Investigation of α-Thioglycoside Donors: Reactivity Studies toward Configuration-Controlled Orthogonal Activation in One-Pot Systems

Article abstract of DOI:10.1021/acs.orglett.6b01572

The influence of anomeric configuration upon thioglycoside donors remains relatively unexplored. Utilizing methodology developed for the stereoselective and high-yielding synthesis of α-glycosyl thiols, a series of α-thioglycosides were synthesized, and their reactivity was compared to that of their β-counterparts. The highly selective activation observed for anomeric pairs containing a 2-O-acyl moiety and additional findings are reported. Application of a pair of superarmed thioglycosides to a one-pot oligosaccharide system is also described, in which selectivity is a result of configuration-based orthogonal activation.

Full text of DOI:10.1021/acs.orglett.6b01572

Letter
pubs.acs.org/OrgLett
Investigation of α‑Thioglycoside Donors: Reactivity Studies toward
Configuration-Controlled Orthogonal Activation in One-Pot Systems
Raymond Smith, Helge Muller-Bunz, and Xiangming Zhu*
̈
Centre for Synthesis and Chemical Biology, UCD School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
S
* Supporting Information
ABSTRACT: The influence of anomeric configuration upon
thioglycoside donors remains relatively unexplored. Utilizing
methodology developed for the stereoselective and high-yielding
synthesis of α-glycosyl thiols, a series of α-thioglycosides were
synthesized, and their reactivity was compared to that of their β-
counterparts. The highly selective activation observed for anomeric
pairs containing a 2-O-acyl moiety and additional findings are
reported. Application of a pair of “superarmed” thioglycosides to a one-pot oligosaccharide system is also described, in which
selectivity is a result of configuration-based orthogonal activation.
One potential contributor to thioglycoside reactivity which
ver the last few decades, a series of developments have led
Oto thioglycosides becoming one of the most versatile and remains relatively unexplored is the role of anomeric
frequently employed classes of glycosyl donor.1,2 Acting as quite
configuration. The bearing this can have upon reactivity is well
documented in the context of other donor classes, for example,
generation of α-glycosides from α-glycosyl bromides and
chlorides using halide ion-catalyzed glycosylation to exploit
higher β-glycosyl halide reactivity.13 Fraser-Reid also observed
consistently higher β-donor reactivity for a series of n-pentenyl
glycosides.14 Configuration-based reactivity modulation was also
briefly investigated by Seeberger et al. during studies of glycosyl
phosphate esters as donors.15 They also recorded a faster
reaction for β-anomers. While this quality has been explored
quite well for the above glycosyl donors, relatively little
investigation has been carried out for thiolgycoside donors.
Of course, the relative lack of investigation into this area is
somewhat understandable. α-Thioglycosides are notoriously
difficult to synthesize by conventional means. Reactions of
alternative donors with aglycon thiols typically lead to anomeric
mixtures heavily in favor of the β-product.16,17 Similarly, α-
thioglycoside synthesis from the corresponding α-glycosyl thiols
has always been hampered by the lack of efficient procedures to
generate these precursors, with β-thiols being the favored
products of standard synthetic routes.18,19
The past decade has seen the development of several new
approaches which can circumvent this issue, for example,
stereoselective generation of α-thioglycoside precursors by
rearrangement of p-nitrobenzoylxanthate glycosides20 and
TiCl4-mediated anomerization of S-glucuronides.21 Recently, a
high-yielding method for the synthesis of pure α-glycosyl thiols
has been developed in our laboratory by stereoselective ring-
opening of 1,6-anhydrosugars using (TMS)2S and TMSOTf.22
This method was subsequently applied to the synthesis of a series
of α-thioglycosides including the first S-linked analogues of
efficient donors in their own right, as well as serving as
convenient precursors to a variety of alternative donors,3,4 their
high stability under a wide range of conditions and their ability
for selective activation has made them key building blocks in
many oligosaccharide synthetic strategies from a variety of
different perspectives.5 The use of thioglycosides was central to
Nicolaou’s solid-supported total synthesis of a heptasaccharide
phytoalexin elicitor,6 in which all the glycosylations were carried
out using thiophenyl and thiomethyl donors. Wong’s famous
reactivity study toward the development of a system for
automated oligosaccharide synthesis involved extensive inves-
tigation of protecting group patterns applied to S-tolyl
thioglycosides.7 Such dependence on the stability and versatility
of thioglycosides continues to be demonstrated in new and
innovative ways, with recent examples including the develop-
ment by Bowers and co-workers of a system for activation of S-
PMP glycosides with visible light.8
As with all other varieties of glycosyl donor, reactivity
modulation of thioglycosides is a continually developing field.
