Iridium-promoted deoxyglycoside synthesis: stereoselectivity and mechanistic insight

Article abstract of DOI:10.1039/d0sc06529c

Herein, we devised a method for stereoselectiveO-glycosylation using an Ir(i)-catalyst which enables both hydroalkoxylation and nucleophilic substitution of glycals with varying substituents at the C3 position. In this transformation, 2-deoxy-α-O-glycosides were acquired when glycals equipped with a notoriously poor leaving group at C3 were used; in contrast 2,3-unsaturated-α-O-glycosides were produced from glycals that bear a good leaving group at C3. Mechanistic studies indicate that both reactions proceedviathe directing mechanism, through which the acceptor coordinates to the Ir(i) metal in the α-face-coordinated Ir(i)-glycal π-complex and then attacks the glycal that contains theO-glycosidic bond in asyn-addition manner. This protocol exhibits good functional group tolerance and is exemplified with the preparation of a library of oligosaccharides in moderate to high yields and with excellent stereoselectivities.

Full text of DOI:10.1039/d0sc06529c

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Iridium-promoted Deoxyglycoside Synthesis: Stereoselectivity and
Mechanistic Insight
Kumar Bhaskar Pal,ab Aoxin Guo,b Mrinmoy Das,b Jiande Lee,bc Gábor Báti,b Benjamin Rui Peng Yip,b
Received 00th January 20xx,
Accepted 00th January 20xx
Teck-Peng Lohabd and Xue-Wei Liu*b
DOI: 10.1039/x0xx00000x
Herein, we devised
a method for the stereoselective O-glycosylation using Ir(I)-catalyst which enables both
hydroalkoxylation and nucleophilic substitution of glycals with varying substituent at C3 position. In this transformation, 2-
deoxy-α-O-glycosides were acquired when glycals equipped with a notoriously poor leaving group at C3 were used, on the
contrary 2,3-unsaturated-a-O-glycosides were produced from glycals that bear a good leaving group at C3. Mechanistic
studies indicate that both reactions proceed via directing mechanism, through which the acceptor coordinates to the Ir(I)
metal in the a-face-coordinated Ir(I)-glycal p-complex and then attacks the glycal that entails O-glycosidic bond in a syn-
addition manner. This protocol exhibits good functional group tolerance and is exemplified with the preparation of a library
of oligosaccharides in moderate to high yields and excellent stereoselectivities.
www.rsc.org/
saturated glycosyl donors consume stoichiometric amounts of
activating agents.
Introduction
Deoxy sugars, constituting essential structural components in a
variety of biologically active natural products, have drawn
significant attention from carbohydrate chemists lately.1 Over
the past few years, acid and base promoted synthesis of 2-
deoxy sugars became popular in the field of carbohydrate
chemistry.2 However, glycosylation by these approaches are
often conducted at either low or high temperatures, with the
possibility of getting appreciable amounts of unwanted
hemiacetal side products.2b,2c,2e,3 In comparison, transition
metal catalyzed glycosylation with glycals, compatible with acid
and base-labile substates and amenable to moderate
conditions, promise improved alternatives to the conventional
methods. During recent years, transition metal has featured an
important role in the chemical synthesis of oligosaccharides,
with a flow of intriguing glycosylation methodologies involving
a variety of transition metal catalysts reported.4-16 Conceptually,
by installing specific substituents onto the donors6 and/or
control of the oxidation state of the transition metal in the
catalysts, face-selective coordination of the catalytic metal
complex with the olefinic pyranose ring can be feasibly
achieved,7 enabling stereoselective construction of glycosidic
linkages. Additionally, glycal donors can be activated with a
catalytic amount of transition metal catalyst, while in
conventional acid or base promoted glycosylation reactions,
Previous Works
Pd-Catalysed O-glycosylation:
R
R
R
PO
PO
PO
Pd(0) or Pd(II)/Ligand
O
O
O
OR'
or
LG
R'OH
OR'
LG = Leaving group
P = Protecting group
R = H, OP
Ligand dependent and catalyst
controlled stereoselectivity
R
R
PO
PO
PO
Pd/Ligand
O
O
PO
R'OH
OR'
α-selectivity
Acid catalysed O-glycosylation:
R
R
R
PO
PO
PO
PO
TsOH or TfOH or CSA
O
O
O
or
PO
R'OH
OR'
OR'
Temperature dependent
chemoselective glycosylation
This work
R
PO
O
when P, P' = Ac
P'O
AgOTf (10.5 mol%)
OR'
[Ir(cod)Cl]2
(3.5 mol%)
R
PO
2-deoxy glycosides
O
P'O
when P = Ac;
P' = Ac
AgOTf (14 mol%)
R
R'OH
CH2Cl2, rt
PO
O
P, P' = protecting group
R = OP, H
Ag2CO3 (1 equiv.)
