Fluoride Migration Catalysis Enables Simple, Stereoselective, and Iterative Glycosylation

Article abstract of DOI:10.1021/jacs.0c03165

Challenges in the assembly of glycosidic bonds in oligosaccharides and glycoconjugates pose a bottleneck in enabling the remarkable promise of advances in the glycosciences. Here, we report a strategy that applies unique features of highly electrophilic b

Full text of DOI:10.1021/jacs.0c03165

Subscriber access provided by UNIV OF WESTERN ONTARIO
Article
Fluoride Migration Catalysis Enables Simple,
Stereoselective, and Iterative Glycosylation
Girish Sati, Joshua Martin, Yishu Xu, Tanmay Malakar, Paul M. Zimmerman, and John Montgomery
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03165 • Publication Date (Web): 24 Mar 2020
Downloaded from pubs.acs.org on March 26, 2020
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 19
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
Fluoride Migration Catalysis Enables Simple, Stereoselective, and Iterative
Glycosylation
Girish C. Sati, Joshua L. Martin, Yishu Xu, Tanmay Malakar, Paul M. Zimmerman, and John
Montgomery*
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
Department of Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA
*Corresponding author. Email: jmontg@umich.edu
Abstract: Challenges in the assembly of glycosidic bonds in oligosaccharides and glycoconjugates
pose a bottleneck in enabling the remarkable promise of advances in the glycosciences. Here, we
report a strategy that applies unique features of highly electrophilic boron catalysts, such as
tris(pentafluorophenyl)borane, in addressing a number of the current limitations of methods in
glycoside synthesis. This approach utilizes glycosyl fluoride donors and silyl ether acceptors while
tolerating the Lewis basic environment found in carbohydrates. The method can be carried out at
room temperature using air- and moisture stable forms of the catalyst, with loadings as low as 0.5
mol %. These characteristics enable a wide array of glycosylation patterns to be accessed,
including all C1-C2 stereochemical relationships in the glucose, mannose and rhamnose series.
This method allows one-pot, iterative glycosylations to generate oligosaccharides directly from
monosaccharide building blocks. These advances enable the rapid and experimentally
straightforward preparation of complex oligosaccharide units from simple building blocks.
Introduction:
Advances in the glycosciences present enormous promise in the understanding of disease
and the development of strategies for improving human health.1-3 The structural diversity and
resulting biological properties of oligosaccharides and glycoconjugates are amplified by the
stereochemical variations present within monosaccharide building blocks, the positioning (or
absence) of oxygen and nitrogen functionality, and the multitude of possible points of connection
between monosaccharide units. These features, paired with the multivalency of binding
interactions, provide oligosaccharide chains with exquisite properties that govern many molecular
recognition events in biology.
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 19
1
2
3
4
5
6
7
8
9
The diversity of structural variations in carbohydrates present inherent complexities in their
preparation that have been addressed by enzymatic and synthetic approaches. Enzymatic methods
are generally unmatched in preparative efficiency once developed and optimized,4-6 but organic
synthesis methods have the advantages of being more accessible to non-specialists and are readily
adapted to diverse structural motifs. State-of-the-art chemical synthesis methods in carbohydrate
chemistry, however, often require specialized equipment and/or expert control of experimental
variables including rigorous exclusion of moisture and air, precise temperature control, and the
handling of sensitive and unstable reagents.7 Despite the promise and potential generality of
synthetic approaches, the development of rapid, robust, and operationally simple synthetic
methods that are accessible to the broader biomedical research community remains as a critical
need in glycoscience (Scheme 1).8
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
O
O
OR1
R1OH
or
+
RO
RO
RO
LG
OR1
stable and
easily-handled
simple procedure
stable catalyst
high turnover
high yielding
stereoselective
amenable to interative design
Scheme 1. Desirable Features of Catalytic Glycosylation Methods.
Many classes of glycosyl donors have been utilized with a broad range of promoters. The
most commonly utilized anomeric leaving groups in carbohydrate chemistry include
trichloroacetimidates, thioglycosides and glycosyl bromides.9 Glycosyl leaving groups fall along
a reactivity-stability continuum, with the most stable leaving groups, such as n-pentenyl
glycosides,10 requiring strongly electrophilic promoters, whereas the most active leaving groups,
such as trichloroacetimidates,11 are more reactive but challenging to carry through protecting group
manipulations. Thioglycosides and glycosyl fluorides are highly attractive from a stability
standpoint, but developing efficient catalytic protocols become progressively more challenging in
comparison to their more reactive counterparts.12-14 While many catalytic processes have been
described with these various donor classes,15 turnover numbers are often poor, and many of the
most widely-used glycosylation methods require super-stoichiometric loadings of promotors.
While stepwise approaches to oligosaccharide assembly are most commonly employed,
innovative strategies for iterative assembly have been described.10, 16-21 In order to enable the
desired glycosylation sequence to be designed, these methods often require technically challenging
2
ACS Paragon Plus Environment

Page 3 of 19
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
procedures with extensive variation of protecting groups, anomeric leaving groups, and/or
activating reagents to impart stereoselectivity and regiocontrol. Automated methods provide the
most promising non-enzymatic approaches towards the programmed synthesis of
oligosaccharides,22-25 but experimentally simple, iterative synthesis through conventional, non-
automated methods without specialized equipment and procedures remains as a major gap in the
field. In this study, we report a new boron catalyzed glycosylation method pairing glycosyl fluoride
donors with silyl ether acceptors in an approach that addresses many of the current limitations of
glycoside synthetic methods.