Ever since Fraser-Reid’s first description of the armed−disarmed
concept,9 researchers have put painstaking effort into finding the
correct protecting group patterns to achieve their desired relative
donor reactivities. Such methods have been incorporated in the
development of an automated system for oligosaccharide
synthesis.7 Knowledge of the influence of protecting groups
was further enhanced by Demchenko’s observations on the
specific contributions of protecting groups in the 2-position
along with the combined influence of substituents on the
remaining positions, later coined the “O2-O5 co-operative
effect.”10 One of the most recent developments has been Bols’
work on conformational arming, whereby bulky silyl protecting
groups have been employed to force donors into a twist-boat
conformation to enhance leaving group ability.11,12
Received: May 31, 2016
© XXXX American Chemical Society
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Table 1. Determination of α-Thioglycoside Reactivity Using Competitive Glycosylation
a
b
Calculated from isolated product mass following column chromatography. Determined by integration of representative signals in the 1H NMR and
c
d
1
total recovered donor mass. Not observable on the H NMR spectrum. No additional products observed.
maradolipid23 and the immunostimulant glycolipid KRN7000.24
Following on from the importance of thioglycosides in
oligosaccharide synthesis, we saw an opportunity to explore
the role that could be played by α-thioglycoside donors,
particularly those containing a 2-O-acyl functionality. On the
basis of the relative lack of knowledge on the influence of
anomeric configuration upon thioglycoside reactivity, we felt the
most obvious avenue to explore was whether we could carry out
selective activation of thioglycosides with the orientation of the
leaving group as the key differentiating factor.
We originally hypothesized that we could synthesize a series of
α-linked thioglycoside donors which would have lower reactivity
than their β-counterparts, thus introducing another group of
donors of intermediate reactivity. However, some studies have
indicated that the reactivity of different anomers can vary
depending on the leaving group and protecting groups.25,17 This
seemingly contradictory information led us to speculate on
whether a combination of several factors could govern the
relative reactivities of anomers. If so, which ones would
predominate under different conditions? We theorized that the
higher α-reactivity observed for sulfonium salts was most likely a
consequence of the anomeric effect. Interaction of the lone pair
of O5 with the σ* orbital of the leaving group should theoretically
result in a slight lengthening of the anomeric bond, thus making it
more labile upon activation.
7 were derived from α-thiols synthesized using our ring-opening
procedure.
To ascertain relative reactivity of these thioglycosides, we
performed a series of competitive glycosylations (Table 1) in
which galactoside 9 was placed in a flask with both anomers of a
donor before reaction with 1.0 equiv promoter. We employed
NIS for the initial tests due to its widespread usage for
glycosylation with thioglycosides, with TMSOTf as a Lewis
acid catalyst. Reactions were carried out with slow warming from
−78 °C. Relative reactivity was determined by recovery of the
donor starting materials and examination of the relative
intensities of representative peaks on the 1H NMR spectrum.
As displayed in Table 1 (entries 1−4), all thioglycoside pairs
demonstrate a noticeable difference in reactivity. It seems that 2-
O-acyl substituents, as well as enhancing the reactivity of β-
donors, seem to cause a far greater disparity in α/β reactivity
relative to compounds lacking any neighboring participating
group. This agrees with recent work by Demchenko and Bols, in
which comparison between two anomers of a conformationally
armed system containing a 2-O-benzoyl group demonstrated a
significant disarming influence of the benzoyl group upon the α-
donor.26 It is also supported by examples provided by Boons25
and Crich16 for S-dicyclohexylmethyl thioglycosides and SBox
glycosides, respectively.
