Installation of electron-donating protective groups, a strategy for glycosylating unreactive thioglycosyl acceptors using the preactivation-based glycosylation method

Article abstract of DOI:10.1021/jo801462r

(Chemical Equation Presented) Preactivation-based chemoselective glycosylation is a powerful strategy for oligosaccharide synthesis with its successful application in assemblies of many complex oligosaccharides. However, difficulties were encountered in r

Full text of DOI:10.1021/jo801462r

Installation of Electron-Donating Protective Groups, a Strategy for
Glycosylating Unreactive Thioglycosyl Acceptors using the
Preactivation-Based Glycosylation Method1
Youlin Zeng,† Zhen Wang,† Dennis Whitfield,‡ and Xuefei Huang*,†
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824, and Institute for
Biological Sciences, National Research Council Canada, 100 Sussex Dr.,
Ottawa, Ontario K1A 0R6, Canada
xuefei@chemistry.msu.edu
ReceiVed July 3, 2008
Preactivation-based chemoselective glycosylation is a powerful strategy for oligosaccharide synthesis
with its successful application in assemblies of many complex oligosaccharides. However, difficulties
were encountered in reactions where glycosyl donors bearing multiple electron-withdrawing groups failed
to glycosylate hindered unreactive acceptors. In order to overcome this problem, it was discovered that
the introduction of electron-donating protective groups onto the glycosyl donors can considerably enhance
their glycosylating power, leading to productive glycosylations even with unreactive acceptors. This
observation is quite general and can be extended to a wide range of glycosylation reactions, including
one-pot syntheses of chondroitin and heparin trisaccharides. The structures of the reactive intermediates
formed upon preactivation were determined through low-temperature NMR studies. It was found that for
a donor with multiple electron-withdrawing groups, the glycosyl triflate was formed following preactivation,
while the dioxalenium ion was the major intermediate with a donor bearing electron-donating protective
groups. As donors were all cleanly preactivated prior to the addition of the acceptors, the observed reactivity
difference between these donors was not due to selective activation encountered in the traditional armed-
disarmed strategy. Rather, it was rationalized by the inherent internal energy difference between the
reactive intermediates and associated oxacarbenium ion like transition states during nucleophilic attack
by the acceptor.
Introduction
and the acceptor. The glycosyl donor is activated by the
promoter, which undergoes in situ nucleophilic addition or
displacement reaction with the acceptor, leading to the glycoside
With the increasing recognition of the important biological
functions of carbohydrates, carbohydrate synthesis is a very
active research area, with many innovative methodologies
developed during the past two decades.2-5 In most glycosylation
reactions, a promoter is added to a mixture of the glycosyl donor
(4) Code´e, J. D. C.; Litjens, R. E. J. N.; van den Bos, L. J.; Overkleeft,
H. S.; van der Marel, G. A. Chem. Soc. ReV. 2005, 34, 769–782.
(5) Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W., Sinay¨,
P., Eds.; Wiley-VCH: Weinheim, 2000.
(6) Lu, Y.-S.; Li, Q.; Zhang, L.-H.; Ye, X.-S. Org. Lett. 2008, 10, 3445–
3448.
(7) Sun, B.; Srinivasan, B.; Huang, X. Chem. Eur. J. 2008, 14, 7072–7081.
(8) Huang, L.; Huang, X. Chem. Eur. J. 2007, 13, 529–540.
(9) Kim, J.-H.; Yang, H.; Park, J.; Boons, G.-J. J. Am. Chem. Soc. 2005,
127, 12090–12097.
(10) Yamago, S.; Yamada, T.; Ito, H.; Hara, O.; Mino, Y.; Maruyama, T.;
Yoshida, J.-I. Chem. Eur. J. 2005, 11, 6159–6194.
(11) Huang, X.; Huang, L.; Wang, H.; Ye, X.-S. Angew. Chem., Int. Ed.
2004, 43, 5221–5224.
† Michigan State University.
‡ National Research Council Canada.
(1) Part of this work was carried out at the Department of Chemistry,
University of Toledo.
(2) Wang, Z.; Huang, X. In ComprehensiVe Glycoscience from Chemistry
to Systems Biology; Kamerling, J. P., Ed.; Elsevier: New York, 2007; Vol. 1, pp
379-413.
(3) Wang, H.; Ye, X.-S.; Zhang, L.-H. Org. Biomol. Chem. 2007, 5, 2189–
2200.
7952 J. Org. Chem. 2008, 73, 7952–7962
10.1021/jo801462r CCC: $40.75 2008 American Chemical Society
Published on Web 09/23/2008

Glycosylating UnreactiVe Thioglycosyl Acceptors
product. As an alternative, a glycosyl donor can be activated in
the absence of an acceptor (preactivation).6-18 Upon complete
donor activation, the acceptor is then added to the reaction
mixture, initiating glycoside formation. Using the preactivation
strategy, unique stereochemical outcomes6,9,16,17 and chemo-
selectivities10-13,15 can be obtained. Boons and co-workers
developed a novel R-selective glycosylation strategy,9 where
preactivation of a trichloroacetimidate donor allowed for the
2-O protective group to participate and stabilize the oxacarbe-
nium ion from the ꢀ face. Thus, SN2-like displacement by the
acceptor gave R-glycosides highly selectively. The Crich group
discovered that preactivation of a benzylidene-protected thiom-
annoside or mannosyl sulfoxide generated an R-mannosyl
triflate,17 which upon triflate displacement by an acceptor led
to the ꢀ-mannoside stereoselectively, overcoming this long-
standing challenge. Gin and co-workers reported that the
preactivated hemiacetal donor could chemoselectively glyco-
sylate a hemiacetal acceptor.15 The glycoside product could then
be directly activated using the identical condition, and glyco-
sylation can be carried out iteratively.
A wide range of thioglycosyl donor and acceptor pairs have
been examined using the preactivation protocol.7,8,11,12,19-23 In
many cases, the chemoselective glycosylation reactions pro-
ceeded smoothly with good yields. It is particularly noteworthy
that a disarmed donor (e.g., 1) can glycosylate an armed acceptor
(e.g., 2).11,20 This reversal of anomeric reactivity is not possible
using the reactivity-based armed-disarmed method.24,25 The
preactivation-based strategy has been successfully applied to
total synthesis of a wide range of complex linear and branched
oligosaccharides, including LewisX,21 dimeric LewisX,21 Globo-
H,20 hyaluronic acid oligosaccharides,8 chito-oligosaccharides,13,22
and complex type sialylated core fucosylated N-glycan dode-
casaccharide.7 However, difficulties were encountered in reac-
tions of very unreactive secondary carbohydrate acceptors such
as 3 and 4 with electron-poor donors 1 and 5.11 In this article,
we will explore a strategy to overcome this problem. We will
also study the intermediates generated upon preactivation to
provide insights to design even better glycosylation strategies.
Recently, we7,8,11,19-22 and others12,13,23 applied the preac-
tivation scheme to the chemoselective glycosylation of a
thioglycoside acceptor by a thioglycosyl donor. In this approach,
the glycosyl donor is preactivated by a stoichiometric promoter.
Upon complete donor activation, a thioglycosyl acceptor is
added to the reaction mixture. Nucleophilic attack on the
activated donor by the acceptor yields a disaccharide product
containing a thioether aglycon, which can be directly activated
for the next round of glycosylation without any aglycon
adjustment as typically required by other selective activation
strategies. With the preactivation scheme, because donor activa-
tion and addition of the acceptor are performed in two distinct
steps, the anomeric reactivity of the thioglycosyl donor is
independent of that of the thioglycosyl acceptor. This confers
much freedom in protective group selection, greatly simplifying
the overall synthetic design. This is in contrast with the
traditional reactivity-based armed-disarmed chemoselective gly-
cosylation method,24-26 where the glycosyl donor must possess
much higher anomeric reactivity (typically at least 10 times
higher) than the glycosyl acceptor,24 as the donor is activated
in the presence of the acceptor.
Results and Discussion
The reaction of donor 5 with acceptor 3 was performed by
first preactivating donor 5 with the promoter system p-TolSCl/
AgOTf11 followed by addition of acceptor 3 and a sterically
hindered base tri-tert-butyl pyrimidine (TTBP)27 (Table 1, entry
1). Although no desired disaccharide was formed, complete
disappearance of the donor was observed by TLC and NMR
(vide infra). Analysis of the reaction mixture showed that donor
5 was converted to the expected breakdown products (the
hemiacetal or the glycal) of the oxacarbenium ion corresponding
to 5, with most of the acceptor 3 recovered. This demonstrated
that despite the presence of multiple electron-withdrawing
benzoyl groups, the electron-poor donor 5 was activated by the
powerful promoter p-TolSCl/AgOTf. Similar phenomena were
observed in the reaction of 4 with 5 (Table 1, entry 2) or donor
1.11 Interestingly, reaction of perbenzylated glucose donor 8 with
(12) Code´e, J. D. C.; van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft,
H. S.; van Boeckel, C. A. A.; van Boom, J. H.; van der Marel, G. A. Tetrahedron
2004, 60, 1057–1064.
(13) Yamago, S.; Yamada, T.; Maruyama, T.; Yoshida, J.-I. Angew. Chem.,
Int. Ed. 2004, 43, 2145–2148.
(14) Callam, C. S.; Gadikota, R. R.; Krein, D. M.; Lowary, T. L. J. Am.
Chem. Soc. 2003, 125, 13112–13119.
(15) Nguyen, H. M.; Poole, J. L.; Gin, D. Y. Angew. Chem., Int. Ed. 2001,
40, 414–417.
TABLE 1. Glycosylation Results of Various Donor/Acceptor Pairs
(16) Kim, K. S.; Kim, J. H.; Lee, Y. J.; Lee, Y. J.; Park, J. J. Am. Chem.
Soc. 2001, 123, 8477–8481.
(17) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321–8348.
(18) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc.
1989, 111, 6881–6882.
(19) Teumelsan, N.; Huang, X. J. Org. Chem. 2007, 72, 8976–8979.
(20) Wang, Z.; Zhou, L.; El-boubbou, K.; Ye, X.-S.; Huang, X. J. Org. Chem.
2007, 72, 6409–6420.
(21) Miermont, A.; Zeng, Y.; Jing, Y.; Ye, X.-S.; Huang, X. J. Org. Chem.
2007, 72, 8958–8961.
(22) Huang, L.; Wang, Z.; Li, X.; Ye, X.-S.; Huang, X. Carbohydr. Res.
2006, 341, 1669–1679.
(23) Crich, D.; Li, W.; Li, H. J. Am. Chem. Soc. 2004, 126, 15081–15086.
(24) Koeller, K. M.; Wong, C.-H Chem. ReV 2000, 100, 4465–4493, and
references therein.
(25) Fraser-Reid, B.; Wu, Z.; Udodong, U. E.; Ottosson, H. J. Org. Chem.
