Diastereoselective sp3C-O Bond Formation via Visible Light-Induced, Copper-Catalyzed Cross-Couplings of Glycosyl Bromides with Aliphatic Alcohols

Article abstract of DOI:10.1021/acscatal.0c01470

Copper-catalyzed cross-coupling reactions have become one of the most powerful methods for generating carbon-heteroatom bonds, an important framework of many organic molecules. However, copper-catalyzed C(sp3)-O cross-coupling of alkyl halides with alkyl

Full text of DOI:10.1021/acscatal.0c01470

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Article
Diastereoselective sp3 C-O Bond Formation via Visible
Light-Induced, Copper-Catalyzed Cross Couplings
of Glycosyl Bromides with Aliphatic Alcohols
Fei Yu, Jalen L. Dickson, Ravi S. Loka, Hengfu Xu, Richard N.
Schaugaard, H. Bernhard Schlegel, Long Luo, and Hien M. Nguyen
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 29 Apr 2020
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ACS Catalysis
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Diastereoselective sp3 C-O Bond Formation via Visible
Light-Induced, Copper-Catalyzed Cross Couplings of
Glycosyl Bromides with Aliphatic Alcohols
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†
†
†
Fei Yu, Jalen L. Dickson, Ravi S. Loka, Hengfu Xu, Richard N. Schaugaard, H. Bernhard
Schlegel, Long Luo,* and Hien M. Nguyen*
* Correspondence to: hmnguyen@wayne.edu and long.luo@wayne.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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KEYWORDS
Copper Catalysis, Visible Light, C(sp3)-O Bond, Cross Coupling, Stereoselective
ABSTRACT
Copper-catalyzed cross coupling reactions have become one of the most powerful
methods for generating carbon-heteroatom bonds, an important framework of many organic
molecules. However, copper-catalyzed C(sp3)-O cross coupling of alkyl halides with alkyl
alcohols remains elusive because of the sluggish nature of oxidative addition to copper. To
address this challenge, we have developed a catalytic copper system, which overcomes the
copper oxidative addition barrier with the aid of visible light and effectively facilitates the cross
couplings of glycosyl bromides with aliphatic alcohols to afford C(sp3)-O bonds with high levels
of diastereoselectivity. Importantly, this catalytic system leads to a mild and efficient method for
stereoselective construction of -1,2-cis glycosides, which are of paramount importance, but
challenging. In general, stereochemical outcomes in -1,2-cis glycosidic C-O bond-forming
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processes are unpredictable and dependent on the steric and electronic nature of protecting
groups bound on carbohydrate coupling partners. Currently, the most reliable approaches rely
on the use of chiral auxiliary or hydrogen-bond directing group at C2- and C4-position of
carbohydrate electrophiles to control -1,2-cis selectivity. In our approach, earth-abundant
copper not only acts as a photocatalyst and a bond-forming catalyst, but also enforces
stereocontrolled formation of anomeric C-O bonds. This cross-coupling protocol enables highly
diastereoselective access to a wide variety of -1,2-cis-glycosides and biologically relevant -
glycan oligosaccharides. Our work provides a foundation for developing new methods for the
stereoselective construction of natural and unnatural anomeric carbon(sp3)-heteroatom bonds.
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INTRODUCTION
Copper has been considered a privileged metal because it is non-toxic and abundant. In addition,
high-valent Cu(III) complexes have the propensity to undergo facile reductive elimination with a variety
of coupling partners.1 As a result, copper-catalyzed cross coupling reactions have become one of
the most versatile carbon-heteroatom bond-forming methodologies2 for constructing
pharmaceutical targets, agrochemicals, and polymers.3 For instance, Buchwald and others illustrated
the utility of copper catalysis in the cross couplings of aryl halides with alkyl alcohols (Scheme
1A) as a powerful method for C(sp2)-O bond formation.4 However, the incorporation of alkyl halides
to generate C(sp3)-O bonds remains elusive. The limited capacity of copper to promote C(sp3)-O bond
formation could be attributed to its relatively slow rate of oxidative addition to alkyl halide to generate
the alkylcopper(III) intermediate, which has been determined to be the rate-determining step in such
catalytic cycles.5 Although studies in ligand design have improved the rates of the copper oxidative
addition, the scope of copper-catalyzed carbon-oxygen cross coupling has remained largely restricted to
aryl halides.6
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ACS Catalysis
4
A
. Previous work: copper-catalyzed coupling of aryl halides with aliphatic alcohols
Catalytic
1
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4
X
O
R2
LnCuX
OH
R1
+
R
R
R1
80 - 130 °C
12 - 30 h
R1
5
X = Br, I
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9
B
. This work: visible-light mediated copper-catalyzed coupling of anomeric alkyl
bromides with aliphatic alcohols
Catalytic
LnCuI
OH
R1
O
O
(RO)n
+
(RO)n
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R2
R1
1
2
R1
25 °C, 24 - 48 h
Blue LED
X
X
Br
O
-1,2-cis glycoside
Scheme 1. Copper-Catalyzed C-O Bond Formation
Recently, Fu and coworkers reported the photoinduced copper-catalyzed cross couplings
of alkyl halides with nitrogen nucleophiles to form C(sp3)-N bonds.7 Their method effectively
overcomes the copper oxidative addition problem with a copper(II) species capturing alkyl
radicals, which are generated from carbon-halide bond cleavage in the presence of light and
copper. Realizing that this concept could be adapted to afford C(sp3)-O bonds, we sought to design a
