Direct, stereoselective thioglycosylation enabled by an organophotoredox radical strategy

Article abstract of DOI:10.1039/d0sc04136j

While strategies involving a 2e- transfer pathway have dictated glycosylation development, the direct glycosylation of readily accessible glycosyl donors as radical precursors is particularly appealing because of high radical anomeric selectivity and atom- and step-economy. However, the development of the radical process has been challenging owing to notorious competing reduction, elimination and/or SN side reactions of commonly used, labile glycosyl donors. Here we introduce an organophotocatalytic strategy through which glycosyl bromides can be efficiently converted into corresponding anomeric radicals by photoredox mediated HAT catalysis without a transition metal or a directing group and achieve highly anomeric selectivity. The power of this platform has been demonstrated by the mild reaction conditions enabling the synthesis of challenging α-1,2-cis-thioglycosides, the tolerance of various functional groups and the broad substrate scope for both common pentoses and hexoses. Furthermore, this general approach is compatible with both sp2 and sp3 sulfur electrophiles and late-stage glycodiversification for a total of 50 substrates probed.

Full text of DOI:10.1039/d0sc04136j

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Direct, Stereoselective Thioglycosylation Enabled by an
Organophotoredox Radical Strategy
Peng Ji, Yueteng Zhang, Feng Gao, Fangchao Bi, and Wei Wang*
Received 00th January 20xx,
Accepted 00th January 20xx
While strategies involved 2e‐ transfer pathway have dictated glycosylation development, direct glycosylation of readily
accessible glycosyl donors as radical precursors is particularly appealing because of high radical anomeric selectivity and
atom‐ and step‐economy. However, the development of the radical process has been challenging owning to notorious
competing reduction, elimination and/or SN side reactions of commonly used, labile glycosyl donors. Here we introduce an
organophotocatalytic strategy that glycosyl bromides can be efficiently converted into corresponding anomeric radicals by
a photoredox mediated HAT catalysis without a transition metal or a directing group and achieve highly anomeric selectivity.
The power of this platform has been demonstrated by the mild reaction conditions enabling synthesis of challenging α‐1,2‐
cis‐thioglycosides, the tolerance of various functional groups and the broad substrate scope for both common pentoses and
hexoses. Furthermore, this general approach is compatible to both sp2 and sp3 sulfur electrophiles and late‐stage
glycodiversification for total 48 substrates probed.
DOI: 10.1039/x0xx00000x
Nonetheless, the anomeric stereoselectivity of these processes
depends on the nature of the anomeric thiols. In particular, few
methods are capable of selectively constructing the challenging
Introduction
Despite the fact that O‐linked glycosides are a dominant form in
biologically important glycoconjugates,1 replacement of “O” by
C‐, N‐ and S‐linked glycosides offers the merits of improved
hydrolytic stability and/or bioactivity while maintaining similar
conformational preferences.2 In particular, thioglycosides have
emerged as a privileged class of structures owing to their broad
spectrum of biological activities (see representative examples in
Scheme 1).2‐5 Moreover, they are widely used as glycosyl donors
in glycosylation reactions.6 The broad biological and synthetic
utility has triggered significant interest in the development of
efficient methods to construct the C‐S bond with defined
anomeric configuration, which plays key roles in biological
activities.
α‐1,2‐cis‐thioglycosides,8b featured in a number of nature
products and bioactive molecules (Scheme 1).
Strategies involved ionic 2e‐ transfer pathway have dictated the
C‐S bond formation development.7‐13 Direct replacement by a
thiol with a glycosyl donor is an attractive approach in that both
starting materials are readily accessible, but gives a mixture of
α/β anomers in most cases (Scheme 2a).8 To overcome these
limitations, the methods by reversing the polarity at the
anomeric carbon have been developed (Scheme 2b).9 These
elegant methods enable the stereoselective control formation
of both α and β anomers but with limited scope of saccharides.9a
Indirect methods using preformed anomeric thiols offer
versatile approaches to thioglycosides (Scheme 2c).10‐13
Scheme 1. Selected examples of thioglycosides with α‐1,2‐cis‐configuration.
