Stereoretentive C(sp3)-S Cross-Coupling

Article abstract of DOI:10.1021/jacs.8b11211

We report a stereoretentive cross-coupling reaction of configurationally stable nucleophiles with disulfide and N-sulfenylsuccinimide donors promoted by Cu(I). We demonstrate the utility of this method in the synthesis of thioglycosides derived from simple alkyl and aryl thiols, thioglycosides, and in the glycodiversification of cysteine residues in peptides. These reactions operate well with carbohydrate substrates containing common protective groups and reagents with free hydroxyl and secondary amide functionalities under standardized conditions. Competition experiments in combination with computational DFT studies established that the putative anomeric intermediate is an organocopper species that is configurationally stable and resistant to epimerization due to its short lifetime. The subsequent reductive elimination from the Cu(III) intermediate is rapid and stereoretentive. Taken together, the glycosyl cross-coupling is ideally suited for late stage glycodiversification and bioconjugation under highly controlled installation of the aliphatic carbon-sulfur bonds.

Full text of DOI:10.1021/jacs.8b11211

Subscriber access provided by UNIV OF ALABAMA BIRMINGHAM
Article
3
Stereoretentive C(sp)–S Cross-Coupling
Feng Zhu, Eric Miller, Shuo-Qing Zhang, Duk Yi, Sloane O'Neill, Xin Hong, and Maciej A. Walczak
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b11211 • Publication Date (Web): 26 Nov 2018
Downloaded from http://pubs.acs.org on November 26, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 12
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Stereoretentive C(sp3)–S Cross-Coupling
Feng Zhu,a# Eric Miller,a# Shuo-qing Zhang,b Duk Yi,a Sloane O’Neill,a Xin Hong,b* Maciej A.
Walczaka*
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
aDepartment of Chemistry, University of Colorado, Boulder, CO 80309, United States; bDepartment of Chemistry, Zhejiang
University, Hangzhou, Zhejiang 310027, P. R. China
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: We report a stereoretentive cross-coupling reaction of configurationally stable nucleophiles with disulfide and N-
sulfenylsuccinimide donors promoted by Cu(I). We demonstrate the utility of this method in the synthesis of thioglycosides derived
from simple alkyl and aryl thiols, thioglycosides, and in the glycodiversification of cysteine residues in peptides. These reactions
operate well with carbohydrate substrates containing common protective groups and reagents with free hydroxyl and secondary amide
functionalities under standardized conditions. Competition experiments in combination with computational DFT studies established
that the putative anomeric intermediate is an organocopper species that is configurationally stable and resistant to epimerization due
to its short lifetime. The subsequent reductive elimination from the Cu(III) intermediate is rapid and stereoretentive. Taken together,
the glycosyl cross-coupling is ideally suited for late stage glycodiversification and bioconjugation under highly controlled installation
of the aliphatic carbon-sulfur bonds.
preparation of thioglycosides and glycoconjugates starts from a
glycosyl donor activated with a Lewis acid in the presence of a
thiol nucleophile.16 Reactions with substrates already equipped
with anomeric thiols proceed via displacement of a halide11, 17
or via a thiol-ene reaction with dehydroalanine 4.18 However,
these processes lack stereochemical control at the anomeric car-
bon and/or the newly-formed amino acid α-carbon center.4, 19-20
Davis and co-workers established an alternative protocol that
involves a disulfide exchange followed by reductive contraction
of the glycosyl disulfide with a phosphine.21-22 All of the above
methods are limited by the nature of the anomeric thiols which
are often available only as the thermodynamic anomer or re-
quire multistep syntheses.4, 23 Thus, in order to access both
anomers of thioglycosides, an alternative synthetic platform
would be necessary, and a complementary approach capitalizes
on reversal of polarity at the anomeric carbon. Organolithium24
and Grignard25 reagents have been engaged in reactions with
sulfur electrophiles; however, this class of reagents is limited
only to 2-deoxy sugars due to inherent instability and presents
a challenge to bioconjugation due to their incompatibility with
various functional groups commonly found in peptides and pro-
teins.26-27 The formation of a C(sp2)-S bond in small molecules
and proteins has been accomplished with various aryl nucleo-
philes such as boronic acids,28-31 organopalladium,32 and or-
ganogold33 reagents. Unlike aryl nucleophiles, the synthesis of
C-S bonds with saturated carbons via transition metal-catalyzed
reactions is limited. In fact, the cross-coupling of primary and
INTRODUCTION
The stereoselective synthesis of carbon-heteroatom bonds
constitutes a central goal of synthetic chemistry given their
functional importance in the activities of commercial drugs,
natural products, and biologics.1 An example in which the hand-
edness of the saturated carbon plays an imperative role is in the
synthesis of bioactive glycosides where the configuration of the
anomeric carbon is essential in determining the shape, recogni-
tion, localization, and, in general, the biological activities.2 In
addition to O-linked glycosides, both synthetic and natural
modifications of saccharides frequently involve the introduc-
tion of a sulfur atom, and many of the commercially available
bioactive thioacetals displaying important biological activities
are in the form of thioglycosides (Scheme 1A). Numerous syn-
thetic applications of thioglycosides highlight their utility as
versatile glycosyl donors in chemical glycosylation reactions.3
Thioglycosides are also common glycomimetics (e.g., S-linked
galactosylceramides) and demonstrate enhanced hydrolytic sta-
bilities relative to their natural O-linked congeners while retain-
ing similar conformational preferences.4 Considering biologics,
carbohydrate modifications of cysteine residues in peptides and
proteins is of special interest.5 In addition to the S-glycosidic
bond found in natural peptides (e.g., sublancin),6-9 synthetically
modified S-linked glycopeptides are abundant given their re-
sistance to chemical and enzymatic degradation,10-12 improved
anti-bacterial activities,13 and ability to act as stable surrogates
of the natural O-GlcNAc in proteins and peptides.4, 14 Within the
family of α-substituted thioethers, aminothioacetals in the form
of β-lactams are one of the most common broad-spectrum anti-
biotics consisting of penicillins, cephalosporins, and car-
bapenems.15 In all of the above examples, the configuration of
the C-S linkage is crucial for preserving the relevant physico-
chemical and biological properties.
Given the significance of glycosyl thioacetals, various meth-
ods for their synthesis have been described (Scheme 1B). The
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 12
Scheme 1. (a) Selected bioactive thio(amino)acetals. (b) Representative methods for the synthesis of S-linked glycosides
and thioacetals.