We believe that arming through anchimeric assistance by 2-O-
acyl groups, as discussed by Demchenko in his first description of
the O2/O5 co-operative effect, is rendered impossible in the case
of α-configured donors. The relative orientation of orbitals
brought about by the axially oriented leaving group means that
the carbonyl lone pairs are incapable of the required interaction
with the σ* orbital of the C−S bond. The reactivity-enhancing
To carry out a thorough analysis we began by synthesizing
anomers representative of each 4C1 donor reactivity class, that is,
superdisarmed (1, 2), disarmed (3, 4), armed (5, 6), and
superarmed (7, 8, Table 1). Donors 2, 4, 6, and 8 were
synthesized from tetra-O-acetyl-β-D-glucosyl thiol in accordance
with literature procedures and data. α-Linked donors 1, 3, 5, and
B
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Figure 1. Thioglycoside reactivity sequence incorporating α-thioglycoside donors.
qualities previously associated with 2-O-acyl groups as a result of
As predicted, the combined influences of an acyl participating
neighboring group participation are thus negated, preventing any
co-operative effect from taking place and leaving them to act in a
solely electron-withdrawing capacity as originally put forward by
Fraser-Reid.
group and an α-configured leaving group had a major impact on
where lie the relative positions of these donors within the known
order of reactivity. This combination was seen to render
disarmed donor 3 less reactive than either superdisarmed
species, while very little activation of 7 was observed in the
presence of armed anomers 5 and 6. Interestingly, the presence
of a 2-O-benzyl group in α-donor 1 led to increased reactivity
greater than that of 4, an unexpected result which indicates the
effects of an arming substituent in the 2-position acting in
tandem with an α-oriented leaving group are enough to surpass
the reactivity enhancing qualities of anchimeric assistance in
these less reactive systems. Again, a contrasting pattern when
examining the more electron-rich donors 5 and 8 indicates that
electronic effects upon the endocyclic oxygen could be playing a
significant role in these relative reactivities. Overall, these results
indicate a reactivity order as laid out in Figure 1. We can therefore
conclude that disarmed thioglycoside 3 is the least reactive donor
in the entire study, not just in the α-series.
It should be noted that, although the recovery ratios for the
armed, disarmed, and superdisarmed systems may seem poor at
first glance, this is a consequence of the sluggish nature of these
reactions at low temperatures which can often lead to incomplete
conversion. For these two comparisons the reactivity difference is
best illustrated by examination of the percentage donor recovery.
While preferential activation of a single anomer could be
achieved in all cases to some extent, we were particularly
surprised by the degree of selectivity for the so-called
“superarmed” system. Despite being theoretically the most
reactive pairing, this showed almost exclusive activation of the β-
donor to the extent that it could not be observed by 1H NMR of
the recovered starting material.
Anomeric bond length was briefly considered as another
contributing factor to the observed reactivity patterns. However,
X-ray analysis of the superdisarmed, disarmed (acetylated for
crystallization purposes), and armed systems indicated longer
α−C-S bonds of 0.023, 0.026, and 0.025 Å respectively (see
Supporting Information). Such small differences would indicate
that such a contribution, if any, would be negligible.
The high degree of selectivity between superarmed anomers,
in addition to them being two of the most synthetically useful
donors involved in the study, led us to explore this disparity in
reactivity further in the context of one-pot oligosaccharide
chemistry (Scheme 1). For this purpose we synthesized α-
Scheme 1. One-Pot Synthesis of Trisaccharides 17, 19, and 21
An unexpectedly higher reactivity was observed for 6 in
comparison with 5; this appears to go against known trends for
thioglycoside donors with nonparticipating substituents in the 2-
position.27,28 However, repeated tests verified that this result was
legitimate. Additionally, competition between superdisarmed
pair 1 and 2 conforms to literature datamost likely a
consequence of lower β-nucleophilicity due to electron-with-
drawing effects upon the endocyclic oxygen by the 3-, 4-, and 6-
O-benzoyl groups. It is our suggestion that this decreases the
electron density of this atom, reducing lone-pair repulsion with
the nucleophilic sulfur. Coupled with the optimal antiperiplanar
alignment of the O5 lone pair and the C−S σ* orbital29,12 in
compound 1 the outcome is higher α-reactivity. Conversely, the
armed system possesses greater electron density at O5 due to the
use of benzyl substituents, thus increasing the nucleophilicity of
the β-configured sulfur atom and its tendency to interact with
electrophiles. As such, it may be possible that the preferential
reaction of 6 over 5 is determined by initial interaction with the
activated NIS as opposed to the relative reactivities of the
sulfonium intermediates.
