How the arming participating moieties can broaden the scope of chemoselective oligosaccharide synthesis by allowing the inverse armed-disarmed approach

Article abstract of DOI:10.1021/jo801551r

(Chemical Equation Presented) A new method for stereocontrolled glycosylation and chemoselective oligosaccharide synthesis has been developed. It has been determined that complete 1,2-trans selectivity can be achieved with the use of a 2-O-picolyl moiety,

Full text of DOI:10.1021/jo801551r

How the Arming Participating Moieties can Broaden the Scope of
Chemoselective Oligosaccharide Synthesis by Allowing the Inverse
Armed-Disarmed Approach
James T. Smoot and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, UniVersity of Missouri - St. Louis, One UniVersity BouleVard,
St. Louis, Missouri 63121
demchenkoa@umsl.edu
ReceiVed July 21, 2008
A new method for stereocontrolled glycosylation and chemoselective oligosaccharide synthesis has been
developed. It has been determined that complete 1,2-trans selectivity can be achieved with the use of a
2-O-picolyl moiety, a novel neighboring group that is capable of efficient participation via a six-membered
intermediate. The application of the picolyl concept to glycosidations of thioimidoyl, thioglycosyl, and
trichloroacetimidoyl glycosyl donors is demonstrated. The picolyl moiety also retains the glycosyl donor
in the armed state, as opposed to conventional acyl participating moieties. We name this new approach
the “inverse armed-disarmed” strategy, because it allows for the chemoselective introduction of a 1,2-
trans glycosidic linkage prior to other linkages. In the context of the oligosaccharide synthesis, the strategy
provides trans-trans and trans-cis patterned oligosaccharides as opposed to classic Fraser-Reid’s
armed-disarmed approach leading to cis-trans and cis-cis linkages.
Introduction
sciences.3 Among possible solutions for this need is the
development of reliable methods for stereoselective glycosyla-
tion4 and efficient strategies for expeditious oligosaccharide
assembly.5,6 In spite of significant progress that has already been
made in the area of synthetic carbohydrate chemistry, complex
glycostructures remain among the most challenging targets of
modern synthetic chemistry.2
Many known expeditious strategies for oligosaccharide
synthesis are based on the selective activation of one leaving
group over another, which significantly reduces the number of
synthetic steps required for assembly.5 Among the most efficient
procedures developed to date, Fraser-Reid’s armed-disarmed
approach is based on the chemoselectivity principle.7,8 It was
The involvement of complex glycostructures, polysaccharides
and glycoconjugates, in many cellular processes has been
directly linked to the progression of many fatal diseases of the
21st century including AIDS, cancer, meningitis, hepatitis,
septicemia, etc.1,2 Elucidation of the exact mechanisms of the
disease pathogenesis in many cases would be significantly
facilitated if scientists could rely on the comprehensive knowl-
edge of the structure, conformation, and properties of the
carbohydrate molecules involved. One of the main drawbacks
in studying the biological functions of complex glycostructures
is their limited availability in pure form from natural sources.
Therefore, there are expectations that efficient chemical or
chemo-enzymatic syntheses would make complex carbohydrates
more accessible to keep pace with exploding areas of glyco-
(3) Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357–2364.
(4) Handbook of Chemical Glycosylation: AdVances in StereoselectiVity and
Therapeutic ReleVance; Demchenko, A. V., Ed.; Wiley-VCH: Weinheim, 2008.
(5) Demchenko, A. V. Lett. Org. Chem. 2005, 2, 580–589.
(6) Galonic, D. P.; Gin, D. Y. Nature 2007, 446, 1000–1007.
(7) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J. Am.
Chem. Soc. 1988, 110, 5583–5584.
(1) Witczak, Z. J. In Carbohydrates in Drug Design; Witczak, Z. J., Nieforth,
K. A., Eds.; Marcel Dekker, Inc.: New York, 1997; pp 1-37.
(2) Seeberger, P. H.; Werz, D. B. Nature 2007, 446, 1046–1051.
8838 J. Org. Chem. 2008, 73, 8838–8850
10.1021/jo801551r CCC: $40.75 2008 American Chemical Society
Published on Web 10/22/2008

InVerse Armed-Disarmed Approach
trans-cis- or trans-trans-linked oligosaccharide fragments.
This arguably limits its versatility and flexibility in the context
of practical oligosaccharide synthesis, whereas the use of other,
usually more laborious techniques, such as orthogonal,20 semi-
orthogonal,21 and two-step activation (or preactivation)22,23
strategies allow for the synthesis of such patterns.
To overcome this major drawback of chemoselective glyco-
sylations and expand the scope and applicability of this excellent
technique to other oligosaccharide sequences (trans-trans and
trans-cis), we initiated studies of an approach that we call
“inverse armed-disarmed strategy”. Conceptually, we should
be able to perform the chemoselective introduction of 1,2-trans
linkage prior to another 1,2-trans or 1,2-cis linkage if a
neighboring substituent capable of both activation and participa-
tion (arming participating moiety, APG, Figure 1) were avail-
able. Our preliminary results related to this approach have
already been communicated.24 Herein we present the full
account of these studies and our initial steps toward broadening
the concept in the context of its application to other classes of
compounds and targets. Other types of moieties that allow for
excellent ꢀ-stereoselectivities while keeping the glycosyl donor
in the armed state have recently been developed.25
FIGURE 1. Concept of arming participating group.
determined that a benzylated (electronically activated, armed)
glycosyl donor can be chemoselectively activated over an
acylated (electronically deactivated, disarmed) derivative bearing
the same type of leaving group. At this stage, 1,2-cis-linked
disaccharide is preferentially obtained due to the necessity to
use the ether-type substituent (arming nonparticipating group,
Figure 1). A key feature of such an approach is the availability
of a suitable mild activator (promoter) that would allow for
differentiating the reactivity levels between the armed and
disarmed building blocks.
Initially being designed for O-pentenyl glycosides, this
concept was further explored in chemoselective glycosidations
of other glycosyl donors, including thioglycosides,9 selenogly-
cosides,10 fluorides,11 phosphoroamidates,12 substituted thio-
formimidates,13 glycals,14 S-benzoxazolyl glycosides,15 and
S-thiazolinyl (STaz) glycosides.16 The obtained 1,2-cis linked
disaccharides (usually a mixture) can be then used for 1,2-trans
glycosylation directly in the presence of a more potent promoter,
capable of activating the disarmed leaving group. This two-
step activation leads to efficient assembly of cis-trans-patterned
oligosaccharide sequences. In the context of the glycoside
synthesis in general, the use of an acyl-type disarming partici-
pating group (Figure 1) remains virtually the only common
approach to achieve excellent 1,2-trans stereoselectivity.
The attractive concept of chemoselective oligosaccharide
synthesis was further analyzed, summarized and expanded by
Ley,17 Wong,18 and others.19 As a result, excellent program-
mable multistep reactivity-based techniques including highly
efficient one-pot approaches have become available. The
armed-disarmed strategy thus offers an efficient tool for the
synthesis of oligosaccharides with a cis-trans glycosylation
pattern. While the synthesis of cis-cis-linked derivatives is also
possible by means of additional protecting group manipulations,7,8
this concept is not directly applicable to the synthesis of
Results and Discussion
Since the inverse armed-disarmed approach would require
the use of a neighboring substituent capable of both activation
and participation, we investigated a number of substituents to
be used as an APG. We reasoned that since the benzyl
substituent has proven to be excellent arming moiety, the
investigation of modified benzyls would be a good starting point.
It should be appreciated that the modification at the benzylic
R-carbon however could result in altering its arming properties;
hence, to design a suitable moiety that would be capable of
participation, and to investigate its possible influence on the
outcome of glycosylations, we decided to focus these studies
on the ortho-substituted/modified benzyl ethers.
Investigation of Thioglycosides. This novel concept was first
investigated using ethyl thioglycosides, which are known to be
common and versatile glycosyl donors.23,26 The synthesis of
the 2-hydroxyl intermediate 4 was achieved from known
thioorthoester 1a,27 as shown in Scheme 1. Thus, a deacetyla-
tion-benzylation sequence followed by opening of the resulting
orthoester 2a afforded 2-acetyl thioglycoside 3. Deacetylation
of the latter compound resulted in the formation of the key
intermediate 4. Subsequently, alkylation of the 2-hydroxyl under
typical reaction conditions (alkyl bromide, NaH in DMF)
afforded 2-O-(o-bromobenzyl, BrBn) 6, 2-O-(o,o-dimethoxy-
(8) Fraser-Reid, B.; Udodong, U. E.; Wu, Z. F.; Ottosson, H.; Merritt, J. R.;
Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927–942.
(9) Veeneman, G. H.; van Boom, J. H. Tetrahedron Lett. 1990, 31, 275–
278.
(10) Baeschlin, D. K.; Chaperon, A. R.; Charbonneau, V.; Green, L. G.; Ley,
S. V.; Lucking, U.; Walther, E. Angew. Chem., Int. Ed. 1998, 37, 3423–3428.
(11) Barrena, M. I.; Echarri, R.; Castillon, S. Synlett 1996, 675–676.
(12) Hashimoto, S. I.; Sakamoto, H.; Honda, T.; Abe, H.; Nakamura, S. I.;
Ikegami, S. Tetrahedron Lett. 1997, 38, 8969–8972.
(13) Chiba, H.; Funasaka, S.; Kiyota, K.; Mukaiyama, T. Chem. Lett. 2002,
746–747.
(20) Kanie, O.; Ito, Y.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 12073–
12074.
(21) Demchenko, A. V.; De Meo, C. Tetrahedron Lett. 2002, 43, 8819–
8822.
(14) Friesen, R. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111, 6656–
6660.
(15) Kamat, M. N.; Demchenko, A. V. Org. Lett. 2005, 7, 3215–3218.
(16) Pornsuriyasak, P.; Demchenko, A. V. Chem.-Eur. J. 2006, 12, 6630–
6646.
(17) Douglas, N. L.; Ley, S. V.; Lucking, U.; Warriner, S. L. J. Chem. Soc.,
Perkin Trans. 1 1998, 51–65.
(22) (a) Huang, X.; Huang, L.; Wang, H.; Ye, X. S. Angew Chem., Int. Ed.
2004, 43, 5221–5224. (b) Huang, L.; Wang, Z.; Huang, X. Chem. Commun.
2004, 1960–1961.
(23) Codee, 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.
(24) Smoot, J. T.; Pornsuriyasak, P.; Demchenko, A. V. Angew. Chem., Int.
Ed. 2005, 44, 7123–7126.
(18) (a) Zhang, Z.; Ollmann, I. R.; Ye, X. S.; Wischnat, R.; Baasov, T.;
Wong, C. H. J. Am. Chem. Soc. 1999, 121, 734–753. (b) Ye, X. S.; Wong,
C. H. J. Org. Chem. 2000, 65, 2410–2431. (c) Burkhart, F.; Zhang, A.;
Wacowich-Sgarbi, S.; Wong, C. H. Angew. Chem., Int. Ed. 2001, 40, 1274–
1277.
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4, 281–283. (b) Wang, Y.; Huang, X.; Zhang, L. H.; Ye, X. S. Org. Lett. 2004,
6, 4415–4417.
(25) Crich, D.; Jayalath, P. J. Org. Chem. 2005, 70, 7252–7259.
(26) (a) Garegg, P. J. AdV. Carbohydr. Chem. Biochem. 1997, 52, 179–
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Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim, NY, 2000; Vol. 1, pp
93-116.
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J. F. G. Bioorg. Med. Chem. 1994, 2, 1309–1317. (b) Kochetkov, N. K.;
Backinowsky, L. V.; Tsvetkov, Y. E. Tetrahedron Lett. 1977, 41, 3681–3684.
J. Org. Chem. Vol. 73, No. 22, 2008 8839