OR'
Ferrier type products
Substrate controlled, ligand free, room temperature α-selective O-glycosylation
Scheme 1. (a) Recent development on stereoselective conversion of glycals to 2-deoxy
glycosides and 2,3-unsaturated glycosides; (b) Ir(I)-catalyzed substrate controlled a
stereoselective-O-glycosylation of glycals.
a. Institute of Advanced Synthesis, Northwestern Polytechnical University, Xi’an
710072, China
b. Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link,
Singapore 637371
An important class of the transition metal catalyzed
glycosylation methodologies are those which exploit Palladium
catalysts for stereoselective synthesis of 2,3-unsaturated and 2-
deoxy glycosides from glycals, under anhydrous reaction
c. Nanyang Environment and Water Research Institute, Nanyang Technological
University, 1 Cleantech Loop, Singapore 637141
d. Yangtze River Delta Research Institute of Northwestern Polytechnical University,
Taicang Jiangsu, 215400, China
*Corresponding Author: xuewei@ntu.edu.sg
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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conditions to preclude formation of the hydrolyzed products.7,8
Nevertheless, to access different types of glycoside structures,
glycosylation of glycals require different Pd-catalytic systems
with various phosphine ligands. And with certain Pd-catalysts,
chemo-selectivity is achieved by conducting the reaction at
varying temperatures.7,8 Analogous to the established
Palladium catalysts, iridium complexes have been well known to
be efficient catalysts for allylic substitution reactions9 and
hydro-functionalisation10 of olefins, while the aptness of iridium
catalysts for glycosylation has scarcely been explored. Though
Nishimura et al.17 had reported a pioneering iridium-catalyzed
stereoselective C-glycosylation of glycals via C-H activation of
arenes, no iridium-catalyzed-O-glycosylation with direct
activation of glycal scaffolds has been reported to date.
Inspired by the success of Pd-catalyzed glycosylation
methodologies and advancements in development of Ir(I)-
catalyst towards allylic addition, substitution reactions and as a
part of our continuing effort on exploring the advanced stereo-
and regioselective glycosylation, we envisioned that the Ir-
catalyzed chemistry can be applied to the olefinic glycal
substrates to achieve stereoselective O-glycosylation. In this
article, we describe the novel ligand free iridium-catalyzed O-
glycosylation, that enables substrate-controlled access to both
2-deoxy glycosides and 2,3-unsaturated glycosides from easily
accessible protected glycals at room temperature, with
View Article Online
DOI: 10.1039/D0SC06529C
[Ir(COD)Cl]2 (3.5 mol%)
AgOTf (10.5 mol%)
OBn
O
OBn
BnO
BnO
BnO
O
BnO
R'OH (2a-2k, 2r-2t)
CH2Cl2, 24 h
OR'
1a
3a-3n
α:β = >5:1 to α only
OBn
OBn
O
OBn
OBn
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OMe
O
O
O
O
O
O
3d, 77%
α only
3a, 77%
α only
3b, 67%
α:β = >5:1
3c, 85%
α:β = 17:1
OBn
BnO
OBn
O
OBn
BnO
BnO
BnO
BnO
O
O
O
O
Ph
O
BnO
O
BnO
OMe
O
O
O
O
OBz
OBz
BnO
BnO
O
Ph
O
O
O
O
BzO
BnO
BzO
OBn
O
SEt
SPh
O
3g, 75%
α only
3h, 67%
α only
3f, 65%
α only
3e, 79%
α:β = >14:1
OBn
OBn
O
BnO
BnO
BnO
BnO
O
O
O
O
Ph
Ph
O
O
O
O
BnO
O
AcO
OMe
OMe
BnO
O
O
O
BnO
BnO
O
O
BnO
AcO
SEt
NPhth
BnO
OBn
OBn
3i, 53%
α only
3k, 47%
α only
3l, 63%
α only
3j, 70%
α only
exclusive a-stereoselectivity (Scheme 1).
OBn
O
BnO
BnO
OBn
BnO
BnO
H
H
O
O
O
H
H
O
N
O
Results and discussion
Our attempt commenced with the screening of catalyst
3m, 78%
α only
3n, 69%
α only
employing 3,4,6-tri-O-benzyl-D-galactal (1a) as glycosyl donor
Figure 1. Stereoselective a-O-glycosylation of 2a with a range of glycosyl acceptors (2a-
and 1,2:3,4-di-O-isopropylidene-
a
-D-galactopyranose (2a) as 2n). Reactions were carried out under N2 atmosphere using 1.5 equiv. 3,4,6-Tri-O-benzyl-
D-galactal (1a), 1.0 equiv. of acceptor, 3.5 mol% [Ir(COD)Cl]2, and 10.5 mol% AgOTf in dry
model glycosyl acceptor (Table 1). Not a trace amount of the 2-
deoxy-O-glycoside was detected when 3.5 mol% [Ir(COD)Cl]2
was used as the catalyst. It provided the desired 2-
deoxyglycoside (3a) with the addition of [Ir(COD)Cl]2/AgOTf and
CH2Cl2 for 24 h at rt. Stereoselectivity was determined by crude 1H NMR. Isolated yields.
to our satisfaction yield of the reaction was improved
significantly to 77% with 10.5 mol% loading of AgOTf in CH2Cl2
(Table 1, entry 4). Screening of the silver salts implied that the
O-glycosylation occurred most efficiently in the presence of
AgOTf (10.5 mol%). While assessing the solvents, we found that
the reaction didn’t proceed in 1,4-dioxane, however, the use of
MeCN, toluene, DCE and CHCl3 as solvent provided 27%, 41%,
52% and 66% yield of the desired 2-deoxyglycoside respectively,
but turned out to be less effective compare to CH2Cl2 (Table 1).