copper-catalyzed cross coupling of a glycosyl bromide with an aliphatic alcohol under excitation by a
blue light-emitting diode (LED) (Scheme 1B). We recognized that this light-driven copper catalysis
process could lead to a mild and efficient method for diastereoselective construction of -1,2-cis
glycosides via a glycosyl radical which tends to favor -substitution.8 Despite extraordinary efforts
and significant advances over the past several decades, the translation of most modern organic
methodologies to diastereoselectively construct anomeric -1,2-cis carbon-oxygen bonds
remains challenging.9 Most current coupling methods rely on the nature of the protecting groups
bound to the carbohydrate substrates to effect stereoselectivity.10 However, there are only a few
catalyst and reagent controlled approaches reported for the construction of challenging -1,2-
cis glycosides without relying on protecting groups to direct selectivity at the newly-formed
glycosidic bond.11
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In the field of photoredox catalysis, utilization of glycosyl halides in cross coupling
reactions with aliphatic alcohols to form C(sp3)-O bonds has never been achieved.12 Therefore,
it was apparent at the outset of our investigations that the adaptation of the visible-light mediated
copper catalysis system to anomeric C-O bond formation would present several obstacles. First,
although it has been reported that copper-nucleophile complexes can undergo excitation in the
photoinduced process,13 it was unclear if a complex formed between a copper catalyst and
carbohydrate alkyl alcohol would have the necessary absorption and reactivity profile to engage
in a copper-catalyzed C-O bond formation. Another issue is whether the coupling proceeds via
a radical mechanism,13 wherein the anomeric carbon-halide bond is cleaved in the presence of
copper and light to form glycosyl radical. Finally, questions still remain concerning how this
approach could provide catalyst control of the selectivity for -1,2-cis C-O bond formation. As a
consequence, the development of methods that simultaneously construct anomeric C(sp3)-O
bonds and control -1,2-cis stereochemistry is of paramount importance, although challenging.
Here, we describe a distinct approach for stereocontrolled formation of -1,2-cis glycosides,
through the action of a visible-light-mediated copper catalyst. Many of the synthetic limitations
for the synthesis of these anomeric C-O linkages are overcome by this method.
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RESULTS AND DISCUSSION
In our pursuit of photoinduced copper-catalyzed anomeric C(sp3)-O bond formation, we
initially evaluated various combinations of ligands, copper sources, acid scavenger, solvents,
and reaction time (Figure S1-S6. This search revealed that blue LED irradiation of -1-bromo-
D-glucoside 1 (0.2 mmol, 1 equiv)14 and primary alcohol 2 (0.3 mmol, 1.5 equiv) as model
substrates with CuI (10 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos,
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ACS Catalysis
25 mol %), 4,7-diphenyl-1,10-phennathroline (BPhen 25 mol %), and acid scavenger di-tert-
butylmethyl pyridine (DTBMP) in acetonitrile at 25 oC for 24 h afforded the coupling product 3 in
good yield with excellent levels of diastereoselectivity (70%, : = 13:1, Table 1, entry 1).15,16
Control experiments established that copper, both ligands (XantPhos and BPhen), acid
scavenger (DTBMP), and blue LED irradiation are essential to achieve anomeric C(sp3)-O bond
formation (entries 2-10). Interestingly, the coupling proceeded in a simple 10 mol% CuI solution
to provide 3 in only 9% yield as a 9:1 mixture of  and -diastereomers (entry 11), suggesting
that CuI acts as a Lewis acid. Employing stoichiometric amount of CuI only provided 31% of the
desired product 3 with a similar selectivity (entry 12).
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Table 1. Effect of Reaction Parametersa
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AcO
AcO
AcO
O
1
2
3
4
5
6
7
OH
O
CuI(10 mol %)
BPhen (25 mol %)
XantPhos (25 mol %)
Me
Me
BnO
O
O
AcO
AcO
AcO
O
O
Me
Me
+
O
DTBMP (1.5 equiv)
CH3CN, 24 h, 25 °C
Blue LED
"standard" conditions
BnO
O
Br
O
O
O
Me
1
2
O
O
3
Me
Me
8
9
Me
____________________________________________________________________
entry
yieldb
:
ratioc
variation from the "standard" condtions
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(%)
____________________________________________________________________
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2
none
70
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13:1
10:1
no light
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no BPhen
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46
13:1
13:1
no XantPhos
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no DTBMP
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<1
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<1
<1
13:1
n/a
no CuI
no BPhen and no DTBMP
no CuI and no DTBMP
no CuI and no XantPhos
10:1
n/a
n/a
10
11
no CuI and no BPhen
<1
9
n/a
9:1
10 mol % CuI, 1.5 equiv of DTBMP only
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100 mol % CuI, 1.5 equiv of DTBMP only
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5
9:1
9:1
10:1
4:1
10 mol % Cu(XantPhos)(BPhen)BF4, DTBMP, blue LED
25 mol % BPhen and 1.5 equiv of DTBMP only
100 mol% AgOTf, 1.5 equiv of DTBMP only
55
Me Me
Me
Ph
Ph
O
N
N
t-Bu
N
t-Bu
PPh2
PPh2
BPhen
XantPhos
DTBMP
____________________________________________________________________
a The reaction was conduct with 1 (0.2 mmol, 1 equiv) and 2
(0.3 mmol, 1.5 equiv). b Isolated yield. c Diastereoselective (:)
ratio of the isolated product determined by 1H NMR.
