Methyl 1,2-orthoesters as useful glycosyl donors in glycosylation reactions: A comparison with n-pent-4-enyl 1,2-orthoesters

Article abstract of DOI:10.1002/ejoc.201200089

Mannopyranose-derived methyl 1,2-orthoacetates (R = Me) and -benzoates (R = Ph) can function as glycosyl donors - upon BF₃·Et ₂O activation in CH₂Cl₂ - in glycosylation reactions with monosaccharide acceptors to afford disaccharides in good yields. In the process, glycosylation is preferred to acid-catalyzed rearrangement leading to methyl mannopyranosides. Methyl 1,2-orthoesters can be also used in regioselective glycosylation protocols with monosaccharide diols, in which they display good regioselectivity. Copyright

Full text of DOI:10.1002/ejoc.201200089

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FULL PAPER
DOI: 10.1002/ejoc.201200089
Methyl 1,2-Orthoesters as Useful Glycosyl Donors in Glycosylation Reactions:
A Comparison with n-Pent-4-enyl 1,2-Orthoesters
Clara Uriel,[a] Juan Ventura,[a] Ana M. Gómez,[a] J. Cristóbal López,*[a] and
Bert Fraser-Reid*[b]
Dedicated to Professor Dr. Serafín Valverde (IQOG-CSIC) on the occasion of his retirement
Keywords: Carbohydrates / Glycosylation / Glycosyl donors / Regioselectivity
Mannopyranose-derived methyl 1,2-orthoacetates (R = Me)
and -benzoates (R = Ph) can function as glycosyl donors –
upon BF3·Et2O activation in CH2Cl2 – in glycosylation reac-
tions with monosaccharide acceptors to afford disaccharides
in good yields. In the process, glycosylation is preferred to
acid-catalyzed rearrangement leading to methyl mannopyr-
anosides. Methyl 1,2-orthoesters can be also used in regiose-
lective glycosylation protocols with monosaccharide diols, in
which they display good regioselectivity.
tered by Emil Fischer and co-workers in 1920,[20] although
it required 10 years before the then unusual structure was
elucidated independently by Freudenberg,[21] Braun,[22]
Haworth,[23] and their co-workers. The structural assign-
ment was facilitated by observation of the acid-catalyzed
rearrangement 1Ǟ2 (Scheme 1, a), in which the alkoxy resi-
due was transferred from the orthoester to the anomeric
center. This stereoselective process indicated that orthoes-
ters such as 1 could function as glycosyl donors, and this
feature played a seminal role in Isbell’s discovery of neigh-
boring-group participation.[24,25]
Introduction
The biological importance of oligosaccharides and glyco-
conjugates is now generally recognized.[1] Most carbo-
hydrates found in nature exist as polysaccharides, glycocon-
jugates, or glycosides, in which sugar units are attached to
one another or to aglycons through O-glycosidic bonds.[2]
The stereoselective formation of O-glycosidic bonds is
therefore the key process in most glycoside syntheses.[3]
Over the years a variety of methods for the construction
of interglycosidic bonds have been introduced. The most
popular glycosylation donors include glycosyl trichloroacet-
imidates,[4] fluorides,[5] and sulfoxides,[6] as well as n-pent-
4-enyl glycosides[7] and thioglycosides.[8] As well as these
established donors, a variety of additional glycosyl donors
have also been used in glycosylation protocols; examples
include glycosyl bromides,[9] glycals,[10] glycosyl phos-
phates,[11] glycosyl phosphites,[12] glycosyl iodides,[13] thi-
azolyl thioglycosides,[14] benzoxazolyl thioglycosides,[15] 2Ј-
carboxybenzyl (CB) glycosides,[16] glycosyl pent-4-en-
oates,[17] glycosyl benzyl and aryl phthalates,[18] and glyc-
osyl ortho-alkynylbenzoates.[19]
Our research groups have recently been interested in the
use of glycosyl 1,2-orthoesters as glycosyl donors. Glycosyl
1,2-orthoesters, such as 1 (Scheme 1), were first encoun-
Scheme 1. Transformations involving alkyl 1,2-orthoesters.
[a] Instituto de Química Orgánica General, IQOG-CSIC,
Juan de la Cierva 3, 28006 Madrid, Spain
E-mail: jc.lopez@csic.es
In spite of this promising beginning, the use of 1,2-or-
thoesters as glycosyl donors was impeded by the process
summarized in Scheme 1 (b). Under acid catalysis condi-
tions, the departing alkoxy entity (OR) competed with the
intended acceptor (R2OH) for the anomeric center, re-
sulting in a mixture of glycosides 2 and 3.
[b] Natural Products and Glycotechnology Research Institute Inc.
(NPG),
595F Weathersfield Road, Pittsboro, NC 27312, USA
E-mail: Dglucose@aol.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200089.
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Extensive studies by Kotchetkov and co-workers directed
The data in Scheme 2 showed that the self-coupling ten-
towards overcoming this dilemma by modifying the ortho- dency was greater with orthoacetates than with the corre-
ester leaving group did not solve the fundamental prob- sponding orthobenzoates. It was thus of interest to see
lem.[26,27] However the results were instructive, and led to whether or not this tendency could be reduced so that
much innovative chemistry.[28]
methyl orthoacetates could serve as glycosyl donors in acid-
Fraser-Reid and co-workers introduced n-pent-4-enyl or- catalyzed reactions without the intrusion of self-condensa-
thoesters (NPOEs, 1, R = n-pent-4-enyl)[29] as useful glyc- tion or acid-catalyzed rearrangement. Along these lines, we
osyl donors, the success of which is based on activation by reasoned that the presence of external nucleophiles in the
halonium ion in a process in which the liberated pent-4- reaction media could lead to different glycosyl coupling de-
enyloxy moiety is trapped as a non-nucleophilic 2-(halo- rivatives.
methyl)tetrahydrofuran.[30,31] The intended glycosyl ac-
ceptor therefore faces no significant competition.
In this work we have evaluated the potential of methyl
1,2-orthoesters (MeOEs) as glycosyl donors with monosac-
On the other hand, the acid-catalyzed rearrangement charide alcohols as nucleophiles, and disclose here that
1Ǟ2 is a well-known process that has been successfully ap- MeOEs can be used as glycosyl donors and that they dis-
plied to the preparation of trans-(1–2) glycosides.[32] Indeed play good regioselectivities in glycosylation reactions with
in our groups the method of choice for preparing n-pent-4- diol-acceptors leading to disaccharides.
enyl glycosides (e.g., 2, R = n-pent-4-enyl) requires prepara-
tion and rearrangement of the corresponding NPOEs (e.g.,
1, R = n-pent-4-enyl).[33]
Results and Discussion
In light of these precedents, we were surprised by the
exceptional course of the reaction shown in Scheme 2.[34]
The methyl mannopyranose orthoacetate 4a, upon treat-
Glycosylation of Monosaccharide Acceptors with MeOEs
Initial glycosylation experiments were performed with
ment with BF3·Et2O, gave 1α,1Јβ-disaccharide 6a (R = MeOE 4a (Table 1, 2.0 equiv.) and benzyl glycoside 8 in the
CH3) with minor amounts of the expected methyl manno- presence of different acid promotors. The use of
[35]
pyranose 7a (R = CH3). The corresponding orthobenzoate Yb(OTf)3
(0 °C, 30 min) resulted in the formation of
4b behaved similarly, although the proportions of products mixed orthoester 9 (99% yield), whereas extended reaction
6b and 7b were very different.
times (12 h) led to reduced yields of rearranged disaccha-
rides 10a and 11, as well as hydrolysis and rearrangement
products arising from 4a (Table 1, Entries i and ii, respec-
tively). When TMSOTf was used as the promoter, 2Ј-O-tri-
methylsilyl disaccharide 12 was obtained (80% yield,
Table 1, Entry iii).[36] Finally, the use of pTsOH did not
yield any disaccharide 10a and resulted in the formation of
hemiacetal 13 (Table 1, Entry iv).
