On the origin of the regioselectivity in glycosylation reactions of 1,2-diols

Article abstract of DOI:10.1039/b819452a

The assistance of neighboring protecting groups with different orientations in 1,2-diol acceptors and the reactivity of both reaction partners, the donor and the acceptor, have been evaluated as factors that determine the regioselectivity of glycosylation

Full text of DOI:10.1039/b819452a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
On the origin of the regioselectivity in glycosylation reactions of 1,2-diols†
M. Bele´n Cid,*a Francisco Alfonso,b Ine´s Alonsoa and Manuel Mart´ın-Lomas*c
Received 4th November 2008, Accepted 19th January 2009
First published as an Advance Article on the web 25th February 2009
DOI: 10.1039/b819452a
The assistance of neighboring protecting groups with different orientations in 1,2-diol acceptors and
the reactivity of both reaction partners, the donor and the acceptor, have been evaluated as factors that
determine the regioselectivity of glycosylation reactions. It has been established, by experimental and
theoretical studies, that the regioselectivity for the glycosylation of a given OH group can be
considerably increased by the presence of groups able to form a hydrogen bond with that OH group.
Moreover higher regioselectivities are observed when armed donor/activated acceptor combinations
are avoided.
sylation reactions. Throughout our studies we have observed an
unprecedented dependence of the regiochemistry in glycosylation
Introduction
reactions on the absolute configuration of the acceptor.8a Most
of the results could be rationalized by DFT calculations, which
indicated that stereoelectronic factors, H bonds between the donor
and the acceptor and the assistance of the protecting groups
adjacent to the OH group to be glycosylated played an important
role in the complex prior to the transition state.8a Fig. 1 shows in
a simple model system how, according to DFT calculations, the
OH group to be glycosylated (on C2 in this case) is activated by
the adjacent acetyl group increasing its nucleophilicity (compare
atomic distances for both OH groups with their corresponding
neighboring group).
Despite the important role of carbohydrates in many biological
processes,1 considerable effort is still required for the preparation
of highly complex oligosaccharides. An important advance in this
context is the development of strategies that avoid protecting-
group manipulations.2,3 A good understanding of the factors that
affect the stereo-4 and regioselectivity5,6 of glycosylation reactions
would be highly desirable.7
Regarding the regiochemical outcome of glycosylation reactions
in diol systems very interesting studies addressed at understand-
ing the factors that determine the regiochemistry have been
described.5,6,8 Nevertheless, there are many basic aspects that
remain unsolved and prediction of the regiochemistry of the
processes is still not possible. The majority of the studies described
are due to the group of Fraser-Reid, who invoked the MATCH
concept for regioselectivity based on Reciprocal Donor Acceptor
Selectivity (RDAS), paying special attention to the role of glycosyl
donors and particularly the C2 substituent of mainly pentenyl
derivatives, with different kind of acceptors.5 It is noteworthy, that
from these studies no apparent relationship between reactivity
and selectivity of the donor has been found.9 On the other
hand, the group of Vasella pointed out the importance of all the
Fig. 1 Model system proposed to explain the regioselectivity observed in
the reaction of 2-benzyloxy glycosyl donors with the 1,2-trans-diequatorial
diol system obtained from a D-chiro-inositol partially benzoylated.8a
1
possible H bonds in the acceptor, diagnosed by its IR and H
NMR spectra, when studying the glycosylation reactions of diol
acceptors, principally with diazirine glycosyl donors.6
Herein, considering both donor and acceptor partners we
describe a deeper assessment of some of the basic factors that
can affect the regiochemical outcome of glycosylation reactions.
In particular, the assistance of benzyl or benzoyl substituents,
showing different orientations within the trans (1) and cis (2)
1,2-diol acceptors in their reactions with armed and disarmed
trichloroacetimidate donors 3, has been evaluated along with the
effect of the reactivity of both the donor and the acceptor on
the regioselectivity of the glycosylation (Fig. 2).9 For the sake
of clarity, acceptors with benzyl and benzoyl substituents will be
denoted as a and d indicating activated or deactivated acceptors
respectively. The same reasoning has been followed with armed (a)
and disarmed (d) glycosyl donors.
During the past decade, we have been working on the synthesis
of inositolphosphoglycans as potential mediators in the insulin
signaling process.10,11 In this context, we have studied several
factors, such as the influence of the nature of the glycosyl acceptor
on reactivity,12 stereoselectivity,13 and regioselectivity8a in glyco-
aDepartamento de Qu´ımica Orga´nica Universidad Auto´noma de Madrid,
Cantoblanco 28049, Spain. E-mail: belen.cid@uam.es; Fax: (+)34 91 497
3966
bGrupo de Carbohidratos. Instituto de Investigaciones Qu´ımicas, CSIC
Ame´rico Vespucio, Isla de La Cartuja, 41092, Seville, Spain
cParque Tecnolo´gico de San Sebastia´n, Paseo Miramo´n 182, 20009 San
Sebastia´n, Guipu´zcoa, Spain. E-mail: mmartinlomas@cicbiomagune.es;
Fax: (+)34 94 300 53 01
† Electronic supplementary information (ESI) available: Results of gly-
cosylation reactions related to Fig. 6, 7 and 8; Cartesian coordinates of
all the optimized structures, electronic energies and ZPVEs. See DOI:
10.1039/b819452a
From the analysis of the obtained results it can be deduced
that, if the stereoelectronic effects do not determine the opposite
(which it is difficult to predict),8a the sense of the regioselectivity
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Table 1 Glycosylation reactions of trichloroacetimidates 3 and D-chiro-inositol acceptors 1
Yield of glycosylation (%)
a
Entry
Donor/acceptor
a(1–2) 4
a(1–3) 5
b(1–3) 6
b(1–2) 7
trisac.
Overall yield
Ratio C2/C3
1
2
3
4
3a + 1d
3a + 1a
3d + 1d
3d + 1a
43
35
32
40
17
14
9
–
7
–
–
–
4
–
–
–
60
76
41
46
2.5/1
1.5/1
3.8/1
8/1
16b
–
6
–
a Selectivities have been calculated on isolated yields after flash chromatography. b As a mixture of isomers.
reactivities was evaluated. The mannosyl trichloroacetimidates 3a
and 3d15were chosen as armed and disarmed donors to minimize
the formation of the b isomers and steric interactions with the
equatorial substituent at C2 that may play a decisive role in the re-
gioselectivity of the process.8a The results of these reactions under
the same experimental conditions are summarized in Table 1.
Both glycosyl acceptors 1a and 1d are glycosylated at C2 by both
armed and disarmed mannosyl donors 3a and 3d. Good overall
yields were observed with the armed donor 3a (entries 1 and 2);
however, better regioselectivities were found with the disarmed
donor 3d (entries 3 and 4). The best regioselectivity (C2/C3 =
8:1) was observed when the less reactive donor 3d was treated with
the more reactive acceptor 1a affording the pseudodisaccharides
in a modest combined yield of 46% yield (entry 4). When the
reaction was carried out with the most reactive partners 1a
and 3a, no control of stereoselectivity or regioselectivity was
observed, and a mixture of all possible pseudodisaccharides 4–
7 and pseudotrisaccharides was obtained (entry 2).
Fig. 2 Diol acceptors trans 1 and cis 2 and donors 3 used in this study.
Activated and armed groups are denoted as a, deactivated and disarmed
groups as d.
seems to be mainly determined by the strength of the hydrogen
bonds formed between each OH group with the neighboring
protecting group in the acceptor, which can be predicted by a
simple theoretical calculation. Additionally, the reactivity of both
donor and acceptor determines the degree of the regioselectivity.
In order to establish a general rule that allows some prediction of
the regiochemical outcome of a given glycosylation reaction, we
have corroborated the theory of neighboring group assistance in
the transition state by analyzing, not only the results obtained in
the cases mentioned above (Fig. 2), but also the regiochemistry
obtained in other representative cases described in the literature.
The regioselectivity of these acceptors had been previously
studied with other glycosyl donors (Fig. 3). Donor I reacted
with moderate regioselectivity with both acceptors 1a and 1d to
form preferentially the (1–2) pseudodisaccharides.11c The regios-
electivity towards this position dramatically increased when the
Results and discussion
Regioselectivity of the reactions of D-chiro-inositol 1,2-trans diol
acceptors (1) with donors (3)
In order to assess the significance of the reactivity/selectivity bal-
ance in the regiochemical outcome of the reaction,9 the behavior
of acceptors 1a and 1d14 when treated with donors of different
Fig. 3 Regioselectivity observed in the reactions of glycosyl donors I–III
with diol acceptors trans (1).
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benzoylated acceptor 1d reacted with donor II,8a which shows a
participating group at C2. Reaction with donor III,11e used by us in
the preparation of fagopyritol (B1),16 afforded the corresponding
pseudodisaccharide with complete regioselectivity.
Therefore donors 3, as well as donors I–III of a different nature,
react with acceptor 1d preferentially or exclusively at the C2
position. According to our previous investigations, we postulated
that, in the absence of other stereoelectronic effects which are
difficult to predict, the O(2)-H bond should be weaker than the
O(3)-H one as a consequence of a stronger hydrogen bond between
the O(2)-H and the axial C1-substituent than between the O(3)-
H and the equatorial C4-substituent. These interactions favor
glycosylation towards position 2 (Fig. 4).
◦
˚
Fig. 5 Representative distances (A) and angles ( ) of the hydrogen bonds
found between OH groups and the adjacent protecting groups in the model
acceptors. The total amounts (kcal mol-1) of small orbital interactions
evaluated by means of a second-order perturbational analysis of the Fock
matrix on the NBO basis are also indicated. W represents the Wiberg bond
indexes between selected atoms.
According to our previous studies8a in which complexes prior
to TSs were modeled (see Fig. 1), the small differences observed
between both hydrogen bonds of the acceptor in the ground state
are expected to become greater in the corresponding transition
states, when the bond between donor and acceptor is being formed
˚
=
(compare distances C2OH. . ..O C-C1: 2.23 A of D in Fig. 5 with
˚
the corresponding complex shown in Fig. 1 :1.57 A). Thus, we
can conclude that a prediction of the regiochemical outcome of
the reaction can be made by a careful analysis of the strength of
the hydrogen bonds in which the OHs that can be glycosylated are
involved.
Regioselectivity of the reactions of mannosyl donors with
D-chiro-inositol 1,2-cis diol acceptors (2)
With the aim of analyzing the effect of the same factors on the
regioselectivity of the glycosylation of 1,2-cis diols, the acceptors
2a and 2d were also subjected to treatment with donors 3.
