Synthesis of Glycosyl Chlorides and Bromides by Chelation Assisted Activation of Picolinic Esters under Mild Neutral Conditions

Article abstract of DOI:10.1021/acs.orglett.0c00078

A general method has been developed for the formation of glycosyl chlorides and bromides from picolinic esters under mild and neutral conditions. Benchtop stable picolinic esters are activated by a copper(II) halide species to afford the corresponding products in high yields with a traceless leaving group. Rare β glycosyl chlorides are accessible via this route through neighboring group participation. Additionally, glycosyl chlorides with labile protecting groups previously not easily accessible can be prepared.

Full text of DOI:10.1021/acs.orglett.0c00078

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Letter
Synthesis of Glycosyl Chlorides and Bromides by Chelation Assisted
Activation of Picolinic Esters under Mild Neutral Conditions
Peng Wen,§ Christopher J. Simmons,§ Zhi-xiong Ma, Stephanie A. Blaszczyk, Paul G. Balzer, Wenjing Ye,
Xiyan Duan, Hao-Yuan Wang, Dan Yin, Christopher M. Stevens, and Weiping Tang*
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ABSTRACT: A general method has been developed for the formation of glycosyl
chlorides and bromides from picolinic esters under mild and neutral conditions.
Benchtop stable picolinic esters are activated by a copper(II) halide species to afford
the corresponding products in high yields with a traceless leaving group. Rare β
glycosyl chlorides are accessible via this route through neighboring group participation. Additionally, glycosyl chlorides with labile
protecting groups previously not easily accessible can be prepared.
arbohydrates have garnered significant interest from the
scientific community due to their heavy prevalence in
structural diversity.13 Therefore, methods that can expand the
functional group compatibility of halogenation have been
developed over the past several years.14 Nevertheless, in view
of the increasing popularity of glycosyl halides in carbohydrate
synthesis, a set of general, mild, and neutral conditions for their
preparation from readily available benchtop stable precursors is
still highly demanded.
Glycosyl picolinic esters (Pico) have been developed as
stable and easily accessible glycosyl donors, which can be
activated by nontoxic copper(II) salts under mild conditions,15
through remote activation.16 In response to the potential
transesterification side reactions, we recently reported
isoquinoline-1-carboxylate (ISQ) as a readily available, trace-
less, and bulkier anomeric leaving group, which successfully
blocks the attack of hydroxylic acceptors on the carbonyl
carbon center (Scheme 1).17 While screening potential
copper(II) sources for the activation of isoquinolinic esters,
C
biological systems and indispensable functionality as mediators
of intra- and intercellular interactions.1 Given the heteroge-
neous nature of carbohydrates in biological sources, the
structurally defined synthetic glycans have proved as invaluable
tools for studies in glycobiology.2 In synthetic carbohydrate
chemistry, glycosylation is arguably one of the most important
and challenging reactions,3 and the need for a more efficient
and general glycosylation method has stimulated tremendous
efforts to develop glycosyl donors with novel anomeric leaving
groups.4 Interestingly, glycosyl halides, which are among the
earliest known activated glycosyl donors, have always been one
of the most versatile glycosyl donors for complex carbohydrate
synthesis since its discovery over a century ago.5 On the basis
of Koenigs’ and Knorr’s conditions for activating glycosyl
bromides with silver salt, a wide variety of methods have been
developed by employing different silver or mercury salts, or
even metal-free reagents.6 Meanwhile, the toolbox of glycosyl
halides as glycosyl donors has expanded from traditionally used
glycosyl bromides and chlorides to include more stable
glycosyl fluorides7 and more reactive glycosyl iodides,8
rendering the opportunity of fine-tuning the reactivities of
glycosyl donors for particular circumstances. Glycosyl halides
also display unique properties in controlling the anomeric
stereochemistry of glycosylation products by invoking classical
neighboring group participation,9 halide exchange,10 or
invertive SN2 mechanisms, making 1,2-trans-, 1,2-cis-, and 2-
deoxy-β-glycosides11 accessible from one set of glycosyl
donors.