In line with our previous observations,[34] BF3·Et2O
proved to be the best acid promoter for employment in
glycosylation reactions with MeOEs (see Table 2). In this
context, the results obtained in a study directed towards
optimization of the amounts of BF3·Et2O, together with the
MeOE/glycosyl acceptor ratios in these glycosylation reac-
tions, are displayed in Table 2. According to these, the best
results in the glycosylation of benzyl glucopyranoside 8
with MeOEs 4a and 4b were obtained with the use of an
excess of BF3·Et2O (3.0 equiv.) when compared with the use
of catalytic amounts of acid (0.05 equiv.) (Table 2, compare
Entry i with Entries ii and iii and Entries iv and v with En-
tries vi and vii). On the other hand, the use of 2 equiv. of
MeOE proved to be beneficial in increasing the observed
yield of disaccharide 10, when compared with the use of
Scheme 2. An “unusual” reaction pathway for methyl orthoesters.
Clearly, self-coupling of two molecules of 4 had oc- equimolar amounts of MeOE (Table 2, compare Entries ii
curred, and the α/β orientations of compounds 6 provided and iii and Entries iv and v). From the data in Table 2, it
vital mechanistic clues. The α-oriented anomeric centers in also seems that methyl orthobenzoate 4b gave slightly better
compounds 6 indicated that the manno orthoesters 4 func- yields of disaccharide 10 than orthoacetate 4a (compare
tioned as glycosyl donors. In contrast, the β-orientations in Entry i in Table 2 with Entry iv, Entry ii with Entry vi, and
compounds 6 implied that the C1–O1 bonds in precursors Entry iii with Entry vii). Comparison of Entries vi and vii
4 had been preserved during the coupling. One equivalent in Table 2 shows that a twofold excess of MeOE 4b might
of a compound 4 thus served as the donor, whereas another be obviated when highly reactive glycosyl acceptors are
equivalent served as the acceptor.
glycosylated.
2
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Methyl 1,2-Orthoesters as Donors in Glycosylation Reactions
Table 1. Glycosylation of benzyl glucoside 8 with MeOE 4a in the
presence of different acid promotors.
Table 2. Glycosylation of benzyl glucoside 8 with MeOEs 4a and
4b.
[a] Complex reaction mixture. [b] Other minor compounds were
also isolated; see Exp. Sect. for details.
Table 3. Glycosylation of diacetone glucose 14 with MeOEs 4a and
4b.
[a] Other minor compounds were isolated, see Exp. Sect. for details.
Glycosyl coupling of secondary hydroxy groups, repre-
sented by diacetone glucose 14 (Table 3), worked relatively
well with orthobenzoate 4b to give disaccharide 15b
(Table 3, Entries ii and iii), but failed when orthoacetate 4a
was used as the glycosyl donor (Table 3, Entry i). In these
examples, the use of a twofold excess of MeOE 4b resulted
in a moderate yield increase from 53 to 70% in the forma-
tion of 15b (Table 3, Entries ii, iii).
[a] Complex reaction mixture. [b] Other minor compounds were
isolated; see Exp. Sect. for details.
To complete this study, we selected glycosyl acceptors charides 20 to 23 than orthoacetate 4a (see Entries i
16–19 (Table 4) and treated them with MeOEs 4a or 4b through viii, Table 4), although we do not at present have
(2.0 equiv.) in CH2Cl2 at –30 °C in the presence of an explanation to account for these results.
BF3·Et2O (3.0 equiv.) to give disaccharides 20–23.
The observed glycosylation byproducts arose from the
Under these reaction conditions, good to excellent yields orthoester employed (2.0 equiv.) and in the case of glycos-
of disaccharides were obtained (Entries i–viii, Table 4). A ylations with 4b included variable amounts of the corre-
low yield of disaccharide 23a was observed in the reaction sponding methyl mannopyranoside 7b (12–28%, relative to
between 4a and tribenzoyl derivative 19 (Entry vii, Table 4). MeOE), most likely arising from acid rearrangement of the
In keeping with our previous observations, methyl ortho- excess MeOE employed. Small amounts of 1α,1Јβ-disac-
benzoate 4b consistently gave slightly better yields of disac- charides could also be observed.[37]
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Table 4. Glycosylation of monosaccharides 16–19 with MeOEs 4a charides was obtained (31, 35%), along with traces of tri-
and 4b.
saccharide 32 (3%). Again, improved regioselective forma-
tion of the major product 31 was observed when the reac-
tion was repeated at –50 °C (Table 5, Entry v), with both
products being obtained in better yields (41% and 5%,
respectively). With the NPOE 24 (Table 5, Entry vi) prefer-
ential glycosylation at the primary 6-OH group gave 31 as
the only disaccharide, and with no evidence of the trisac-
charide 32.[39]
Three experiments designed to evaluate the influence of
the iodonium ion on the regioselective glycosylation of diol
26 with NPOE 24 were then devised. In the first two experi-
ments (Table 5, Entries vii, viii) the amount of NIS used
earlier (Entry vi) was reduced to 1.0 equiv., whereas in the
third experiment, NIS was omitted altogether (Table 5, En-
try ix).
Comparison of Entries viii and ix make it clear that
iodonium ion has a salutary effect on regioselective glyc-
osylation. The yield of disaccharide 31 in the purely acid-
catalyzed process (Entry ix) was raised from 40% in En-
try ix to 50% in Entry viii by addition of one equivalent
of iodonium. The effectiveness of iodonium vis-à-vis acid
catalysis was further emphasized by comparing the results
in Entries vii and viii. Substantial reduction of the
BF3·Et2O concentration caused the formation of 31 to in-
crease from 50% to 65%. The last result emphasizes the
catalytic role that Lewis acids have on NIS in the pro-
duction of iodonium ion.
Finally, glycosylation of diol 27 with 4b at either –30 or
–50 °C (Table 5, Entries x and xi) led to a single disaccha-
ride 33 (49% and 50%, respectively) resulting from glyc-
osylation of the primary OH group. Similar behavior
towards diol 27 had also been observed for NPOE 24
(Table 5, Entry xii).[39]
[a] Other minor compounds were also isolated; see Exp. Sect. for
details.
Glycosylation of Monosaccharide Diol Acceptors with
MeOEs – A Comparative Regioselectivity Study
A Proposed Explanation for the Regioselective
Discrimination of MeOEs versus NPOEs
As a continuation of our interest in the study of regiose-
lective glycosylation strategies,[38] we examined the behavior
of methyl orthobenzoate 4b towards monosaccharides 25–
Our explanation for the differences in regioselectivity dis-
27, containing primary/secondary diol pairs. The results ob- played by MeOEs and NPOEs is based on the assumption
tained are displayed in Table 5, in which previous data from of differences in the activation of NPOEs and MeOEs, as
glycosylations of the same monosaccharide-diols with illustrated in Scheme 3. NPOEs are remotely activated with
NPOE 24[39] have also been included for purposes of com- iodonium ion and activity is transmitted to the OR residue
parison.
(R = n-pent-4-enyl), as in furanylium ion 34, which gives
Treatment of glucose-derived diol 25 with 4b at –30 °C rise to dioxolenium ion 35.[40] On the other hand, we postu-
(Table 5, Entry i) led to a mixture of the two possible disac- late that acid activation of MeOEs with BF3·Et2O takes
charides 28 (32%) and 29 (9%), as well as the doubly glyc- place preferentially at the glycosyl oxygen (O-1) leading to
osylated trisaccharide product 30 (13%). When the reaction 36 and thence 37. In the latter, the alkoxy moiety (R =
was repeated at –50 °C, slightly better regioselectivity was methyl) is still connected to the remains of the donor spe-
observed, with disaccharide 28 being obtained in higher cies (i.e., 37, Scheme 3). These two cationic intermediates,
yield (Table 5, Entry ii). With the NPOE 24 (Table 5, En- 35 and 37, might then display different regioselectivities
try iii) preferential glycosylation at the primary 6-OH group towards the hydroxy groups of the acceptor, with the diox-
gave 28 as the only disaccharide, albeit with some trisaccha- olenium ion 35 being more regiochemically demanding.[41]
ride 30.