It is noteworthy that not a trace of desired glycosylated product
was observed with the bulky P(OPh)3 ligand, possibly due to the
Table 1. Optimization of the Ir(I)-catalyzed glycosylation for the synthesis of 2-deoxy
glycosides with glycal 1a and model acceptor 2a.
Entry
Catalyst (mol%)
[Ir(COD)Cl]2 (3.5)
[Ir(COD)Cl]2 (2.5)
[Ir(COD)Cl]2 (3.5)
[Ir(COD)Cl]2 (3.5)
[Ir(COD)Cl]2 (3.5)
-
Ag-Salt (mol%)
-
Solvent
DCM
yield
-
a
:
ba
1
2
NA
1:0
1:0
1:0
NA
1:0
AgOTf (5)
DCM
30%
45%
77%
-
3
AgOTf (7)
DCM
4
5b
AgOTf (10.5)
AgOTf (10.5)
AgOTf (10.5)
AgOTf (10.5)
AgOTf (10.5)
AgOTf (10.5)
AgOTf (10.5)
DCM
DCM
6
DCM
29%
27%
41%
52%
66%
7
[Ir(COD)Cl]2 (3.5)
[Ir(COD)Cl]2 (3.5)
[Ir(COD)Cl]2 (3.5)
[Ir(COD)Cl]2 (3.5)
MeCN
Toluene
DCE
15:1 obstruction of the nucleophile acceptor from approaching the
8
1:0
glycal considering the sterically hindered Ir[P(OPh)3]-glycal
p-
9
1:0
1:0
complex (Table 1, entry 5). As summarized in Table 1,
[Ir(COE)2Cl]2 afforded the desired glycosylated product 3a, but
lower yield (33%) was attained. With optimized conditions in
hand, a range of nucleophilic acceptors was reacted with the
3,4,6-tri-O-benzyl-D-galactal (1a) to investigate the donor scope
of the Ir-catalyzed hydro-alkoxy addition (Figure 1). A large
variety of substituents on the glycosyl acceptors were well
tolerated, constituting commonly used carbohydrate protecting
10
CHCl3
1,4-
11
[Ir(COD)Cl]2 (3.5)
AgOTf (10.5)
-
NA
Dioxane
DCM
12
13
14
15
[Ir(COD)Cl]2 (3.5)
[Ir(COD)Cl]2 (3.5)
[Ir(COD)Cl]2 (3.5)
[Ir(COE)2Cl]2 (3.5)
AgSbF6 (10.5)
AgBF4 (10.5)
AgPF6 (10.5)
AgOTf (10.5)
23%
40%
-
1:0
1:0
NA
1:0
DCM
DCM
DCM
33%
All the reactions were carried out with 0.15 mmol 1a and 0.1 mmol 2a. aStereoselectivity
was determined by crude 1H NMR. bP(OPh)3 was used as a ligand. Isolated yields.
2 | J. Name., 2012, 00, 1-3
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Table 2. Reaction of Glycals 1b−1i, 1j−1k, and 1l with model glycoside acceptor 2a
Table 3. Optimization of the Ir(I)-catalyzed glycosylation for the synthesis of 2, 3-
View Article Online
DOI: 10.1039/D0SC06529C
unsaturated glycosides with glycal 1n and model acceptor 2a.
OR3
OR3
R2
R1
O
O
O
OH
O
O
R2
R1
O
O
O
Entry
1
2
3
4
5
6
7
8
Catalyst (mol%)/Ag-Salt (mol%)
[Ir(cod)Cl]2 (2.5)/ AgOTf (5)
[Ir(cod)Cl]2 (3.5)/ AgOTf (7)
[Ir(cod)Cl]2 (3.5)/ AgOTf (10.5)
[Ir(cod)Cl]2 (3.5)/ AgOTf (14)
AgOTf (14)
[Ir(cod)Cl]2 (3.5)/ AgOTf (14)
[Ir(cod)Cl]2 (3.5)/ AgOTf (14)
[Ir(cod)Cl]2 (3.5)/ AgOTf (14)
[Ir(cod)Cl]2 (3.5)/ AgOTf (14)
[Ir(cod)Cl]2 (3.5)/ AgOTf (14)
Base
Solvent
DCM
DCM
DCM
DCM
yield
23%
42%
66%
73%
36%
39%
52%
34%
57%
45%
O
O
O
OR3
O
O
R2
O
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
O
O
O
1j-1k
O
R1
O
OR3
O
O
R2
O
2a
O
[Ir(COD)Cl]2 (3.5 mol%)
O
R1
O
O
O
3w, 3y
AgOTf (10.5 mol%)
CH2Cl2, 24 h
O
1b-1i
O
O
O
O
DCM
MeCN
3o-3v
O
O
O
Si
O
O
O
Si
O
O
Ag2CO3 Toluene
O
1l
Si
O
O
Si
Ag2CO3
Ag2CO3
Cs2CO3
DCE
CHCl3
DCM
9
10
3x (74%)
α:β = >4:1
All the reactions were carried out with 0.15 mmol 1n, 0.1 mmol 2a and 1 mmol of base
for 48 h. For all entry we got exclusively a selectivity. Isolated yields.
