Catalytic and Photochemical Strategies to Stabilized Radicals Based on Anomeric Nucleophiles

Article abstract of DOI:10.1021/jacs.0c03298

Carbohydrates, one of the three primary macromolecules of living organisms, play significant roles in various biological processes such as intercellular communication, cell recognition, and immune activity. While the majority of established methods for the installation of carbohydrates through the anomeric carbon rely on nucleophilic displacement, anomeric radicals represent an attractive alternative because of their functional group compatibility and high anomeric selectivities. Herein, we demonstrate that anomeric nucleophiles such as C1 stannanes can be converted into anomeric radicals by merging Cu(I) catalysis with blue light irradiation to achieve highly stereoselective C(sp3)-S cross-coupling reactions. Mechanistic studies and DFT calculations revealed that the C-S bond-forming step occurs via the transfer of the anomeric radical directly to a sulfur electrophile bound to Cu(II) species. This pathway complements a radical chain observed for photochemical metal-free conditions where a disulfide initiator can be activated by a Lewis base additive. Both strategies utilize anomeric nucleophiles as efficient radical donors and achieve a switch from an ionic to a radical pathway. Taken together, the stability of glycosyl nucleophiles, a broad substrate scope, and high anomeric selectivities observed for the thermal and photochemical protocols make this novel C-S cross coupling a practical tool for late-stage glycodiversification of bioactive natural products and drug candidates.

Full text of DOI:10.1021/jacs.0c03298

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Article
Catalytic and Photochemical Strategies to Stabilized
Radicals Based on Anomeric Nucleophiles
Feng Zhu, Shuo-Qing Zhang, Zhenhao Chen, Jinyan Rui, Xin Hong, and Maciej A. Walczak
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03298 • Publication Date (Web): 01 Jun 2020
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Catalytic and Photochemical Strategies to Stabilized Radicals Based on
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Feng Zhu,a Shuo-qing Zhang,b# Zhenhao Chen,a# Jinyan Rui,a Xin Hong,b* Maciej A. Walczaka*
aUniversity of Colorado, Department of Chemistry, Boulder, CO 80309, USA; bZhejiang University, Department of
Chemistry, 38 Zheda Rd., Hangzhou, Zhejiang, CN 310027, P. R. C.
KEYWORDS (Word Style “BG_Keywords”). If you are submitting your paper to a journal that requires keywords, provide
significant keywords to aid the reader in literature retrieval.
ABSTRACT: Carbohydrates, one of the three primary macromolecules of living organisms, play significant roles in various
biological processes such as intercellular communication, cell recognition, and immune activity. While the majority of estab-
lished methods for the installation of carbohydrates through the anomeric carbon rely on nucleophilic displacement, ano-
meric radicals represent an attractive alternative because of their functional group compatibility and high anomeric selectiv-
ities. Herein, we demonstrate that anomeric nucleophiles such as C1 stannanes can be converted into anomeric radicals by
merging Cu(I)-catalysis with blue light irradiation to achieve highly stereoselective C(sp3)-S cross-coupling reactions. Mech-
anistic studies and DFT calculations revealed that the C-S bond-forming step occurs via the transfer of the anomeric radical
directly to a sulfur electrophile bound to Cu(II) species. This pathway complements a radical chain observed for photochem-
ical metal-free conditions where a disulfide initiator can be activated by a Lewis base additive. Both strategies utilize anomeric
nucleophiles as efficient radical donors and achieve a switch from an ionic to a radical pathway. Taken together, the stability
of glycosyl nucleophiles, a broad substrate scope, and high anomeric selectivities observed for the thermal and photochemical
protocols make this novel C-S cross-coupling a practical tool for late-stage glycodiversification of bioactive natural products
and drug candidates.
limitations and the need to prepare “inverse” radical do-
nors, the use of inherently unstable anomeric halides, and
acyl 1,2-migrations19 remain as several of the key obstacles
reducing their practical value.
INTRODUCTION
As one of the main classes of biopolymers, carbo-
hydrates are a structural element frequently found in bioac-
tive natural products.1 While the O-linked saccharides con-
stitute the bulk of known carbohydrates, modifications at
the anomeric position such as C-, N-, and S-glycosylations
represent an important class of glycoconjugates (Scheme
1A).2 In expanding the synthetic toolbox of preparative car-
bohydrate chemistry to access these valuable materials,
chemical methodologies that capitalize on a (formal) nucle-
ophilic displacement at the anomeric carbon have domi-
nated the mechanistic thinking.3 Certain limitations of these
methodologies such as suboptimal chemo- and regioselec-
tivities still require general and broadly applicable solu-
tions. In this regard, reactions that proceed through radical
intermediates are an unexplored class of transformations.
Anomeric radicals 6 are an established species and their re-
activity has been studied mostly in the context of C-glyco-
sylations.4 Methods for generating anomeric radicals in-
clude photochemical activation of anomeric halides,5 nitro
compounds,6 sulfones,7 and selenoglycosides8 (Scheme 1B).
“Inverse” anomeric radicals located at the C5 position in py-
ranoses can be derived from the Hantzsch9, 10 and redox-ac-
tive esters11-14 or through decarbonylation of alkoxyacyl tel-
lurides 8.15 Radicals generated with these methods have
been utilized in the synthesis ofcomplextargets such asses-
quiterpenoids16 and diterpenoids17, 18 – demonstrating their
synthetic utility. However, these strategies are not without
Considering the potential utility of anomeric radi-
cals as synthetic intermediates, the merger of transition
metal-based catalysis and photochemical activation repre-
sents a fruitful strategy.20 However, despite their great po-
tential, very little is known about transition metal-mediated
transformations that proceed through anomeric radicals.
Compared to known strategies that utilize transition metals
21-42
and photocatalysis,11,
this represents a significant
knowledge gap, and only recent studies have outlined the
promise of this approach.43, 44 Cross-coupling reactions with
anomeric bromides/chlorides 5 and aryl organometallic re-
agents (ArZnX, ArMgX) using Co,45 Fe,46 and Ni9, 10, 47-49 cata-
lysts indicate that the anomeric selectivities are dictated by
the anomeric preference of the transition metal center pro-
vided that the C-C bond forming step occurs through a ste-
reoretentive reductive elimination. Molander reported that
under the photoredox conditions, the Hantzsch esters de-
rived from C6 aldehydes form acyl C-glycosides.9, 10 The au-
thors postulated that the putative anomeric radicals un-
dergo recombination with a Ni(0) center followed by reduc-
tive elimination leading to a new C-C bond. Collectively,
these studies show that anomeric control can be achieved
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Page 2 of 12
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Scheme 1.