Indeed, some of the experiments displayed in Table 5 were
Glycosylation of the analogous manno diol 26 with designed to evaluate this hypothesis: glycosylation of diol
MeOE 4b, at –30 °C, gave significantly different results 26 with NPOE 24, upon iodonium activation, thus led ex-
(Table 5, Entry iv). Only one of the two possible disac- clusively to disaccharide 31 (64%, Table 5, Entry vi).
4
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Methyl 1,2-Orthoesters as Donors in Glycosylation Reactions
Table 5. Regioselective glycosylation of diols 25–27 with methyl orthobenzoate 4b and with n-pent-4-enyl orthoester 24 in CH2Cl2.
try ix) of 31 (40%) and 32 (6%). Most notably, this product
distribution was also obtained on BF3·Et2O-mediated glyc-
osylation of diol 26 with MeOE 4b [31 (41%), 32 (5%),
Table 5, Entry v].
Conclusions
In summary, mannose-derived methyl 1,2-orthoacetates
and -orthobenzoates are useful glycosyl donors in glycosid-
ation protocols on activation with BF3·Et2O. The reaction
works better with stoichiometric amounts of BF3·Et2O (two
or three equivalents could be used without significant dif-
Scheme 3. Proposed reaction intermediates from NPOEs (1 R = n-
pent-4-enyl) and MeOEs (1, R = Me) upon activation with NIS/
BF3·Et2O (iodonium ion) or BF3·Et2O.
ference), and use of a twofold excess of a MeOE normally
results in increased disaccharide yields. MeOEs could also
be used in regioselective glycosyl couplings with regioselec-
tivity sometimes similar to that displayed by NPOEs. An
Upon BF3·Et2O activation (no NIS present), however, explanation for these observations has been advanced, in
these reactants gave a product distribution (Table 5, En- which different cationic species arising from MeOEs (acti-
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(ϫ2), 127.7 (ϫ2), 129.1 (ϫ2), 129.6, 131.1 (ϫ2), 135.4, 135.7
(ϫ2), 136.1 (ϫ2) ppm.
vation at O-1) and NPOEs (chemoselective remote iodon-
ium activation at the n-pent-4-enyl residue) might result in
different regiochemical preferences. Even though similar
transformations have already been carried out with NPOEs,
the use of MeOEs might have the advantage of the low cost
of methanol in relation to that of n-pent-4-enyl alcohol. Ex-
periments to test these regiochemical issues are underway
and will be reported in due course.
A sample of this material (553 mg, 1 mmol) was dissolved in THF
(20 mL), cooled to 0 °C and then treated with tetrabutylammonium
fluoride (52 mg, 2 mmol). The reaction mixture was stirred for 3 h
and then concentrated in vacuo. The residue was purified by flash
chromatography (hexane/EtOAc 6:4) to give phenyl-2,3,4-tri-O-
methyl-1-thio-α-d-mannopyranoside (18, 283 mg, 90%). [α]D
=
+156.2 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 3.48
(s, 3 H), 3.50 (m, 1 H), 3.53 (s, 3 H), 3.57 (s, 3 H), 3.77 (dd, J =
11.8, 4.6 Hz, 1 H), 3.84 (dd, J = 11.9, 2.9 Hz, 1 H), 3.85 (m, 2 H),
4.04 (m, 1 H), 5.61 (d, J = 1.3 Hz, 1 H), 7.28–7.49 (m, 5 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 57.7, 58.3, 60.7, 62.0, 73.2, 76.5,
78.8, 81.7, 85.1, 127.6, 129.1 (ϫ2), 131.7 (ϫ2), 134.1 ppm. API-
ES positive: 337.0 [M + Na]+. C15H22O5S (314.4): calcd. C 57.30,
H 7.05; found C 57.23, H 7.15.
Experimental Section
1
General Methods: H NMR and 13C NMR spectra were obtained
with solutions in CDCl3 and a 300, 400 or 500 MHz spectrometer.
Optical rotations were determined with solutions in chloroform.
Column chromatography was performed on silica gel (230–
400 mesh). TLC was conducted on precoated Kieselgel 60 F254
plates (Merck). Detection was achieved first with UV light
(254 nm) and then by charring with a solution of sulfuric acid/
acetic acid/H2O (1:20:4). All solvents were purified by standard
techniques. Reactions requiring anhydrous conditions were per-
formed under argon. Anhydrous magnesium sulfate was used to
dry solutions. Methyl orthoacetate 4a,[42] methyl orthobenzoate
4b,[42] and n-pent-4-enyl orthoester 24[33] were prepared as de-
scribed previously. Acceptors 8,[43] 19,[44] 21–22,[45] and 23[46,47]
were prepared by published procedures.
Glycosylation Reaction of Methyl Orthoester 4a in the Presence of
Different Acid Catalysts
With Yb(OTf)3: A dry mixture of the methyl orthoester 4a (50 mg,
0.138 mmol) and acceptor 8 (37.3 mg, 0.069 mmol) was dissolved
in dry CH2Cl2 (3 mLmmol–1), the solution was cooled to 0 °C, and
Yb(OTf)3 (344 mg, 0.552 mmol) was added. After 30 min all the
starting material had disappeared and the reaction mixture was
treated with Et3N (500 μL). The crude mixture was concentrated
and purified by flash chromatography (hexane/EtOAc 7:3) to yield
mixed orthoester 9 (60 mg, 99%). [α]D = –17 (c = 0.25, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 1.74 (s, 3 H), 1.98 (s, 3 H), 2.02 (s,
3 H), 2.05 (s, 3 H), 3.39 (ddd, J = 9.3, 5.2, 1.9 Hz, 1 H), 3.47 (m,
1 H), 3.51 (t, J = 9.0 Hz, 1 H), 3.57–3.66 (m, 3 H), 3.74 (dd, J =
12.0, 1.9 Hz, 1 H), 4.12 (dd, J = 15.0, 2.7 Hz, 1 H), 4.21 (dd, J =
12.2, 4.9 Hz, 1 H), 4.43–4.47 (m, 2 H), 4.59 (d, J = 10.8 Hz, 1 H),
4.63 (d, J = 11.8 Hz, 1 H), 4.68 (d, J = 10.9 Hz, 1 H), 4.74 (d, J =
10.9 Hz, 1 H), 4.81 (d, J = 10.9 Hz, 1 H), 4.88 (d, J = 9.3 Hz, 1
H), 4.89 (d, J = 2.1 Hz, 1 H), 4.92 (d, J = 9.1 Hz, 1 H), 5.09 (dd,
J = 9.9, 3.9 Hz, 1 H), 5.26 (t, J = 9.7 Hz, 1 H), 5.36 (d, J = 2.7 Hz,
1 H), 7.32–7.37 (m, 20 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
20.8 (ϫ2), 20.9, 24.7, 61.9, 62.6, 65.7, 70.5, 71.2, 71.6, 74.0, 75.0,
75.8 (ϫ2), 76.6, 77.8, 82.4, 84.8, 97.5, 102.5, 124.3, 127.7, 127.8,
127.9, 128.0 (ϫ2), 128.2 (ϫ2), 128.3 (ϫ4), 128.5 (ϫ4), 128.6 (ϫ4),
137.5, 138.4, 138.5, 138.7, 169.6, 170.4, 170.8 ppm. API-ES posi-
tive: 894.3 [M + Na]+. C48H54O15 (870.93): calcd. C 66.19, H 6.25,
O 27.56; found C 66.24, H 6.30.