Following our results for direct anomeric comparisons, we
decided to investigate the relative order of reactivity within the α-
donor series (entries 9−11). On the basis of the observation that
the change in configuration clearly restores the typical electron-
withdrawing properties of the 2-O-acyl group, we expected
donors 3 and 7 to be less reactive than the corresponding 2-O-
benzyl compounds. Therefore, we also chose to examine α- and
β-donors of different reactivity categories to establish a complete
picture of their reactivity relationships (entries 5−8).
superarmed acceptor 14. Glycosylation of 14 with 8 under
identical conditions to those for the competitive studies allowed
for efficient conversion to disaccharidyl thioglycoside 15, which
was isolated as a white solid in 67% yield.
This success led us to attempt one-pot synthesis of
trisaccharides. As such, upon completion of glycosidation of
C
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donor 8 with acceptor 14, 6-OH α-methylglucoside acceptor 16
was introduced followed by additional NIS. As expected,
trisaccharide 17 was produced in a very good yield of 54%
(average of 73% per glycosylation step), with unreacted 16 and
17 also isolated. This was, to the best of our knowledge, the first
example of a one-pot oligosaccharide where the relative reactivity
of two anomers was a controlling factor in selective donor
activation. Encouraged by this result, we chose to explore the
scope of this chemistry further by varying the position of the
glycosidic linkage. Hence, 2-OH acceptor 18 was used in place of
16 in order to obtain 1 → 6;1 → 2 trisaccharide 19 in 63% yield
(79% per step). Following this success with electron-rich
acceptors, the compatibility of this system with less reactive
acceptors was tested. Glycosylation with benzoylated thioglyco-
side acceptor 20 generated trisaccharide donor 21 in a reasonable
yield of 49% (70% per step). Not only did this demonstrate the
flexibility of this one-pot system with regard to acceptor
reactivity, but it also served to show the potential for
configuration-controlled orthogonal activation to be used in
the construction of larger oligosaccharides.
In conclusion, this investigation has shown that anomeric
configuration can have a strong bearing on thioglycoside
reactivity, the degree of which is heavily dependent on the
nature of the 2-O-substituent. The extent of this influence is such
that differences in reactivity due to configuration can be observed
even under relatively strong NIS-promoted competitive
conditions. Of particular importance is that an α-configured
leaving group removes the stabilizing, arming capabilities of 2-O-
acyl substituents such that a perbenzoylated α-thioglycoside can
remain unreacted under conditions capable of promoting a
typical “superdisarmed” system. Hence, α-configuration in
combination with a neighboring 2-O-acyl group can be said to
have a disarming effect. The synthetic utility of this phenomenon
was demonstrated through efficient coupling of two superarmed
anomers. The resulting disaccharidyl thioglycoside can be readily
reacted with a variety of acceptors, making this system easily
applicable to one-pot oligosaccharide strategies. We also
observed that the influence of 2-O-benzyl substituents in these
comparisons is heavily dependent on the nature of remote
protecting groups. This seems to suggest that electron density at
O5 may also have an impact on the relative reactivity of α- and β-
thioglycosides. We believe that these observations will have a
significant impact on future approaches to designing one-pot
oligosaccharide syntheses.
Department of Zhejiang Province (2013C24004) for financial
support.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01572.
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2839.
Experimental details, X-ray data and characterization
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xiangming.zhu@ucd.ie
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors would like to acknowledge University College
Dublin, Meath County Council and the Science & Technology
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DOI: 10.1021/acs.orglett.6b01572
Org. Lett. XXXX, XXX, XXX−XXX