Phenanthroline-Catalyzed Stereoretentive Glycosylations

Article abstract of DOI:10.1002/anie.201901346

Carbohydrates are essential moieties of many bioactive molecules in nature. However, efforts to elucidate their modes of action are often impeded by limitations in synthetic access to well-defined oligosaccharides. Most of the current methods rely on the

Full text of DOI:10.1002/anie.201901346

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Phenanthroline-Catalyzed Stereoretentive Glycosylations
Authors: Hien M. Nguyen, Fei Yu, Jiayi Li, Paul M DeMent, Yi-Jung Tu,
and H. Bernhard Schlegel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901346
Angew. Chem. 10.1002/ange.201901346
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10.1002/anie.201901346
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Organocatalysis
Phenanthroline-Catalyzed Stereoretentive Glycosylations
Fei Yu, Jiayi Li, Paul M. DeMent, Yi-Jung Tu, H. Bernhard Schlegel, and Hien M. Nguyen*
afford α-1,2-cis glycoside. However, it was apparent from the outset
of our studies that the adaption of the pyridine system could present
challenges. As an axial pyridinium ion can also be generated, from
the reaction of an electrophile with pyridine, to compete for access to
β-1,2-trans glycoside,[7,8] pyridine-mediated reaction proceeds with
marginal bias for the α-selectivity. Herein, we report the discovery of
a commercially available phenanthroline to stereoselectively catalyze
formation of α-1,2-cis glycosides (Scheme 1C). Phenanthroline is a
rigid and planar structure with two fused pyridine rings whose
nitrogen atoms are positioned to act cooperatively. We postulated that
the first nitrogen atom serves as a catalytic nucleophile to react with
an electrophile to generate a covalent β-glycosyl phenanthrolium ion
preferentially as phenanthroline is more sterically demanding than
pyridine. The second nitrogen atom could non-covalently interact
with carbohydrate moiety or form a hydrogen bond with the alcohol
nucleophile to facilitate invertive substitution. These features should
effectively promote a double SN2 mechanism.
Abstract: Carbohydrates are essential moieties of many bioactive
molecules in nature. However, efforts to elucidate their modes of
action are often impeded by limitations in synthetic access to well-
defined oligosaccharides. Most of the current methods rely on the
design of specialized coupling partners to control selectivity during
formation of glycosidic bonds. Herein, we report a commercially
available phenanthroline to catalyze stereoretentive glycosylation
with glycosyl bromides. The method provides efficient access to α-
1,2-cis glycosides. This protocol has been performed for the large-
scale synthesis of an octasaccharide adjuvant. Density functional
theory calculations, together with kinetic studies, suggest that the
reaction proceeds via double SN2 mechanism.
Glycosylations are fundamental methods for constructing complex
carbohydrates. Key reactions involve glycosidic bond formation that
connects glycosyl electrophiles to glycosyl nucleophiles to generate
oligosaccharides, which play a critical role in cellular functions and
disease processes.[1] As a result, the efficient preparation of well-
defined oligosaccharides has been a major focus in carbohydrate
synthesis. Despite recent advances,[2] the ability to forge α-1,2-cis
glycosidic bonds in a stereoselective fashion is not easily predictable
(Scheme 1A), due to the reaction’s high degree of variables and
shifting SN1-SN2 mechanistic paradigm.[3] Most established methods
have focused on tuning the steric and electronic nature of the
protecting groups bound on electrophilic partners to achieve α-1,2-
cis selectivity.[4] Recently, catalyst-controlled methods have emerged
as a way to eliminate the need for the design of specific glycosyl
electrophiles.[5] Although catalytic glycosylations concentrate on the
use of catalysts to control the desired stereochemsitry, only limited
examples for forming α-1,2-cis glycosides are known.[5d]
In an effort to identify an effective strategy for a stereoselective
synthesis of α-1,2-cis glycosides that would obviate the necessity for
substrate prefunctionalization, we consider whether the anomeric
selectivity could be controlled by a simple catalyst. We recognized
that retaining glycosyltransferases are known to catalyze α-glycosidic
bond formation with the net retention of anomeric configuration
(Scheme 1B).[6] As such, we envisioned that a catalyst capable of
acting as a glycosyltransferase to provide 1,2-cis glycosides with
predictable α-selectivity and in high yields would likely find broad
applications. Pyridine has been reported by Lemieux and Morgan to
serve as a nucleophilic catalyst to displace the anomeric leaving group
of a glycosyl electrophile.[7] The glycosyl pyridinium ion formed in
the reaction prefers the equatorial position to avoid the steric and
electrostatic interactions associated with positioning that group in the
axial orientation.[7] Invertive substitution by a nucleophile would then
A.
