally restricted mannuronate ester 81.
Table 4
Glycosylation of mannuronates 81 and 85
OH
O
Ph
OBn
O
MeO2C
HO
BnO
BnO
BnO
O
OMe
O
Ph2SO, Tf2O, TTBP, DCM À60 °C to rt
BnO
O
OMe
Yield (a:b)
86
OpMP
HO
62
46
BnO
MeO2C OBn
O
BnO
LevO
87, 93% (0:1)
90, 56% (2:1)
88, 73% (0:1)
91, 56% (1:0)
89, 55% (0:1)
92, 49% (3:1)
SPh
85
MeO
MeO2C OBn
O
O
O
SPh
81
OMe
Table 5
Glycosylations of mannosaziduronic acid ester 93a
Entry
Donor
Acceptor
Product
N3
OH
O
N3
MeO2C
AcO
BnO
MeO2C
AcO
BnO
O
O
BnO
BnO
SPh
O
O
1
BnO
BnO
93
OMe
BnO
46
BnO
OMe
94
(90%, α:β = 1:7)
OBn
O
N3
MeO2C
AcO
BnO
BnO
O
HO
O
O
BnO
2
3
93
93
BnO
BnO
BnO
OMe
OMe
95
96
α β
:
(55%,
O
= 1:4)
O
O
H
O
H
O
O
N3
O
MeO2C
AcO
BnO
O
O
HO
O
O
O
97
98 (85%, α:β = 0:1)
a
Reagents: Ph2SO, Tf2O, TTBP.

M. T. C. Walvoort et al. / Carbohydrate Research 345 (2010) 1252–1263
1261
MeO2C
N3
O
N3
O
MeO2C
MeO2C
AcO
Ph2SO, Tf2O
DCM, -80 oC
OBn
O
AcO
OTf
N3
X
BnO
BnO
OTf
100: 4C1
OAc
101: 1C4
93
99
= SPh
= OC(NPh)CF3
Figure 2. Part of the 1H NMR spectrum obtained after activation of donors 93 and 99 at À80 °C.
Considering the lack of anomeric stabilization and the destabiliz-
ing 1,3-diaxial interactions in the 1C4 species, the preferential forma-
tion of equatorial triflate 101 was highly unexpected. The unusual
conformationalflipfromthe 4C1 tothe1C4 conformationcanbe ratio-
nalized by considering the half chair oxacarbenium ion structures
102 and 103 (Scheme 12). As for mannuronate ester 73, the 3H4 con-
former 102 places all substituents in the most favorable position to
accommodate the positive charge at the anomeric center. The pres-
ence of the electron-withdrawing triflate at C-1 and the methyl ester
at C-5 render the anomeric center of the mannuronate triflate so
electron-depleted that the structure of the covalent triflate ap-
proaches the conformation of the oxacarbenium ion half chair 102.
To further the hypothesis that the lack of electron-density at
C-1 is the driving force for the ring inversion, the mannosazide
methyl ester lactone 104 was synthesized. The C-1 of this lactone
carries a significant positive charge and is sp2 hybridized. NMR
and X-ray crystallography revealed that lactone 104 indeed adopts
an inverted conformation approaching the 3H4 half chair at room
temperature (Scheme 12), providing support for the above-men-
the pyranosyl ring of the mannuronate triflates to flip. Rather, the
extra stabilization that the C-5 carboxylate ester provides to the
electron depleted anomeric center when occupying an axial position
in the 1C4 chair is at the basis of the ring flip.
The existence of triflates 100 and 101 (Fig. 2) has significant
bearing on the mechanism through which glycosylations of man-
nuronate ester donors proceed and provides evidence for both an
SN2-like and SN1-like reaction pathway. On one hand, the identifi-
cation of the
a-triflates lends support to an SN2-like mechanism.
On the other hand, the stereoelectronic effects responsible for the
conformational flip of the mannopyranosyl chair point to an SN1-
like pathway. These stereoelectronic effects which stabilize the
structure of the neutral anomeric triflate 101 and lactone 104 will
become even more important when positive charge develops at
the anomeric center upon substitution of the anomeric triflate.