A.
HO
HO
L
W
OH
O
A
L
HO
G
A
A
F
3
S
V
G
G
A
Q
Q
HO
S
OH
OH
C
S
S
C
A
Q
T
OH
G
L
G
K
C
H
I
sublancin 168
antibacterial
S-linked glycopeptide
O
O
S
S
G
O
C
O
H
7
8
9
O
HN
G
N
HO
-D-Man
C
G
HO
A
R
HO
Q
-D-Glc
NHAc
N
R
Y
OH
OAc
(AA)
N
H
N
H
-D-Glc
-D-GlcNAc
O
Me
Me
O
N
H
O
O
AcO
AcO
O
Me
N
AcO
AcO
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S
S
O
O
OAc
OAc
2
N
N
1
-D-Xyl
N-linked glycoproteins
5
C-mannosylation
4
hSGLT2 inhibitor
antimicrobial thioglycoside
B.
C.
O
X
[Ir[dF(CF3)2ppy]2(bpy)]PF6
(2 mol%)
7
Anomeric radicals
• synthetic applications limited
to C-glycosylations
CF3
X = Br, I, Cl, NO2, SePh
F
-
Ni(cod)2 (3 mol%)
dtbbpy (3 mol%)
2,6-lutidine (3.5 equiv)
26W CFL, 24 h
PF6
• stabilized by the anomeric effect
• unprecedted formation from
C1-nucleophiles
N
Ir
OBn
h , Bu3SnH
OBn
BF3K
N
N
F
F3C
R
R
N
O
Br
CN
Cu(I) or
O
11
O
SnBu3
13
CN
O
Et3B, O2
PhTe
blue LED
12
F
F
herein
[Ir[dF(CF3)2ppy]2(bpy)]PF6
8
6
9
O
X
M catalyst
Nu
A. -Cl, Ni(cod)
Ar
O
Ar
2
• limited to deactivated
anomeric halides and
C-C cross-couplings
Ir[dF(CF3)ppy]2(dtbbpy)PF6
dtbbp,K3PO4, blue LED
Cl or t-BuO
RO
RO
Ar
RO
• incompatible with 2-deoxy
substrates
• mostly axial selectivities
10
7
B. -H, Co(acac) , DTBP
Ar
= Co(II), Fe(III), Ni(II)
M
2
HCl or t-BuOH
=
ZnX, MgX
Ar
Nu Ar
15
16
14
by invoking kinetic anomeric effects of C1 radicals, repre-
senting a productive strategy to attach saccharides to vari-
ous C(sp2) acceptors.
glycosyl group proceed from a Cu(II) intermediate through
a radical rebound pathway. Additionally, we show that bi-
pyridine additives facilitate the disulfide cleavage step by a
previously unknown mechanism of chalcogen bonding,
therefore representing a novel approach for merging or-
ganocatalysis with light-mediated activation.59 Because sta-
ble anomeric nucleophiles of all common saccharides are
available or can be readily prepared from commercial rea-
gents, this method establishes a platform for a direct incor-
poration of glycosides into various carbon- and heteroa-
tom-based acceptors.
We recently described carbohydrate C1-stan-
nanes, a class of anomeric nucleophiles, as competent part-
ners in C-C,50 C-S(e),51, 52 and C-O53 cross-coupling reactions.
These processes proceedwith highlevels ofstereoretention
across a broad range of substrates, including saccharides
with free hydroxyl groups. Inspired by the prior work with
α-alkoxy boronates 11 that can generate heteroatom-sub-
stituted carbon-centered radicals54 and direct arylation re-
actions involving alkoxy radical intermediates 15 produced
through a C-H cleavage reported with Co55 and Ni26, 34 cata-
lysts (Scheme 1C), we wondered if anomeric nucleophiles 9
could also function as a source of C1 radicals. This concep-
tually novel approach requires the generation of radicals
from C1 nucleophiles with mildly oxidizing reagents, which
could be realized with late transition metals56 or under light
irradiation. The first methodcalls for a set ofconditionsthat
can weaken the putative C1-metal bond and generate a rad-
ical species as opposed to the formation of oxocarbenium
intermediates. Alternatively, the C-Sn bond in anomeric nu-
cleophiles can be cleaved homolytically with a suitable rad-
ical initiators such as thiyl radicals.57, 58 Here, we show that
anomeric stannanes are a convenient source of anomeric
radicals under thermal conditions using Cu(I) pre-catalyst
or generated directly through light-mediated cleavage of a
disulfide. Both pathways display high anomeric selectivities
and are operational for a broad collection of saccharides re-
sulting in the synthesis of thioglycosides. Mechanistic and
computational studies revealed that the transfer of a
RESULTS AND DISCUSSION
A. Reaction development with Cu(I) catalysts. At the out-
set of our studies, we investigated reactions of anomeric
stannanes as the source of carbanionic reactivity using cop-
per(I) catalysts and various bidentate ligands.50 A stereore-
tentive transfer of glycosyl nucleophiles to Pd/Cu is con-
sistent with the observed retention of configuration in C-
C,50, 60-62 C-S,51 and C-Se52 bond-forming processes. The se-
lection of C-S cross-coupling was dictated by the use of cop-
per as the sole catalyst, therefore minimizing the mechanis-
tic analysis. Our investigations on a potential anomerization
were prompted by experiments resulting in the erosion of
stereochemical integrity correlated with the nature of a
substituent at C2 (Scheme 2A). D-Glucose stannane 17a
protected as a p-methoxybenzyl (PMB) ether afforded 21a
in exclusive β selectivity using symmetrical disulfide
(PMP)2S (18) as the sulfur electrophile. The anomeric ratio
was slightly compromised when a benzyl ether containing a
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Scheme 2. Reaction development with C1-stannanes.
1
2
A.