1990, 55, 6068–6070.
(26) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155–173.
(27) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323–326.
entry
donor
acceptor
product
yield (%)
1
2
3
4
5
6
7
8
5
5
8
8
11
13
13
16
13
20
23
11
3
4
3
4
4
3
4
17
17
21
21
25
6
7
9
<10
<10
67
10
12
14
15
18
19
22
24
26
65
56 (48% ꢀ + 8% R)
74
70
<10
75
<10
73
9
10
11
12
65 (51% ꢀ + 14% R)
J. Org. Chem. Vol. 73, No. 20, 2008 7953

Zeng et al.
acceptors 3 and 4 gave the corresponding disaccharides 9 and
10 smoothly in good yields following the identical reaction
protocol (Table 1, entries 3 and 4).11 The contrasting outcome
in these glycosylations using the same acceptor can be due to
two possible factors: (1) with donor 8, R-glycoside product is
predominantly formed, whereas donor 5 would favor the
ꢀ-product due to neighboring group participation; and (2)
electronic properties of the two glycosyl donors are quite
different with donor 8 bearing multiple electron-donating
protective groups and donor 5 containing electron-withdrawing
protective groups only. These two factors correspond to an
inherent R/ꢀ facial selectivity at the TS for 5 and 8 (Figure 1a)
or an inherently lower transition state (TS) energy in reaction
coordinates of 8 versus 5 (Figure 1b).
possess higher glycosylating activity following the reaction
scheme of Figure 1b.
This observation turns out to be quite general and can be
extended to a wide range of reactions, which are synthetically
useful. Per-acylated thioglucoside 16 failed to react with
glucosamine 17. Replacement of its 3,4,6-tri-O-acetyl groups
with electron-donating silyl and ether protective groups (donor
13) renders it an effective donor to glycosylate 17, producing
disaccharide 19 (Table 1, entry 9).8 Glucuronic acid residues
exist in many naturally occurring oligosaccharides. However,
due to the presence of the electron-withdrawing carboxylic acid,
glucuronic acid thioglycoside derivatives have been rarely used
as glycosyl donors.28-31 Instead, thioglucosides are typically
employed, which require oxidation state adjustment after the
glycosylation.28,32 It will be desirable to be able to use protected
glucuronic acid derivatives directly as glycosyl donors. How-
ever, the electron-poor glucuronic acid donor 20 did not undergo
glycosylation with acceptor 21 at all. This problem was solved
by using its electron-rich counterpart 23, which gave hyaluronic
acid precursor disaccharide 24 in 73% yield (Table 1, entry 11).
The electron-rich thiogalactoside donor 11 also glycosylated the
sterically hindered acceptor 25 in good yield (Table 1, entry
12).
There are high interests in acquiring glycosaminoglycans,
such as chondroitin and heparin, due to their important biological
functions.33-38 Heparin synthesis requires glycosylation of the
4-OH of a glucosamine acceptor, which is known to be
notoriously unreactive.39 A similar challenge is also present for
chondroitin preparation as the 3-hydroxyl group of most
galactosamine acceptors is sterically hindered. We envision that
the high glycosylating power of donor 13 bestowed by the
electron-donating protective groups can overcome the low
reactivities of glucosamine and galactosamine acceptors. More-
over, we want to examine whether these syntheses can be
performed in a one-pot fashion.
Preactivation of donor 13 by p-TolSCl/AgOTf at -60 °C was
followed by the addition of acceptor 25 (Scheme 1a). Upon
complete consumption of the acceptor, a second acceptor 2740
and an additional 1 equiv of the promoter p-TolSCl/AgOTf were
added to the same reaction flask. Chondroitin precursor trisac-
charide 28 was successfully produced from this three-component
one-pot synthesis in 67% overall yield within just 5 h. A heparin
(28) van den Bos, L. J.; Codee, J. D. C.; Litjens, R. E. J. N.; Dinkelaar, J.;
Overkleeft, H. S.; van der Marel, G. A. Eur. J. Org. Chem. 2007, 3963–3976.
(29) Code´e, J. D. C.; Stubba, B.; Schiattarella, M.; Overkleeft, H. S.; van
Boeckel, C. A. A.; van Boom, J. H.; van der Marel, G. A. J. Am. Chem. Soc.
2005, 127, 3767–3773.
(30) van den Bos, L. J.; Codee, J. D. C.; van der Toorn, J. C.; Boltje, T. J.;
van Boom, J. H.; Overkleeft, H. S.; van der Marel, G. A. Org. Lett. 2004, 6,
2165–2168.
(31) Magaud, D.; Dolmazon, R.; Anker, D.; Doutheau, A.; Dory, Y. L.;
Deslongchamps, P. Org. Lett. 2000, 2, 2275–2277.
(32) Huang, L.; Teumelsan, N.; Huang, X. Chem. Eur. J. 2006, 12, 5246–
5252.
(33) Gama, C. I.; Hsieh-Wilson, L. C. Curr. Opin. Chem. Biol. 2005, 9, 609–
619.
(34) Raman, R.; Sasisekharan, V.; Sasisekharan, R. Chem. Biol. 2005, 12,
267–277.
(35) Petitou, M.; van Boeckel, C. A. A. Angew. Chem., Int. Ed. 2004, 43,
3118–3133.
(36) Linhardt, R. J.; Toida, T. Acc. Chem. Res. 2004, 37, 431–438.
(37) Yeung, B. K. S.; Chong, P. Y. C.; Petillo, P. A. In Glycochemistry.
Principles, Synthesis, and Applications; Wang, P. G., Bertozzi, C. R., Eds.; Marcel
Dekker, Inc.: New York, 2001; pp 425-492.
(38) Koeller, K. M.; Wong, C.-H. Nat. Biotechnol. 2000, 18, 835–841.
(39) Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2001, 123, 6819–6825.
(40) Carter, M. B.; Petillo, P. A.; erson, L.; Lerner, L. E. Carbohydr. Res.
1994, 258, 299–306.
To better differentiate the factors governing the glycosylation,
donor 1120 was prepared, which bears multiple electron-donating
groups and a participating protective group at O-2. After
preactivation by p-TolSCl/AgOTf, donor 11 successfully gly-
cosylated acceptor 4 producing disaccharide 12ꢀ in 48% yield
(Table 1, entry 5), suggesting that facial selectivity is not the
dominating factor for determining the donor’s ability to react
with 4. The identity of the sugar is not crucial as the electron-
rich glucoside donor 138 also smoothly glycosylated acceptors
3 and 4 to give disaccharides 14 and 15 (Table 1, entries 6 and
7). Thus, the observed dichotomy in reaction outcome must be
resulting from different electronic properties of the glycosyl
donors. To glycosylate unreactive acceptors, donors containing
more electron-donating groups are preferred as they inherently
7954 J. Org. Chem. Vol. 73, No. 20, 2008

Glycosylating UnreactiVe Thioglycosyl Acceptors
FIGURE 1. Schematic demonstrations of (a) inherent R/ꢀ facial selectivity at the TS for 5 and 8 glycosylations with an acceptor and (b) TS energy
difference in reaction coordinates of donor 8 versus 5.
SCHEME 1
precursor trisaccharide 30 was prepared in a similar manner
through sequential reactions of 13, 29,41 and 27 in one pot in
49% yield (Scheme 1b).
Why do the more electron-rich donors have higher glycosy-
lating power? To answer this question, the reactive intermediates
formed following preactivation were examined. In general, it
is a difficult task to thoroughly characterize the reactive
intermediates due to their limited lifetime, especially when donor
activation is carried out in the presence of an acceptor. With
the preactivation scheme, because the activation and glycosy-
lation are two distinct steps, it will be possible to observe the
intermediates at low temperature following preactivation.
Recently, low-temperature NMR has been shown to be a
powerful tool to monitor the glycosylation process.9,14,42-47
Crich and colleagues have carried out ground-breaking work
in studying the reactive intermediates of a glycosylation
reaction.47 They demonstrated that in the absence of neighboring
group participation, glycosyl triflates, which have characteristic
1H, 13C, and 19F NMR profiles, were the dominant intermediates
when several thiophenyl mannosylpyranosides and thiophenyl
glucosylpyranosides were preactivated by PhSOTf at low
temperatures. The identification of glycosyl triflate was used to
rationalize the high ꢀ-selectivity in glycosylation of benzylidene-
protected mannothiopyranosides. Lowary and co-workers showed
that in the activation of a furanosyl sulfoxide, although multiple
intermediates existed at -60 °C, glycosyl triflate was the
dominant one when the reaction was warmed up to -40 °C.
This observation enabled them to modify the operations and
enhance the yield and stereoselectivity of their synthesis.14
In our glycosylation reaction, upon addition of p-TolSCl to
a mixture of p-tolylthioglycoside donor and AgOTf, p-TolSOTf
is formed, which electrophilically attacks the anomeric sulfur
atom of the donor to generate disulfonium ion 31 (step 1,
Scheme 2). The disulfonium ion 31 can further evolve to several
possible intermediates prior to the addition of the nucleophilic
acceptor (step 2): (1) oxacarbenium ion pair 32; (2) glycosyl
triflate 33 by addition of the triflate anion to the anomeric center;
(3) disulfonium ion 34 formed by equilibrating with the p-tolyl
disulfide side product; and (4) dioxalenium ion 35 in the cases
where the donor contains an O-2 acyl participating protective
group. Nucleophilic attack of the reactive intermediate(s) by
the acceptor will then generate the glycoside product (step 3).
Although drawn as free ion pairs, 32, 34, and 35 can also
possibly exist as either solvent-separated ion pairs or contact
ion pairs.
Because the intermediates upon activation of glycosyl donors
without 2-O participating neighboring groups have been quite
extensively studied,14,17,47-49 we focused on donors containing
O-2 acyl groups in this study. The preactivation of per-O-
benzoylated galactose donor 5 was monitored first by NMR.
No significant differences in product yields or NMR spectra
were observed when the reactions were performed in CD2Cl2,
CDCl3, CD2Cl2/Et2O-d10 (1:1), or CDCl3/Et2O-d10 (1:1). There-
fore, all subsequent studies were performed in anhydrous CDCl3.
Addition of p-TolSCl to a mixture of donor 5 and AgOTf at
-60 °C led to rapid dissipation of the characteristic yellow color
of p-TolSCl within seconds. Inspection of the 1H NMR spectrum
revealed that the donor was transformed within a few minutes
to one major new carbohydrate species characterized by its
(41) Fan, Q.-H.; Li, Q.; Zhang, L.-H.; Ye, X.-S. Synlett 2006, 1217–1220.
(42) Nokami, T.; Shibuya, A.; Tsuyama, H.; Suga, S.; Bowers, A. A.; Crich,
D.; Yoshida, J. J. Am. Chem. Soc. 2007, 129, 10922–10928.