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
Results and Discussion:
The goals of our work include the development of a rapid and simple approach that
proceeds at room temperature, avoids the rigorous exclusion of moisture and air, provides flexible
control of stereochemistry, and offers opportunities for iterative assembly of oligosaccharides
using common building blocks (Scheme 1). Our approach employs the use of anomeric fluoride
building blocks as the glycosyl donor and silyl ethers as the glycosyl acceptor. Glycosyl fluorides
have long been recognized as a useful building block for glycosylations, and they are typically
activated by stoichiometric promoters that sequester the fluoride leaving group.14, 26 Their ease of
access, shelf life, and stability towards chromatographic purification position them as one of the
most desirable classes of glycosyl donors, but more efficient and experimentally simple activation
methods are needed in order to broaden their appeal. A potentially attractive but rarely employed
glycosylation protocol involves the coupling of glycosyl fluorides with silyl ethers, which allows
glycoside bond formation along with a stable silicon fluoride byproduct.27-31 A challenge in
developing more practical versions of this process is the need for a stable and catalytically active
Lewis acid to activate the glycosyl fluoride donor and a nucleophilic Lewis base to render cleavage
of the stable silicon-oxygen bond of the glycosyl acceptor (Scheme 2A). While the self-quenching
characteristic of most Lewis acid-Lewis base pairs renders this approach untenable for efficient
catalysis, we were attracted by the unique reactivity32 and Frustrated Lewis Pair (FLP)
characteristics33-35 exhibited by B(C6F5)3 (Scheme 2B). Specifically, the equilibrium concentration
of free Lewis acids and Lewis bases that coexist with structures of this type seemed ideally suited
for glycosyl fluoride couplings with silyl ethers while avoiding deactivation of the Lewis acid by
the Lewis-basic oxygen-rich nature of the carbohydrate building blocks. In support of this
rationale, a unique fluoride-rebound mechanism was recently elucidated in B(C6F5)3 catalyzed
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 19
1
2
3
4
5
6
7
8
9
trifluoromethylations (Scheme 2C),36-37 wherein the electrophilic triarylborane abstracts and then
redelivers a fluoride ion in an efficient catalytic sequence. These observations in B(C6F5)3 catalysis
form the basis of a key hypothesis that electrophilic triarylborane catalysts might abstract the
fluoride ion from a glycosyl donor, and then efficiently redeliver it as the Lewis base to activate
the silyl ether component (Scheme 2D). Furthermore, we anticipated that silyl structure variation
in the acceptor reagent might be used as an approach to reverse stereoselectivity using inter- and
intramolecular versions and also to sequence the reactivity of multiple hydroxyls in iterative one-
pot couplings.
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
O
• LG (leaving group): requires Lewis acid activation.
• R1OSiR3 (stable precursor): requires Lewis base for Si-O cleavage.
O
OR1
or
A
RO
RO
RO
LG
OR1
1
+
• Challenge: Lewis acids and bases complex and deactivate each other.
R OSiR3
B
C
L
F3C
CF3
CH3
B(C6F5)3
:CF2
L
F3C
Au
+
F
B(C6F5)3
B(C6F5)3
Au
CH3
LB
+
:
LA
LB
methyl migration
LA
fluoride
rebound
CF2CH3
CF3
+
F
F3C CH3
L
Au
• Hindered electrophilic boranes exhibit “frustrated” characteristics.
• Fluoride-rebound mechanism involved in trifluoromethylations.
D
O
O
B(C6F5)3
R1O
O
O
O
OR1
RO
RO
or
B(C6F5)3
RO
SiR3
RO
RO
F
OR1
F
+ B(C6F5)3
+ FSiR3
R1OSiR3
R1OSiR3
F
B(C6F5)3
Lewis acidic activation of glycosyl fluoride
Lewis basic activation of Si-O bond
thermodynamic driving force for catalyst turnover
Scheme 2. Key design considerations of B(C6F5)3 catalyzed glycosylations. (A) Challenges in
direct utilization of silyl ethers in glycosylations. (B) Key characteristic of Frustrated Lewis Pairs
(FLPs). (C) Fluoride rebound mechanism in trifluoromethylations using B(C6F5)3. (D) Central
hypothesis for the design of B(C6F5)3-catalyzed coupling of glycosyl fluorides and silyl ethers.
The feasibility of this approach was examined in glycosidic couplings to install trans C1-
C2 linkages using C2, C3, C4 and C6 acceptors across a range of monosaccharide combinations
with various protecting groups (Scheme 3). Utilizing 5 mol % B(C6F5)3 at room temperature in
toluene or dichloromethane, high-yielding, rapid, and highly stereoselective glycosylations were
observed. Acetate protection at the C2 position was typically employed since this protecting group
is well established to direct the formation of C1-C2-trans glycosides through neighboring group
participation. Orthoester formation between the C2 and C1 oxygenation was not observed, and an
independently synthesized orthoester was illustrated to rearrange to the C2 acetate-protected
4
ACS Paragon Plus Environment

Page 5 of 19
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
glycoside upon treatment with B(C6F5)3 (see Scheme S3 in the supporting information).
Glycosylations of armed glycosyl donors10 that possess benzyl ether protecting groups at C3 to C6
were exceedingly efficient, often proceeding to completion in 5-10 min using equimolar quantities
of the monosaccharide donor and acceptor, providing access to a-mannoside (1-6) products.
