Unexpected orthogonality of S-benzoxazolyl and S-thiazolinyl glycosides: Application to expeditious oligosaccharide assembly

Article abstract of DOI:10.1021/ol802740b

Thorough mechanistic studies of the alkylation pathway for the activation of glycosyl thioimidates have led to the development of the " thioimidateonly orthogonal strategy". Discrimination among S-thiazolinyl (STaz) and S-benzoxazolyl (SBox) anomeric leav

Full text of DOI:10.1021/ol802740b

ORGANIC
LETTERS
2009
Vol. 11, No. 4
799-802
Unexpected Orthogonality of
S-Benzoxazolyl and S-Thiazolinyl
Glycosides: Application to Expeditious
Oligosaccharide Assembly
Sophon Kaeothip, Papapida Pornsuriyasak, Nigam P. Rath, and
Alexei V. Demchenko*
Department of Chemistry and Biochemistry, UniVersity of MissourisSt. Louis,
One UniVersity BouleVard, St. Louis, Missouri 63121
demchenkoa@umsl.edu
Received November 26, 2008
ABSTRACT
Thorough mechanistic studies of the alkylation pathway for the activation of glycosyl thioimidates have led to the development of the “thioimidate-
only orthogonal strategy”. Discrimination among S-thiazolinyl (STaz) and S-benzoxazolyl (SBox) anomeric leaving groups was achieved by
fine-tuning of the activation conditions. Preferential glycosidation of a certain thioimidate is not simply determined by the strength of activating
reagents; instead, the type of activationsdirect vs indirectscomes to the fore and plays the key role.
Traditional linear approaches to oligosaccharide assembly are
often cumbersome, and consequently, the availability of com-
plex glycostructures remains insufficient to address the chal-
lenges of modern glycosciences.1 Recent improvements in
strategies for oligosaccharide assembly, have significantly
shortened the number of synthetic steps required by minimizing
protecting group manipulations between glycosylation steps.2
One of the most flexible assembly strategies is the orthogonal
concept.3 Unlike the armed-disarmed approach,4 the orthogonal
activation is not reliant on the nature of the protecting groups,
which can interfere with stereoselectivity. The only requirement
for the orthogonal approach is a set of two orthogonal leaving
groups and a pair of suitable activators. Unfortunately, this
simple concept is still limited to the following two examples:
Ogawa’s S-ethyl and fluoride,3 and thioimidate S-thiazolinyl
(STaz) and S-alkyl/aryl.5 In addition, a related, albeit less
flexible, semiorthogonal approach with the use of S-ethyl and
O-pentenyl glycosides was reported6 and was recently extended
to fluoride/pentenyl leaving groups.7 OVerall, the orthogonal
(3) Kanie, O.; Ito, Y.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 12073–
12074. (a) Ito, Y.; Kanie, O.; Ogawa, T. Angew Chem. Int. Ed. 1996, 35,
2510–2512.
(1) Prescher, J. A.; Bertozzi, C. R. Nature Chem. Biol. 2005, 1, 13–21.
(a) Galonic, D. P.; Gin, D. Y. Nature 2007, 446, 1000–1007. (c) Seeberger,
P. H.; Werz, D. B. Nature 2007, 446, 1046–1051.
(4) 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.
(5) Demchenko, A. V.; Pornsuriyasak, P.; De Meo, C.; Malysheva, N. N.
Angew. Chem., Int. Ed. 2004, 43, 3069–3072. (a) Pornsuriyasak, P.;
Demchenko, A. V. Chem.sEur. J. 2006, 12, 6630–6646.
(6) Demchenko, A. V.; De Meo, C. Tetrahedron Lett. 2002, 43, 8819–
8822.
(2) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40,
1576–1624. (a) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1380–1419. (b) Roy, R.; Andersson, F. O.; Letellier, M.
Tetrahedron Lett. 1992, 33, 6053–6056. (c) Boons, G. J.; Isles, S.
Tetrahedron Lett. 1994, 35, 3593–3596. (d) Douglas, N. L.; Ley, S. V.;
Lucking, U.; Warriner, S. L. J. Chem. Soc., Perkin Trans. 1 1998, 51–65.
(e) Zhang, Z.; Ollmann, I. R.; Ye, X. S.; Wischnat, R.; Baasov, T.; Wong,
C. H. J. Am. Chem. Soc. 1999, 121, 734–753.
(7) Lopez, J. C.; Uriel, C.; Guillamon-Martin, A.; Valverde, S.; Gomez,
A. M. Org. Lett. 2007, 9, 2759–2762.
10.1021/ol802740b CCC: $40.75
Published on Web 01/22/2009
2009 American Chemical Society