Yield
(%)
Entry Donor
R1
R2
R3
Me
Et
Allyl
Product
:
a b
Table 4. Ferrier type glycosylation of various glycals 1n-1r with glycoside acceptor 2a.
1
2
3
4
5
1b
1c
1d
1e
1f
Me
Et
Allyl
Me
Et
Allyl
3o
3p
3q
3r
3s
3t
3u
3v
3w
3y
83%
78%
82%
80%
76%
79%
86%
81%
78%
8%
1:0
23:1
1:0
1:0
1:0
10:1
>30:1
1:0
1:0
1:0
OR2
O
R1O
OH
O
O
TBDMS TBDMS TBDMS
TBDMS
Bn
Bn
Bn
[Ir(COD)Cl]2 (3.5 mol%)
AgOTf (14 mol%)
OR2
O
O
O
O
R1O
AcO
Ac
Bn
Bn
Ac
TBDMS
TBDPS
Ac
Bn
TBDPS
+
O
O
O
O
Ag2CO3 (1 equiv.)
CH2Cl2, 48-72 h
O
6
7
8
1g
1h
1i
O
1n-1r
2a
4a-4e
9
10a
1j
1k
O[Si(iPr)2]2
TBDMS TBDMS TBDMS
Entry
Donor
1n
1o
1p
1q
R1
Allyl
Et
Bn
PMB
PX
R2
Allyl
Et
Bn
PMB
PX
Product
4a
4b
4c
4d
Yield (%)
73%
61%
79%
75%
a
:
ba
All the reactions were carried out under N2 atmosphere using 1.5 equiv. glycosyl donors
(1b-1k), 1.0 equiv. acceptor (2a) in dry CH2Cl2 for 24 h. a4r obtained as a major product
(71%). Stereoselectivity was determined by crude 1H NMR. Isolated yields.
1
2
3
4
5
1:0
>8:1
9:1
>13:2
19:1
groups, e.g. acetal, ester, ether, and phthalimide, and all the
reactions afforded desired 2-deoxy glycosides in a yield range of
1r
4e
70%
All the reactions were carried out under N2 atmosphere using 1.5 equiv. glycosyl donors
(1n-1r), 1.0 equiv. acceptor (2a) in dry CH2Cl2 for 48-72 h. aStereoselectivity was
determined by crude 1H NMR. Isolated yields. PX = p-Xylyl.
47-85% with
case of 3b
isomers were identified from H NMR but with the favourable
-stereoselectivity and good yield (67%, 85% and 79%
a
-stereoselectivity. It is worth noting that, in the
(
a
:
b
= >5:1), 3c =17:1) and 3e = >14:1) b-
(
a
:
b
(
a
:
b
1
a
We have shown that glycals bearing poor leaving group at C3
respectively, Figure 1). The reaction proceeded equally well
with secondary hydroxyl groups positioning at variable
positions of pyranose ring of different carbohydrates including
reacted with alcohols to provide 2-deoxy-a-O-glycosides, thus
we became intrigued about the possible outcome of repeating
the same transformation on glycals with good leaving group at
C3 position. We initiated our studies by employing 3-O-acetyl-
glucose (2h
,
2i and 2j, see ESI), glucosamine (2k, see ESI),
2g, see ESI), and fructose (2d, see ESI). To our
mannose (2f
,
4,6-di-O-allyl-D-glucal with 1,2:3,4-di-O-isopropylidene-a-D-
satisfaction, the transformation provided the desired glycosides
in moderate to high yield while maintaining excellent
stereoselectivity. The reported method enabled glycosylations
of the sterically hindered alcohols (2f 2r, see ESI) that gave the
corresponding products (3f and 3l respectively, Figure 1) in high
yields with stereoselectivity upon isolation. We then assessed
galactopyranose (2a) and found that optimal conditions (3.5
mol% [Ir(COD)Cl]2, 14 mol% AgOTf, and 1 equiv. of Ag2CO3)
worked just as effectively as it did for the 2-deoxy-O-glycoside
synthesis (entry 4, table 3). We examined the effect of solvation
and found that solvents like MeCN (39%, entry 6, table 3), DCE
(34%, entry 8) constrained the desired product formation (table
3). Toluene (entry 7, table 3) and CHCl3 (entry 9, table 3)
provided the product in 52% and 57% yield respectively, but we
attained finest yield (73%) for the allylic substitution reaction
when we carried out the reaction in CH2Cl2 (entry 4, table 3).