Scheme 1. Copper(II) Activated Leaving Groups for
Glycosylations of Sugars
Glycosyl halides, particularly acetohalogenoses, have been
prepared from their anomeric acetate or hemiacetal precursors
under strong Lewis or Brønsted acidic conditions.12 However,
toxic halogenating reagents are frequently employed, and these
forcing conditions are usually incompatible with acid-labile
protecting groups or interglycosydic linkages and only allow
the preparation of glycosyl halides with a limited level of
Received: January 7, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00078
© XXXX American Chemical Society
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we discovered that using CuCl2 produced no O-glycosides but
instead led to the formation of the corresponding glycosyl
chloride in high yield. The glycosyl halide was formed under
conditions that were mild enough to facilitate inclusion of
previously unavailable protecting groups that have low stability
in acidic solutions. No strong Lewis acid is required for the
reaction to proceed, and the pH of the solution remains
neutral. Herein we report the formation of a range of glycosyl
chlorides and bromides in high yields under mild and neutral
conditions using copper(II) salts as both the activator and
halogen source. The picolinic ester acts as a traceless leaving
group and facilitates quick separation of the products from the
reaction mixtures with no workup required.
Scheme 3. Scope of Benzylated Glycosyl Chlorides
The isoquinolinic ester was advantageous over the picolinic
ester for the glycosylation reaction, because the carbonyl group
in the latter could be attacked by the OH group in the glycosyl
acceptor to form a transesterification product while no
transesterification was observed for the former.17 We began
our investigation by comparing the isoquinolinic esters and
picolinic esters and their ability to produce the corresponding
glycosyl chloride in order to examine potential differences in
reactivity. We determined that both carboxylate species
produced the desired products in essentially the same yield
with similar rates of reaction (Scheme 2). While both picolinic
a
b
c
Scheme 2. Comparison of Picolinic and Isoquinolinic Esters
for the Formations of Glycosyl Halides
Yield of reaction run on 1 mmol scale. Yield of crude product. 2.2
a
equiv of CuCl2 was used.
unsubstituted counterpart, was also well tolerated with 2i
isolated in 95% yield. A second picolinic ester at the C2-
position did not change the stereochemical outcome of the
reaction, and the α-chloride 2j was isolated in 81% yield. A
satisfactory result was also obtained when the reaction was run
on the 1 mmol scale, as exemplified by the isolation of 2a in
essentially quantitative yield.
The high α-selectivity in all cases, which was independent of
the anomeric configurations of the starting picolinic esters,
suggests that an oxocarbenium intermediate is involved, and
the thermodynamic products are likely formed through halide
exchange via an SN1 pathway. Although the current method-
ology is applicable to the synthesis of a wide variety of α-
glycosyl chlorides with different configurations and deoxyge-
nation patterns, it is worthwhile to mention that the
preparation of the per-benzylated 2-deoxy glucopyranosyl
chloride was hampered by the concomitant formation of a
significant amount of glucal byproduct due to the elimination
side reaction.
Carbohydrate picolinic esters with electron-withdrawing
protecting groups were then examined for the preparation of
disarmed glycosyl chlorides (Scheme 4). In the presence of
ester-type protecting groups, the reactions required increased
amounts of CuCl2 (2.2 equiv) and longer reaction times (48−
72 h) to ensure the completion of the reaction. Nevertheless,
the corresponding glycosyl chlorides were isolated in good to
excellent yields. Carbohydrate picolinic esters with gluco-
configurations led to the formation of thermodynamically
unstable β-glucosyl chlorides18 as exclusive products (2k−
2m). This revealed that the neighboring group participation
from the ester at the C2-position was the major contributor to
the stereoselectivity at the anomeric position during the
chlorination. The low isolation yield of 2m was a result of the
low conversion of the α-glycosyl picolinic ester. With a strong
electron-withdrawing carboxylate group at the 6-position, the
a
Reactions run on 0.1 mmol scale with 0.3 mL of solvent and 150 mg
of molecular sieves.
acid and isoquinolinic acid are commercially available and can
be easily coupled to a pyranose moiety, the lower cost of the
picolinic acid made it the preferred candidate for further study.
Thus, we carried forward using picolinic esters as substrates for
further examination of the reaction potential and scope.