strategy is an excellent concept for flexible sequencing of
oligosaccharides that remains underexplored, with too few
examples to become uniVersal.
these, results obtained with common alkylating (and acylating)
reagents were of particular attractiveness. For example, MeI
was only effective for glycosidation perbenzylated STaz gly-
coside 1 (entry 4). Surprisingly, when these reaction conditions
were applied to the glycosidation of expectedly more reactive
SBox and SBaz glycosides, no glycosylation took place (entry
5). Also, BnBr was only effective for glycosidation STaz
derivative 1, whereas glycosyl donors 2 or 3 gave only trace
amounts of products (entries 6-8).
Subsequently, similar observations have been made with
less reactive perbenzoylated glycosyl donors. Thus, all
reactions of benzoylated glycosyl donors 6-8 with glycosyl
acceptor 4 promoted with MeOTf were very effective, and
disaccharide 9 was obtained in high yields (Table 2, entries
The excellent glycosyl donor properties of glycosyl
thioimidates and their unique activation conditions have led
to a number of useful developments for oligosaccharide
synthesis, including the orthogonal approach.5 From our
previous studies, we had determined the S-benzoxazolyl
(SBox) glycosyl donors8 to be significantly more reactive
than their STaz counterparts,5 and although direct selec-
tive activations of the SBox donors over STaz acceptors were
reported in the presence of Cu(OTf)2,5 no comprehensive
side-by-side comparisons had been performed.
With the main purpose of determining relative reactivity
patterns of thioimidates, we set up a series of glycosidations
including STaz,5 SBox,8 and structurally related Mukaiya-
ma’s S-benzothiazolyl (SBaz) derivatives.9 All reactions of
benzylated glycosyl donors 1-3 with glycosyl acceptor 4
promoted with MeOTf were very effective, and disaccharide
5 was obtained in high yields (Table 1). Although the
Table 2. Alkylation-Initiated Glycosidation of Benzoylated
Thioimidates 6-8
Table 1. Alkylation-Initiated Glycosidation of Benzylated
Thioimidates 1-3
promoter
product, 9
entry
donor
(equiv, T (°C))
time (h)
(yield %)
1
2
3
4
5
6
6
MeOTf (3, rt)
MeOTf (3, rt)
MeOTf (3, rt)
MeI (9-15, rt)
BnBr (3, 55)
2
1
97
7
95
8
2
84
6-8
6
120
72
120
no reaction
79
7 or 8
BnBr (3-9, 55)
no reaction
promoter
(equiv, temp)
product 5
time (h) (yield (%), R/ꢀ)
1-3). With MeI though, no glycosidation of benzoylated
glycosyl donors 6-8 took place (entry 4). BnBr was only
effective for the STaz derivative 6, (entry 5), whereas
glycosidation of glycosyl donors 7 or 8 gave no products
(entry 6). It should be noted that all reactions with benzylated
glycosyl donors (Table 1) were significantly faster than those
with their benzoylated counterparts (Table 2).
This discovery signified the gap in our understanding of
the thioimidate activation and created a basis for the
development of the STaz-SBox orthogonal strategy. The
uniqueness of this approach would be that both leaving
groups employed are of essentially the same class. Although
certain pathways for the activation of thioimidates were
postulated (Scheme 1),10,11 little proof had been available
until our recent mechanistic study,8 wherein we showed that
MeOTf-promoted activation of the SBox glycosyl donor 10
proceeds via the anomeric sulfur atom (direct activation).
This was confirmed by isolating the departed S-methylated
aglycon MeSBox (11, Scheme 1).
entry donor
1
2
3
4
5
6
7
8
1
2
3
1
MeOTf (3, rt)
MeOTf (3, rt)
MeOTf (3, rt)
MeI (9, rt)
0.75
0.33
0.58
120
120
24
87, 1.4/1
88, 1.6/1
89, 1.6/1
89, 8.0/1
no reaction
90, 3.5/1
traces
2 or 3 MeI (9-15, rt)
1
2
3
BnBr (3, 55 °C)
BnBr (3-9, 55 °C)
BnBr (3-9, 55 °C)
120
120
no reaction
disparity among the reaction times was unremarkable, it was
evident that glycosidation of the STaz glycoside 1 (entry 1)
was about two times slower than that of its SBox counterpart
2 (entry 2), with the reactivity of the SBaz glycoside 3 (entry
3) somewhere in the middle.
To gain better control of the glycosylations and to achieve a
more precise differentiation of reactivity between the different
thioimidates, we turned to investigating other activators. Among
(8) Kamat, M. N.; De Meo, C.; Demchenko, A. V. J. Org. Chem. 2007,
72, 6947–6955. (a) Kamat, M. N.; Rath, N. P.; Demchenko, A. V. J. Org.
Chem. 2007, 72, 6938–6946.
(10) Hanessian, S.; Bacquet, C.; Lehong, N. Carbohydr. Res. 1980, 80,
c17–c22. Demchenko, A. V.; Malysheva, N. N.; De Meo, C. Org. Lett.
(9) Mukaiyama, T.; Nakatsuka, T.; Shoda, S. I. Chem. Lett. 1979, 487–
490.
2003, 5, 455–458
.
(11) Mereyala, H. B.; Reddy, G. V. Tetrahedron 1991, 47, 6435–6448
.
800
Org. Lett., Vol. 11, No. 4, 2009

