Stereoselective Synthesis of 2-Deoxyglycosides from Glycals by Visible-Light-Induced Photoacid Catalysis

Article abstract of DOI:10.1002/anie.201800909

The direct, photoacid-catalyzed synthesis of 2-deoxyglycosides from glycals is reported. A series of phenol-conjugated acridinium-based organic photoacids were rationally designed, synthesized, and studied alongside the commercially available phenolic catalyst eosin Y. In the presence of such a photoacid catalyst and light, synthetic glycals were activated and coupled with a range of alcohols to afford 2-deoxyglycosides in good yields and with excellent α-selectivity.

Full text of DOI:10.1002/anie.201800909

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Accepted Article
Title: Stereoselective Synthesis of 2-Deoxyglycosides from Glycals via
Visible-Light-Induced Photoacid Catalysis
Authors: Gaoyuan Zhao and Ting Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800909
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10.1002/anie.201800909
Angewandte Chemie International Edition
COMMUNICATION
Stereoselective Synthesis of 2-Deoxyglycosides from Glycals via
Visible-Light-Induced Photoacid Catalysis
Gaoyuan Zhao[a] and Ting Wang*[a]
Dedication to Prof. Craig J. Forsyth on the occasion of his 60th birthday
Abstract: A direct, photoacid catalyzed synthesis of 2-deoxy-
glycosides from glycals was developed. series of phenol-
and the resulting radical cation of the mesitylene moiety exhibits
a high single electron oxidation potential.[15] Recently, Nicewicz
and DiRocco reported their studies on developing an acridinium-
based photoredox catalyst series, delineating the impact of
structural changes on catalyst excitation, emission and excited
state lifetimes.[16] Inspired by these studies, we designed and
synthesized acridinium-based, phenol-substituted compounds A
and B (Scheme 1). Catalyst A was minimally designed by the
direct substitution of hydroxyl at the 2’-position resulting in a
phenolic variant of the Fukuzumi catalyst X. In the excited state
(i.e. A ! A*), we hypothesized that the radical cation phenol
moiety may exhibit increased acidity. Catalyst B was designed
with analogous reactivity in mind, yet we reasoned the 1,1’-bi-2-
napthol (BINOL) derived scaffold might offer potential chiral
environment of the catalyst for future studies. With early success
of synthetic catalyst A and B, we also included commercially
available eosin Y (C) in the studies of this ArOH-type photoacid
catalysis. We herein describe these studies that led to the
development of a direct, visible-light photoactivation method[17],
A
conjugated acridinium-based organic photoacids (A and B) was
rationally designed, synthesized and studied alongside commercially
available phenolic catalyst, eosin Y. In the presence these photoacid
catalysts and light, synthetic glycals undergo activation and couple
with a range of alcohols to afford 2-deoxy-glycosides in good yields
with excellent α-selectivity.
2-Deoxy-sugars
are
well-appreciated
and
widely
represented carbohydrates among bioactive natural products
such as antibiotics, anti-cancer and cardiotonic agents.[1],[2]
Moreover, the 2-deoxysugar motif within oligosaccharides can
often play a dictating role in the corresponding biological activity
of the parent compound.[3],[4] As a result, considerable efforts
toward the synthesis of 2-deoxy-glycosides have been made in
recent decades.[5] However, the stereoselective assembly of the
2-deoxy-glycosidic linkage remains a significant challenge due
to the absence of functionality at C-2 that generally serves as a
stereo-directing group. The temporary installation of a directing
group at C-2 is enabling albeit inherently inefficient.[6] Although
several direct methods have been developed,[7] they rely on
stoichiometric promoters or synthetic precursors that require
several steps to prepare. The direct addition of an alcohol to an
activated glycal via catalysis remains the most atom-efficient
route to 2-deoxy-glycosides.[8]
[18]
for the catalytic conversion of glycals into 2-deoxy-glycosides
with stereoselectivity.
Visible-Light-Induced Photoacids
Me
Me
450 nm LEDs
R1
N
Me
BF4
R1
N
Me
BF4
Me
Me
R2
R2
In addition to a clear interest in 2-deoxy-glycosides at both
biological and synthetic levels, we also viewed the challenge as
a compelling opportunity for the development of visible-light-
induced organic photoacid catalysis. Through subtle tuning
photoacidity of the catalysts, we would like to exam their
reactivity towards reaction efficiency, stereoselectivity, and
potential suppression of the Ferrier-type byproducts from glycals.