Acceptor 2a had been previously used by us in the synthesis
of the glycosaminyl a(1→2) L-chiro-inositol structural motif
by regioselective glycosylation with 2-deoxy-2-azidohexosaminyl
trichloroacetimidates.11c Acceptor 2d was prepared as shown in
Scheme 1 following a synthetic strategy similar to that used in
the preparation of 2a from a monoisopropylidene derivative of
D-chiro-inositol.
Fig. 4 Structures A and D will be used as model systems for diol acceptors
trans 1a and 1d.
In order to corroborate this hypothesis, we decided to carry out
a theoretical study of these interactions at the DFT (B3LYP)17
level by using the Gaussian 03 program.18,19 As model structures
for this study the glycosyl acceptors 1a and 1d were simplified by
locating methyl instead of benzyl (A) and acetyl instead of benzoyl
(D) groups in only positions 1 and 4, adjacent to both hydroxy
groups, of the cyclitol ring with axial and equatorial orientation
respectively (Fig. 4).
Structures A and D20 show both hydroxy groups involved in
hydrogen bonds with the adjacent protecting groups (Fig. 5). The
effects produced by these bonds are similar in both structures
although a bit smaller in the case of the methoxylated model A. The
small differences in distances and angles reveal that the hydrogen
bond between OH(2) and the axial group at position 1 is slightly
stronger than the bond between OH(3) and the equatorial group at
position 4. NBO analyses21 show small charge donations from the
=
lone pairs of the carbonylic oxygen along with the p-C O bond
to the O–H antibonding orbital that weakens this bond (slight
variations in the Wiberg bond indexes of the O–H bonds are also
observed). These data show the same trend: a slightly stronger
hydrogen bond between OH(2) and the adjacent axial group and,
as a consequence, a weaker O(2)–H bond that favors glycosylation
at this position.
Scheme 1 Synthesis of acceptors 2.
The reactions of the armed and disarmed mannosyl donors
3 with the 1,2-cis diol acceptors 2 were carried out under the
experimental conditions used in previous experiments (Table 2).
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Table 2 Glycosylation reactions of trichloroacetimidates 3 with D-chiro-inositol acceptors 2
Yield of glycosylation (%)
Entry
Donor/acceptor
a(1–2) 8
b(1–2) 9
a(1–1) 10
trisac.
Overall yield.
Ratio C2/C1a
1
2
3
4
3a + 2d
3a + 2a
3d + 2d
3d + 2a
61
21
28
45
–
6
–
–
–
10
–
–
16b
–
61
53
28
45
1/0
2.7/1
1/0
–
–
1/0
a Selectivities have been calculated on isolated yields after flash chromatography. b Mixture of pseudotrisaccharides (1–1:1–2).
The disarmed donor 3d reacted with complete regioselectivity
with both 2d and 2a to afford the a(1→2) pseudodisaccharides
8dd and 8da in 28 and 45% yield, respectively. Complete re-
gioselectivity for the a(1→2) product was also observed in the
reaction of the armed glycosyl donor 3a with the less reactive
acceptor 2d: the pseudodisaccharide 8ad was obtained in 61%
yield. However, the reaction of the armed donor 3a with the
activated acceptor 2a afforded a 21:6:10:16 mixture of the a(1→2),
b(1→2), and a(1→1) pseudodisaccharides 8–10 along with a
mixture of pseudotrisaccharides in 53% combined yield. This
considerable decrease in the regio- and stereoselectivity clearly
evidenced that with donor/acceptor pairs in which both reaction
partners are reactive, low regioselectivities and the formation of
pseudotrisaccharides can be expected.
Apart from the reasonable influence of reactivity on
regioselectivity,9 a number of interesting features were observed
in the examples analyzed, such as the high regioselectivity for
glycosylation at the equatorial hydroxy group in the two 1,2-
cis diols 2a and 2d. The reactions of these acceptors had also
been carried out with other 2-azido-2-deoxy-D-glucopyranosyl
trichloroacetimidates to mainly afford the (1–2) disaccharides.11c
The low tendency shown by these acceptors to undergo gly-
cosylation at the axial hydroxy group, that contrasts with other
examples described in the literature (see below), can also be
explained on the basis of the results of the DFT calculations
(Fig. 5) carried out to gain an understanding of the regiochemical
outcome of the reactions of 1,2-trans diol acceptors 1 collected
in Table 1. According to these calculations, a hydrogen bond
from a vicinal substituent can assist glycosylation at a given
position. Both acyloxy and alkoxy substituents can have such
an effect, although the latter to a lesser extent. Thus, because
of the presence of the acyloxy substituent at the 3-position, the
hydroxy group at C2 in compound 2d will be more activated
toward glycosylation than the hydroxy group at C1, which cannot
be assisted by the axial substituent at C6 (Fig. 2). As a consequence,
even the reaction with the armed donor 3a proceeds with complete
regioselectivity (entry 1, Table 2). Nevertheless, the regioselectivity
dramatically decreases in the reaction of the armed donor 3a with
the more reactive acceptor 2a (entry 2, Table 2) due probably to the
higher reactivity of both donor and acceptor and the less efficient
assistance of the alkoxy group at C3 compared with the acyloxy
group present in 2d.
Regioselectivity with other cis and trans diols
Our hypothesis of neighboring group assistance is supported by
most of the examples described in the literature, which show
the same tendency even with several glycosyl donors (for more
details of each case see the ESI†). Such is the case of mannose
6
acceptors IVa and IVb (Fig. 6). It can be seen that in IVb
the axial and equatorial hydroxyl groups are glycosylated with
benzylated a-glucopyranosyl trichloroacetimidate in similar ratios
(a/e = 46:54), whereas the axial hydroxy group in IVa, unable
to form hydrogen bonds with neighbouring protecting groups,
remains almost unreactive (a/e = 12:88). It is remarkable that
although Vasella pointed out the importance of hydrogen bonds
in the regioselectivity of glycosylation reactions, the different
regioselectivity obtained for IVa and IVb is attributed to possible
Fig. 6 Regioselectivity observed for diol acceptors IVa and IVb.
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stereoelectronic factors and not to neighboring group activation
through hydrogen bonds. It is also important to note that in
acceptors IV an additional hydrogen bond with the oxygen in
the ring is possible producing an activation of the hydroxyl group
in the axial position, decreasing the regioselectivity that could be
expected.
The glycosylations of other 1,2-cis diol acceptors described in
the literature are represented in Fig. 7 and Fig. 8. Although the
axial hydroxy group in the allose acceptor V would be expected
to be less reactive than the equatorial one due to steric factors,
it undergoes glycosylation preferentially.6 However it must be
taken into account that this axial hydroxy group could also form
hydrogen bonds with the neighboring groups located at position
4 as well as with the methoxy group at position 1. This latter
bond is the strongest one in Va, as revealed a simple theoretical
calculation.22
Fig. 9 Regioselectivity observed for some diol acceptors. The arrows
indicate the hydroxy groups that undergo glycosylation preferentially,
probably due to hydrogen bond activation.
the best donor/acceptor pair for a given glycosylation reaction,
our results indicate that it is reasonable to avoid reactions with
activated acceptors and armed donors, as such combinations tend
to lead to lower regioselectivities and the formation of undesirable
pseudotrisaccharides. We also confirmed that glycosylation at a
particular position can be favored by the presence of substituents
able to form a hydrogen bond with the hydroxy group at that
position. A careful analysis of the strength of the hydrogen bonds
of the OHs that can be glycosylated with the neighboring groups
through a simple computationally inexpensive calculation could
be used to predict the regiochemical outcome of glycosylation
reactions of a given 1,2-diol system.
Experimental
Fig. 7 Regioselectivity observed for diol acceptors Va and Vb. The ar-
rows indicate the hydroxy groups that undergo glycosylation preferentially,
probably due to hydrogen bond activation.
General
Diethyl ether and dichloromethane were distilled from sodium
benzophenone and calcium hydride, respectively. Molecular sieves
(4A, powdered) were dried in an oven at 100 ◦C and activated
˚
for 5 min under vacuum at 500 ◦C. All reactions were carried out
under an atmosphere of dry argon with oven-dried glassware and
freshly distilled and dried solvents, unless otherwise stated. TLC
was performed on silica gel GF254. Silica gel (230–400 mesh) was
used for flash chromatography, and eluents are given as volume to
volume ratios (v/v). All aqueous solutions were saturated unless
otherwise stated. 1H (300, 400 and 500 MHz) and 13C NMR
(125 and 75 MHz) spectra were recorded at 25 ◦C in CDCl3
unless otherwise noted; chemical shifts are given in ppm relative
to CDCl3 (7.27 ppm), and coupling constants are reported in
Hz. Resonances were assigned by means of 2D spectra (COSY,
HMQC).
Fig. 8 Regioselectivity observed for 1,2-cis diol acceptor VI.
The ratio of glycosylation at the equatorial or axial position
in inositol VI depends on the glycosyl donor (RDAS),5a,23 the re-
gioselectivity being higher with a disarmed donor.9 The equatorial
OH group is preferred for the glycosylation, probably due to steric
hindrance, as was pointed out by the authors, as well as to a
stronger hydrogen bond with the adjacent benzyl group, again in
agreement with our theoretical calculations.23
General method of glycosylation
In the case of 1,2-trans-diequatorial diols most of the exam-
ples described in the literature afforded low regioselectivities.6,24
However, the reasoning of neighboring group assistance could
also explain some results observed with diaxial diols, such as
altrose25 and iduronic and glucuronic derivatives26 that glycosylate
preferentially at the OH indicated in each case (Fig. 9).27
A mixture of the donor and the acceptor was co-evaporated 3 times
˚
with toluene, 4-A molecular sieves were added, and the residue was
dried under vacuum overnight. The mixture was dissolved in ether
under an argon atmosphere and stirred at room temperature for
30 min, then TMSOTf (0.1 M solution; 0.08 equiv.) was added at
-40 ◦C, and the reaction mixture was stirred for 1 h at -40 ◦C.
The reaction was then quenched with Et3N, and the mixture was
concentrated and purified by flash chromatography.