General structures of 1,2-cis- and 1,2-trans-glycosidic bonds:
O
O
n
(HO)
n
(HO)
O-R
1
2
2
1
HO
HO
O-R
α
β
1,2-trans glycoside (
-glycoside)
1,2-cis glycoside (
-glycoside)
α
B.
Retaining glycosyltransferases-catalyzed
-glycosylation:
O
O
O
O
O
O
n
O
O
(HO)
O
n
(HO)
n
(HO)
α
O
P
O-R
H
O
O-R
O
P
-glycoside
OH
H
O-R
O
O
O
OR
OR
glycosyl-enzyme
O
P
O
M+2
M+2
OR
M+2
intermediate
α
C.
Phenanthroline-catalyzed
-1,2-cis glycosylation (this work):
R
R
R
Br
Phen =
O
N
N
n
(PO)
N
N
R-OH
SN2
BnO
O
n
(PO)
SN2
R
2
PO
1
β
Br
R
-glycosyl
phenanthrolinium
α
-glycosyl bromide
Br
O
O
N
n
(PO)
n
(PO)
1
2
PO
R-OH
PO
O-R
1,2-cis glycoside
N
Phen, HBr
R
Scheme 1. Introduction and synopsis of current work
To initiate our investigation, α-glycosyl bromide 1 was chosen as a
model electrophilic partner and galactopyranoside 2 as a nucleophile
to simplify the analysis of coupling product mixtures (Table 1).
Previous reports have documented the ability of glycosyl bromides to
function as the effective electrophiles under various conditions.[9] The
reaction of 2 with 1, having a C(2)-benzyl (Bn) group,[2] often
proceeds via an SN1-like pathway. As expected, use of Lewis acid,
silver triflate (AgOTf), provided a 4:1 (α:β) mixture of disaccharide
3. Upon exploring a wide range of reaction parameters (Figures S1 -
S6), we discovered that coupling of 2 with 1 in 15 mol% of 4,7-
[∗] Dr F. Yu, J. Li, P. M. DeMent, Dr. Y-J. Tu, Prof. H. B.
Schlegel, and Prof. H. M. Nguyen
Department of Chemistry
Wayne State University
Detroit, Michigan 48202 (USA)
Email: hmnguyen@wayne.edu
Supporting information and the ORCID identification
number(s) for the author(s) of this article can be found
under: http://doi.org/10.1002/anie.
1
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10.1002/anie.201901346
Angewandte Chemie International Edition
Table 2: Scope with respect to glycosyl electrophiles.[a]
diphenyl-1,10-phennathroline (4) as a catalyst and isobutylene oxide
(IBO) as a hydrogen bromide scavenger in tert-butyl methyl ether
(MTBE) at 50 oC for 24 h provides the highest yield and selectivity
of 3 (73%, α:β > 20:1). In the absence of catalyst 4, no reaction was
apparent after 24 h. We also conducted the reaction with catalysts 5 -
8, and three trends are observed. First, the yield of 3 is correlated with
the ability of the catalyst to displace the C(1)-bromide. The C(2)- and
C(9)-methyl groups of 5 reduce the accessibility of the pyridine
nitrogen for displacing the anomeric bromide. Second, the catalyst’s
conformation can influence the efficiency and selectivity. For
instance, 2,2’-bipyridine (6) is less α-selective than 4 potentially due
the two nitrogen atoms being disrupted by the free-rotation about the
bond linking the pyridine rings. Third, the selectivity is correlated
with the efficiency of the catalyst. As expected, pyridine (7) is not as
selective as catalyst 4. Since 4-(dimethylamino)pyridine (8) is a more
effective catalyst than 7,[10] disaccharide 3 was obtained in higher
yield. To explore if this catalytic system could be suitable for a large
scale synthesis, we examined the reaction on a 4 mmol scale of 1 and
4.4 mmol of 2. At high concentration (2 M), use of 5 mol% of catalyst
4 proved sufficient to provide 3 (70%, α:β >20:1) (Figure S7).