Acr+-Mes ion (X)
Fukuzumi15
Nicewicz & DiRocco16
X*
photoredox activity
Me
Me
450 nm LEDs
Me
N
Me
BF4
Me
N
Me
BF4
2'
O
H
HO
We envisioned the design and synthesis of
a tunable
A
A*
photocatalyst and were thus drawn to phenolic derivatives (i.e.
phenol, naphthol) which have been shown to exhibit marked
increases in acidity—by several pKa units—upon light
irradiation.[9] Similar photoacids have been utilized in polymer
synthesis,[10] proton-transfer processes,[9]c,[11] acid-catalyzed
reactions,[12] molecular switching events,[13] and photodynamic
therapy.[14] In 2004, Fukuzumi reported the 9-Mesityl-10-
methylacridinium ion (X) as a novel photoredox catalyst. The
catalyst undergo electron reorganization upon excitation (X*),
this work
photoacidic activity
Me
N
O
BF4
O
Br
Br
OH
OH
HO
O
OH
B
Br
Br
BF4
Me
N
C: eosin Y
Stereoseletive Synthesis of 2-Deoxyglycosides from Glycals
[a]
Dr. G. Zhao and Prof. T. Wang
Department of Chemistry
University at Albany, State University of New York
1400 Washington Avenue, Albany, NY 12222 (USA)
E-mail: twang3@albany.edu
Photoacid (1 mol %)
O
R1OH
O
RO
RO
α-selective
OR1
Blue LEDs
CH2Cl2
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Photoacid Catalyzed Stereoselective Synthesis of 2-
deoxyglycosides from Glycals.
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10.1002/anie.201800909
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COMMUNICATION
Table 1. Optimization of the Reaction Conditions[a]
glycosylation. Moreover, reaction rates are significantly
attenuated when light irradiation is non-continuous, suggesting
that both synthetic catalyst A and eosin Y are reversible
photoacids (SI, Figure S3 and S4).
OBn
O
BnO
BnO
OH
O
Catalyst (1 mol %)
OBn
O
BnO
BnO
O
O
O
O
Blue LEDs
CH2Cl2
+
O
O
O
O
O
O
1
3
2
OP
O
OP
OP
eosin Y (1 mol %)
PhSSPh ( 2 mol %)
PO
PO
PO
PO
PO
PO
O
O
+
ROH
entry
catalyst
additive[b]
yield (%)[c]
Blue LEDs
CH2Cl2
OR
potential Ferrier-type
byproducts (4)
P= Bn or Ac
1
2
A
B
C
A
B
C
C
C
37
40
56
75
56
90[e]
74
0
OBn
OBn
BnO
BnO
OBn
O
BnO
BnO
BnO
O
O
OBn
O
3
BnO
OBn
BnO
O
O
BnO
O
O
O
BnO
O
4
PhSSPh
PhSSPh
PhSSPh
PhSH
BnO
O
OMe
BnO
BnO
1
O
O
O
BnO
OMe
5
6
67%
α / β > 20 : 1
3
90%
5 88%
α / β > 30 : 1
α / β > 20 : 1
6
O
7
OBn
O
BnO
BnO
OBn
O
O
O
O
BnO
BnO
OMe
O
O
O
O
8
Et3N[f]
OMe
O
BnO
BnO
BnO
O
O
O
O
BnO
BnO
O
O
O
O
BzO
BzO
O
9
eosin Y disodium salt
no catalyst
0
Ph
OBn
BzO
OBn
OMe
7
82%
8
84%
10
11[d]
0
10 69%
9
87%
α / β = 16 : 1
α / β > 20 : 1
α / β > 20 : 1
α / β > 30 : 1
no light
0
O
O
N
[a] Reaction irradiated with two 12 W, 450 nm LED flood lamps. [b] 2 mol %
additive was used. [c] Isolated yield. [d] Reactions conducted in the dark. [e] α/β
> 20:1; α/β ratio was determined by 1H NMR analysis of crude products. [f] 1
equiv. of Et3N was added.