Conclusions
The experiments described herein show clearly the importance
of an adequate reactivity balance between the donor and the
acceptor for glycosylation reactions to proceed in good yield with
good regio- and stereoselectivity. Although it is difficult to predict
Competitive experiment of acceptors (1d) and (1a) with 3,4,6-tri-
O-benzyl-2-azido-2-deoxy-a-D-glucopyranosyl-trichloroacetimi-
date. A mixture of 3,4,6-tri-O-benzyl-2-azido-2-deoxy-a-D-
glucopyranosyl-trichloroacetimidate (87 mg, 0.14 mmol),
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1,4,5,6-tetra-O-benzoyl-D-chiro-inositol 1d (83 mg, 0.14 mmol)
and 1,4,5,6-tetra-O-benzyl-D-chiro-inositol 1a (76 mg, 0.14 mmol)
was co-evaporated 3 times with toluene, 4-A molecular sieves
8.27–7.40 (4 H ortho, 8H); 7.30–6.77 (m, 20H, 4Bn and 12H,
4Bz); 6.64 (t, 1H, J= 10.4 Hz, H4); 6.46 (dd, 1H, J= 10.5 and
3.7 Hz, H5); 6.42 (bt, 1H, J= 3.7 Hz, H6); 6.21 (bt, 1H, J= 3.7 Hz,
H1); 5.50 (s, 1H, H1¢); 4.97–4.30 (4 AB syst, 8H); 4.73 (dd, 1H, J=
9.4 and 3.6 Hz, H2); 4.56 (m, 1H, H3); 4.48 (m, 1H, H5¢); 4.23 (t,
1H, J= 9.4 Hz, H4¢); 4.04 (bs, 1H, H2¢); 4.02 (dd, 1H, J= 9.4 and
3.0 Hz, H3¢); 3.82 (m, 2H, 2H6¢) and 3.40 (s, 1H, C3OH). 13C NMR
(125 MHz, CDCl3): d = 166.5, 165.9, 165.3 and 165.1 (4CO),
138.7, 138.6, 138.6 and 138.2 (4C, Bn), 134.1, 134.0, 133.6 and
133.5 (4CH para), 130.3–127.7 (16CH, Bz and 20CH, Bn), 129.8,
129.4, 129.2 and 129.1 (4C, Bz), 97.8 (C1¢a, JC1¢-H1¢= 171.7 Hz), 79.7
(CH), 77.6 (CH), 75.0 (CH2), 74.9 (CH), 74.8 (CH), 73.7 (CH2),
72.9 (CH2), 72.7 (CH), 72.5 (CH), 72.0 (CH2), 71.6 (CH), 70.3
(CH), 69.6 (CH2), 69.2 (CH) and 68.2 (CH). HSQC (500 MHz,
CDCl3): JC1¢-H1¢: 171.7 Hz. Elemental analysis calcd. for C68H62O15:
72.97% C and 5.58% H; found: 72.79% C and 5.89% H. Data
of the acetylated a(1→2) pseudodisaccharide 4ad: 1H NMR
(500 MHz, C6D6): d = 6.53 (t, 1H, J= 10.0 Hz, H3). Data of the
˚
were added and the residue was dried under vacuum. The
mixture was disolved in ether (3 mL) in an argon atmosphere
and stirred at room temperature for 30 min, then 0.08 equiv.
(112 ml of a solution 0.1 M) of TMSOTf was added at -40 ◦C
and the reaction mixture stirring for 1 h at -40 ◦C. Then it
was quenched with Et3N, concentrated and purified by flash
chromatography (Hexane/EtOAc 4:1 to 1:1), to give 37 mg
(26%) of a mixture (2:1) of 2-azido-3,4,6-tri-O-benzyl-2-deoxy-
D-glucopyranosyl-a(1→2)-1,4,5,6-tetra-O-benzyl-D-chiro-inosi-
tol and 2-azido-3,4,6-tri-O-benzyl-2-deoxy-D-glucopyranosyl-
a(1→3)-1,4,5,6-tetra-O-benzyl-D-chiro-inositol, 17 mg (12%) of
2-azido-3,4,6-tri-O-benzyl-2-deoxy-D-glucopyranosyl-b(1→2)-
1,4,5,6-tetra-O-benzyl-D-chiro-inositol, 16 mg (11%) of 2-azido-
3,4,6-tri-O-benzyl-2-deoxy-D-glucopyranosyl-b(1→3)-1,4,5,6-
tetra-O-benzyl-D-chiro-inositol, 14 mg (9%) of a mixture (5:1) of
2-azido-3,4,6-tri-O-benzyl-2-deoxy-D-glucopyranosyl-a(1→2)-
1,4,5,6-tetra-O-benzoyl-D-chiro-inositol and 2-azido-3,4,6-tri-O-
benzyl-2-deoxy-D-glucopyranosyl-a(1→3)-1,4,5,6-tetra-O-ben-
1
a(1→3) pseudodisaccharide 5ad: H NMR (500 MHz, CDCl3):
d = 8.15–8.00 (4 Hortho, 8H); 7.75–7.00 (m, 20H, 4Bn and 12H,
4Bz); 5.99 (m, 1H, H4); 5.94 (t, 1H, J= 3.7 Hz, H6); 5.80 (dd, 1H,
J= 10.6 and 3.6 Hz, H5); 5.77 (t, 1H, J= 3.7 Hz, H1); 5.04 (d, 1H,
J= 2.3 Hz, H1¢); 4.75–4.00 (4 AB syst, 8H); 4.29 (m, 1H, H2); 4.20
(m, 1H, H5¢); 4.17 (t, 1H, J= 9.9 Hz, H3); 3.88 (dd, 1H, J= 8.9
and 2.5 Hz, H3¢); 3.74 (t, 1H, J= 9.0 Hz, H4¢); 3.57 (m, 2H, 2H6¢);
3.54 (t, 1H, J= 2.3 Hz, H2¢) and 3.44 (s, 1H, C2OH). 13C NMR
(125 MHz, C6D6): d = 166.4, 166.3, 165.7 and 165.3 (4CO), 139.7,
139.5, 139.3 and 138.8 (4C, Bn), 134.2, 133.9, 133.8 and 133.6
(4CH para), 130.7–128.0 (16CH, Bz and 20CH, Bn), 129.7, 129.5,
129.5 and 129.2 (4C, Bz), 101.5 (C1¢a, JC1¢-H1¢= 170.3 Hz.), 82.2
(CH), 80.4 (CH), 76.8 (CH), 76.6 (CH), 74.6 (CH2), 73.3 (CH2),
73.2 (CH), 72.7 (CH2), 72.2 (CH), 71.5 (CH2), 71.1 (CH), 70.6
(CH), 70.4 (CH), 69.7 (CH2) and 69.0 (CH). Elemental analysis
calcd. for C68H62O15: 72.97% C and 5.58% H; found: 73.03% C
and 5.69% H.
zoyl-D-chiro-inositol,
3 mg (2%) 2-azido-3,4,6-tri-O-benzyl-
2-deoxy-D-glucopyranosyl-b(1→2)-1,4,5,6-tetra-O-benzoyl-D-
chiro-inositol, 68 mg (81%) of the unreactive acceptor 1d and
37.8 mg (50%) of the unreactive acceptor 1a. Data of 2-azido-
3,4,6-tri-O-benzyl-2-deoxy-D-glucopyranosyl-b(1→2)-1,4,5,6-
20
tetra-O-benzoyl-D-chiro-inositol: [a]D +20.6 (c = 0.15, CHCl3).
1H NMR (500 MHz, CDCl3): d = 8.17–7.76 (4 Hortho, 8H); 7.60–
7.10 (m, 15H, 3Bn and 12H, 4Bz); 6.00–5.95 (m, 2H, H4 and H6);
5.85 (bt, 1H, J= 3.7 Hz, H1); 5.77 (dd, 1H, J= 10.4 and 3.3 Hz, H5);
4.80–4.32 (3 AB syst, 6H); 5.22 (d, 1H, J= 8.1 Hz, H1¢); 4.54 (ddd,
1H, J = 12.8, 9.7 and 3.1 Hz, H3); 4.36 (dd, 1H, J= 9.7 and 3.7 Hz,
H2); 3.64 (dd, 1H, J= 11.0 and 4.0 Hz, H6¢a); 3.60 (m, 1H, H5¢);
3.55 (dd, 1H, J= 11.0 and 1.8 Hz, H6¢b); 3.41–3.37 (m, 3H, H3¢, H4¢
and H2¢) and 3.20 (d, 1H, J= 3.3 Hz, C3OH). 13C NMR (125 MHz,
CDCl3): d = 166.6, 165.7, 165.2 and 164.9 (4CO), 138.4, 138.1 and
138.1 (3C, Bn), 134.0, 133.8, 133.7 and 133.5 (4CH para), 130.4–
127.8 (15CH, Bn and 16CH, Bz), 129.7, 129.6, 129.4 and 129.2 (4C,
Bz), 103.3 (C1¢), 83.3 (CH), 79.0 (CH), 77.8 (CH), 77.7 (CH2), 75.7
(CH), 75.3 (CH2), 73.7 (CH2), 72.3 (CH), 72.2 (CH), 70.8 (CH),
70.1 (CH), 68.9 (CH), 68.5 (CH2) and 66.5 (CH). FAB HRMS
calcd. for C61H55O14N3+Na+: 1076.3581, found: 1076.3613. Data
of the other pseudodisaccharides have been previously described in
ref 11c.