1
2
3
4
5
6
7
8
a
PEt3
OH
Au
S
OH
OH
O
S
O
AcO
AcO
O
Et
OAc
O
S
N
H
R
OAc
(RO)n
NH2
Cl
9
Ridaura (Auranofin)
(antiinflammatory and
antirheumatic)
Cl
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
Thioglycosides
(common glycosyl
donors)
Pirlimycin hydrochloride
(OH)n
O
(antibiotic)
H
R
N
S
S
X
S
O
R
N
N
H
O
CO2H
O
Penicillins
Cysteine
modifications
(many examples)
Leu
Trp
Ala
Ala
Leu
Gly
Ala
Ser
Gly
Gly
Ala
Ala
Gln
Cys
S
Thr
Gly
Ala Gln
Lys
Gly Leu Gly
Cys
H
Ile
Gly
Cys
Gly
S
S
Sublancin
S
S
OH
OH
OH
(antibacterial)
Cys
Cys
Gln
Phe
Val
Arg
Gln
Arg Tyr
HO
O
Asn
OH
H
b
O
Li/MgX
(RO)n
H
6
O
LG
(RO)n
Sulfenylation
2
Stereoretentive cross-coupling
(herein)
S
R'
LG = Cl, Br,
OAc, OH, OTs
Direct displacement
RSH
R
S
S
O
LG
R
R-Br / R-I
O
SnBu3
(RO)n
O
S
(RO)n
R
SH
(RO)n
7
Cu(I)
1
3
(only one anomer shown)
C1-Thiol manipulations
O
H
N
Me2N
NMe2
exclusive anomeric control
operational for and anomers
broad carbohydrate scope
sp2 and sp3 thiol partners
P
R'
R''
O
NMe2
SH
(RO)n
4
O
3
R
S
(RO)n
S
C1-Thiol manipulations
suitable for peptide conjugation
anomeric Cu(III) intermediates
5
Reductive desulfurization
secondary alkyl boronic acids and a trifluoromethylthiol elec-
trophile in the presence of copper(I) and a 2,2’-bipyridine lig-
and represents the sole example of C(sp3)-S bond formation.34-
strategies (i.e., nucleophilic substitution). To the best of our
knowledge, this work is the first example of a stereospecific
metal-catalyzed C(sp3)-S cross-coupling reaction characterized
by a broad substrate scope with potential applications in high-
precision bioconjugation.
35
Curiously, a stereospecific C(sp3)-S cross-coupling process
has not been reported despite its obvious advantages such as
predictable stereochemical outcomes and the myriad prepara-
tive methods for accessing chiral nucleophiles. Here, we report
a stereoretentive cross-coupling reaction between configura-
tionally stable nucleophiles and sulfur electrophiles resulting in
the formation of thioacetals and thioglycosides. This method
represents a conceptually novel approach to C-S bond for-
mation as it signifies a departure from previously established
RESULTS AND DISCUSSION
Motivated by the importance of C(sp3)-S linkages, we set out
to identify conditions that would establish a C-S bond in high
stereoselectivity. Our previous work involving the stereospe-
cific transformations of anomeric stannanes36-39 led us to
2
ACS Paragon Plus Environment

Page 3 of 12
Journal of the American Chemical Society
hypothesize that the controlled formation of new C(sp3)-S
changing the solvent to either 1,2-dicholoroethane or m-xylene
1
2
3
4
5
6
7
8
bonds would result from a stereoretentive cross-coupling pro-
cess of anomeric nucleophiles. Configurationally-stable glyco-
syl stannanes were elected for their excellent stability, availa-
bility as either anomer, as well as their amenability toward the
preparation of glycoconjugates and protein bioconjugation. For
optimization of the reaction conditions, we chose 2,3,4,6-tetra-
O-benzyl-β-D-glucopyranosylstannane 8 and phenyl disulfide
9a as the model substrates (Table 1). First, various solvents
were assayed using CuCl (3 equiv) at 130 °C. Although m-xy-
lene and 1,2-dicholoroethane produced the desired product 10
in 20% and 42% yield, respectively, with exclusive β selectiv-
ity, the reaction in 1,4-dioxane afforded 10 in 28% yield as an
α:β (1:2.1) mixture of anomers (entries 1-3). The latter case was
intriguing as it represented the first instance in which we ob-
served an erosion of stereoselectivity when running the glycosyl
cross-coupling in an ethereal solvent. We rationalized this result
by the coordinating ability of 1,4-dioxane and its propensity to
stabilize copper in high oxidation states which presumably led
to the erosion of anomeric configuration. Exclusive selectivity
was restored by extending the reaction time to 72 h and
which afforded thioglycoside 10 in 45% and 62% yield, respec-
tively (entry 4 and 5). We further improved the yield by using a
2:1 mixture of m-xylene and 1,2-dicholoroethane, furnishing 10
in up to 72% yield (entry 6 and 7).
Having established the feasibility of the sulfenylation reac-
tion with symmetrical disulfides, we next tested various unsym-
metrical sulfide donors equipped with competent leaving
groups (entries 7-10). Our investigation of these electrophiles
stemmed from the hypothesis that, in order to access a diverse
selection of S-linked glycans, the various sulfide donors might
require a suitable leaving group to facilitate the coupling. We
discovered that succinimide-containing thiophenol 9b was less
effective than disulfide 9a and provided 10 in only 52% yield.
Additional studies with phthalimide-containing thiophenols, re-
gardless of their electronic nature (e.g., 9c; electron-deficient
phthalimides with 4-NO2 in 9d and 4,5-Cl2 in 9e), resulted in no
improvement to the yield. When testing the reaction with un-
symmetrical sulfide donors, we had to consider the competition
for transfer to the C1 position introduced by the liberated leav-
ing group. With the understanding that optimal results would
only be viable if the leaving group’s nucleophilicity was rela-
tively low, we employed pentafluorophenyl disulfide 9f and, to
our delight, isolated 71% of the desired product 10 (entry 12).
Finally, S-phenyl benzenethiosulfonate 9g was coupled with b-
stannane 8 to afford 10 in a moderate yield (39%, entry 13) and
only a slight preference for the β-anomer (α:β 1:2.9). Again, we
reasoned that the destabilizing effects exerted by poorly coordi-
nating ligands, such as sulfonates, on highly-oxidized copper
species generated a configurationally-labile intermediate which
ultimately led to the observed scrambling of stereochemistry.
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
Table 1. Identification of glycosyl cross-coupling condi-
tions.a
OBn
OBn
O
O
BnO
BnO
S
BnO
BnO
+
S
SnBu3
X
Ph
Ph
OBn
10
OBn
9
8
Entry
1
2
3
4
5
6
7
8
Solvent
m-xylene
(CH2Cl)2
1,4-dioxane
(CH2Cl)2
El
9a
9a
9a
9a
9a
9a
9a
9b
9c
9d
9e
9f
Time
24 h
24 h
24 h
72 h
72 h
72 h
96 h
72 h
72 h
72 h
72 h
72 h
72 h
72 h
72 h
α:β b
Yield (%)c
20
β only
β only
1.0:2.1
β only
β only
β only
β only
β only
β only
β only
β only
β only
1.0:2.9
β only
β only
42
28
45
62
68
72
52
50
30
49
71
39
15
58
When we assessed the reaction’s performance using sub-
stoichiometric amounts of CuCl, we found that N-phenylsulfen-
ylsuccinimide 9b was more effective than symmetrical disul-
fide 9a (entries 14 and 15) at 50 mol% of CuCl. The catalyst
loading of CuCl could be reduced as low as 20 mol%, but this
resulted in ~10% decrease in the yield albeit with no change in
diastereoselectivity (data not shown). It is also interesting to
note that, under these conditions, only the β anomer was de-
tected in 1,4-dioxane when JackiePhos (55 mol%) was included
as an external phosphine ligand.40 The bulky phosphine ligand
prevents anomerization of the organocopper intermediate(s)
and ensures substrate compatibility with coordinating solvents.