Scheme 1
.
Activation of Thioimidates: A Study with SBox
Scheme 2. Mechanism of Thioimidate Activation with BnBr
Glycoside 108
was concentrated in vacuo, and the high running UV-active
spot, corresponding to the benzylated aglycon, was separated
from the disaccharide product 5 by column chromatography
on silica gel. The structure of the isolated alkylated aglycone
was assigned as thioamide 13 (BnNTaz) by X-ray (see the
Supporting Information) and UV (λ ) 277 nm, CdS).
A similar reaction between 2 and 4 was significantly
slower; nevertheless, we succeeded in isolating the departed
aglycon, which was assigned as thioimide 14 (BnSBox) by
X-ray (see the Supporting Information) and UV (λ ) 280,
287 nm, CdN), as anticipated. To exclude the impact of
tautomerization of the products both reactions were moni-
tored by HPLC (see the Supporting Information).
With a better understanding of the mechanistic pathway,
we were well positioned to undertake further studies of
expeditious oligosaccharide assembly. First, the activation
of STaz donors 1 and 6 over SBaz/SBox acceptors 15a-c
was investigated in the presence of BnBr or MeI. As a result,
disaccharides 16a-c were obtained in good yields (70-82%,
Table 3). Conversely, SBox donor 7 was also activated over
the STaz acceptor 15d. This activation could be accomplished
in the presence of a variety of activators, among which
Bi(OTf)3 was the most promising; disaccharide 16d was
obtained in 69% yield. The terminal SBox moieties of 16b
or 16c could be glycosidated either with model acceptor 4
or with STaz acceptor (15d). Conversely, the STaz moiety
of 16d could be glycosidated with 4 or activated over the
SBox acceptor (15c). The resulting trisaccharides 17a-d
were isolated in 62-92% yields (Table 3), with 1,6-anydro
and hemiacetal being the major byproduct identified. Among
trisaccharides generated, 17c and 17d can be used in
subsequent sequencing.
Since the exact nature of the STaz activation was not
known, our working hypothesis for this study was based on
our previous findings with the SBox moiety, taking into
consideration the structural differences between the two
moieties. We anticipated that the activation of the STaz
moiety proceeds via the nitrogen (remote activation), as
opposed to the direct activation of the SBox moiety. This
remote activation of STaz would lead to a marginally slower
reaction with a powerful promoter, such as MeOTf (refer to
Tables 1 and 2). When weak alkylating reagents are used
(MeI, BnBr), a powerful nucleophile is needed to replace
the iodine or bromine, respectively. Evidently, this can be
predominantly achieved with STaz glycosides that bear the
reactive nitrogen atom, but not with the SBox glycosides,
which can only be activated via the exocyclic sulfur8 (Figure
1). For comparison, previous reports suggest that SPh
In conclusion, a mechanistic study of the alkylation
pathway for the activation of glycosyl thioimidates has led
to the development of the “thioimidate-only orthogonal
strategy”. The synthesis of trisaccharides 17a-d clearly
illustrates the entirely orthogonal character of the SBox and
STaz derivatives. Further studies and application of the new
concept to glycosylation of secondary glycosyl acceptors are
currently being pursued in our laboratory.
Figure 1. Working hypothesis for thioimidate activation.
glycosides do not react with MeI (direct activation), while
S-pyridyl derivatives do (remote activation is postulated).11
The credibility of this working hypothesis was verified
by a series of experiments in which glycosyl donor 1 was
reacted with the standard acceptor 4 in the presence of BnBr
(Scheme 2). Upon disappearance of 1, the reaction mixture
Acknowledgment. We thank NIGMS (GM077170) and
AHA (0660054Z, 0855743G) for financial support of this
work, as well as NSF (MRI, CHE-0420497) for the purchase
of the ApexII diffractometer. Dr. Winter and Mr. Kramer
(UMsSt. Louis) are thanked for HRMS determinations.
Org. Lett., Vol. 11, No. 4, 2009
801

Table 3. Orthogonal Activations for Oligosaccharide Synthesis
a Conditions: All glycosylations were performed in 1,2-dichloroethane in the presence of molecular sieves (3 Å). Promoters: BnBr (3 equiv, 55 °C);
AgBF4 (3 equiv, rt); MeI (9 equiv, rt); AgOTf (2 equiv, rt); Bi(OTf)3 (3 equiv, 0 °C f rt). Reaction time: 16a, 24 h; 16b, 16 h; 16c, 24 h; 16d, 1 h; 17a,
30, 30, and 40 min (entries 1, 3, and 5, respectively); 17b, 15 min; 17c, 2 h; 17d, 36 h.
and 14. This material is available free of charge via the
Supporting Information Available: Experimental pro-
Internet at http://pubs.acs.org.
1
13
cedures, H and C NMR spectra for all new compounds,
and the crystal structure and geometrical parameters for 13
OL802740B
802
Org. Lett., Vol. 11, No. 4, 2009