Pent-4-enyl 3,4-Di-O-benzoyl-2-deoxy-2-phthalimido-β-D-glucopyr-
anoside (17): Tetrabutylammonium fluoride (52 mg, 2 mmol) was
added to a cooled (0 °C) solution of pent-4-enyl 3,4-di-O-benzoyl-
6-O-tert-butyldimethylsilyl-2-deoxy-2-phthalimido-β-d-glucopyr-
anoside[48] (700 mg, 1 mmol) in THF (20 mL). The reaction mix-
ture was stirred for 3 h and then concentrated in vacuo. The residue
was purified by flash chromatography (hexane/EtOAc 7:3) to give
pent-4-enyl 3,4-di-O-benzoyl-2-deoxy-2-phthalimido-β-d-glucopyr-
anoside (17, 498 mg, 85%). [α]D = +13.0 (c = 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 1.57 (qd, J = 13.8, 7.1 Hz, 1 H),
1.86–1.95 (m, 2 H), 3.52 (dt, J = 9.7, 6.7 Hz, 1 H), 3.75 (dd, J =
13.1, 4.8 Hz, 1 H), 3.86–3.94 (m, 3 H), 4.55 (dd, J = 10.9, 8.4 Hz,
1 H), 4.73–4.82 (m, 2 H), 5.52 (t, J = 9.5 Hz, 1 H), 5.54 (d, J =
8.4 Hz, 1 H), 5.61 (ddd, J = 16.9, 6.6, 3.7 Hz, 1 H), 6.33 (dd, J =
10.9, 9.2 Hz, 1 H), 7.25–7.96 (m, 15 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 28.6, 29.9, 55.0, 61.5, 69.4, 70.3, 71.1, 98.4, 114.9,
123.7, 128.4, 128.6, 128.7, 128.8, 129.9, 130.1, 131.5, 133.4, 133.8,
134.3, 137.8, 165.8, 166.2 ppm. API-ES positive: 608.7 [M + Na]+.
C33H31NO9 (585.6): calcd. C 67.68, H 5.34; found C 67.70, H 5.38.
In a different run, orthoester 4a (50 mg, 0.138 mmol), acceptor 8
(37.3 mg, 0.069 mmol), and Yb(OTf)3 (86 mg, 0.138 mmol) were
allowed to react at 0 °C for 12 h. The reaction mixture was then
treated with Et3N (500 μL). The crude mixture was then concen-
trated and purified by flash chromatography (hexane/EtOAc 7:3)
to yield disaccharide 10a (10 mg, 17%), disaccharide 11 (5 mg,
Ͻ10%), hemiketal 13 (16 mg, 33%) and methyl 3,4,6-tri-O-acetyl-
α-d-mannopyranose (8 mg, 18%).
Phenyl 2,3,4-Tri-O-methyl-1-thio-α-D-mannopyranoside (18): So-
dium hydride (566 mg, 23.6 mmol) was added at 0 °C to a stirred
solution of phenyl 6-O-tert-butyldiphenylsilyl-1-thio-α-d-manno-
pyranoside[49] (2 g, 3.9 mmol) in dry THF (15 mL). After 15 min,
methyl iodide (1.46 mL, 23.6 mmol) was added, the reaction mix-
ture was allowed to reach room temperature, and stirring was then
continued for 12 h. The mixture was diluted with Et2O and washed
successively with saturated aqueous NH4Cl and brine. The organic
phase was dried and concentrated, and the crude mixture was puri-
fied by flash chromatography (hexane/EtOAc 8:2) to give phenyl 6-
O-tert-butyldiphenylsilyl-2,3,4-tri-O-methyl-1-thio-α-d-mannopyr-
1
Compound 11: [α]D = +22 (c = 0.2, CHCl3). H NMR (400 MHz,
CDCl3): δ = 1.93 (s, 3 H), 2.07 (s, 3 H), 2.08 (s, 3 H), 3.47–3.51
(m, 2 H), 3.48 (dd, J = 7.9, 1.2 Hz, 1 H), 3.66 (t, J = 9.0 Hz, 1 H),
4.01 (ddd, J = 9.6, 4.4 Hz, 1 H), 4.07 (dd, J = 12.3, 2.2 Hz, 1 H),
4.21 (dd, J = 12.3, 4.4 Hz, 1 H), 4.51 (d, J = 7.8 Hz, 1 H), 4.60 (d,
J = 11.3 Hz, 1 H), 4.67 (d, J = 11.9 Hz, 1 H), 4.72 (d, J = 11.3 Hz,
1 H), 4.77 (d, J = 10.9 Hz, 1 H), 4.91–4.97 (m, 5 H), 5.29 (dd, J =
9.8, 3.0 Hz, 1 H), 5.34 (t, J = 9.8 Hz, 1 H), 7.26–7.40 (m, 20
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 20.8, 20.9, 21.1, 62.4,
66.3, 66.6, 68.4, 69.4, 71.2, 71.7, 74.3, 75.1 (ϫ2), 75.9, 78.0, 82.5,
1
anoside (1.77 g, 87%). H NMR (300 MHz, CDCl3): δ = 1.08 (s, 9
H), 3.50 (s, 3 H), 3.51–3.55 (m, 1 H), 3.56 (s, 3 H), 3.58 (s, 3 H),
3.77 (t, J = 9.4 Hz, 1 H), 3.86–3.92 (m, 1 H), 3.91 (dd, J = 3.4,
1.7 Hz, 1 H), 4.00–4.09 (m, 2 H), 5.71 (d, J = 1.2 Hz, 1 H), 7.25–
7.78 (m, 15 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.5, 26.9 84.9, 99.6, 102.4, 127.8 (ϫ2), 127.9 (ϫ2), 128.0 (ϫ4), 128.1 (ϫ2),
(ϫ3), 57.7, 57.8, 60.8, 63.3, 74.2, 76.5, 78.9, 82.0, 84.8, 127.2, 127.6
128.3 (ϫ2), 128.5 (ϫ4), 128.6 (ϫ4), 137.4, 138.1, 138.4, 138.5,
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

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/KAP1
Date: 11-04-12 17:17:19
Pages: 11
Methyl 1,2-Orthoesters as Donors in Glycosylation Reactions
169.9 (ϫ2), 170.9 ppm. API-ES positive: 846.3 [M + NH4]+, 851.3
[M + Na]+. C46H52O14 (828.89): calcd. C 66.65, H 6.32, O 27.02;
found C 66.70, H 6.38.
ane/EtOAc 7:3) afforded 10a (111 mg, 92%). [α]D = +28.7 (c = 1.0,
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.90 (s, 3 H), 1.96 (s, 3
1
H), 2.05 (s, 3 H), 2.13 (s, 3 H), 3.40–3.51 (m, 3 H), 3.64 (t, J =
8.8 Hz, 1 H), 3.73 (m, 2 H), 4.01–4.05 (m, 1 H), 4.05 (dd, J = 12.4,
2.1 Hz, 1 H), 4.20 (dd, J = 12.4, 4.9 Hz, 1 H), 4.49 (d, J = 7.8 Hz,
1 H, 1 H), 4.56 (d, J = 11.3 Hz, 1 H), 4.64 (d, J = 11.9 Hz, 1 H),
4.69 (d, J = 10.9 Hz, 1 H), 4.74 (d, J = 10.9 Hz, 1 H), 4.87 (d, J =
1.6 Hz, 1 H), 4.90 (d, J = 10.9 Hz, 1 H), 4.91 (d, J = 10.0 Hz, 1
H), 4.92 (d, J = 11.6 Hz, 1 H), 4.94 (d, J = 10.8 Hz, 1 H, 1 H),
5.26 (t, J = 10.1 Hz, 1 H), 5.28 (dd, J = 3.4, 1.8 Hz, 1 H), 5.36 (dd,
J = 10.1, 3.4 Hz, 1 H), 7.22–7.37 (m, 20 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 20.7, 20.8, 20.9, 21.0, 62.4, 66.1, 66.7, 68.6,
69.2, 69.5, 71.1, 74.1, 74.9, 75.0, 75.8, 78.0, 82.4, 84.8, 97.5, 102.3,
127.7, 127.8, 127.9 (ϫ5), 128.0 (ϫ2), 128.2 (ϫ2), 128.4 (ϫ2), 128.5
(ϫ2), 128.6 (ϫ4), 137.4, 138.0, 138.4, 138.5, 169.8, 169.9, 170.0,
170.7 ppm. API-ES positive: 888.3 [M + NH4]+. C48H54O15
(870.93): calcd. C 66.19, H 6.25, O 27.56; found C 66.23, H 6.22.