3
4
5
6
7
8
9
(PMPS)2 (18)
(1 equiv)
CuCl (3 equiv)
OBn
O
OBn
O
OBn
O
OBn
O
Ln
Cu
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
SPMP
SnBu3
CuLn
R'
O
O
1,2-dichloroethane
xylene
130 C, 24 h
R
R
21a, 80%, only
21b, 73%,
21c, 68%,
17a, R = OPMB
17b, R = O(p-CF3C6H4)
17c, R = OMe
20
19
(1:50)
(1:17)
(3.7:1)
R'
21d, 43%,
17d, R = H
10
11
12
13
14
15
16
17
18
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20
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B.
C.
12
10
8
O
CuCl (20 mol%)
Ligand (25 mol%)
OBn
OBn
11
y = 24.448x + 2.0003
R² = 0.904
O
O
BnO
BnO
BnO
BnO
N
SPMP
SnBu3
KF (3 equiv)
1,4-dioxane
Me 7.7
23 SPMP
only
17d
22
O
7.1
6
Ligands
R
4
2.9
O
N
O
2
1.3
R
R
N
N
N
0
N
N
-0.1
0
0.1
0.2
0.3
0.4
Mulliken charge on C5/C5’
L3, (3aS,8aR), 28%
L4, (3aR,8aS), 28%
L1, R = H, 31%
L2, R = t-Bu, 23%
D.
El
22
22
22
22
24
18
18
25
18
Light
No
No
No
No
No
No
No
No
Entry
Cu/ligand
Yield
Ph
R
Ph
R
1
2
3
4
5
6
7
8
9
CuCl (40 mol%), L1 (45 mol%)
CuBr (40 mol%), L1 (45 mol%)
CuI (40 mol%), L1 (45 mol%)
CuTc (40 mol%), L1 (45 mol%)
CuCl (20 mol%), L1 (45 mol%)
CuCl (20 mol%), L1 (40 mol%)
CuCl (20 mol%), L1 (45 mol%)
CuCl (20 mol%), L1 (45 mol%)
CuCl (20 mol%), L11 ( 25 mol%)
52%
41%
<5%
38%
28%
50%
50%
50%
74%
L5, R = H, 24%
L6, R = Ph, 20%
L7, R = OMe, 19%
N
N
N
N
Me
Me
t-Bu
O
L8, 11%
t-Bu
H
N
Yes
PMP
S
PMP
S
N
N
H
N
N
N
PhthN SPMP
S
PMP
S
C6F5
L9, 18%
L10, 26%
24
18
25
L11, 30%
aReaction conditions: 17d (1.5 equiv), 22 (0.100 mmol, 1.0 equiv), CuCl (20 mol%), ligand (25 mol%), and 1,4-dioxane (2.0 mL) under N2,
130 °C, 24 h. Unless otherwise specified, only the α anomer was detected. Anomeric selectivities determined by 1H NMR analysis of unpu-
rified reaction mixtures. bMulliken charge on C5/C5’ calculated at B3LYP/6-31G(d) level of theory. c 96 h reaction time. Entry 9 - 5W blue
LED lamp was used.
p-CF3 group was placed at C2 (21b, dr >50:1). This observa-
tion led us to propose that the aromatic ring located in the
vicinity of the putative C1 organocopper intermediate can
be stabilized by π-bonding (20).63, 64 The extent of this sta-
bilization, and consequently the anomeric selectivity, can
correlate with the electronic factors of the benzyl group.
This proposal is consistent with the observations reported
by Molander in Pd-catalyzed cross-coupling reactions of α-
alkoxytrifluoroborates.64 Next, we wondered if removal of a
coordinating group at C2 could further compromise the se-
lectivity. Indeed, installation of a methyl ether in 17c re-
duced the α:β ratio to 1:17, and with a complete removal of
oxygen in 17d, a reversal of the anomeric preference was
noted (21d). The high anomeric selectivity could be re-
stored through a stereoretentive pathway using a bulky
phosphine (JackiePhos)65 as the ligand stabilizing the puta-
tive Cu(III) intermediate (for details, see the SI). The results
with 17 indicate that, in the absence of an aromatic ether at
C2 or in electron-rich 2-deoxy pyranoses, dissociation of the
C1-Cu bond may be a reasonably facile process and the
product distribution is likely a result of a competition
between the stereoretentive and stereoconvergent path-
ways (vide infra).
Intrigued by these results, we next wondered if
stereoretentive reactions observed in ligand-free C-S cross-
couplings51 could be diverted into a completely stereocon-
vergent pathway provided that the putative C1-Cu bond
could be weakened to allow for a reversible anomerization
prior to the reductive elimination step. This process could
be induced by external ligands, and amines that can stabi-
lize Cu(II/III) were selected as the likely candidates based
on prior studies.66 A number of asymmetric copper-cata-
lyzed C-C or C-heteroatom bond-forming reactions which
proceed via intermediacy of a carbon-centered radical with
copper(II) to generate an organocopper(III) species67-69
were reported to operate with nitrogen-containing ligands.
In addition to electronic stabilization of Cu in a high oxida-
tion state, large ligands may (a) enhance dissociation of a
C1-Cu bond due to a steric clash between the ligand and the
pyranose ring and (b) reduce the rate of oxidative addition
across the S-S bond, hence enabling a more facile epimeri-
zation.
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Scheme 3. Scope of Cu(I)-catalyzed thio(seleno)glycosylation.
Page 4 of 12
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General reaction conditions: diaryl disulfides or diaryl diselenides (0.100 mmol, 1 equiv), CuCl (20-40 mol%), 26 (1.5 equiv), L11 (25-
o
45 mol%), KF (3 equiv), blue LED (5W), 1,4-dioxane (2 mL), 120 C, 96 h; isolated yields. Anomeric selectivities determined by 1H
NMR analysis of unpurified reaction mixtures. aCuCl (20 mol%), 26 (1.5 equiv), L1 (25 mol%), KF (3 equiv), 1,4-dioxane (2 mL), 130
oC, 96 h. bCuCl (20 mol%), 26 (1.5 equiv), L1 (25 mol%), KF (3 equiv), m-xylene:1,4-dioxane (1:1, 2.00 mL), 130 oC, 96 h.