(43) Honda, E.; Gin, D. Y. J. Am. Chem. Soc. 2002, 124, 7343–7352.
(44) Liu, J.; Gin, D. Y. J. Am. Chem. Soc. 2002, 124, 9789–9797.
(45) Garcia, B.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122, 4269–4279.
(46) Gildersleeve, J.; Pascal, R. A., Jr.; Kahne, D. J. Am. Chem. Soc. 1998,
120, 5961–5969.
anomeric proton signal, a doublet at δ 6.57 ppm with J1,2
)
3.2 Hz (Figure 2). No signals around δ 9.5 ppm due to the
anomeric proton of the possible oxacarbenium ion 36 were
observed.50
(48) Crich, D.; Vinogradova, O. J. Org. Chem. 2006, 71, 8473–8480.
(49) Crich, D.; Cai, W. J. Org. Chem. 1999, 64, 4926–4930.
(47) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217–11223.
J. Org. Chem. Vol. 73, No. 20, 2008 7955

Zeng et al.
SCHEME 2
The methyl group of the p-tolyl moiety after preactivation
appeared as a singlet in its H NMR spectrum, which was the
ion 36 as the positively charged anomeric carbon in the
oxacarbenium ion was expected to appear above 210 ppm47
through analogy with other sp2 hybridized alkoxy carbenium
ions.50,52,53 By electrochemical oxidation, Crich, Yoshida, and
co-workers generated a series of glycosyl triflates for glucosides,
galactosides, and mannosides without participating neighboring
groups on O-2. The anomeric protons of these glycosyl triflates
appeared around 6.2 ppm and anomeric carbons around 106
ppm.42 Our NMR data is consistent with the intermediate
structure following preactivation of 5 being the R-glycosyl
triflate 38. Prior to the activation, the 19F NMR spectrum showed
a single peak at δ -4.2 ppm due to the triflate anion from
AgOTf. The corresponding 19F NMR after activation revealed
two signals, δ -1.2 and δ -4.2 ppm assigned to glycosyl triflate
38 and excess AgOTf, respectively. The glycosyl triflate 38 was
found to be quite stable because no significant changes were
observed by NMR when the temperature was raised to -20
°C. The triflate 38 was a competent glycosyl donor with reactive
acceptors as the addition of the primary galactoside acceptor
39 to the NMR tube led to the desired disaccharide 40 cleanly.
Yet, adding the unreactive acceptor 3 to 38 did not produce
any disaccharide 6. This is consistent with a model that some
nucleophilic push is required in order to activate anomeric
triflates.
1
case for all p-tolyl thioglycosides examined. If the glycosyl
disulfonium ion 37 were formed, the two p-TolS groups would
have become nonequivalent, leading to two separate methyl
1
1
peaks in H NMR. This was supported by the fact that the H
NMR of dimethyl(methylthio)sulfonium triflate (DMTST) ex-
hibits two singlets at 3.27 and 2.92 ppm with the integration
ratio of 2:1.51 Furthermore, in glycosylation of 2 by 8, addition
of exogenous p-tolyl disulfide to the reaction did not cause
significant changes in either reaction yield or stereoselectivity
(data not shown). Thus, the glycosyl disulfonium ion does not
play a significant role in the thioglycoside glycosylation but
rather a transient function on route to other species.
When the more electron-rich donor 11 was preactivated by
p-TolSCl/AgOTf, one major intermediate was formed along with
1
several minor ones. The H NMR of activated donor 11 was
considerably broader than that of activated donor 5, presumably
due to residual silver cation complexation with aromatic
residues54 possibly the benzyl protecting groups of 11 (Figure
3). A gCOSY correlation experiment showed that the anomeric
proton of the major intermediate had undergone significant
downfield shift from 4.98 ppm in donor 11 to 7.34 ppm, while
H-2 shifted slightly to 5.77 ppm (Supporting Information, Figure
S1). To better probe this intermediate by 13C NMR, a 13C-labeled
benzoyl group was introduced onto O-2 of the galactoside (donor
The 13C NMR spectrum of the activated intermediate from
donor 5 at -60 °C corroborated the clean formation of a new
carbohydrate species with its anomeric carbon signal resonating
at δ 104.4 ppm and four carbonyl carbon signals at δ 166.4,
165.9, 165.8, 165.5 ppm (Figure 2). The chemical shift of the
anomeric carbon also excluded the possibility of oxacarbenium
(52) Forsyth, D. A.; Osterman, V. M.; DeMember, J. R. J. Am. Chem. Soc.
1985, 107, 818–822.
(53) Olah, G. A.; Parker, D. G.; Yoneda, N. J. Org. Chem. 1977, 42, 32–37.
(54) Lindeman, S. V.; Rathore, R.; Kochi, J. K. Inorg. Chem. 2000, 39, 5707–
5716.
(50) Suga, S.; Suzuki, S.; Yamamoto, A.; Yoshida, J.-I. J. Am. Chem. Soc.
2000, 122, 10244–10245.
(51) Ravenscrof, M.; Robert, R. M. G.; Tillet, J. G. J. Chem. Soc., Perkin
Trans 2 1982, 1569–1572.
7956 J. Org. Chem. Vol. 73, No. 20, 2008

Glycosylating UnreactiVe Thioglycosyl Acceptors
FIGURE 2. 1H NMR and 13C NMR spectra of the intermediate formed after preactivation of donor 5 in CDCl3 at -60 °C.
1
FIGURE 3. (a) H NMR and (b) 13C NMR spectra of the intermediates formed after preactivation of donor 11; (c) 13C NMR after preactivation
of donor 11a in CDCl3 at -60 °C.
11a), which showed a chemical shift of 165.5 ppm by 13C NMR.
An HMBC spectrum of the 13C labeled donor 11a displayed
correlations between the 13C 165.5 ppm peak and protons at
8.02 ppm (Ho, Ho′protons of the Bz phenyl ring) and 5.66 ppm
(H-2) with no correlations with the anomeric proton at 4.98
ppm (Supporting Information, Figure S2a). Upon activation, a
strong new resonance at δ 180.8 ppm appeared in the 13C NMR
with the concomitant decrease of the resonance at δ 165.5 ppm
(Figure 3c). For this new carbon signal, in addition to its HMBC
1
correlations with H NMR signals at 8.02 ppm (Ho, Ho′) and
5.77 ppm (H-2), a new correlation with the H-1 proton signal
at 7.34 ppm was observed (Supporting Information, Figure S2b).
These correlations strongly suggest the bridging dioxalenium
ion 41 formed through participation by the neighboring O-2
benzoyl group. The chemical shift of 180.8 ppm for the bridging
carbon in 41 was similar to the value of 180.3 ppm observed
for the dioxalenium ion 42 formed from xyloside 43.55 The
at -60 °C (Figure 4a,b). Based on the resonances at δ 6.21
HSQC spectrum of 41 indicated that the anomeric carbon was
ppm (J1,2 ) 2.4 Hz) and δ 104.1 ppm of the anomeric proton
also downfield shifted to 114.2 ppm (Supporting Information,
and carbon atoms, the first intermediate was assigned to be the
Figure S3). The positive charge of the dioxalenium ion 41 could
R-glycosyl triflate 44. The second intermediate has 13C NMR
be distributed over O-5, C-1, O-1 and C-7, explaining the
resonances at δ 191.7, 113.3 ppm for C-7 and C-1, and 1H NMR
significant downfield shift of H-1, C-1 and C-7. By quantum
resonances at δ 7.35 and 2.82 ppm for H-1 and H-8 of the
mechanical calculation the LUMO of dioxalenium ions has been
dioxalenium ion 45. The glycosyl triflate 44 and dioxalenium
shown to be a vacant p-like orbital centered on C-7 in agreement
ion 45 were shown to interconvert by warming the mixture to
with these observations.56 Compared with the glycosyl triflate
-20 °C, which led to the disappearance of 45 (Figure 4c,d)
38, the dioxalenium ion 41 was less stable with decomposition
with it reappearing upon recooling to -60 °C. Addition of the
setting in when the temperature was raised to above -30 °C.
primary galactoside acceptor 39 to the preactivated donor 16 at
Interestingly, preactivation of the tetra-O-acetyl glucose 16
-60 °C generated disaccharide 46 in 85% yield with both the
converted it into two reactive intermediates in roughly 1:1 ratio
glycosyl triflate 44 and the dioxalenium ion 45 consumed at
comparable rates.
Why do donors 5, 11, and 16 form different intermediates
(55) Crich, D.; Dai, Z.; Gastaldi, S. J. Org. Chem. 1999, 64, 5224–5229.
(56) Nukada, T.; Berces, A.; Zgierski, M. Z.; Whitfield, D. M. J. Am. Chem.
Soc. 1998, 120, 13291–13295.
following preactivation? This can be explained by the fact that
J. Org. Chem. Vol. 73, No. 20, 2008 7957

Zeng et al.
1
1
FIGURE 4. (a) H NMR and (b) 13C NMR spectra of the intermediates formed after preactivation of donor 16 in CDCl3 at -60 °C; (c) H NMR
and (d) 13C NMR spectra after warming to -20 °C.
SCHEME 3. Competitive Glycosylation of Acceptor 39 by a Mixture of Donors 5 and 11
there are more electron-withdrawing protecting groups (Bz is
more deactivating than Ac) on the glycan ring of donors 5,
which greatly disfavor the formation of positively charged
dioxalenium ions. On the other hand, the presence of multiple
electron-donating benzyl groups on 41 stabilizes the positive
charge sufficiently, rendering it unnecessary for the covalent
attachment of the poor nucleophile triflate anion. The tetraacetyl
glucoside 16 presents the intermediate case between donors 5
and 11, leading to a mixture of glycosyl triflate and dioxalenium
ion upon preactivation. Crich and co-workers reported the
dioxalenium ion 42 as the major intermediate when they
activated the per-benzoylated thioxyloside 43.55 As xylose is a
pentose, it contains one fewer highly electron-withdrawing group
on the sugar ring,57,58 which is likely the reason why the
dioxalenium ion 42 was formed as the major intermediate.