R-OH
O
4
catalyst
O
+
n
(RO)
n
(RO)
IBO (2 equiv)
MTBE (c = 0.5 M)
(2 equiv)
BnO
BnO
Br
O-R
D
-Glucose
AcO
AcO
Me
Me
BnO
BnO
BnO
BnO
O
AcO
O
O
BnO
BnO
BnO
O
BnO
O
O
BnO
O
Me
Me
O
O
BnO
BnO
O
O
O
O
BnO
11
only
OMe
O
10
9
O
α
Me
O
O
α
:
= 14:1
α
β
:
63%c
= 14:1
β
Me
63%e
Me
95%e
Me
AcO
AcO
BnO
AcO
AcO
AcO
O
OMe
O
Me
OMe
O
BnO
TrocHN
O
BnO
O
O
12
only
O
MeO
MeO
13
only
O
α
α
Me
50%c
73%c
Me
AcO
AcO
AcO
BnO
BnO
BnO
O
O
BnO
NHFmoc
Allyl
Table 1: Reaction development.[a]
BnO
O
BnO
O
O
14
15
CO2
BnO
AcO
AcO
AcO
α
α
:
:
= 7:1
= 20:1
β
β
BnO
O
OMe
55%c
79%c
OH
Me
Me
O
AcO
AcO
AcO
BnO
O
(15 mol%)
O
OBn
O
D
-Galactose
OAc
O
Catalyst
IBO (2 equiv)
+
BnO
BnO
BnO
Me
Me
O
O
O
BnO
OBn
O
O
Br
O
BnO
MTBE (c = 0.5 M)
AcO
OMe
O
2
1
50 o
Me
O
3
O
C,
24 h
BnO
O
BnO
BnO
Me
O
O
BnO
O
Me
Me
Me
O
Me
O
Me
BnO
BnO
O
O
O
BnO
OMe
O
O
Ph
Ph
AgOTf
18
only
17
16
α:β
= 4:1
55%
α
only
O
Me
α
α
O
:
= 10:1
β
Me
85%b
58%f
Me
77%e
N
N
N
N
Me
1
0% of recovered
Me
Me
L-Arabinose
4
5
L-Fucose
α:β
> 20:1
73%
α:β
= 17:1
12%
RO
No Catalyst
OAc
O
<1%
O
O
OMe
RO
1
20% of recovered
1
75% of recovered
1
>99% of recovered
AcO
O
OAllyl
Me
O
BnO
BnO
O
NHCbz
OBn
O
Me
RO
O
O
O
BnO
BnO
O
Me2N
N
OR
Me
BnO
N
N
N
Me
OMe
only)e
23
only
= 6:1)e
= 20:1)b
α
α
α
:
7
α
6
8
19: R = Bn, 80% (
20: R = Ac, 88% (
21:
22:
R = Bn, 47% (
R = Ac, 84% (
β
β
α:β
α:β
α:β
= 13:1
= 18:1
= 14:1
73%b
b
:
α
only)
25%
40%
51%
0% of recovered
0% of recovered
D-Arabinose
1
1
1
54% of recovered
OMe
BnO
_____________________________________________
OMe
MeO
BnO
BnO
O
MeO
O
[a] The reaction was conducted with 0.2 mmol of 1 and 0.4 mmol of
2. Isolated yields averaged three runs. The (α/β) ratios were
determined by 1H NMR analysis.