31P NMR was conducted on the in situ generated complex to probe the active catalyst in the
reaction. The chemical shift was determined to be  = -11.99 ppm, generated from the combination of
CuI, BPhen, and Xantphos, and this chemical shift matched with that of the isolated complex,
[Cu(BPhen)(Xantphos)]BF4, ( = -11.87 ppm). As such, we conducted the cross coupling of 1 with 2 in
the presence of [Cu(BPhen)(Xantphos)]BF4 (Table 1, entry 13), and the 1,2-cis product 3 was obtained in
similar yield and -selectivity (60%, : = 9:1) to that promoted by in situ generated copper catalyst from
the combination of CuI, BPhen, and Xantphos. This result suggests that the [Cu(BPhen)(Xantphos)]+
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ACS Catalysis
complex is likely to be active in catalysis. We recently reported the use of BPhen as the
organocatalyst to promote the coupling of glycosyl bromide 1 with carbohydrate alcohol 2 at 50
oC.17 To validate that the cross coupling is promoted by the copper complex, we conducted the
reaction of 1 with 2 in the presence of 25 mol % BPhen (Table 1, entry 14) and the desired
disaccharide 3 was isolated in less than 5% yield. For comparison, we also conducted the
coupling reaction using traditional Lewis acid, silver triflate (entry 15), wherein an oxocarbenium
ion is likely to be the key intermediate in the reaction. An alcohol is then approached on either
- or -face of the oxocarbenium intermediate to provide a mixture of -1,2-cis- and -1,2-trans
products. As expected, the use of stoichiometric amount of silver triflate provided the coupling
product 3 as a 4:1 mixture of - and -diastereomers (entry 15).
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Having established the ability of the photoinduced copper catalyst to promote the
formation of anomeric C(sp3)-O bond with high levels of selectivity, we studied the current
system in comparison to our previously developed phenanthroline-catalyzed stereoretentive
glycosylation method (Table 2).17 There are two major limitations associated with the
o
phenanthroline-catalyzed method. First, the reaction must be conducted at 50 C to achieve
high conversion. Second, the diastereoselectivity of the coupling products decreases when
sterically hindered alcohols are coupled to the electron-rich glycosyl bromides. Our
computational and experimental studies indicate a double SN2 pathway involving
phenanthroline-catalyzed reaction with -glycosyl bromide wherein a covalent -glycosyl
phenanthrolium ion is the key intermediate, and the SN1-SN2 reaction paradigm was slightly
shifted in the presence of the hindered alcohols. Since the visible light-mediated copper catalysis
is unlikely to proceed through the traditional SN2-SN1 pathway and the stereochemical outcome
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of the coupling product is likely to be controlled by the [Cu(BPhen)(Xantphos)]+ complex, we
1
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hypothesize that this catalytic copper system could overcome the limitations previously associated with
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the phenanthroline system. To validate our hypothesis, the coupling of -glycosyl bromide 4 with
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the C4-hydroxy of L-rhamnoside 5 was conducted to afford the desired product 6 (Table 2, entry
1) in good yield and excellent levels of diastereoselectivity (74%, : >20:1). In contrast, our
previous phenanthroline-catalyzed method provided 6 in 42% yield with : = 7:1. Similar
outcome was observed with the coupling of -fucosyl bromide 7 with the secondary alcohol 5
(entry 2). To our excitement, the photoinduced copper system is also applicable with the
challenging glucuronic acid electrophile 9 to provide the coupling product 10 in 53% yield with
: >20:1 (entry 3). To compare, the phenanthroline-catalyzed method provided 10 in 11% yield
with moderate selectivity (: = 5:1). To further demonstrate the broad applicability of the visible
light-mediated copper method, we investigated the coupling of -glycosyl bromides 4 and 13
with the hindered C4-hydroxy of glucoside 11 (entries 4 and 5). As expected, the photoinduced
copper catalysis (12 and 14, : >20:1) is more -selective than the phenanthroline catalysis
(12, : = 7:1 and 14, : = 5:1). We previously observed that -1-bromo L-arabinoside 15
(entry 6) decomposed during the course of the reaction under phenanthroline-catalyzed
conditions (17, 47%).17 We questioned whether this electrophile 15 could be a suitable substrate
under photoinduced copper-catalyzed conditions. To our excitement, the coupling of 15 with
primary alcohol 16 proceeded smoothly to provide disaccharide 17 in much higher yield (79%,
entry 6). Overall, the results in Table 2 highlights that the visible-light-mediated copper system
is efficient and highly selective for the cross couplings of the electron-rich -glycosyl bromides
with the hindered alcohols of carbohydrates. More importantly, this copper method is conducted
at room temperature and effective for constructing anomeric C(sp3)-O bond with reduced levels
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ACS Catalysis
of waste through the use of sub-stoichiometric amounts of metal and a high reaction
concentration (0.5 M).