2,3,4,6-Tetra-O-benzyl-D-manopyranosyl-a(1→2)-1,4,5,6-
tetra-O-benzyl-D-chiro-inositol (4aa), 2,3,4,6-tetra-O-benzyl-D-
manopyranosyl-a(1→3)-1,4,5,6-tetra-O-benzyl-D-chiro-inositol
(5aa) 2,3,4,6-tetra-O-benzyl-D-manopyranosyl-b(1→2)-1,4,5,6-
tetra-O-benzyl-D-chiro-inositol (6aa) and 2,3,4,6-tetra-O-benzyl-
D-manopyranosyl-b(1→3)-1,4,5,6-tetra-O-benzyl-D-chiro-inositol
(7aa). These pseudodisaccharides were prepared from 2,3,4,6-
tetra-O-benzyl-a-D-mannopyranosyl-trichloroacetimidate
3a
2,3,4,6-Tetra-O-benzyl-D-manopyranosyl-a(1→2)-1,4,5,6-
tetra-O-benzoyl-D-chiro-inositol (4ad) and 2,3,4,6-tetra-O-
benzyl-D-manopyranosyl-a(1→3)-1,4,5,6-tetra-O-benzoyl-D-
chiro-inositol (5ad). These pseudodisaccharides were prepared
(42 mg, 0.061 mmol) and 1,4,5,6-tetra-O-benzyl-D-chiro-inositol
1a (33 mg, 0.061 mmol) as described in the general method,
adding 0.08 equiv. (49 ml of a solution 0.1 M) of TMSOTf at
-40 ◦C to rt, in dry ether (1.7 ml) and stirring the reaction
mixture for 1 h at -40 ◦C, yielding after flash chromatography
(Hexane/EtOAc 6:1 to 4:1), 23 mg of the pseudodisaccharide 4aa
(35%), 9 mg of the pseudodisaccharide 5aa (14%), 5 mg of the
pseudodisaccharide 6aa (8%) and 3 mg of the pseudodisaccharide
from
2,3,4,6-tetra-O-benzyl-a-D-mannopyranosyl-trichloro-
acetimidate 3a (62 mg, 0.09 mmol) and 1,4,5,6-tetra-O-benzoyl-
D-chiro-inositol (1d) (53 mg, 0.09 mmol) as described in the
general method, adding 0.08 equiv. (72 ml of a solution 0.1 M) of
◦
20
TMSOTf at -40 C, in dry ether (2 ml) and stirring the reaction
7aa (4%). Data of the a(1→2) pseudodisaccharide 4aa: [a]D
mixture for 1 h at -40 ◦C, yielding after flash chromatography
(Hexane/EtOAc 6:1 to 4:1), 32 mg of the pseudodisaccharide 4ad
(32%) and 30 mg of a mixture (1:1.5) of the pseudodisaccharides
4ad and 5ad (28%). Data of the a(1→2) pseudodisaccharide 4ad:
+15.0 (c = 0.9, CHCl3). 1H NMR (500 MHz, C6D6): d = 7.50–7.15
(m, 40H, 8Bn); 5.24 (s, 1H, H1¢); 5.11–4.42 (8 AB syst, 16H);
4.60 (m, 1H, H5¢); 4.40 (m, 1H, H4¢); 4.39 (m, 1H, H3); 4.29–420
(m, 3H, H3¢, H2 and H4); 4.10 (dd, 1H, J= 9.6 and 2.6 Hz, H5);
3.94–3.81 (m, 6H, H2¢, H1, H6 and 2H6¢) and 3.38 (bs, 1H, C3OH).
20
1
[a]D +71.1 (c = 1.3, CHCl3). H NMR (500 MHz, C6D6): d =
1476 | Org. Biomol. Chem., 2009, 7, 1471–1481
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13C NMR (125 MHz, C6D6): d = 140.7, 140.1, 140.1, 139.9, 139.8,
139.8, 139.7 and 138.5 (8C, Bn), 129.3–128.0 (40CH, Bn), 98.3
(C1¢a, JC1¢-H1¢ = 170.3 Hz), 83.1 (CH), 81.2 (CH), 80.5 (CH), 79.7
(CH), 77.0 (CH), 77.0 (CH), 76.6 (CH), 76.5 (CH), 76.4 (CH2),
75.6 (CH2), 74.6 (CH2), 74.5 (CH2), 74.4 (CH), 74.2 (CH2),
74.1 (CH2), 73.7 (CH2), 73.6 (CH), 73.1 (CH2) and 70.5 (CH2).
Elemental analysis calcd. for C68H70O11: 76.81% C and 6.63% H;
found: 77.25% C and 6.82% H. Data of the acetylated a(1→2)
pseudodisaccharide 4aa: 1H NMR (500 MHz, C6D6): d = 6.13 (t,
1H, J = 9.5 Hz, H3). Data of the a(1→3) pseudodisaccharide
2,3,4,6-Tetra-O-acetyl-D-manopyranosyl-a(1→2)-1,4,5,6-
tetra-O-benzoyl-D-chiro-inositol (4dd), 2,3,4,6-tetra-O-acetyl-D-
manopyranosyl-a(1→3)-1,4,5,6-tetra-O-benzoyl-D-chiro-inositol
(5dd). These pseudodisaccharides were prepared from 2,3,4,6-
tetra-O-acetyl-a-D-mannopyranosyl-trichloroacetimidate
3d
(61 mg, 0.124 mmol) and 1,4,5,6-tetra-O-benzoyl-D-chiro-inositol
1d (74 mg, 0.124 mmol) as described in the general method,
adding 0.08 equiv. (99 ml of a solution 0.1 M) of TMSOTf at
-40 ◦C, in dry ether (2 ml) and stirring the reaction mixture for 1
h at -40 ◦C, yielding after flash chromatography (Hexane/EtOAc
1:1), 37 mg of the pseudodisaccharide 4dd (32%) and 10 mg
of the pseudodisaccharide 5dd (9%). Data of the a(1→2)
20
1
5aa: [a]D -4.0 (c = 0.45, CHCl3). H NMR (500 MHz, C6D6):
d = 7.40–7.10 (m, 40H, 8Bn); 5.54 (s, 1H, H1¢); 5.14–4.43 (8 AB
syst, 16H); 4.75 (m, 1H, H5¢); 4.46 (m, 1H, H2); 4.32 (t, 1H, J=
9.1 Hz, H3); 4.22 (t, 1H, J= 9.2 Hz, H4); 4.21 (s, 1H, H3¢); 4.16 (t,
1H, J= 9.5 Hz, H4¢); 4.12 (dd, 1H, J= 9.3 and 2.9 Hz, H5); 4.06
(t, 1H, J= 3.4 Hz, H1); 4.00 (s, 1H, H2¢); 3.90 (d, 1H, J= 9.3 Hz,
H6¢a); 3.86 (t, 1H, J = 3.4 Hz, H6) and 3.77 (dd, 1H, J = 10.1
and 7.5 Hz, H6¢b). 13C NMR (125 MHz, C6D6): d = 140.6, 140.0,
139.9, 139.9, 139.8, 139.8, 139.7 and 138.5 (8C, Bn), 129.2–127.6
(40CH, Bn), 101.5 (C1¢a, JC1¢-H1¢= 170.0 Hz), 86.1 (CH), 82.3 (CH),
81.4 (CH), 80.8 (CH), 78.8 (CH), 77.4 (CH), 76.4 (CH), 76.1
(CH), 75.6 (CH2), 75.0 (CH2), 74.1 (CH2), 74.0 (CH2), 73.8 (CH),
73.8 (CH2), 73.8 (CH2), 73.5 (CH2), 72.7 (CH2), 72.4 (CH) and
70.9 (CH2). Elemental analysis calcd. for C68H70O11: 76.81% C
and 6.63% H; found: 76.55% C and 6.87% H. Data of the b(1→3)
pseudodisaccharide 4dd: [a]D +81.7 (c = 0.5, CHCl3). 1H NMR
20
(500 MHz, C6D6): d = 8.37–8.05 (4 H ortho, 8H); 7.20–6.80 (m,
12H, 4Bz); 6.43 (t, 1H, J= 9.9 Hz, H4); 6.35–6.31 (m, 2H, H6 and
H5); 5.99 (bt, 1H, J= 3.3 Hz, H1); 5.80–5.69 (m, 1H, H2¢, H3¢ and
H4¢); 5.45 (s, 1H, H1¢); 4.74 (m, 1H, H5¢); 4.66 (dd, 1H, J= 9.7 and
3.3 Hz, H2); 4.55 (dd, 1H, J = 12.1 and 2.0 Hz, H6¢a); 4.37 (dd, 1H,
J = 12.1 and 6.4 Hz, H6¢b); 4.14 (m, 1H, H3); 2.60 (s, 1H, C3OH);
2.00, 1.77, 1.75 and 1.73 (4 s, 12H, 4CH3). 13C NMR (125 MHz,
CDCl3): d = 170.8, 169.9, 169.8 and 169.7 (4OCOCH3), 166.4,
166.1, 165.6 and 165.1 (4CO), 133.9, 133.8, 133.6 and 133.5 (4CH
para), 130.6–128.1 (16CH, Bz), 130.4, 130.1, 129.9 and 129.8 (4C,
Bz), 96.6 (C1¢), 75.6, 73.4, 71.5, 71.1, 70.7, 70.1, 69.8, 69.6, 67.4,
67.2 and 63.1 (10CH and 1CH2), 20.9, 20.6, 20.6 and 20.5 (4CH3).
FAB HRMS calcd. for C48H46O19+Na: 949.2531, found: 949.2517.
pseudodisaccharide 6aa: [a]D -30.0 (c = 0.2, CHCl3). 1H NMR
20
20
(500 MHz, C6D6): d = 7.65–7.10 (m, 40H, 8Bn); 5.44–4.32 (8
AB syst, 16H); 5.11 (s, 1H, H1¢); 4.55–4.45 (m, 2H, H3 and H2);
4.33 (t, 1H, J= 9.5 Hz, H4); 4.20 (t, 1H, J= 9.1 Hz, H4¢); 4.14
(dd, 1H, J= 2.9 Hz, H2¢); 4.04 (dd, 1H, J= 9.6 and 2.7 Hz, H5);
3.91–3.85 (m, 3H, H1, H6 and H6¢a); 3.79 (dd, 1H, J= 11.0 and
5.7 Hz, H6¢b); 3.60 (m, 1H, H5¢); 3.51 (dd, 1H, J= 9.0 and 2.9 Hz,
H3¢) and 2.98 (bs, 1H, OH). 13C NMR (125 MHz, C6D6): d =
141.0, 140.3, 140.2, 140.1, 140.1, 139.7, 139.6 and 139.2 (8C,
Bn), 129.4–128.3 (40CH, Bn), 101.8 (C1¢b, JC1¢-H1¢= 153.6 Hz),
83.6 (CH), 82.8 (CH), 81.0 (CH), 80.5 (CH), 79.2 (CH), 77.2
(CH), 76.5 (CH), 76.3 (CH2), 75.8 (CH), 75.7 (CH), 75.4 (CH2),
75.2 (CH2), 74.3 (CH2), 74.3 (CH2), 74.2 (CH2), 74.2 (CH2), 72.9
(CH), 72.2 (CH2) and 70.8 (CH2). Elemental analysis calcd. for
C68H70O11: 76.81% C and 6.63% H; found: 76.90% C and 6.77%
Data of the a(1→3) pseudodisaccharide 5dd: [a]D +68.2 (c =
0.5, CHCl3).1H NMR (500 MHz, CDCl3): d = 8.17–7.75 (4 H
ortho, 8H); 7.65–7.20 (m, 12H, 4Bz); 6.09 (t, 1H, J= 10.1 Hz,
H4); 5.92 (t, 1H, J= 3.8 Hz, H6); 5.81–5.77 (m, 1H, H1 and H5);
5.34 (dd, 1H, J= 9.6 and 3.3 Hz, H3¢); 5.10 (t, 1H, J= 9.6 Hz,
H4¢); 5.05 (d, 1H, J= 1.8 Hz, H1¢); 5.00 (m, 1H, H2¢); 4.46 (m, 1H,
H5¢); 4.41 (m, 1H, H2); 4.30 (t, 1H, J= 9.7 Hz, H3); 4.15 (dd, 1H,
J= 12.1 and 6.4 Hz, H6¢a); 4.04 (dd, 1H, J= 12.3 and 2.4 Hz,
H6¢b), 2.90 (s, 1H, C2OH); 2.00, 1.90, 1.80 and 1.75 (4 s, 12H,
4OCH3).13C NMR (125 MHz, CDCl3): d = 170.9, 170.1, 169.9
and 169.3 (4OCOCH3), 165.9, 165.8, 165.5 and 165.1 (4CO),
134.3, 134.2, 133.7 and 133.6 (4CH para), 130.4–128.7 (16CH,
Bz), 130.4, 130.2, 130.0 and 129.1 (4C, Bz), 99.5 (C1¢), 80.3, 71.9,
71.2, 70.3, 69.9, 69.6, 69.5, 68.8, 68.8, 66.7 and 63.0 (10CH and
1CH2), 21.0, 20.8, 20.8 and 20.7 (4CH3). FAB HRMS calcd. for
C48H46O19+Na: 949.2531, found: 949.2526.