Smoot and Demchenko
TABLE 1. Investigation of Glycosyl Donors 5-8 Bearing Various Arming Participating Groups
entry
donor
Ra
Bn
BrBn
BrBn
DMB
DMB
DMB
Pic
Pic
Pic
Pic
Pic
promoter
temp.
product
yield
R/ꢀ ratio
1
2
3
4
5
6
7
8
5
6
6
7
7
7
8
8
8
8
8
IDCP
IDCP
IDCP
IDCP
IDCP
IDCP
IDCP
MeOTf
NIS/TfOH
DMTST
DMTST
rt
rt
10
11
11
12
12
12
13
13
13
13
13
80%
78%
87%
58%
87%
89%
n.d.b
n.d.
2.7/1
1.8/1
2.3/1
1.8/1
2.3/1
1.8/1
-
-
-
ꢀ only
ꢀ only
-40 °C f rt
rt
-35 °C f rt
-40 °C f rt
rt
rt
rt
rt
9
10
11
n.d.
5%
45%
rt f 45 °C
a Bn, benzyl; BrBn, -o-bromobenzyl; DMB, o,o-dimethoxybenzyl; Pic, picolyl. b Not detected.
SCHEME 1
not steric hindrance. The synthesis of the glycosyl donor 8
bearing a picolyl substituent at C-2 was achieved as described
in Scheme 1 with the commercial picolyl bromide hydrobromide.
Unfortunately, nearly all of our attempts to glycosidate donor
8 have failed. Thus, common promoters for thioglycoside
activation26 have been screened, but each experiment performed
at ambient temperature led to the reaction between the electro-
philic promoter and nucleophilic nitrogen in the pyridine moiety
in lieu of the anomeric sulfur atom (entries 7-10, Table 1).
Mildly electrophilic dimethyl(thiomethyl)sulfonium triflate
(DMTST)30 commonly used as the promoter for thioglyco-
sides,31 was the most promising in this respect, but even upon
prolonged heating at 45 °C (16 h) the reaction provided the
disaccharide 13 in a modest yield of 45% (entry 11). The
stereoselectivity though exceeded all of our expectations as the
reaction was found to be completely ꢀ-stereoselective. In this
context, although an approach for controlling the anomeric
stereoselectivity with a neighboring substituent capable of the
six-membered participation is relatively unexplored, a number
of moieties for stereoselective R-glycosylation have recently
been reported.32
Investigation of 2-O-Picolylated Glycosyl Donors. Although
the latter result could serve as the ultimate proof of the concept,
low efficiency would the major burden for subsequent practical
applications. To investigate this concept further and with the
hopes to avoid the interference of the picolyl group with the
leaving group activation we decided to apply these findings to
S-thiazolinyl (STaz) glycosyl donors. The rationale for selecting
the STaz moiety for subsequent studies was the fact that this
type of leaving group can be activated by mildly electrophilic
metal salt-based promoters.33 Another important motivation for
selecting the STaz glycosides was related to their excellent
glycosyl donor properties and the compatibility with the classic
Fraser-Reid’s armed-disarmed strategy.16
benzyl, DMB) 7, and 2-O-picolyl (2′-pyridylmethyl, Pic)
derivatives 8 in 98, 77, and 83%, respectively (Scheme 1).
Preliminary experiments with novel glycosyl donors 6-8
were performed in direct comparison with standard glycosidation
of per-benzylated glycosyl donor 5.28 These couplings were
performed using model glycosyl acceptor 9 in the presence of
iodonium(di-γ-collidine)perchlorate (IDCP).9,29 Although gly-
cosyl donors 6 and 7 allowed slightly improved ꢀ-stereoselec-
tivity in comparison to that achieved with 2-benzyl donor 5
(Table 1, entries 1-6), it remained uncertain whether this
marginally improved ꢀ-stereoselectivity should be attributed to
the anticipated participation via a seven-membered intermediate
(Figure 1) or would rather be a result of the increased steric
hindrance of the bottom face of the ring. Not being able to
differentiate between these two possible pathways, and being
discouraged by the negligibly improved stereoselectivity of the
formation of disaccharides 11 and 12 in comparison to that of
10 (Table 1), our subsequent studies refocused on the investiga-
tion of the picolylated glycosyl donor 8. We reasoned that the
picolyl moiety would offer a more efficient participation via
six-membered cyclic intermediate (Figure 1) while being about
the same size as conventional benzyl substituent. Therefore, if
the anticipated increase in stereoselectivity takes place, this could
be exclusively attributed to the anchimeric participation, but
For the purpose of synthesizing picolylated STaz glycosyl
donor, the orthoester 2a was opened with 2-mercaptothiazoline
(30) Ravenscroft, M.; Roberts, R. M. G.; Tillett, J. G. J. Chem. Soc. Perkin
Trans. 2 1982, 1569–1972.
(31) Fugedi, P.; Garegg, P. J. Carbohydr. Res. 1986, 149, c9–c12.
(32) (a) Kim, J. H.; Yang, H.; Park, J.; Boons, G. J. J. Am. Chem. Soc. 2005,
127, 12090. (b) Kim, J. H.; Yang, H.; Boons, G. J. Angew. Chem., Int. Ed.
2005, 44, 947–949.
(28) Andersson, F.; Fugedi, P.; Garegg, P. J.; Nashed, M. Tetrahedron Lett.
1986, 27, 3919–3922.
(29) Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2190–2198.
(33) Demchenko, A. V.; Pornsuriyasak, P.; De Meo, C.; Malysheva, N. N.
Angew. Chem., Int. Ed. 2004, 43, 3069–3072.
8840 J. Org. Chem. Vol. 73, No. 22, 2008

InVerse Armed-Disarmed Approach
SCHEME 2
TABLE 2. Synthesis of 1,2-trans-Linked Disaccharides 23-28
from 2-O-Picolyl Donors
FIGURE 2. Glycosyl donor 17 and glycosyl acceptors 18-22.
entry
donor
acceptor
promoter
product
yield, %
1
2
3
4
5
6
7
8
16a
16a
16a
16a
16a
16a
16a
16a
16a
16a
16a
16a
16b
8
18
18
18
19
19
20
21
21
Cu(OTf)2
Cu(OTf)2/ TfOH
AgOTf
23
23
23
25
25
26
27
27
80
84
78
83
80
85
69
80
63
56
78
72
76
70
84
Cu(OTf)2
Cu(OTf)2/TfOH
Cu(OTf)2/TfOH
Cu(OTf)2
Cu(OTf)2/TfOH
AgOTf
Cu(OTf)2
Cu(OTf)2
AgOTf
Cu(OTf)2
9
21
27
10
11
12
13
14
15
22a
22b
22b
18
18
18
28a
28b
28b
24
23
23
DMTST
TESOTf
31
FIGURE 3. Disaccharides 23-29.
(HSTaz) in the presence of TMSOTf to give the intermediate
14a in 90% yield. The deacetylation of 14a was carried out
over 72 h with NaOMe/MeOH to give compound 15a (95%).
Although the STaz moiety was generally found to be stable in
the presence of strong bases,16 careful optimization of the
following transformation allowed us to obtain the target
2-picolylated derivative 16a in an excellent yield of 90%. Thus,
picolyl bromide hydrobromide was first reacted with NaH in
DMF to quench the HBr and to exclude possible interference
of the STaz group at this stage. Subsequently, the 2-hydroxyl
derivative 15a was added to the resulting mixture at -30 °C
followed by further addition of NaH to give the target glycosyl
donor 16a (Scheme 2).
Having synthesized 2-picolyl STaz glycoside 16a, we turned
our attention to studying its glycosyl donor properties. For this
purpose, a range of differently protected glycosyl acceptors
18-22 was selected (Figure 2).9,34-37 Per-benzylated STaz
glycosyl donor 1716 was used as a stereoselectivity/reactivity
control. After screening a variety of suitable activators ranging
from common activators for the thioglycoside activation to metal
salts that are unique for the thioimidates, we chose Cu(OTf)2
to be applied alone or in combination with catalytic TfOH. To
our encouragement, all glycosylations summarized in Table 2
proceeded with complete 1,2-trans stereoselectivity: no traces
of the R-anomer were detected in every reaction. The corre-
sponding disaccharide derivatives 23-28 (Figure 3) were
isolated in good yields in the range of 56-85%. In comparison,
glycosidations of benzylated STaz glycoside 17 provided
predominantly R-linked disaccharide with predominant R-ste-
reoselectivity (R/ꢀ ) 2-4/1).16
at elevated temperature. It was determined that the reaction
temperature of 42 °C was optimal in terms of both conversion
ratesall couplings were completed in 12-16 hsand yields (see
Table 2). While the efficiency of silver(I) triflate was similar to
that achieved with Cu(OTf)2 (compare entries 1 and 3), in a
variety of cases the use of catalytic TfOH additive along with
stoichiometric Cu(OTf)2 resulted in significantly higher reaction
yields (e.g., entries 1, 2, 7, and 8). It should be noted that all
reactions were performed with each promoter (or promoter
combination) mentioned herein, yet only the most representative
results are summarized in Table 2. Upon completion, the
glycosylations were quenched with an excess of triethylamine
(∼20 equiv) to ensure that the copper-pyridinium complex of
the product with promoter that could have been formed during
the prolonged reactions has been completely decomposed.
Being satisfied with the utilization of an array of structurally
diverse glycosyl acceptors, we decided to evaluate whether the
developed technique could be applied to other classes of glycosyl
donors. First of all, we decided to investigate glycosyl donor
of the D-galacto series, which is among the most abundant
monosaccharides in nature, thus representing an important target.
As in the case of the D-gluco counterpart 16a, the synthesis of
picolylated galactosyl donor 16b (compound numbers for the
D-galacto series are essentially the same as shown for the D-gluco
series and designated with index b and a, respectively) was
initiated from the derivatization of the orthoester. Thus, the
orthoester 1b was deacetylated and benzylated without the need
for the intermediate purification to give 2b in 79% yield. The
latter orthoester then was opened to give STaz galactoside 14b
in 83% yield, which was deprotected to give 2-hydroxyl
derivative 15b in 95% yield. The picolyl group was then
installed to give the desired galactose donor 16b in 85% yield.
As indicated in Table 2, the galactosyl donor 16b was
glycosidated with acceptor 18 to give the desired disaccharide
24 with complete 1,2-trans stereoselectivity in 76% yield (entry
13).
We have also noticed that glycosidation of 16a required
significantly more time at rt than that of its per-benzylated
counterpart 17 (48 h vs 1-3 h, respectively). To enhance the
efficiency of this approach and shorten the reaction time, all
glycosylations with 16a were performed in 1,2-dichloroethane
(34) Kuester, J. M.; Dyong, I. Justus Liebigs Ann. Chem. 1975, 2179–2189.
(35) Garegg, P. J.; Hultberg, H. Carbohydr. Res. 1981, 93, C10–C11.
(36) Koto, S.; Takebe, Y.; Zen, S. Bull. Chem. Soc. Jpn. 1972, 45, 291–293.
(37) Pearce, A. J.; Sinay, P. Angew. Chem., Int. Ed. 2000, 39, 3610–3612.
Having demonstrated that the picolyl moiety could be simply
introduced under conventional alkylation conditions and applied
J. Org. Chem. Vol. 73, No. 22, 2008 8841