Reaction in the Presence of TMSOTf: TMSOTf (50 μL,
0.276 mmol) was added at –30 °C to a stirred solution of methyl
orthoester 4a (50 mg, 0.138 mmol) and acceptor 8 (37.3 mg,
0.069 mmol) in anhydrous CH2Cl2 (3 mL). After 1 h, the reaction
mixture was diluted with CH2Cl2 and quenched by addition of sat-
urated aqueous NaHCO3. The layers were separated, the aqueous
phase was extracted with CH2Cl2, and the combined organic layers
were washed with saturated aqueous NaCl. The resultant organic
phase was dried with Na2SO4, filtered, and concentrated.
The resulting residue was purified by silica gel flash column
chromatography (hexane/EtOAc 85:15) to yield silylated disac-
charide 12 (49 mg, 80%). 1H NMR (400 MHz, CDCl3): δ = 0.14
(s, 9 H), 1.93 (s, 6 H), 2.04 (s, 3 H), 3.42–3.55 (m, 3 H), 3.66 (t, J
= 8.9 Hz, 1 H), 3.76 (dd, J = 11.5, 2.0 Hz, 1 H), 3.81 (dd, J = 11.8,
5.1 Hz, 1 H), 3.96 (ddd, J = 9.8, 4.8, 2.6 Hz, 1 H), 4.04–4.11 (m, 2
H), 4.13 (dd, J = 12.3, 2.5 Hz, 1 H), 4.50 (d, J = 7.8 Hz, 1 H), 4.63
(d, J = 12.6 Hz, 1 H), 4.66 (d, J = 12.2 Hz, 1 H), 4.72 (d, J =
10.7 Hz, 1 H), 4.75 (d, J = 12.9 Hz, 1 H), 4.80 (d, J = 2.0 Hz, 1
H), 4.91–4.98 (m, 4 H), 5.22 (dd, J = 9.9, 3.0 Hz, 1 H), 5.33 (t, J
= 9.9 Hz, 1 H), 7.27–7.39 (m, 20 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 0.05, 20.7, 21.0, 26.8, 62.2, 65.9, 66.5, 68.8, 69.7, 70.9,
71.5, 74.4, 74.9, 75.0, 75.8, 77.8, 82.3, 84.7, 100.5, 102.3, 127.7
(ϫ2), 127.8 (ϫ2), 127.9 (ϫ4), 128.2 (ϫ2), 128.3 (ϫ2), 128.4 (ϫ4),
128.5 (ϫ4), 137.3, 138.0, 138.3, 138.4, 169.6, 170.1, 172.8 ppm.
API-ES positive: 924.3 [M + Na]+. C49H60O14Si (901.07): calcd. C
65.31, H 6.71, O 24.86, Si 3.12; found C 65.37, H 6.77.
Benzyl
6-O-(2,3,4,6-Tetra-O-benzoyl-α-
D-mannopyranosyl)-2,3,4-
tri-O-benzyl-α-D-glucopyranoside (10b): This compound was pre-
pared from orthoester 4b (122 mg, 0.20 mmol), benzyl 2,3,4-tri-O-
benzyl-β-d-glucopyranoside (8, 54 mg, 0.10 mmol) and BF3·Et2O
(71 μL, 0.60 mmol). Purification by flash chromatography (hexane/
EtOAc 8:2) afforded 10b (106.3 mg, 95%). [α]D = –19.4 (c = 1.0,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 3.49–3.60 (m, 2 H),
3.62–3.70 (m, 1 H), 3.75 (t, J = 8.9 Hz, 1 H), 3.88–3.93 (m, 1 H),
3.96 (dd, J = 10.9, 6.5 Hz, 1 H), 4.46 (dd, J = 12.1, 4.2 Hz, 1 H),
4.53–4.57 (m, 1 H), 4.63–4.85 (m, 6 H), 4.97–5.09 (m, 4 H), 5.19
(d, J = 1.6 Hz, 1 H), 5.81 (dd, J = 2.9, 1.6 Hz, 1 H), 6.01 (dd, J =
10.1, 3.2 Hz, 1 H), 6.16 (t, J = 10.1 Hz, 1 H), 7.23–7.65 (m, 30 H),
7.85–8.18 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 62.8,
67.0, 67.1, 69.1, 70.2, 70.5, 71.3, 74.2, 75.0, 75.1, 75.8, 78.2, 82.4,
84.9, 97.7, 102.4, 127.7, 127.8, 127.9 (ϫ2), 128.0 (ϫ3), 128.2 (ϫ2),
128.3 (ϫ2), 128.4 (ϫ2), 128.5 (ϫ6), 128.6 (ϫ8), 128.7 (ϫ4), 129.0,
129.3, 129.5, 129.8 (ϫ2), 129.9 (ϫ4), 130.0 (ϫ2), 130.1, 133.2,
133.3, 133.4, 133.5, 137.4, 138.1, 138.5, 138.7, 165.4, 165.5, 165.6,
Reaction in the Presence of TsOH: A solution of methyl orthoester
4a (50 mg, 0.138 mmol) and acceptor 8 (37.3 mg, 0.069 mmol) in
anhydrous CH2Cl2 (3 mL) was treated with p-toluenesulfonic acid
(47.5 mg, 0.276 mmol). After it had been stirred for 2 h at room
temp., the reaction mixture was treated with Et3N (500 μL,
3.6 mmol) and the solvent was removed under reduced pressure.
The residue was purified by flash silica gel column chromatography
(hexane/EtOAc 1:1) to afford hemiketal 13[50] (33 mg, 69%).
166.2 ppm. API-ES positive: 1141.6 [M
(1119.2): calcd. C 72.97, H 5.58, O 21.44; found C 72.98, H 5.53.
+
Na]+. C68H62O15
1,2:5,6-Di-O-isopropylidene-3-O-(2,3,4,6-tetra-O-benzoyl-α-D-man-
Glycosylation Reactions of Methyl Orthoesters 4a and 4b with
Monosaccharides 8 and 14 – Optimization of Reaction Conditions:
A dry mixture of the 1,2-orthoester 4a or 4b (number of equivalents
shown in Table 2 and Table 3) and the corresponding acceptor (8
or 14) was dissolved in dry CH2Cl2 (5 mLmmol–1), the solution
was cooled to –30 °C, and BF3·Et2O (number of equivalents shown
in Table 2 and Table 3) was added. After TLC analysis indicated
full disappearance of the starting materials, the reaction was
quenched by addition of saturated aqueous NaHCO3. The layers
were separated, the aqueous phase was extracted with CH2Cl2, and
the combined organic layers were washed with saturated aqueous
NaCl. The resultant organic phase was dried with Na2SO4, filtered,
and concentrated. The residue was purified by flash silica gel col-
umn chromatography. The yields of the corresponding pure disac-
charide always refer to the acceptor employed in each case. On the
other hand, when two equiv. of donor were used, byproducts aris-
ing from the orthoester transformation are detected in the reaction.
In some instances these byproducts were quantified and charac-
terized, and included the corresponding 1α,1Јβ-disaccharide (i.e.,
6) and methyl glycoside (i.e. 7).[34]
nopyranosyl)-α-
-glucofuranose (15b):[51] This compound was pre-
D
pared from orthoester 4b (183 mg, 0.3 mmol), 1,2:5,6-di-O-isopro-
pylidene-α-d-glucofuranose (14, 39 mg, 0.15 mmol) and BF3·Et2O
(320 μL, 0.90 mmol). Purification by flash chromatography (hex-
ane/EtOAc 7:3) afforded 15b (88 mg, 70 %), along with methyl
2,3,4,6-tetra-O-benzoyl-α-d-mannopyranoside (7b, 27 mg, 15%),
2,3,4,6-tetra-O-benzoyl-α-d-mannopyranosyl fluoride (25 mg,
0.14%), and 2,3,4,6-tetra-O-benzoyl-α-d-mannopyranoside (7 mg,
4%). For 15b:[51] 1H NMR (CDCl3, 400 MHz): δ = 8.12–7.26 (m,
20 H), 6.06 (t, J = 10.0 Hz, 1 H), 6.02 (d, J = 2 3.0 Hz, 1 H), 5.88
(dd, J = 3.3, 10.0 Hz, 1 H), 5.76 (dd, J = 1.7, 3.3 Hz, 1 H), 5.41
(d, J = 1.7 Hz, 1 H), 4.73–4.69 (m, 2 H), 4.56–4.51 (m, 2 H), 4.44
(d, J = 2.8 Hz, 1 H), 4.35–4.30 (m, 1 H), 4.23 (dd, J = 6.2, 8.6 Hz,
1 H), 4.11 (dd, J = 2.8, 8.8 Hz, 1 H), 4.01 (dd, J = 4.0, 8.6 Hz, 1
H, 6-H), 1.50 (s, 3 H), 1.38 (s, 3 H), 1.31 (s, 3 H), 1.28 (s, 3 H) ppm.