1
H. Data of the acetylated b(1→3) pseudodisaccharide 6aa H
NMR (500 MHz, C6D6): d = 5.79 (dd, 1H, J= 10.1 and 3.4 Hz,
20
H2). Data of the b(1→2) pseudodisaccharide 7aa: [a]D -38.0
(c = 0.15, CHCl3).1H NMR (500 MHz, CDCl3): d = 7.38–7.12
(m, 40H, 8Bn); 4.98–4.39 (8 AB syst, 16H); 4.65 (s, 1H, H1¢); 4.11
(t, 1H, J= 3.6 Hz, H1); 3.98 (d, 1H, J= 2.9 Hz, H2¢); 3.95 (t, 1H,
J= 9.5 Hz, H3); 3.91 (t, 1H, J= 9.6 Hz, H4¢); 3.89 (dd, 1H, J= 9.6
and 3.3 Hz, H2); 3.81 (dd, 1H, J= 9.7 and 3.5 Hz, H5); 3.76 (m,
2H, H6¢a and H4); 3.68 (dd, 1H, J= 10.7 and 1.5 Hz, H6¢b); 3.62
(t, 1H, J= 3.6 Hz, H6); 3.49 (dd, 1H, J= 9.5 and 2.9 Hz, H3¢);
3.43 (m, 1H, H5¢) and 2.40 (bs, 1H, C3OH). 13C NMR (125 MHz,
C6D6): d = 140.4, 140.3, 140.2, 140.1, 139.8, 139.8, 139.7 and
2,3,4,6-Tetra-O-acetyl-D-manopyranosyl-a(1→2)-1,4,5,6-tetra-
O-benzyl-D-chiro-inositol (4da), 2,3,4,6-tetra-O-acetyl-D-mano-
pyranosyl-a(1→3)-1,4,5,6-tetra-O-benzyl-D-chiro-inositol
(5da).
These pseudodisaccharides were prepared from 2,3,4,6-tetra-
O-acetyl-a-D-mannopyranosyl-trichloroacetimidate 3d (28 mg,
0.057 mmol) and 1,4,5,6-tetra-O-benzyl-D-chiro-inositol 1a
(31 mg, 0.057 mmol) as described in the general method, adding
0.08 equiv. (45 ml of a solution 0.1 M) of TMSOTf at -40 ◦C
in dry ether (2 ml) and stirring the reaction mixture for 1 h at
-40 ◦C, yielding after flash chromatography (Hexane/EtOAc
2:1), 20 mg of the pseudodisaccharide 4da (40%) and 3 mg
of the pseudodisaccharide 5da (6%). Data of the a(1→2)
138.6 (8C, Bn), 129.3–128.2 (40CH, Bn), 104.4 (C1¢b, JC1¢-H1¢
=
161.6 Hz), 83.6 (CH), 82.8 (CH), 82.1 (CH), 80.7 (CH), 78.2
(CH), 78.1 (CH), 76.7 (CH), 76.5 (CH), 76.1 (CH2), 75.9 (CH),
75.7 (CH2), 75.3 (CH2), 74.7 (CH2), 74.3 (CH2), 74.1 (CH), 73.6
(CH2), 73.5 (CH2), 72.2 (CH2) and 70.8 (CH2).Elemental analysis
calcd. for C68H70O11: 76.81% C and 6.63% H; found: 77.02% C and
6.86% H.
20
pseudodisaccharide 4da: [a]D +11.3 (c = 1.0, CHCl3). 1H NMR
(500 MHz, CDCl3): d = 7.35–7.13 (m, 20H, 4Bn); 5.37 (dd, 1H,
J = 10.2 and 3.5 Hz, H3¢); 5.24 (t, 1H, J = 10.3 Hz, H4¢); 5.18
(m, 1H, H2¢); 4.97–4.35 (4 AB syst, 8H); 4.74 (s, 1H, H1¢); 4.40
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(m, 1H, H5¢); 4.20 (dd, 1H, J= 12.3 and 5.8 Hz, H6¢a); 4.10 (dd,
1H, J= 12.1 and 2.2 Hz, H6¢b); 3.92 (t, 1H, J= 9.5 Hz, H3); 3.86
(dd, 1H, J= 9.6 and 2.7 Hz, H2); 3.82 (dd, 1H, J= 9.6 and 2.4 Hz,
H5); 3.73 (t, 1H, J= 9.5 Hz, H4); 3.67 (m, 2H, H6 and H1); 2.75
(s, 1H, C3OH); 2.15, 2.02, 2.00 and 1.97 (4 s, 12H, 4CH3). 13C
NMR (125 MHz, CDCl3): d = 171.0, 170.4, 170.2 and 170.2
(4OCOCH3), 139.3, 138.8, 138.5 and 138.3 (4C, Bn), 128.7–127.9
(20CH, Bn), 96.2 (C1¢), 82.1 (CH), 79.6 (CH), 78.6 (CH), 75.9
(CH2), 75.2 (CH), 74.4 (CH), 73.9 (CH2), 73.7 (CH2), 73.5 (CH2),
72.6 (CH), 70.3 (CH), 69.4 (CH), 69.0 (CH), 66.4 (CH) and 62.8
(CH2), 21.3, 21.1, 21.0 and 21.0 (4CH3).Elemental analysis calcd.
O-benzoyl-D-chiro-inositol (0.18 g, 0.301 mmol). The reaction
mixture was stirred for 3 h, whereupon the solvent was evaporated,
the residue co-evaporated 4 times with toluene and purified by
flash chromatography (Hexane/EtOAc 4:1→1:1) to give 2d as a
white solid (0.164 g, 91%). [a]D20 +99.8 (c = 0.6, CHCl3);1H NMR
(500 MHz, CDCl3): d = 8.06 (d, 2H, J= 8.0 Hz, H ortho); 7.98
(d, 2H, J= 8.0 Hz, H ortho); 7.86 (d, 2H, J= 8.0 Hz, H ortho);
7.81 (d, 2H, J= 8.0 Hz, H ortho); 7.63–7.22 (m, 12H, 4Bz); 6.18
(t, 1H, J= 10.1 Hz, H4); 5.99 (dd, 1H, J= 10.1 and 3.4 Hz, H5);
5.95 (t, 1H, J= 3.4 Hz, H6); 5.83 (t, 1H, J= 10.1 Hz, H3); 4.41
(bs, 1H, H1); 4.30 (m, 1H, H2); 3.37 (bs, 1H, C1OH) and 3.33
(bs, 1H, C2OH). 13C NMR (125 MHz, CDCl3): d = 167.8, 166.2,
165.8 and 165.6 (4CO); 134.0, 133.8, 133.5 and 133.5 (4CH para);
129.4, 129.3, 129.3 and 129.1 (4C, Bz); 130.3–128.6 (16CH, Bz);
74.8 (CH); 71.5 (CH); 71.0 (CH); 70.4 (CH); 70.3 (CH) and 70.3
(CH). FAB HRMS calcd. for C34H28O10+Na: 619.1580, found:
619.1574. Elemental analysis calcd. for C34H28O10: C, 68.45%; H,
4.73%; found: C, 68.47% and H, 4.77%.
for C48H54O15: 66.19% C and 6.24% H; found: 66.23% C and
20
6.39% H. Data of the a(1→3) pseudodisaccharide 5da: [a]D
+
10.0 (c = 0.3, CHCl3).1H NMR (500 MHz, CDCl3): d = 7.40–7.20
(m, 20H, 4Bn); 5.36–5.32 (m, 2H, H3¢ and H2¢); 5.20–5.15 (m, 1H,
H1¢ and H4¢); 4.96–4.25 (4 AB syst, 8H); 4.57 (m, 1H, H5¢); 4.20
(dd, 1H, J= 12.1 and 6.0 Hz, H6¢a); 4.00 (dd, 1H, J= 12.1 and
2.4 Hz, H6¢b); 3.90 (t, 1H, J= 9.2 Hz, H4); 3.85 (dd, 1H, J= 9.7
and 3.5 Hz, H2); 3.75–3.64 (m, 4H, H5, H1, H3 and H6); 2.33 (d,
1H, JH2-OH= 10.1 Hz, C2OH); 2.15, 2.00, 1.95 and 1.92 (4 s, 12H,
4CH3). 13C NMR (125 MHz, CDCl3): d = 171.0, 170.3, 170.2
and 169.9 (4OCOCH3), 139.2, 138.7, 138.6 and 138.4 (4C, Bn),
128.9–127.7 (20CH, Bn), 99.3 (C1¢a, JC1¢-H1¢= 178.1 Hz), 82.0 (CH),
81.4 (CH), 79.8 (CH), 78.5 (CH), 76.0 (CH2), 73.8 (CH2), 73.7
(CH2), 73.7 (CH), 73.6 (CH2), 70.4 (CH), 69.8 (CH), 69.7 (CH),
68.6 (CH), 66.4 (CH) and 63.3 (CH2), 21.1, 21.0, 21.0 and 20.9
(4CH3). Elemental analysis calcd. for C48H54O15: 66.19% C and
6.24% H; found: 66.37% C and 6.51% H. Data of the acetylated
2,3,4,6-Tetra-O-benzyl-D-manopyranosyl-a(1→2)-3,4,5,6-
tetra-O-benzoyl-D-chiro-inositol (8ad). This pseudodisaccharide
was prepared from 2d (30 mg, 0.050 mmol) and 3a (34 mg,
0.050 mmol) as described in the general method, adding 0.1 equiv.