The reaction of D-glucopyranosylstannane 17d
and N-(4-methoxyphenyl)sulfenylsuccinimide 22 was se-
lected to assess the impact of nitrogen-containing ligands
on the anomeric selectivity in 23 (Scheme 2B). To minimize
the effect of the substituents at C2, we focused on 2-deoxy
substrates at this stage of reaction development. Tridentate
ligands (L1-L4) in the presence of CuCl (20 mol%) and KF
(2 equiv) in 1,4-dioxane at 130 oC were assayed first. Ter-
pyridine L1 and 4,4′,4″-tri-tert-butyl-2,2′:6′,2″-terpyridine
L2 produced the desired thioglycoside 23 in 31% and 23%
yield, respectively, with exclusive α selectivity. To test the
impact of more congested ligands, both enantiomers of
PYBOX L3 and L4 were also evaluated under the identical
conditions and both led to identical results with a 28% iso-
lated yield of 23 and exclusive α anomer. Other chiral pyri-
dines tested had no effect on the selectivity, indicating that
the stereodetermining step is not controlled by the environ-
ment around the copper center but likely is a result of the
inherent stereochemical preferences of the anomeric radi-
cal intermediate.
promote the reaction in high α preference although a nota-
ble erosion of anomeric integrity was noted when com-
pared to other ligands described earlier (e.g., L11). Elec-
tron-withdrawing substituents, on the other hand, such as
CF3 resulted in almost equimolar amounts of both anomers.
The observed α:β ratio correlates well with the calculated
Mulliken charges on C5/C5’ (Scheme 2D). This direct rela-
tionship between the electronic nature of the group at
C5/C5’ and selectivity sharply contrasts with a clean con-
version of 17d into the axial anomer 23 with tert-butyl bi-
pyridine L11. We note that other modifications of the 2,2’-
bipyridine scaffold at C4 and C6 revealed a similar trend,
where the electron-donating groups diminished the ratio of
the axial anomer (for details, see the SI). Collectively, these
results indicate that electron-rich substituents favor high
axial selectivity likely because of their propensity to pro-
mote the cleavage of the equatorial C-Cu bond to generate
anomeric radicals rather than a direct stereoretentive re-
ductive elimination from a Cu(III) species to produce the
equatorial anomer.
In order to improve the yield, we next evaluated bi-
dentate nitrogen ligands (L5-L11). Phenanthroline (L5)
and its derivatives such as L6-L8 slightly decreased the
overall yield while the stereoselectivity remained unaf-
fected likely due to the rigidity of the planar phenanthroline
scaffold. 4,5-Diazafluoren-9-one (L9) and sparteine (L10)
were equally less efficient, while 4,4’-diterbutyl pyridine
L11 provided an interesting lead for further optimizations
because of its exclusive axial selectivity and a slightly im-
proved yield (31%). Assessment of various bipyridine lig-
ands indicates that the electronic nature of the substituent
at C5/C5’ controls the selectivity of the reaction (Scheme
2C). Electron-donating groups such as ethers and esters
From the initial optimizations, terpyridine L1
emerged as the optimum ligand for the subsequent studies.
We next focused on fine-tuning the catalytic transformation
with L1 in the presence of CuCl and a fluoride source in a
mixture of m-xylene and 1,4-dioxane at 130 oC. Different flu-
oride sources were first assayed (LiF, NaF, CsF) but they all
produced 23 in yields lower than KF. By increasing the
amount of CuCl to 40 mol% (entry 1), 23 could be obtained
in 52% yield as a single α anomer. Other common copper
salts were also screened (entries 2-4), but again, CuBr and
CuTc afforded 23 only in moderate yields with a trace
amount of the product found for CuI (entry 3). To further
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Scheme 4.
1
2
A.
B.
OBn
OBn
3
18 (2 equiv)
O
4
5
6
7
8
9
CuCl (3 equiv)
O
BnO
BnO
O
BnO
BnO
SnBu3
SPMP
O
KF (3 equiv)
1,2-dichloroethane/o-xylene
SnBu3
BnO
37
SR
BnO
38
H/D
H/D
N
CuI
34
9
X
N
kH/kD = 1.03
XSnBu3
N
C.
O
stereoretentive
RE
28
OBn
OBn
N
CuIII
RS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
O
X
O
O
BnO
BnO
BnO
BnO
CuI
N
see table
N
H/D
SnBu3
path D
N
N
N
33
N
N
SPMP
39 H/D
40
29
N
N
Entry
Conditions
Electrophile
Light
No
kH/kD
RS-X
30
RS-X
30
N
1
2
3
4
CuCl (40 mol%), L11 (45 mol%)
CuCl (20 mol%), L11 (45 mol%)
CuCl (40 mol%), L11 (45 mol%)
L11 (45 mol%)
18
22
18
18
0.83
0.90
0.92
0.74
path C
No
Yes
Yes
N
CuII
N
D.
O
X
O
N
+
N
32
CuIII
OBn
RS
OBn
N
N
RS
8
X
31
O
BnO
BnO
O
BnO
BnO
path B
stereoretentive
RE
path A
18 (2 equiv)
CuCl (3 equiv)
SnBu3
SnBu3
41
SPMP
43
N
CuII
OBn
O
KF (3 equiv)
1,2-dichloroethane
o-xylene
OBn
X
O
SR
N
34
RS
O
BnO
BnO
O
N
BnO
BnO
35
from : k12C/k13C = 1.033
from : k12C/k13C = 1.031
36
SPMP
42
13C-labelled position
23
=
(A) Proposed mechanism of Cu(I)-catalyzed thioetherification. (B) Deuterium kinetic isotope effect studies of stereoretentive C(sp3)−S
cross-coupling. (C) Deuterium kinetic isotope effect studies for stereoconvergent C(sp3)−S cross-coupling. (D) 13C kinetic isotope effect
studies of stereoconvergent C(sp3)−S cross-coupling.
improve the yield, we next evaluated various unsymmet-
improved. Indeed, under blue LED irradiation, disulfide 18
and 4,4′-di-tert-butyl-2,2′-dipyridine L11 furnished 23 in
73% yield (entry 9). To our delight, the optimal yield was
achieved when the amount of CuCl was kept below 20
mol%.