Smoot and Demchenko
SCHEME 3
SCHEME 4
to the successful stereoselective synthesis of 1,2-trans-linked
disaccharides, we decided to investigate the pathways for its
deprotection. Indeed, the development of a novel protecting
group would be totally impractical if it could not be removed.
Along these lines, the 2-O-picolyl moiety could be removed
under conventional catalytic hydrogenation conditions (Pd/C).49
Thus, hydrogenolysis of O-picolyl moiety in 23 was achieved
along with concomitant removal of benzyls affording a fully
unprotected disaccharide 29 (Figure 3) in 98% yield.
Upon establishing the reaction conditions with the STaz
glycosides, we decided to investigate the compatibility of the
picolyl moiety with other types of glycosylations. First of all,
we have reinvestigated the thioglycoside donor by applying a
procedure similar to that developed for the STaz glycosides.
When 2-picolyl thioglycoside 8 and acceptor 18 were mixed
with DMTST at room temperature followed by heating at 42
°C for 18 h, only modest yield of the disaccharide 23 could be
obtained (∼50%). However, a significantly improved yield was
reached by cooling the reaction mixture to -50 °C prior to the
addition of promoter followed by slow warming to rt and
subsequent heating at 42 °C for 18 h. This modified approach
led to the disaccharide 23 in a significantly improved yield of
70% (entry 14, Table 2).
We then turned our attention to the investigation of the
trichloroacetimidate approach to glycosylation, arguably the
most widespread method of glycosylation.38 The trichloroace-
timidate donor 31 was obtained from the STaz (or SEt) glycoside
16a (or 8) via sequential hydrolysis of the anomeric moiety with
Cu(OTf)2 (or DMTST) leading to the hemiacetal 30 followed
by the introduction of the trichloroacetoimidoyl moiety by
reaction with trichloroacetonitrile in the presence of potassium
carbonate as a base (Scheme 3). The target trichloroacetimidate
31 was sufficiently stable to be purified by chromatographic
column, and the R- and ꢀ-isomers could be isolated individually
in 48% and 34% yield, respectively. A TESOTf-promoted
glycosidation of 31 with glycosyl acceptor 18 led to the
formation of disaccharide 23 with complete 1,2-trans stereo-
selectivity in a yield of 84% (entry 15, Table 2).
Novel Applications of Chemoselective 1,2-trans Gly-
cosylations in Oligosaccharide Synthesis. Having established
general conventions for simple one-step 1,2-trans glycosylations,
we turned our attention to investigating the applicability of this
novel methodology to expeditious oligosaccharide synthesis. As
aforementioned, the major motivation for these studies was to
invent new chemoselective pathways for the rapid synthesis of
various oligosaccharide sequences. As aforementioned, in our
previous work we have already established that the STaz
glycosides also follow general armed-disarmed strategy.16
Thus, the armed STaz glycoside donor 17 was chemoselectively
activated over the disarmed STaz glycosyl acceptor 3216 in the
presence of Cu(OTf)2 or AgOTf (Scheme 4). As a result, the
disaccharide 33 was obtained in 88% yield (R/ꢀ ) 1.5/1) and
79% yield (R/ꢀ ) 2.0/1) respectively. The disarmed reducing
end of the intermediate 33 could be activated with a more potent
promoter AgOTf for the coupling with glycosyl acceptor 18
that resulted in the formation of the cis-trans-patterned
trisaccharide 34 in 83% yield.16
Since in our simple glycosylation experiments we have
noticed that glycosidation of picolylated glycosyl donors
required prolonged experiments in comparison to that of their
per-benzylated counterparts, it seemed essential to establish
whether the 2-picolyl derivatives could be chemoselectively
activated over the disarmed glycosyl acceptors. As a matter of
fact, the direct coupling between picolylated glycosyl donor 16a
and the tribenzoylated STaz acceptor 3216 clearly demonstrates
the proof of concept of the APG and the feasibility of the
chemoselective introduction of the 1,2-trans glycosidic linkage
early in the synthetic sequence prior to other linkages. Thus,
disaccharide 35 was obtained in 74% yield as the sole ꢀ-anomer
(Scheme 4). Subsequently, the activation of the disarmed
disaccharide 35 for the reaction with 18 in the presence of
AgOTf afforded the trans-trans-linked trisaccharide 36 in 91%
yield. It should be noted that prior to our studies, this type of
sequence could not be accessed via chemoselective armed-
disarmed activations.
After successfully obtaining both the cis-trans and
trans-trans oligosaccharide sequences we turned our focus to
the investigation of the other sequences i.e. cis-cis and
trans-cis, the latter being “inverse oligosaccharide pattern” as
opposed to that achieved by the classic Fraser-Reid approach
(cis-trans). In this context, although the synthesis of the cis-cis
pattern does not require the use of APG, its exploration herein
seemed essential as it would complete the comprehensive tool-
kit for synthesizing all types of sequences using a simple set of
building blocks requiring only one type of anomeric moiety.
Recently we demonstrated the two-step synthesis of the cis-cis
linked oligosaccharide by exploring a new effect that we call
O-2/O-5 cooperative effect in glycosylation,15 yet its application
to the STaz methodology had not been explored. Alternatively,
the same concept could be realized by using the so-called
disarming nonparticipating moieties in the glycosyl acceptor
unit.39
Utilizing the general principle of the cooperative effect we
obtained 3,4-di-O-benzoyl-2-O-benzyl protected STaz glycosyl
acceptor 38 from known derivative 3716 via conventional
(38) Schmidt, R. R.; Jung, K. H. In Carbohydrates in Chemistry and Biology;
Ernst, B., Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim, NY, 2000; Vol.
1, pp 5-59.
(39) Crich, D.; Hutton, T. K.; Banerjee, A.; Jayalath, P.; Picione, J.
Tetrahedron: Asymmetry 2005, 16, 105–119.
8842 J. Org. Chem. Vol. 73, No. 22, 2008

InVerse Armed-Disarmed Approach
SCHEME 5
SCHEME 6
tritylation-acylation-detritylation sequence (78% overall yield,
Scheme 5). Performing direct chemoselective activations sub-
stantiated our anticipation that the building block 38, bearing
the remote electron-withdrawing acyl groups, would be less
reactive than the per-benzylated derivative 17. The reaction of
glycosyl donor 17 with glycosyl acceptor 38 was performed in
the presence of Cu(OTf)2 in 1,2-dichloroethane/dioxane to give
predominantly R-linked disaccharide 39 in 89% yield (R/ꢀ )
2/1, Scheme 5). The disarmed disaccharide 39 was then
glycosidated with standard glycosyl acceptor 18 in the presence
of AgOTf to give the desired cis-cis-linked trisaccharide 40
in 75% yield (R/ꢀ ) 1.6/1).
Lastly, we needed to combine the trans-directing picolyl
functionality of glycosyl donor 16a and the cis-directing
functionality of the cooperative glycosyl acceptor 38 that could
potentially lead to the inverse trans-cis glycosylation pattern.
To achieve this, glycosyl donor 16a was coupled with glycosyl
acceptor 38 in the presence of stoichiometric Cu(OTf)2 and
catalytic TfOH at 30 °C for 18 h to give the disaccharide 41 in
70% yield (Scheme 5). The yield could be further increased by
executing the preactivation of the glycosyl donor 16a followed
by the addition of the glycosyl acceptor 38. Although deemed
unnecessary, the latter modification allows one to significantly
reduce the impact of the major competing side reaction of the
intramolecular self-condensation of the glycosyl acceptor leading
to formation of the 1,6-anhydro derivative. The disaccharide
41 was then coupled to the glycosyl acceptor 18 in the presence
of AgOTf to give the desired trisaccharide 42 in 54% yield (R/ꢀ
) 1.7/1).
Mechanistic Investigations. Being encouraged by the com-
plete 1,2-trans stereoselectivity achieved in all glycosidations
of 2-O-picolylated glycosyl donors, we decided to investigate
whether this remarkable selectivity is actually due to the
anticipated anchimeric participation. We also had hoped that
the in depth mechanistic studies would help to answer other
questions that have surfaced during the preliminary experimen-
tations. These include relatively slow glycosidation reaction,
partial complexation/salt formation, and good, yet not excep-
tional yields in glycosylations. Among these, low reactivity was
particularly intriguing because while the direct chemoselective
activation of 16a over benzoylated acceptor 32 was possible,
the stand alone glycosylations with per-benzoylated STaz
glycoside were significantly faster (1-20 h at rt)33 than those
with 16a (24-48 h at rt). Therefore, this discrepancy could not
be simply rationalized by the lower reactivity of 2-O-picolylated
glycosyl donors.
As aforementioned, our working hypothesis for these studies
was based on the anticipation that upon promoter-assisted
leaving group departure, the oxocarbenium ion is converted into
a stable intermediate of the six-membered cyclic structure A
(Scheme 6). Although this pathway involving formal participa-
tion of the nitrogen atom on the O-2 protecting moiety via the
anomeric center seemed very credible, we could not entirely
eliminate other possibilities. For example, an alternative expla-
nation exploring the possibility of the intramolecular promoter
complexation of the two nitrogen atoms of the glycosyl donor
has also come to our attention. We believed that the bidentate
complex depicted in Scheme 6 would cause sufficient distur-
bance to the leaving group to stimulate its departure followed
by the formation of the anomeric R-triflate B (Scheme 6). Since
glycosyl triflates are known to allow for the concerted bimo-
lecular nucleophilic substitution,40 the second pathway also
deemed as a viable explanation to the stereoselective formation
of the 1,2-trans-linked products.
At this stage it seemed impossible to differentiate between
the two plausible intermediates A and B, therefore, to clarify
this we decided to undertake mechanistic studies. We anticipated
that if it were possible to trap the reaction intermediate, this
would provide sufficient information to clarify the reaction
(40) Crich, D. J. Carbohydr. Chem. 2002, 21, 667–690.
(41) (a) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217–11223. (b)
Callam, C. S.; Gadikota, R. R.; Krein, D. M.; Lowary, T. L. J. Am. Chem. Soc.
2003, 125, 13112–13119. (c) Rencurosi, A.; Lay, L.; Russo, G.; Caneva, E.;
Poletti, L. Carbohydr. Res. 2006, 341, 903–908. (d) Nokami, T.; Shibuya, A.;
Tsuyama, H.; Suga, S.; Bowers, A. A.; Crich, D.; Yoshida, J. J. Am. Chem.
Soc. 2007, 129, 10922–10928.
J. Org. Chem. Vol. 73, No. 22, 2008 8843

Smoot and Demchenko
FIGURE 4. Spectral characterization of the reaction intermediates.
8844 J. Org. Chem. Vol. 73, No. 22, 2008

InVerse Armed-Disarmed Approach
SCHEME 7. Proposed Reaction Mechanism
pathway. A number of recent reports described the spectral
properties of the anomeric triflates,41 hence we thought that if
our reaction were proceeding via the intermediate B, it could
be easily detected by recording a simple proton NMR spectrum.
The spectral properties of the previously reported glycosyl
triflates differ based on their chemical structure, but what they
all had in common is small coupling constant doublet (or even
a singlet) corresponding to the anomeric proton (H-1) in a
relatively low field (between 6.0-6.3 ppm).41
Having recorded the proton spectrum of the glycosyl donor
16a (Figure 4a), we noted that no signals were present between
5.5 and 7.0 ppm. This would significantly facilitate the monitor-
ing of the formation of plausible glycosyl triflate species by
avoiding undesirable signal overlaps that is often an unavoidable
burden in complex molecules. Subsequently, AgOTf (2 equiv)
was added to the standard 5 mm NMR tube containing 16a
and CDCl3, and upon complete disappearance of the glycosyl
donor (1 h, TLC analysis) the spectrum was recorded again.
Indeed, as can be seen in Figure 4b, no starting material
remained at this stage; as a matter of fact, we determined that
16a gets entirely consumed in about 1 h regardless of the
temperature (studied range 0-50 °C). At this stage, the 1H NMR
spectrum clearly shows the anomeric signals of two compounds:
(major, 6.15 ppm, J ) 4.6 Hz) and H-1R (minor, 5.75 ppm, J
) 8.2 Hz), corresponding to the R- and ꢀ-glycosyl linkage,
respectively. The anomeric ratio, determined by comparison of
the integral intensities of the corresponding signals in proton
spectra, varied depending on the reaction conditions from 5/1
(50 °C) to 20/1 (rt or 0 °C).
the cyclic intermediate that has formed as a result of the
anchimeric assistance of the 2-O-picolyl participatory moiety.
Furthermore, the bicyclic intermediate A (43) could be
isolated in the pure form from the reaction of 16a with Cu(OTf)2
(1 h, rt) followed by conventional postglycosylation workup
and flash column chromatography on silica gel. Although we
do not yet have experimental evidence regarding the counter-
anion of 43, the isolated intermediate was found to be reactive
with potent nucleophiles such as NaOMe, to allow glycoside
44 (Scheme 7), even in the absence of the promoter. Similarly,
we determined that compound 43 could be obtained from
glycosyl donor 16a by reaction with bromine.
It was also determined that minor NMR signals (e.g., doublet
at 5.75 ppm) seen in the spectrum of A/43 (Figure 4b)
correspond to the ꢀ-linked cyclic intermediate 45 (Scheme 7).
It is noteworthy that 1H and 13C NMR data of 43 and 45 are in
good correlation with those recorded for R- and ꢀ-N-pyridinium
salts.43 Interestingly, while 43 was found to be reactive leading
to 1,2-trans glycosides, the ꢀ-intermediate 45 remained com-
pletely inert and could be typically isolated from the final
reaction mixture. Even purposeful prolonged reactions per-
formed with potent charged nucleophiles in refluxing DMF did
not stimulate compound 45 to react. It is possible that this
stability is to be attributed to the reverse anomeric effect that
favors charged ꢀ-N-glycosidic species,44 although no direct
experimental data clarifying this high stability of 45 is yet
available.
Apparently, experimental data acquired at this stage has not
yet provided sufficient information to distinguish whether the
obtained reaction intermediate is postulated A, B, or neither.
In principle, both anomeric triflate and R-N-glycoside could
display H-1 signals in the observed region. Therefore, the NMR
studies were continued by using advanced two-dimensional
techniques. These NMR determinations we found to be very
informative and allowed for the unambiguous structure elucida-
tion of the reaction intermediate. Thus, correlations in the
NOESY experiment between protons H-1 (δ 6.15 ppm) and the
aromatic proton adjacent to the picolyl nitrogen atom (Hc, δ
9.00 ppm) indicated that these two protons were situated in close
proximity (Figure 4d). This has become good, yet not explicit
indication on the reaction intermediate being the proposed six-
membered cyclic intermediate A (Figure 4e). Also, the TOCSY
data revealed that H-1 and the benzylic protons of the picolyl
group (Ha and Hb, δ 5.15 ppm) are a part of the same spin
system (Figure 4c and e), another indication on the ring system.
Also from the 1D data (Figure 4a and b), it was evident that
the R-benzylic protons underwent significant modifications
reflected in their spectral properties (singlet in 16a vs double
of doublets in A/B). This was another indication on the ring
system and the equivalent protons Ha,b have become “fixed” in
a more rigid cyclic substructure and thus could be differentiated
in the proton spectrum. Finally, by determining the long-range
coupling between C-1 (δ 84.89 ppm) and Hc in the HMBC
spectrum (Figure 4f) we confirmed that the C-1 and Hc atoms
are positioned three bonds apart.42
Conclusions
In conclusion, a new method for stereocontrolled and
chemoselective glycosylation has been developed. It has been
demonstrated that complete 1,2-trans selectivity can be achieved
with the use of a 2-O-picolyl moiety, a novel neighboring group
that is capable of efficient participation via a six-membered
intermediate while retaining the glycosyl donor in the armed
state, as opposed to the conventional acyl participating moieties.
Initially developed for the S-thiazolinyl glycosides, this approach
was also proven compatible with the most common glycosy-
lation methodologies developed to date based on thioglycosides
and glycosyl trichloroacetimidates. The application of a novel
arming participating moiety to complement chemoselective
oligosaccharide synthesis has been also developed. This new
armed-disarmed glycosylation strategy allows for chemose-
lective introduction of a 1,2-trans glycosidic linkage prior to
other linkages, as opposed to the classic Fraser-Reid approach.
Based on our chemoselective studies, we conclude that the
developed technique, along with the classic armed-disarmed
Based on the experimental spectral data presented herein, we
conclude that there is a solid evidence for the R-N-picolyl
glycosidic linkage, as in A (Figure 4e), a clear indication for
(43) Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2205–2213.
(44) Tvaroska, I.; Bleha, T. AdV. Carbohydr. Chem. Biochem. 1989, 47, 45–
123.
(42) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293–297.
J. Org. Chem. Vol. 73, No. 22, 2008 8845