It is known that donor 11 is more reactive than donor 5 toward
a thiophilic promoter.24 Wong and co-workers quantified relative
reactivity values of a wide range of thiotolyl donors by having
two different donors competing with a limiting amount of
promoter in the presence of excess acceptor. Donor 11 was
found to react with a promoter about 800 times faster than donor
5,24 which mostly reflected the internal free energy difference
between the reactants and the activated intermediate (steps 1
and 2 for the glycosylation process). In contrast, preactivation
of a mixture of donors 11 and 5 completely converted both
donors into reactive intermediates, thus removing the rate
difference in reaction with the promoter. Upon addition of 1
equiv of galactoside 39 to a preactivated mixture of 1 equiv of
donor 5 and 1 equiv of donor 11 at -60 °C, disaccharide 40
and 47 were isolated in a 1: 2.9 ratio with a combined yield of
90% based on the amount of the acceptor added, suggesting
the activated intermediates from donor 11 were 2.9 times more
reactive than that from donor 5 (Scheme 3). When the reactivity
of the acceptor decreased, the reaction became more selective
as donor 5 failed to glycosylate acceptor 4 while donor 11 gave
disaccharide 12 in 56% yield. Since the glycosyl triflate 38 is
more stable than the dioxalenium ion 41, the different glyco-
sylation outcome using donors 5 and 11 is not due to
decomposition of the activated intermediate. The higher reactiv-
ity of dioxalenium ion 41 can be resulting from the lower free
energy difference between 41 and the corresponding oxacar-
benium ion like TS during nucleophilic attack of the acceptor
(step 3) due to the higher electron density of the glycan ring
and better stabilization of the TS. At the mean time, anomeric
triflates may require some additional activation, which is
dependent on the electron-donating potential of the protecting
groups of the donor. Possible mild activators include residual
Ag+ ions or the protonated base. In the absence of such
promoters the reaction temperature needs to be raised to activate
the anomeric triflates toward unreactive acceptors.
A TS connecting the dioxalenium ion derived from the
reaction of methanol with 2-O-acetyl-3,4,6-tri-O-methyl-D-
glucopyranosyl oxacarbenium ion has been found by quantum
mechanical calculations.59 This TS is only 12.9 kJ mol-1 above
the complex between methanol and the dioxalenium ion and is
initiated by C-2sO-2 bond rotation. The ease of C-2sO-2 bond
(57) Bu¨low, A.; Meyer, T.; Olszewski, T. K.; Bols, M. Eur. J. Org. Chem.
2004, 32, 3–329.
(58) Zhang, Z.; Ollman, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong,
C.-H. J. Am. Chem. Soc. 1999, 121, 734–753.
(59) Whitfield, D. M.; Nukada, T. Carbohydr. Res. 2007, 342, 1291–1304.
7958 J. Org. Chem. Vol. 73, No. 20, 2008

Glycosylating UnreactiVe Thioglycosyl Acceptors
rotation is expected to depend on the protecting groups of the
donor. This TS is also stabilized by intramolecular H-bonding
from the hydroxylic proton to electronegative oxygens of the
donor. Such H-bonding is reasonably expected to be sensitive
to the steric accessibility of the hydroxyl and the electronega-
tivity of the donor’s H-bonding acceptor oxygen. It was further
postulated that in the absence of intramolecular H-bonding,
species like the counterions such as triflate or others such as
added bases, molecular sieves, etc. could act as the proton
acceptor.
Although we primarily focused on the preactivation strategy
using thioglycosides, there have been reports that electron-rich
glycosyl donors possessing higher glycosylation power in other
glycosylation protocols and other glycosyl building blocks.60-63
Matta and co-workers discovered that while fucosylation of the
hindered disaccharide 48 failed with donor 49, mixing the more
electron-rich counterpart (donor 50) with 48 under the in situ
anomerization protocol led to trisaccharide 51 in high yield.63
Similarly, substituting the electron-withdrawing benzoyl groups
on a per-O-benzoylated propargyl glycoside donor (donor 52)
with benzyl groups (donor 53) transformed the failed glycosy-
lation with donor 52 to one with 68% yield.62 Therefore, we
propose that when a glycosylation reaction fails to yield the
desired glycoside product, the installation of electron-donating
protective groups onto glycosyl donors can be explored in order
to enhance the glycosylation yield. However, cautions need to
be taken as the more electron-rich donors become less stable
after activation, and thus the usage of lower reaction temperature
is preferred for this type of reactions.
groups onto glycosyl donors can overcome the low reactivities
of glycosyl acceptors using the preactivation protocol. This can
be applied to one-pot synthesis leading to chondroitin and
heparin trisaccharide precursors in high yields. It should be
emphasized that the high reactivity bestowed by electron-
donating groups in our study is observed in the glycosylating
step, rather than in the selective donor activation step encoun-
tered in the armed-disarmed strategy. The installation of
electron-donating protective groups onto glycosyl donors may
be a general strategy to enhance the glycosylation yield,
especially for difficult glycosylation reactions with unreactive
acceptors.
Experimental Section
General Procedure for Single-Step Preactivation-Based Gly-
cosylation. A solution of donor (0.060 mmol), AgOTf (0.18 mmol),
and freshly activated molecular sieve MS 4 Å (200 mg) in diethyl
ether/CH2Cl2 (v:v ) 2:2 mL), CH2Cl2 (3 mL), or CDCl3 (3 mL)
was stirred at room temperature for 30 min and cooled to -60 °C.
After 5 min, orange colored p-TolSCl (9.5 µL, 0.060 mmol) was
added through a microsyringe. Since the reaction temperature was
lower than the freezing point of p-TolSCl, p-TolSCl was added
directly into the reaction mixture to prevent it from freezing on
the flask wall. The characteristic yellow color of p-TolSCl in the
reaction solution dissipated rapidly within a few seconds, indicating
depletion of p-TolSCl. After the donor was completely consumed
according to TLC analysis (less than 5 min at -60 °C), a solution
of acceptor (0.054 mmol) and TTBP (1 equiv) in CH2Cl2 (0.2 mL)
was slowly added dropwise via a syringe. The reaction mixture
was warmed to -20 °C under stirring in 2 h. Then the mixture
was diluted with CH2Cl2 (20 mL) and filtered over Celite. The Celite
was further washed with CH2Cl2 until no organic compounds were
observed in the filtrate by TLC. All CH2Cl2 solutions were
combined and washed twice with saturated aqueous solution of
NaHCO3 (20 mL) and twice with water (10 mL). The organic layer
was collected and dried over Na2SO4. After removal of the solvent,
the desired disaccharide was purified from the reaction mixture via
silica gel flash chromatography.
General Procedure for Monitoring Preactivation by NMR.
Reactions were carried out in NMR tubes with anhydrous CDCl3
at -60 °C. The donor (1.0 equiv) and AgOTf (3.0 equiv) were
added to an NMR tube and dried in vacuo for 3 h. CDCl3 (0.75
mL) was added slowly at -60 °C. Then the donor was preactivated
by the addition of p-TolSCl (1.0 equiv) at -60 °C and the 1H, 13C,
19F, and 2D NMR were acquired. Chemical shifts are downfield
from tetramethylsilane for 1H and 13C NMR and from 1%
trifluoroacetic acid in CDCl3 for 19F NMR.
p-Tolyl 2-O-Benzoyl-3,4,6-tri-O-benzyl-1-thio-ꢀ-D-galactopyra-
noside (11). Compound 11 was synthesized following the literature
procedure.16 [R]D20 +34.5° (c 1.0, CHCl3); H NMR (600 MHz,
1
CDCl3) δ 8.03-6.90 (m, 24 H, COPh, SPhMe, 3 CH2Ph), 5.66 (t,
1 H, J2,1 ) J2,3 ) 9.6 Hz, H-2), 4.98 (d, 1 H, J ) 12.0 Hz, CHHPh),
4.70 (d, 1 H, J1,2 ) 9.6 Hz, H-1), 4.64-4.44 (m, 4 H, CHHPh, 2
CH2Ph), 4.03 (d, 1 H, J4,5 ) 3.0 Hz, H-4), 3.70-3.65 (m, 4 H,
H-3, H-5, H-6a, H-6b), 2.27 (s, 3 H, SPhMe); 13C NMR (150 MHz,
CDCl3) δ 165.5 (1 C, 1 COPh), 138.7, 138.1, 137.9, 137.8, 133.2,
132.9, 130.4, 130.1, 130.0, 129.7, 128.7, 128.6, 128.5, 128.4, 128.3,
128.2, 128.1, 128.0, 127.7 (CH2Ph, COPh, SPhMe, some signals
overlapped), 87.5 (1 C, JC-1,H-1 ) 166.3 Hz, C-1), 81.4, 77.9, 74.6,
73.9, 72.9, 72.0, 70.7, 69.0, (C-2∼6, 3 CH2Ph), 21.4 (1 C, SPhMe).
ESI-MS [M + Na]+ calcd for C41H40NaO6S 683.2, found 683.2.
p-Tolyl 2-O-Benzoyl-3,4,6-tri-O-benzyl-r,ꢀ-D-galactopyranosyl-
(1f4)-2,3-di-O-benzoyl-6-O-benzyl-1-thio-ꢀ-D-galactopyranoside
(12r and 12ꢀ). Donor 11 (25 mg, 37.8 µmol, 1.0 equiv) and AgOTf
(29.9 mg, 113.5 µmol, 3.0 equiv) were placed in an NMR tube
and dried in vacuo for 3 h. CDCl3 (0.75 mL) was added slowly at
-60 °C. Then the donor was preactivated by the addition of
Conclusions
We have investigated the intermediate structures following
preactivation of several representative thioglycosyl donors
bearing 2-O acyl groups by low-temperature NMR. It was found
that glycosyl triflates were the major intermediates formed for
donors bearing multiple electron-withdrawing groups, while with
the electron-rich donors the dioxalenium ions were produced.
We demonstrated that the introduction of electron-donating
(60) Mydock, L. K.; Demchenko, A. V. Org. Lett. 2008, 10, 2107–2110.
(61) Mydock, L. K.; Demchenko, A. V. Org. Lett. 2008, 10, 2103–2106.
(62) Hotha, S.; Kashyap, S. J. Am. Chem. Soc. 2006, 128, 9620–9621.
(63) Xia, J.; Alderfer, J. L.; Locke, R. D.; Piskorz, C. F.; Matta, K. L. J.
Org. Chem. 2003, 68, 2752–2759.
J. Org. Chem. Vol. 73, No. 20, 2008 7959

Zeng et al.
p-TolSCl (6.0 µL, 37.8 µmol, 1.0 equiv) at -60 °C. After 1H, 13C,
19F, and 2D NMR were acquired at -60 °C, a solution of the
acceptor 4 (20.0 mg, 34.2 µmol, 0.9 equiv) and TTBP (9.0 mg,
37.8 µmol, 1.0 equiv) in CDCl3 (0.25 mL) was added to the NMR
tube. The reaction mixture was gradually warmed up to rt in 3 h.
The reaction mixture was quenched by Et3N and filtered through
Celite. The filtrate was concentrated and purified by flash column
chromatography (toluene/hexanes/ethyl acetate ) 10:10:1) to give
12r (6.0 mg, 5.0 µmol, 8%) and 12ꢀ (37.0 mg, 33 µmol, 48%).