Radical cross coupling offers
a distinct paradigm for
stereoselective construction of glycosidic bonds.14 Anomeric
radicals have been elegantly explored for the highly
stereoselective C‐glycosidic bond formation with a transition
metal (TM).15‐17 However, the stereoselective C‐S bond
formation through glycosyl radical has remained elusive
(Scheme 2d).17 This attributes to: 1) reduction of glycosyl
radicals by HAT (hydrogen atom transfer) donors;18 2)
elimination reaction of labile glycosyl donors by a TM catalyst;19
3) competing SN2 reaction with thiols, which could compromise
the anomeric selectivity.2b,7 Therefore, stable radical precursors
such as glycosyl stannanes are designed to minimize these
issues.17 Given the fact that the glycosyl radical can favour
formation of anomeric C1 conformation, we deliberately push
Departments of Pharmacology and Toxicology and Chemistry and Biochemistry,
BIO5 Institute, and University of Arizona Cancer Centre, University of Arizona,
Tucson, AZ 85721, USA
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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the limit by developing an organophotocatalytic approach 3a in high yield. Among the thiosulfonates probed (entries 6‐
without a directing group or a TM for stereoselective S‐ 12), methanethiosulfonate 2a was the best, possibly
(
)
glycosylation. Herein, we wish to disclose the results of the attributing to the less hindrance and relatively redox stability
investigation, which has led to a general organophotocatalyzed (Ered = ‐1.65 V vs SCE, Figure S3). Glycosyl chloride (1b) did not
thiolation of glycosyl bromides with highly stereoselective
control (Scheme 2d).
undergo the dechlorination presumably due to strong C‐Cl bond
(entry 13). To further improve the stereoselectivity (entry 6), we
conducted reaction optimization including solvent and reaction
temperature (Table 1, entries 14‐15 and Tables S3 and S6). It
was found that the biphasic solvent (DCE:H2O = 2:1) could not
only retain the high anomeric selectivity but also increase the
yield (76%, entry 1), and low temperature (‐ 5°C) is also required
to maintain good yield and anomeric selectivity (entry 14, 15).
The control experiments confirmed that base, light,
(TMS)3SiOH, and PS were essential for this transformation
(entries 16‐17).
Ionic Approach to Thioglycosides
a) Direct approach: glycosides as electrohiles
and thiols/thiolates as nucleophiles
b) Direct reversed polarity approach: glycosides as
nucleophiles and thiol derivatives as electrophiles
O
O
O
LG
(RO)n
[M]
(RO)n
[M] = Li, SnBu4
SR'
(RO)n
LG = F, Cl, Br, OH, OAc, OTs,
OC(NH)CCl3, OC(NPh)CF3
c) Indirect approach: converting of glycosides to nucleophilic thioglycoside precursors
O
O
O
(RO)n
LG = OH, OAc, Br,
OC(NHCCl3)
LG
(RO)n
SX
(RO)n
SR'
X = H, Na+, C(NH2)+
Table 1. Reaction Optimization.
Radical Approach to Thioglycosides
d) Direct radical approach: glycosides as radical precurosrs (This Work)
Challenges
anomeric,
nucleophilic,
glycosyl radical
intermediate
O
Competing reduction,
elimination,
and SN reaction
O
(RO)n
Entry Variation
from
the
“Standard Yield
(3a, %)[b]
α : β[c]
m
X
(RO)n
m = 0, 1
Conditions”[a]
Solvent- and temperature-mediated
stereoselectivity
Cl
Cl
1
2
none
76 (72)[d] >20:1
O
O
N
4ClCzIPN, (TMS)3SiOH
NC
CN
(R/HO)n
+
R'S LG
(R/HO)n
m
Cl
m
Cl
N
N
K3PO4, DCE/DMSO or DCE/H2O
Blue LEDs, -5 oC, 18-24 h
m = 0, 1
Br
N
SR'
4CzIPN (5 mol%), 2c, Na2CO3 (4.0 equiv), 37
DMSO, rt
<10:1
<10:1
<10:1
‐
Cl
Cl
sulfur electrophile
LG: Leaving Group
glycosyl radical
precursor
Cl
Cl
4ClCzIPN
 Both (hetero)aryl(sp2) and alkyl(sp3) thiol partners
 Tolerate diverse functional groups
 Both pentoses and hexoses, or disarmed and
armed saccharides
 Transition-metal-free, mild reaction conditions
 Anomeric selectivity without directing group or TM
 Synthesis of challenging 1,2-cis--thioglycosides
 Distinct radical bond connection approach
3
4
5
4BrCzIPN (5 mol%), 2c, Na2CO3 (4.0 33
equiv), DMSO, rt
4ClCzIPN (5 mol%), 2c, Na2CO3 (4.0 65
equiv), DMSO, rt
Scheme 2. Ionic and Radical Thioglycosylation.