Me
O
O
O
O
MeO
O
O
OMe
O
O
O
OBn
OBn
OBn
Me
OR
OAc
AcO
Me
OAc
RO
AcO
27
only
26
only
There are several underlying factors that potentially influence the
efficiency and the selectivity of the coupling products, including the
protecting group nature of glycosyl electrophiles,[2-4] the reactivity of
nucleophiles, and the reaction conditions. As a result, a number of α-
1-bromo electrophiles were investigated (Table 2). To validate that
catalyst 4 could overturn the “remote” participation of the C(3)-,
C(4)-, and C(6)-acyl protecting groups, we first explored the coupling
with glucosyl bromides having non-participatory benzyl protecting
groups. No significant compromise to the α-selectivity was observed
with disaccharides 9 and 10 with use of tetrabenzyl glucosyl bromide.
This protocol is more α-selective than other approaches. For example,
while our system provided 10 with α:β = 14:1, TMSOTf-mediated
coupling with imidate electrophiles provided 10 with marginal α-
selectivity (α:β = 1:1.2 - 4:1).[11] In addition, these glucosyl bromides
effectively coupled secondary alcohols to afford 11-13 with high α-
selectivity. For the challenging C(4)-hydroxy, the SN1-SN2 reaction
paradigm was slightly shifted (14: α:β = 7:1). A protected serine
nucleophile also exhibited high α-selectivity (15: α:β = 20:1).
= 9:1)e
α
:
α
α
24:
25: R = Ac, 83% (
R = Bn, 49% (
β
82%c
71%c
b
α
only)
2-Azido-D
Trisaccharide
-Galactose 2-Fluoro-
-Glucose
D
RO
OBn
BnO
O
RO
RO
BnO
OAc
AcO
O
O
O
F
BnO
O
O
BnO
O
BnO
AcO
N3
Me
OMe
NHCbz
OAllyl
O
31
only
Me
AcO
O
O
Me
O
28
OBn
α
O
only
OAc
86%c
α
O
O
O
50%d
Me
> 20:1)c
= 16:1)f
α
:
Me
29: R = Ac, 61% (
30: R = Bn, 83% (
β
β
α
:
[a] All reactions were conducted on a 0.15 - 0.3 mmol of glycosyl
bromides. Isolated yields of products averaged 2-3 runs. The (α/β)
ratios were determined by 1H NMR analysis. [b] 15 mol% 4, 24 h, 50
oC. [c] 30 mol% 4, 24 - 48 h, 50 oC. [d] 50 mol% 4, 50 oC, 48 h. [e]
20 mol% 4, 25 oC, 24 - 48 h. [f] 20 mol% 4, 50 oC, 24 h.