1′,H-1′ ) 165.4 Hz, C-1′), 87.5 (1 C, JC-1,H-1 ) 163.6 Hz, C-1), 76.6,
76.5, 75.2, 74.8, 74.3, 73.3, 73.2, 71.2, 69.2, 68.5, 65.4 (12 C,
C-2-6, CH2Ph, CH2PhOMe, some signals overlapped), 55.4 (1 C,
CH2PhOMe), 26.1, 21.4, 18,2 (5 C, SPhMe, C(Me)3, C(Me)3, some
signals overlapped), -3.64, -4.63 (2 C, SiMe). ESI-MS [M + Na]+
calcd for C68H72O15NaSSi 1211.4, found 1211.4. HRMS [M + Na]+
calcd for C68H72O15NaSSi 1211.4259, found 1211.4252.
p-Tolyl 2-O-Benzoyl-3-O-benzyl-4-O-tert-butyldimethylsilyl-6-
O-p-methoxylbenzyl-ꢀ-D-glucopyranosyl-(1f4)-2,3-di-O-benzoyl-
6-O-benzyl-1-thio-ꢀ-D-galactopyranoside (15). Compound 15 (32
mg, 26.5 µmol, 70%) was prepared according to the general
procedure for glycosylation using donor 13 (31 mg, 43.4 µmol,
1.0 equiv) and acceptor 4 (20.0 mg, 34.2 µmol, 0.9 equiv) and
purified by flash column chromatography (hexanes/ethyl acetate )
For R-isomer 12r: [R]D20 +44.6° (c 1.0, CHCl3); H NMR (600
1
MHz, CDCl3) δ 8.23-7.00 (m, 34 H, 2 COPh, SPhMe, 4 CH2Ph),
5.77 (t, 1 H, J2,1 ) J2,3 ) 9.6 Hz, H-2), 5.70 (dd, 1 H, J2′,1′ ) 3.2
Hz, J2′,3′ ) 8.4 Hz, H-2′), 5.24 (dd, 1 H, J3,2 ) 9.6 Hz, J3,4 ) 2.4
Hz, H-3), 5.20 (d, 1 H, J1′,2′ ) 3.2 Hz, H-1′), 4.84 (d, 1 H, J )
11.2 Hz, CHHPh), 4.83 (d, 1 H, J1,2 ) 9.6 Hz, H-1), 4.70-4.44
(m, 4 H, CHHPh, CH2Ph), 4.30-3.77 (m, 8 H, H-4, H-5, H-6a,H-
6b, 2 CH2Ph), 3.60-3.33 (m, 2 H, H-3′, H-6′a), 3.33 (dd, 1 H, J6’b,5′
4:1). [R]2D0 +69.3° (c 1.0, CHCl3); H NMR (600 MHz, CDCl3) δ
1
8.00-6.80 (m, 33 H, 3 COPh, SPhMe, 2 CH2Ph, CH2PhOMe),
5.47 (dd, 1 H, J2,1 ) J2,3 ) 9.6 Hz, H-2), 5.37 (dd, 1 H, J3,2 ) 9.6
Hz, J3,4 ) 3.0 Hz, H-3), 5.28 (dd, 1 H, J2′,1′ ) 7.8 Hz, J2′,3′ ) 8.4
) J6’b,6’a ) 8.8 Hz, H-6′b), 2.80 (dd, 1 H, J5′,6’b ) 5.2 Hz, J5′,6’a
)
8.8 Hz, H-5′), 2.17 (s, 3 H, SPhMe); HRMS [M + Na]+ calcd for
C68H64NaO13S 1143.3965, found 1143.3972. For ꢀ-isomer 12ꢀ:
[R]2D0 +57.5° (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ
8.10-6.90 (m, 34 H, 2 COPh, SPhMe, 4 CH2Ph), 5.64 (dd, 1 H,
J2′,1′ ) 7.8 Hz, J2′,3′ ) 9.6 Hz, H-2′), 5.48 (t, 1 H, J2,1 ) J2,3 ) 9.6
Hz, H-2), 5.38 (dd, 1 H, J3,2 ) 9.6 Hz, J3,4 ) 2.4 Hz, H-3), 4.98
(d, 1 H, J ) 11.8 Hz, CHHPh), 4.79 (d, 1 H, J1,2 ) 9.6 Hz, H-1),
4.71 (d, 1 H, J1′,2′ ) 7.8 Hz, H-1′), 4.60 (d, 1 H, J ) 12.6 Hz,
CHHPh), 4.57 (d, 1 H, J ) 12.0 Hz, CHHPh), 4.55 (d, 1 H, J )
12.0 Hz, CHHPh), 4.50 (d, 1 H, J ) 11.8 Hz, CHHPh), 4.45-4.41
(m, 2 H, H-4, CHHPh), 4.26 (s, 1 H, CH2Ph), 3.92-3.73 (m, 3 H,
H-4′, H-5, H-6a, H-6b), 3.55 (dd, 1 H, J6’a,5′ ) J6’a,6’b ) 8.4 Hz,
H-6′a), 3.43 (dd, 1 H, J3′,2′ ) 9.6 Hz, J3′,4′ ) 2.4 Hz, H-3′), 3.32
(dd, 1 H, J6’b,5′ ) 5.4 Hz, J6’b,6’a ) 8.4 Hz, H-6′b), 3.26 (dd, 1 H,
Hz, H-2′), 4.80 (d, 1 H, J1,2 ) 9.6 Hz, H-1), 4.79 (d, 1 H, J1′,2′
)
7.8 Hz, H-1′), 4.66 (d, 1 H, J ) 10.8 Hz, CHHPh), 4.56 (d, 1 H,
J ) 10.8 Hz, CHHPh), 4.52 (d, 1 H, J ) 11.4 Hz, CHHPh),
4.47-4.45 (m, 2 H, CHHPh, H-4), 4.41 (d, 1 H, J ) 12.0 Hz,
CHHPh), 4.29 (d, 1 H, J ) 12.0 Hz, CHHPh), 3.90-3.83 (m, 3 H,
H-5, H-6a,H-6b), 3.75-3.71 (m, 4 H, H-4′, CH2PhOMe), 3.54-3.21
(m, 4 H, H-3′, H-6′a, H-6′b, H-5′), 2.21 (s, 3 H, SPhMe), 0.77 (s,
9 H, tert-butyl), -0.07 (s, 3 H, Me), -0.12 (s, 3 H, Me); 13C
NMR(150 MHz, CDCl3) δ 165.9, 165.7, 164.8 (3 C, COPh), 159.4,
138.8, 138.1, 137.8, 133.3, 133.1, 132.8, 130.4, 130.2, 130.1, 129.9,
129.8, 129.3, 129.2, 128.6, 128.5, 128.4, 128.3, 127.8, 127.7, 127.6,
127.5, 114.0, (CH2Ph-C, CH2PhOMe, SPhMe, some signals
overlapped), 103.8 (1 C, JC-1′,H-1′ ) 166.0 Hz, C-1′), 87.2 (1 C,
JC-1,H-1 ) 159.0 Hz, C-1), 83.4, 78.7, 76.6, 75.6, 74.7, 74.3, 73.7,
73.2, 72.8, 71.0, 70.9, 69.1, 68.7, 68.2, 66.7 (13C, C-2∼6, 2 CH2Ph,
CH2PhOMe, some signals overlapped), 55.5 (1 C, CH2PhOMe),
26.1, 26.1, 21.3, 18,5 (5 C, SPhMe, C(Me)3, C(Me)3, some signals
overlapped), -3.66, -4.67 (2 C, SiMe); HRMS [M + Na]+ calcd
for C68H74O14NaSSi 1197.4466, found 1197.4451.
J5′, 6’b ) 5.4 Hz, J5′,6’a ) 8.4 Hz, H-5′), 2.21 (s, 3 H, SPhMe); 13
C
NMR (150 MHz, CDCl3) δ 166.0, 165.8, 164.7 (3 C, 3 COPh),
138.8, 138.7, 137.9, 137.9, 133.6, 133.1, 132.8, 132.7, 130.8, 130.3,
130.0, 129.9, 129.7, 129.3, 129.2, 128.7, 128.6, 128.5, 128.4, 128.3,
128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, (CH2Ph, COPh,
SPhMe, some signals overlapped), 101.0 (1 C, JC-1,H-1 ) 165.3 Hz,
C-1), 87.0 (1 C, JC-1′,H-1′ ) 162.4 Hz, C-1′), 80.5, 78.4, 75.7, 74.8,
73.8, 73.7, 72.8, 72.2, 72.1, 71.9, 70.0, 68.7, 68.3, (C-2-6, 4 CH2Ph,
some signals overlapped), 21.3 (1 C, SPhMe). HRMS [M + H]+
calcd for C68H65O13S 1121.4146, found 1121.4130.
p-Tolyl (Benzyl 2-O-benzoyl-3-O-benzyl-4-O-tert-butyldimeth-
ylsilyl-ꢀ-D-glucopyranosyluronate)-(1f3)-4,6-O-benzylidene-2-(2,2,2-
trichloroacetylamino)-2-deoxy-1-thio-ꢀ-D-glucopyranoside (24). Com-
pound 24 was synthesized from donor 23 and acceptor 21 in 73%
yield following the general procedure of single step glycosylation and
purified by flash column chromatography (hexanes/ethyl acetate ) 3:1).