Smoot and Demchenko
SCH2CH3), 3.47-3.55 (m, 2H, H-2, 5), 3.60-3.79 (m, 4H, H-3,
4, 6a, 6b), 4.40 (d, 1H, J1,2 ) 9.7, H-1) 4.53-4.64 (m, 3H, CH2Ph),
4.83 (d, 1H, CH2Ph), 4.93 (d, 1H, CH2Ph), 4.94 (d, 1H, CH2Ph),
7.28-7.47 (m, 16H, aromatic) 7.60 (d, 1H, aromatic), 7.76 (dt,
1H, aromatic), 8.65 (d, 1H, aromatic) ppm. 13C NMR: δ, 15.3, 25.0,
69.3, 73.6, 75.2, 75.9, 76.2, 78.1, 79.3, 82.4, 85.0, 86.6, 121.9,
122.5, 127.8, 127.8, 127.9, 128.0, 128.1, 128.1, 128.5, 128.6, 128.6
136.6, 138.2, 138.4, 138.5, 149.2, 158.4, ppm; HR-FAB MS calc
for C35H39NO5S [M + H]+: 586.2549 found 586.2548 m/z.
Thiazolinyl 3,4,6-Tri-O-benzyl-2-O-picolyl-1-thio-ꢀ-D-glucopy-
ranoside (16a). A solution of 15a (1.40 g, 2.55 mmol) in DMF (22
mL) was added to a stirred suspension of NaH (0.32 g, 7.90 mmol)
and picolyl bromide hydrobromide (1.94 g, 7.65 mmol) in DMF
(22 mL) at -25 °C. Additional NaH (60% in mineral oil, 0.20 g,
5.01 mmol) was added, the reaction mixture was stirred 30 min
and then allowed to warm to rt over 90 min. Upon completion, the
reaction was quenched by adding crushed ice (10 g), stirred until
cessation of H2 evolution, and then extracted with ethyl acetate/
diethyl ether (1/1 v/v, 3 × 80 mL). The combined organic phase
was washed with water (3 × 40 mL), separated, dried with MgSO4,
and evaporated in vacuo. The residue was and purified by column
chromatography on silica gel (ethyl acetate-hexane gradient
elution) to afford the title compound as colorless syrup (1.39 g,
90%). Analytical data for 16a: Rf ) 0.37 (ethyl acetate-hexane,
2/1, v/v); [R]D ) +13.2° (c ) 1, CHCl3); H NMR: δ, 3.34 (t,
2H, SCH2), 3.62 (m, 1H, H-5), 3.65-3.83 (m, 5H, H-2, 3, 4, 6a,
6b), 4.21 (m, 2H, CH2N), 4.60 (dd, 2H, J2 ) 12.0 Hz, CH2Ph),
4.70 (dd, 2H, J ) 10.8 Hz, CH2Ph), 4.87 (dd, 2H, J ) 10.8 Hz,
CH2Ph), 5.00 (s, 2H, CH2Ph), 5.32 (d, 1H, J1,2 ) 9.7 Hz, H-1),
7.15-7.38 (m, 16H, aromatic) 7.48 (d, 1H, aromatic), 7.66 (m,
1H, aromatic), 8.55 (br. d, 1H, aromatic) ppm; 13C NMR: δ, 35.2,
64.5, 68.8, 73.6, 75.2, 75.9, 76.2, 77.4, 79.7, 81.6, 84.7, 86.6, 122.0,
122.6, 127.8, 127.9, 128.0, 128.1, 128.1, 128.2, 128.5, 128.6, 136.8,
138.3, 138.4, 149.1, 158.1, 163.9, ppm; HR-FAB MS [M + H]+
calcd for C36H39N2O5S2 643.2300, found 643.2293.
Thiazolinyl 3,4,6-Tri-O-benzyl-2-O-picolyl-1-thio-ꢀ-D-galacto-
pyranoside (16b). was prepared as yield off-white amorphous solids
(85%) as described for the synthesis of 16a. Analytical data for
16b: Rf ) 0.29 (ethyl acetate-hexane, 3/2, v/v); [R]D24 ) +11.9°
(c ) 1, CHCl3); 1H NMR: δ, 3.32 (t, 2H, JCH2CH2N ) 8.0,
SCH2CH2), 3.62-3.75 (m, 4H, H-3, 5, 6a, 6b), 3.95 (d, 1H, H-2),
4.02 (m, 1H, H-4), 4.07-4.28 (m, 2H, CH2N), 4.41 (d, 1H, CH2Ph),
4.50 (d, 1H, CH2Ph) 4.60 (d, 1H, CH2Ph), 4.71 (s, 1H, CH2Ph),
4.91-5.05 (m, 3H, CH2Ph), 5.37 (d, 1H, J1,2 ) 9.8 Hz, H-1), 7.17
(m, 1H, aromatic), 7.22-7.39 (m, 15H, aromatic) 7.46 (d, 1H,
aromatic), 7.62 (dt, 1H, aromatic), 8.54 (d, 1H, aromatic) ppm;
13C NMR: δ, 35.3, 64.5, 68.5, 72.8, 73.7, 73.7, 74.9, 76.6, 77.4,
77.8, 78.6, 83.9, 85.2, 122.0, 122.4, 127.8, 127.9, 128.0, 128.2,
128.3, 128.4, 128.6, 128.6, 136.6, 138.1, 138.2, 138.8, 149.1, 158.6,
164.2, ppm; HR-FAB MS calc for C36H37N2O5S2Na [M + Na]+:
665.2120, found 665.2124.
approach, allows for expeditious access to any oligosaccharide
sequence (cis-cis, cis-trans, trans-trans, and trans-cis) from
only one type of a leaving group. Thorough mechanistic studies
led to the discovery that the picolyl-assisted 1,2-trans stereo-
selective glycosylations proceed via the formal six-membered
cyclic intermediate.
Experimental Section
Preparation of Glycosyl Donors Containing APG. Ethyl
3,4,6-Tri-O-benzyl-2-O-(o-bromobenzyl)-1-thio-ꢀ-D-glucopyrano-
side (6). To a solution of the thioglycoside 4 (50 mg, 0.101 mmol)
in DMF (1.0 mL) NaH (60% in mineral oil, 8.1 mg, 0.203 mol)
and 2-bromobenzyl bromide (30 µL, 0.122 mmol) were added at
rt. The reaction mixture was stirred for 20 min, then poured into
ice-water (20 mL), stirred for 30 min, and extracted with EtOAc/
Et2O (1/1, v/v, 3 × 15 mL). The combined organic extract was
washed with cold water (3 × 20 mL), separated, dried with MgSO4,
filtered, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (EtOAc/toluene gradient
elution) to allow the title compound as a white amorphous solid in
98% yield. Analytical data for 6: Rf ) 0.49 (ethyl acetate-hexane,
27
1
1/4, v/v); [R]D ) -11.7° (c ) 1, CHCl3); H NMR: δ, 1.34 (t,
3H, SCH2CH3), 2.78 (m, 2H, SCH 2CH3), 3.50-3.57(m, 2H, H-1,
5), 3.63-3.85 (m, 5H, H-2, 3, 4, 6a, 6b), 4.51 (d, 1H, CH2Ph),
4.56-4.65 (m, 2H, CH2Ph), 4.82-5.03 (d, 5H, CH2Ph), 7.11-7.37
(m, 17H, aromatic) 7.53 (d, 1H, aromatic), 7.63 (dd, 1H, aromatic)
ppm; 13C NMR: δ, 15.4, 25.1, 69.3, 73.6, 74.4, 75.2, 75.9, 78.2,
79.3, 82.1, 85.0, 86.8, 122.3, 127.5, 127.8, 127.8, 127.9, 128.0,
128.0, 128.1, 128.5, 128.6, 129.0, 129.5, 132.5, 138.0, 138.2, 138.4,
138.5 ppm; HR-FAB MS calc for C36H40BrNO5S [M + H]+:
663.1780, found 663.1802.
24
1
Ethyl 3,4,6-Tri-O-benzyl-2-O-(o,o-dimethoxybenzyl)-1-thio-ꢀ-
D-glucopyranoside (7). To a solution of the thioglycoside 4 (150
mg, 0.304 mmol) and 2,6-dimethoxybenzyl bromide (105 mg, 0.456
mmol) were dissolved in DMF (1.5 mL) and NaH (60% in mineral
oil, 24 mg, 0.609 mmol) was added at rt. The reaction mixture
was stirred for 2 h, then quenched with ice (5 g) and extracted
with EtOAc/Et2O (1/1, v/v, 3 × 25 mL). The combined organic
extract was washed with cold water (3 × 20 mL), separated, dried
with magnesium sulfate, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(EtOAc/toluene gradient elution) to afford the title compound as
colorless syrup (77%). Analytical data for 7: Rf ) 0.48 (ethyl
27
1
acetate-hexane, 1/3, v/v); [R]D ) -9.1° (c ) 1, CHCl3); H
NMR: δ, 1.31 (t, 3H, J ) 7.1, SCH2CH3), 2.75 (m, 2H, SCH2CH3),
3.45 (m, 1H, H-2), 3.58-3.86 (m, 5H, H- 3, 4, 5, 6a, 6b), 3.76 (s,
6H, OMe), 3.93 (m, 1H, NCH2CH3), 4.45 (d, 1H, J1,2) 9.1 Hz,
H-1), 4.70 (d, 1H, CH2Ph), 4.76 (d, 1H, CH2Ph), 5.01-5.06 (m,
3H, CH2Ph), 6.51 (d, 2H, aromatic), 7.11 (m, 2H, aromatic),
7.18-7.34 (m, 14H, aromatic) ppm. 13C NMR: δ, 15.3, 25.0, 29.9,
55.8, 63.6, 69.6, 73.6, 75.2, 75.4, 77.4, 78.2, 79.2, 82.0, 85.5, 87.0,
103.9, 114.6, 127.4, 127.7, 127.8, 127.9, 128.2, 128.4, 128.5, 130.0,
138.4, 138.5, 139.4, 159.6 ppm; HR-FAB MS calc for C38H44O7SNa
[M + Na]+: 667.2705 found 667.2700 m/z.
3,4,6-Tri-O-benzyl-1-thio-r and ꢀ-D-Glucopyranosyl Trichlo-
roacetimidate (r- and ꢀ-31). To a suspension of the hemiacetal
r,ꢀ-30 (51 mg, 0.094 mmol), in dry CH2Cl2 (1.5 mL) trichloro-
acetonitrile (95 µL, 0.942mmol) was added followed by the addition
of K2CO3 (26 mg, 0.1885 mmol). The reaction mixture was stirred
for 30 min at rt, then diluted with CH2Cl2 (10 mL) and washed
with water (2 × 20 mL). The organic phase was separated, dried
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate/hexane gradient elution)
to yield ꢀ-31 as colorless syrup (34%) and r-31 as light brown
syrup (48%). Analytical data for ꢀ-31: Rf ) 0.32 (ethyl
Ethyl 3,4,6-Tri-O-benzyl-2-O-picolyl-1-thio-ꢀ-D-glucopyranoside
(8). To a solution of the thioglycoside 4 (150 mg, 0.304 mmol) in
DMF (4 mL) NaH (60% in mineral oil, 36 mg, 0.912 mmol) and
picolyl bromide hydrobromide (231 mg, 0.365 mmol) were added
at rt. The reaction mixture was stirred for 30 min, then quenched
with ice (5 g) and extracted with EtOAc/Et2O (1/1, v/v, 3 × 25
mL,). The combined organic extract was washed with cold water
(3 × 20 mL), separated, dried with magnesium sulfate, filtered,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc/hexane gradient) to give the
title compound as off-white amorphous solid (83%). Analytical data
26
1
acetate-hexane, 1/2, v/v); [R]D ) +11.5° (c ) 1, CHCl3); H
NMR: δ, 3.69 (m, 1H, H-5), 3.76-3.83 (m, 5H, H-2, 3, 4, 6a, 6b),
4.56 (d, 1H, J ) 15.4 Hz, CH2Ph), 4.64 (d, 1H, J ) 12.2 Hz,
CH2Ph), 4.81 (d, 1H, J ) 12.3 Hz, CH2Ph), 4.83 (d, 1H, J ) 10.9
Hz, CH2Ph), 4.89 (d, 1H, J ) 10.8 Hz, CH2Ph), 4.92 (d, 1H, J )
13.0 Hz, CH2Ph), 5.01 (d, 1H, J ) 13.0 Hz, CH2Ph), 5.84 (dd, 1H,
J1,2 ) 8.4 Hz, H-1), 7.13-7.21 (m, 3H, aromatic), 7.26-7.34 (m,
27
for 8: Rf ) 0.20 (ethyl acetate-hexane, 1/4, v/v); [R]D ) +7.0°
(c ) 1, CHCl3); 1H NMR: δ, 1.44 (t, 3H, SCH2CH3), 2.77 (m, 2H,
8846 J. Org. Chem. Vol. 73, No. 22, 2008