Having found these conditions, the sulfenylation was now ame-
nable to the coupling of unsymmetrical donors and could pro-
vide entry into the glycodiversification of complex substrates
which might be otherwise challenging to access in the form of
symmetrical disulfides.
m-xylene
m-xylene:(CH2Cl)2 (2:1)
m-xylene:(CH2Cl)2 (2:1)
m-xylene:(CH2Cl)2 (2:1)
m-xylene:(CH2Cl)2 (2:1)
m-xylene:(CH2Cl)2 (2:1)
m-xylene:(CH2Cl)2 (2:1)
m-xylene:(CH2Cl)2 (2:1)
m-xylene:(CH2Cl)2 (2:1)
1,4-dioxane
9
10
11
12
13
14d
15d
9g
9a
9b
1,4-dioxane
aReaction conditions: sulfide 9a-9g (0.100 mmol, 1.0 equiv),
8 (1.5 equiv), CuCl (3.0 equiv), and dry solvent (3.0 mL) un-
b
1
der N2, 130 °C. Anomeric selectivities determined by H
c
NMR using unpurified reactions mixtures. Isolated yields.
dCuCl (50 mol%), JackiePhos (55 mol%) in 1,4-dioxane (3.0
mL).
The inevitable loss of one thiol moiety in the reaction of sym-
metrical donors presented an opportunity for further reaction
improvement and led us to focus our concluding optimization
studies on finding the ideal stoichiometry of the coupling part-
ners. We reasoned that, under oxidative conditions, the thiol by-
product generated over the course of the reaction could be recy-
cled into a disulfide which would allow for only 0.5 equiv of
the sulfide electrophile to be used. Thus, when we attempted the
cross-coupling reaction in an open flask using 9a (0.50 equiv),
CuCl (3 equiv), and 8 (1 equiv), 10 was isolated in 58% (data
O
O
O
PhS SPh
N
SPh
N
SPh
N
SPh
9a
O2N
O
O
O
9b
9c
9d
F
O
O
S
Cl
Cl
F
F
S
Ph
SPh
SPh
N
SPh
O
F
O
F
9e
9g
9f
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 12
Scheme 2. Scope of C(sp3)-S cross-coupling of β-D-glucose stannane 8 with aryl and alkyl sulfur electrophiles.
1
2
3
4
5
6
7
CuCl (50 mol% or 3 equiv)
O
OBn
OBn
m-xylene:(CH2Cl)2 (2:1)
130 oC, 96 h
O
or
O
RS SR
N
SR
BnO
BnO
BnO
BnO
SnBu3
S
R
11
OBn
8
OBn
13
O
12
8
9
OBn
O
OBn
OBn
OBn
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
BnO
BnO
O
O
O
BnO
BnO
BnO
BnO
BnO
BnO
S
S
S
S
OBn
OBn
OBn
OBn
t-Bu
F
NHAc
14, 73%
β only
15, 70%
β only
17, 82%
β only
16, 86%
β only
OBn
OBn
OBn
O
OBn
O
O
O
BnO
BnO
BnO
BnO
OMe
S
S
BnO
BnO
BnO
BnO
S
S
OBn
OBn
OBn
OBn
20, 50%a
β only
OCF3
OMe
18, 96%
β only
21, 62%
α:β 1:14
19, 56%
α:β <1:20
OBn
O
OBn
O
OBn
OBn
O
BnO
BnO
BnO
BnO
BnO
BnO
O
OMe
OMe
S
BnO
BnO
S
S
S
NHBoc
R
OBn
OBn
OBn
OBn
22, 60%a
α:β <1:20
26, 69%a,b
β only
24, R = i-Pr, 41%
25, R = Cy, 58%
β only
23, 73%
β only
OBn
OBn
O
BnO
BnO
O
S
BnO
BnO
O
S
OBn
OBn
O
O
28, 68%a
α:β <1:50
27, 67%a,b
β only
General reaction conditions: β-D-glucose 8 (1.5 equiv), sulfur electrophile (1 equiv), CuCl (3 equiv), anh. m-xylene:(CH2Cl)2 (2:1, 3.0
mL) under N2, 130 °C, 96 h. aCuCl (50 mol%), JackiePhos (55 mol%), 1,4-dioxane (3.0 mL), 130 °C, 96 h. b110 °C. Compounds 14-19,
21, and 23 were prepared with 11; compounds 20, 22, and 24-28 were prepared with 12.
not shown). The sole role of air in this process was to dimerize
a thiol into a disulfide and, because these conditions also af-
forded exclusive anomeric control, we excluded the possible in-
termediacy of a radical organocopper species. This protocol en-
sures full consumption of the thiol and offers an alternative to
reactions where modifications of the thiol with another leaving
group could be problematic.
27). We also found that the addition of a bulky phosphine ligand
(JackiePhos) helped to stabilize the putative anomeric organo-
copper intermediate by preventing elimination of the C2 sub-
stituent which allowed for an increase in the reaction yields.
Additionally, the reaction of a succinimide derived from δ-to-
copherol furnished the S-linked glycoside 28, demonstrating the
potential value of the cross-coupling method for late-stage func-
tionalization.
The optimized conditions were applied to reactions with β-
D-glucose stannane 8 and various disulfides 10 and succin-
imides 11 (Scheme 2). For simple and commercially available
thiol substrates, disulfides 10 were used with 3 equivalents of
CuCl in a mixture of m-xylene and 1,2-dichloroethane. These
conditions afforded aryl glycosides containing electron-with-
drawing (14) and electron-donating (15-20) groups on the aro-
matic ring, along with polysubstituted (21, 22) and polycyclic
(23) aryls. For the reactions forming alkyl glycosides 24-27, we
found that N-sulfenylsuccinimides 12 were better suited based
on the improved yields, the ability to use catalytic amounts of
copper, and the ease of preparation of complex substrates (e.g.,
Further studies were aimed at establishing the generality of
the cross-coupling method with different saccharides (Scheme
3). A series of monosaccharide nucleophiles was prepared for
each anomer and subjected to the optimized conditions from
Table 1 using p-methoxyphenyl disulfide 31 or succinimide 32
as the common electrophile. We were pleased to find that the
4
ACS Paragon Plus Environment

Page 5 of 12
Journal of the American Chemical Society
Scheme 3. Reaction scope of mono- and disaccharides - carbohydrate diversity explored with (PMPS)2 or N-(4-methoxy-
phenyl)sulfenylsuccinimide as the sulfur electrophiles.
1
2
3
4
5
6
7
8
CuCl (50 mol% or 3 equiv)
O
m-xylene:(CH2Cl)2 (2:1)
O
SPMP
O
SnBu3
130 oC, 96 h
or
N
SPMP
PMPS SPMP
(RO)n
(RO)n
30
29
α and β anomers
32
O
31
9
Glc
Glc
Gal
BnO
Gal
BnO
Man
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
OBn
OBn
OBn
OBn
OBn
OBn
37, R = Ac, 58%
38, R = Piv, 84%
39, R = TBDPS, 76%
O
O
O
O
O
BnO
BnO
BnO
BnO
BnO
BnO
SPMP
BnO
SPMP
BnO
BnO
BnO
β only
BnO
33, 88%
α only
BnO
SPMP
SPMP
SPMP
36, 85%
α only
34, 91%
β only
35, 60%
α only
Glc
dGlc
dGal
BnO
BnO
Fuc
Qui
OBn
O
OBn
O
OBn
O
SPMP
OBn
SPMP
OBn
O
O
BnO
BnO
40, R = PMB, 70%
41, R = Nap, 97%
BnO
BnO
BnO
SPMP
OBn
OBn
BnO
SPMP
BnO
β only
44, 53%
β only
SPMP
45, 54%
β only
43, 52%a
α only
42, 77%a
α only
OTBDPS
Sop
Mal
Ara
Lac
BnO
OBn
O
BnO
BnO
OBn
O
SPMP
OBn
O
OBn
O
O
BnO
BnO
SPMP
OBn
OBn
O
O
O
BnO
BnO
O
BnO
SPMP
O
BnO
SPMP
OBn
BnO
OBn
BnO
BnO
OBn
OBn
OBn
48, 66%
β only
46, 83%
α only
47, 72%
β only
49, 66%
β only
General reaction conditions: 29 (1.5 equiv), (PMPS)2 30 (1 equiv), CuCl (3 equiv), anh. m-xylene:(CH2Cl)2 (2:1, 3.0 mL) under N2, 130
°C, 96 h. 31 (1.5. equiv), CuCl (50 mol%), JackiePhos (55 mol%), KF (3 equiv), 1,4-dioxane (3.0 mL), 130 °C, 96 h. PMP – p-
a
methoxyphenyl, Ac – acetyl, Piv – pivaloyl, TBDPS – tert-butyldiphenylsilyl, PMP – p-methoxyphenyl, Nap – 2-naphthylmethyl. Ano-
meric selectivities determined by 1H NMR using unpurified reactions mixtures.