Cs2CO3 instead of K3PO4, DCE:DMSO (1:1, trace
v:v), rt
Results and discussion
6
DCE:DMSO (1:1, v:v), rt
80
<10:1
In our own efforts, recently we have developed visible‐light‐
7
2b instead of 2a, DCE:DMSO (1:1, v:v), rt 72
2d instead of 2a, DCE:DMSO (1:1, v:v), rt 66
2d instead of 2a, DCE:DMSO (1:1, v:v), rt 68
2e instead of 2a, DCE:DMSO (1:1, v:v), rt trace
<10:1
mediated glycosyl radical reactions for synthesis of C‐
glycosylsides.15
In
addition,
we
reported
an
8
<10:1
organophotocatalytic thiolation of acyl radial method with
thiosulfonates.20 These chemistries guided us to explore the
new thioglycosylation reaction. The reaction of α‐
glucopyranosyl bromide 1a with thiosulfonate 2a and 4CzIPN21
as photocatalyst (PS) was probed (Table 1 and Tables S1‐6).
First, we examined several commonly used reductants including
iPr2NEt, Hantzsch ester, and ascorbic acid (Table S1, entries 2, 6
and 7) for the generation of the glycosyl radical. Disappointedly,
9
<10:1
10
11
12
13
14
15
16
17
‐
2f instead of 2a, DCE:DMSO (1:1, v:v), rt
2g instead of 2a, DCE:DMSO (1:1, v:v), rt
1b instead of 1a
66
<10:1
trace
trace
60
‐
‐
only the reduced product
4 was obtained. It should be pointed
DCE instead of DCE:H2O (2:1, v:v), rt
DCE instead of DCE:H2O (2:1, v:v), ‐5 °C
without 4ClCzIPN, (TMS)3SiOH or K3PO4
under dark condition
17:1
out that this is a general problem in using glycosyl halides as
radical progenitors in glycosylation.18 Minimizing the issue
requires a radical capable of effective dehalogenation whereas
the hydrogenated product should be a weak H‐donor. A silyl or
a silyloxy radical can induce dehalogenation while the strong Si‐
H and Si‐O‐H makes them more difficult to be abstracted.22
Therefore, various silanes were screened and (TMS)3SiOH was
the best, giving 3a in 37% yield (Table S1, entries 3‐5 and 8‐9).
Survey of PSs revealed 4ClCzIPN21b,c as the optimal promoter
(65% yield, Table S2 and Table 1, entries 2‐4). The process was
also sensitive to bases (entries 4‐6 and Table S4) and K3PO4 gave
67
>20:1
trace
trace
‐
‐
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For even less electrophilic substrates, p‐tolylthiosulfonates (3q
3u) displayed better performance than methylthiosulfonates.
Particularly, the long alkyl chain with Z‐double bond product
‐
[a] Standard conditions: unless specified, a mixture of glycosyl bromide (0.2
mmol), sulfur electrophile (0.1 mmol), 4ClCzIPN (0.005 mmol), K3PO4 (0.4
mmol), and (TMS)3SiOH (0.15 mmol) in DCE/DMSO (1 mL, 1:1, v/v) or DCE/H2O
(1.5 mL, 2:1, v/v) was irradiated with 40 W Kessil blue LEDs in a N2 atmosphere
at ‐5 °C for 24 h. [b] Yield determined by 1H NMR using 1,1,2,2‐
tetrachloroethane as internal reference. [c] Ratio determined by crude 1H
NMR. [d] Isolated yield.