InVerse Armed-Disarmed Approach
13H, aromatic), 7.43 (d, 1H, aromatic), 7.57 (dt, 1H, aromatic),
8.53 (d, 1H, aromatic), 8.68 (s, 1H, NH), ppm; 13C NMR; δ, 29.9,
68.4, 73.6, 75.2, 75.1, 76.2, 77.4, 77.5, 81.9, 84.6, 91.1, 98.5, 121.4,
122.5, 127.8, 128.0, 128.1, 128.1, 128.2, 128.6, 128.6, 136.7, 138.2,
138.3, 138.5, 149.2, 158.5, 161.5 ppm; FAB MS [M + H]+ HR-
FAB MS calc for C35H35Cl3N2O6Na [M + Na]+: 707.1458 found
707.1412. Analytical data for r-31: Rf ) 0.14 (ethyl acetate-hexane,
1/2, v/v); [R]D25 ) +47.7° (c ) 1, CHCl3); 1H NMR: δ, 3.64 (dd,
1H, J ) 10.9 Hz, H-6a), 3.74-3.82 (m, 3H, H-2, 4, 6b), 3.87 (m,
1H, H-5), 4.56 (dd, 1H, J2,3 ) 9.3 Hz, H-3), 4.42-4.60 (m, 3H,
CH2Ph), 4.78-4.93 (m, 3H, CH2Ph), 6.57 (d, 1H, J1,2 ) 3.4 Hz,
H-1), 7.10-7.29 (m, 16H, aromatic), 7.40 (d, 1H, aromatic), 7.55
(dt, 1H, aromatic), 8.47 (d, 1H, aromatic), 8.52 (s, 1H, NH) ppm;
13C NMR; δ, 29.9, 68.2, 73.5, 73.7, 73.9, 75.6, 75.9, 77.1, 77.4,
80.1, 81.5, 91.5, 94.5, 121.3, 122.5, 127.8, 127.9, 128.1, 128.2,
128.3, 128.6, 128.6, 128.6, 136.8, 138.1, 138.2, 138.7, 149.1, 158.5,
161.4 ppm; FAB MS [M + H]+ HR-FAB MS calc for
C35H35Cl3N2O6Na [M + Na]+: 707.1458 found 707.1412.
Preparation of Di- and Trisaccharides. Method A: Typical
Cu(OTf)2-Promoted Glycosylation Procedure (Activation of the
STaz Glycosides). A mixture the glycosyl donor (0.13 mmol),
glycosyl acceptor (0.10 mmol), and freshly activated molecular
sieves (4 Å, 200 mg) in DCE (1.6 mL) was stirred under an
atmosphere of argon for 1 h followed by the addition of freshly
conditioned Cu(OTf)2 (0.39 mmol). The reaction mixture was stirred
for 16 h at 40 °C, then quenched with TEA and stirred 30 min.
The mixture was then diluted with CH2Cl2, the solid was filtered-
off and the residue was washed with CH2Cl2. The combined filtrate
(30 mL) was washed with water, the organic phase was separated,
dried with MgSO4 and concentrated in Vacuo. The residue was
purifiedbycolumnchromatographyonsilicagel(ethylacetate-hexane
gradient elution).
Method B: Typical Cu(OTf)2/TfOH-Promoted Glycosylation
Procedure (Activation of the STaz Glycosides). A mixture the
glycosyl donor (0.13 mmol), glycosyl acceptor (0.10 mmol), and
freshly activated molecular sieves (4 Å, 200 mg) in DCE (1.6 mL)
was stirred under an atmosphere of argon for 1 h. TfOH (0.08
mmol) was then added and stirred at rt until donor was fully
complexed. Freshly conditioned Cu(OTf)2 (0.26 mmol) was added
and the reaction mixture was stirred for 16 h at 40 °C. The reaction
was quenched with TEA, stirred for additional 30 min, then diluted
with CH2Cl2, the solid was filtered-off and the residue was washed
with CH2Cl2. The combined filtrate (30 mL) was washed with water
(4 × 10 mL), the organic phase was separated, dried with MgSO4
and concentrated in Vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate-toluene gradient
elution).
filtered-off and the residue was washed with CH2Cl2. The combined
filtrate (30 mL) was washed with water (4 × 10 mL), the organic
phase was separated, dried with MgSO4 and concentrated in Vacuo.
The residue was purified by column chromatography on silica gel
(ethyl acetate-hexane gradient elution).
Method E: Typical TESOTf-Promoted Glycosylation Procedure
(Activation of the Glycosyl Trichloroacetimidates). A mixture the
glycosyl donor (0.13 mmol), glycosyl acceptor (0.10 mmol), and
freshly activated molecular sieves (4 Å, 200 mg) in DCE (1.6 mL)
was stirred under an atmosphere of argon for 1 h. TESOTf (0.065
mmol) was added and the reaction mixture was stirred for 16 h at
40 °C. The reaction was quenched with TEA, stirred for additional
30 min, diluted with CH2Cl2, the solid was filtered-off and the
residue was washed with CH2Cl2. The combined filtrate (30 mL)
was washed with water (4 × 10 mL), the organic phase was
separated, dried with MgSO4 and concentrated in Vacuo. The residue
was purified by column chromatography on silica gel (ethyl
acetate-hexane gradient elution).
Method F: Typical IDCP-Promoted Glycosylation Procedure
(Activation of the SEt Glycosides). A mixture the glycosyl donor
(0.13 mmol), glycosyl acceptor (0.10 mmol), and freshly activated
molecular sieves (4 Å, 200 mg) in CH2Cl2 (1.6 mL) was stirred
under an atmosphere of argon for 1 h. The mixture was chilled to
-40 °C (or started directly at rt, see Table 1) and IDCP (0.39 mmol)
was added. The reaction mixture was allowed to warm to rt over
1 h and stirred for additional 16 h at 42 °C, then quenched with
TEA and stirred 30 min. The mixture was then diluted with CH2Cl2,
the solid was filtered-off and the residue was washed with CH2Cl2.
The combined filtrate (30 mL) was washed with water (4 × 10
mL), the organic phase was separated, dried with MgSO4 and
concentrated in Vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate-hexane gradient
elution).
Method G: Typical MeOTf-Promoted Glycosylation Procedure
(Activation of the SEt Glycosides. A mixture the glycosyl donor
(0.13 mmol), glycosyl acceptor (0.10 mmol), and freshly activated
molecular sieves (4 Å, 200 mg) in CH2Cl2 (1.6 mL) was stirred
under an atmosphere of argon for 1 h. MeOTf (0.39 mmol) was
added, the reaction mixture was allowed to warm to rt over 1 h
and stirred for additional 16 h at 42 °C, then quenched with TEA
and stirred 30 min. The mixture was then diluted with CH2Cl2, the
solid was filtered-off and the residue was washed with CH2Cl2.
The combined filtrate (30 mL) was washed with water (4 × 10
mL), the organic phase was separated, dried with MgSO4 and
concentrated in Vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate-hexane gradient
elution).
Method C: Typical AgOTf-Promoted Glycosylation Procedure
(Activation of the STaz Glycosides). A mixture the glycosyl donor
(0.13 mmol), glycosyl acceptor (0.10 mmol), and freshly activated
molecular sieves (3 Å, 200 mg) in DCE (1.6 mL) was stirred under
an atmosphere of argon for 1 h. Freshly conditioned AgOTf (0.26
mmol) was added and the reaction mixture was stirred for 16 h. at
rt, then quenched with TEA and stirred 30 min. The mixture was
then diluted with CH2Cl2, the solid was filtered-off and the residue
was washed with CH2Cl2. The combined filtrate (30 mL) was
washed with water (4 × 10 mL), the organic phase was separated,
dried with MgSO4 and concentrated in Vacuo. The residue was
purifiedbycolumnchromatographyonsilicagel(ethylacetate-toluene
gradient elution).
Method D: Typical DMTST-Promoted Glycosylation Procedure
(Activation of the SEt Glycosides). A mixture the glycosyl donor
(0.13 mmol), glycosyl acceptor (0.10 mmol), and freshly activated
molecular sieves (4 Å, 200 mg) in CH2Cl2 (1.6 mL) was stirred
under an atmosphere of argon for 1 h. The mixture was chilled to
-50 °C (or started at rt) and DMTST (0.39 mmol) was added. The
reaction mixture was allowed to warm to rt over 1 h and stirred
for additional 16 h at 42 °C, then quenched with TEA and stirred
30 min. The mixture was then diluted with CH2Cl2, the solid was
Method H: Typical NIS/TfOH-Promoted Glycosylation Proce-
dure (Activation of the SEt Glycosides). A mixture the glycosyl
donor (0.13 mmol), glycosyl acceptor (0.10 mmol), and freshly
activated molecular sieves (4Å, 200 mg) in CH2Cl2 (1.6 mL) was
stirred under an atmosphere of argon for 1 h. NIS (0.26 mmol)
and TfOH (0.013 mmol) were added, the reaction mixture was
allowed to warm to rt over 1 h and stirred for additional 16 h at 42
°C, then quenched with TEA and stirred 30 min. The mixture was
then diluted with CH2Cl2, the solid was filtered-off and the residue
was washed with CH2Cl2. The combined filtrate (30 mL) was
washed with water (4 × 10 mL), the organic phase was separated,
dried with MgSO4 and concentrated in Vacuo. The residue was
purifiedbycolumnchromatographyonsilicagel(ethylacetate-hexane
gradient elution).
O-(2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl)-(1f3)-1,2:5,6-di-
O-isopropylidine-r-D-glucofuranoside (10). The title compound was
obtained from donor 5 and acceptor 9 by Method F in 80% yield.
The spectroscopic and analytical data for 10 were in good agreement
with those reported previously.45
O-[3,4,6-Tri-O-benzyl-2-O-(o-bromobenzyl)-D-glucopyranosyl]-
(1f3)-1,2:5,6-di-O-isopropylidine-r-D-glucofuranoside (11). The
title compound was obtained as a colorless syrup from donor 5
J. Org. Chem. Vol. 73, No. 22, 2008 8847