Whereas the catalyst was typically weighed and handled under inert atmosphere conditions, no
reduction in yield was observed when the catalyst was weighed in air. As the examples illustrate,
mannose fluoride donors underwent efficient couplings with a range of sugars, including the C3-
and C4-hydroxyls of glucose and the axial C4-hydroxyl of galactose. Notably, cyclic acetal
protecting groups (3) and more hindered silyl ethers (1b, 1c, and 6) were cleanly tolerated in the
method, allowing for selective deprotection and further synthetic elaboration. n-Pentenyl
glycosides (4) were also tolerated, which thus allows subsequent couplings with orthogonal
activation conditions. Glucosyl fluoride donors were also employed with C2-acetate direction,
providing access to b-glucoside products (9-12). This stereochemical series was effective with
hindered C2, C3, and C4 hydroxyls of the acceptors. Galactosyl fluoride donor also smoothly
underwent glycosylation under the reaction conditions to provide a β-galactoside containing
product 13. Couplings with a fucose donor were also efficient, enabling the synthesis of product 8
with exclusive β-selectivity. Commonly employed 2-azidosugars underwent efficient coupling
(14) with poor stereocontrol, as expected in the absence of a C2-directing group. The
corresponding 2-phthalimido sugars were highly efficient with an improved 5:1
diastereoselectivity favoring the b-anomer (15). Therefore, while functional group compatibility
with these nitrogen-containing groups is excellent, improvements in stereocontrol will require
further variations of protecting groups and experimental variables. The glycosylation of disarmed
glycosyl donors, which are deactivated by inductively withdrawing peracetylation, are also
effective with this method as the above examples illustrate (5b, 7, 8 and 9c), although reaction
times at room temperature typically extend to several hours. A silyl ether of phenol reacted
efficiently, producing the O-aryl glycoside product in high yield as a single diastereomer (16).
Disaccharide products such as 1a were deacetylated and then further utilized as the acceptor to
allow efficient formation of a trisaccharide product (17). Furanose donors were well tolerated in
the chemistry, with ribose and xylose based donors rapidly and cleanly proceeding to the
corresponding glycosylated products as a single β-anomer (18 and 19).
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
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 19
1
2
3
4
5
6
7
8
9
Additionally, free hydroxyls can be used as the acceptor (i.e. example 2) although reactions
require more than 3 hours and proceed in reduced yield compared with the corresponding
trimethylsilyl ether acceptor. The reaction of glycosyl fluorides with free alcohols was not pursued
further as these reactions have been shown to produce free HF which can etch glassware and itself
act as a catalyst for glycosylation, resulting in diminished selectivity.38 Furthermore, prior studies
on the silylation of alcohols with B(C6F5)3 illustrated that alcohols bind to and lower the reactivity
of the catalyst, with less hindered alcohols exhibiting the most pronounced inhibitory effects.39
The use of silyl ethers provides superior rates compared with alcohol acceptors because the
inhibitory effect of free hydroxyls is avoided in this protocol.
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
Scheme 3. B(C6F5)3-catalyzed couplings of glycosyl fluorides and silyl ethers. Reactions were
conducted with 1.0 equiv of glycosyl fluoride and 1.1 equiv of silyl ether using 5 mol % B(C6F5)3
in toluene at room temperature. Isolated yields are reported. A single diastereomer of each product
was observed unless otherwise noted.
6
ACS Paragon Plus Environment

Page 7 of 19
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
The method developed herein allows intermolecular couplings to provide highly selective
access to the C1-C2-trans glycosides using glucose and mannose donors. Since this approach
utilizes substrate control as the feature that enables a highly stereoselective outcome, we
envisioned pairing inter- and intramolecular versions of the method to enable access to all possible
C1-C2 stereochemical outcomes. Silicon linkages have been used, typically with thioglycosides
or anomeric sulfoxides, in an intramolecular aglycone delivery (IAD) strategy to access C1-C2-
cis glycosides.40-43 A prior report from our lab utilized glycosyl fluorides in intramolecular silicon-
directed glycosylations using a superstoichiometric TiF4/AgBF4 promotor system,44 but catalytic
and operationally simple methods have not been described. To illustrate the stereochemical
complementarity of inter- and intramolecular approaches, the C1-C2 trans glycosides 20 and 22
were first prepared utilizing C2-acetate direction. Alternatively, by assembling a silicon
connection between C2 of the donor and the desired reactive hydroxyl on the acceptor (in this case
C6), the IAD strategy using glycosyl fluorides with B(C6F5)3 catalysis provided an effective way
to access the C1-C2-cis a-glucoside 21 and b-mannoside 23 stereochemical relationships (Scheme
4A and 4B). This versatile strategy of coupling glycosyl fluorides of glucose or mannose with silyl
ethers in either an inter- or intramolecular sense allows all four C1-C2 stereochemical relationships
to be accessed in high yield with exceptional stereocontrol, without requiring modification of the
protecting group pattern on the C3, C4, and C6 hydroxyls of the glycosyl donor. While powerful
methods have been developed for accessing challenging b-mannosides using cyclic acetal
protecting groups as a key design element,45 a notable feature of the entry to glycosides 20 to 23
described herein is the access to all four stereochemical outcomes using a common protecting
group pattern and a single catalyst and experimental protocol. To further highlight the utility of
this methodology, we extended this approach to the synthesis of analogous α and β-L-rhamnosides
(Scheme 4C, 24 and 25). β-L-Rhamnosides are one of the most challenging glycosidic linkages
to construct and there are only limited literature examples in this area.46-49 Recent work has
focused on creative strategies for catalyst control to enable access to multiple stereochemical
outcomes in glycosylations50-51 and on the development of invertive52 or retentive53-54 strategies
based on anomeric stereochemistry. The B(C6F5)3-catalyzed approach for both inter- and
intramolecular glycosylations described herein provides an alternative versatile and effective
approach for the divergent assembly of diastereomeric glycosides from common building blocks.