(50 ml of a solution 0.1 M) of TMSOTf at -40 ◦C in dry ether
(1.7 ml) and stirring the reaction mixture for 1 h at -40 ◦C.
After flash chromatography (Hexane/EtOAc 3:1→1:1) 34 mg of
pseudodisaccharide 8ad (61%) and 11 mg of acceptor 2d (55%)
20
1
were obtained. Data of 8ad: [a]D +79.0 (c = 0.5, CHCl3), H
NMR (500 MHz, CDCl3): d = 8.07–7.80 (4 H ortho, 8H); 7.63–
7.18 (m, 20H, 4Bn and 12H, 4Bz); 6.15 (t, 1H, J= 10.1 Hz, H4);
6.07 (t, 1H, J= 10.1 Hz, H3); 5.96 (dd, 1H, J= 10.1 and 3.3 Hz,
H5); 5.89 (bt, 1H, J= 3.4 Hz, H6); 5.01 (d, 1H, J= 1.6 Hz, H1¢);
4.74–4.34 (8H, 4 AB systems); 4.35 (m, 1H, H2); 4.29 (m, 1H,
H1); 3.79 (t, 1H, J= 9.5 Hz, H4¢); 3.68 (m, 1H, H5¢); 3.65 (dd, 1H,
J= 9.3 and 2.5 Hz, H3¢); 3.55 (bt, 1H, J= 2.2 Hz, H2¢); 3.41 (dd,
1H, J= 10.6 and 2.2 Hz, H6¢a); 3.38 (dd, 1H, J= 10.6 and 5.5 Hz,
H6¢b) and 3.32 (bs, 1H, C1OH). 13C NMR (125 MHz, CDCl3): d =
166.1, 166.1, 165.6 and 165.4 (4CO); 138.8, 138.6, 138.5 and 138.4
(4C, Bn); 133.9, 133.5, 133.5 and 133.4 (4CH para); 130.2–127.6
(20CH, Bn and 16CH, Bz); 129.5, 129.4, 129.4 and 129.3 (4C, Bz);
95.0 (C1¢a, JC1¢-H1¢: 168.6 Hz); 79.5 (CH); 77.5 (CH); 75.7 (CH); 74.8
(CH2); 74.7 (CH); 73.6 (CH2); 73.2 (CH2); 72.8 (CH); 72.8 (CH2);
70.9 (CH); 70.7 (CH); 70.3 (CH); 70.2 (CH); 69.0 (CH2) and 67.4
(CH). Elemental analysis calcd. for C68H62O15+2H2O: C, 70.74%
and H, 5.64%; found: C, 70.83% and H, 5.47%.
1
a(1→3) pseudodisaccharide 5da: H NMR (500 MHz, CDCl3):
d = 5.08 (dd, 1H, J= 10.7 and 2.7 Hz, H2).
1,2-O-Isopropyliden-3,4,5,6-tetra-O-benzoyl-D-chiro-inositol
Benzoyl chloride (0.32 ml, 2.80 mmol) was added to a solution
of 1,2-O-isopropyliden-D-chiro-inositol (77 mg, 0.35 mmol) and
DMAP (4 mg, 0.035 mmol) in dry pyridine (2 ml) at room
temperature. The reaction mixture was stirred for 24 h. The
solvent was evaporated, the residue redissolved in CH2Cl2, washed
with cold water and brine, dried over Na2SO4 and the solvent
evaporated. The crude was purified by flash chromatography
(Hexane/EtOAc= 8:1) to give the title compound quantitatively
20
as a white solid (0.22 g). [a]D +78.8 (c = 0.6, CHCl3); 1H NMR
(500 MHz, CDCl3): d = 8.08 (d, 2H, J= 8.0 Hz, H ortho); 7.96 (d,
2H, J= 8.0 Hz, H ortho); 7.87 (d, 2H, J= 8.0 Hz, H ortho); 7.83
(d, 2H, J= 8.0 Hz, H ortho); 7.60–7.22 (m, 12H, 4Bz); 6.07 (t, 1H,
J= 3.2 Hz, H6); 6.02 (t, 1H, J= 8.9 Hz, H4); 5.91 (dd, 1H, J= 9.1
and 3.2 Hz, H5); 5.86 (dd, 1H, J= 6.4 and 8.8 Hz, H3); 4.62 (dd,
1H, J= 6.3 and 5.4 Hz, H2); 4.55 (dd, 1H, J= 6.3 and 3.3 Hz, H1);
1.73 (s, 3H, CH3) and 1.40 (s, 3H, CH3). 13C NMR (125 MHz,
CDCl3): d = 166.0, 165.8, 165.5 and 165.4 (4CO); 133.9, 133.6,
133.5 and 133.5 (4CHpara); 130.4–128.5 (16CH, Bz); 129.5, 129.3,
129.2 and 129.1 (4C); 76.8 (C2); 75.2 (C1); 73.7 (C3); 70.4 (C5); 70.0
(C4); 69.6 (C6); 27.9 (CH3) and 26.2 (CH3). FAB HRMS calcd. for
C37H32O10+Na+: 659.1893, found: 659.1880. Elemental analysis
calcd. for C37H32O10: C, 69.80%; H, 5.07%; found: C, 69.90% and
H, 5.17%.
2,3,4,6-Tetra-O-benzyl-D-manopyranosyl-a(1→2)-3,4,5,6-
tetra-O-benzyl-D-chiro-inositol (8aa) and 2,3,4,6-tetra-O-benzyl-
D-manopyranosyl-b(1→2)-3,4,5,6-tetra-O-benzyl-D-chiro-inositol
(9aa), 2,3,4,6-tetra-O-benzyl-D-manopyranosyl-a(1→1)-3,4,5,6-
tetra-O-benzyl-D-chiro-inositol (10aa). These pseudodisaccha-
rides 8aa (23 mg, 21%), 9aa (7 mg, 6%) and 10aa (11 mg, 10%)
were prepared from donor 3a (66 mg, 0.096 mmol) and acceptor
2a (52 mg, 0.096 mmol) as described in the general method,
adding 0.08 equiv. (77 ml of a solution 0.1 M) of TMSOTf at
-40 ◦C in dry ether (2 ml) and stirring the reaction mixture for
1 h at -40 ◦C. The crude was purified by flash chromatography
20
3,4,5,6-Tetra-O-benzoyl-D-chiro-inositol (2d). A TFA:H2O =
9:1 (4 ml) solution was added at room temperature to a round-
bottomed flask charged with 1,2-O-isopropyliden-3,4,5,6-tetra-
(Hexane/EtOAc 6:1→4:1). Data of 8aa: [a]D +35.2 (c = 0.9,
1
CHCl3), H NMR (500 MHz, C6D6): d = 7.50–7.15 (m, 40H,
8Bn); 5.28 (s, 1H, H1¢); 5.11–4.34 (16H, 8 AB systems); 4.57
1478 | Org. Biomol. Chem., 2009, 7, 1471–1481
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(m, 1H, H4); 4.47–4.43 (m, 2H, H4¢ and H5¢); 4.33 (m, 1H, H2);
4.24 (dd, 1H, J= 8.9 and 2.5 Hz, H3¢); 4.21–4.18 (m, 2H, H1 and
H5); 4.06 (m, 1H, H6); 4.05 (t, 1H, J= 9.8 Hz, H3); 3.90 (t, 1H,
J= 2.4 Hz, H2¢); 3.76 (dd, 1H, J= 11.1 and 4.1 Hz, H6¢a) and 3.65
(bd, 1H, J= 11.1 Hz, H6¢b). 13C NMR (125 MHz, C6D6): d =
140.5, 140.2, 140.0, 139.9, 139.8, 139.7, 139.7 and 138.4 (8C, Bn);
and 2.9 Hz, H1); 4.15 (dd, 1H, J= 12.1 and 2.6 Hz, H6¢b); 3.73
(m, 1H, H5¢); 2.68 (d, 1H, JH1-OH= 11.0 Hz, C1OH); 2.07–1.95 (4
s, 12H, 4CH3). 13C NMR (125 MHz, CDCl3): d = 171.1, 170.7,
170.2 and 169.8 (4OCOCH3); 134.1, 133.6, 133.5 and 133.4 (4CH
para); 130.2–125.2 (16CH, Bz); 129.9, 129.3, 129.3 and 129.1 (4C,
Bz); 97.9 (C1¢a, JC1¢-H1¢: 176.2 Hz); 73.7, 72.1 (CH); 71.7, 70.6, 70.3,
70.1, 69.9, 69.8, 66.1, 62.5 and 62.2 (10CH and 1CH2); 21.1, 21.0,
21.0 and 20.9 (4CH3). FAB HRMS calcd. for C48H46O19+Na+:
949.2531, found: 949.2524.