[R]2D0 + 11.2 (c 1, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.87-7.85
(m, 2H, aromatic), 7.52-7.49 (m, 1H, aromatic), 7.36-7.25 (m, 9H,
aromatic), 7.16-7.08 (m, 6H, aromatic), 6.93-6.89 (m, 1H, aromatic),
5.30 (s, 1H, CHPh), 5.27 (d, 1H, J1,2 ) 10.2 Hz, H-1), 5.17-5.10 (m,
3H, CH2Ph, H-2′), 4.99 (d, 1H, J1′,2′ ) 7.2 Hz, H-1′), 4.64-4.56 (m,
2H, CH2Ph), 4.52 (t, 1H, J ) 9.6 Hz, H-4′), 4.29-4.26 (m, 1H, H-6a),
4.15-4.12 (m, 1H, H-4′), 3.80 (d, 1H, J4′,5′ ) 6.0 Hz, H-5′), 3.67-3.63
(m, 2H, H-4, H-6b), 3.52-3.47 (m, 2H, H-2, H-5), 3.27-3.25 (m,
1H, H-3′), 2.34 (s, 3H, SPhCH3); 13C NMR (150 MHz, CDCl3) δ
168.3, 165.1, 161.5, 139.0, 137.6, 137.0, 135.0, 133.9, 133.2, 130.0,
129.8, 129.4, 129.1, 128.7, 128.6, 128.3 (x2), 128.1, 127.5, 127.4,
127.0, 126.2, 101.5, 98.8, 84.2, 81.0, 79.9, 77.3, 76.2, 74.0, 71.2, 70.5,
67.2, 57.2, 25.7, 21.2, 17.8, -4.5, -5.3; ESI-MS [M + Na]+ calcd
for C55H60Cl3NNaO12SSi 1114.3, found 1114.6; HRMS [M + Na]+
calcd for C55H60Cl3NNaO12SSi 1114.2569, found 1114.2573; gHMQC
p-Tolyl 2-O-Benzoyl-3-O-benzyl-4-O-tert-butyldimethylsilyl-6-
O-p-methoxylbenzyl-ꢀ-D-glucopyranosyl-(1f4)-2,3,6-tri-O-benzoyl-
1-thio-ꢀ-D-glucopyranoside (14). Compound 14 (60 mg, 74%) was
prepared according to the general procedure for glycosylation using
donor 13 (50 mg, 69.9 µmol, 1.0 equiv) and acceptor 3 (37.7 mg,
63.0 µmol) and purified by flash column chromatography (hexanes/
ethyl acetate ) 4:1). [R]D20 +61.3° (c 1.0, CHCl3); H NMR (600
1
MHz, CDCl3) δ 8.10-6.70 (m, 33 H, 4 COPh, SPhMe, CH2Ph,
CH2PhOMe), 5.52 (t, 1 H, J2,1 ) J2,3 ) 9.6 Hz, H-2), 5.38 (dd, 1
H, J3,2 ) 9.6 Hz, J3,4 ) 3.0 Hz, H-3), 5.35 (dd, 1 H, J2′,1′ ) J2′,3′
) 8.4 Hz, H-2′), 4.81 (d, 1 H, J1,2 ) 9.6 Hz, H-1), 4.74 (d, 1 H,
J1′,2′ ) 7.8 Hz, H-1′), 4.72 (dd, 1 H, J6a,5 ) 3.0 Hz, J6a,6b ) 12.6
Hz, H-6a), 4.69 (d, 1 H, J ) 11.4 Hz, CHHPh), 4.62 (dd, 1 H, J6b,5
) 8.4 hz, J6a,6b ) 12.6 Hz, H-6b), 4.60 (d, 1 H, J ) 11.4 Hz,
CHHPh), 4.52 (d, 1 H, J4,3 ) 3.0 Hz, H-4), 4.47 (d, 1 H, J ) 11.4
Hz, CHHPhOMe), 4.35 (d, 1 H, J ) 11.4 Hz, CHHPhOMe), 4.08
(dd, 1 H, J5,6a ) 3.0 Hz, J5,6b ) 8.4 Hz, H-5), 3.72-3.62 (m, 4 H,
H-4′, CH2PhOMe), 3.61 (dd, 1 H, J6’a,5′ ) 1.8 Hz, J6’a,6’b ) 10.2
Hz, H-6’a), 3.53 (dd, 1 H, J3′,2′ ) J3,4 ) 8.4 Hz, H-3′), 3.50 (dd, 1
H, J6’b,5′ ) 6.0 Hz, J6’a,6’b ) 10.2 Hz, H-6’b), 3.33 (ddd, 1 H, J5′,4′
) 7.8 Hz, J5′,6’a ) 1.8 Hz, J5′,6’b ) 6.0 Hz, H-5′), 2.19 (s, 3 H,
SPhMe), 0.76 (s, 9 H, tert-butyl), -0.05 (s, 3 H, Me), -0.10 (s, 3
H, Me); 13C NMR (150 MHz, CDCl3) δ 166.5, 166.0, 165.6, 164.8
(4 C, COPh), 159.3, 138.1, 137.8, 133.6, 133.3, 133.2, 133.1, 132.4,
130.4, 130.2, 130.1, 130.0, 129.9, 129.8, 129.7, 129.6, 129.1, 128.7,
128.6, 128.5, 128.4, 128.3, 127.7, 127.5, 114.0, (CH2Ph-C,
CH2PhOMe, SPhMe, some signals overlapped), 100.9 (1 C, JC-
(without 1H decoupling): 1JC1,H1 ) 161.9 Hz, 1JC1′ H1′
) 164.6 Hz.
,
p-Tolyl 2-O-Benzoyl-3,4,6-tri-O-benzyl-ꢀ-D-galactopyranosyl-
(1f3)-4,6-O-benzylidene-2-deoxy-2-N-phthalimido-1-thio-ꢀ-D-ga-
lactopyranoside (26). Compound 26 was synthesized from donor
11 and acceptor 25 in 65% yield (51% ꢀ + 14% R) following the
general procedure of single step glycosylation. [R]2D0 +33.6 (c 1,
1
CH2Cl2); 26ꢀ H NMR (600 MHz, CDCl3) δ 7.70-7.68 (m, 2H),
7.56-7.55 (m, 1H), 7.50-7.42 (m, 4H, aromatic), 7.36-7.16 (m,
19H, aromatic), 7.12-7.10 (m, 1H, aromatic), 7.04-6.95 (m, 6H,
aromatic), 5.53-5.50 (m, 1H), 5.52 (d, 1H, J1,2 ) 7.8 Hz, H-1),
5.28 (s, 1H, CHPh), 4.93 (d, 1H, J ) 12 Hz), 4.80-4.78 (m, 1H),
7960 J. Org. Chem. Vol. 73, No. 20, 2008

Glycosylating UnreactiVe Thioglycosyl Acceptors
4.66 (d, 1H, J1′,2′ ) 8.4 Hz, H-1′), 4.62-4.56 (m, 2H), 4.50 (d,
1H, J ) 12 Hz), 4.43-4.42 (m, 1H), 4.33-4.23 (m, 4H), 3.90-3.88
(m, 2H), 3.54 (s, 1H), 3.46-3.42 (m, 3H), 3.05-3.03 (m, 1H),
2.26 (s, 3H, SPhCH3); 13C NMR (150 MHz, CDCl3) δ 168.9, 166.9,
165.3, 138.8, 138.1, 138.0, 137.6, 134.1, 133.9, 133.6, 133.0, 131.9,
131.7, 129.9, 129.8, 129.6, 128.8, 128.7, 128.5 ( × 2), 128.4, 128.1
(×3), 127.9, 127.8, 127.7 (×2), 127.6, 126.8, 123.7, 122.9, 101.3,
100.4, 82.9, 80.3, 75.1, 74.4, 73.6 (×2), 73.2, 72.1, 71.7, 71.4, 70.4,
(5 mL), the solution was cooled to -60 °C, followed by addition
of AgOTf (54 mg, 209 µmol) in Et2O (1.5 mL). The mixture was
stirred for 5 min at -60 °C and then p-TolSCl (11.1 µL, 69.9 µmol)
was added into the solution. (See the general procedure for single-
step preactivation-based glycosylation for precautions.) The mixture
was vigorously stirred for 10 min, followed by addition of a solution
of acceptor 29 (32.7 mg, 66.4 µmol) and TTBP (17.4 mg, 69.9
µmol) in CH2Cl2 (1 mL). The reaction mixture was stirred for 2 h
from -60 to -20 °C, and then the mixture was cooled down to
-60 °C, followed by sequential addition of AgOTf (18 mg, 69.9
µmol) in Et2O (1 mL), acceptor 27 (27.7 mg, 55.9 µmol), and TTBP
(17.4 mg, 69.9 µmol) in CH2Cl2 (1 mL). The mixture was stirred
for 5 min at -60 °C, then p-TolSCl (10.5 µL, 66.4 µmol) was
added to the solution, and the reaction mixture was stirred for 2 h
from -60 to -20 °C. The reaction was quenched with Et3N (50
µL) and concentrated under vacuum to dryness. The resulting
residue was diluted with CH2Cl2 (20 mL), followed by filtration.
The organic phase was washed with saturated aqueous NaHCO3
and H2O and then dried over Na2SO4, filtered, and concentrated.
Silica gel column chromatography (5:1:1 hexanes/ethyl acetate/
CH2Cl2) afforded 30 as a gel (39.7 mg, 49%). [R]2D0 +34.3 (c 1,
CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.77-7.75 (m, 2H,
aromatic), 7.44-7.20 (m, 21H, aromatic), 7.12-7.06 (m, 9H,
aromatic), 6.98-6.97 (m, 2H, aromatic), 6.84-6.82 (m, 2H,
aromatic), 6.77-6.76 (m, 2H, aromatic), 5.66 (d, 1H, J ) 4.2 Hz),
5.19 (t, 1H, J ) 8.4 Hz), 5.13 (d, 1H, J ) 11.4 Hz), 5.00 (d, 1H,
J ) 10.2 Hz), 4.89 (d, 1H, J ) 11.4 Hz), 4.75-4.59 (m, 6H),
4.47-4.42 (m, 3H), 4.24 (d, 1H, J ) 7.8 Hz),4.11 (d, 1H, J ) 12
Hz), 4.02-3.95 (m, 3H), 3.87-3.84 (m, 1H), 3.79-3.61 (m, 9H),
3.60-3.58 (m, 1H), 3.51-3.50 (m, 4H), 3.41-3.25 (m, 8H),
3.12-3.06 (m, 2H), 3.43-3.37 (m, 4H), 3.32-3.28 (m, 3H),
3.14-3.10 (m, 2H), 2.96 (s, 1H), 0.87 (s, 9H, (CH3)3CSi), -0.02(s,
3H, CH3Si), -0.04 (s, 3H, CH3Si). 13C NMR (150 MHz, CDCl3)
δ 164.7, 158.9, 158.8, 138.7, 138.3 (×2), 137.8, 137.7, 133.2, 130.6,
130.2, 129.5 (×2), 129.0, 128.9 (×2), 128.7, 128.4 (×2), 128.3
(×3), 128.2, 128.0 (×2), 127.7, 127.6, 127.5 (×2), 127.4, 127.3,
113.6, 113.4, 104.5, 99.7, 97.3, 84.9, 83.1, 82.6, 77.5, 76.8, 75.6,
75.1 (×2), 75.0, 74.5 (×2), 74.0, 73.7, 73.0, 72.4, 72.3, 71.3, 70.8,
69.0, 68.3, 66.8, 62.4, 57.0, 55.2 (×2), 25.9 (×2), 17.9, -3.8, -4.7;
HRMS [M + Na]+ calcd for C83H97N3NaO18Si 1474.6434; obsd
69.5, 68.2, 50.7, 21.4; ESI-MS [M
+
Na]+ calcd for
C62H57NNaO12S 1063.3, found 1063.2; HRMS [M + NH4]+ calcd
for C62H61N2O12S 1057.3945, found 1057.3933; gHMQC (without
1
1
1H decoupling): JC1,H1 ) 161.1 Hz, JC1′ H1′
) 159.3 Hz.