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
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 19
1
2
3
4
5
6
7
8
9
A
B
BnO
BnO
OAc
O
BnO
BnO
OAc
O
BnO
BnO
BnO
BnO
O
O
F
BnO
O
BnO
B(C6F5)3 (5 mol %)
toluene, rt
BnO
BnO
B(C6F5)3 (5 mol %)
toluene, rt
AcO
AcO
OTMS
O
OTMS
O
BnO
BnO
O
F
O
BnO
BnO
BnO
BnO
BnO
BnO
O
BnO
OMe
20, 86 %
BnO
BnO
OMe
OMe
BnO
β-Glucosylation, >98:2 dr
OMe
22, 90 %
α-Mannosylation, >98:2 dr
BnO
BnO
BnO
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
O
BnO
F
Me Me
Si
OH
BnO
BnO
B(C6F5)3 (5 mol %)
toluene, rt
BnO
O
O
B(C6F5)3 (5 mol %)
toluene, rt
HO
O
BnO
O
O
O
BnO
BnO
BnO
O
Me Si
Me
O
BnO
O
then (n-Bu)4NF
BnO
BnO
O
BnO
O
BnO
BnO
then (n-Bu)4NF
O
BnO
BnO
BnO
BnO
OMe
F
BnO
BnO
OMe
23, 83 %
β-Mannosylation, >98:2 dr
OMe
BnO
21, 85 %
OMe
α-Glucosylation, >98:2 dr
F
C
F
O
BnO
O
O
O
O
BnO
BnO
B(C6F5)3 (5 mol %)
toluene, rt
B(C6F5)3 (5 mol %)
BnO
O
AcO
O
BnO
BnO
O
BnO
BnO
Me Si
AcO
BnO
O
BnO
BnO
BnO
toluene, rt
then (n-Bu)4NF
then Ac2O, Py
BnO
O
OTMS
O
BnO
OMe
AcO
24, 89 %
α-Rhamnosylation, >98:2 dr
OMe
O
Me
BnO
BnO
25, 67 %
β-Rhamnosylation, >98:2 dr
BnO
BnO
BnO
BnO
OMe
OMe
Scheme 4. Evaluation of Inter- and Intramolecular glycosylation strategies for divergent
stereoselectivity. (A) Stereoselective synthesis of b- and a-glucosides. (B) Stereoselective
synthesis of a- and b- mannosides. (C) Stereoselective synthesis of a- and b-L-rhamnosides.
Finally, we sought to develop iterative, one-pot glycosylations using multiple
monosaccharide building blocks. Such an approach through chemical catalysis requires several
demanding features, namely fast couplings without an excess of any of the monosaccharide
building blocks, paired with a strategy for differentiating the glycosyl donor leaving groups and
the acceptor hydroxyls. We envisioned that the glycosyl fluorides could be differentiated through
order of addition while the hydroxyls could be differentiated by varying the steric hindrance of the
silicon protecting group. To explore this objective, we first examined three-component couplings
of monosaccharides 26-28 (Scheme 5). Initial coupling of 26 and 27a or 27b proceeded through
completely regioselective glycosylation of the trimethylsilyl-protected C4 hydroxyl of 27a/b.
Injecting 28 after 30 min led to the regio- and stereoselective production of 31a or 31b through
glycosylation of the tert-butyldimethysilyl-protected C6 hydroxyl. Simply changing the order of
addition (initial addition of 27a and 28 followed by addition of 26 led to the regio- and
stereoselective production of 33. Similarly, monosaccharides 26, 29a, and 30 were utilized to allow
production of trisaccharide 32a by adding 29a and 30 first, followed by addition of 26 after 30
min. Similarly, coupling of 26, 29b, and 30 by following the same protocol allowed production of
32b in slightly diminished yield. The addition of catalytic amounts of 2,6-di-tert-butyl-4-methyl-
8
ACS Paragon Plus Environment

Page 9 of 19
Journal of the American Chemical Society
1
2
3
4
5
6
pyridine was found to improve the yield of this reaction by approximately 5%, although this trend
was not generalizable across other glycosylation examples (see supporting information).
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
Scheme 5. Iterative Assembly of Oligosaccharides. B(C6F5)3-catalyzed reactions were
conducted using 5 mol % B(C6F5)3 in toluene at room temperature. Isolated yields are reported
and a single diastereomer of products was obtained.
These examples (Scheme 5) illustrate that the relative reactivity of hydroxyls is exclusively
controlled by silicon protecting group rather than by the innate reactivity of the acceptor employed.
Utilizing two or more silicon units on the acceptor (i.e. 27a/b) enables installation of branched
patterns, whereas utilizing one or more silicon units and a glycosyl fluoride on the same
monosaccharide (i.e. 29a/b) enables installation of linear patterns. Notably, n-pentenyl glycosides
are tolerated (31b) and can be used in subsequent couplings using activation by N-
iodosuccinimide/Et3SiOTf. This approach allows hexasaccharide 34 to be produced as a single
regio- and stereoisomer from monosaccharide precursors 26-30 in three linear steps (four total
steps: three glycosylations and a single deprotection). The convergency of this approach
demonstrates the practical advantages of the multicomponent nature of B(C6F5)3-catalyzed
glycosylations.
9
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 19
1
2
3
4
5
6
7
8
9
Finally, we sought to address the procedure practicality and better understand mechanism.