general conditions were operational for both anomers of D-glu-
yields. Similarly, other electron-rich monosaccharides such as
L-fucose (44), L-quinovose (45), and even a pentose (D-arabi-
nose 46) furnished the corresponding thioglycosides with a
complete transfer of anomeric configuration. Encouraged by
these results, we also tested reactions with disaccharides. In ad-
dition to maltose 47 and lactose 48, which were viable sub-
strates in this coupling, the C2-linked disaccharide sophose also
underwent smooth conversion into S-linked disaccharide 49 de-
spite possessing a heavily congested anomeric position. We be-
lieve the preparation of 49 strongly highlights the utility of the
presented glycosyl thiol coupling since other methods fre-
quently used to install glycosidic linkages in high selectivities
often rely on neighboring-group participation and, considering
the poor anomeric preferences exerted by 1,2-linked disaccha-
rides together with the lack of participating group at C2, this
particular synthesis would present them with a formidable chal-
lenge.
cose (33), D-galactose (34, 35), as well as the α-anomer of D-
mannose (36), all proceeding with retention of configuration for
each substrate. Moreover, the nature of the protective group had
no impact on the selectivity, and groups commonly used in pre-
parative carbohydrate chemistry such as esters (37, 38), and si-
lyl (39) and benzyl ethers (40, 41) were also tolerated. We ulti-
mately employed benzyl groups in many of our examples be-
cause they are highly convenient for the preparation and manip-
ulation of anomeric nucleophiles. Historically, the removal of
benzyl ethers has required harsh conditions, potentially render-
ing their use incompatible with sensitive groups such as the C-
S linkage. Cognizant of this restraint, we were able to demon-
strate that benzyl groups in the thioglycosides (e.g., 10) could
be removed without cleavage of the C-S bond and concomitant
C1-epimerization using a strong Lewis acid (BCl3) in the pres-
ence of a carbocation scavenger (mesitylene) in 71% (for de-
tails, see the SI). This protocol, in addition to other known
methods for the debenzylation of thioglycosides,41 could be eas-
ily extended to other S-linked glycans.
S-linked glycosides are frequently employed as surrogates of
O-linked glycans due to their increased hydrolytic stability44
2-Deoxy glycosides, notorious for their reluctance toward
stereocontrolled manipulations,42-43 were easily prepared from
the corresponding stannanes 42 and 43 in synthetically useful
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 12
Scheme 4. (a) Scope of reactions with various mono- and disaccharides. (b) Conjugation of saccharides via sulfur in cys-
teine.
1
2
3
4
5
6
7
8
O
CuCl (55 mol%)
O
SnBu3
O
S
JackiePhos (55 mol%)
R
N
SR
(RO)n
(RO)n
1,4-dioxane, 90 or 130 oC, 96 h
O
50
29
12
α and β anomers
a
OBn
OBn
OBn
9
OBn
OBn
BnO
BnO
O
BnO
O
O
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
BnO
BnO
BnO
BnO
OBn
O
BnO
O
O
BnO
S
S
BnO
BnO
BnO
S
O
S
S
BnO
BnO
BnO
BnO
BnO
BnO
BnO
O
O
OBn
BnO
BnO
O
BnO
BnO
O
O
BnO
BnO
BnO
BnO
OMe
53, 75%
β only
BnO
OMe
OMe
55, 61%a
α only
BnO
BnO
OMe
OMe
51, 74%
β only
52, 88%
β only
54, 86%
α only
OBn
O
BnO
BnO
OBn
O
OBn
OBn
BnO
BnO
OBn
OBn
BnO
OBn
BnO
BnO
OMe
S
BnO
O
O
OBn
BnO
BnO
BnO
O
O
O
S
BnO
S
BnO
S
BnO
OBn
OBn
O
BnO
BnO
BnO
OMe
OMe
BnO
56, 48%
β only
58, 56%
β only
59, 61%
β only
OMe
57, 54%
α only
OBn
OBn
OBn
OBn
O
BzO
AcO
O
OBz
BnO
BnO
OAc
OAc
O
O
BnO
BnO
BnO
BnO
OBn
BnO
BnO
S
S
AcO
O
O
BnO
OAc
OAc
OBz
BnO
BnO
S
O
BnO
OAc
S
BzO
BnO
O
BnO
60, 55%
α only
61, 42%
β only
62, 40%
β only
63, 51%
β only
OMe
AcO
OBn
O
b
OBn
OBn
OBn
O
BnO
BnO
OBn
BnO
BnO
O
O
BnO
BnO
S
O
BnO
O
BnO
BnO
BnO
S
S
S
BnO
BnO
O
OBn
OBn
BocHN
CO2Et
Ph
N
CO2t-Bu
BocHN
CO2Et
BocHN
CO2Et
H
NHBoc
67, 60%b
β only
64, 52%b
β only
65, 46%b
α only
66, 36%b
β only
General reaction conditions: 29 (1.5 equiv), 12 (1.0 equiv), CuCl (50 mol%), JackiePhos (55 mol%), 1,4-dioxane (3.0 mL), 130 °C, 96
h. a KF (3 equiv). b29 (1.0 equiv), 12 (1.5 equiv), CuCl (50 mol%), JackiePhos (55 mol%), 1,4-dioxane (3.0 mL), 90 °C, 96 h. Anomeric
selectivities determined by 1H NMR using unpurified reactions mixtures.
and retention of conformational preferences similar to the natu-
ral cognates.12 We found consistently high anomeric selectivi-
ties in reactions using 6-thio-6-deoxy-D-glucose, modified at
C6 with a succinimide group, which resulted in the formation
of α- and β-linked glycosides 51-56 (Scheme 4a). We reasoned
that the synthetic endeavor might be unnecessarily complicated
by the preparation of symmetrical disulfide glycosyl donors,
and oxidative conditions under air or oxygen to regenerate the
disulfide might produce sub-optimal results, especially for
those disulfides derived from congested (e.g., C4) thiols. A
more challenging reaction with the succinimide at the axial po-
sition resulted in a diminished but synthetically useful yield of
57 (54%). An accessible C4 equatorial N-sulfenylsuccinimidate
of D-glucose was coupled with β and α anomers of D-glucose
and D-galactose to smoothly furnish disaccharides 58-60 in im-
proved yields (55-61%). With this protocol we were able to pre-
pare a precursor to thiocellobiose (58), an inducer of cellulose-
degrading enzymes.45 Finally, reactions with sensitive thiol
electrophiles at C1 are particularly interesting and allow for ac-
cess to 1,1-S-linked glycans with exclusive selectivities for both
anomers (61-63). The synthesis of this unique class of disaccha-
rides demonstrates yet another important feature of the glycosyl
cross-coupling platform; the electronic effects of various pro-
tective groups in either the glycosyl donor (i.e., stannane) and
6
ACS Paragon Plus Environment

Page 7 of 12
Journal of the American Chemical Society
the acceptor (i.e., (di)sulfide) do not bear any impact on the
yield or selectivities. This observation stands in striking con-
trast to more classical glycosylation reactions where reactivity
differences form the conceptual basis for armed-disarmed reac-
tivities of various glycosyl donors.46
1
2
3
4
Scheme 5. Cross-coupling with unfunctionalized heterocy-
cles.