After optimizing the parameters, we turned our attention to
exploring the feasibility of the donor scope and we found that
our reaction condition worked well with the set of commonly
used carbohydrate protecting groups with 61-79% yield (table
4). The protecting groups at C4 and C6 positions in the glycosyl
donors had a pronounced effect on the yields and outcome of
the reactions. Specifically, applying m-nitrobenzyl protection
a-
,
a-
the reaction with an array of glycal donors embedded with a
variety of ether and ester protections and satisfactorily all the
tested donors were well compatible, afforded desired
a-
glycosides in good to excellent yields (summarized in Table 2). It
is important to note that when we have carried out the reaction
with conformationally unrestricted glucal 1k, we obtained more
Ferrier product (71%, entry 10, table 2) than 2-deoxy glycoside
(8%), whereas we acquired only 2-deoxy glycoside with
conformationally restricted glucal (1j, entry 9, table 2) and
rhamnal (1l). Thus, the formation of either glycosidic product
greatly depends both on the stereochemistry and conformation
of the protecting groups in the glycals.3b, 3c
(
1s, see ESI) on the donor didn’t afford the desired product as
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providing only a complex mixture. Taking the strong electron- generated in moderate to good yields (54%, 72%, and 61%
View Article Online
DOI: 10.1039/D0SC06529C
withdrawing nature of m-nitro group into account, we suggest respectively, Figure 2).
that it disrupts the positively charged
leading the reaction to fail. We observed a similar outcome in and secondary alcohols, yielding desired disaccharides in high
case of peracetylated glucal, perhaps due to the same sort of efficiency and good -selectivity. To interpret the mechanism of
p-allylic system, thus Moreover, this method is quite amenable with several primary
a
electron-withdrawing nature of the acetyl group. The reported this reaction, we carried out DFT study. We proposed that to
method also failed to provide the desired glycoside with 4,6-O- start the catalytic cycle, [Ir(COD)Cl]2 first reacts with AgOTf to
p-methoxybenzylidene-3-O-acetyl-D-glucal
(
1t
,
see ESI) generate active species [Ir(COD)OTf]2 (Figure 3).18 The dimer
signifying the requirement of conformationally flexible C4 and complex then dissociates into two transient monomeric
C6 protecting groups.
Ir(COD)OTf complexes (see ESI), which in turn coordinate to the
OAllyl
OAllyl
O
OAllyl
O
2-Deoxyglycoside
[Ir(COD)Cl]2
O
AllylO
AllylO
AllylO
OR
AgOTf
RO
RO
O
O
O
O
O
OBz
O
AgCl
O
OR
O
OR'
O
O
[Ir(COD)OTf]2
O
RO
RO
O
BzO
O
O
BzO
O
O
OMe
R'OH
OR
OR
Ir
4f, 65%
α only
4g, 62%
α only
4h, 54%
α:β = >14:1
RO
TfO
O
RO
O
OR
OR'
OR
OR'
OAllyl
O
OAllyl
TfO
Ir
H
OAllyl
O
B
O
H
AllylO
AllylO
A
AllylO
O
O
O
O
NPhth
2,3-Unsaturated glycoside
O
O
O
SEt
BnO
BnO
BzO
BzO
[Ir(COD)Cl]2
O
OR
Ph
AgOTf
AgCl
RO
BnO
BzO
OMe
OMe
O
OR'
4i, 72%
α:β = >8:1
4j, 61%
α only
4k, 76%
α:β = >6:1
OR
[Ir(COD)OTf]2
RO
O
AcO
OBn
BnO
OAllyl
O
OR
O
RO
OAllyl
OTf
AllylO
O
OR
O
AllylO
OBn
O
BnO
O
O
O
OR'
AcO
O
O
Ir
O
OR
O
PMBO
O
O
H
SEt
OPMP
O
O
O
Ir
OTf
Ph
O
D
R'OH
BnO
O
C
4l, 76%
α:β = >13:1
4m, 70%
α only
4n, 69%
α:β = 10:1
Figure 3. Schematic representation of the proposed mechanism giving rise to 2-deoxy-
a-glycoside and 2,3-unsaturated-a-glycoside arising from Ir(I)-catalyzed O-glycosylation.
OBn
O
BnO
OBn
O
O
O
O
O
BnO
OR
OR
OR
Ir
O
OH
O
RO
TfO
RO
RO
OMe
O
O
O
OR
OR'
O
O
O
R'OH =
BnO
O
OR
OR
O
O
O
O
O
Ir
TfO
Ir
TfO
OR'
BnO
BnO
O
Ph
O
H
H
O
R = Bn
BnO
BnO
2a
OMe
IM1α
IM2α
TSα
4o, 79%
α:β = 14:1
4p, 57%
α only
4q, 76%
α only
Ir(COD)OTf
15.3
Figure 2. a-Selective Ferrier type O-glycosylation of 1n, 1u and 1v with a variety of
glycosyl acceptors. Reactions were carried out under N2 atmosphere using 1.5 equiv.
glycosyl donor (1), 1.0 equiv. of acceptor (2), 3.5 mol% [Ir(COD)Cl]2, 14.0 mol% AgOTf,
and 1.0 equiv. of Ag2CO3 in dry CH2Cl2 for 48-72 h at rt. Stereoselectivity was determined
by crude 1H NMR. Isolated yields.