Glycosylation Reactions of Methyl Orthoesters 4a and 4b with
Monosaccharides 16–19 – General Procedure: A dry mixture of the
appropriate 1,2-orthoester (2.0 equiv.) and the appropriate acceptor
(1.0 equiv.) in toluene (5 mL) was azeotroped to dryness, and sub-
Benzyl 6-O-(2,3,4,6-Tetra-O-acetyl-α-
D-glucopyranosyl)-2,3,4-tri-O- sequently kept overnight under high vacuum. This mixture was
benzyl-β- -glucopyranoside (10a): This compound was prepared
D
then dissolved in dry CH2Cl2 (5 mLmmol–1), the solution was co-
oled to –30 °C, and BF3·Et2O (3.0 equiv.) was added. After TLC
analysis indicated full disappearance of the starting materials, the
reaction was quenched by addition of saturated aqueous NaHCO3.
from orthoester 4a (100 mg, 0.276 mmol), benzyl 2,3,4-tri-O-
benzyl-β-d-glucopyranoside 8 (75 mg, 0.138 mmol) and BF3·Et2O
(289 μL, 0.81 mmol). Purification by flash chromatography (hex-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

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/KAP1
Date: 11-04-12 17:17:19
Pages: 11
B. Fraser-Reid et al.
FULL PAPER
The layers were separated, the aqueous phase was extracted with
CH2Cl2, and the combined organic layers were washed with satu-
rated aqueous NaCl. The resulting organic phase was dried with
Na2SO4, filtered, and concentrated. The residue was purified by
flash silica gel column chromatography to afford the corresponding
pure disaccharide. The yields shown for each compound refer to
the acceptor employed in each case. On the other hand, because
two equiv. of donor were used, byproducts arising from the ortho-
ester transformation were commonly detected in the reaction. In
some instances these byproducts were quantified and characterized,
and included the corresponding 1α,1Јβ-disaccharide (i.e., 6) and
methyl glycoside (i.e., 7).
7.25–7.95 (m, 15 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.7,
20.8 (ϫ2), 21.0, 28.6, 29.9, 54.9, 62.2, 66.1, 66.6, 68.6, 69.0, 69.3,
69.4, 70.3, 71.2, 72.8, 97.4, 98.3, 114.9, 123.6, 128.4, 128.5, 128.6,
128.7, 129.8, 129.9, 131.5, 133.3, 133.6, 134.3, 137.7, 165.3, 165.7,
169.8, 170.0, 170.7 ppm. API-ES positive: 938.2 [M + Na]+.
C47H49NO18 (915.9): calcd. C 61.63, H 5.39, N 1.53, O 31.44; found
C 61.65, H 5.37, N 1.45.
Pent-4-enyl 3,4-Di-O-benzoyl-6-O-(2,3,4,6-tetra-O-benzoyl-α-
D-
mannopyranosyl)-2-deoxy-2-phthalimido-β- -glucopyranoside (21b):
D
This compound was prepared by the general method from orthoes-
ter 4b (94 mg, 0.15 mmol) and pent-4-enyl 3,4-di-O-benzoyl-
2-deoxy-2-phthalimido-β-d-glucopyranoside
(17,
44.5 mg,
6-O-(2,3,4,6-Tetra-O-acetyl-α-
D
-mannopyranosyl)-1:2,3:4-di-O-iso-
0.076 mmol). Purification by flash chromatography (hexane/EtOAc
8:2) afforded 21b (81.3 mg, 92%) along with methyl glycoside 7b[34]
(16 mg, 17%) and 1α,1β-disaccharide 6b[34] (26 mg, 15%). For 21b:
propylidene-α-
D
-galactopyranoside (20a):[52] This compound was
prepared from orthoester 4a (100 mg, 0.28 mmol) and 1,2:3,4-di-
O-isopropylidene-α-d-galactopyranose (16, 36 mg, 0.138 mmol) by
the general procedure for glycosylation. Purification by flash
chromatography (hexane/EtOAc 6:4) afforded 20a (67 mg, 82%),
the spectroscopic data for which are identical to those described
previously.[52] 1H NMR (300 MHz, CDCl3): δ = 1.32 (s, 6 H), 1.41
(s, 3 H), 1.55 (s, 3 H), 1.98 (s, 3 H), 2.03 (s, 3 H), 2.09 (s, 3 H),
2.15 (s, 3 H), 3.70 (dd, J = 10.2, 6.4 Hz, 1 H), 3.78 (dd, J = 10.2,
6.2 Hz, 1 H), 3.94–3.96 (m, 1 H), 4.06–4.11 (m, 2 H), 4.24 (dd, J
= 7.9, 1.7 Hz, 1 H), 4.29–4.33 (m, 2 H), 4.61 (dd, J = 7.9, 2.4 Hz,
1
[α]D = –12.7 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ =
1.42–1.60 (m, 2 H), 1.78–1.85 (m, 2 H), 3.55 (dt, J = 9.8, 6.5 Hz,
1 H), 3.70 (dd, J = 10.5, 1.7 Hz, 1 H), 3.92 (dt, J = 9.8, 6.1 Hz, 1
H), 4.03 (dd, J = 10.5, 6.4 Hz, 1 H), 4.13 (m, 1 H), 4.27 (dd, J =
12.0, 4.7 Hz, 1 H), 4.37 (ddd, J = 9.6, 4.6, 2.2 Hz, 1 H), 4.47 (d, J
= 8.8 Hz, 1 H), 4.49 (t, J = 10.9 Hz, 1 H), 4.63 (m, 2 H), 5.04 (d,
J = 1.3 Hz, 1 H), 5.52 (d, J = 8.4 Hz, 1 H), 5.42–5.56 (m, 1 H),
5.65 (dd, J = 3.2, 1.7 Hz, 1 H), 5.88 (dd, J = 10.1, 3.2 Hz, 1 H),
5.98 (t, J = 9.9 Hz, 1 H), 6.23 (dd, J = 10.1, 9.9 Hz, 1 H), 7.16–
1 H), 4.86 (d, J = 1.2 Hz, 1 H), 5.22–5.34 (m, 3 H), 5.49 (d, J = 8.03 (m, 35 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.7, 30.0,
5.0 Hz, 1 H) ppm.
55.1, 62.8, 66.9, 67.0, 69.1, 69.4, 70.1, 70.4, 70.5, 71.4, 73.0, 97.6,
98.4, 114.9, 123.7, 128.4 (ϫ4), 128.5 (ϫ4), 128.6 (ϫ8), 128.7 (ϫ4),
128.8 (ϫ2), 129.2 (ϫ2), 129.3, 129.4, 129.8 (ϫ4), 129.9 (ϫ8), 131.6
(ϫ2), 133.1, 133.2, 133.3, 133.5, 133.6, 134.3, 137.8, 165.4 (ϫ3),
165.6, 165.8, 166.2 ppm. API-ES positive: 1187.1 [M + Na]+.
C67H57NO18 (1164.2): calcd. C 69.12, H 4.94, N 1.20; found C
69.20, H 4.90, N 1.22.