O
CuCl (10 mol%)
KF or LiF (3 equiv)
X
SnBu3
X
SAr
(PMPS)2 or
N
SR
Next, we expanded the cross-coupling protocol to reactions
with amino acids and peptides (Scheme 4b). In addition to nat-
ural S-linked glycopeptides, cysteine glycosylation is an estab-
lished method for the glycodiversification of peptides and pro-
teins, providing entry into wide scope of glycoconjugates with
improved stabilities and activities.14 While many methods are
available for glycopeptide and glycoprotein synthesis, their
scope is often limited to reactions with the b-anomers of C1-
thiols.21 With the newly developed glycosyl thiol coupling, ac-
cess to both configurations is possible as exhibited in the syn-
thesis of α- and β-linked cysteine derivatives 64 and 65. Fur-
thermore, we demonstrated that disaccharide 66 and dipeptide
67 underwent smooth conversion into the corresponding b-
linked cysteine glycoconjugates in 36-62% yield. Our concerns
that the peptide substrates could be incompatible with elevated
reaction temperatures causing epimerization at the α-carbonyl
through the probable elimination of the anomeric thiol followed
by addition to the α,β-unsaturated system were unwarranted.
This undesired pathway was completely suppressed by lower-
ing the reaction temperature to 90 °C, allowing for glycoconju-
gates 64-67 to be isolated as a single diastereomer in each case.
Based on these encouraging results, we believe the developed
method is suitable for the late-stage coupling of fully assembled
oligopeptide chains, thus providing an unprecedented oppor-
tunity to pursue bioconjugation of therapeutics and biologics.
5
6
7
8
PhMe, 130 °C
96 h
30
70
68
O
31, R = PMP
69, R = 3,4-(MeO)2C6H3
O
O
S
O
S
OMe
OMe
S
O
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
OMe
OMe
71, 56%
72, 54%
73, 71%
Bn
Boc
N
S
N
S
OMe
OMe
S
O
OMe
OMe
76, 69%b
74, 63%
75, 64%a
General reaction conditions: 68 (2.0 equiv), 31 or 69 (1.0
equiv), CuCl (10 mol%), KF (55 mol%), KF (3 equiv), toluene
(2.0 mL), 130 °C, 96 h. a68 (1.0 equiv), 30 (1.5 equiv). b68 (1.0
equiv), 30 (2.0 equiv), CuI (10 mol%), LiF (3 equiv), 1,4-diox-
ane (2.0 mL).
the benzyl groups at the neighboring positions in protected sac-
charides to stabilize the anomeric organocopper cannot be ruled
out.47
The high anomeric selectivities produced by the C-S cross-
coupling reactions prompted us to undertake mechanistic and
computational studies summarized in Schemes 6-9. From the
outset of the investigations, we excluded the possibility that, un-
der the optimized conditions with either a disulfide or N-sulfen-
ylsuccinimide donor, the cross-coupling proceeds via radical in-
termediates.48-50 The consistently high diastereoselectivities ob-
served for both anomers suggested no intercession of radical
species and control studies of the reactions involving 8 with di-
sulfide 9a or succinimide 9b in the presence of a radical scav-
enger (1,1-diphenylethylene, 1 equiv; for details, see the SI) had
no impact on yield or selectivity, confirming our initial assump-
tion. Additional experimental results lead us to propose that the
C-S bond-forming step occurs intramolecularly. We base this
assertion on the cross-coupling reaction of disulfide 9a or suc-
cinimide 9b in the presence of thiol 77 which resulted in the
exclusive formation of 10. This result indicates that (a) the sul-
fur ligands at the copper center do not undergo exchange with
external thiols; (b) the formation of a C-S bond occurs via re-
ductive elimination from the copper intermediate as opposed to
substitution at C1; and (c) under the reaction conditions,
To further highlight our method’s potential in general biodi-
versification, we pursued the synthesis of thioacetals and thio-
aminoacetals derived from unfunctionalized heterocyclic build-
ing blocks (Scheme 5). The general conditions optimized for
complex substrates were successfully translated to oxygen-
bearing saturated heterocycles 71-74. We were also able to
demonstrate that these conditions were compatible with N-het-
erocyclic substrates and successfully merged pyrrolidine- and
azetidine-derived α-aminostannanes 75 and 76 with disulfide
30. Thioaminoacetal 76 is a noteworthy example given the pres-
ence of this structural element in b-lactam antibiotics. In these
reactions, addition of KF (3 equiv) was critical to achieve high
yields despite being unnecessary in the correlative reaction us-
ing saccharides. We postulated that the fluoride source must
play an important role in activating the C1-tin as it is compara-
tively less reactive in simple tetrahydropyran and tetrahydrofu-
ran substrates which lack oxygen substitution and are thus con-
sidered more electron-rich in nature. Additionally, the ability of
Scheme 6. Competition experiments between disulfide 9a and N-sulfenylsuccinimide 9b in the presence of external thiol 77.
O
8 (1 equiv)
CuCl (3 equiv)
8 (1 equiv)
CuCl (3 equiv)
9b
1 equiv
PhS SPh
9a
1 equiv
N
SPh
m-xylene:(CH2Cl)2 (2:1)
m-xylene:(CH2Cl)2 (2:1)
OBn
130 oC, 72 h
130 oC, 72 h
O
O
BnO
BnO
S
42%
40%
SH
SH
Ph
OBn
10
MeO
MeO
only product
observed
77
1 equiv
77
1 equiv
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 12
N bond leading to the formation of Cu(III) species, 79 (Scheme
7).51 Intermediate 79 then undergoes a reductive elimination to
form the new C-S bond in 80,52 which releases a thiol or imide
by-product and restores a Cu(I) catalyst. In the presence of an
external oxidant, such as O2, the thiol generated is dimerized
into a disulfide that can reenter the catalytic cycle. This mecha-
nistic proposal is consistent with in silico studies,53 and the free
energy diagrams describing the most favorable pathways for the
Cu(I)-catalyzed C(sp3)-S cross coupling of β- and α-D-glucosyl
stannanes with N-phenylsulfenylsuccinimide 9b are shown in
Schemes 8 and 9. With the β-stannane (Scheme 8), the initial
glucose-CuCl complex int1 undergoes a sequential oxidative
addition via TS2 to give int3 followed by a reductive elimina-
tion via TS4 to achieve the overall transmetallation and furnish
glycosyl cuprous intermediate int5. The formation of this or-
ganocopper species is endergonic, with a Gibbs free energy dif-
ference of +13.4 kcal/mol between int1 and int5. Despite ex-
tensive efforts, the cyclic concerted transmetallation transition
state could not be located. Subsequent transformations of inter-
mediate int5 involve a ligand exchange with 9b to form succin-
imide-coordinated intermediate int7 followed by an oxidative
addition via five-centered transition state TS8, which results in
the cleavage of the S–N bond and the formation of int9. The
imide carbonyl assists the oxidative transformation of Cu(I) into
Cu(III), presumably by its ability to stabilize copper centers in
high oxidation states. The structural instability of int9–due to
the highly oxidized Cu center—causes a rapid, heterolytic dis-
sociation of the C–Cu bond via TS10 and, facilitated by a
charge transfer concurrent with bond cleavage, results in equa-
torial organocopper int11 with a reduced Cu(I) center. While
Scheme 7. Proposed mechanism of stereoretentive
1
2
3
4
5
6
7
8
C(sp3)-S cross-coupling.
