Direct synthesis of 2-deoxy-β-glycosides via anomeric O-alkylation with secondary electrophiles

Article abstract of DOI:10.1021/ja4116956

An approach for direct synthesis of biologically significant 2-deoxy-β-glycosides has been developed via O-alkylation of a variety of 2-deoxy-sugar-derived anomeric alkoxides using challenging secondary triflates as electrophiles. It was found a free hydroxyl group at C3 of the 2-deoxy-sugar-derived lactols is required in order to achieve synthetically efficient yields. This method has also been applied to the convergent synthesis of a 2-deoxy-β-tetrasaccharide.

Full text of DOI:10.1021/ja4116956

Article
pubs.acs.org/JACS
Direct Synthesis of 2‑Deoxy-β-Glycosides via Anomeric O‑Alkylation
with Secondary Electrophiles†
Danyang Zhu, Kedar N. Baryal, Surya Adhikari, and Jianglong Zhu*
Department of Chemistry and School of Green Chemistry and Engineering, The University of Toledo, 2801 West Bancroft Street,
Toledo, Ohio 43606, United States
S
* Supporting Information
ABSTRACT: An approach for direct synthesis of biologically
significant 2-deoxy-β-glycosides has been developed via O-alkylation
of a variety of 2-deoxy-sugar-derived anomeric alkoxides using
challenging secondary triflates as electrophiles. It was found a free
hydroxyl group at C3 of the 2-deoxy-sugar-derived lactols is required in
order to achieve synthetically efficient yields. This method has also been
applied to the convergent synthesis of a 2-deoxy-β-tetrasaccharide.
Scheme 1. Synthesis of Complex Glycosides via Anomeric O-
Alkylation
INTRODUCTION
■
2-Deoxy-β-glycosides, especially 2,6-dideoxy-β-glycosides, are
biologically important carbohydrates existing in numerous
natural products/clinical agents1 and play critical roles in
their biological activity as well as stability and solubility.2
Despite the development of numerous glycosylation methods
and technologies,3 the efficient stereoselective synthesis of
complex oligosaccharides and glycoconjugates remains a
nontrivial problem. Among various types of glycosidic linkages,
the stereocontrolled synthesis of 2-deoxy-β-glycosides is
notoriously challenging due to the absence of a directing
group at C2.4 A most common indirect approach for
stereoselective synthesis of 2-deoxy-β-glycosides involves
preinstallation of a directing group at C2 followed by its
removal after glycosylation.5 Other indirect strategies, such as
the use of alkoxy-substituted anomeric radicals,6 and de novo
synthesis via palladium-catalyzed stereoselective glycosylation7
were also reported. Alternatively, in order to improve overall
synthetic efficiency, direct methods for the synthesis of 2-
deoxy-β-glycosides involving the use of glycosyl phosphites,8
glycosyl halides,9 glycosyl imidates,10 conformationally re-
stricted 4,6-O-benzylidene-2-deoxyglucosyl donors,11,12 and
stereoselective synthesis of β-glycosides via anomeric O-
alkylation does not demand the participation of C2 substituent,
which would be an ideal approach for the synthesis of 2-deoxy-
β-glycosides. Early in 2009, Shair and co-workers reported
stereoselective synthesis of 2-deoxy-β-glycosides (4, Y = H) via
anomeric O-alkylation/arylation using primary or aromatic
electrophiles (b, E+ = 1° RX or ArX, Scheme 1).16 However,
the use of more challenging secondary electrophiles failed in O-
alkylation of 2-deoxy-sugar-derived anomeric alkoxides.16 In
view of the fact that a vast majority of naturally occurring 2-
deoxy-β-glycosides, especially 2,6-dideoxy-β-sugars, contain 1→
3 or 1→4 linkages, it would be appealing to develop
stereoselective anomeric O-alkylation protocols tolerating
secondary electrophiles. On the basis of our previous success
in umpolung S-glycosylation for stereoselective synthesis of 2-
deoxy-thioglycosides,17 we describe herein a direct stereo-
specific synthesis of 2-deoxy-β-(1→3) and (1→4)-linked
glycosides via anomeric O-alkylation using secondary electro-
philes (b, E+ = 2° RX, Scheme 1).
13
glycosyl tosylates have also been developed.