(
3u) , which exhibits intriguing antitumor activity (Scheme 1),
isefficiently prepared with high diastereoselectivity. The
limitation of the method is also realized. C2‐N‐Ac‐saccharides
such as D‐glucosamine failed to react due to the lability of these
reactants (see Figure S5 in SI).
The generality of the new S‐glycosylation was examined. We
first evaluated the performance using glucosyl bromide (1a) as
radical donor for coupling with various thiosulfonates
2
(Scheme 3). The process serves as a general approach to both
aryl and alkyl thioglycosides. Uniformly high axial selectivities
are observed regardless of the nature of the sulfur
electrophiles. With respect to aryls, electron‐neutral (3b), ‐
donating (3c‐3d, 3h), and ‐withdrawing (3e‐3f) groups on the
phenyl ring and fused aromatic (3g) can be tolerated. Moreover,
heteroaromatic thiosulfonates such as the thiophenyl (3i) and
furanyl (3j) enabled access to medicinally valued thioglycosides.
The tetrazole derived disulfide instead of labile thiosulfonate
could serve as alternative and delivered the desired 3k. The
reaction performed in DCE:H2O failed for pyridinyl
thiosulfonate. Decent results (3l, 79%, α:β > 20:1) were
obtained with DCE:DMSO (condition B). The protocol can also
be applied in gram scale synthesis. Notably, less reactive sp3
alkyl glycosides 3o‐
3s could be synthesized with the protocol.17
Scheme 4. Scope of Saccharides and Selenoglycosylation. [a] Reaction
conditions: unless specified see footnote a and SI; isolated yield; the ratio of
α and β anomers determined by crude 1H NMR. [b] 3.0 equiv of glycosyl
bromide used. [c] Disulfide used.
Alternation of sugars was probed next (Scheme 4). Both
common hexoses (glucose 3v
fucose 3aa, rhamnopyranose 3ab, glucuronic acid 3ac) and
pentoses (3ad 3af) gave good yields and high stereoselectivity.
Among the tested monosaccharides, except ribose (3af
‐3x, galactose 3y, mannose 3z,
‐
)
adopting expected β selectivity owning to the steric effect, the
others gave expected α‐selectivity. Furthermore, disaccharides
(
3ag and 3ah) could participate in the process smoothly. For
xyloses (3ai‐3aj), the obtained products adopted β orientation
since the anomeric xylosyl radical is β selective.23 Besides
pyridyl (Py), other pharmaceutically relevant heteroaromatics
such as benzothiazole and oxadiazole (3ai, 3aj) could be
Scheme 3. Scope of Thiosulfonates. [a] Reaction conditions: unless specified,
see footnote a and SI; isolated yield; the ratio of α and β anomers determined
by crude 1H NMR. [b] Yield after hydrolysis of acyl group. [c] Disulfide used.
[d] Toluenethiosulfonate used. [e] Z/E ratio determined by1H NMR.
efficiently incorporated. This offers a viable strategy for the
synthesis of the xylose‐derived bioactive analogs.4c Finally, the
strategy can also be extended for the synthesis of synthetically
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challenging α‐1,2‐cis‐selenoglycosides (Scheme 4 and Table attribute to the strong O‐H bond (calculated BDE = 98 kcal/mol,
S7).24 As showcase, under the reaction conditions (DCE:H2O see SI, BDE of S‐H: 83 kcal/mol)26,27 and steric hindrance, making
(2:1, v:v), coupling of 4 different glycosyl bromides with methyl the H difficult to be abstracted by 8. This strong bond also
phenylselenyl sulfonate delivered the corresponding α‐seleno‐ echoes the use of stronger 4ClCzIPN (E*/E•− = 1.58 V vs SCE)21
glycosides 3ak
‐
3an with uniformly high stereoselectivity (α:β > to oxidize the silyloxide (TMS)3SiO− [(TMS)3SiO−/TMS)3SiO• =
20:1).