Cu(I)
O
O
SR'
SnBu3
78
81
SR'
O
O
Cu
X
Cu
Ln
9
L
79
80
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
X = SR', NR'2
R'S NR'2
or
R'S SR'
disulfide 77 does not partake in a thiol exchange with 9a or 9b
to form mixed disulfide 4-MeOC6H4S-SC6H5 (Scheme 6). We
also established that weakly coordinating solvents (e.g., 1,4-di-
oxane, t-BuOH) diminish the anomeric selectivity by facilitat-
ing the dissociation of copper from C1. This result stands in
contrast to the C-C cross-coupling process in which no scram-
bling of stereochemistry was observed regardless of the solvent
used.37 The loss of stereochemical integrity could be averted by
inclusion of JackiePhos which, in addition to suppressing the
elimination of the C2 group (e.g., OBn), restores high anomeric
selectivities for reactions involving either anomer and functions
to stabilize Cu(III) species. This beneficial effect is likely
caused by facilitating the reductive elimination step from a
short-lived anomeric Cu(III) intermediate (vide infra).
Taken together, we propose that the Cu(I)-mediated stereore-
tentive C(sp3)-S cross coupling proceeds via an oxidative addi-
tion of anomeric organocopper species 78 across the S-S or S-
Scheme 8. DFT-computed free energy profile of Cu(I)-catalyzed C(sp3)-S cross-coupling of β-glycosyl-stannanes.
8
ACS Paragon Plus Environment

Page 9 of 12
Journal of the American Chemical Society
Scheme 9. DFT-computed free energy profile of Cu(I)-catalyzed C(sp3)-S cross-coupling of α-glycosyl-stannanes.
1
2
3
4
5
6
7
8
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
complex int11 displayed noticeable ion-pair character, we pre-
than the corresponding value for the β pathway. The lower bar-
rier for this conversion, which is also the rate-determining step,
could be attributed to the destabilizing interactions in int22
originating from a 1,2-cis arrangement of the C2-OMe group
and the anomeric copper center. Finally, to complement the
studies on the redox pathway, we also considered an alternative
mechanism in which anomeric organocopper intermediates int7
and int22 form the C-S bond through a nucleophilic substitution
at the sulfur center without a change in oxidation state of the
metal. However, a relevant transition state could not be located
despite extensive efforts.
sumed the overall likelihood of full separation between the gly-
cosyl moiety and metal–which would result in loss of anomeric
configuration–was small.54 Results from additional studies on
the dissociation of int11 and int26 into neutral radical species
int15 and copper complex int14 supported this hypothesis; the
transformations from int9 and int26 required +20.5 and +16.8
kcal/mol, respectively, to generate the corresponding products–
an endergonicity that seemed too high to make such pathways
feasible (Scheme 8). Furthermore, we determined that the dis-
sociations of int11 and int26 into two, separated ions were
equally as improbable given that they were even more ender-
gonic and significantly less favorable (for details, see the SI).
The subsequent three-centered C–S bond formation proceeds
through an early transition state TS12, which has a shallow bar-
rier of only 3.4 kcal/mol and also precludes the anomerization
of int11. The rapid conversion of int9 into int13 is reminiscent
of a C-heteroatom reductive elimination with well-defined aryl-
Cu(III) complexes studied by Rivas and Stahl.52, 55 Based on the
Gibbs free energy profile, the rate-determining step of the ste-
reoretentive glycosyl C(sp3)-S cross-coupling is the oxidative
addition of N-sulfenylsuccinimide with an overall barrier of
27.2 kcal/mol.
The C-S cross-coupling with disulfide donors was also inves-
tigated computationally and the overall reaction profiles is strik-
ingly similar to the computed pathway with N-sulfenylsuccin-
imide with the oxidative addition stop across a S-S bond in in-
termediates int5 and int20 being the rate-determining step (data
not shown).
CONCLUSIONS
In conclusion, we have presented a stereoretentive method
for the formation of a C(sp3)-S bond and its applications in the
synthesis of chiral thioacetals and thioglycosides. This novel re-
action is characterized by a uniformly high transfer of configu-
ration from the glycosyl donor to the product under standard-
ized conditions and is compatible with a multitude of functional
groups. The electrophilic sulfur component, in the form of a di-
sulfide or succinimide, can be installed into a wide range of
small molecules, including various saccharides and a selection
of peptides, making this method suitable for late-stage
The mechanism of the C(sp3)-S cross-coupling with α-gluco-
syl substrate is similar to the reaction pathway computed for the
β anomer (Scheme 9). The initial transformations of Cu-succin-
imide complex int16 into int22 are comparable in profile to the
equatorial stannane. However, the rearrangement of int22 into
unstable int24 is more facile than the analogous step with the β
glucoside, with a calculated activation barrier 4.7 kcal/mol less
9
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 12
8.
Hsieh, Y. S. Y.; Wilkinson, B. L.; O’Connell, M. R.;
glycodiversification. Furthermore, the availability of anomeric
nucleophiles in either configuration offers unprecedented ac-
cess to a chemical glycosylation platform that accommodates
the predictable and programmable preparation of both anomers.
A combination of experimental and theoretical studies estab-
lished that the transfer of anomeric configuration and the gen-
eration of glycosyl copper species involves sequential oxidative
addition and reductive elimination steps, which are both stere-
oretentive in nature. Once the glycosyl copper intermediate un-
dergoes the oxidative addition, the lifetime of the anomeric or-
ganocopper(III) species is too short for epimerization at the ano-
meric center due to the low barriers of C-Cu bond cleavage and
C-S bond formation. Taken together, the C(sp3)-S cross-cou-
pling method establishes a novel mechanistic platform for the
discovery of stereoretentive reactions in preparative carbohy-
drate chemistry and beyond.
Mackay, J. P.; Matthews, J. M.; Payne, R. J., Synthesis of the
Bacteriocin Glycopeptide Sublancin 168 and S-Glycosylated Variants.
Org. Lett. 2012, 14, 1910-1913.
1
2
3
4
5
6
7
8
9.
Biswas, S.; Garcia De Gonzalo, C. V.; Repka, L. M.; van der
Donk, W. A., Structure–Activity Relationships of the S-Linked
Glycocin Sublancin. ACS Chem. Biol. 2017, 12, 2965-2969.
10.
Novel S-Neoglycopeptides from Glycosylthiomethyl Derivatives. Org.
Lett. 2004, 6, 1083-1085.
11.
General Strategy toward S-Linked Glycopeptides. Angew. Chem. Int.
Ed. 2005, 44, 4596-4599.
12.
Thiooligosaccharides and Thioglycopeptides. Chem. Rev. 2006, 106,
160-187.
13.
Wright, T. H.; Navo, C. D.; Patchett, M. L.; Norris, G. E.; Brimble, M.
A., Total chemical synthesis of glycocin F and analogues: S-
glycosylation confers improved antimicrobial activity. Chem. Sci.