rical and symmetrical sulfides equipped with competent
leaving groups (entries 5-8). Our investigation of these elec-
trophiles was based on the hypothesis that a suitable leav-
ing group in the electrophilic component might facilitate C-
S cross-coupling by accelerating the oxidative addition
Scheme 3 lists thioglycosides 27 obtained under
the optimized conditions. Common monosaccharides such
as D-glucose, D-galactose, and L-fucose could be converted
into thioglycosides efficiently. We observed that the ano-
meric selectivities in reactions with D-glucose are corre-
lated with the size of the protective group at C2. For in-
stance, large groups such as benzyl ethers show only a slight
preference toward the axial anomer 27a while a reduced
steric bulk at C2 improved the selectivity as well as yields
(27b, 27c). These results can be rationalized by the stabiliz-
ing interactions betweenC1-Cu andthe electron-richgroup,
as depicted in Scheme 2A. Considering the effect of 1,2-cis
interactions between the Cu(I)/Cu(III) center, the kinetic
ability of anomeric radicals to undergo dissociation has to
be taken into account as well. In general, negligible effects
of the nature of the protective group on the anomeric selec-
tivities were noted (27d, 27e). Similarly, the identity of the
saccharide core (e.g., D-galactose 27f andL-fucose 27g) had
little impact on the overall efficiency of the process as long
as the positions neighboring the putative radical are a meth-
ylene group. Along the same lines, strong axial preferences
were observedregardless ofthe nature ofthe sulfur electro-
phile, although electron-rich thiols resulted in better yields
71
step.70,
During these studies, we discovered that
phthalimide-containing thiophenol 24 was less effective
than succinimide-modified thiophenol 22 and provided 23
in only 28% yield (entry 5). Disulfides such 18 and 25 fur-
nished 23 ina moderate yield(50%, entry 6) but with a very
good α selectivity (α:β >30:1). We reasoned that the compe-
tition between terpyridine and thiophenolate bound a
highly oxidized copper center resulted in the observed
scrambling of stereochemistry. Curiously, only the α
anomer was detected when a small excess (45 mol%) of L1
was employed (entry 7). When testing the reaction with un-
symmetrical disulfide 25, 23 was isolated in 36% and the
competing transfer of the pentafluorophenyl thiolate to C1
position was not detected (entry 8).
When conducting the thioglycosylation reaction
for extended time (4 days), we observed that the reaction
stopped at about 70% conversion of the sulfur electrophile.
According to the literature report, disulfides can undergo a
homolytic cleavage to formthiyl radicals under blue light ir-
radiation.72 We next hypothesized that if two sulfur radicals
could combine with Cu(I) to form a Cu(III) intermediate,
then the overall efficiency of the reaction could be
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 12
(27i-27l). This protocol represents a viable solution to the thioglycoside 23 in exclusive selectivities but variable
1
2
3
4
5
6
7
8
general synthesis of 2-deoxy sugars which cannot be easily
prepared from anomeric halides due to a rapid elimination
and formation of glycals.46 To further extend the scope of
this transformation to other electrophiles, we investigated
diselenides, which are known to partake in retentive C-Se
cross-couplings (Scheme 3B).52 We found, similarly to the
C-S bond-forming processes, that these products could be
formed in high axial selectivities (27m-27o). However, sub-
stantial competition between a stereoretentive manifold
and radical anomerization was observed, likely due to a di-
rect substitution mechanism operational for the synthesis
of selenoglycosides from anomeric nucleophiles.52
yields (16-28%). Interestingly, CoCl2(PPh3)2 com-
pletely suppressed the reaction and 17d was recov-
ered. In the absence of CuCl, no products were found in
a reaction of disulfides and N-sulfenylsuccinimide un-
der thermal conditions with 2-deoxy-stannane 17d.
-
Radical trapping experiments with TEMPO (2 equiv)
reduced the yield of thioglycoside 23 to 25% (from
53%) without erosion of anomeric selectivity under the
optimized protocol from Scheme 2D. Under the same
conditions, TEMPO trapping product was isolated in
49% (independently confirmed by synthesis from a di-
sulfide, see the SI for details). Efforts to trap the puta-
tive C1radical withan alkene acceptor suchas 2-O-allyl
group afforded D-glucal as the only product (68%).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
B. Mechanistic studies on Cu(I)-catalyzed C-S cross-cou-
pling. Consistently high anomeric selectivities led us to un-
dertake mechanistic studies to test the overarching mecha-
nistic hypothesis summarized in Scheme 4A. After the initial
transmetalation step of stannanes 9 to Cu(I) complex 28,
the organocopper intermediate 29 undergoes oxidative ad-
dition with a disulfide or N-thiosuccinimide 30 forming
transient Cu(III) species 31. Although these two steps can
be, in principle, reversed and transmetalation from or-
ganostannane 9 to Cu(III) can be envisioned as a possible
pathway, we believe this order of events would likely be
characterized by unfavorable thermodynamics due to the
necessary ligand dissociation step. Four pathways for the
ultimate formation of a new C(sp3)-S bond in 34 and 35
were considered: (i) stereoretentive reductive elimination
from 31 that leads to the overall retention at the anomeric
carbon (path A), (ii) homolytic cleavage of the C1-Cu bond
in 31 resulting in the formation of a pair of radicals 8 and
32 that subsequently transfer the sulfur groupdirectlyfrom
32 through a rebound pathway involving 36 (path B), (iii)
recombination of radicals 8 and 32 followed by a stereore-
tentive reductive elimination resulting in the axial anomer
33 followed by reductive elimination (path C), and (iv) a di-
rect reaction of disulfides or N-thiosuccinimides 30 with
anomeric radicals8 (path D). All these pathwaysaccount for
the observed catalytic nature of the studied process and the
radical chain reactions described for pathway D can be ini-
tiated by Cu(I).
-
To distinguish between a stereoretentive and a radical
pathway, we performed a CuCl-catalyzed glycosylation
of β-stannane 17d and 18 in the presence of an elec-
tron-deficient 5,5′-bis(trifluoromethyl)-2,2′-bipyridine
(45 mol%) that furnished 23 in a 2.7:1 ratio of α:β
anomers. In contrast, identical conditions applied to
the α-stannane resulted in exclusive α-selectivity in 23.
Furthermore, under identical reaction conditions but
without CuCl, both anomers afforded the axial anomer
of 23 exclusively. This set of experiments, further con-
firmed computationally, demonstrates that the for-
mation of the β-anomers is a consequence of two com-
peting pathways and the β-anomer is likely a result of a
direct reductive elimination from 31.