,
Methyl 2-O-Benzoyl-3-O-benzyl-4-O-tert-butyldimethylsilyl-6-
O-p-methoxybenzyl-ꢀ-D-glucopyranosyl-(1f3)-4,6-O-benzylidene-
2-deoxy-2-N-phthalimido-ꢀ-D-galactopyranosyl-(1f4)-2,3-di-O-
benzyl-6-O-p-methoxybenzyl-ꢀ-D-glucopyranoside (28). Compound
28 was synthesized by a three-component one-pot synthesis
procedure. After the donor 13 (50 mg, 69.93 µmol) and activated
molecular sieve MS 4 Å (500 mg) were stirred for 30 min at room
temperature in CH2Cl2 (5 mL), the solution was cooled to -60 °C,
followed by addition of AgOTf (54 mg, 209 µmol) in Et2O (1.5
mL). The mixture was stirred for 5 min at -60 °C, and then
p-TolSCl (11.1 µL, 69.9 µmol) was added to the solution. (See the
general procedure for single-step preactivation-based glycosylation
for precautions.) The mixture was vigorously stirred for 10 min,
followed by addition of a solution of building block 25 (28.2 mg,
56.0 µmol) and TTBP (17.4 mg, 69.9 µmol) in CH2Cl2 (1 mL).
The reaction mixture was stirred for 2 h from -60 to -20 °C and
then the mixture was cooled down to -60 °C, followed by
sequential addition of AgOTf (18 mg, 69.9 µmol) in Et2O (1 mL),
acceptor 27 (20.8 mg, 42.0 µmol), and TTBP (17.4 mg, 69.9 µmol)
in CH2Cl2 (1 mL). The mixture was stirred for 5 min at -60 °C
and then p-TolSCl (8.9 µL, 56.0 µmol) was added into the solution,
and the reaction mixture was stirred for 2 h from -60 to -20 °C.
The reaction was quenched with Et3N (50 µL), concentrated under
vacuum to dryness. The resulting residue was diluted with CH2Cl2
(20 mL), followed by filtration. The organic phase was washed
with saturated aqueous NaHCO3 and H2O and then dried over
Na2SO4, filtered, and concentrated. Silica gel column chromatog-
raphy (3:1:1 hexanes/ethyl acetate/CH2Cl2) afforded 28 as a white
solid (41.2 mg, 67%). Mp 82-84 °C; [R]2D0 +30.4 (c 1, CH2Cl2);
1H NMR (600 MHz, CDCl3) δ 7.50-7.34 (m, 7H. aromatic),
7.31-7.16 (m, 16H, aromatic), 7.12-7.00 (m, 8H, aromatic),
6.92-6.90 (m, 2H, aromatic), 6.83-6.79 (m, 4H, aromatic), 5.40
(s, 1H, CHPh), 5.30 (d, 1H, J ) 8.4 Hz), 5.12 (t, 1H, J ) 7.8 Hz),
5.02 (d, 1H, J ) 11.4 Hz), 4.85 (d, 1H, J ) 12 Hz), 4.76 (d, 1H,
J ) 11.4 Hz), 4.70 (d, 1H, J ) 7.2 Hz), 4.66-4.64 (m, 1H),
4.60-4.57 (m, 2H), 4.46-4.32 (m, 5H), 4.10 (d, 1H, J ) 7.8 Hz),
4.09-4.07 (m, 1H), 3.99-3.97 (m, 1H), 3.78-3.76 (m, 7H),
3.65-3.64 (m, 1H), 3.59-3.55 (m, 2H), 3.53-3.46 (m, 3H),
3.43-3.37 (m, 4H), 3.32-3.28 (m, 3H), 3.14-3.10 (m, 2H), 2.96
(s, 1H), 0.78 (s, 9H, (CH3)3CSi), -0.11(s, 3H, CH3Si), -0.15 (s,
3H, CH3Si); 13C NMR (150 MHz, CDCl3) δ 169.4, 167.3, 164.4,
159.5, 159.1, 139.6, 138.7, 138.3, 137.8, 133.8, 133.6, 132.7, 131.4,
131.2, 130.7, 130.2, 129.6 (×2), 129.1, 128.7, 128.4 (×2), 128.3,
128.2 (×2), 128.1, 127.7, 127.5, 127.3 (×2), 127.1, 126.7, 123.4,
122.6, 114.0, 113.7, 104.5, 101.8, 100.7, 98.5, 83.6, 83.3, 82.3,
76.5, 76.3, 76.0, 75.1, 74.9, 74.8, 74.7, 74.3, 74.1, 73.3, 72.4, 71.3,
70.0, 69.0, 68.2, 67.0, 57.1, 55.5 (×2), 52.5, 26.1, 18.1, -3.7, -4.5;
HRMS [M + Na]+ calcd for C84H93NNaO20Si 1486.5958, found
1486.5946; gHMQC (without 1H decoupling): 1JC1,H1 ) 159.3 Hz,
162.2 Hz, 162.2 Hz.
1474.6414; gHMQC (without 1H decoupling): 1JC1′ H1′
) 172.6 Hz,
,
1
other two JC1,H1 ) 160.2 Hz, 162.8 Hz.
2,3,4,6-Tetra-O-benzoyl-r-D-galactopyranosyl Triflate (38). Com-
pound 38 was obtained according to the general procedure. 1H NMR
(400 MHz, CDCl3, -60 °C) δ 8.12-7.20 (m, 28 H, 4 COPh,
(SPhMe)2), 6.57 (d, 1 H, J1,2 ) 3.2 Hz, H-1), 6.17 (d, 1 H, J1,2
2.0 Hz, H-4), 6.11-5.80 (m, 2 H, H-2, H-3), 4.94 (dd, 1 H, J5,6a
8.0 Hz, J5,6b ) 5.2 Hz, H-5), 4.66 (dd, 1 H, J6a,5 ) 8.0 Hz, J6a,6b
)
)
)
11.6 Hz, H-6a), 4.43 (dd, 1 H, J6b,5 ) 5.2 Hz, J6b,6a ) 11.6 Hz,
H-6b), 2.44 (s, 6 H, (SPhMe)2);13C NMR (100 MHz, CDCl3, -60
°C) δ 166.4, 165.8, 165.8, 165.5 (4 C, COPh), 134.7, 134.3, 134.2,
131.9, 130.4, 130.3, 130.2, 130.0, 129.3, 129.2, 129.0, 128.9, 128.8,
128.3, 128.2, 127.7 (COPh-C, (SPhMe)2, some signals overlapped),
104.4 (1 C, C-1), 71.6, 67.7, 67.4, 66.7, 62.4 (5C, C-2-6), 22.4 (2
C, (SPhMe)2).
2,3,4,6-Tetra-O-benzoyl-ꢀ-D-galactopyranosyl-(1f6)-1,2:3,4-di-
isopropylidene-r-D-galactopyranoside (40). Donor 5 (31 mg, 44.1
µmol, 1.0 equiv) and AgOTf (33.9 mg, 132.3 µmol, 3.0 equiv)
were added to an NMR tube and dried in vacuo for 3 h. CDCl3
(0.75 mL) was added slowly at -60 °C. Then the donor was
preactivated by the addition of p-TolSCl (7.1 µL, 44.1 µmol, 1.0
equiv) at -60 °C and 1H, 13C, 19F, and 2D NMR were acquired at
-60 °C. This was followed by the addition of acceptor 39 (10.3
mg, 39.7 µmol, 0.9 equiv) and TTBP (11.0 mg, 44.1 µmol, 1.0
equiv) as acid scavenger in CDCl3 (0.25 mL). The reaction mixture
was quenched by Et3N, and purified by flash column chromatograph
(hexanes/ethyl acetate ) 4:1) to give 40 (29.9 mg, 35.7 µmol, 90%)
Methyl 2-O-Benzoyl-3-O-benzyl-4-O-tert-butyldimethylsilyl-6-
O-p-methoxybenzyl-ꢀ-D-glucopyranosyl-(1f4)-2-azido-3,6-di-O-
benzyl-2-deoxy-r-D-glucopyranosyl-(1f4)-2,3-di-O-benzyl-6-O-p-
methoxybenzyl-ꢀ-D-glucopyranoside (30). Compound 30 was
synthesized by a three-component one-pot procedure. After the
donor 13 (50 mg, 69.93 µmol) and activated molecular sieve MS
4 Å (500 mg) were stirred for 30 min at room temperature in CH2Cl2
as a colorless syrup. [R]D20 +37.4° (c 1.0, CHCl3); H NMR (600
1
MHz, CDCl3) δ 8.07-7.20 (m, 20 H, 4 COPh), 5.83 (d, 1 H, J4′,3′
J. Org. Chem. Vol. 73, No. 20, 2008 7961

Zeng et al.
) 3.6 Hz, H-4′), 5.80 (dd, 1 H, J2′,1′ ) 7.8 Hz, J2′,3′ ) 10.8 Hz,
H-2′), 5.60 (dd, 1 H, J3′,2′ ) 10.8 Hz, J3′,4′ ) 3.6 Hz, H-3′), 5.40
(d, 1 H, J1,2 ) 3.2 Hz, H-1), 5.01 (d, 1 H, J1′,2′ ) 7.8 Hz, H-1′),
4.67 (dd, 1 H, J6a′,5′ ) 5.4 Hz, J6a′,6b′ ) 11.4 Hz, H-6’a), 4.42-3.38
(m, 2 H, H-5′, H-6’b), 4.33 (t, 1 H, J3,2 ) J3,4 ) 6.6 Hz, H-3), 4.20
CDCl3 (0.75 mL) was added slowly at -60 °C. Then the donor
was preactivated by addition of the p-TolSCl (7.0 µL, 44.0 µmol,
1
1.0 equiv) at -60 °C, and the H, 13C, 19F, and 2D NMR spectra
were acquired. This was followed by addition of the acceptor 39
(10.3 mg, 39.7 µmol, 0.9 equiv) and TTBP (10.9 mg, 44.0 µmol,
1.0 equiv) as acid scavenger in CDCl3 (0.25 mL). After reaching
-20 °C, the reaction mixture was quenched by Et3N and purified
by flash column chromatograph (hexanes/ethyl acetate ) 3:1) to
give 46 (20.0 mg, 33.7 µmol, 85.0%) as a white foam. [R]2D0 -50.8°
(dd, 1 H, J2,1 ) 3.2 Hz, J2,3 ) 6.6 Hz, H-2), 4.06 (dd, 1 H, J6a,5
)
7.2 Hz, J6a,6b ) 10.8 Hz, H-6a), 3.95-3.70 (m, 2 H, H-5, H-6b),
1.38 (s, 3 H, CH3), 1.23 (s, 3 H, CH3), 1.20 (s, 3 H, CH3), 1.18 (s,
3 H, CH3); 13C NMR (150 MHz, CDCl3) δ 166.3, 165.8, 165.7,
165.5 (4 C, 4 COPh), 133.8, 133.5, 133.3, 130.3, 130.2, 130.0,
129.6, 129.2, 129.0, 128.8, 128.7, 128.5, (COPh-C, some signals
overlapped), 109.4 (1 C, C(CH3)2), 108.7 (1 C, C(CH3)2), 101.9 (1
C, JC-1′,H-1′ ) 165.4 Hz, C-1′), 96.4 (1 C, JC-1,H-1 ) 176.1 Hz, C-1),
72.0, 71.5, 71.2, 70.7, 70.5, 69.9, 68.6, 68.4, 67.7, 62.3 (C-2-6,
some signals overlapped), 26.1, 25.9, 25.1, 24.4 (4 C, 2 C(CH3)2);
ESI-MS [M + Na]+ calcd for C46H46NaO15 861.3, found 861.2;
HRMS [M + NH4]+ calcd for C46H50NO15 856.3180, found
856.3162.