2018, 9, 1686-1691.
Zhu, X.; Pachamuthu, K.; Schmidt, R. R., Synthesis of
Thayer, D. A.; Yu, H. N.; Galan, M. C.; Wong, C.-H., A
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
Pachamuthu, K.; Schmidt, R. R., Synthetic Routes to
Amso, Z.; Bisset, S. W.; Yang, S.-H.; Harris, P. W. R.;
ASSOCIATED CONTENT
Detailed experimental procedures, copies of NMR spectra for all
new compounds. The Supporting Information is available free of
charge on the ACS Publications website.
14.
De Leon, C. A.; Levine, P. M.; Craven, T. W.; Pratt, M. R.,
The Sulfur-Linked Analogue of O-GlcNAc (S-GlcNAc) Is an
Enzymatically Stable and Reasonable Structural Surrogate for O-
GlcNAc at the Peptide and Protein Levels. Biochemistry 2017, 56,
3507-3517.
AUTHOR INFORMATION
Corresponding Author
15.
Fisher, J. F.; Meroueh, S. O.; Mobashery, S., Bacterial
Resistance to β-Lactam Antibiotics:ꢀ Compelling Opportunism,
Compelling Opportunity. Chem. Rev. 2005, 105, 395-424.
X. H. (hxchem@zju.edu.cn)
16.
Calce, E.; Digilio, G.; Menchise, V.; Saviano, M.; De Luca,
M. W. (maciej.walczak@colorado.edu)
S., Chemoselective Glycosylation of Peptides through S-Alkylation
Reaction. Chem. Eur. J. 2018, 24, 6231-6238.
17.
Analogue of the Immunostimulant KRN7000. Org. Lett. 2008, 10,
4641-4644.
18.
modified proteins via functionalization of dehydroalanine. Curr. Opin.
Chem. Biol. 2018, 46, 71-81.
19.
G., Facile Conversion of Cysteine and Alkyl Cysteines to
Dehydroalanine on Protein Surfaces: Versatile and Switchable Access
to Functionalized Proteins. J. Am. Chem. Soc. 2008, 130, 5052-5053.
Author Contributions
F. Z. and E. M. contributed equally.
Dere, R. T.; Zhu, X., The First Synthesis of a Thioglycoside
ACKNOWLEDGMENT
Dadová, J.; Galan, S. R. G.; Davis, B. G., Synthesis of
This work was supported by the University of Colorado Boulder,
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 Cen-
tral Universities”. Calculations were performed on the high-perfor-
mance computing system at the Department of Chemistry, Zhejiang
University.
Bernardes, G. J. L.; Chalker, J. M.; Errey, J. C.; Davis, B.
20.
Gutiérrez-Jiménez, M. I.; Aydillo, C.; Navo, C. D.;
Avenoza, A.; Corzana, F.; Jiménez-Osés, G.; Zurbano, M. M.; Busto,
J. H.; Peregrina, J. M., Bifunctional Chiral Dehydroalanines for Peptide
Coupling and Stereoselective S-Michael Addition. Org. Lett. 2016, 18,
2796-2799.
REFERENCES
1.
Ilardi, E. A.; Vitaku, E.; Njardarson, J. T., Data-Mining for
21.
Bernardes, G. J. L.; Gamblin, D. P.; Davis, B. G., The Direct
Sulfur and Fluorine: An Evaluation of Pharmaceuticals To Reveal
Opportunities for Drug Design and Discovery. J. Med. Chem. 2014, 57,
2832-2842.
Formation of Glycosyl Thiols from Reducing Sugars Allows One-Pot
Protein Glycoconjugation. Angew. Chem. Int. Ed. 2006, 45, 4007-4011.
22.
J. M.; Errey, J. C.; El Oualid, F.; Claridge, T. D. W.; Davis, B. G., From
Disulfide‐ to Thioether‐Linked Glycoproteins. Angew. Chem. Int.
Ed. 2008, 47, 2244-2247.
Bernardes, G. J. L.; Grayson, E. J.; Thompson, S.; Chalker,
2.
Rodriguez, J.; O'Neill, S.; Walczak, M. A., Constrained
saccharides: a review of structure, biology, and synthesis. Nat. Prod.
Rep. 2018, 35, 220-229.
3.
Demchenko, A. V., Handbook of Chemical Glycosylation:
23.
Dere, R. T.; Wang, Y.; Zhu, X., A direct and stereospecific
Advances in Stereoselectivity and Therapeutic Relevance. Wiley-VCH
Verlag: Weinheim, Germany, 2008.
approach to the synthesis of α-glycosyl thiols. Org. Biomol. Chem.
2008, 6, 2061-2063.
24.
in the Stereoselective Synthesis of S-Linked 2-Deoxyglycosides.
Angew. Chem. Int. Ed. 2013, 52, 8012-8016.
4.
Aydillo, C.; Compañón, I.; Avenoza, A.; Busto, J. H.;
Baryal, K. N.; Zhu, D.; Li, X.; Zhu, J., Umpolung Reactivity
Corzana, F.; Peregrina, J. M.; Zurbano, M. M., S-Michael Additions to
Chiral Dehydroalanines as an Entry to Glycosylated Cysteines and a
Sulfa-Tn Antigen Mimic. J. Am. Chem. Soc. 2014, 136, 789-800.
25.
Reeves, J. T.; Camara, K.; Han, Z. S.; Xu, Y.; Lee, H.;
5.
Bédard, F.; Biron, E., Recent Progress in the Chemical
Busacca, C. A.; Senanayake, C. H., The Reaction of Grignard Reagents
with Bunte Salts: A Thiol-Free Synthesis of Sulfides. Org. Lett. 2014,
16, 1196-1199.
26.
Protein Modification. Chem. Rev. 2015, 115, 2174-2195.
27. Gunnoo, S. B.; Madder, A., Chemical Protein Modification
through Cysteine. ChemBioChem 2016, 17, 529-553.
Synthesis of Class II and S-Glycosylated Bacteriocins. Front.
Microbiol. 2018, 9.
6.
the glycosidic linkage. Tetrahedron 1998, 54, 11317-11362.
7. Oman, T. J.; Boettcher, J. M.; Wang, H.; Okalibe, X. N.; van
Taylor, C. M., Glycopeptides and glycoproteins: Focus on
Boutureira, O.; Bernardes, G. J. L., Advances in Chemical
der Donk, W. A., Sublancin is not a lantibiotic but an S-linked
glycopeptide. Nat. Chem. Biol. 2011, 7, 78-80.
10
ACS Paragon Plus Environment

Page 11 of 12
Journal of the American Chemical Society
28.
Herradura, P. S.; Pendola, K. A.; Guy, R. K., Copper-
47.
Molander, G. A.; Wisniewski, S. R., Stereospecific Cross-
Mediated Cross-Coupling of Aryl Boronic Acids and Alkyl Thiols.
Org. Lett. 2000, 2, 2019-2022.
Coupling of Secondary Organotrifluoroborates: Potassium 1-
(Benzyloxy)alkyltrifluoroborates. J. Am. Chem. Soc. 2012, 134, 16856-
16868.
1
2
3
4
5
6
7
8
29.
Taniguchi, N., Convenient Synthesis of Unsymmetrical
Using Organoboronic Acids with
Organochalcogenides
48.
Gong, H.; Sinisi, R.; Gagné, M. R., A Room Temperature
Dichalcogenides via Cleavage of the S−S, Se−Se, or Te−Te Bond by a
Copper Catalyst. J. Org. Chem. 2007, 72, 1241-1245.