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Table 2. Comparative Studies Between Photoinduced Copper Catalysis and Organocatalysis
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ACS Catalysis
O
(RO)n
O
O
Condition A
1
2
3
4
5
6
7
2
HO
(RO)n
+
O
2
BnO
O
or
BnO
OMe
Br
Condition B
OMe
Conditions A
Conditions B
: CuI(10 mol %), BPhen (25 mol %), XantPhos (25 mol %), DTBMP (1.5 equiv), CH3CN, 24 h, 25 °C, Blue LED
: BPhen (30 mol %), IBO (2 equiv), MTBE, 48 h, 50 °C
________________________________________________________________________________________________________________
8
9
B
A
conditions
nucleophiles
products
conditions
electrophiles
entry
yieldb (:)c
yieldb (:)c
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________________________________________________________________________________________________________________
BnO
OMe
O
BnO
BnO
BnO
BnO
BnO
OMe
O
Me
O
1
74% (: > 20:1)
42% (: = 7:1)
HO
Me
O
BnO
O
O
BnO
O
Br
O
6
4
O
Me
Me
Me
5
Me
OMe
Me
O
Br
O
O
5
2
3
O
57% (: > 20:1)
53% (: > 20:1)
58% (: = 4:1)
11% (: = 5:1)
Me
O
Me
O
OBn
OBn
Me
OBn
OBn
Me
BnO
BnO
7
8
CO2Me
O
CO2Me
O
BnO
BnO
OMe
BnO
BnO
5
Me
O
O
2
BnO
BnO
Br
O
9
10
O
Me
Me
BnO
O
BnO
BnO
BnO
BnO
O
BnO
HO
BnO
4
4
5
60% (: > 20:1)
55% (: = 7:1)
BnO
O
O
BnO
OMe
12
BnO
OMe
11
11
OBn
O
BnO
BnO
OBn
BnO
BnO
61% (: > 20:1)
43% (: = 5:1)
O
BnO
O
BnO
O
BnO
BnO
Br
13
14
BnO
OMe
BnO
BnO
BnO
BnO
15
O
HO
O
O
BnO
6
BnO
BnO
79% (: > 20:1)
47% (: > 20:1)
BnO
BnO
O
BnO
OMe
O
Br
16
BnO
BnO
OMe
________________________________________________________________________________________________________________
17
a
The reaction was conduct with 1 equiv (0.2 mmol) of glycosyl bromides and 1.5 equiv (0.3
mmol) of aliphatic alcohols. b Isolated yield. Diastereoselective (:) ratio determined by H
c
1
NMR analysis.
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Page 12 of 30
1
2
3
4
5
6
7
8
9
The -1,2-cis glycosidic C-O bonds have also been reported by Boons and Demchenko using the
chiral auxiliary and hydrogen bond directing group at C2- and C4-position of carbohydrate electrophiles,
respectively.10 For instance, the Boons approach is based on neighboring participation of a (1S)-phenyl-
2-sulfanyl)ethyl auxiliary at C2-position of glycosyl electrophiles to control the formation of the -1,2-
cis products.10a The Demchenko approach utilizes the picolinyl and picoloyl groups at C4-position of
electrophiles to control the -1,2-cis selectivity through intermolecular hydrogen bonding between a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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32
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59
60
nitrogen atom of picolinyl and picoloyl groups and a hydroxyl group of a nucleophile. In contrast, our
method utilizes the commonly used benzyl ether protecting group whose non-assisting
functionality often leads to a mixture of - and -diastereomeric products. Since our system
relies on copper complex to act as a photocatalyst and a C-O bond-forming catalyst as well as
to enforce stereocontrolled formation of -diastereomer, the coupling products are likely to form
with high levels of selectivity. For instance, cross-coupling of -glycosyl bromide 4 with sterically
hindered secondary alcohol 11 under photoinduced, copper-catalyzed conditions provided the desired
disaccharide 12 in 60% yield with high levels of -selectivity (: > 20:1, Table 2, entry 5). To compare,
use of a stoichiometric amount of silver triflate as Lewis acid afforded 12 (Figure S7) as a 2:1
mixture of - and -diastereomers. Recently, Mong and co-workers reported the use of N,N-
dimethylforamide (DMF) as an -modulating additive to direct the selectivity.11c In their seminal
work, glycosylation of alcohol 11 with phenylthiol derivative of 4 using a reagent combination of
o
NIS (1.5 equiv.) and TMSOTf (1.5 equiv.) in -10 C as a promoter and DMF (6 equiv.) as -
modulator provided 12 in 75% yield with : = 9:1.11c
Moving forward, we evaluated the scope of the electron-withdrawing -glycosyl bromides
with respect to various secondary alcohols (Table 3). In our study, we chose to investigate the
couplings with hindered secondary alcohols as they have been reported to provide the
carbohydrate products with poor to moderate levels of diastereoselectivities.18Accordingly, -1-
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ACS Catalysis
bromo-D-glucosides bearing acetyl and benzyl protecting groups were examined in the coupling to C4-
1
2
3
and C3-hydroxys. In all cases, the reactions proceeded at room temperature to provide the
4
5
6
7
8
desired disaccharide products (18 to 20) in good yields (56% to 61%) and excellent stereocontrol
(: > 20:1). To determine whether the selectivity of the coupling products obtained under
copper-catalyzed conditions depends on a reaction concentration, the cross coupling of -
glycosyl bromide 4 with C3-hydroxy of galactoside was conducted at three different
concentrations (0.25 M, 0.5 M, and 1 M). The selectivity of the coupling product 20 remained
the same (: >20:1) for three reaction concentrations. The standard 0.5 M reaction
concentration provided 20 in 60% yield, while a slightly higher yield (64%) was obtained at a
higher (1 M) concentration (Figure S8). On the other hand, the reaction was sluggish at a lower
(0.25 M) concentration (Figure S8). To compare to the current method for the highly
diastereoselective synthesis of -1,2-cis glycosides, the selectivity of the Demchenko approach
using the C4-picoloyl functionality as the hydrogen-bond directing group appears to depend on a reaction
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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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
concentration.10b For instance, while a low reaction concentration (5 mM) provided the coupling
derivative of product 20 with excellent selectivity (: >20:1), the reaction was less selective at a high
concentration (50 mM, : = 10:1).10b We observed that while the electron-withdrawing glycosyl
bromides can proceed efficiently at room temperature under visible-light-mediated copper
conditions, the yields of the coupling products are lower than those obtained under
phenanthroline-catalyzed conditions.17 For instance, the copper system provided the product 19
in 61% yield while the phenanthroline system afforded 19 in 73% yield.17 Variation in the
structure of -glycosyl bromides was also tested, delivering the products containing
D-galactose
(21 and 22) and -rhamonose (24) with high -diastereoselectivity (: > 20:1). Interestingly, the
L
visible-light-mediated copper system is also effective at promoting the coupling with the electron-
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Page 14 of 30
withdrawing of a five-member ring ribosyl bromide to provide the desired product 23 with high
-1,2-cis selectivity (: = 12:1).