BocHN
OMe
H
H
N
O
O
O
H
O
O
BnO
BnO
O
O
O
BnO
BnO
BnO
BnO
O
O
OBn
OBn
11 74%
12 91%
α only
OBn
13 80%
α / β > 20 : 1
α / β > 30 : 1
We began our studies with synthetic photocatalyst A and
blue light-emitting diode (LED) irradiation to activate glycal 1 in
the presence of alcohol 2. Happily, 2-deoxysugar 3 was formed
and isolated in 37% yield (Table 1, entry 1). We carefully
screened solvents (CH2Cl2, CH3CN, DMF, DMSO, THP, 1,4-
dioxane, and toluene) to find CH2Cl2 as the optimal solvent.
Synthetic BINOL derived catalyst B and commercial available
eosin Y (C) could also deliver the desired product 3 with
improved yields, 40% and 56%, respectively (entries 2 and 3).
We discovered that PhSSPh as an additive improved yields
across the catalyst series (entries 4-6)[19]. Thiophenol (PhSH)
was also an effective additive, albeit with slightly diminished
yield (entry 7). Tertiary amine additive shut down the reaction
completely (entry 8) and the disodium salt of eosin Y failed to
promote any reaction (entry 9). These results suggest an acid
catalyzed process is operative. Further control experiments
(entries 10 and 11) verified that a photocatalyst, together with
LED irradiation, are necessary to promote this transformation. In
addition, Stern-Volmer emission quenching experiments reflect
OAc
OAc
AcO
AcO
Ph
O
AcO
AcO
O
O
OMe
O
O
O
O
O
BnO
OMe
AcO
AcO
AcO
AcO
O
O
O
O
O
O
O
O
OAc
O
OAc
BnO
BnO
O
O
BnO
O
18 53%
OMe
17 59%
α / β > 20 : 1
15 62%
α / β > 20 : 1
16 66%
α / β > 20 : 1
α / β > 20 : 1
O
O
BocHN
N
H
OMe
OAc
AcO
N
O
O
H
H
O
O
O
AcO
O
AcO
AcO
14
O
AcO
AcO
AcO
AcO
O
O
O
O
OAc
OAc
OAc
19 41%
21 66%
20 77%
α / β > 20 : 1
α / β > 30 : 1
α / β > 20 : 1
Scheme 2. Scope of OH Nucleophiles. General conditions: Reaction irradiated
with two 12 W, 450 nm LED flood lamps. In each case, the yield of the isolated
product is given. α/β ratio was determined by 1H NMR analysis of crude
products. Bn = bynzyl, Bz = benzoyl, Boc = t-butoxycarbonyl, Ac = acetyl.
redox inactivity between perbenzyl galactal
1 and either
photocatalyst A or C (Supporting Information, Figure S1 and S2).
This data suggests the operative mechanism does not involve a
photoredox process. These information taken together, support
a
proposed photoacid catalysis pathway for productive
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10.1002/anie.201800909
Angewandte Chemie International Edition
COMMUNICATION
O
the accepting hydroxyl group. Coupling to a variety of different
carbohydrates[8]a,b,[20] bearing primary alcohols (3, 5, 8 and 9) or
secondary hydroxyl groups at C3 or C4 (6, 7, and 10) position
proceeded well with good isolated yield and high α-stereocontrol.
Moreover, the glycosylation of N-Boc-protected serine,
cholesterol and a protected nucleotide proceeded uneventfully to
form the corresponding products (11-13) in 74%, 91%, and 80%
yields respectively.
RO
OH
O
eosin Y (1 mol %)
O
O
PhSSPh (2 mol %)
O
O
O
RO
+
O
Blue LEDs
CH2Cl2
O
O
O
O
O
22
23
24
OAc
O
OMe
O
O
O
AcO
AcO
MeO
MeO
O
A
major drawback of existing methods for the direct
OR
O
RO
O
O
synthesis of 2-deoxyglycosides from glycals is the competitive
potential formation of Ferrier-type byproducts 4 (Scheme 2).
Numerous acid catalysts (Bronstead or Lewis-type) and
transition metal catalysts fail to efficiently convert glycals bearing
C-3 acetates to their corresponding 2-deoxyglycosides.8a-d This
is in part due to the facile nature of C-3 acetate elimination (i.e.
Ferrier rearrangement). Excitingly, the unique activity of
photoacid catalysts (A and C) permits direct glycosylation
between peracetyl galactals 14 and a range of alcohols (15-21).