-
2-Deoxys sugars and substrates with the C2 position
substituted with oxygen show substantially different
rates of C(sp3)-S cross-coupling. For example, irradia-
tion of (2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)tri-
n-butylstannane and 18 afforded 27a in a trace yield
(<5%) when CuCl was absent but a moderate yield, and
α:β 2.7:1 selectivity was obtained with CuCl under the
same condition (Scheme 3). The disparate reactivity of
2-deoxy sugars in the absence of CuCl indicates the pro-
pensity of anomeric stannanes to form C1 radical is
markedly higher when a copper(I) catalyst is absent.
We attribute this to a difference in electronic stabiliza-
tion of anomeric radicals that are located within a more
electron-rich ring.
To supplement the mechanistic studies described earlier,
we conducted additional investigations summarized below:
-
Under the thermal or photochemical conditions, β-
linkedthioglycosidesandglycosyl stannanes donot un-
dergo anomerization to the axial isomers. These obser-
vations exclude the possibility that thermodynamic
preferences of the thioglycoside products or stannanes
control the selectivity of the C-S cross-coupling.
-
A summary of deuterium kinetic isotope effects
(DKIEs) is presented in Scheme 4B. For stereoretentive
C(sp3)-S cross-couplings, normal kH/kD was observed in
a reaction with β-anomer 37. This result is consistent
withDKIEs for C(sp2)-C(sp3) cross-couplings with other
configurationally stable C1 nucleophiles.61 Starting
from the β-anomer of 2-deoxy-D-glucose 37, inverse
DKIEs were observed under thermal conditions with
disulfide 18 (entry 1) and succinimide 22 (entry 2) as
well as the photochemical conditions with a disulfide
(entry 3, Scheme 4C). The magnitude of these effects is
dependent on the conditions, and entries 1-3 show sim-
ilar DKIEs indicating analogous rate-determining steps
for these processes. However, in the absence of CuCl
but with blue LED (entry 4), much lower DKIE was rec-
orded supporting the proposal that the mechanism of
-
Copper(II) pre-catalysts such as CuCl2 (20 mol%) with
terpyridine L1 do not promote the cross-coupling of
anomeric stannanes with disulfides and N-sulfenylsuc-
o
cinimides (1,4-dioxane, 130 C). Using the identical
conditions but with blue light irradiation, α anomer 23
was formed in 16% and 52% in reactions of 17d with
18 and 22, respectively.
-
C-S cross-couplings can be accomplished with other
late transition metal catalysts; reactions of (PMPS)2,
stannane 17d and terpyridine ligand L1 (45 mol%)
with various pre-catalysts (40%) such as NiCl2(DME),
PdCl2(MeCN)2, or AuCl(PPh3)3 afforded only α-
-
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Journal of the American Chemical Society
Scheme 5.
1
2
A.
3
G at B3LYP-D3(BJ)/def2-TZVPP-SMD(1,4-dioxane)//B3LYP-D3(BJ)/def2-SVP
4
5
6
OMe
O
OMe
O
MeO
MeO
MeO
MeO
7
8
9
OMe
SPh
O
SPh
(tpy)Cu
O
MeO
MeO
(tpy)Cu
N
O
O
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
SPh
O
(tpy)Cu
TS7
9.9
OMe
O
N
O
TS3
MeO
MeO
8.7
TS5
O
int2
0.0
O
3.2
0.3
OMe
O
(tpy)Cu
N
(tpy)Cu
N
SPh
O
O
int4
O
int4
(tpy)Cu
MeO
MeO
N
O
(tpy)Cu SPh
N
int1
O
O
int6
inner-sphere pathway
29.5
29.5
OMe
O
OMe
O
outer-sphere pathway
MeO
MeO
MeO
MeO
SPh
SPh
PAx
PAx
B.
G at B3LYP-D3(BJ)/def2-TZVPP-SMD(1,4-dioxane)//B3LYP-D3(BJ)/def2-SVP
O
OMe
PhS
OMe
O
O
O
N
MeO
MeO
(tpy)Cu
Ph
S
MeO
MeO
N
O
TS9
21.6
Cu
(tpy)
OMe
O
O
Ph
O
N
S
TS8
16.7
OMe
O
MeO
MeO
Cu
(tpy)
MeO
MeO
O
TS11
int2
6.9
O
4.2
O
N
O
N
0.0
OMe
PhS
(tpy)Cu
N
(tpy)Cu
O
SPh
O
MeO
MeO
Cu
(tpy)
(tpy)Cu
O
O
int4
int4
O
N
O
int10
int1
28.8
28.8
OMe
O
OMe
O
inner-sphere pathway
outer-sphere pathway
MeO
MeO
MeO
MeO
SPh
SPh
PEq
PEq
DFT-computed Gibbs free energy diagrams of proposed reaction pathways for the generation of α- and β-glycosides (trivial hydrogens
are omitted for clarity for optimized structures of key transition states).
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Journal of the American Chemical Society
Page 8 of 12
the light-mediated reaction is different from the metal- Cu(II) species int1 and the anomeric glycosyl radical int2,
1
2
3
4
5
6
7
8
catalyzed reactions (under the identical conditions, N-
arylthiosuccinimides were found inert). Under blue
LED, the formation of C(sp3)-S bond is the product-lim-
iting step (consistent with the kinetic anomeric effect
observed in the reactions of radicals generated fromse-
lenoglycosides with alkene acceptors8 or earlier work
by Giese5). Secondary DKIEs for Cu(I) catalyzed reac-
tions indicate that either the oxidative addition step
(29à31) or radical recombination are the rate-deter-
mining steps in the catalytic cycle, whereas reductive
elimination is the product-determining step. The mag-
nitude of inverse DKIEs for the reactions with Cu(I)
suggests also that the light-mediated reactions are
likely to procced by pathD (Scheme 4A)and the control
of anomeric configuration via the kinetic anomeric ef-
fect of C1 radical in this path is different from the reac-
tions in the presence of Cu(I).