Smoot and Demchenko
and acceptor 9 by Method F in 78% (R/ꢀ ) 1.8/1, rt) or 87% (R/ꢀ
) 2.3/1, -40 °C f rt) yield. Analytical data for r-11: Rf ) 0.37
4.42-5.15 (m, 14H, CH2Ph), 4.54 (d, 1H, H-1), 6.96-7.43 (m,
33H, aromatic), 8.42 (d, 1H, aromatic) ppm; 13C NMR: δ, 55.3,
69.2, 69.9, 73.6, 73.6, 75.0, 75.2, 75.3, 75.5, 75.8, 75.9, 77.4, 78.1,
78.1, 82.2, 82.5, 98.2, 103.8, 121.5, 122.3, 127.7, 127.7, 127.8,
127.8, 127.9, 127.9, 128.0, 128.1, 128.3, 128.5, 128.5, 128.6, 128.6,
138.3, 138.4, 138.4, 138.5, 138.6, 158.5 ppm; HR-FAB MS calcd
for C61H66NO11 [M + H]+: 988.4636, found 988.4630.
1
(ethyl acetate-hexane); H-NMR data: δ, 1.09 (s, 3H, Me), 1.28
(s, 3H, Me), 1.42 (s, 3H, Me), 1.49 (s, 3H, Me), 2.61-3.69 (m,
2H, H-2′, 3′), 3.72-3.75 (m, 2H, H-6a′, 6b′), 3.84 (m, 1H, H-5′),
3.92 (dd, 1H, J6a,6b ) 8.7 Hz, H-6a), 3.99-4.07 (m, 2H, H-4′, 6b),
4.12 (dd, 1H, J ) 8.0 Hz, H-4), 4.26 (dd, 1H, J ) 2.8 Hz, H-3),
4.39-4.66 (m, 7H, H-2, 5, CH2Ph), 4.71 (dd, 1H, J1,2 ) 6.3 Hz,
H-2), 4.79-4.87 (m, 3H, CH2Ph), 4.95 (d, 1H, CH2Ph), 5.35 (d,
1H, J1′,2′ ) 3.5 Hz, H-1′), 5.90 (d, 1H, J1,2 ) 3.6 Hz, H-1),
7.13-7.36 (m, 20H, aromatic), 7.44-7.63 (m, 2H, aromatic) ppm.
13C NMR: δ, 1.2, 14.3, 22.9, 25.2, 25.3, 26.4, 26.7, 26.9, 27.0,
27.2, 29.6, 29.9, 31.2, 32.2, 67.1, 68.9, 71.6, 72.4, 72.6, 80.6, 81.7,
83.9, 98.2, 101.6, 105.5, 109.2, 112.0, 127.6, 127.8, 128.0, 128.1,
129.0, 132.5, 137.9, 138.0, 138.1, 138.2, 138.4, 138.6, 138.7 ppm;
HR-FAB MS calc for C46H53BrO11 [M + H]+: 860.2771 found
860.2777.
Methyl 2,3,4-Tri-O-benzyl-6-O-(3,4,6-tri-O-benzyl-2-O-picolyl-ꢀ-
D-glucopyranosyl)-r-D-galactopyranoside (24). The title compound
was obtained from 16b and 18 via Method A as off-white
amorphous solid in 76% yield (ꢀ-only). Analytical data for 24: Rf
24
) 0.44 (ethyl acetate-hexane, 2/3, v/v); [R]D ) -9.3° (c ) 1,
CHCl3); 1H NMR: δ, 3.21 (s, 3H, OMe), 3.29-3.57 (m, 7H, H-2,
4, 6a, 3′, 4′, 6a′, 6b′), 3.71 (m, 1H, H-5), 3.77-3.89 (m, 3H, H-3,
2′, 5′), 4.05 (dd, 1H, J6a,6b ) 10.7 Hz, H-6b), 4.27 (d, 1H, J1′,2′
)
7.6 Hz, H-1′), 4.34-4.53 (m, 4H, CH2Ph), 4.50 (d, 1H, J1,2 ) 7.6
Hz, H-1), 4.57-4.70 (d, 6H, CH2Ph), 4.81-4.90 (m, 3H, CH2Ph),
5.03 (d, 1H, CH2Ph), 6.96 (m, 1H, aromatic), 7.07-7.26 (m, 31H,
O-[3,4,6-Tri-O-benzyl-2-O-(o,o-dimethoxybenzyl)-D-glucopyra-
nosyl]-(1f3)-1,2:5,6-di-O-isopropylidine-r-D-glucofuranose (12).
The title compound was obtained as a colorless semisolid from
donor 7 and acceptor 9 by Method F in 58-89% yield (R/ꢀ )
1.8-2.3/1). Analytical data for 12: Rf ) 0.43 (ethyl acetate-hexane,
aromatic), 7.38 (d, 2H, aromatic), 8.38 (d, 1H, aromatic) ppm. 13
C
NMR: δ, 55.4, 68.7, 68.8, 70.0, 72.9, 73.5, 73.6, 73.7, 74.8, 74.9,
75.8, 77.4, 78.3, 79.9, 80.1, 82.2, 82.4, 98.1, 104.2, 122.1, 122.5,
127.7, 127.7, 127.8, 127.9, 128.0, 128.0, 128.1, 128.2, 128.4, 128.4,
128.5, 128.6, 138.1, 138.4, 138.6, 138.6, 138.9, 139.1 ppm; HR-
FAB MS calc for C61H65NO11Na [M + Na]+: 1010.4455 found
1010.4467.
1
2/3, v/v); H-NMR data: δ, 1.23, (s, 3H, Me), 1.26 (s, 3H, Me),
1.40 (s, 3H, Me), 1.49 (s, 3H, Me), 3.50 (dd, 1H, J2,3 ) 9.7, H-3′),
3.62 (dd, 1H, J2,3 ) 9.7 Hz, H-2′), 3.67-3.84 (m, 4H, H-4′, 5′,
6a′, 6b′), 3.75 (s, 6H, OMe), 4.03 (dd, 1H, J3,4 ) 8.6 Hz, H-4),
4.15 (dd, 1H, J6a,6b ) 9.8 Hz, H-6a), 4.25 (dd, 1H, J5,6 ) 6.0 Hz,
H-6b), 4.35-4.52 (m, 4H, H-3, 5, CH2Ph), 4.57-4.65 (m, 2H,
CH2Ph), 4.73 (dd, 1H, J2,3 ) 3.6 Hz, H-2), 4.78-4.90 (m, 3H,
CH2Ph), 5.02 (d, 1H, J1′,2′ ) 3.57, H-1′), 5.89 (d, 1H, J1,2 ) 3.6
Hz, H-1), 6.54 (d, 2H, aromatic), 7.09-7.34 (m, 18H, aromatic)
ppm. 13C NMR: δ, 24.9, 25.5, 26.4, 26.8, 27.0, 29.9, 36.8, 55.9,
60.7, 66.7, 69.3, 71.1, 73.3, 72.7, 75.3, 75.4, 77.4, 80.3, 80.3, 81.4,
81.5, 81.9, 83.75, 98.6, 103.9, 105.5, 108.8, 111.8, 114.5, 127.4,
127.9, 128.0, 128.1, 128.3, 128.4, 128.6, 130.1, 138.21, 138.4, 159.5
ppm; HR-FAB MS calc for C48H58O13 [M + H]+: 842.3877 found
842.3881.
Methyl 2,3,6-Tri-O-benzyl-4-O-(3,4,6-tri-O-benzyl-2-O-picolyl-
ꢀ-D-glucopyranosyl)-r-D-glucopyranoside (25). The title compound
was obtained from 16a and methyl 2,3,6-tri-O-benzyl-R-D-glu-
copyranoside35 (19) by Method A or B as white amorphous solid
in 83 and 80% yield. Analytical data for 25: Rf ) 0.29 (ethyl
22
1
acetate/hexane, 2/3, v/v); [R]D ) +12.5° (c ) 1, CHCl3); H
NMR: δ, 3.28-4.02 (m, 12H, H-2, 2′, 3, 3′, 4, 4′, 5, 5′, 6a, 6a′, 6b,
6b′), 3.36 (s, 3H, OCH3), 4.37-5.12 (m, 14H, CH2Ph), 4.45 (d,
1H, J1′,2′ ) 9.2 Hz, H-1′), 4.57 (d, 1H, J1,2 ) 3.8 Hz, H-1),
7.11-7.68 (m, 33H, aromatic) 8.53 (d, 1H, aromatic) ppm; 13C
NMR: δ, 29.9, 55.5, 69.3, 70.1, 73.6, 73.8, 75.0, 75.5, 75.6, 75.6,
75.8, 78.3, 79.1, 80.5, 83.2, 85.0, 98.7, 102.7, 121.5, 122.4, 127.3,
127.5, 127.7, 127.8, 127.9, 127.9, 128.0, 128.0, 128.2, 128.2, 128.2,
128.3, 128.4, 128.5, 128.7, 138.1, 138.6, 138.8, 139.8, 149.1, 158.9
ppm; HR-FAB MS calcd for C61H66NO11 [M + H]+: 988.4636,
found 988.4609.
O-(3,4,6-Tri-O-benzyl-2-O-picolyl-ꢀ-D-glucopyranosyl)-(1f3)-
1,2:5,6-di-O-isopropylidine-r-D-glucofuranose (13). The title com-
pound was obtained as a colorless syrup from donor 8 and acceptor
9 by Method D in 45% yield. Analytical data for 13: Rf ) 0.48
1
(ethyl acetate-hexane, 1/1, v/v); H-NMR data: δ, 1.26, (s, 3H,
Methyl 2,4,6-Tri-O-benzyl-3-O-(3,4,6-tri-O-benzyl-2-O-picolyl-
ꢀ-D-glucopyranosyl)-r-D-glucopyranoside (26). The title compound
was obtained from 16a and methyl 2,4,6-tri-O-benzyl-R-D-glu-
copyranoside36 (20) by Method B as white amorphous solid in 85%
yield. Analytical data for 26: Rf ) 0.45 (ethyl acetate/hexane, 2/3,
Me), 1.28 (s, 3H, Me), 1.32 (s, 3H, Me), 1.44 (s, 3H, Me),
3.46-3.54 (m, 2H, H-4,5′), 3.60-3.72 (m, 5H, H-5, 3′, 4′, 6a′,
6b′), 3.81 (m, 1H, H-6a), 4.15-4.24 (m, 3H, H-6b, 1′, 2′),
4.49-4.58 (m, 4H, H-2, 3, CH2Ph), 4.63 (d, 1H, CH2Ph), 4.78-4.95
(m, 4H, CH2Ph), 5.17 (d, 1H, CH2Ph), 5.97 (d, 1H, J1,2 ) 3.7 Hz,
H-1), 7.15 (m, 3H, aromatic), 7.26-7.35 (m, 13H, aromatic), 7.59
(d, 1H, aromatic), 7.60 (dt, 1H, aromatic), 8.54 (d, 1H, aromatic)
ppm. 13C NMR: δ, 24.0, 24.1, 26.8, 27.4, 29.9, 69.1, 70.7, 71.8,
73.8, 75.1, 75.2, 75.8, 77.4, 78.0, 79.7, 82.7, 84.2, 84.6, 101.2,
104.3, 106.6, 112.4, 121.7, 122.3 127.8, 127.8, 128.0, 128.0, 128.2,
128.5, 128.6, 138.4, 138.8 ppm; HR-FAB MS calc for C45H53NO11
[M + H]+: 783.3619 found 783.3618 m/z.
23
1
v/v); [R]D ) +20.1° (c ) 1, CHCl3); H NMR: δ, 3.28 (s, 3H,
OCH3), 3.39-3.71 (m, 10H, H-2, 2′, 3′, 4, 4′, 5′, 6a, 6a′, 6b, 6b′),
3.76 (m, 1H, H-5), 3.92 (dd, 1H, J6a,6b ) 9.2 Hz, H-3), 4.37 (d,
1H, J1’2′ ) 7.7 Hz, H-1′), 4.42-5.11 (m, 14H, CH2Ph), 6.96-7.43
(m, 33H, aromatic) 8.42 (d, 1H, aromatic) ppm; 13C NMR: δ 29.7,
35.7, 63.0, 64.0, 66.4, 71.2, 72.6, 76.8, 77.2, 82.0, 128.3, 128.4,
128.4, 128.6, 128.8, 129.0, 129.8, 129.8, 130.0, 133.0, 133.3, 133.5,
133.6, 162.5, 165.2, 165.5, 166.1 ppm; HR-FAB MS calcd for
C61H66NO11 [M + H]+: 988.4636, found 988.4652.
Methyl 2,3,4-Tri-O-benzyl-6-O-(3,4,6-tri-O-benzyl-2-O-picolyl-
ꢀ-D-glucopyranosyl)-r-D-glucopyranoside (23). The title compound
was obtained from 16a and methyl 2,3,4-tri-O-benzyl-R-D-glu-
copyranoside34 (18) by Methods A, B and C as white amorphous
solid in 80, 84, and 78% yield, respectively. Alternatively, the title
compound was obtained from 8 and 18 by Method D and from
r,ꢀ-31 and 18 by Method E in 70 and 84%, respectively.
Analytical data for 23: Rf ) 0.36 (ethyl acetate-hexane, 2/3, v/v);
[R]D 24 ) +14.3° ( c ) 1, CHCl3); 1H NMR: δ, 3.28 (s, 3H, OCH3),
3.39-3.70 (m, 9H, H-2, 2′, 3′, 4, 4′, 5′, 6b, 6a′, 6b′), 3.76 (m, 1H,
J5,6a ) 1.6 Hz, H-5), 3.92 (dd, 1H, J3,4 ) 9.2 Hz, H-3), 4.14 (dd,
1H, J6a,6b ) 11.0 Hz, H-6a), 4.37 (d, 1H, J1′,2′ ) 7.7 Hz, H-1′),
Methyl 3,4,6-Tri-O-benzyl-2-O-(3,4,6-tri-O-benzyl-2-O-picolyl-
ꢀ-D-glucopyranosyl)-r-D-glucopyranoside (27). The title compound
was obtained from 16a and methyl 3,4,6-tri-O-benzyl-R-D-glu-
copyranoside46 (21) by Method A, B and C as white amorphous
solid in 69, 80, and 63% yield. Analytical data for 27: Rf ) 0.27
(ethyl acetate-hexane, 2/3, v/v); [R]D 23 ) +31.7° (c ) 1, CHCl3);
1H NMR: δ, 3.44 (s, 3H, OCH3), 3.46 (m, 1H, H-5), 3.60-3.85
(m, 10H, H-2′, 3′, 4, 4′, 5, 5′, 6a, 6a′, 6b, 6b′), 3.88 (dd, 1H, J2,3
)
9.8 Hz, H-2), 4.06 (dd, 1H, J3,4 ) 9.6 Hz, H-3), 4.46-4.70 (m,
8H, CH2Ph), 4.75-25 (m, 6H, CH2Ph), 4.77 (d, 1H, J1′,2′ ) 9.8
Hz, H-1′), 5.01 (d, 1H, J1,2 ) 3.5 Hz, H-1), 7.02-7.46 (m, 33H,
(45) Vankayalapati, H.; Singh, G.; Tranoy, I. Tetrahedron: Asymmetry 2001,
12, 1373–1381.
(46) Sollogoub, M.; Das, S. K.; Mallet, J.-M.; Sinay, P. C. R. Acad. Sci.
Ser. 2 1999, 2, 441–448.
8848 J. Org. Chem. Vol. 73, No. 22, 2008