Under optimized conditions, 2-deoxy-3-acetoxyglycosides are
accessed in good yields (41%-77%) with excellent α-selectivity
(α/β >20:1).
O
O
O
O
O
RO
O
O
O
O
O
22a
O
O
O
O
O
O
O
25 80%
26 78%
16 66%
α / β = 18 : 1
α / β > 20 : 1
α / β > 20 : 1
MeO
MeO
Me
BnO
BnO
AcO
AcO
O
O
O
Me
Me
O
O
O
O
O
O
O
O
OR
OR
O
O
O
O
O
22b
O
O
O
O
O
O
27 93%
28 81%
29 74%
Next, we evaluated the scope of the glycal donors (Scheme
3). A series of differentially protected galactals 22a, L-rhamnals
22b, and glucals 22c were prepared,[8]a,b,[21] and subjected to
α / β > 20 : 1
α / β > 30 : 1
α / β > 30 : 1
OTBS
OBn
O
OMe
O
reaction conditions with 23 (bearing a primary OH) as
O
nucleophiles. Pleasingly, high yields (66%-93%) and excellent
selectivity (α/β ratio 16:1 to >30:1) for α-linked glycosides were
obtained in all examples. These results also highlight that the
reaction is tolerant of most functional groups in glycals (22),
which are methyl, methoxymethyl, benzyl, silyl, allyl ethers, and
acetyl esters (25-35).
TBSO
TBSO
BnO
BnO
MeO
MeO
OR
O
O
O
O
O
O
O
RO
RO
O
O
O
O
O
O
22c
O
O
O
O
O
O
30 85%
α / β = 17 : 1
32 83%
31 78%
α / β > 30 : 1
α / β > 30 : 1
OTBS
OH
OTBS
O
O
OBn
O
OMOM
BnO
BnO
OH
O
O
MeO
MeO
BnO
BnO
O
O
MOMO
MOMO
O
BzO
BzO
O
SPh
36
O
O
O
OBn
O
O
O
O
BzO
BnO
BnO
2
O
O
O
O
O
BzO
BzO
O
O
O
O
O
O
eosin Y (1 mol %)
PhSSPh ( 2 mol %)
Blue LEDs, CH2Cl2
O
O
TMSOTf, NIS
CH2Cl2, 0 °C
O
BzO
O
O
O
O
O
O
1
O
37 60%
34 81%
α / β > 20 : 1
35 83%
α / β = 16 : 1
33 87%
α / β = 17 : 1
Scheme 4. One-pot Synthesis of Trisaccharide.
Scheme 3. Scope of Glycals. General conditions: Reaction irradiated with two
12 W, 450 nm LED flood lamps. In each case, the yield of the isolated product
is given. α/β ratio was determined by 1H NMR analysis of crude products. Bn =
bynzyl, Ac = acetyl, TBS = t-butyldimethylsilyl, MOM = methoxymethyl.
Having demonstrated the mild nature of this photoacid
catalytic protocol, we then tested the new strategy in a one-pot
synthesis of trisaccharide 37 (Scheme 4). Excitingly, the
photoglycosylation was accommodated with acceptor 36 that
contained a sulfide (SPh) functional group at the anomeric
position. Such success allowed an in situ second glycosylation,
Encouraged by these results, we focused our attention on
exploring the scope of the photocatalytic glycosylation reaction.
Scheme 2 highlights the 2-deoxyglycoside products formed from
17 experiments probing ten different alcohols (acceptors) and
two glycal donors, perbenzylgalactal (1) and peracetyl galactal
(14). In all cases of galactals 1, the reaction proceeded smoothly
in excellent yields (67% to 91%) and with remarkable α-
selectivity (16:1 to α only). These examples demonstrate that the
catalytic system is tolerant of common alcohol (acetals, ethers,
esters) and amine (carbamate) protecting groups (3-11).
Intriguingly, high selectivity and efficiency are maintained
regardless of carbohydrate acceptor type or the positioning of
promoted by TMSOTf and NIS, with acceptor
stereospecifically furnish trisaccharide 37 in great yield (60%).
plausible mechanism for the reaction is outlined in
2
to
A
Scheme 5. Upon light irradiation, we proposed the excited
photocatalyst (PC*) would protonate the glycal 38, generating
the oxacarbenium intermediate 39 and
a
deprotonated
photocatalyst (42). Axial nucleophilic attack of ROH onto 39
afforded intermediate 40, which was then converted to the
glycosylation product 41 after a proton transfer process (with 46).