1
2
3
4
5
6
7
Table 3: Coupling of Secondary Alcohols with Various Glycosyl Bromides.[a]
8
9
CuI(10 mol %)
BPhen (25 mol %)
XantPhos (25 mol %)
DTBMP ,CH3CN, 24 h, 25 °C
Blue LED
O
O
OH
R2
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
(RO)n
(RO)n
+
R1
R2
1
1
2
2
R1
BnO
BnO
Br
O
____________________________________________________________________________________________________________________
D-Glucose
BnO
AcO
AcO
AcO
AcO
AcO
BnO
O
O
OBn
O
BnO
BnO
OMe
BnO
OMe
O
Me
O
BnO
Me
O
BnO
O
BnO
O
O
20b
18a
56%
(: > 20:1)
19a
61%
(: > 20:1)
O
O
O
BnO
OMe
O
60%
Me
Me
Me
Me
(: > 20:1)
L-Rhamnose
D-Furanose
D-Galactose
OMe
OAc
OBn
BzO
AcO
AcO
BnO
BnO
Me
O
O
O
OMe
O
O
O
OMe
OMe
O
Me
BnO
O
Me
O
O
OBn
Me
O
Me
OBn
24c
Me
O
BnO
BnO
BnO
BzO
O
O
Me
O
O
O
O
O
O
21c
22c
Me
23c
56%
(: = 12:1)
Me
Me
Me
65%
59%
(: > 20:1)
Me
84%
Me
(: > 20:1)
(: > 20:1)
____________________________________________________________________________________________________________________
a Reactions performed with R-Br (0.2 mmol, 1.0 equiv.) and R-OH (0.3 mmol, 1.5 equiv). Yields isolated.
The diastereomeric ratios (:) were determined by 1H NMR. b R-Br (0.3 mmol, 1.5 equiv), R-OH (0.2
mmol, 1.0 equiv). c R-Br (0.4 mmol, 2.0 equiv), R-OH (0.2 mmol, 1 equiv).
Motivated by the high efficiency of the photoinduced copper system to promote the
reaction of -glycosyl bromides with secondary alcohols, we next examined the cross couplings
of a variety of electron-withdrawing and electron-donating glycosyl bromides with primary
alcohols (Table 4). The reactions were highly diastereoselective to produce the coupling
products (25 to 31) in good yields and excellent selectivity, underscoring broad applications of
the visible-light mediated copper-catalyzed anomeric C(sp3)-O bond formation. To compare, the
reaction of thioglycoside derivative of -glycosyl bromide 4 with primary alcohol 16 under traditional
glycosylation conditions provided the desired product 26 as a 2:1 mixture of - and -diastereomers.10b
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ACS Catalysis
In stark contrast, the photoinduced copper-catalyzed cross-coupling provided 26 with excellent
-1,2-cis selectivity (: > 20:1). Compared to the Demchenko approach with use of primary
alcohol 16, the picoloyl group at C4-position is -1,2-cis selective while the picolinyl group at
remote positions (C2, C3, C4, and C6) favors the -1,2-trans selectivity.10b Next, we tested
whether our catalytic copper system could override the substrate’s inherent selectivity bias. We
conducted the coupling with -galactosyl bromide whose axial C4-benzyl, picolinyl and picoloyl
groups have been reported to favor the -1,2-trans product.10b,19 To our excitement, the visible-
light-mediated copper-catalyzed cross-reaction favored the -1,2-cis product (30: : = 13:1).
An additional feature that highlights this system is the tolerance of the method to protected serine
nucleophiles, delivering glycoconjugate 32 (74%, : = 9:1), which is a thrombospondin type 1
repeating unit associated with an autosomal recessive disorder.20 Next, we explored the effect of
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
the C2 substituents of -glycosyl bromides on the selectivity (Table 4) to gain insight into the mechanism
of the copper system. The ability of a C2-F bond to have an impact on the diastereoselectivity of anomeric
C-O bond formation has been reported.21 The tetrabenzylated D-glucose and D-galactose
substrates, having the C2-fluoro group, are highly -selective under Lewis acid-mediated
conditions.21 In stark contrast, the photoinduced, copper-catalyzed approach is highly -
selective, providing the -1,2-cis disaccharides containing D-glucose (33, : = 13:1) and D-
galactose (34, : =19:1). On the other hand, -glycosyl bromide lacking C2-oxygen
functionality exhibited moderate selectivity (35, : = 4:1)22 due to its conformational flexibility.