The parent catalyst B(C6F5)3 is hygroscopic and is typically stored and handled under inert
atmosphere conditions. With an eye towards improving experimental ease and efficiency, we
sought to explore the extent to which catalyst loadings can be lowered, and also to examine more
stable catalyst variations (Scheme 6A). While the above studies employed 5 mol % catalyst, in a
representative case (1a), catalyst loadings could be lowered to 0.5 mol %, which is markedly below
the loading levels reported in other catalytic glycosylation methods. A recent extensive review of
catalytic glycosylation methods15 illustrates that most catalytic methods operate at the 10-50 mol
% loading of catalyst, and examples operating effectively at the 1-2 mol % level are rare. The
unique electrophilic properties of B(C6F5)3, the frustrated character of its association with Lewis
bases, and the absence of free hydroxyls in this silyl ether-based method combine to provide the
exceptional catalytic efficiencies of this protocol. A number of catalyst structure modifications
were examined, but most promising was the direct utilization of the simple hydrate
H2O•B(C6F5)3.32, 55 This species is stable to air and moisture, and is an easily-handled, crystalline,
highly-soluble catalyst that enables a simple benchtop setup for the catalytic glycosylations. The
activity of this catalyst is lower than observed for the commercial form of B(C6F5)3, but it still
possesses sufficient reactivity for fast, room temperature reactions at the 5 mol % level in a 1 hour
reaction time. Using the hydrate H2O•B(C6F5)3, a preparative experiment conducted on a 1.0 g
scale afforded the mannose-a-(1-4)-glucose linkage in 1a in high yield (Scheme 4A). To further
benchmark the operational ease of this method, the preparation of 1a was conducted with
H2O•B(C6F5)3 as catalyst, using unpurified ACS grade dichloromethane in an open flask at room
temperature. Under these conditions, glycoside 1a was obtained in 77 % isolated yield.
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
10
ACS Paragon Plus Environment

Page 11 of 19
Journal of the American Chemical Society
1
2
3
4
Scheme 6. Optimization of catalyst structure, turnover capabilities and mechanism.
5
6
7
8
(A) Optimization of catalyst turnover and pre-catalyst stability and ease of handling. (B)
Computational study of reaction mechanism using ωB97X-D3/(SMD, dichloromethane)/def2-
TZVP//B97-D/B1 level of theory/method. Solvent phase Gibbs free energy (enthalpy in
parentheses) values referenced against the starting value for the substrates and catalyst are in
kcal/mol. Optimized bond distances and angles are in Å and degrees respectively.
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
Other common Lewis acids such BF3•Et2O and TMSOTf are also competent in promoting
the glycosylations, but B(C6F5)3 and its hydrate were the simplest, fastest, and most effective
across the range of applications described in this study. Reaction progression plots comparing the
reactivity of B(C6F5)3, BF3•Et2O and TMSOTf are provided in the supporting information.
Notably, the effectiveness of B(C6F5)3 in 10 mol % loadings was described in glycosylations of
free alcohols using trichloroacetimidate donors,56-57 but its use with glycosyl fluoride donors or
silyl ether acceptors has not been previously described. The very high catalytic activity of B(C6F5)3,
paired with its crystallinity, ease of handling, water tolerance, and tunable structure make this the
optimum catalyst choice for these studies. While the hydrate H2O•B(C6F5)3 may offer advantages
for long-term air and moisture stability, commercially available anhydrous B(C6F5)3 is the catalyst
of choice for most applications. Gradual exposure of B(C6F5)3 to moisture up to the level of
complete formation of the monohydrate reduces catalyst activity, but high yields and good
turnovers with satisfactory reaction rates can still be obtained even after complete formation of the
hydrate. Whereas B(C6F5)3 was routinely stored and weighed under nitrogen, no significant change
in rates or yields were noted when the anhydrous catalyst was handled and weighed in air.
While the mechanistic hypothesis for this work is outlined above, computational
experiments58 have been carried out to better understand the features of this catalytic system
(Scheme 4B).59-60 Using a mannose-a-fluoride donor, B(C6F5)3 rapidly abstracts fluoride via
transition state TS1 from intermediate 35 to provide the charged glycosyl donor 36 with
stabilization from the neighboring C2-acetate and ion pairing with the F-B(C6F5)3 anion. The
lowest energy pathway for glycosylation involves formation of adduct 37 followed by rate-
determining addition of the silyl ether to the charged intermediate to form 38 via transition state
TS2, and then the F-B(C6F5)3 anion rapidly delivers fluoride to produce the a-mannoside product
11
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 19
1
2
3
4
5
6
and the Me3Si-F byproduct while releasing the active B(C6F5)3 catalyst. These mechanistic features
elucidate the operative pathway of this procedure and are consistent with silyl group structure
controlling the site-selectivity in iterative couplings.
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
Conclusions:
In summary, a boron-catalyzed glycosylation method involving the coupling of glycosyl
fluorides and silyl ethers addresses a number of key challenges in the synthesis of glycosidic bonds.
The preparative ease of the method allows simple reaction setup using a commercially-available
catalyst, without requiring specialized equipment or expertise. Reactions are often completed in
minutes at room temperature across a range of glycosyl donor and acceptor classes. Through the
combination of inter- and intramolecular strategies, all possible C1-C2 stereochemical
relationships may be accessed by this method. Computational studies illustrate a fluoride migration
catalysis mechanism where the B(C6F5)3 catalyst abstracts fluoride from the glycosyl donor and
then delivers fluoride to silicon as the glycoside product and active catalyst are released. The
relative reactivity of hydroxyls on the acceptor substrate are governed by silane structure rather
than by the innate reactivity present in the substrates. This feature enables the regioselective,
iterative assembly of oligosaccharides in a simple, one-pot operation utilizing monosaccharide
precursors. The above features position this method as a powerful approach for addressing a
number of synthetic challenges in glycoscience.
Acknowledgments:
Prof. Pavel Nagorny, Prof. Nathaniel Szymczak, Prof. David Sherman (University of Michigan)
are thanked for helpful discussions and Dr. Andrew Robertson is thanked for assistance with HPLC
purifications. The authors thank the National Institutes of Health Common Fund Program in
Glycoscience (U01GM125274) for support for this work, and JLM acknowledges support from
the National Institutes of Health through the Michigan CBI Training program (T32GM008597).