An array of carbohydrate picolinic esters with armed ether-
type protecting groups were synthesized and treated with
CuCl2 in dichloromethane in the presence of 4 Å molecular
sieves as the only additive (Scheme 3). The reactions
proceeded smoothly at room temperature with good yields
and high α-selectivity observed for all of the per-benzylated
monosaccharides screened (2a−2e). While most of the
glycosyl chloride products were isolable by flash column
chromatography, the crude reaction products were generally
pure for further use without purification, as determined by
NMR of the crude products. With the mild and neutral
reaction conditions, the benzylidene protected glycosyl
chlorides (2f and 2g) and silyl ether protected glycosyl
chloride (2h) were prepared in good yields with no
degradation of the protecting groups observed. The PMB
group, which can be more readily cleaved oxidatively than its
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a
Scheme 4. Scope of Benzoylated and Acetylated Glycosyl
Chlorides
Scheme 5. Scope of Glycosyl Bromides
a
Yield of crude product.
departure of the picolinate from the α-anomer is reduced
without the anchimeric assistance of a trans-ester group at the
C2-position.
a
b
c
Yield of reaction run on 1 mmol scale. Yield of crude product. 2.2
equiv of CuBr2 was used.
In comparison, per-benzoylated galactopyranosyl, fucopyr-
anosyl, and xylopyranosyl picolinic esters afforded glycosyl
chlorides as mixtures of anomers (2p−2r), as indicated by
NMR of the crude products. Such a deviation in anomeric
selectivity can be interpreted as a function of the stabilization
(or destabilization) effect of substituents on sugar rings on the
putative glycosyl oxocarbenium ion. With all electron-with-
drawing substituents on equatorial position, or an axial
electron-withdrawing group at the C2-position, their destabi-
lization effect on the electron-deficient oxocarbenium ion
intermediate was maximized.19 This resulted in the attack of a
chloride ion on the relatively more stable dioxalenium ion
formed by neighboring group participation, leading to the
formation of 1,2-trans glycosyl chloride products 2k−2o.
Conversely, an axially oriented substituent further away from
the oxocarbenium carbon center, or a deoxygenation
modification, reduces the inductive effect,20 therefore, shifting
the reaction toward a mechanism involving a more stabilized
oxocarbenium ion intermediate.
To further demonstrate the utility of glycosyl halides
obtained from this method, we synthesized two disaccharides
from benzoylated glycosyl bromides (Scheme 6). Using silver
a
Scheme 6. Glycosylations of Glycosyl Bromides
a
Reactions run on 0.05 mmol scale with 0.3 mL of solvent and 180
Not only were we successful in obtaining glycosyl chlorides,
but using copper(II) bromide as the activator we could also
obtain glycosyl bromides in high yields (Scheme 5). While
both armed and disarmed glycosyl bromides were obtained in
high yields, unlike the previous examples where a β-glycosyl
chlorides could be obtained from neighboring group
participation from a C2 ester, using copper(II) bromide with
a C2-benzoylated or acetylated monosaccharide only gave the
α-glycosyl bromide products (3f−3j). These results are in
accordance with bromide ion’s better leaving group ability and
the high reactivity of β-glycosyl bromides. Again, the reaction
can be scaled up to 1 mmol without any loss of reaction
efficiency (3a). Attempts to prepare glycosyl fluorides using
copper(II) fluoride salt under the same conditions were not
successful. Because copper(II) oxidizes iodide to iodine, we
tried to prepare glycosyl iodides using copper(I) iodide salt
under the same conditions, but no reaction occurred.
mg of molecular sieves.
triflate as the activator and taking advantage of neighboring
group participation of a C2 ester, we obtained the
disaccharides (4a and 4b) in good yields with high
stereoselectivity.
In summary, we have successfully developed a new method
to obtain glycosyl chlorides and bromides without the use of
strong Brønsted or Lewis acids and thus can accommodate a
wider variety of protecting groups in target compounds. This
method utilizes readily available benchtop stable precursors
and can access various β-glycosyl chlorides through neighbor-
ing group participation using benzoyl and acetyl protected
sugars.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
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Authors
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Christopher J. Simmons − Department of Chemistry,
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Author Contributions
§P.W. and C.J.S. contributed equally.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the University of WisconsinMadison and NIH
(U01GM125290), and S.A.B. thanks the NIH Chemistry−
Biology Interface Training Grant (T32 GM008505) for
financial support. We would also like to thank the Analytical
Instrumentation Center and the Medicinal Chemistry Center
within the UWMadison School of Pharmacy for their
assistance.
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