2
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10.1002/anie.201901346
Angewandte Chemie International Edition
Next, we investigated the ability of catalyst 4 to overturn the
inherent bias of D-galactose whose axial C(4)-benzyl group has been
reported to favor β-product formation.[12] Under our catalytic system,
galactosyl bromides served as effective electrophiles to deliver 16-18
(Table 2) with high α-selectivity. In contrast, the amide-promoted
reaction provided 16 with α:β = 3:1.[13] We discovered that while
tribenzyl L-fucosyl bromide afforded 19 with α:β = 6:1, use of
triacetyl L-fucose provided exclusively α-20. Both 19 and 20 are key
units of a thrombospondin type 1 associated an autosomal recessive
disorder.[14] Use of tribenzyl L-arabinosyl bromide also provided
exclusively α-21, albeit with 47% yield due to decomposition during
the course of the reaction. The yield could be improved with use of
the acetyl protecting groups (22: 84%). The diacetyl L-arabinose was
compatible with C(4)-hydroxy to afford α-23.[15] A similar trend was
observed with D-arabinose (24 - 27). For comparison, this protocol to
produce 24 (α:β = 9:1) is more α-selective than the thioglycoside
method with use of NIS/AgOTf as the activating agent (α:β = 3:1).[15]
We also sought to explore the selectivity trends with electrophiles
bearing C(2)-azido and C(2)-fluoro groups (Table 2). Use of C(2)-
azido galactose substrate provided exclusively α-28, a tumor-
associated mucin TN antigen precursor.[16] To compare, 28 had been
previously prepared as a 4:1 (α:β) mixture with use of AgClO4 as the
activating reagent.[17] Next, we turned our attention to 2-fluoro-D-
glucose substrate. The ability of C(2)-F bond to have an impact on
the stereochemistry of the product has been reported.[18] While the 2-
fluoro-glucose having benzyl protecting groups is highly β-selective
under TMSOTf-mediated reactions, the analogous acetyl electrophile
affords a 1:1 (α:β) mixture. In contrast, both substrates are α-
selective under phenanthroline conditions (29, α:β > 20:1; 30, α:β =
16:1). This catalyst system is also amendable to the synthesis of a
protected human milk α-trisaccharide 31 (86%).[19]
the potential vaccine adjuvants. These α-glucans are heterogeneous
in size and composition. As such, well-defined oligosaccharides are
required to study bioactive fragments. In our approach, a catalyst
loading of 5 mol% proved efficient to promote the coupling of
commercially available 33 with glycosyl bromide 32 to provide 8.4 g
of product 34 in 89% yield with α:β >20:1. Disaccharide 34 was then
converted into glycosyl bromide 36,21 which was used in the coupling
to 35 to afford tetrasaccharide 37 (86%, α:β >20:1). Another coupling
iteration afforded octasaccharide 40 (77%, α:β >20:1).
Having obtained 1,2-cis product in high yield and α-selectivity, we
sought to investigate the mechanism of this catalytic glycosylation.
We first attempted to detect a transient β-covalent phenanthrolinium
ion using mass spectrometry. In the event, α-bromide 1 was treated
with stoichiometric amount of 4 in MTBE (0.5 M) for 24 h at 50 oC.
Formation of phenanthrolinium ion 41 (Figure 1A) was confirmed
using electrospray ionization (ESI) with an m/z ratio of 711.2710.[22]
We next evaluated if the stereochemistry of the α-1,2-cis product
would be dictated by the anomeric configuration of glycosyl bromide
(Figure 1B).[23] We observed that β-bromide 42[24] only slowly
anomerized to α-bromide 1 without catalyst 4 (Figure S10). However,
β-bromide 42 rapidly converted into α-bromide 1 in the presence of
15 mol% of 4 within 1 h at 25 oC (Figure 1B).[25] We also performed
the reaction of β-anomer 42 with nucleophile 2 in the presence of 4,
and we observed that isomerization of β-42 to α-1 is faster than
formation of product 3.[26,27] Collectively, these results suggest that β-
bromide 42 is not the reacting partner in the phenanthroline system.
o
Next, the kinetic studies were conducted at 50 C, using C6D6 as
the NMR solvent and toluene as a quantitative internal standard, with
α-bromide 1 and 2-propanol as coupling partners in the presence of
IBO and catalyst 4. The rates of reaction were plotted as functions of
the concentrations of catalyst 4 (Figure 1C-1) and 2-propanol (Figure
1C-2). Overall, the kinetic data suggested that the reaction proceeds
via double SN2-like mechanism (Figures 1C and S11-S15), as the rate
of the reaction is both catalyst and nucleophile dependent. The
biphasic kinetic in Figure 1C-2 suggests a shift in the rate-
determining step (RDS) at different concentrations of 2-propanol. At
high concentration of 2-propanol, the RDS is formation of the
phenanthrolinium ion (first step in Scheme 1C), which is further
supported by the linear dependence of rate on catalyst concentration
(Figure 1C-1). At low concentration of 2-propanol, nucleophilic
attack (second step in Scheme 1C) is the RDS.