The University of Michigan has submitted a provisional patent application based on this work.
Supporting information:
12
ACS Paragon Plus Environment

Page 13 of 19
Journal of the American Chemical Society
1
2
3
4
Methods and Materials, supplementary graphics, characterization data, and references.
5
6
7
8
9
References
1.
Bertozzi, C. R.; Kiessling, L. L., Chemical Glycobiology. Science 2001, 291, 2357-2364.
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
2.
Agre, P.; Bertozzi, C.; Bissell, M.; Campbell, K. P.; Cummings, R. D.; Desai, U. R.;
Estes, M.; Flotte, T.; Fogleman, G.; Gage, F.; Ginsburg, D.; Gordon, J. I.; Hart, G.; Hascall, V.;
Kiessling, L.; Kornfeld, S.; Lowe, J.; Magnani, J.; Mahal, L. K.; Medzhitov, R.; Roberts, R. J.;
Sackstein, R.; Sarkar, R.; Schnaar, R.; Schwartz, N.; Varki, A.; Walt, D.; Weissman, I., Training
the Next Generation of Biomedical Investigators in Glycosciences. J. Clin. Invest. 2016, 126,
405-408.
3.
Kiessling, L. L., Chemistry-Driven Glycoscience. Bioorg. Med. Chem. 2018, 26, 5229-
5238.
4.
Wen, L. Q.; Edmunds, G.; Gibbons, C.; Zhang, J. B.; Gadi, M. R.; Zhu, H. L.; Fang, J.
Q.; Liu, X. W.; Kong, Y.; Wang, P. G., Toward Automated Enzymatic Synthesis of
Oligosaccharides. Chem. Rev. 2018, 118, 8151-8187.
5.
Prudden, A. R.; Liu, L.; Capicciotti, C. J.; Wolfert, M. A.; Wang, S.; Gao, Z. W.; Meng,
L.; Moremen, K. W.; Boons, G. J., Synthesis of Asymmetrical Multiantennary Human Milk
Oligosaccharides. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 6954-6959.
6.
Am. Chem. Soc. 2019, 141, 3735-3754.
7. Chatterjee, S.; Moon, S.; Hentschel, F.; Gilmore, K.; Seeberger, P. H., An Empirical
Understanding of the Glycosylation Reaction. J. Am. Chem. Soc. 2018, 140, 11942-11953.
Krasnova, L.; Wong, C. H., Oligosaccharide Synthesis and Translational Innovation. J.
8.
9.
https://commonfund.nih.gov/Glycoscience.
Handbook of Chemical Glycosylation: Advances in Stereoselectivity and Therapeutic
Relevance. Demchenko, A. V., Ed. Wiley: Weinheim, 2008.
10. 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.
Schmidt, R. R., New Methods for the Synthesis of Glycosides and Oligosaccharides - Are
There Alternatives to the Koenigs-Knorr Method. Angew. Chem. Int. Ed. 1986, 25, 212-235.
13
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 14 of 19
1
2
3
4
12.
Goswami, M.; Ellern, A.; Pohl, N. L. B., Bismuth(V)-Mediated Thioglycoside
5
6
7
8
Activation. Angew. Chem. Int. Ed. 2013, 52, 8441-8445.
13. Fügedi, P.; Garegg, P. J.; Lönn, H.; Norberg, T., Thioglycosides as Glycosylating Agents
in Oligosaccharide Synthesis. Glycoconjugate Journal 1987, 4, 97-108.
14. Shimizu, M.; Togo, H.; Yokoyama, M., Chemistry of Glycosyl Fluorides. Synthesis 1998,
799-822.
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
15.
Nielsen, M. M.; Pedersen, C. M., Catalytic Glycosylations in Oligosaccharide Synthesis.
Chem. Rev. 2018, 118, 8285-8358.
16.
Kulkarni, S. S.; Wang, C. C.; Sabbavarapu, N. M.; Podilapu, A. R.; Liao, P. H.; Hung, S.
C., "One-Pot" Protection, Glycosylation, and Protection-Glycosylation Strategies of
Carbohydrates. Chem. Rev. 2018, 118, 8025-8104.
17.
Programmable One-Pot Oligosaccharide Synthesis. J. Am. Chem. Soc. 1999, 121, 734-753.
18. Raghavan, S.; Kahne, D., A One-Step Synthesis of the Ciclamycin Trisaccharide. J. Am.
Chem. Soc. 1993, 115, 1580-1581.
19. Ley, S. V.; Priepke, H. W. M., A Facile One-Pot Synthesis of a Trisaccharide Unit from
Zhang, Z. Y.; Ollmann, I. R.; Ye, X. S.; Wischnat, R.; Baasov, T.; Wong, C. H.,
the Common Polysaccharide Antigen of Group-B Streptococci Using Cyclohexane-1,2-Diacetal
(Cda) Protected Rhamnosides. Angew. Chem. Int. Ed. 1994, 33, 2292-2294.
20.
Oligosaccharides. Angew. Chem. Int. Ed. 2004, 43, 5221-5224.
21. Hoang, K. M.; Lees, N. R.; Herzon, S. B., Programmable Synthesis of 2-
Deoxyglycosides. J. Am. Chem. Soc. 2019, 141, 8098-8103.
22. Plante, O. J.; Palmacci, E. R.; Seeberger, P. H., Automated Solid-Phase Synthesis of
Oligosaccharides. Science 2001, 291, 1523-1527.
23. Seeberger, P. H., The Logic of Automated Glycan Assembly. Acc. Chem. Res. 2015, 48,
1450-1463.