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Page 16 of 30
1
2
3
4
5
6
7
8
Table 4: Scope of Primary Alcohols and Glycosyl Bromides.[a]
9
CuI(10 mol %)
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
BPhen (25 mol %)
O
O
(RO)n
(RO)n
XantPhos (25 mol %)
DTBMP ,CH3CN, 24 h, 25 °C
Blue LED
1
2
1
2
+
HO
R
BnO
O
R
BnO
Br
____________________________________________________________________________________________________________________
D-Glucose
BnO
O
BnO
AcO
AcO
AcO
BnO
BnO
O
O
BnO
BnO
BnO
O
Me
Me
O
BnO
BnO
O
O
25a
O
26b
64%
O
O
BnO
BnO
27a
BnO
BnO
O
71%
O
76%
O
BnO
BnO
(: > 20:1)
OMe
(: > 20:1)
OMe
Me
(: = 15:1)
Me
D-Galactose
OAc
L-Fucose
OAc
BnO
AcO
OAc
AcO
AcO
AcO
O
O
O
O
Me
O
AcO
Me
O
BnO
O
OBn
Me
BnO
O
O
O
O
BnO
Me
Me
Me
Me
O
O
OAc
AcO
O
BnO
BnO
O
O
O
O
O
O
31a
71%
(: > 20:1)
Me
28a
72%
(: > 20:1)
30a
29a
69%
(: = 13:1)
O
BnO
OMe
O
O
O
Me
Me
Me
75%
(: = 13:1)
Me
Me
2-Fluoro- -Glucose
D
2-Fluoro- -Galactose
D
2-Deoxy- -Glucose
D
L-Fucose
OBn
BnO
AcO
BnO
O
O
O
AcO
AcO
BnO
O
BnO
O
OAllyl
NHCbz
OBn
BnO
F
O
O
F
Me
O
O
Me
O
Me
O
Me
O
O
Me
O
O
Me
OBn
BnO
O
Me
32c
O
O
35a
33a
34a
O
O
O
74%
O
O
O
Me
67%
70%
Me
78%
(: = 9:1)
Me
Me
(: = 4:1)
(: = 13:1)
(: = 19:1)
Me
Me
____________________________________________________________________________________________________________________
a Reactions performed with R-Br (0.2 mmol, 1.0 equiv.) and R-OH (0.3 mmol, 1.5 equiv). Yields isolated.
The diastereomeric ratios (:) were determined by 1H NMR. b R-Br (0.3 mmol, 1.5 equiv), R-OH (0.2
mmol, 1.0 equiv). c R-Br (0.4 mmol, 2.0 equiv), R-OH (0.2 mmol, 1 equiv).
We expect that the visible-light-induced copper approach will be particularly useful when applied
to the synthesis of biologically relevant -glycans. Well-defined construction of the oligosaccharide
motifs of these natural -glycans will allow studying these bioactive fragments as potential prebiotics.23
To illustrate this potential, the stereocontrolled synthesis of the branched dextran oligosaccharides 40 and
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ACS Catalysis
42 was investigated (Scheme 2). Accordingly, we subjected -1-bromo D-glucoside 36 (2.3 g, 4.9 mmol,
1.2 equiv) and primary alcohol 16 (.19 g, 4.1 mmol, 1.0 equiv) to the standard photoinduced copper
conditions. In this case, 1,2-cis disaccharide 37 (3.028 g) was isolated in 83% yield with high levels of -
selectivity (: > 20:1). It is worth mentioning that this reaction was done on a gram scale and still
maintained an excellent result, illustrating the scalability and reproducibility of our method. Subsequent
hydrolysis of 37 provided the corresponding diol 38, which serves as a nucleophilic coupling partner for
another cross-coupling iteration with -glycosyl bromides 39 and 41 to afford tetrasaccharide 40 (224
mg, 63%, :>20:1) and hexasaccharide 42 (212 mg, 58%, : > 20:1), respectively, under standard
coupling conditions.
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
RO
O
BnO
HO
BnO
BnO
AcO
BnO
AcO
36
83%
(: > 20:1)
Standard
Conditions
RO
O
O
+
BnO
BnO
O
O
BnO
BnO
OMe
Br
BnO
16
BnO
OMe
37
38
: R = Ac
: R =H
NaOMe, 90%
AcO
BnO
BnO
39
O
BnO
AcO
BnO
BnO
O
Br
Standard Condtions
AcO
BnO
BnO
O
O
41
O
BnO
BnO
BnO
AcO
O
BnO
BnO
BnO
O
BnO
Br
O
BnO
BnO
O
O
BnO
O
BnO
BnO
BnO
BnO
BnO
BnO
AcO
O
O
O
BnO
O
BnO
O
40
BnO
BnO
BnO
OMe
O
63%
BnO
BnO
BnO
O
(: > 20:1)
O
O
BnO
BnO
O
BnO
BnO
OMe
BnO
BnO
42
58%
(: > 20:1)
O
AcO
Scheme 2. Copper-Catalyzed Oligosaccharide Synthesis
Although reaction development is the major focus of this investigation, we performed
preliminary mechanistic studies. It has been reported that an anomeric C1-radical generated in
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Page 18 of 30
the coupling reaction would undergo a 5-exo-trig cyclization with a C2-pendant olefin to generate
the bicyclic product.24 As such, we conducted the coupling of -glycosyl bromide 43 (Scheme
3A) bearing a C2-pendant olefin with primary alcohol 2. The coupling product 44 was, however,
observed in the reaction, and no cyclization product was isolated. Kochi and coworkers have
previously demonstrated that carbon radicals can be oxidized rapidly by copper complex to
generate alkyl copper intermediates;25,26 therefore, it is possible that oxidation of anomeric C1-
radical by a copper(II) complex to form alkylcopper(III) complex is faster than a radical 5-exo-
trig cyclization.25,27 Next, we hypothesize that if C-O bond formation occurs through out-of-cage,
addition of TEMPO (5 equiv.) to the reaction mixture would lead to the formation of a TEMPO
adduct. As can be seen in Scheme 3B, the TEMPO-trapping product 45 was not detected in the
coupling reaction, suggesting that electron transfer and subsequent interactions with anomeric
radical intermediate are likely to take place within the same solvent cage.