To complement DKIE studies, we measured 13C kinetic
isotope effect for stereoconvergent couplings with both
anomers of 13C-labelled stannanes 41 and 42 (Scheme
4D). These compounds were easily obtained from com-
mercial 13C1-enriched D-glucose in 3 steps (see the SI
for details). At 130 °C in 1,4-dioxane, both anomers
showed comparable k12C/k13C values (within experi-
mental error) suggesting that these reactions share
similar/identical first irreversible step(s). This obser-
vation also implies that the transmetalation steps for
both anomers may have similar rates and identical in-
termediates.
the outer-sphere C–S bond formation transition state TS3
requiresan 8.7 kcal/mol barrier and leads tothe α-2-deoxy-
1-thioglucoside product. Alternatively, the facile C–Cu bond
formation via TS5 generates the intermediate int6. This α-
Cu(III) intermediate int6 has a similar stability as the sepa-
rated Cu(II) int1 and glycosyl radical int2, indicating the re-
versible nature of the C–Cu bond formation and a fast equi-
librium between the two states. int6 can undergo an inner-
sphere C–S bond formation through TS7 to form the same
α-2-deoxy-1-thioglucoside product. TS7 is 1.2 kcal/mol less
favorable than TS3, thus the generation of α-2-deoxy-1-thi-
oglucoside occurs through the outer-sphere pathway.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The same preference for the outer-sphere pathway
exists for the β-2-deoxy-1-thioglucoside formation. The
outer-sphere C–S bond formation via TS8 is 4.9 kcal/mol
more favorable than the C–Cu bond formation via TS9. This
suggests that the β-Cu(III) species int10 is not involved in
the reaction. It should be emphasized that the intrinsic re-
ductive elimination barrier of int10 is only 2.7 kcal/mol;
thus the stereospecific functionalization of glycosyl is feasi-
ble if β-Cu(III) species can be generated from a different ap-
proach. Comparing the outer-sphere pathways, the for-
mation of α-2-deoxy-1-thioglucoside is 8.0 kcal/mol more
favorable than that of β-2-deoxy-1-thioglucoside (TS3 vs.
TS8), consistent with our studies on stereoretentive C-S
cross-coupling. This is in line with the anomeric nature of
the glycosyl radical73 and elucidates the molecular basis for
the observed stereoconvergent C–S bond formation in a thi-
oglycosylation reaction.
-
Stereoretentive pathway A is likely operational for
ligands that show a weak propensity to stabilize Cu(II) rad-
icals or, in general, for reactions that would be termed as
“ligand-free”. Studies with various 2,2’-bipyridine ligands
(Scheme 2C) in combination with the reactions of 2-deoxy-
α-D-glucose stannane in the presence of 2,2-bipyridine lig-
ands known to lead to scrambling of stereochemistry
demonstrated that the formation of the β-anomers is a re-
sult of the stereoretentive reaction rather than a reaction of
anomeric radicals from the equatorial face. Pathway B,
where the anomeric radical reacts directly with sulfur
bound to Cu(II) cannot be excluded because no difference of
anomeric selectivity was found when chiral ligands L3/L4
were used (Scheme 2B). These observations suggest that
the steric environment around copper does not impact the
stereochemistry of the newly formed bond and C-S bond
formation does not proceed from Cu(III) via reductive elim-
ination. PathwayC combinesthe kinetic anomeric effect and
thermodynamic stabilization of anomeric copper interme-
diates in the axial configuration. Different secondary DKIEs
for the metal-catalyzed and metal-free processes support
the proposal that pathway B and C have different rate-de-
termining steps, although in the case of Cu-catalyzed reac-
tions, the more appropriate term would be a turnover-lim-
iting step as the reaction with disulfide is a stoichiometric
process.
C. Photochemical thioglycosylationwith anomeric stan-
nanes. Studies of the Cu-catalyzed thioetherifications indi-
cate a likely role of anomeric radicals in the outer-sphere
transfer of the glycosyl group. Intrigued by these results, we
next investigated reactions promoted solely by light. Based
on the mechanistic proposal presented in Scheme 4A, a di-
rect reaction of a disulfide under blue LED with anomeric
radical 8 may generate a thiyl radical, which then can be en-
gaged in a productive chain reaction with anomeric stan-
nanes 9 (path D). To test this hypothesis, we conducted a
reaction screen with symmetrical disulfide 18 and 2-deoxy-
saccharide 17d, and these studies revealed an interesting
trend regarding the role of 2,2’-bipyridine additives on the
yield of 23 and the rate of cross-coupling (Scheme 6A). By
testing a series of 2,2’-bipyridine additives, 4,4’-di-tert-bu-
tyl-2,2’-bipyridine L11 emerges as a ligand that improved
the reaction yield by approx. 20% (entry 1) with a 2x in-
crease of the reaction rate when compared to ligand-free
conditions (entry 3). Other pyridines showed a similar ac-
celerating effect but to a lesser extent (for details, see the
SI). Interactions of disulfides with electron-rich alkenes
such as styrene were proposed in visible light-mediated
cleavage of olefins.74 We extend this mechanistic hypothesis
to bipyridine additives, which can engage in chalcogen
bonding with a disulfide effectively weakening the S-S bond
in 44 (Scheme 6B).75 We tested this hypothesis by measur-
ing changes in 1H NMR spectra of mixtures of 18 with L11
and other 2,2’-bipyridine additives. The MeO group in 18
(3.83 ppm, CDCl3) was used as a diagnostic signal indicative
of electronic interactions with Lewis basic additives. At a
To shed light on pathway B and C for the genera-
tion of phenyl α- and β-2-deoxy-1-thioglucosides, we re-
sorted to density functional theory (DFT) calculations. The
computed free energy profiles and the optimized structures
of key transition states are shown in Scheme 5. From the
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Scheme 6. Photochemical thioglycosylation with anomeric stannanes.
1
2
A.
B.
3
4
5
6
7
8
9
O
OBn
O
OBn
O
L11 (45 mol%)
KF (3 equiv)
SnBu3
RSSnBu3
9
BnO
BnO
BnO
BnO
(PMPS)2
SnBu3
none
blue LED
1,4-dioxane, 120 °C
N
R
N
R
18
SPMP
23
17d
hv
O
RSH
Variation from
standard conditions
45
Entry
Yield
6
S
S
1
2
3
4
5
6
7
72%
N.R.