RO OR
O
TSβ
+5.8
RO
OR'
α-glycoside
0.0
[Ir(COD)OTf]2
+ 1a + 2a
IM1β
-8.2
TSα
To evaluate the synthetic applicability of this method, we set
out the use of a series of glycosyl acceptors for the Ferrier-type
nucleophilic substitution reactions (Figure 2). To our delight, the
versatility proved to be highly efficient since glycosylations
proceeded smoothly to furnish the desired glycosides in yields
-10.4
IM2β
β-glycoside +
Ir(COD)OTf
-12.9
-9.5
IM1α
-15.4
-16.5
α-glycoside +
Ir(COD)OTf
of 54-79% and high
Notably, sterically hindered alcohols 2l
coupling stereoselectively to give 4h
>13:1), in 54% and 76% yield respectively. Glycosyl acceptors
containing benzoate and phthalimide protecting groups (2l 2m
a
-selectivity (>6:1
a
,
:
b
to
2p (see ESI) underwent
, >14:1) and 4l (a:b,
a only, Figure 2).
-27.1
IM2α
(
a:
b
Reaction direction
,
Figure 4. Free energy profile for the catalytic cycle of Ir (I)-catalyzed glycosylation of
and 2n, see ESI) are also well tolerated by this procedure, with 3,4,6-tri-O-benzyl galactal (1a) with model acceptor 2a.
desired disaccharides 4h, 4i (a:b, >8:1) and 4j (a only)
4 | J. Name., 2012, 00, 1-3
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ARTICLE
glycal. We rationalize that for the 3,4,6-tri-O-benzyl glycal donor iridium coordinated glycal intermediate by the acceptor,
View Article Online
DOI: 10.1039/D0SC06529C
1a, the iridium metal center coordinates to the olefinic C1 and determine the favored reaction routes and have a major
C2 carbon to form stable h
2 π-allyl intermediates; while for the influence on the stereochemical outcome of the glycosylation
3-O-acetaly-4,6-di-O-benzyl-D-galactal donor 1u, which carries reaction. Upon formation of the major iridium-glycal π-allyl
a better leaving group at 3-position, the Ir(COD)OTf species first complex intermediates, anomeric carbon on the glycal become
coordinates to C1 and C2 to form
upon dissociation of the triflate anion from the metal center, to the iridium center in the metal-glycal complex first (See ESI
the metal center further coordinates with C3 to form a
3 π-allyl for a detailed discussion), then attacks the adjacent anomeric
h
2 π-allyl intermediates, then, activated, and we hypothesized that the acceptor coordinates
h
complex, expelling the 3-acetyl substituent as an acetate anion, carbon in a syn-addition manner, leading to the formation of
which may then coordinates to the metal center as a free ligand corresponding 2-deoxy or 2,3-unsaturated glycosides, while
(Figure 3). Importantly, Ir(COD)OTf can coordinate to the glycal regenerating the catalytic complex (Figure 3). DFT computed
energetic profile of important intermediates and transition
OR
OR
OR
O
OH
O
states are shown in Figure 4 and Figure 5.
For galactal 1a
intermediates arising from h2 π-allyl
coordination of Ir(COD)OTf to the glycal donor from both faces
IM1 and IM1 ) are energetically similar (Figure ). The
stronger steric repulsion in -face coordinated IM1 might be
RO
O
O
O
O
OR
OTf
O
OR
OR'
O
R'OH =
O
,
O
OR
O
Ir
Ir
AcO
Ir
OR'
O
H
H
R = Bn
2a
(
a
b
4
Ir(COD)OTf
15.3
IM1α'
IM3α'
TSα'
b
b
OR
Ir
OR
O
RO
compensated by the stabilization of hydrophobic interactions
between the C3 benzyl group and the cyclohexadiene group in
O
O
OR
O
OR'
α-glycoside
the complex. Contrarily, for galactal 1u
Ir(COD)OTf from -face (IM1 ) is sizably more stable than the
-face counterpart IM1 (Figure ), probably due to the
, h
2 π-allyl complex with
IM1β'
-2.3
0.0
TSβ'
-9.3
a
a
’
IM2α'
[Ir(COD)OTf]2
+ 1u + 2a
b
b
’
5
difficulty of covalently linked C3 acetyl to interact with the
iridium metal center and stabilize the intermediate complex.
-7.3
IM1α'
IM2β'
-15.4
h
3 π-allyl
β-glycoside +
-22.3 Ir(COD)OAc
The explanation is corroborated by the results that the
coordinated complexes IM2 and IM2 , both having the
-16.0
TSα'
IM2α'
a
’
b
’
-18.6
α-glycoside +
Ir(COD)OAc
-23.2
dissociated acetate ligand coordinating to the iridium metal
center, are rather similar in energy level.