1.54 V vs SCE)]. A spontaneous Brook rearrangement of silyloxy
radical
effective debrominator. The anomeric effect makes the radical
axially positioned and directs α‐selective coupling with
thiosulfonate . In the reactions, we still observed a notable
amount of the reduction product . It is believed that it is
produced from the reaction of with (TMS)3SiOH, which was
6 , which acts as an
forms silicon‐centred radical 7 28,21b
8
2
4
8
confirmed by deuteration experiments with observed
deuterated product 4‐d (Scheme 6b). This also rationalizes that
2 equiv of glycosyl bromide
1 is used to ensure high efficiency
of the thioglycosylation process. Finally, a radical trapping study
with TEMPO and methyl acrylate16d further confirms the radical
engaged process (Scheme 6c)
Scheme 5. Thiodiversification of Pharmaceutically Relevant Structures. [a]
Reaction conditions: unless specified, see footnote a and SI; isolated yield;
ratio of α and β anomers determined by crude 1H NMR. [b] The product after
hydrolysis. [c] Methylthiosulfonate used. [d] DCE:H2O (1.5 mL, 2:1, v/v) used
as solvent.
The capacity of selective functionalization of biologically
relevant structures and therapeutics is the testament to the
synthetic power of a methodology. As demonstrated (Scheme
5), C1‐6’ connected thioglycosides 3ao‐3aq were efficiently
synthesized. It is noted that native unprotected saccharide
thiosulfonate could be used for the efficient cross coupling
(
3aq). Moreover, it is particularly noteworthy that the protocol
is amenable for synthesis of α‐S‐linked 1,1’‐disaccharides with
C1 thiol electrophiles, a synthetic challenge in glycosylation,25
as demonstrated in 1‐thiodisaccharides
(
3ar
)
and
thiotrisaccharide (3as). Furthermore, α‐linked thioglycosyl
amino acid 3at and peptide 3au could be efficiently
constructed. The synthetic manifold was further exemplified by Scheme 6. Proposed mechanism and mechanism studies.
late‐stage thioglycosylation of therapeutics. Installation of
thioglycosyl moieties into estrone (3av), Captopril (3aw), and
flavone (3ax) has been realized smoothly.
In the new thioglycosylation reaction, critically (TMS)3SiOH was
identified as a HAT reagent, which could efficiently suppress the
Conclusions
In conclusion, we have developed a metal‐free, glycosyl radical
strategy for the stereoselective synthesis of thioglycosides by
employing commonly used glycosyl bromides as radical
undesired reduction of the radical
8 (Scheme 6a). This may
4 | Chem. Sci., 2020, 00, 1‐6
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H.‐Y. Wang, S. A. Blaszczyk, G. Xiao, W. Tang, Chem. Soc. Rev.,
2018, 47, 681.
precursors. The uncovered organophotoredox mediated HAT
radical pathway can highly stereoselectively induce the
formation of the anomeric C‐S bond while minimizing the side
reactions. The preparing power of the platform has been
underscored by the mild reaction conditions enabling synthesis
of challenging α‐1,2‐cis‐thioglycosides, the tolerance of various
functional groups and the broad substrate scope for both
common pentoses and hexoses. Furthermore, this general
approach is compatible to both sp2 and sp3 sulfur electrophiles
and late‐stage glycodiversification. It is expected that the
strategy enabling the efficient generation of glycosyl radicals
from labile glycosyl bromides can offer a reliable alternative for
the synthesis of C‐ and other hetero‐glycosides.
7
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Conflicts of interest
There are no conflicts to declare.
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DOI: 10.1039/D0SC04136J
ARTICLE
stereoselective thioglycosylation of glycosyl stannanes with
Chemical Science
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DOI: 10.1039/D0SC04136J
Direct, Stereoselective Thioglycosylation Enabled by an
Organophotoredox Radical Strategy
Peng Ji, Yueteng Zhang, Feng Gao, Fangchao Bi, and Wei Wang*
An organophotoredox mediated HAT catalysis is developed for achieving high
anomerically selective thioglycosylation of glycosyl bromides.