129.3–128.0 (40CH, Bn); 95.4 (C1¢a, JC1¢-H1¢: 171.5 Hz); 83.1 (CH);
81.2 (CH); 80.9 (CH); 80.9 (CH); 77.1 (CH); 77.1 (CH); 76.6
(CH2); 76.4 (CH2); 76.2 (CH); 76.1 (CH); 75.7 (CH2); 74.4 (CH2);
73.9 (CH2); 73.9 (CH2); 73.8 (CH2); 73.4 (CH); 73.2 (CH2); 70.1
(CH2) and 67.7 (CH). Elemental analysis calcd. for C68H70O11: C,
76.81% and H, 6.63%; found: C, 76.64% and H, 6.32%. Data of
acetylated 8aa : 1H NMR (500 MHz, C6D6): d = 5.82 (bt, 1H, J=
2,3,4,6-Tetra-O-acetyl-D-manopyranosyl-a(1→2)-3,4,5,6-tetra-
O-benzyl-D-chiro-inositol (8da). This pseudodisaccharide 8da
(48 mg, 45%) was prepared from donor 3d (60 mg, 0.121 mmol)
and acceptor 2a (66 mg, 0.121 mmol) as described in the general
method, adding 0.08 equiv. (96 ml of a solution 0.1 M) of TMSOTf
3.8 Hz, H1). Data of 9aa: [a]D -3.7 (c = 0.3, CHCl3), 1H NMR
20
(500 MHz, C6D6): d = 7.55–7.10 (m, 40H, 8Bn); 5.19–4.36 (16H,
8 AB systems); 4.64 (m, 1H, H1); 4.41 (t, 1H, J= 9.6 Hz, H4);
4.35 (m, 1H, H1¢); 4.29 (dd, 1H, J= 9.7 and 3.2 Hz, H5); 4.23 (dd,
1H, J= 9.7 and 3.0 Hz, H2); 4.19 (bt, 1H, J= 3.3 Hz, H6); 4.13 (t,
1H, J= 9.7 Hz, H3); 4.11 (t, 1H, J= 9.7 Hz, H4¢); 3.77 (d, 1H, J=
4.1 Hz, H2¢); 3.71 (m, 2H, H6¢a and H6¢b); 3.29–3.26 (m, 2H, H3¢ and
H5¢). 13C NMR (125 MHz, C6D6): d = 140.8, 140.6, 140.2, 140.1,
139.9, 139.8, 139.7 and 138.3 (8C, Bn); 129.4–127.8 (40CH, Bn);
103.5 (C1¢); 83.4 (CH); 83.3, 83.2, 82.7, 81.3, 77.8, 76.3, 76.3, 76.2,
76.1, 75.6, 75.6, 75.4, 74.3, 74.0, 73.7, 72.3, 70.5 and 70.4 (10CH
and 9CH2). Elemental analysis calcd. for C68H70O11: C, 76.81%
and H, 6.63%; found: C, 76.70% and H, 6.44%. Data of 10aa:
◦
at -40 C in dry ether (1.7 ml) and stirring the reaction mixture
for 1 h at -40 ◦C. The crude was purified by flash chromatography
(Hexane/EtOAc 2:1) recovering 35 mg of acceptor 2a (52%).
[a]D +32.2 (c = 2.1, CHCl3). 1H NMR (500 MHz, CDCl3): d =
20
7.35–7.20 (m, 20H, 4Bn); 5.26 (dd, 1H, J= 9.7 and 3.1 Hz, H2¢);
5.25–5.20 (m, 1H, H3¢); 5.22 (t, 1H, J= 9.7 Hz, H4¢); 5.03–4.58
(8H, 4 AB systems); 4.89 (s, 1H, H1¢); 4.22 (m, 1H, H5¢); 4.09–4.05
(m, 1H, H2 and H1); 3.97 (t, 1H, J= 9.7 Hz, H4); 3.95 (m, 1H,
H6); 3.93 (dd, 1H, J= 9.7 and 2.6 Hz, H5); 3.87 (dd, 1H, J=
12.6 and 4.2 Hz, H6¢a); 3.82 (dd, 1H, J= 12.5 and 2.2 Hz, H6¢b);
3.79 (t, 1H, J= 9.6 Hz, H3); 2.50 (s, 1H, C1OH); 2.15, 2.00, 1.98
and 1.85 (4 s, 12H, 4CH3). 13C NMR (125 MHz, CDCl3): d =
170.9, 170.6, 170.4 and 169.8 (4OCOCH3); 138.9, 138.8, 138.8
and 138.5 (4C, Bn); 128.9–127.5 (20CH, Bn); 94.2 (C1¢); 82.2,
80.4, 80.0, 76.1, 75.8, 75.8, 75.7, 74.0, 73.6, 69.9, 69.6, 68.7,
66.4, 65.6 and 61.9 (11 CH and 5CH2); 21.2, 21.0, 20.9 and
20.9 (4CH3). Elemental analysis calcd. for C48H54O15+H2O: C,
64.85% and H, 6.34%; found: C, 65.10% and H, 6.58%. Data of
[a]D +44.9 (c = 0.5, CHCl3), 1H NMR (500 MHz, CDCl3):
20
d = 7.35–7.20 (m, 40H, 8Bn); 4.90–4.43 (16H, 8 AB systems);
4.64 (s, 1H, H1¢); 4.00 (m, 1H, H5¢); 3.98 (t, 1H, J= 3.6 Hz, H1);
3.92–3.88 (m, 2H, H2 and H4¢); 3.87 (t, 1H, J= 9.3 Hz, H4); 3.71
(dd, 1H, J= 8.8 and 2.6 Hz, H3¢); 3.66 (dd, 1H, J= 10.6 and
5.1 Hz, H6¢a); 3.62 (dd, 1H, J= 10.6 and 2.1 Hz, H6¢b); 3.56 (t,
1H, J= 3.1 Hz, H6); 3.54 (dd, 1H, J= 9.4 and 3.0 Hz, H5); 3.48
(t, 1H, J= 9.3 Hz, H3); 3.43 (t, 1H, J= 2.6 Hz, H2¢) and 2.50
(s, 1H, C2OH). 13C NMR (125 MHz, CDCl3): d = 139.2, 139.1,
138.8, 138.6, 138.5, 138.5, 138.3 and 137.9 (8C, Bn); 128.8–127.7
(40CH, Bn); 98.5 (C1¢); 82.6 (CH); 82.0 (CH); 80.4 (CH); 79.6
(CH); 76.5 (CH); 76.1 (CH2); 75.8 (CH); 75.7 (CH2); 75.3 (CH2);
75.2 (CH); 74.4 (CH); 73.6 (CH2); 73.5 (CH2); 73.4 (CH2); 73.3
(CH2); 73.0 (CH2); 72.5 (CH); 70.8 (CH) and 69.4 (CH2). HSQC
(500 MHz, C6D6): C1¢a, JC1¢-H1¢: 170.2 Hz. Elemental analysis calcd.
for C68H70O11: C, 76.81% and H, 6.63%; found: C, 76.98% and
H, 6.78%.
1
acetylated 8da: H NMR (500 MHz, CDCl3): d = 5.29 (bt, 1H,
J= 2.8 Hz, H1).
Acknowledgements
This research was supported by the Direccio´n General de Investi-
gacio´n Cient´ıfica y Te´cnica (Grant BQU 2002–03734). A generous
allocation of computer time at the Centro de Computacio´n
Cient´ıfica de la UAM is also acknowledged as well as Prof. Jose
Luis Garc´ıa Ruano and Dr Nicole Frost for helpful discussions.
2,3,4,6-Tetra-O-acetyl-D-manopyranosyl-a(1→2)-3,4,5,6-tetra-
O-benzoyl-D-chiro-inositol (8dd). This pseudodisaccharide 8dd
(13 mg, 28%) was prepared from donor 3d (33 mg, 0.067 mmol)
and acceptor 2d (40 mg, 0.067 mmol) as described in the general
method, adding 0.1 equiv. (67 ml of a solution 0.1 M) of TMSOTf
Notes and references
1 (a) R. A. Dwek, Chem Rev., 1996, 96, 683–720; (b) A. Varki,
Glycobiology, 1993, 3, 97–130; (c) Carbohydrates in Chemistry and
Biology; B. Ernst, G. W. Hart, P. Sinay¨, Eds.; Wiley-VCH, Weinheim,
2000, Vols. 1-4. (d) D. B. Werz, H. Seeberger, Chem.–Eur., J. 2005, 11,
3194–3206.
2 (a) B. Fraser-Reid, Z. F. Wu, C. W. Andrews, E. Skowronski and J.
P. Bowen, J. Am. Chem. Soc., 1991, 113, 1434–5; (b) N. L. Douglas,
S. V. Ley, U. Lu¨cking and S. L. Warriner, J. Chem. Soc., Perkin
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Wischnat, T. Baasov and C. H. Wong, J. Am. Chem. Soc., 1999, 121,
734.
3 (a) See, for example: T. K. Ritter, K.-K. T. Mong, H. Liu, T. Nakatani
and C.-H. Wong, Angew. Chem., Int. Ed. Engl., 2003, 42, 5221–5224 and
references cited therein. For a review of one-pot glycosylation reactions,
see: K. M. Koeller and C. H. Wong, Chem. Rev., 2000, 100, 4465–
4493.
◦
at -40 C in dry ether (1.7 ml) and stirring the reaction mixture
for 1 h at -40 ◦C. The crude was purified by flash chromatography
(Hexane/EtOAc 3:1→1:1) recovering 18 mg of acceptor 2d.
(45%). [a]D +56.4 (c = 0.6, CHCl3). 1H NMR (500 MHz,
20
CDCl3): d = 8.05–7.80 (4 H ortho, 8H); 7.63-7.23 (m, 12H, 4Bz);
6.12 (t, 1H, J= 10.1 Hz, H3); 5.93 (t, 1H, J= 3.5 Hz, H5); 5.76
(m, 2H, H4 and H2); 5.68 (d, 1H, J= 2.2 Hz, H1¢); 5.39 (dd, 1H,
J= 9.9 and 4.2 Hz, H3¢); 5.28 (t, 1H, J= 9.9 Hz, H4¢); 4.96 (dd,
1H, J= 4.0 and 2.4 Hz, H2¢); 4.38 (t, 1H, J= 3.7 Hz, H6); 4.25
(dd, 1H, J= 12.1 and 4.9 Hz, H6¢a); 4.21 (ddd, 1H, J= 13.5, 10.3
This journal is
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4 (a) Handbook of Chemical Glycosylation: Advances in Stereoselectivity
and Therapeutic RelevanceA. V. Demchenko, Ed.; Wiley-VCH, New
York, 2008; (b) A. V. Demchenko, Synlett, 2003, 1225 and references
therein.
S. V. Ley, in Protecting Groups: Effects on Reactivity, Glycosylation
Stereoselectivity, and Coupling Efficiency. Carbohydrates in Chemistry
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Vol 1, pp 427–448.
5 (a) B. Fraser-Reid, J. C. Lo´pez, A. M. Go´mez and C. Uriel, Eur. J. Org.
Chem., 2004, 1387 and references therein; (b) C. Uriel, A. M. Go´mez,
J. C. Lo´pez and B. Fraser-Reid, J. of Carbohydr. Chem., 2005, 24, 665;
(c) C. Uriel, A. Agocs, A. M. Go´mez, J. C. Lo´pez and B. Fraser-Reid,
Org. Lett., 2005, 7, 4899; (d) J. C. Lo´pez, A. Agocs, C. Uriel, A. M.
Go´mez and B. Fraser-Reid, Chem. Commun., 2005, 5088; (e) B. Fraser-
Reid, J. C. Lopez, K. V. Radhakrishnan, M. Mach, M. U. Schlueter,
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Jayaprakash, S. R. Chaudhuri, C. V. S. R. Murty and B. Fraser-Reid,
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6 (a) P. R. Muddasani, E. Bozo´, B. Bernet and A. Vasella, Helv. Chem.