6-O-(2,3,4,6-Tetra-O-benzoyl-α-D-mannopyranosyl)-1:2,3:4-di-O-iso-
propylidene-α-D
-galactopyranoside (20b):[53] This compound was
prepared by the general method from orthoester 4b (171 mg,
0.28 mmol) and 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose
(16, 20 mg, 0.138 mmol). Purification by flash chromatography
(hexane/EtOAc 7:3) afforded 20b (63 mg, 99%) along with methyl
glycoside 7b[34] (48 mg, 28%) and 1α,1Јβ-disaccharide 6b[34] (39 mg,
12%). The spectral data for 20b are in agreement with those de-
scribed previously.[53] 1H NMR (300 MHz, CDCl3): δ = 1.36 (s, 3
Phenyl 6-O-(2,3,4,6-Tetra-O-acetyl-α-
O-methyl-1-thio-α- -mannopyranoside (22a): This compound was
prepared from orthoester 4a (100 mg, 0.276 mmol) and phenyl
(18, 50 mg,
D-mannopyranosyl)-2,3,4-tri-
D
H), 1.43 (s, 3 H), 1.63 (s, 3 H), 3.90 (dd, J = 10.4, 6.0 Hz, 1 H), 2,3,4-tri-O-methyl-1-thio-α-d-glucopyranoside
3.98 (dd, J = 10.4, 6.3 Hz, 1 H), 4.07–4.17 (m, 1 H), 4.32–4.39 (m,
2 H), 4.51 (dd, J = 12.1, 3.9 Hz, 1 H), 4.57–4.64 (m, 1 H), 4.65–
4.73 (m, 2 H), 5.17 (d, J = 1.8 Hz, 1 H), 5.57 (d, J = 5.0 Hz, 1 H),
5.75 (dd, J = 3.2, 1.8 Hz, 1 H), 5.92 (dd, J = 10.1, 3.3 Hz, 1 H),
0.138 mmol) by the general procedure for glycosylation. Purifica-
tion by flash chromatography (hexane/EtOAc 6:4) afforded 17a
(65 mg, 73%). [α]D = +81.4 (c = 0.4, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 1.99 (s, 3 H), 2.05 (s, 3 H), 2.10 (s, 3 H), 2.14 (s, 3 H),
6.14 (t, J = 10.0 Hz, 1 H), 7.24–7.62 (m, 12 H), 7.83–8.14 (m, 8 3.46 (s, 3 H), 3.48 (m, 1 H), 3.49 (m, 1 H), 3.52 (s, 3 H), 3.56 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.5, 25.1, 26.1, 26.3,
63.0, 66.8, 66.9, 67.7, 68.9, 70.3, 70.5, 70.8 (ϫ2), 71.1, 96.5, 98.0,
108.9, 109.6, 128.4 (ϫ2), 128.5 (ϫ4), 128.7 (ϫ 2), 129.2, 129.3,
129.5, 129.8 (ϫ2), 129.9 (ϫ4), 130.0 (ϫ2), 130.1, 133.1, 133.2,
133.5 (ϫ2), 165.5 (ϫ2), 165.6, 166.3 ppm.
H), 3.75 (dd, J = 11.1, 1.8 Hz, 1 H), 3.86 (t, J = 1.9 Hz, 1 H), 3.91
(dd, J = 11.1, 5.8 Hz, 1 H), 4.04 (ddd, J = 9.4, 5.0, 2.1 Hz, 1 H),
4.11 (dd, J = 12.2, 2.2 Hz, 1 H, 1 H), 4.15–4.22 (m, 1 H), 4.26 (dd,
J = 12.2, 5.1 Hz, 1 H), 4.93 (d, J = 1.5 Hz, 1 H), 5.27 (t, J = 9.8 Hz,
1 H), 5.31 (dd, J = 3.2, 1.5 Hz, 1 H), 5.35 (dd, J = 9.8, 3.2 Hz, 1
H), 5.59 (d, J = 1.9 Hz, 1 H), 7.24–7.51 (m, 5 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 20.8, 20.9 (ϫ2), 21.1, 57.6, 58.1, 61.0, 62.4,
66.4, 67.2, 68.5, 69.1, 69.6, 72.0, 76.5, 78.4, 81.7, 84.7, 97.9, 127.7,
129.3 (ϫ2), 131.6 (ϫ2), 134.5, 169.7, 169.9, 170.0, 170.8 ppm. API-
ES positive: 667.2 [M + Na]+. C29H40O14S (664.68): calcd. C 54.03,
H 6.25, S 4.97; found C 54.07, H 6.27, S 4.79.
Pent-4-enyl 3,4-Di-O-benzoyl-6-O-(2,3,4,6-tetra-O-acetyl-α-
D-man-
nopyranosyl)-2-deoxy-2-phthalimido-β- -glucopyranoside (21a):
D
This compound was prepared from orthoester 4a (100 mg,
0.276 mmol) and pent-4-enyl 3,4-di-O-benzoyl-2-deoxy-2-phthal-
imido-β-d-glucopyranoside (17, 81 mg, 0.138 mmol) by the general
procedure for glycosylation. Purification by flash chromatography
(hexane/EtOAc 6:4) afforded 21a (112 mg, 87%). [α]D = +42.6 (c =
Phenyl 6-O-(2,3,4,6-Tetra-O-benzoyl-α-
D-mannopyranosyl)-2,3,4-
1
1.0, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.58 (dq, J = 13.9,
tri-O-methyl-1-thio-α- -mannopyranoside (22b): This compound
D
7.5 Hz, 2 H), 1.90 (m, 2 H), 1.98 (s, 3 H), 2.01 (s, 3 H), 2.05 (s, 3
H), 2.12 (s, 3 H), 3.54 (dt, J = 9.8, 6.6 Hz, 1 H), 3.67 (dd, J = 10.8,
2. 3 Hz, 1 H), 3.88–4.03 (m, 4 H), 4.13 (ddd, J = 9.3, 6.6, 2.3 Hz,
1 H), 4.20 (dd, J = 12.1, 5.1 Hz, 1 H), 4.56 (dd, J = 10.8, 8.4 Hz,
was prepared by the general method from orthoester 4b (168 mg,
0.28 mmol) and phenyl 2,3,4-tri-O-methyl-1-thio-α-d-glucopyran-
oside (18, 50 mg, 0.138 mmol). Purification by flash chromatog-
raphy (hexane/EtOAc 7:3) afforded 22b (117 mg, 95%). [α]D = +7.8
1
1 H), 4.77 (m, 1 H), 4.85 (d, J = 1.6 Hz, 1 H), 5.26 (t, J = 10.0 Hz, (c = 0.6, CHCl3). H NMR (300 MHz, CDCl3): δ = 3.41 (s, 3 H),
1 H), 5.27 (dd, J = 3.5, 1.7 Hz, 1 H), 5.38 (dd, J = 10.1, 3.5 Hz, 1
H), 5.53 (dd, J = 10.1, 9.3 Hz, 1 H), 5.54 (d, J = 8.4 Hz, 1 H), 5.62
(ddt, J = 17.0, 10.3, 6.7 Hz, 1 H), 6.27 (dd, J = 10.8, 9.2 Hz, 1 H),
3.47–3.49 (m, 2 H), 3.48 (s, 3 H), 3.53 (s, 3 H), 3.82 (m, 2 H), 4.01
(dd, J = 11.0, 6.0 Hz, 1 H), 4.23 (m, 1 H), 4.41 (m, 2 H), 4.59 (dd,
J = 13.7, 4.3 Hz, 1 H), 5.13 (d, J = 1.8 Hz, 1 H), 5.58 (d, J =
8
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Methyl 1,2-Orthoesters as Donors in Glycosylation Reactions
1.5 Hz, 1 H), 5.70 (dd, J = 3.3, 1.8 Hz, 1 H), 5.86 (dd, J = 10.1,
3.3 Hz, 1 H), 6.04 (t, J = 9.7 Hz, 1 H), 7.01–7.57 (m, 17 H), 7.72–
ous phase was extracted with CH2Cl2, and the combined organic
layers were washed with saturated aqueous NaCl. The resulting
8.09 (m, 8 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 57.7, 58.1, organic phase was dried with Na2SO4, filtered and concentrated.