Negishi Cross-Coupling Approach to C-Alkyl Glycosides. J. Am.
Chem. Soc. 2007, 129, 1908-1909.
30.
Xu, H.-J.; Zhao, Y.-Q.; Feng, T.; Feng, Y.-S., Chan–Lam-
49.
Gong, H.; Gagné, M. R., Diastereoselective Ni-Catalyzed
Type S-Arylation of Thiols with Boronic Acids at Room Temperature.
J. Org. Chem. 2012, 77, 2878-2884.
Negishi Cross-Coupling Approach to Saturated, Fully Oxygenated C-
Alkyl and C-Aryl Glycosides. J. Am. Chem. Soc. 2008, 130, 12177-
12183.
31.
Qiao, Z.; Ge, N.; Jiang, X., CO2-promoted oxidative cross-
9
coupling reaction for C-S bond formation via masked strategy in an
odourless way. Chem. Commun. 2015, 51, 10295-10298.
50.
Kozlowski, M. C., Nickel-Catalyzed Cross-Coupling of Photoredox-
Generated Radicals: Uncovering General Manifold for
Gutierrez, O.; Tellis, J. C.; Primer, D. N.; Molander, G. A.;
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
32.
Vinogradova, E. V.; Zhang, C.; Spokoyny, A. M.; Pentelute,
a
B. L.; Buchwald, S. L., Organometallic palladium reagents for cysteine
bioconjugation. Nature 2015, 526, 687.
Stereoconvergence in Nickel-Catalyzed Cross-Couplings. J. Am.
Chem. Soc. 2015, 137, 4896-4899.
33.
Messina, M. S.; Stauber, J. M.; Waddington, M. A.;
51.
complexes in homogeneous catalysis. Chem. Sci. 2013, 4, 2301-2318.
52. Font, M.; Parella, T.; Costas, M.; Ribas, X., Catalytic C–S,
Casitas, A.; Ribas, X., The role of organometallic copper(III)
Rheingold, A. L.; Maynard, H. D.; Spokoyny, A. M., Organometallic
Gold(III) Reagents for Cysteine Arylation. J. Am. Chem. Soc. 2018,
140, 7065-7069.
C–Se, and C–P Cross-Coupling Reactions Mediated by a CuI/CuIII
Redox Cycle. Organometallics 2012, 31, 7976-7982.
34.
Beletskaya, I. P.; Ananikov, V. P., Transition-Metal-
Catalyzed C−S, C−Se, and C−Te Bond Formation via Cross-Coupling
and Atom-Economic Addition Reactions. Chem. Rev. 2011, 111, 1596-
1636.
53.
Lefèvre, G.; Franc, G.; Tlili, A.; Adamo, C.; Taillefer, M.;
Ciofini, I.; Jutand, A., Contribution to the Mechanism of Copper-
Catalyzed C–N and C–O Bond Formation. Organometallics 2012, 31,
7694-7707.
35.
Shao, X.; Liu, T.; Lu, L.; Shen, Q., Copper-Catalyzed
Trifluoromethylthiolation of Primary and Secondary Alkylboronic
Acids. Org. Lett. 2014, 16, 4738-4741.
54.
Hosoya, T.; Takano, T.; Kosma, P.; Rosenau, T., Theoretical
Foundation for the Presence of Oxacarbenium Ions in Chemical
Glycoside Synthesis. J. Org. Chem. 2014, 79, 7889-7894.
36.
Zhu, F.; Rourke, M. J.; Yang, T.; Rodriguez, J.; Walczak,
M. A., Highly stereospecific cross-coupling reactions of anomeric
stannanes for the synthesis of C-aryl glycosides. J. Am. Chem. Soc.
2016, 138, 12049-12052.
55.
Huffman, L. M.; Casitas, A.; Font, M.; Canta, M.; Costas,
M.; Ribas, X.; Stahl, S. S., Observation and Mechanistic Study of
Facile C-O Bond Formation between a Well-Defined Aryl–Copper(III)
Complex and Oxygen Nucleophiles. Chem. Eur. J. 2011, 17, 10643-
10650.
37.
Zhu, F.; Rodriguez, J.; Yang, T.; Kevlishvili, I.; Miller, E.;
Yi, D.; O’Neill, S.; Rourke, M. J.; Liu, P.; Walczak, M. A., Glycosyl
Cross-Coupling of Anomeric Nucleophiles: Scope, Mechanism, and
Applications in the Synthesis of Aryl C-Glycosides. J. Am. Chem. Soc.
2017, 139, 17908-17922.
38.
Zhu, F.; O'Neill, S.; Rodriguez, J.; Walczak, M. A.,
Stereoretentive Reactions at the Anomeric Position: Applications in the
Synthesis of Selenoglycosides. Angew. Chem. Int. Ed. 2018, 57, 7091-
7095.
39.
Yang, T.; Zhu, F.; Walczak, M. A., Stereoselective oxidative
glycosylation of anomeric nucleophiles with alcohols and carboxylic
acids. Nat. Commun. 2018, 9, 3650.
40.
Hicks, J. D.; Hyde, A. M.; Cuezva, A. M.; Buchwald, S. L.,
Pd-Catalyzed N-Arylation of Secondary Acyclic Amides: Catalyst
Development, Scope, and Computational Study. J. Am. Chem. Soc.
2009, 131, 16720-16734.
41.
Ané, A.; Josse, S.; Naud, S.; Lacône, V.; Vidot, S.; Fournial,
A.; Kar, A.; Pipelier, M.; Dubreuil, D., Unusual anomeric
rearrangement of para-nitrobenzoylxanthate d-glycosides: a new direct
stereoselective access to α-thioglycosides from pyranose sugars.
Tetrahedron 2006, 62, 4784-4794.
42.
Synthesis. Chem. Rev. 2018, 118, 7931–7985.
43. Issa, J. P.; Lloyd, D.; Steliotes, E.; Bennett, C. S., Reagent
Bennett, C. S.; Galan, M. C., Methods for 2-Deoxyglycoside
Controlled β-Specific Dehydrative Glycosylation Reactions with 2-
Deoxy-Sugars. Org. Lett. 2013, 15, 4170-4173.
44.
Sylla, B.; Legentil, L.; Saraswat-Ohri, S.; Vashishta, A.;
Daniellou, R.; Wang, H.-W.; Vetvicka, V.; Ferrières, V., Oligo-β-(1
→ 3)-glucans: Impact of Thio-Bridges on Immunostimulating
Activities and the Development of Cancer Stem Cells. J. Med. Chem.
2014, 57, 8280-8292.
45.
Rho, D.; Desrochers, M.; Jurasek, L.; Driguez, H.; Defaye,
J., Induction of cellulose in Schizophyllum commune: thiocellobiose
as a new inducer. J. Bacteriol. 1982, 149, 47-53.
46.
Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid,
B., Armed and disarmed n-pentenyl glycosides in saccharide couplings
leading to oligosaccharides. J. Am. Chem. Soc. 1988, 110, 5583-5584.
11
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 12
1
2
3
TOC
4
5
6
7
RS-X
CuI
SR
CuIII
X
Y
Y
Y
SR
n
n
Y = O, NR’
n = 0 - 2
DFT
calculations
8
9
O
HO
SR
SR
SR
O
O
S
HO
SR
NH
O
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
NR'
n
N
H
thioacetals thioglycosides
β-lactams aminoacetals
O
glycopeptides
12
ACS Paragon Plus Environment