3,4,6-Tri-O-benzyl-D-galactopyranosyl Benzoxonium Ion (41).
Compound 41 was obtained according to the general experimental
procedure. 1H NMR (400 MHz, CDCl3, -60 °C) δ 8.10-7.24 (m,
29 H, H-1, 3 CH2Ph, CPh, (SPhMe)2), 5.77 (bs, 1 H, H-2),
4.89-4.67 (m, 3 H, 2 CHHPh, CHHPh), 4.62-4.58 (m, 2 H,
CHHPh, H-5), 4.42-4.34 (m, 2 H, CHHPh, H-3), 4.30-4.20 (m,
2 H, CHHPh, H-4), 3.79-3.76 (1 H, H-6a), 3.64-3.58 (1 H, H-6b),
2.44 (s, 6 H, (SPhMe)2);13C NMR (100 MHz, CDCl3, -60 °C) δ
180.8 (1 C, C-7), 140.9, 137.7, 137.5, 133.9, 131.8, 131.0, 130.3,
130.0, 129.4, 128.8, 128.7, 128.5, 128.3, 128.1, 127.5, 125.0, 121.8,
118.6, 118.0 (CPh-C, CH2Ph, (SPhMe)2, some signals overlapped),
114.2 (1 C, C-1), 83.9 (1 C, C-2), 75.6, 74.8, 73.6, 71.6, 69.0 (7 C,
C-3-6, CH2Ph), 22.4 (1 C, (SPhMe)2).
2,3,4,6-Tetra-O-acetyl-r-D-glucopyranosyl Triflate (44) and 3,4,6-
Tri-O-acetyl-D-glucopyranosyl Acetoxonium Ion (45). The mixture
of intermediates 44 and 45 was obtained following the general
experimental procedure. For the mixture of 44 and 45 in 1:1 ratio:
1H NMR (400 MHz, CDCl3, -60 °C) δ 7.41-7.24 (m, 9 H, H-1,
2 (SPhMe)2), 6.21 (d, 1 H, J1,2 ) 2.4 Hz, H-1 from 44), 5.73 (1 H,
H-3 from 45), 5.57 (3 H, H-2 from 45, H-3 from 44, H-4 from
45), 5.31 (2 H, H-2 from 44, H-4 from 44), 4.82 (1 H, H-5 from
45), 4.44 (1 H, H-5 from 44), 4.14 (4 H, 2 H-6 from 44, 2 H-6
from 45), 2.82 (3 H, CCH3 from 45), 2.44 (s, 12 H, 2 (SPhMe)2),
2.19, 2.15, 2.14, 2.09, 2.07, 2.03 (21 H, 7 COCH3); 13C NMR (100
MHz, CDCl3, -60 °C) δ 191.7 (1 C, C-7 from 45), 171.4, 171.3,
170.8, 170.8, 170.7, 170.5, 169.6 (7 C, 4 COCH3 from 44 and 3
COCH3 from 45), 132.2, 128.8, 121.9, 118.7 ((SPhMe)2, some
signals overlapped), 113.3 (1 C, C-1 from 45), 104.1 (1 C, C-1
from 44), 80.3, 72.5, 70.9, 68.9, 66.7, 66.6, 65.8, 64.2, 62.5, 61.5
(12 C, C-2∼6, some signals overlapped), 22.5, 21.4, 21,4, 21.3,
21.2, 21.0, 17.6 (9 C, 7 COCH3, CCH3, (SPhMe)2, some signals
overlapped). For 44: 1H NMR (400 MHz, CDCl3, -20 °C) δ
7.34-7.09 (m, 8 H, H-1, (SPhMe)2), 6.21 (d, 1 H, J1,2 ) 2.4 Hz,
H-1), 5.57 (s, 1 H, H-3), 5.33-5.30 (m, 2 H, H-2, H-4), 4.46-4.41
(m, 1 H, H-5), 4.18-4.10 (m, 4 H, 2 H-6), 2.44 (s, 6 H, (SPhMe)2),
2.18, 2.15, 2.14, 2.07, 2.03 (s, 12 H, 4 COCH3); 13C NMR (100
MHz, CDCl3, -20 °C) δ 171.3, 170.5, 170.5,170.5 (4 C, 4 COCH3),
130.4, 129.4, 128.7, 118.7 ((SPhMe)2, some signals overlapped),
104.1 (1 C, C-1), 71.0, 66.8, 66.7, 65.9, 61.4 (5 C, C-2-6), 21.6,
21,3, 21.2, 21.1, 21.0 (5 C, (5 C, 5 COCH3, (SPhMe)2).
(c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3) δ 5.47 (d, 1 H, J1,2
)
4.8 Hz, H-1), 5.35 (d, 1 H, J4,3 ) 3.0 Hz, H-4), 5.18 (dd, 1 H, J2′,1′
) 8.4 Hz, J2′,3′ ) 10.2 Hz, H-2′), 4.98 (dd, 1 H, J3′,2′ ) 10.8 Hz,
J3′,4′ ) 3.0 Hz, H-3′), 4.57-4.54 (m, 2 H, H-1′, H-4′), 4.26 (dd, 1
H, J2,1 ) 4.8 Hz, J2,3 ) 2.4 Hz, H-2), 4.15-4.07 (m, 3 H, H-5′,
H-6’a, H-6’b), 4.01 (dd, 1 H, J6a,5 ) 3.0 Hz, J6a,6b ) 10.8 Hz, H-6a),
3.91-3.84 (m, 2 H, H-3, H-5), 3.65 (dd, 1 H, J6b,5 ) 3.0 Hz, J6b,6a
) 10.8 Hz, H-6b), 2.11 (s, 3 H, COCH3), 2.04 (s, 3 H, COCH3),
2.02 (s, 3 H, COCH3), 1.95 (s, 3 H, COCH3), 1.45(s, 3 H, C(CH3)2),
1.42(s, 3 H, C(CH3)2), 1.29(s, 3 H, C(CH3)2), 1.29 (s, 3 H, C(CH3)2);
13C NMR (150 MHz, CDCl3) δ 170.7, 170.5, 170.4, 170.0 (4 C, 4
COCH3), 109.6, 108.9 (2 C, 2 C(CH3)2), 102.2 (1 C, JC-1′,H-1′
)
167.4 Hz, C-1′), 96.4 (1 C, JC-1,H-1 ) 177.6 Hz, C-1), 71.5, 71.0,
70.8, 70.7, 70.6, 69.8, 68.8, 68.1, 67.2, 61.4 (C-2-6, some signals
overlapped), 26.2, 26.1, 25.3, 24.5 (4 C, 2 C(CH3)2), 21.0, 20.9,
20.9, 20.8 (4 C, 4 COCH3). ESI-MS [M + Na]+ calcd for
C26H38NaO15 613.2, found 613.3; HRMS [M + Na]+ calcd for
C26H38NaO15 613.2108, found 613.2114.
2-O-Benzoyl-3,4,6-tri-O-benzyl-ꢀ-D-galactopyranosyl-(1f6)-1,2:
3,4-diisopropylidene-r-D-galactopyranoside (47). [R]2D0 -19.7 (c 1.0,
CHCl3); 1H NMR (600 MHz, CDCl3) δ 8.05-7.11 (m 20 H, COPh,
3 CH2Ph), 5.64 (dd, 1 H, J2′,1′ ) 7.8 Hz, J2′,3′ ) 10.2 Hz, H-2′),
5.37 (d, 1 H, J1,2 ) 4.8 Hz, H-1), 4.98 (d, 1 H, J ) 12.0 Hz,
CHHPh), 4.66-4.60 (3 H, H-1′, CHHPh, CHHPh), 4.50-4.42 (3
H, 2 CHHPh, CHHPh), 4.40 (dd, 1 H, J6a′,5′ ) 1.8 Hz, J6a′,6b′ ) 8.4
Hz, H-6a′), 4.16 (dd, 1 H, J2,1 ) 4.8 Hz, J2,3 ) 4.8 Hz, H-2), 4.10
(dd, 1 H, J6b′,5′ ) 1.8 Hz, J6b′,6a′ ) 8.4 Hz, H-6b′), 4.01 (d, 1 H,
J3′,4′ ) 2.4 Hz, H-4′), 3.96 (dd, 1 H, J6a,5 ) 4.8 Hz, J6a,6b ) 10.8
Hz, H-6a), 3.80-3.50 (m, 6 H, H-3, H-3′, H-4, H-5, H-5′, H-6b),
1.37(s, 3 H, C(CH3)2), 1.21(s, 3 H, C(CH3)2), 1.15(s, 3 H, C(CH3)2),
1.09 (s, 3 H, C(CH3)2); 13C NMR (150 MHz, CDCl3) δ 1165.6 (C,
COPh), 138.7, 138.1, 137.9, 133.0, 130.5, 130.3, 128.7, 128.6,
128.5, 128.4, 128.2, 128.1, 127.9 (CH2Ph-C, COPh-C, some signals
overlapped), 109.2, 108.5 (2 C, 2 C(CH3)2), 102.0 (1 C, JC-1′,H-1′
)
164.3 Hz, C-1′), 96.3 (1 C, JC-1,H-1 ) 175.3 Hz, C-1), 80.9, 74.7,
73.8, 72.6, 72.0, 71.9, 71.0, 70.7, 70.6, 68.7, 68.0, 67.9, 67.6 (C-
2-6, some signals overlapped), 26.1, 25.8, 25.1, 24.3 (4 C, 2
C(CH3)2); ESI-MS [M + Na]+ calcd for C46H52NaO16 819.3, found
819.4; HRMS [M + NH4]+ calcd for C46H56NO16 814.3803, found
814.3806.
Acknowledgment. We are grateful for financial support from
the National Institutes of Health (R01-GM-72667). We would
like to thank Dr. Yong Wah Kim (University of Toledo) and
Dr. Eugenio Alvarado (University of Michigan) for their expert
help on NMR.
Supporting Information Available: General experimental
procedures and selected 1H, 13C, 19F, and 2D NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
2,3,4,6-Tetra-O-acetyl-ꢀ-D-glucopyranosyl-(1f6)-1,2:3,4-diiso-
propylidene-r-D-galactopyranoside (46). Donor 16 (20.0 mg, 44.0
µmol, 1.0 equiv) and AgOTf (33.9 mg, 132.0 µmol, 3.0 equiv)
were added to an NMR tube and dried under in vacuo for 3 h.
JO801462R
7962 J. Org. Chem. Vol. 73, No. 20, 2008