61.1, 63.0, 67.1, 67.7, 68.9, 70.2, 70.5, 72.2, 76.7, 78.5, 81.9, 85.0,
98.1, 127.9, 128.5, 128.6, 128.7, 128.8, 129.2, 129.4 (ϫ2), 129.7,
130.0 (ϫ2), 130.1 (ϫ2), 130.2, 132.1 (ϫ2), 133.2, 133.3, 133.6,
133.7, 134.5, 165.3, 165.4, 165.7, 166.4 ppm. API-ES positive: 915.2
[M + Na]+. C49H48O14S (892.9): calcd. C 65.91, H 5.42; found C
65.88, H 5.38.
The residue was purified by flash silica gel column chromatography.
Glycosidation of Diol 25 with 4b: In two different experiments, or-
thobenzoate 4b (92 mg, 0.15 mmol) was treated with diol 25
(46 mg, 0.15 mmol) at –30 °C or –50 °C. After workup and column
chromatography (hexane/EtOAc 7:3), trisaccharide 30[39] (19 mg,
13% and 16 mg, 7%, respectively), and a single spot containing an
inseparable mixture of disaccharides 28[39] and 29[39] (55 mg, 41%,
ratio 28/29 3.0:1; and 63 mg, 47%, ratio 28/29 4.8:1, respectively)
were isolated.
Methyl 6-O-(2,3,4,6-Tetra-O-acetyl-α-
D-mannopyranosyl)-2,3,4-tri-
O-benzoyl-α-
D
-glucopyranoside (23a):[54] This compound was pre-
pared from orthoester 4a (50 mg, 0.14 mmol) and methyl 2,3,4 tri-
O-benzoyl-α-d-mannopyranosyl (19, 35 mg, 0.07 mmol) by the ge-
neral procedure for glycosylation. Purification by flash chromatog-
raphy (hexane/EtOAc 6:4) allowed the isolation of 23a (23 mg,
40%) along with methyl 2,3,4,6-tetra-O-acetyl-α-d-mannopyran-
oside (7a, 5 mg, 10%), and unchanged methyl 2,3,4-tri-O-benzoyl-
α-d-mannopyranosyl (19, 5 mg, 14%), together with a lower run-
ning mixture of compounds appearing as a single spot on tlc.
Acetylation of this mixture (consisting of partially de-O-acetylated
materials) resulted after additional chromatography (hexane/
Glycosidation of Diol 26 with 4b: In two different experiments, or-
thobenzoate 4b (92 mg, 0.15 mmol) was treated with diol 26
(46 mg, 0.15 mmol) at –30 °C or –50 °C. After workup and column
chromatography (hexane/EtOAc 7:3), trisaccharide 32[39] (7 mg, 3%
and 13 mg, 5% respectively), and disaccharide 31[39] (47 mg, 35%
and 56 mg, 41%, respectively) were obtained.
Glycosidation of Diol 27 with 4b: In two different experiments, or-
thobenzoate 4b (92 mg, 0.15 mmol) was treated with diol 27
EtOAc 6:4) in the isolation of 1α,1Јβ-disaccharide 6a (8 mg, 17%) (60 mg, 0.15 mmol) at –30 °C or –50 °C. After workup and column
and disaccharide 23a (7 mg, 12%). Spectral data for 23a are in
agreement with those described previously.[54] 1H NMR (300 MHz,
CDCl3): δ = 7.92–7.79 (m, 6 H), 7.48–7.19 (m, 9 H), 6.08 (t, J =
9.6 Hz, 1 H), 5.45 (t, J = 9.9 Hz, 1 H), 5.31 (dd, J = 10.2, 3.3 Hz,
1 H), 5.19 (m, 4 H), 4.77 (s, 1 H), 4.21 (m, 1 H), 4.12 (dd, J = 12.0,
5.4 Hz, 1 H), 3.97 (m, 2 H), 3.83 (dd, J = 10.8, 6.3 Hz, 1 H), 3.58
(dd, J = 10.8, 1.8 Hz, 1 H), 3.43 (s, 3 H), 2.07, 1.984, 1.978, 1.92
(4s, 12 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.8, 170.1,
169.9, 166.0, 165.5, 133.7, 133.5, 133.3, 130.15, 130.08, 129.9,
129.4, 129.3, 129.0, 128.7, 128.6, 128.5, 97.6, 97.1, 72.3, 70.7, 69.7,
69.2, 68.9, 68.5, 66.7, 66.3, 62.6, 55.8, 21.0, 20.93, 20.87 ppm.
chromatography (hexane/EtOAc 7:3), disaccharide 33[39] (72 mg,
49% and 74 mg, 50%, respectively) was obtained.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra.
Acknowledgments
The authors are grateful to the Ministerio de Ciencia e Innovación
(MICINN) and the Comunidad de Madrid for financial support
through grants CTQ2009-10343 and S2009/PPQ-1752, respectively.
B. F. R. thanks the National Science Foundation (USA) (grant
number CHE 0717702).
Methyl 6-O-(2,3,4,6-Tetra-O-benzoyl-α-
D-mannopyranosyl)-2,3,4-
tri-O-benzoyl-α-
D
-glucopyranoside (23b):[53] This compound was
prepared by the general method from orthoester 4b (100 mg,
0.163 mmol) and methyl 2,3,4-tri-O-benzoyl-α-d-glucopyranoside
(19, 41.5 mg, 0.082 mmol). Purification by flash chromatography
(hexane/EtOAc 8:2) afforded 23b (90 mg, 99%), the spectroscopic
data for which are identical to those described previously.[53] 1H
NMR (300 MHz, CDCl3): δ = 3.59 (s, 3 H), 3.74 (dd, J = 10.8,
1.8 Hz, 1 H), 4.07 (dd, J = 10.6, 6.2 Hz, 1 H), 4.31–4.40 (m, 2 H),
4.51 (ddd, J = 9.7, 4.6, 1.8 Hz, 1 H), 4.60 (dd, J = 12.2, 2.0 Hz, 1
H), 5.13 (d, J = 1.2 Hz, 1 H), 5.24 (dd, J = 10.2, 3.7 Hz, 1 H), 5.31
(d, J = 3.7 Hz, 1 H), 5.56 (t, J = 9.9 Hz, 1 H), 5.74 (dd, J = 2.9,
1.8 Hz, 1 H), 5.96 (dd, J = 10.1, 3.1 Hz, 1 H), 6.07 (t, J = 10.0 Hz,
1 H), 6.19 (t, J = 9.8 Hz, 1 H), 7.24–8.10 (m, 35 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 55.8, 62.8, 66.5, 66.9, 68.4, 69.1, 69.4, 70.1,
70.4, 72.2, 97.0, 97.5, 128.4 (ϫ3), 128.5 (ϫ3), 128.6 (ϫ4), 128.7
(ϫ2), 128.9, 129.2 (ϫ2), 129.3, 129.4, 129.8 (ϫ4), 129.9 (ϫ4),
130.1 (ϫ3), 133.1, 133.2 (ϫ2), 133.4, 133.5 (ϫ2), 133.6, 165.4,
165.5 (ϫ2), 165.6, 165.8, 165.9, 166.2 ppm.
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Received: January 26, 2012
Published Online: ᭿
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20089
/KAP1
Date: 11-04-12 17:17:19
Pages: 11
Methyl 1,2-Orthoesters as Donors in Glycosylation Reactions
Glycosyl Donors
Methyl 1,2-orthoesters are useful glycosyl
donors upon acid activation with boron tri-
fluoride etherate. They react smoothly with
monosaccharide alcohols or diols, leading
to disaccharides in good to excellent yields.
When monosaccharide diols are used as
glycosyl acceptors, good regioselectivity in
the glycosyl coupling is observed.
C. Uriel, J. Ventura, A. M. Gómez,
J. C. López,* B. Fraser-Reid* ......... 1–11
Methyl 1,2-Orthoesters as Useful Glycosyl
Donors in Glycosylation Reactions:
Comparison with n-Pent-4-enyl 1,2-Ortho-
esters
A
Keywords: Carbohydrates / Glycosylation /
Glycosyl donors / Regioselectivity
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