Act., 1994, 77, 257; (b) P. R. Muddasani, B. Bernet and A. Vasella,
Helv. Chem. Act., 1994, 77, 334. However, according to the following
reference: R. A. Klein, J. Comput. Chem., 2003, 24, 1120, IR or
NMR spectroscopic shifts are not necessarily sufficient to diagnose
the unequivocal presence or even to be indicative of hydrogen bonding.
7 (a) H. Paulsen, in: Selectivity a Goal for Synthetic Efficiency, W.
Bartmann, B. M. Trost,. Eds. 1984, chapter 1; (b) H. Paulsen, Angew.
Chem., Int. Ed., 1982, 21, 155–177.
15 Trichloroacetimidates 3a and 3d were prepared as described in: R.
R. Schmidt, J. Michel and M. Roos, Liebigs Ann. Chem., 1984, 7,
1343.
16 Nevertheless the reaction of the same donor III with the benzylated
derivative 1a gave a mixture of pseudotrisaccharides and the b(1–3)
pseudodisaccharide (unpublished result).
17 (a) C. Lee, W. Yang and R. G. Parr, Phys. Rev. B, 1988, 37, 785; (b) A.
D. Becke, J. Chem. Phys., 1993, 98, 1372.
18 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C.
Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci,
M. Cossi , G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M.
Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E.
Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi,
C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth,
P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D.
Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K.
Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S.
Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz,
I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y.
Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez and J. A. Pople, Gaussian 03, Revision
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8 (a) M. B. Cid, I. Alonso, F. Alfonso, J. B. Bonilla, J. Lo´pez-Prados
and M. Mart´ın-Lomas, Eur. J. Org. Chem., 2006, 3947; (b) M. B. Cid,
S. Valverde, J. C. Lo´pez, A. M. Go´mez and M. Garc´ıa, Synlett, 2005,
1095.
9 According to the reasoning of Fraser-Reid and co-workers, orthoester
derivatives are the most reactive ones, on the basis of their rate of
hydrolysis, although usually participate in more regioselective processes
than armed donors. Therefore they consider that there is no apparent
correlation between reactivity and selectivity (see ref 5a). However, in
a glycosylation reaction, it must be taken into account that the rate
and regioselectivity-determining step has to be the glycosidic bond
formation, in which both donor and acceptor participate because
otherwise regioselectivity would never be observed. Moreover, accord-
ing to calculations in ref 5a, orthoesters and disarmed donors afford
more stable intermediates that probably in turn form more stable
complexes with the acceptor allowing a higher differentiation in the
activation barrier during the glycosidic bond formation and a higher
degree of regioselectivity.
10 (a) N. Khiar, M. Mart´ın-Lomas, in Carbohydrate Mimics. Concepts
and Methods (Ed. Y. Chapleur,), Wiley VCH, 1998, pp 433–462 and
references cited therein; (b) H. Dietrich, J. F. Espinosa, J. L. Chiara,
J. Jime´nez-Barbero, Y. Leo´n, I. Varela-Nieto, J. M. Mato, F. H. Cano,
C. Foces-Foces and M. Mart´ın-Lomas, Chem.–Eur. J., 1999, 5, 320;
(c) M. Mart´ın-Lomas, M. Flores-Mosquera and J. L. Chiara, Eur. J.
Org. Chem., 2000, 1547–1561; (d) N.-C. Reichardt and M. Mart´ın-
Lomas, Angew. Chem., Int. Ed., 2003, 40, 4674; (e) M. Mart´ın-Lomas,
N. Khiar, S. Garcia, J. L. Koessler, P. M. Nieto and T. W. Rademacher,
Chem.–Eur. J., 2000, 6, 3608.
19 (a) The 6-31+G(d,p) basis set was used for all of the atoms: P. C.
Hariharan and J. A. Pople, Theor. Chim. Acta, 1973, 28, 213; (b) M.
M. Francl, W. J. Petro, W. J. Hehre, J. S. Binkley, M. S. Gordon, D. J.
DeFrees and J. A. Pople, J. Chem. Phys., 1982, 77, 3654; (c) T. Clark, J.
Chandrasekhar, G. W. Spitznagel and P. v. R. Schleyer, J. Comp. Chem.,
1983, 4, 294. Harmonic frequencies were calculated at the same level
of theory to characterize the stationary points and to determine the
zero-point energies (ZPE).
20 Structure D is the most stable conformation found for the acetylated
model. In the case of the methoxylated model, another structure (A¢
see ESI†) in which one of the H3CO ◊ ◊ ◊ H–O has been replaced by
a hydrogen bond O–H ◊ ◊ ◊ O between both OH groups along with a
OCH2–H ◊ ◊ ◊ O bond resulted in being about 2 kcal mol-1 more stable
than A. However, structure A has been chosen in this study in order to
simultaneously assess the activating ability of each adjacent group and
for comparative purposes with D. Besides, according to our previous
work (ref. 8a), with structures such as A during the glycosidic bond
formation, the other OH group could participate in the formation of
additional hydrogen bonds between the donor and the acceptor in the
transition state.
21 (a) A. E. Reed, L. A. Curtiss and F. Weinhold, Chem. Rev., 1988, 88,
899; (b) A. E. Reed, R. B. Weinstock and F. Weinhold, J. Chem. Phys.,
1985, 83, 735.
11 (a) M. B. Cid, J. B. Bonilla, S. Dumarcay, F. Alfonso and M. Mart´ın-
Lomas, Eur. J. Org. Chem., 2002, 881; (b) J. B. Bonilla, J. L. Mun˜oz-
Ponce, P. M. Nieto, M. B. Cid and M. Mart´ın-Lomas, Eur. J. Org.
Chem., 2002, 889; (c) M. B. Cid, J. B. Bonilla, F. Alfonso and M.
Mart´ın-Lomas, Eur. J. Org. Chem., 2003, 3505; (d) M. B. Cid, F.
Alfonso and F. M. Mart´ın-Lomas, Synlett, 2003, 1370; (e) M. B.
Cid, F. Alfonso and M. Mart´ın-Lomas, Carbohydr. Res., 2004, 339,
2303.
22 Differences in the strength of hydrogen bonds of Va and
Vb can be observed by means of
a theoretical calculation
like those indicated in Fig. 5, using the corresponding model
only with methoxy groups in adjacent positions to OH groups
(see ESI†): Va d(OHax ◊ ◊ ◊ OMe1) = 2.03; d(OHeq ◊ ◊ ◊ OHax) =
2.34; d(OHeq ◊ ◊ ◊ OMe1)
=
2.67; Wiberg bond indexes: 0.0264,
0.0133 and 0.0021 respectively; Vb d(OHeq ◊ ◊ ◊ OMe1)
=
2.39;
12 M. B. Cid, F. Alfonso and M. Mart´ın-Lomas, Synlett, 2005,
d(OHax ◊ ◊ ◊ OMe4) = 2.28; Wiberg bond indexes: 0.0089 and 0.0092
2052.
respectively.
13 M. B. Cid, F. Alfonso and M. Mart´ın-Lomas, Chem.–Eur. J., 2005, 11,
928.
23 Small differences in the strength of the hydrogen bonds of VI can be
observed in the corresponding model (see ESI†): d(OHax ◊ ◊ ◊ OMe) =
2.32; d(OHeq ◊ ◊ ◊ OMe) = 2.27; Wiberg bond indexes: 0.0087 and 0.0139
respectively.
14 The higher reactivity of acceptor 1a with respect to that of 1d
was confirmed unambiguously by a competitive glycosylation reac-
tion of both acceptors with 3,4,6-tri-O-benzyl-2-azido-2-deoxy-a-D-
glucopyranosyl-trichloroacetimidate, a donor chosen by us in other
competitive experiments under the same experimental conditions used
in Table 1.12 The higher combined yield of pseudodisaccharides from
1a (R=Bn, 49%) than that from 1d (R=Bz, 12%) demonstrates that
acceptor 1a with electron-donating substituents is more reactive than
acceptor 1d with electron-withdrawing substituents (see experimental
section for details). The influence of the electron density of the
protecting groups on the nucleophilicity of the hydroxy group of the
glycosyl acceptor had been pointed out previously; see: L. G. Green,
24 For some examples of regioselective glycosylation of 1,2-trans-
diequatorial diols in which the steric factors seems to be determinant
see: (a) U. Ellervik and U. G. Magnusson, J. Org. Chem., 1998, 63,
9314; (b) H. Dietrich, J. F. Espinosa, J. L. Chiara, J. Jimenez-Barbero,
Y. Leon, I. Varela-Nieto, J.-M. Mato, F. H. Cano, C. Foces-Foces and
M. Mart´ın-Lomas, Chem.–Eur. J., 1999, 5, 320; (c) M. L. Bohn, M. I.
Colombo, P. L. Pisano, C. A. Storz and E. A. Ru´veda, Carbohydr. Res.,
2007, 342, 2522; (d) B. Mukhopadhyay, S. V. Maurer, R. M. Rudolph,
Nadine, van Well, D. A. Russell and R. A. Field, J. Org. Chem., 2005,
70, 9059.
1480 | Org. Biomol. Chem., 2009, 7, 1471–1481
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©

View Article Online
25 B. Fraser-Reid, G. N. Anikumar, L. G. Nair, K. V. Radhakrishnan, J.
C. Lo´pez, A. M. Go´mez and C. Uriel, Aus. J. Chem., 2002, 55, 123.
26 (a) R. Ojeda, J. L. de Paz, M. Mart´ın-Lomas and J. M. Lassaletta,
Synlett, 1999, 1316; (b) H. N. Yu, J. Furukawa, T. Ikeda and C. Wong,
Org. Lett., 2004, 6, 723.
27 (a) An interesting special regioselective glycosylation in lactose deriva-
tives has been described: H. Paulsen and M. Paal, Carbohydrate Res.,
1985, 137, 39–62; (b) H. Paulsen and K. M. Steiger, Carbohydrate
Res., 1987, 169, 105–25; (c) H. Paulsen, D. Hadamczyk, W. Kutschker
and A. Buensch, Liebigs Ann. Chem., 1985, 1, 129–41. In this case
the regioselectivity (3-OH versus 4-OH) can be inverted depending
on the reaction conditions (homogeneous or heterogeneous) and as
a consequence it is difficult to rationalize and compare. Paulsen
pointed out that the reactivity of the glycosyl donor, acceptor, and
catalyst had to be properly matched for successful regioselective
coupling.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 1471–1481 | 1481
©