InVerse Armed-Disarmed Approach
aromatic) 8.49 (d, 1H, aromatic) ppm; 13C NMR: δ, 55.4, 68.8,
69.0, 70.1, 73.7, 73.8, 75.0, 75.1, 75.2, 75.3, 75.8, 77.4, 78.0, 78.4,
79.3, 81.9, 82.5, 85.1, 100.0, 104.3, 121.5, 122.1, 127.57, 127.8,
127.9, 127.9, 128.0, 128.0, 128.1, 128.2, 128.3, 128.5, 128.6, 128.6,
136.5, 138.2, 138.3, 138.3, 38.5, 138.7, 138.9, 148.94, 158.7 ppm;
HR-FAB MS calcd for C61H66NO11 [M + H]+: 988.4636, found
988.4620.
10.9 Hz, CH2Ph), 5.10 (d, 1H, J ) 12.3 Hz, CH2Ph), 5.49 (dd, 1H,
J4,5 ) 9.7 Hz, H-4), 5.60 (dd, 1H, J2,3 ) 10.0 Hz, H-2), 5.80 (d,
1H, J1,2 ) 10.3 Hz, H-1), 5.94 (dd, 1H, J3,4 ) 9.4 Hz, H-3),
7.12-7.46 (m, 26H, aromatic), 7.63 (m, 1H, aromatic), 7.79 (d,
2H, aromatic), 7.92 (t, 4H, aromatic), 8.55 (d, 1H, aromatic) ppm;
13C NMR: δ, 35.4, 64.2, 68.8, 69.9, 70.5, 73.7, 74.3, 75.1, 75.2,
75.7, 75.9, 77.4, 78.6, 83.0, 83.3, 84.5, 103.6, 122.5, 122.7, 127.8,
127.9, 128.0, 128.1, 128.3, 128.5, 128.5, 128.6, 128.7, 129.0, 129.1,
129.9, 130.1, 130.2, 133.6, 133.7, 136.7, 138.4, 138.8, 149.2, 162.7,
165.4, 165.5, 165.9 ppm; HR-FAB MS calcd for C63H62N2O13S2
[M + H]+: 1117.3615, found 1117.3625.
Ethyl 2,3,4-Tri-O-acetyl-6-O-(3,4,6-tri-O-benzyl-2-O-picolyl-ꢀ-
D-glucopyranosyl)-1-thio-ꢀ-D-glucopyranoside (28a). The title com-
pound was obtained from 16a and ethyl 2,3,4-tri-O-acetyl-1-thio-
ꢀ-D-glucopyranoside (22a)47 by Method A as white amorphous solid
in 56% yield. Analytical data for 28: Rf ) 0.28 (ethyl acetate/
Methyl O-(3,4,6-Tri-O-benzyl-2-O-picolyl-ꢀ-D-glucopyranosyl)-
(1f6)-O-(2,3,4-tri-O-benzoyl-ꢀ-D-glucopyranosyl)-(1f6)-2,3,4-tri-
O-benzyl-r-D-glucopyranoside (36). The title compound was ob-
tained from 35 and 18 by Method C as white foam in 91% yield.
1
hexane, 1/1, v/v); H NMR: δ, 1.12 (t, 3H, SCH2CH3), 2.00 (s,
3H, OAc), 2.00 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.54 (q, 2H,
SCH2CH3), 3.48 (m, 2H, H-2′, 3′), 3.61-3.72 (m, 5H, H-4′, 5′, 6a,
6b, 6a′), 3.79 (m, 1H, H-5), 3.92 (dd, 1H, J6a,6b ) 10.9 Hz, H-6b),
4.46-4.55 (m, 4H, H-1, 1′, CH2Ph), 4.63 (d, 1H, CH2Ph),
4.78-5.00 (m, 6H, H-2, 3, CH2Ph), 5.13 (d, 1H, CH2Ph), 5.21 (dd,
1H, J3,4 ) 9.4 Hz, H-4), 7.11-7.18 (m, 3H, aromatic), 7.25-7.34
(m, 13H, aromatic), 7.49 (d, 1H, 1H, aromatic), 7.61 (dt, 1H,
aromatic), 8.55 (d, 1H, aromatic) ppm; 13C NMR: δ, 14.9, 20.9,
24.2, 29.9, 70.0, 69.5, 70.4, 73.7, 74.2, 75.1, 75.2, 75.6, 76.8, 77.4,
77.9, 82.9, 83.3, 84.7, 103.9, 127.8, 128.0, 128.0, 128.6, 128.6,
138.3, 138.3, 138.7, 169.6, 169.9, 170.4 ppm; HR-FAB MS calc
for C47H56NO13S [M + H]+ 874.3472, found 874.3453.
23
Analytical data for 36: Rf ) 0.60 (acetone-toluene, 1/4, v/v); [R]D
) +3.0° (c ) 1, CHCl3); 1H NMR: δ, 3.12 (s, 3H), 3.30-3.52 (m,
4H), 3.55-3.67 (m, 4H), 3.81 (dd, 1H, J ) 9.2 Hz), 3.86 (dd, 1H,
J ) 8.2 Hz), 4.12-4.17 (m, 4H), 4.31 (d, 1H, J ) 11.0 Hz, CH2Ph),
4.44 (d, 1H, J ) 12.0 Hz, CH2Ph), 4.48-4.90 (m, 14H, CH2Ph),
5.16 (d, 1H, J ) 12.6 Hz, CH2Ph), 5.38 (dd,1H, J ) 9.8 Hz), 5.54
(dd, 1H, J ) 7.9, 9.9 Hz), 5.86 (dd, 1H, J ) 9.4, H-3), 6.90-7.54
(m, 42H, aromatic), 7.75-7.93 (m, 6H, aromatic), 8.50 (d, 1H)
ppm; 13C NMR: δ, 55.4, 68.7, 68.9, 69.6, 70.1, 72.1, 73.2, 73.6
(×2), 73.7 (×2), 74.8, 74.8, 75.1, 75.2, 75,2, 75.6, 76.0, 77.4, 79.8,
82.0, 84.6, 84.7, 98.3, 101.0, 104.1, 127.6, 127.7, 127.8, 127.9,
128.0, 128.0, 128.1, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6, 128.6,
129.0, 129.4, 129.8, 129.9, 130.1, 133.2, 133.4, 133.7, 138.3, 138.4,
138.5, 138.7, 139.1, 165.1, 166.0 ppm; HR-FAB MS calc for
C88H88NO19 [M + H]+: 1462.5951, found 1462.5951.
Ethyl 2,3,4-Tri-O-benzoyl-6-O-(3,4,6-tri-O-benzyl-2-O-picolyl-
ꢀ-D-glucopyranosyl)-1-thio-ꢀ-D-glucopyranoside (28b). The title
compound was obtained from 16a and ethyl 2,3,4-tri-O-benzoyl-
1-thio-ꢀ-D-glucopyranoside9 (22b) by Method A and C as white
amorphous solid in 78 and 72% yield. Analytical data for 28: Rf )
0.36 (ethyl acetate/hexane, 2/3, v/v); [R]D23 ) +2.1° (c ) 1, CHCl3);
1H NMR: δ, 1.10 (t, 3H, SCH2CH3), 2.63 (q, 2H, SCH2CH3),
Thiazolinyl 3,4-O-Benzoyl-2-O-benzyl-6-O-(2,3,4,6-tetra-O-ben-
zyl-r/ꢀ-D-glucopyranosyl)-1-thio-ꢀ-D-glucopyranoside (39). The title
compound was obtained from 17 and 38 by Method A as white
amorphous solid in 89% yield (R/ꢀ ) 2.0/1). Analytical data for
3.40-3.68 (m, 6H, H-2′, 3′, 4′, 5′, 6a′, 6b′), 3.85 (dd, 1H, J5,6b
)
7.7 Hz, J6a,6b ) 11.4 Hz, H-6b), 4.00-4.16 (m, 2H, H-5, 6a),
4.40-5.20 (m, 8H, CH2Ph), 4.55 (d, 1H, J1′,2′ ) 8.8 Hz, H-1′),
4.79 (d, 1H, J1,2 ) 10.0 Hz, H-1), 5.41 (dd, 1H, J4,5 ) 9.8 Hz,
H-4), 5.49 (dd, 1H, J2,3 ) 9.7 Hz, H-2), 5.89 (dd, 1H, J3,4 ) 9.5
Hz, H-3), 7.09-7.95 (m, 33H, aromatic) 8.59 (d, 1H, aromatic)
ppm; 13C NMR: δ, 14.3, 32.2, 68.8, 69.1, 70.2, 73.7, 74.4, 75.1,
75.2, 75.9, 77.4, 77.9, 78.6, 82.9, 84.7, 104.0, 127.8, 128.0, 128.0,
128.2, 128.5, 128.6, 128.6, 128.6, 129.0, 129.1, 129.5, 129.9, 130.1,
133.4, 133.4, 133.7, 138.3, 138.7, 165.4, 165.7, 166.0 ppm; HR-
FAB MS [M + H]+ calc for C62H62NO13S 1060.3942, found
1060.3932.
1
39: Rf ) 0.42 (acetone-toluene, 1/2, v/v); H NMR: δ, 3.42-3.61
(m, 6H, H-2, 6a, 2′, 4′, 5′, 6a′), 3.68 (dd, 1H, J6a,6b ) 11.2 Hz,
H-6b), 3.73-3.92 (m, 4H, H-3′, 6a′, CH2N), 3.96-4.08 (m, 3H,
H-5, CH2S), 4.31-4.38 (m, 3H, CH2Ph), 4.48-4.61 (m, 3H,
CH2Ph), 4.66-4.70 (m, 3H, CH2Ph), 4.75 (d, 1H, J ) 10.4 Hz,
CH2Ph), 4.91 (d, 1H, CH2Ph), 5.32 (dd, 1H, J ) 9.8 Hz, H-4),
5.41 (d, 1H, J ) 10.1 Hz, H-1), 5.63 (dd, 1H, J ) 9.3 Hz, H-3),
7.03-7.31 (m, 29H, aromatic), 7.41 (t, 2H, aromatic), 7.82 (m,
4H, aromatic) ppm; 13C NMR: δ, 22.9, 24.9, 29.2, 31.3, 31.8, 35.0,
36.9, 64.3, 67.1, 68.5, 69.4, 70.3, 73.2, 73.6, 75.3, 75.4, 75.9, 76.2,
77.4, 77.7, 78.3, 80.6, 82.0, 84.6, 97.3, 99.8, 127.8, 127.8, 127.9,
128.0, 128.1, 128.1, 128.2, 128.4, 128.5, 128.6, 128.6, 128.6, 129.9,
130.1, 133.4, 133.6, 137.1, 138.3, 138.6, 138.78, 139.2, 165.5, 165.7
ppm; HR-FAB MS calcd for C64H63NO12S2Na [M + Na]+:
1124.3689, found 1124.3668.
Thiazolinyl 2,3,4-Tri-O-benzoyl-6-O-(2,3,4,6-tetra-O-benzyl-ꢀ-
D-glucopyranosyl)-1-thio-ꢀ-D-glucopyranoside (33). The title com-
pound was obtained from 17 and thiazolinyl 2,3,4-tri-O-benzoyl-
1-thio-ꢀ-D-glucopyranoside16 (32) via Method A or C as white
amorphous solid in 88% (R/ꢀ ) 1.5/1) or 79% (R/ꢀ ) 2.0/1) yields,
respectively. The spectroscopic and analytical data for 33 were in
good agreement with those reported previously.16
Methyl O-(2,3,4,6-Tetra-O-benzyl-r/ꢀ-D-glucopyranosyl)-(1f6)-
O-(2,3,4-tri-O-benzoyl-ꢀ-D-glucopyranosyl)-(1f6)-2,3,4-tri-O-ben-
zyl-r-D-glucopyranoside (34). The title compound was obtained
from 33 and 18 by Method C as white foam in 83% yield. The
spectroscopic and analytical data for 34 were in good agreement
with those reported previously.7
Methyl O-(2,3,4,6-Tetra-O-benzyl-r/ꢀ-D-glucopyranosyl)-(1f6)-
O-(3,4-O-benzoyl-2-O-benzyl-r/ꢀ-D-glucopyranosyl)-(1f6)-2,3,4-
tri-O-benzyl-r-D-glucopyranoside (40). The title compound was
obtained from 39 and 18 by Method C as white amorphous solid
in 75% yield (R/ꢀ ) 1.6/1). Analytical data for 40: Rf ) 0.36
1
(acetone-hexane, 3/7, v/v); H NMR: δ, 3.16 (s, 3H, OMe), 3.39
(m, 1H, H-2), 3.48-4.00 (m, 13H, H-3, 4, 5, 6a, 2′, 6a′, 6b′, 2′′,
3′′, 4′′, 5′′, 6a′′, 6b′′), 4.12 (m, 1H, H-5′), 3.82-4.57 (m, 9H, H-1,
CH2Ph), 4.61-4.84 (m, 9H, H-1′′, CH2Ph), 5.10 (m, 1H, H-1′),
5.31 (m, 1H, H-4′), 5.61 (dd, 1H, H-3′), 6.95-7.35 (m, 44H,
aromatic), 7.49 (m, 2H, aromatic), 7.88 (m, 4H, aromatic) ppm;
13C NMR: δ, 30.0, 55.3, 55.5, 66.1, 66.1, 66.6, 67.0, 68.3, 68.6,
68.6, 68.9, 68.9, 67.0, 69.1, 70.9, 71.0, 72.1, 72.2, 72.3, 72.5, 72.9,
73.1, 73.4, 73.6, 73.6, 74.6, 74.8, 74.9, 75.1, 75.2, 75.4, 75.8, 75.9,
77.5, 78.0, 78.0, 79.2, 80.0, 80.4, 82.0, 82.2, 82.4, 82.5, 84.8, 84.8,
96.9, 97.1, 97.4, 97.5, 98.2, 98.4, 103.5, 104.2, 127.8, 127.9, 127.9,
128.0, 128.1, 128.1, 128.1, 128.2, 128.2, 128.3, 128.3, 128.4, 128.5,
128.6, 128.7, 128.7, 129.4, 129.6, 129.8, 130.0, 130.1, 133.1, 133.2,
133.3, 133.4, 133.5, 137.8, 137.9, 138.0, 138.2, 138.4, 138.4, 138.7,
Thiazolinyl 2,3,4-tri-O-benzoyl-6-O-(3,4,6-tri-O-benzyl-2-O-pi-
colyl-ꢀ-D-glucopyranosyl)-1-thio-ꢀ-D-glucopyranoside (35). The title
compound was obtained from 16a and 32 by Method B as white
amorphous solid in 74% yield. Analytical data for 35: Rf ) 0.40
24
(acetone-toluene, 1/4, v/v); [R]D ) +31.5° (c ) 0.71, CHCl3);
1H NMR: δ, 3.13 (m, 2H, SCH2), 3.38-3.46 (m, 2H, H-2′, 4′),
3.57-3.67 (m, 4H, H-3′, 5′, 6a′, 6b′), 3.87 (dd, 1H, J5,6b ) 7.4 Hz,
J6a,6b ) 12.0 Hz, H-6b), 4.00 (m, 2H, NCH2), 4.11 (dd, 1H, J5,6a
)
1.8 Hz, H-6a), 4.21 (m, 1H, H-5), 4.41-4.58 (m, 4H, J1′,2′ ) 7.6
Hz, H-1′, CH2Ph), 4.72-4.90 (m, 3H, CH2Ph), 4.92 (d, 1H, J )
(47) Pastuch, G.; Wandzik, I.; Szeja, W. Pol. J. Chem. 2003, 77, 995–999.
J. Org. Chem. Vol. 73, No. 22, 2008 8849