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10.1002/anie.201800909
Angewandte Chemie International Edition
COMMUNICATION
coupled to reduction
of 45
coupled to oxidation
of 42
− e
COO
Br
Br
+ e
OP
OP
S
PO
PO
O
O
OH
COO
PO
PO
O
ROH
Br
Br
Br
Br
O
43
46
O
O
O
OH
40
H
R
39
Br
Br
42
hυ
450 nm
COO
S
S
S
−H+
Br
Br
+H+
45
44
O
O
OH
Br
Br
43a
OP
OP
PO
PO
PO
PO
O
O
COO
HAT
with 47
Br
HO
Br
OH
SH
OR
41
38
HAT
O
COO
with 43a
Br
Br
Br
Br
OH
47
PC*
HO
O
hυ
450 nm
Br
Br
±H+
HAT
± e
= Proton Transfer
= H-Atom Transfer
= Redox Couple
photocatalyst (PC)
Keywords: 2-deoxyglycosides • acridinium-based organic
Scheme 5. Proposed Mechanism.
photoacid • photocatalyst • visible light • eosin Y
[1]
[2]
A. Kirschning, A. F. W. Bechthold, J. Rohr, Top. Curr. Chem. 1997,
188, 1.
In the catalyst system, PhSSPh was proposed to serve as a co-
catalyst. Homolysis of the weak S-S bond produced PhS" (45),
which could be redox-coupled with 42 via a single-electron
transfer process to furnish 43 and PhS− (46). PhS− (46) would
then serve as a base to facilitate the proton transfer step with 40
to produce the glycosylation product 41 and H-atom donor PhSH
(47). Intermediate 43a, a resonance structure of 43, would
P. T. Daniel, U. Koert, J. Schuppan, Angew. Chem. Int. Ed. 2006, 45,
872.
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a H-atom from PhSH (47) to regenerate the
photocatalyst (PC) and PhS" (45).
In summary, we have developed a method for the direct
preparation of 2-deoxy-glycosides from glycals by photoacidic
catalysis. A range of hydroxyl nucleophiles can be used in the
glycosylation, to deliver excellent yields and α-selectivity. A
variety of glycals, including acetate protected C-3 hydroxyl,
permitted glyocosylation to afford α-selective 2-deoxy-glycosides.
Further substrate scope and in-depth mechanistic studies with
regard to the importance of organic photoacids and their
applications in organic synthesis are ongoing in our laboratory.
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Acknowledgements
We are grateful to the University at Albany, State University of
New York, for financial support. We thank Prof. Alexander
Shekhtman (SUNY-Albany) and Prof. Zhang Wang (SUNY-
Albany) for NMR assistance. We also thank Prof. Andrew
Roberts (University of Utah) for helpful discussion and
proofreading of the manuscript.
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10.1002/anie.201800909
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This article is protected by copyright. All rights reserved.

10.1002/anie.201800909
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Photoacid (1 mol %)
O
RO
O
R1OH
A photoacid catalyzed synthesis
of 2-deoxy-glycosides from
glycals was developed. A series
of phenol-conjugated acridinium-
based organic photoacids was
rationally designed, synthesized
and studied alongside
commercially available eosin Y.
With such catalysts, glycals
undergo activation and couple
with a range of alcohols to afford
2-deoxyglycosides in excellent
yields and α-selectivity.
Gaoyuan Zhao, and Ting Wang*
RO
OR1
Blue LEDs
CH2Cl2
α-selective
Page No. – Page No.
Stereoselective Synthesis of 2-
Deoxyglycosides from Glycals
via Visible-Light-Induced
Photoacid Catalysis.
O
Me
O
Br
Br
Me
BF4
N
Me
HO
O
OH
Br
HO
Br
synthetic acridium-based
organic photoacid
commercially available
eosinY
Layout 2:
COMMUNICATION
Author(s), Corresponding Author(s)*
((Insert TOC Graphic here))
Page No. – Page No.
Title
Text for Table of Contents
This article is protected by copyright. All rights reserved.