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
AcO
O
AcO
AcO
OH
AcO
Me
Me
O
O
O
O
Standard Conditions
AcO
AcO
(A)
O
O
Me
Me
+
O
O
63%
(: = 12:1)
O
O
Br
O
O
Me
O
43
2
44
O
Me
Me
Me
AcO
AcO
O
AcO
BnO
Standard Conditions
TEMPO (5 equiv)
3
2
+
1
+
(B)
O
N
45
66%
(: = 13:1)
Me
Me
Me
Me
NOT OBSERVED
Scheme 3. Control Experiments
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ACS Catalysis
In UV/Vis absorption experiments, the in situ generated copper catalyst from the
1
2
3
combination of CuI, BPhen, and Xantphos in the ratio of 1:2.5:2.5 shows broad absorption
(Scheme 4A) in the visible region (λmax=408 nm) whereas the mixture of CuI and BPhen or of
CuI and Xantphos shows no absorption, suggesting the importance of these two ligands in
forming the complex. The same absorption peak in the visible light region was also observed for
the isolated copper complex, [Cu(BPhen)(Xantphos)]BF4 (Figure S11). Furthermore, 31P NMR
analysis showed that the in situ generated copper complex ( = -11.99 pm) and the isolated copper
complex ( = -11.87 pm) have similar chemical shift. The isolated copper catalyst was effective at
promoting the coupling to provide the coupling product 3 (entry 13, Table 1) in similar yield and
-selectivity to that promoted by in situ generated copper catalyst (entry 1, Table 1). Collectively,
these results suggest that the [Cu(BPhen)(Xantphos)]+ complex is likely to be the primary
photoreductant in the visible light-mediated copper-catalyzed cross-coupling. In addition, we
observed a clear peak in 630 nm in emission spectra of the in situ generated copper complex
under the irradiation of 450 nm (Scheme 4B), suggesting the existence of the excited state
copper species. The emission spectrum of [Cu(BPhen)(Xantphos)]BF4 (Figure S12) shows a
similar trend to those of the in situ generated copper catalyst (Scheme 4B), further supporting
that [Cu(BPhen)(Xantphos)]+ is the active catalyst.
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
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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
Scheme 4. (A) UV/Vis absorption spectra for CuI, BPhen,
and Xantphos with different mole ratios. The spectra were
acquired with a 0.5 nm interval. (B) Emission spectra of
the copper complex (CuI:BPhen:Xantphos = 1:2.5:2.5) at
0.1 mM concentration with an excitation wavelength of
450 nm.
On the basis of the aforementioned preliminary results (Schemes 3 and 4) and the recent
literature reports,13 a proposed mechanism for the visible-light-mediated copper-catalyzed
anomeric C(sp3)-O bond formation is outlined in Scheme 5. The first step involves the
coordination of the aliphatic oxygen nucleophile to the Cu(I) center to form the corresponding
copper(I)-oxygen complex A.13 Photoexcitation of copper(I) complex A could result in an excited-
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ACS Catalysis
state copper(I) species B that potentially engages in electron transfer with -glycosyl bromide
C.28 This irradiation step corresponds well to the broad absorption and emission observed
experimentally (Scheme 4). However, the results obtained with control experiments (Scheme
3) suggest that the coupling reaction may not proceed via a copper(II) complex D and a long-
lived glycosyl radical E.13 As such, the glycosyl radical E can either react with copper(II) complex
D to form a copper(III) species F (path A)25,26 or be oxidized by copper(II) complex D to generate
oxocarbenium ion G (path B).29 Dissociation of the alkylcopper(III) complex F could also provide
the oxocarbenium ion intermediate G. If path A is operative, reductive elimination from complex
F affords C(sp3)-O bond H and a copper(I) species I. The copper(I) complex A is regenerated to
reset the cycle. Alternatively, nucleophilic attack onto the oxocarbenium ion (path B) also results
in the formation of the desired product H.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
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[LnCuI(OR)]
A
HBr
Blue LED
nucleophile
coordination
excitation
ROH
[LnCuI(OR)]*
[LnCuIBr]
B
I
O
O
(RO)n
(RO)n
2
electron
transfer
BnO
C
coupling
Br
BnO
H
OR
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O
(RO)n
(RO)n
path A
2
BnO1
E
BnO
[LnCuII(OR)]Br
LnCu OR
Br
F
D
path B
O
O
(RO)n
[LnCuI(OR)]
R-OH
(RO)n
2
+
A
BnO
OR
BnO
H
G
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Scheme 5. Proposed Mechanism
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The onsite potential of the reduction of -glycosyl bromide 1 to glycosyl radical
(compound E in Scheme 5) was measured to be ~ -0.5 V using an Ag electrode (Figure S13) as
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Ag is known to be an effective catalyst for reducing alkyl bromide.30 Direct measurement of the oxidation
potential of complex B is challenging because B is the unstable excited state of copper(I) complex A
(Scheme 5). A common strategy to address this challenge is to estimate from the oxidation potential of A
and the emission wavelength of B (Scheme 6a). However, the preliminary attempt on the isolation of A
was not successful. We then noticed that mixing [Cu(BPhen)(Xantphos)]BF4 (equivalent to complex I in
Scheme 5) and MeO-, which presumably generated A, did not change the emission wavelength of copper
complex I (Scheme 6b), suggesting A and I as well as their corresponding excited states B and I* maybe
energetically similar. Therefore, we estimated the oxidation potential of complex B from the oxidation
potential of I*. To obtain the oxidation potential of complex I*, we first measured the emission
wavelength of I to be 630 nm (Scheme 6c), equivalent to 1.97 eV. We then measured the onset potential
for the oxidation of I to be ~0.9 V (Scheme 6d). Collectively, the oxidation potential of I* is the difference
between 0.9 V and 1.97 V, equal to −1.07 V. Overall, the reduction potential of compound C was
measured to be −0.5 V using catalytic Ag electrode (Scheme 7). The oxidation potential of compound B
was estimated to be ~ −1.07 V from spectroscopic and electrochemical measurements (Scheme 7).