Finally, to understand the role of the phenanthroline catalyst in
controlling α-1,2-cis glycosylation, the transition structures and
intermediates for nucleophilic addition of phenanthroline or pyridine
to α-bromide 43 have been optimized utilizing density functional
theory (DFT) calculations at the B3LYP/6-31+G(d,p) level with the
SMD implicit solvent model (Figures 1D and S16). Non-covalent
interaction (NCI) analysis[28] (Figure S18) indicates that the β-
phenanthrolinium ion is stabilized by interactions between the C-1
axial hydrogen of glycosyl moiety and the nitrogen of phenanthroline
(the H1–N2 distance is 1.964 Å and the C1–H1---N2 angle is 137°).[29]
NCI analysis, however, does not show corresponding interactions for
the β-pyridinium ion. DFT calculations find that β-phenanthrolinium
R1
O
AcO
BnO
BnO
32
O
O
BnO
BnO
a
a
BnO
BnO
O
Br
O
BnO
BnO
+
HO
BnO
BnO
33
R2
BnO
O
= Ac, R2 = OMe
= H, R2 = OMe
= Ac, R2 = Br
: R1
: R1
: R1
34
b
BnO
c
OMe
35
36
AcO
BnO
BnO
R1
O
O
O
BnO
BnO
BnO
BnO
O
O
O
a
O
BnO
BnO
BnO
BnO
BnO
O
BnO
O
O
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
O
3
40
O
O
= Ac, R2 = OMe
= H, R2 = OMe
= Ac, R2 = Br
: R1
: R1
: R1
37
O
BnO
BnO
BnO
b
c
38
39
R2
BnO
BnO
OMe
__________________________________________________________________
Scheme 2. Synthesis of octasaccharide 40. [a] 5 - 15 mol% of 4, IBO
(2 equiv.), MTBE (2 M), 50 oC, 24 h, 34: 89%, α:β > 20:1; 37: 86%,
α:β > 20:1; 40: 77%, α:β > 20:1. [b] NaOMe, MeOH, CH2Cl2, 25 oC,
ion is more stable than the α-complex (∆Gβ α = +6.7 kcal/mol, Figure

S19), thereby shielding the β-face and favoring SN2 attack on the α-
face to yield α-1,2-cis glycoside.
o
35: 99%, 38: 70%. [c] PTSA, Ac2O, 70 C, 2 h (glycosyl acetates:
In conclusion, the phenanthroline-catalyzed glycosylation strategy
provides a general platform for α-selective formation of 1,2-cis
glycosides under mild and operationally simple conditions. This
system is not confined to the predetermined nature of the coupling
partners and mimics the glycosyltransferase-catalyzed mechanism.
Our computational and experimental studies indicate a double SN2
pathway involving phenanthroline-catalyzed glycosylation with α-
36S: 61%, 39S: 51%, see SI); then HBr/AcOH, CH2Cl2, 0 oC, 15 min,
and 36 and 39 were used in the next step without further purification.
The critical question remains whether the phenanthronline system
could be applicable for construction of larger oligosaccharides. To
illustrate this potential, we examined the synthesis of octasaccharide
40 (Figure 1), a backbone of the natural α-glucan polysaccharides,[20]
3
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10.1002/anie.201901346
Angewandte Chemie International Edition
glycosyl bromide. Efforts to utilize this method to enable other
glycosidic bonds are underway.
[1] (a) K. Ohtsubo, J. D. Marth, Cell. 2016, 126, 855-867; (b) Y. van Kooyk,
G. Rabinovich, Nat. Immunol. 2008, 9, 593-601.
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[4] (a) J.-H. Kim, H. Yang, G.-J. Boons, Angew. Chem. Int. 2005, 44, 947-
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Chem. Int. Ed. 2014, 53, 10453-10456.
. Identification of
A
β
-phenanthrolium ion using mass spectrometry
AcO
AcO
AcO
Ph
4
O
(3 equiv.)