IM3β'
-32.5
Although the metal coordinated intermediates without the
acceptor coordinating to the metal center show minor facial
preference for both 1a and 1u, for the acceptor coordinated
intermediates arising from 1a, computation results suggest an
appreciable a-face preference. The higher energy level of the b-
face coordinated intermediates with acceptor coordinated to
the metal center can be mainly attributed to the steric crowding
-34.4
IM3α'
Reaction direction
Figure 5. Free energy profile for the catalytic cycle of iridium catalyzed glycosylation of
3-O-acetyl-4,6-di-O-benzyl galactal (1u) with model acceptor 2a.
of the
effect is significantly less pronounced in the IM3
C3 acetyl galactal 1u, which, without the absence of a bulky C3
benzyl substituent, leaves the -face coordinated Ir(COD)
b
-face intermediate IM2
b
(See ESI). The steric repulsion
b
’
arising from
2.46Å
b
2.87Å
2.45Å
group, larger space for accommodating the additional
coordination to the acceptor (See ESI).
For both 1a and 1u, activation energy of the transition state of
TS
a
TS '
a
nucleophilic attack step shows a strong a-face preference. For
all TSs (transition states) arising from nucleophilic attack of the
acceptor on the glycal donor, the iridium metal center
dissociates from C1 yet remain largely coordinated to C2 (Figure
2.61Å
6
). Similar to the scenario of the acceptor coordinated
intermediates, the -face preference of TS arising from
nucleophilic attack on iridium-coordinated 1a mainly results
from steric crowding of the -face TS. While for the TSs arising
from nucleophilic attack on iridium-coordinated 1u, the
a
2.93Å
2.53Å
TS
b
TS '
b
b
a-
Figure 6. Optimized trasition state structures arising from nucleophilic attack of 2a on 1a
(left) and 1u (right).
preference possibly due to a combination of steric factors and
anomeric effect.
at either face of the pyranose ring, with one face preferred over
another due to steric and electronic factors. The relative
stability of possible intermediates species, as well as the
activation energy of the following nucleophilic attack on the
DFT computation results suggest that both the reaction routes
leading to
proceeds through
intermediates generally more stable than the
a
-products are kinetically favored. The reaction
directing mechanism, with -face
-counterparts
a
a
b
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Page 6 of 8
ARTICLE
Journal Name
along the reaction routes, and the energy of the transition state donor anomeric center and facilitates the nucleophilic attack by
View Article Online
DOI: 10.1039/D0SC06529C
for nucleophilic attack from
energy of the TS of the
a-face significantly lower than the alcohol at mild condition.
b
-face nucleophilic attack, which likely To demonstrate the applicability of this newly developed
arises from a combination of the unfavorable steric interactions methodology, synthesis of oligosaccharides has been
between the 3-substituents and the metal complex in the TSs conducted. As shown in scheme 2, disaccharide donor 1m was
and anomeric effect. The theoretically inferred coordination of reacted with the model acceptor 2a, which afforded the
acceptor to the iridium is further corroborated by 1H NMR corresponding trisaccharide,
investigations, in which addition of the iridium catalyst -selectivity (a 20:1). Then previously synthesized
5 in 69% yield with desirable high
a
:b =
(equimolar w.r.t. 2a) to the acceptor in CD2Cl2 result in a disaccharide 3u was subjected for selective deacetylation19
pronounced downfield shifting of the hydroxy proton from using NaOMe in MeOH which afforded acceptor 2u in 75% yield.
1.714 ppm to 2.231 ppm, indicating probable coordination On a similar note, glycosylation of same disaccharide donor 1m
between the OH group and the Ir(I) center. The theoretically with glycosyl acceptor 2u proceeded smoothly to give the
proposed coordination of iridium metal to the glycal substrate corresponding tetrasaccharide,
in the catalytic cycle is also supported by 1H NMR experiments,
-stereoselectivity. Finally, in a separate experiment, we
in which addition of the iridium catalyst to a solution of 1a in employed Ir(I)-catalyst successfully to synthesize 2,3-
CD2Cl2 resulted in an appreciable downfield shifting of the unsaturated O-glycoside containing trisaccharide, with a
alkene protons from 6.333 ppm and 4.843 ppm to 6.613 ppm complete -selectivity from monosaccharide donor 1n and
6 in 63% yield with an absolute
a
7
a
and 5.007 ppm respectively, indicating probable coordination
disaccharide acceptor 2v in a decent yield (53%), which
demonstrate the practical utility of this method in the synthesis
of higher analogue glycans.