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Scheme 6. (a) Energy level diagram for estimating the oxidation potential of B to D from the spectroscopic
measurement of the emission wavelength of B and the electrochemical measurement of the oxidation
potential of the ground state A. (b) Emission spectra of [Cu(BPhen)(Xantphos)]+ (equivalent to compound
I in Scheme 5) with and without MeO−, showing no noticeable difference in emission wavelength. (c)
Absorption and emission of compound I. (d) Cyclic voltammogram of compound I (2 mM) in acetonitrile
containing 0.1 M tetrabutylammonium perchlorate as the electrolyte using GCE. Scan rate = 0.2 V.
AcO
AcO
AcO
AcO
AcO
AcO
O
+e
O
- 0.5 V
BnO
Br
BnO
glycosyl radical
substrate C
(glycosyl bromide
1
)
-e
[LnCuI(OR)]*
[LnCuII(OR)]
-1.07 V
D
complex
B
complex
Scheme 7. Summary of the redox potential of excited state copper(I) complex B and substrate C (-
glycosyl bromide 1) proposed in Scheme 5.
Finally, we hypothesize that the high levels of -1,2-cis diastereoselectivity observed in
the coupling products could be rationalized due to an interaction between the Cu center and C2-
oxygen (complex F, Scheme 5).31 Kochi and coworkers have previously demonstrated that
carbon radicals are oxidized by copper near a diffusion control to form the alkylcopper
intermediate,25,26 further supporting the proposed copper(III) complex F. To further validate that
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copper(III) species F is likely to form in the reaction, the C2-oxygen atom of -glycosyl bromide
was replaced with fluorine atom as fluorine has been proposed to coordinate to the Cu center.32
The 2-fluoro-2-deoxy glycosyl bromides also favored the -1,2-cis products (33 and 34, Table
4). On the other hand, if path B in Scheme 5 is operative, the coupling products should be
obtained with low levels of selectivity as a nucleophile can attack on either face of the
oxocarbenium intermediate G. Glycosyl radicals are more easily oxidized to cations than the
carbon radicals investigated by Kochi.25,26 As such, we hypothesized that substitution of the C2-
oxygen with hydrogen atom could further facilitate the formation of the 2-deoxy oxocarbenium
ion resulted either from dissociation from a copper(III) complex or from oxidation of the anomeric
radical by copper(II) complex. If 2-deoxy cation is generated in the reaction, an alcohol
nucleophile can approach on either its - or -face to provide a mixture of 1,2-cis and 1,2-trans
diastereomers, which was confirmed by an experimental result obtained with the coupling
product 35 (Table 4).33
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CONCLUSIONS
Utilization of visible light to overcome the relatively slow rate of oxidative addition in
copper catalysis has facilitated the development of the cross couplings of -glycosyl bromides
with alkyl alcohols to stereoselectively generate the challenging anomeric C(sp3)-O bonds of -1,2-
cis glycoside products, an important motif of many bioactive carbohydrate molecules. Unlike the
substrate-controlled approaches which rely on the chiral auxiliary group or the directing group
at C2 and C4-position of carbohydrate electrophiles to control the -1,2-cis diastereoselectivity,
our method relies on copper catalyst to enforce stereocontrol. Furthermore, in stark contrast to
nearly all catalytic glycosylation reactions which typically proceeds via either SN1 or SN2
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pathway, this method utilizes copper catalyst induced by visible light to engage in a C-O bond
formation. We anticipate this method would be widely adopted for generating other types of
anomeric bond formations and provide a foundation for investigating cross-couplings of non-
carbohydrate alkyl halides with sp3-hydridized nucleophiles. The detailed mechanism, using a
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combined experimental and computational study, of this visible-light-mediated copper-catalyzed cross
couplings of -glycosyl bromides with alcohol nucleophiles is under investigation and will be reported in
due course.
ASSOCIATED CONTENT
Supporting Information
Supporting Information Available: detailed experimental procedure, characterization data of the new
compounds, including the NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
Hien M. Nguyen – Department of Chemistry, Wayne State University, Detroit, Michigan 48202,
United States; orcid.org/0000-0002-7626-8439; Email:hmnguyen@wayne.edu
Long Luo – Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United
States; orcid.org/0000-0003-2177-2969; Email: long.luo@wayne.edu
Authors
Fei Yu – Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States
Jalen L. Dickon – Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United
States
Ravi S. Loka – Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United
States
Hengfu Xu – Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United
States
Richard N. Schaugaard – Department of Chemistry, Wayne State University, Detroit, Michigan
48202, United States
H. Bernhard Schlegel – Department of Chemistry, Wayne State University, Detroit, Michigan 48202,
United States; orcid.org/0000-0001-7114-2821
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Author Contributions
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† Equal contributions
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Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
This research is supported by NIH (U01 GM120293 for H.M.N.), NSF (CHE1856437 for H.B.S.), and
NSF (CHE1943737 for L.L). We thank the Wayne State University Lumigen Center for instrumental
assistance.
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