50%
61%
50%
46%
43%
no blue LED
44
O
no L11
no KF
R
S
S
R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
no KF and L11
DMAP instead of L11
toluene as a solvent
SR
34
C.
i. Disulfide scope
ii. Carbohydrate scope
OBn
S
X
S
Ph
OBn
BnO
OTBDPS
OAc
SPMP
O
BnO
27h, X = S, 64%
27m, X = Se, 57%
BnO
Me
Me
O
O
O
O
BnO
BnO
BnO
27j, 55%
27i, 53%
BnO
BnO
46
OBn
BnO
S
SPMP
SPMP
47a, 90%
SPMP
S
MeO
MeO
S
S
27d, 72%
27f, 64%
27g, 78%
OPMB
OBz
OH
OH
OMe
AcHN
OMe
27l, 70%
46a, 45%
27k, 60%
46b, 52%
O
O
O
O
BnO
BnO
BnO
BnO
BnO
BnO
HO
HO
S
S
S
S
SPMP
47b, 87%b
SPMP
47c, 70%
SPMP
47d, 88%b
SPMP
F3C
NHBz
46c, 80%a
F
Cl
47e, 82%
46d, 55%
46e, 45%
46f, 67%
iv. Photochemical O-glycosylationc
iii. Cross-coupling with unfunctionalized heterocycles
OBn
O
BnO
BnO
O
18 (1.5 equiv)
L11 (45 mol%) AgOTf (10 mol%)
NIS (2 equiv)
O
S
OMe
OMe
S
OMe
OMe
Boc
N
O
OBn
BnO
BnO
SPMP
NPMB
CH2Cl2, rt, 10 h
KF (3 equiv)
51, 72%
O
O
5:1
OH
SnBu3
SPMP
48c, 88%
blue LED
1,4-dioxane
120 °C
O
48d, 84%
48b, 70%
BnO
BnO
48a, 82%
49
O
BnO
BnO
50
BnO
OMe
BnO
OMe
General reaction conditions: disulfide (0.100 mmol, 1 equiv), anomeric stannanes (1.5 equiv), L11 (45 mol%), KF (3 equiv), blue LED
(5W), 1,4-dioxane (2 mL), 120 oC, 48 h. Unless otherwise specified, only the α anomer was detected. Anomeric selectivities determined
by 1H NMR analysis of unpurified reaction mixtures. aα:β 10:1; bα-stannanes were used; c18 (0.150 mmol, 1 equiv), 49 (1.5 equiv), L11
(45 mol%), KF (3 equiv), blue LED (5W), 1,4-dioxane (3 mL), 120 oC, 48 h, then 2,3,4-tri-O-benzyl-α-D-glucopyranoside 50 (0.100
mmol), NIS (2.0 equiv), AgOTf (10 mol%), CH2Cl2 (5 mL), 23 oC, 10 h.
75:1 ratio of L11 to 18, the MeO signal underwent an up-
field shift to 3.81 ppm and then further to 3.59 ppm when
the ratio of L11:16 was increased to 1000:1. 4,4’-Di-
methoxy-2,2’-bipyridine shows an even more pronounced
effect (Δδ 0.03 ppm at 75:1 ratio), whereas the 4-CF3 group
exerts a much smaller shift (Δδ 0.01 ppm at 75:1 ratio).
These observations are consistent with s-hole bonding be-
tween a disulfide and a Lewis base such as bipyridines. Alt-
hough these interactions are likely to be weak and the equi-
librium between complexed/uncomplexed structures lies
heavily on the side of the free substrates, weakening of the
S-S bondbecomes important in the photochemical initiation
step. Alternatively, a charge-transfer complex formed be-
tween 2,2’-bipyridine-disulfide can lead to a rapid homo-
lytic cleavage of the S-S bond. This new S-S activation mode
is mechanistically similar to a homolytic cleavage of a B-B
bond in diboranes by coordination with a Lewis base or
through a labile EDA complex.76, 77
Scheme 6C lists products obtained in a reaction of
C1 stannanes with symmetric disulfides under blue light ir-
radiation. 2-deoxy-D-glucose thioglucosides 46 were effi-
ciently formed under these conditions irrespective of the
electronic nature of the disulfide electrophile. When com-
paring the two protocols, the light-mediated conditions
complement the Cu-catalyzed transformations, which are
more suitable for the preparation of substituted monosac-
charides whereas2-deoxy sugars are equally competent un-
der both conditions.
Common protecting groups employed in carbohy-
drate chemistry such as Bn, TBDPS, Ac, and Bz are compati-
ble with the optimized protocols and good to excellent
yields were obtained (47a-47c). Saccharides with free hy-
droxyl groups are competent substrates for this transfor-
mation as shown in the preparation of 47d and 47e. We
note that this process is complementary to the direct thio-
glycosylation of anomeric alcohols under the Shoda condi-
tions which produces the 1,2-trans anomers.78, 79 However,
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the new protocol is highly α-selective complementing the
#These authors contributed equally.
1
established β-selectivity with the imidazolium salts. These
results support the notion that the photochemical thiogly-
cosylation can be applied ina late-stage glycodiversification
of complex molecules.80 It is worth noting that thioglycosyl-
ations starting from the a-stannane are more efficient than
the ones using the β-anomers. These semi-quantitative ob-
servations match the measured rates of reactions for both
anomers (approx. 2.5 times; for details, see the SI). To fur-
ther demonstrate the versatility of the protocol, we were
delighted to find that photochemical thioetherifications are
compatible with oxygen-bearing saturated heterocycles
(furanosyl/pyranosyl stannanes; 48a, 48b) and other het-
erocyclic substrates such as azetidine- and pyrrolidine-de-
rived α-aminostannanes (48c, 48d). The reaction of
furanosyl stannane with (PMPS)2 could be accomplished on
a one-gram scale in 67% isolated yield. As an extension of
the light mediated thioglycosylation, we were able to de-
velop a two-step protocol that converted anomeric stan-
nane 49 into O-linked diglycoside 51 in an excellent yield
(76%) and good anomeric selectivity (α:β 5:1).
2
3
4
5
6
7
8
9
ACKNOWLEDGMENT
This work was supported by the University of Colorado Boul-
der, National Science Foundation (CAREER Award No. CHE-
1753225), National Natural Science Foundation of China
(21702182), Zhejiang University, the Chinese “Thousand Youth
Talents Plan”, and the “Fundamental Research Funds for the
Central Universities”. Calculations were performed on the high-
performance computing system at the Department of Chemis-
try, Zhejiang University.
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TOC
CuLn
S
R
R
S
O
O
SnBu3
O
S
TM catalyzed
or
R
organocatalytic
blue
LED
anomeric
anomeric
radicals
thioglycosides
bipy
nucleophiles
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