Huang, X. F.; Huang, L. J.; Wang, H. S.; Ye, X. S., Iterative One-Pot Synthesis of
24.
Panza, M.; Pistorio, S. G.; Stine, K. J.; Demchenko, A. V., Automated Chemical
Oligosaccharide Synthesis: Novel Approach to Traditional Challenges. Chem. Rev. 2018, 118,
8105-8150.
25.
Tang, S.-L.; Pohl, N. L. B., Automated Fluorous-Assisted Solution-Phase Synthesis of Β-
1,2-, 1,3-, and 1,6-Mannan Oligomers. Carbohydr. Res. 2016, 430, 8-15.
14
ACS Paragon Plus Environment

Page 15 of 19
Journal of the American Chemical Society
1
2
3
4
26.
Wadzinski, T. J.; Steinauer, A.; Hie, L. N.; Pelletier, G.; Schepartz, A.; Miller, S. J.,
5
6
7
Rapid Phenolic O-Glycosylation of Small Molecules and Complex Unprotected Peptides in
Aqueous Solvent. Nat. Chem. 2018, 10, 644-652.
8
9
27.
Hashimoto, S.; Hayashi, M.; Noyori, R., Glycosylation Using Glucopyranosyl Fluorides
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
and Silicon-Based Catalysts - Solvent Dependency of the Stereoselection. Tetrahedron Lett.
1984, 25, 1379-1382.
28.
Kim, W. S.; Hosono, S.; Sasai, H.; Shibasaki, M., Rare-Earth Perchlorate Catalyzed
Glycosidation of Glycosyl Fluorides with Trimethylsilyl Ethers. Tetrahedron Lett. 1995, 36,
4443-4446.
29.
Assembly of Oligosaccharides. Tetrahedron Lett. 1998, 39, 2187-2190.
30. Nicolaou, K. C.; Chucholowski, A.; Dolle, R. E.; Randall, J. L., Reactions of Glycosyl
Zhu, T.; Boons, G. J., A Two Directional Glycosylation Strategy for the Convergent
Fluorides - Synthesis of O-Glycosides, S-Glycosides, and N-Glycosides. J. Chem. Soc.-Chem.
Commun. 1984, 1155-1156.
31.
Glycosyl Fluorides and Boron-Trifluoride Etherate. Helv. Chim. Acta 1985, 68, 283-287.
32. Piers, W. E.; Marwitz, A. J. V.; Mercier, L. G., Mechanistic Aspects of Bond Activation
with Perfluoroarylboranes. Inorg. Chem. 2011, 50, 12252-12262.
33. Stephan, D. W., The Broadening Reach of Frustrated Lewis Pair Chemistry. Science
2016, 354, 1248.
Kunz, H.; Sager, W., Stereoselective Glycosylation of Alcohols and Silyl Ethers Using
34.
Caputo, C. B.; Stephan, D. W., Activation of Alkyl C-F Bonds by B(C6F5)3:
Stoichiometric and Catalytic Transformations. Organometallics 2012, 31, 27-30.
35.
Ishihara, K.; Hanaki, N.; Funahashi, M.; Miyata, M.; Yamamoto, H.,
Tris(Pentafluorophenyl)Boron as an Efficient, Air-Stable, and Water Tolerant Lewis-Acid
Catalyst. Bull. Chem. Soc. Jpn 1995, 68, 1721-1730.
36.
Levin, M. D.; Chen, T. Q.; Neubig, M. E.; Hong, C. M.; Theulier, C. A.; Kobylianskii, I.
J.; Janabi, M.; O'Neil, J. P.; Toste, F. D., A Catalytic Fluoride-Rebound Mechanism for C(sp3)-
CF3 Bond Formation. Science 2017, 356, 1272-1275.
37.
Chitnis, S. S.; LaFortune, J. H. W.; Cummings, H.; Liu, L. L.; Andrews, R.; Stephan, D.
W., Phosphorus Coordination Chemistry in Catalysis: Air Stable P(III)-Dications as Lewis Acid
Catalysts for the Allylation of C–F Bonds. Organometallics 2018, 37, 4540-4544.
15
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 16 of 19
1
2
3
4
38.
Nielsen, M. M.; Qiao, Y.; Wang, Y. X.; Pedersen, C. M., Vessel Effect in C-F Bond
5
6
7
Activation Prompts Revised Mechanism and Reveals an Autocatalytic Glycosylation. Eur. J.
Org. Chem.
8
9
39.
Blackwell, J. M.; Foster, K. L.; Beck, V. H.; Piers, W. E., B(C6F5)3-Catalyzed Silation of
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
Alcohols: A Mild, General Method for Synthesis of Silyl Ethers. J. Org. Chem. 1999, 64, 4887-
4892.
40.
Temporary Silicon Connection Method. J. Am. Chem. Soc. 1996, 118, 247-248.
41. Walk, J. T.; Buchan, Z. A.; Montgomery, J., Sugar Silanes: Versatile Reagents for
Stork, G.; LaClair, J. J., Stereoselective Synthesis of Beta-Mannopyranosides Via the
Stereocontrolled Glycosylation Via Intramolecular Aglycone Delivery. Chem. Sci. 2015, 6,
3448-3453.
42.
Buchan, Z. A.; Bader, S. J.; Montgomery, J., Ketone Hydrosilylation with Sugar Silanes
Followed by Intramolecular Aglycone Delivery: An Orthogonal Glycosylation Strategy. Angew.
Chem. Int. Ed. 2009, 48, 4840-4844.
43.
Glycosidation. J. Chem. Soc. Chem. Commun. 1992, 913-914.