Anomeric O-alkylation, an alternative to the traditional
glycosylation, has been successfully developed by Schmidt14
and others15 for stereoselective synthesis of β-linked
oligosaccharides and glycoconjugates (a, Scheme 1). It was
postulated that a rapid equilibrium occurs between axial
anomeric alkoxide 1 and its equatorial isomer 3 via an open
intermediate 2. The equatorial alkoxide should be more reactive
than its axial isomer due to enhanced nucleophilicity by double
electron−electron repulsion in 3 compared to a single gauche
interaction in 1, which was referred to as a kinetic anomeric
effect.14 Subsequent selective O-alkylation of the more reactive
equatorial anomeric alkoxide 3 by suitable electrophiles should
lead to the selective production of β-glycosides 4. Thus,
Received: November 16, 2013
Published: January 29, 2014
© 2014 American Chemical Society
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applying the same condition reported previously (sodium
hydride, 1,4-dioxane, RT) did not provide detectable product 7
(entry 1, Table 1).16 Gratifyingly, addition of 15-crown-5,14b,c
known to chelate with sodium ion and increase the reactivity of
the corresponding anion,18 afforded the desired disaccharide 7
in 51% yield in toluene (β only) (entry 2). Switching the
solvent to 1,4-dioxane slightly dropped the yield to 41% (β
RESULTS AND DISCUSSION
■
Initially, L-oliose-derived lactol 5a was chosen to react with D-
olivose-derived C4-triflate 6a for the formation of disaccharide
7 via anomeric O-alkylation (Table 1). Not surprisingly,
Table 1. Optimization of Synthesis of 2,6-Dideoxy-β-
a
glycosides
1
only) (entry 3). Examination of the H NMR spectra of the
crude reaction mixture indicated that a number of side products
bearing aldehyde functionality were formed, probably due to
the decomposition of anomeric alkoxides A (e.g., base-mediated
elimination of the open intermediate B to form a mixture of E-
and Z-isomers of C, Table 1). Thus, we speculated that
suppressing the decomposition of anomeric alkoxides would
lead to the desired disaccharide in improved yield. Such a
problem may be circumvented by the use of modified lactols
(cf. 5b) bearing a free hydroxyl group at C3.19 Accordingly,
upon deprotonation of both hydroxyl groups at C-1 and C-3 of
5b with excess sodium hydride, the corresponding anomeric
alkoxides, dianions D, may be reversibly opened to form the
open intermediate, aldehyde E. However, due to less acidity of
the α-H of the aldehyde E (as compared to B) and the poor
leaving ability of the sodium oxide anion (NaO−), subsequent
enolization−elimination of the aldehyde E should be sup-
pressed, which would hopefully improve the yield of the desired
disaccharide 8 (Table 1). It should be noted that the C1-
anomeric alkoxide of D was reported to be more nucleophilic
than the C3-alkoxide due to the aforementioned double
electron−electron repulsion.14c,16
b
entry
1
reaction condition
5a, NaH (2 equiv)
yield , (β/α)
c
7, <1%, ND
d
2
5a, NaH (2 equiv), 15-C-5 (1.5 equiv)
5a, NaH (2 equiv), 15-C-5 (1.5 equiv)
5b, NaH (3 equiv), 15-C-5 (1.5 equiv)
5b, NaH (3 equiv), 15-C-5 (1.5 equiv)
5b, NaH (3 equiv), 15-C-5 (1.5 equiv)
5b, NaH (3 equiv), 15-C-5 (30 mol %)
5b, NaH (3 equiv), 15-C-5 (1.0 equiv)
5b, KOtBu (2 equiv), 18-C-6 (1.5 equiv)
7, 51%, β only
7, 41%, β only
8, 81%, β only
8, 70%, β only
8, 45%, β only
8, 22%, β only
8, 48%, β only
3
4
e
5
d,f
6
7
8
9
c
8, <1%, ND
a
General conditions: lactol 5a or 5b (1.0 equiv), sodium hydride, 1,4-
dioxane, RT 10 min; then triflate 6a (2.0 equiv), 15-C-5, RT, 24 h.
Isolated yield. ND = not detected. Toluene was used as solvent.
To our delight, treatment of a solution of lactol 5b in 1,4-
dioxane with 3 equiv of sodium hydride followed by addition of
triflate 6a and 1.5 equiv of 15-crown-5, produced desired
product 8, isolated in 81% yield after 24 h at room temperature
b
c
d
e
f
THF was used as solvent. Lactol 5b is not well soluble in toluene.
a,b
Table 2. Synthesis of Various 2,6-Dideoxy-β-glycosides
a
General conditions: lactol 5 (1.0 equiv), sodium hydride (3 equiv), 1,4-dioxane, RT 10 min; then triflate 6 (2.0 equiv), 15-C-5 (1.5 equiv), RT, 24
b
c
h. Isolated yield. Sodium hydride (2 equiv) was used.
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(β only, entry 4). The yields dropped when THF or toluene
was used as solvent (entries 5 and 6). The use of less 15-crown-
5 also led to the lower yields (entries 7 and 8). Furthermore,
the use of mild base, KOtBu, and 18-C-615b did not afford
noticeable product (entry 9). To the best of our knowledge,
this is the first time that a 2-deoxy-sugar-derived lactol bearing a
C3-hydroxyl group has been successfully used in the anomeric
O-alkylation to form (1→4)-β-linked 2-deoxy-disaccharide in
good yield and excellent anomeric selectivity. In addition, the
C3-free OH in the disaccharide product 8 may be directly
employed in the subsequent glycosylation if needed.