Smoot and Demchenko
138.8, 138.8, 139.1, 139.2, 165.5, 165.8, 166.0, 166.0 ppm; HR-
FAB MS calcd for C89H90O18 [M + Na]+: 1469.6025, found
1469.6023.
138.4, 139.0 ppm; HR-FAB MS calcd for C34H38NO6 [M + H]+:
556.2699, found 556.2704. If the reaction mixture was quenched
after 1 h, expected intermediate 43 could be isolated as a sole
product in 80% yield. Analytical data for 43: Rf ) 0.4 (MeOH
Thiazolinyl 3,4-O-Benzoyl-2-O-benzyl-6-O-(3,4,6-tetra-O-benzyl-
2-O-picolyl-ꢀ-D-glucopyranosyl)-1-thio-r/ꢀ-D-glucopyranoside (41).
The title compound was obtained from 16a and 38 by Method B
as white amorphous solid in 70% yield. Analytical data for 41: Rf
27
1
/CH2Cl2, 1/4, v/v); [R]D ) +20.9 (c ) 1, CHCl3); H NMR: δ,
3.60 (dd, 1H, J5,6b ) 4.5 Hz, H-6b), 3.67 (dd, 1H, J6a,6b ) 11.0 Hz,
H-6a), 3.76 (dd, 1H, J4,5 ) 9.6 Hz, H-4), 3.81 (m, 1H, H-5), 4.10
(dd, 1H, J3,4 ) 3.7 Hz, H-3), 4.43 (dd, 2H, J ) 11.9 Hz, CH2Ph),
4.47 (dd, 2H, J ) 11.4 Hz, CH2Ph), 4.72 (dd, 1H, J2,3 ) 5.7 Hz,
H-2), 4.47 (dd, 2H, J ) 11.6 Hz, CH2Ph), 5.15 (dd, 2H, J ) 12.0
Hz, CH2Ph), 6.15 (d, 1H, J1,2 ) 4.6 Hz, H-1), 7.14-7.36 (m, 18H,
aromatic), 7.88 (d, 1H, aromatic), 8.00 (m, 1H, aromatic), 8.48 (m,
1H, aromatic), 9.00 (d, 1H, aromatic) ppm; 13C NMR: δ, 64.8, 70.1,
73.2, 74.1, 74.2, 74.5, 75.2, 77.0, 77.2, 77.7, 78.5, 84.9, 126.5,
128.1, 129.0, 129.2, 129.3, 129.4, 129.5, 129.6, 129.6, 129.7, 139.1,
139.2, 139.3, 144.2, 147.7, 154.4 ppm; HR-FAB MS calcd for
C33H34NO5 [M + H]+: 524.2431, found 524.2442.
Methyl 6-O-(ꢀ-D-Glucopyranosyl)-r-D-glucopyranoside (29). Pd
(10% on charcoal, 100 mg) was added to a stirred solution of 23
(20 mg, 0.093 mmol) and concentrated aq. HCl (50 µL) in ethanol/
ethyl acetate (1/1, v/v, 3 mL). The reaction mixture was then purged
with H2 and stirred for 4 h at rt. Upon completion, the solid was
filtered off and the filtrate was concentrated under reduced pressure
and dried to give the title compound as colorless film in 98% yield.
The spectroscopic and analytical data for 29 were in agreement
with those reported previously.12,48
1
) 0.42 (acetone-toluene, 2/3, v/v); H NMR: δ, 3.17 (m, 2H,
SCH2), 3.28-3.41 (m, 3H, H-2′, 3′), 3.45-3.62 (m, 4H, H-4′, 5′,
6a′, 6b′), 3.63-3.79 (m, 2H, H-2, 6a), 3.91-4.13 (m, 4H, H-5, 6b,
NCH2), 4.32-4.49 (m, 6H, CH2Ph, H-1′), 4.64-4.84 (m, 5H,
CH2Ph), 5.06 (d, 1H, CH2Ph), 5.27 (dd, 1H, J3,4 ) 9.9 Hz, H-4),
5.43 (d, 1H, J1,2 ) 10.0 Hz, H-1), 5.66 (dd, 1H, J3,4 ) 9.3 Hz,
H-3), 7.04-7.30 (m, 25H, aromatic), 7.41 (m, 3H, aromatic), 7.59
(t, 1H, aromatic), 7.79 (m, 4H, aromatic), 8.48 (d, 1H, aromatic)
ppm; 13C NMR: δ, 29.5, 29.9, 35.3, 54.0, 64.4, 68.,7 68.8, 69.9,
73.8, 75.1, 75.1, 75.2, 75.7, 76.0, 76.7, 77.5, 78.1, 78.3, 82.9, 84.4,
84.8, 127.7, 127.8, 127.9, 128.0, 128.1, 128.1, 128.29, 128.4, 128.5,
128.6, 128.6, 129.1, 129.6, 129.9, 130.1, 137.1, 138.3, 138.8, 142.4,
165.7 ppm; HR-FAB MS calcd for C63H62N2O12S2Na [M + Na]+:
1125.3641, found 1125.3661.
Methyl O-(3,4,6-Tri-O-benzyl-2-O-picolyl-ꢀ-D-glucopyranosyl)-
(1f6)-O-(3,4-O-benzoyl-2-O-benzyl-r/ꢀ-D-glucopyranosyl)-(1f6)-
2,3,4-tri-O-benzyl-r-D-glucopyranoside (42). The title compound
was obtained from 41 and 18 by Method C as white amorphous
solid in 54% yield (R/ꢀ ) 1.7/1). Analytical data for 42: Rf ) 0.43
(acetone-hexane, 2/3, v/v); 1H NMR: δ, 3.18, 3.29 (s, 3H, OMe),
3.19-3.42 (m, 3H, H-4, 2′′, 3′′), 3.46-3.71 (m, 9H, H-2, 5, 5′,
6a′, 6b′, 4′′, 5′′, 6a′′, 6b′′), 3.76-4.08 (m, 4H, H-3, 2′, 6a′, 6b′),
4.15 (m, 1H, H-5′), 4.32-4.89 (m, 17H, H-1, 1′′, CH2Ph), 4.99 (d,
1H, J1′,2′ ) 3.6 Hz, H-1′), 5.03 (m, 2H, H-4′, CH2Ph), 5.84 (dd,
1H, J2′,3′ ) 9.5 Hz, H-3), 6.86-7.26 (m, 44H, aromatic), 7.78 (m,
5H, aromatic), 8.40 (m, 1H, aromatic) ppm; 13C NMR: δ, 30.0,
55.4, 66.3, 68.3, 68.8, 70.0, 70.3, 71.0, 72.2, 73.6, 74.4, 74.8, 75.2,
75.6, 75.8, 77.4, 79.0, 80.0, 80.1, 82.2, 82.9, 84.7, 96.9, 98.3, 98.4,
103.4, 104.1, 121.6, 121.8, 122.3, 122.3, 127.9, 127.9, 128.2, 128.3,
128.6, 129.4, 130.0, 130.1, 133.1, 133.1, 133.5, 133.6, 136.6, 137.6,
138.0, 138.4, 138.9, 139.1, 139.2, 149.2, 149.3, 159.2, 165.9 ppm;
HR-FAB MS calcd for C88H89NO18Na [M + Na]+: 1470.5977,
found 1470.5945.
Acknowledgment. We thank the National Institutes of
General Medical Sciences (GM077170) and ACS PRF (42397-
G1) for financial support of this research; NSF for grants to
purchase the NMR spectrometer (CHE-9974801) and the mass
spectrometer (CHE-9708640) used in this work; Dr. R. S. Luo
for assistance with 500 MHz 2D NMR experiments; and Dr.
R. E. K. Winter and Mr. J. Kramer for HRMS determinations.
Note Added after ASAP Publication. Reference 49 was not
included in the version published on the Web October 22, 2008;
the corrected version was published on the Web October 31,
2008.
Methyl 3,4,6-Tri-O-benzyl-2-O-picolyl-ꢀ-D-glucopyranoside (44).
was obtained from 16a and dry MeOH by method A as white
amorphous solid in 65% yield. Analytical data for 44: Rf ) 0.40
(acetone/toluene, 1/4, v/v); [R]D24 ) +31.5 (c ) 0.71, CHCl3); 1H
NMR: δ, 3.42 (s, 3H, CH3), 3.58-3.82 (m, 5H, H-2, 4, 5, 6a, 6b),
4.03 (dd, 1H, J3,4 ) 9.0 Hz, H-3), 4.46-5.03 (m, 8H, CH2Ph),
4.83 (d, 1H, J1,2 ) 8.9 Hz, H-1), 7.10-7.40 (m, 16H, aromatic),
7.53 (d, 1H, aromatic), 7.64 (t, 1H, aromatic), 8.54 (d, 1H, aromatic)
ppm; 13C NMR: δ, 55.4, 68.7, 70.4, 73.7, 75.3, 75.9, 77.4, 78.0,
80.8, 82.1, 97.9, 127.8, 127.9, 128.0, 128.1, 128.1, 128.6, 138.2,
Supporting Information Available: Experimental proce-
dures for the synthesis of 2a, 3, 4, 14a, 15a, 30, 38, and spectra
of all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO801551R
(48) Jansson, P. E.; Kenne, L.; Kolare, I. Carbohydr. Res. 1994, 257, 163–
174.
(49) Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2001, 123, 6819–6825.
8850 J. Org. Chem. Vol. 73, No. 22, 2008