OBn
O
BnO
BnO
O
OBn
O
O2N BnO
BnO
OH
O
O
[Ir(COD)Cl]2 (3.5 mol%)
AgOTf (10.5 mol%)
O
BnO
BnO
O
O
Conclusion
+
O2N BnO
O
O
CH2Cl2, 24 h
69%
O
O
O
BnO
O
O
To summarize, we have demonstrated two concurrent Ir(I)-
catalyzed glycosylation events, that can be independently
adjusted by exploiting a substrate-controlled approach on the
glycal donors. The Ir(I)-catalyzed glycosylation reaction of glycal
donors with an armed group at C3 affords 2-deoxy-O-glycoside,
while glycosylation of a C3-acetyl glycal donor affords 2,3-
unsaturated-O-glycoside. For both types of the Ir(I)-catalyzed
O
1m
2a
O
5
(α:β = 20:1)
OBn
O
BnO
BnO
O
O2N BnO
BnO
OR
O
BnO
BnO
OBn
O
O
[Ir(COD)Cl]2 (3.5 mol%)
AgOTf (10.5 mol%)
BnO
BnO
O
O
BnO
BnO
+
O2N BnO
BnO
O
O
CH2Cl2, 24 h
63%
O
O
O
O
O
O
O
glycosylation, we optimized the reaction conditions with
a
O
1m
O
O
O
stereoselectivity, then, the generality of the Ir(I)-catalyzed
glycosylation has shown in over 40 examples featuring a range
of glycal donors and acceptors bedecked with commonly used
protecting groups. Our results confirm that the Ir(I)-catalyzed
alcohol glycosylation reaction can be feasibly performed at mild
conditions, requiring a catalytic amount of Ir(I)-catalyst for
activation of glycal donors. The mechanism accounting for the
6
NaOMe/
MeOH
75%
O
3u, R = Ac
2u, R = H
(α only)
OAllyl
O
AllylO
HO
BnO
BnO
OBn
O
O
BnO
BnO
OBn
[Ir(COD)Cl]2 (3.5 mol%)
AgOTf (14 mol%)
OAllyl
O
O
OBn
BnO
OBn
O
BnO
+
AllylO
AcO
O
O
O
Ag2CO3 (1 equiv.)
CH2Cl2, 48 h
53%
BnO
OPMP
BnO
1n
2v
7
OPMP
(α only)
a
-stereoselectivity of the Ir(I)-catalyzed-glycosylation by glycal
Scheme 2. Ir(I)-catalyzed a-stereoselective-O-glycosylation for the synthesis
of model trisaccharides and tetrasaccharide.
donors was investigated with DFT calculations. We further
demonstrated that our Ir(I)-catalyzed glycosylation methods
can be implemented for the construction of trisaccharides and
tetrasaccharides, and presumably oligosaccharides, enabling
facile access to biologically important oligosaccharides
between the glycal
p-system and the iridium center. The
downfield shifting of alkene protons upon coordination to
iridium metal center is rationalized by computation of the
partial charges of the C2 atom in both free 1a substrate and the
stable intermediate arising from 1a complexed to iridium metal
comprising 2-deoxy-sugar structures connected by
linkages.
a-glycosidic
center at
a face, with alcohol coordinated to the iridium. The
computed partial charge of C2 in the coordinated intermediate
is more positive (-0.147) with respect to the partial charge of C2
in free 1a (-0.168), indicating a chemical environment of lower
electron density for alkene protons upon coordination. The
computed partial charge of C1 in same intermediate is also
significantly more positive (0.230) with respect to C1 in free 1a
(0.187), agreeing with our hypothesis that coordination of the
glycal to the iridium catalyst enhances the electrophilicity of the
Conflicts of interest
The authors declare no competing financial interests.
Acknowledgements
K.B.Pal and T.-P.Loh thank Northwestern Polytechnical
University for their financial support. We thank the Nanyang
Technological University (RG9/20) and National Research
6 | J. Name., 2012, 00, 1-3
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(d) S. Pan, T. Shibata, ACS Catal., 2013, 3, 704-712; (e) J. Qu,
G. Helmchen, Acc. Chem. Res., 2017, 50, 2539-2555; (f) K.
Spielmann, G. Niel, R. M. D. Figueiredo, J.-M. Campagne,
Chem. Soc. Rev., 2018, 47, 1159-1173.
Foundation (NRF2016NRF-NSFC002-005), Singapore for their
financial support.
View Article Online
DOI: 10.1039/D0SC06529C
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Chemical Science
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DOI: 10.1039/D0SC06529C
Journal Name
ARTICLE
Ir(I)-catalyzed highly a-selective O-glycosylation of glycals has been developed, providing an efficient access to both 2-deoxy-O-
glycosides and 2,3-unsaturated-O-glycosides with a comprehensive substrate scope. Underlying rationale of a-selectivity was
illustrated by DFT and 1H NMR study, which demonstrated a probable directing mechanism for both conversions.
R
[Ir(COD)Cl]2
AgOTf
[Ir(COD)Cl]2
AgOTf
PO
R
R
PO
PO
O
O
O
P'O
P'O
Ag2CO3
R'OH
CH2Cl2, rt
R'OH
CH2Cl2, rt
P, P' = protecting group
OR'
OR'
R = OP, H
when P = Ac, P' = Ac
18 examples
54-83% (α selective)
when P, P' = Ac
26 examples
47-86% (α selective)
Broad acceptor scope
Wide range of glycal donors
Good functional group tolerance
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