44. Partridge, K. M.; Bader, S. J.; Buchan, Z. A.; Taylor, C. E.; Montgomery, J., A
Bols, M., Stereocontrolled Synthesis of Alpha-Glucosides by Intramolecular
Streamlined Strategy for Aglycone Assembly and Glycosylation. Angew. Chem. Int. Ed. 2013,
52, 13647-13650.
45.
Glycosides from Thioglycosides. J. Am. Chem. Soc. 1998, 120, 435-436.
46. Nishi, N.; Sueoka, K.; Iijima, K.; Sawa, R.; Takahashi, D.; Toshima, K., Stereospecific
Crich, D.; Sun, S. X., Direct Formation of Beta-Mannopyranosides and Other Hindered
Βeta-L-Rhamnopyranosylation through an SNI-Type Mechanism by Using Organoboron
Reagents. Angew. Chem. Int. Ed. 2018, 57, 13858-13862.
47.
J. Am. Chem. Soc. 2008, 130, 6330-6331.
48. Crich, D.; Li, L., Stereocontrolled Synthesis of D- and L-Βeta-Rhamnopyranosides with
Lee, Y. J.; Ishiwata, A.; Ito, Y., Stereoselective Synthesis of Βeta-L-Rhamnopyranosides.
4-O-6-S-Α-Cyanobenzylidene-Protected 6-Thiorhamnopyranosyl Thioglycosides. J. Org. Chem.
2009, 74, 773-781.
49.
Crich, D.; Picione, J., Direct Synthesis of the Βeta-L-Rhamnopyranosides. Org. Lett.
2003, 5, 781-784.
16
ACS Paragon Plus Environment

Page 17 of 19
Journal of the American Chemical Society
1
2
3
4
50.
Park, Y.; Harper, K. C.; Kuhl, N.; Kwan, E. E.; Liu, R. Y.; Jacobsen, E. N., Macrocyclic
5
6
7
Bis-Thioureas Catalyze Stereospecific Glycosylation Reactions. Science 2017, 355, 162-166.
51. Levi, S. M.; Li, Q. H.; Rotheli, A. R.; Jacobsen, E. N., Catalytic Activation of Glycosyl
8
9
Phosphates for Stereoselective Coupling Reactions. Proc. Natl. Acad. Sci. U. S. A. 2019, 116, 35-
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
39.
52.
Zhuo, M. H.; Wilbur, D. J.; Kwan, E. E.; Bennett, C. S., Matching Glycosyl Donor
Reactivity to Sulfonate Leaving Group Ability Permits SN2 Glycosylations. J. Am. Chem. Soc.
2019, 141, 16743-16754.
53.
Yu, F.; Li, J. Y.; DeMent, P. M.; Tu, Y. J.; Schlegel, H. B.; Nguyen, H. M.,
Phenanthroline-Catalyzed Stereoretentive Glycosylations. Angew. Chem. Int. Ed. 2019, 58,
6957-6961.
54.
Anomeric Nucleophiles with Alcohols and Carboxylic Acids. Nat. Commun. 2018, 9, 3650.
55. Bergquist, C.; Bridgewater, B. M.; Harlan, C. J.; Norton, J. R.; Friesner, R. A.; Parkin,
Yang, T. Y.; Zhu, F.; Walczak, M. A., Stereoselective Oxidative Glycosylation of
G., Aqua, Alcohol, and Acetonitrile Adducts of Tris(Perfluorophenyl)Borane: Evaluation of
Bronsted Acidity and Ligand Lability with Experimental and Computational Methods. J. Am.
Chem. Soc. 2000, 122, 10581-10590.
56.
Karimov, R. R.; Tan, D. S.; Gin, D. Y., Rapid Assembly of the Doubly-Branched
Pentasaccharide Domain of the Immunoadjuvant Jujuboside a Via Convergent B(C6f5)3-
Catalyzed Glycosylation of Sterically-Hindered Precursors. Chem. Commun. 2017, 53, 5838-
5841.
57.
Mishra, K. B.; Singh, A. K.; Kandasamy, J., Tris(Pentafluorophenyl)Borane-Promoted
Stereoselective Glycosylation with Glycosyl Trichloroacetimidates under Mild Conditions. J.
Org. Chem. 2018, 83, 4204-4212.
58.
Method. J. Comput. Chem. 2015, 36, 601-611.
59. Hansen, T.; Lebedel, L.; Remmerswaal, W. A.; van der Vorm, S.; Wander, D. P. A.;
Zimmerman, P. M., Single-Ended Transition State Finding with the Growing String
Somers, M.; Overkleeft, H. S.; Filippov, D. V.; Desire, J.; Mingot, A.; Bleriot, Y.; van der Marel,
G. A.; Thibaudeau, S.; Codee, J. D. C., Defining the SN1 Side of Glycosylation Reactions:
Stereoselectivity of Glycopyranosyl Cations. ACS Cent. Sci. 2019, 5, 781-788.
17
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 18 of 19
1
2
3
4
60.
Adero, P. O.; Amarasekara, H.; Wen, P.; Bohe, L.; Crich, D., The Experimental Evidence
5
6
7
in Support of Glycosylation Mechanisms at the SN1-SN2 Interface. Chem. Rev. 2018, 118, 8242-
8284.
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
18
ACS Paragon Plus Environment

Page 19 of 19
Journal of the American Chemical Society
1
2
3
4
TOC Graphic
5
6
7
8
O
B(C6F5)3
O
O
or
OR1
RO
RO
RO
F
OR1
+ FSiR3
• stereoselective
R1OSiR3
9
• simple rt procedure
• water tolerant
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
• one-pot iterative couplings
• catalyst loadings down to 0.5 mol %
• silicon structure dictates regioselectivity
• computational insights
19
ACS Paragon Plus Environment