The glycosylations of mannuronate esters most probably occur
through an asymmetric exploded transition state, such as 105, fol-
lowing an SN2-like pathway with significant SN1 (oxacarbenium
ion) character as depicted in Scheme 12. The nature of the nucleo-
phile determines the place in this SN1–SN2 continuum.43 The ano-
meric triflate and the formation of the 3H4 oxacarbenium ion both
contribute to the excellent b-selectivities observed in the condensa-
tions of mannuronate ester donors.
tioned hypothesis. The fact that 6,6,6-trifluoro-a-rhamnosyl tri-
flate, bearing a strongly electron-withdrawing CF3 functionality
at C-5, exists in the regular 4C1 conformation42 indicates that not
only the electron-withdrawing effect of the C-5 substituent causes
OBn
CO2Me
N3
O
MeO2C
OBn
MeO2C
Nu
OBn
O
δ+
N3
O
N3
O
OAc
102
δ−
OTf
OAc
OAc
N3
BnO
OAc
CO2Me
104
105
O
103
Crystal structure of 104
Scheme 12. Structure of oxacarbenium ions 102 and 103 and lactone 104.

1262
M. T. C. Walvoort et al. / Carbohydrate Research 345 (2010) 1252–1263
7. Larsen, K.; Worm-Leonhard, K.; Olsen, P.; Hoel, A.; Jensen, K. J. Org. Biomol.
3. Summary and conclusion
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Fraser-Reid, B. J. Org. Chem. 1996, 61, 5280–5289; (d) Crich, D.; Vinogradova, O.
J. Org. Chem. 2006, 71, 8473–8480; (e) Crich, D.; Li, L. F. J. Org. Chem. 2007, 72,
1681–1690.
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J. Am. Chem. Soc. 1998, 120, 435–436; (c) Kim, K. S.; Kim, J. H.; Lee, Y. J.; Park, J. J.
Am. Chem. Soc. 2001, 123, 8477–8481; (d) Baek, J. Y.; Choi, T. J.; Jeon, H. B.; Kim,
K. S. Angew. Chem., Int. Ed. 2006, 45, 7436–7440; (e) Codée, J. D. C.; Krock, L.;
Castagner, B.; Seeberger, P. H. Chem. Eur. J. 2008, 14, 3987–3994; (f) Tanaka, K.;
Mori, Y.; Fukase, K. J. Carbohydr. Chem. 2009, 28, 1–11; (g) Koshiba, M.; Suzuki,
N.; Arihara, R.; Tsuda, T.; Nambu, H.; Nakamura, S.; Hashimoto, S. Chem. Asian J.
2008, 3, 1664–1677.
En route to the synthesis of alginate oligosaccharides we found
that the formation of 1,2-cis L-gulosidic and 1,2-cis D-mannuronic
ester linkages proceeds with unexpected high stereoselectivity.
Commonly, a reaction mechanism involving either SN2-like substi-
tution of an anomeric leaving group, such as a triflate, or selective
attack at C-1 directed by the anomeric effect is employed to account
for the formation of 1,2-cis glycosides. Because the stereoselective
formation of the 1,2-cis L-gulosidic linkages is difficult to reconcile
with such a reaction mechanism, we have postulated that the inter-
mediate gulosyl oxacarbenium ion is at the basis of the observed
selectivity. In line with kinetic studies on the hydrolysis of glyco-
sidic bonds,9e,31e computational data and in particular mechanistic
studies on the influence of oxacarbenium ion conformers on the
stereochemical outcome of C-glycosylations by the group of Woer-
pel, it can be reasoned that activation of L-gulopyranosyl donors
leads to the preferential formation of the 3H4 oxacarbenium ion.
An incoming nucleophile selectively attacks this ion on the
diastereotopic face that leads to the chair product, which explains
the observed
a-selectivity. The selective formation of 1,2-cis
D
-mannuronic ester linkages also fits this mechanism, in which
the C-5 carboxylate ester preferentially occupies a pseudo-axial ori-
entation in a half chair oxacarbenium ion. However, the glycosyla-
tions of mannurate esters can also occur via an SN2-like attack on
the a-triflate. Low-temperature NMR studies on mannosaziduronic
acid ester triflates guided us to the point of view that glycosylations
of mannuronate esters most probably occur through an asymmetric
exploded transition state, following an SN2-like pathway with
significant oxacarbenium ion character, the extent of which is
determined by the nature of the nucleophile. The anomeric
a-tri-
flate and the preferential formation of the 3H4 oxacarbenium ion
work in concert in the formation of the 1,2-cis mannuronic ester
linkages. In conclusion, not only the anomeric effect, but also
oxacarbenium ion conformers, their stability and their stereochem-
ical preference in reacting with nucleophiles are to be considered as
contributing factors in the interpretation of the stereochemical
outcome of glycosylation reactions that proceed through interme-
diates which display significant oxacarbenium ion character.
21. (a) Crich, D.; Chandrasekera, N. S. Angew. Chem., Int. Ed. 2004, 43, 5386–5389;
(b) El-Badri, M. H.; Willenbring, D.; Tantillo, D. J.; Gervay-Hague, J. J. Org. Chem.
2007, 72, 4663–4672.
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Acknowledgments
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