Table 3. Synthesis of 2,3,6-Trideoxy-β-glycosides and 2,4,6-
Trideoxy-4-azido-β-glycosides
a,b
Given this encouraging result, we have investigated the
reaction scope for preparation of various 2,6-dideoxy-β-
oligosaccharides (Table 2). Accordingly, three additional 2,6-
deoxy sugar-derived lactols 5c−e bearing a C3-hydroxyl group,
four additional sugar-derived secondary triflates 6b−e, and a
disaccharide-derived C3-triflate 6f were prepared.20 As shown
in Table 2, under optimal conditions these lactols (5b−e)
reacted with secondary triflates (6a−f) via anomeric O-
alkylation to afford a number of desired β-linked oligosacchar-
ides (9−16) in good-to-excellent yields and excellent anomeric
selectivity. Notably, this method has demonstrated its
application in efficient preparation of synthetically challenging
β-oliosides10,21 (e.g., 12 and 14). In addition, we carried out
anomeric O-alkylation of lactol 5d using primary triflates 6g−h
which afforded desired disaccharides 17 and 18 in comparable
yields and anomeric selectivity as reported previously.16
a
General conditions: lactol 5 (1.0 equiv), sodium hydride (3 equiv),
1,4-dioxane, RT 10 min; then triflate 6 (2.0 equiv), 15-C-5 (1.5 equiv),
b
c
RT, 24 h. Isolated yield. Sodium hydride (2 equiv) was used.
Scheme 3. Synthesis of β-Linked 2,6-Dideoxy-Tri- and
-Tetra- saccharides Using Iterative Anomeric O-Alkylation
This anomeric O-alkylation was next applied to the synthesis
of 2-deoxy-β-glycosides (Scheme 2). Treatment of 2-deoxy-D-
Scheme 2. Synthesis of 2-Deoxy-β-glycosides
Accordingly, disaccharide 8, obtained via anomeric O-alkylation
of 5b with triflate 6a, underwent a sequential benzyl protection
(82%), NBS-mediated oxidation of the anomeric phenylsulfide
(94%),10 and DDQ-mediated PMB deprotection (89%) to
afford disaccharide lactol 26 bearing a C3-free OH. As
expected, this lactol 26 reacted with C-4 triflate 6d and
disaccharide-derived C3-triflate 6f via anomeric O-alkylation
under optimal conditions to afford 2-deoxy-trisaccharide 27 and
tetrasaccharide 28 in 76% and 95% yield (β only), respectively.
glucose-derived lactol 5f22 with sodium hydride followed by
addition of secondary triflates, 6b and 6d, afforded desired 2-
deoxy-β-glycosides 19 and 20 in 68% and 62% yield,
respectively. In general, these reactions involving 2-deoxy-
sugar-derived lactols (cf. 5f) afforded the desired disaccharides
in slightly lower yield than those involving 2,6-dideoxy sugar-
derived lactols (cf. 5b−e), probably due to the relatively lower
reactivity of 2-deoxy-sugar-derived anomeric alkoxide as
compared with 2,6-dideoxy-sugar-derived anomeric alkoxide.
We also sought to prepare synthetically demanding 2,3,6-
trideoxy and 2,4,6-trideoxy-4-amino-β-glycosides via anomeric
O-alkylation with secondary triflates (Table 3). Accordingly, we
have prepared three 2,3,6-trideoxy-sugar-derived lactols 5g−i
and a 2,4,6-trideoxy-4-azidosugar-derived lactol 5j. As shown in
Table 3, under optimal conditions these lactols (5g−j) reacted
with secondary triflates 6 via anomeric O-alkylation to afford a
number of desired β-linked oligosaccharides (21−25) in good
yields and excellent anomeric selectivity.
CONCLUSION
■
In summary, an efficient approach for stereospecific synthesis of
2-deoxy-β-(1→3) and (1→4)-linked glycosides via anomeric
O-alkylation using secondary electrophiles has been described.
It is believed that this excellent anomeric stereochemical
outcome is controlled by a kinetic anomeric effect. This type of
glycosylation (anomeric O-alkylation) performed in basic
reaction conditions is beneficial for the synthesis of acid-labile
2-deoxy-glycosides. Application of this methodology to the
synthesis of naturally occurring bioactive molecules bearing 2-
deoxy-sugar subunits is currently underway.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and analytical data and NMR spectra
of the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
In order to further demonstrate the utilization of this method
in the synthesis of complex 2-deoxy-oligosaccharides, we
initiated the synthesis of 2,6-dideoxy-trisaccharide 27 and
tetrasaccharide 28 containing all β-linkages (Scheme 3).
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AUTHOR INFORMATION
Corresponding Author
Jianglong.Zhu@utoledo.edu
Notes
The authors declare no competing financial interest.
†Presented in part at the 246th American Chemical Society
National Meeting, Indianapolis, IN, United States, September
8−12, 2013, CARB-37.
■
ACKNOWLEDGMENTS
■
This research was supported in part by a grant from the
National Science Foundation (CHE-1213352) and The
University of Toledo. We thank Mr. Belal Abdullah and Ms.
De’Jonette Morehead for experimental assistance.
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