2
, IBO
N
MTBE (c = 0.5 M)
50 o
-
α
3
BnO
50 o
1
C, 1 h
> 20:1)
C, 24 h
N
α
:
Br
50% (
β
41
m/z = 711.2710
C
Ph
43H39N2O8
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. Effect of glycosyl bromide configuration
B
4
2
(15 mol%)
(1.3 equiv)
(15 mol%)
AcO
4
O
+
1
3
AcO
1
Br CDCl
CDCl
oC,
oC,
AcO
3, 25
1 h
3, 25
2 h
88%
<1%
BnO
42
= 1:5)
α
:
β
(
Kinetics of the reaction of 2-propanol with
in C
at 50 o
α
C.
1
6D6
(0.5 M)
-bromide
C
(0.5 M)
1
1
C-1:
2-propanol (0.25 - 3.5 M)
IBO (1 M)
2-propanol (1.5 M)
IBO (1 M)
C-2:
4
(15 mol%)
4
(0 - 20 mol %)
0.003
0.003
0.002
0.001
0.000
0.002
0.001
0.000
R2 = 0.9468
R2 = 0.9969
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0.00
0.05
0.10
0.15
0
1
2
3
4
[2-propanol] (M)
[Catalyst 4] (M)
. DFT calculations of anomeric phenanthrolinium and pyridinium ions
D
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12474-12485.
Br
N1
O
N
N
C1
MeO
137o
O
N2
H1
MeO
Br
non-covalent interaction
1.964 Å
43
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Br
N
O
O
N
C
MeO
MeO
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H
43
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Figure 1. Mechanistic studies.
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Acknowledgements
We are grateful for financial support from the National Institutes
of Health (U01 GM120293). We thank Profs. David Crich (Wayne
State) and Daniel Quinn (Iowa) for suggestions with kinetic studies
as well as the Lumigen Center for instrumental assistance.
[25] β-42 rapidly converted into α-1 in the presence of catalyst 4 within 15
min at 50 oC.
[26] Coupling of 2 with β-bromide 42 under standard conditions provided 3
in comparable yield and α-selectivity to that obtained with α-bromide 1.
[27] The α:β ratio of product 3 is kinetically-derived and is not reflective of a
thermodynamic distribution arising from post-coupling isomerization (Figure
S9).
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Cohen, W. Yang, J. Am. Chem. Soc. 2010, 132, 6498-6506.
[29] The optimized geometry of the transition state shows that because of the
back-side displacement nature of the SN2 transition state, the distance is too
large for any stabilizing interaction between the hydrogen of the alcohol and
the nitrogen of phenanthroline (Figure S17).
Conflict of interest
The authors declare no conflict of interest.
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Keywords: organocatalysis ·glycosylation · stereoselectivity ·
oligosaccharides · mechanism
4
This article is protected by copyright. All rights reserved.

10.1002/anie.201901346
Angewandte Chemie International Edition
Entry for the Table of Contents
Organocatalysis
Catalytic Glycosylations: The
commercially available phenanthroline
serves as the efficient catalyst to
F. Yu, J. Li, P. M. DeMent, Y.-J. Tu, H.
B. Schlegel, H. M. Nguyen*
__________ Page – Page
promote the stereoselective formation of
α-1,2-cis glycosides synthesis. This
newly developed catalyst system is not
confined to the nature of the protecting
groups bound on carbohydrate coupling
partners to effect the selectivity.
Phenanthroline-Catalyzed
Stereoretentive Glycosylations
IBO (2 equiv.)
AcO
AcO
BnO
BnO
O
O
BnO
BnO
MTBE (c = 2 M)
50 o
C, 24 h
BnO
BnO
O
Br
+
O
BnO
BnO
Ph
Ph
HO
BnO
BnO
BnO
OMe
O
N
N
BnO
OMe
(5 mol%)
8.4 g
> 20:1)
α
:
89% (
β
5
This article is protected by copyright. All rights reserved.