Glycosyl Cross-Coupling of Anomeric Nucleophiles: Scope, Mechanism, and Applications in the Synthesis of Aryl C-Glycosides

Article abstract of DOI:10.1021/jacs.7b08707

Stereoselective manipulations at the C1 anomeric position of saccharides are one of the central goals of preparative carbohydrate chemistry. Historically, the majority of reactions forming a bond with anomeric carbon has focused on reactions of nucleophiles with saccharide donors equipped with a leaving group. Here, we describe a novel approach to stereoselective synthesis of C-aryl glycosides capitalizing on the highly stereospecific reaction of anomeric nucleophiles. First, methods for the preparation of anomeric stannanes have been developed and optimized to afford both anomers of common saccharides in high anomeric selectivities. We established that oligosaccharide stannanes could be prepared from monosaccharide stannanes via O-glycosylation with Schmidt-type donors, glycal epoxides, or under dehydrative conditions with C1 alcohols. Second, we identified a general set of catalytic conditions with Pd₂(dba)₃ (2.5 mol%) and a bulky ligand (JackiePhos, 10 mol%) controlling the β-elimination pathway. We demonstrated that the glycosyl cross-coupling resulted in consistently high anomeric selectivities for both anomers with mono- and oligosaccharides, deoxysugars, saccharides with free hydroxyl groups, pyranose, and furanose substrates. The versatility of the glycosyl cross-coupling reaction was probed in the total synthesis of salmochelins (siderophores) and commercial anti-diabetic drugs (gliflozins). Combined experimental and computational studies revealed that the β-elimination pathway is suppressed for biphenyl-type ligands due to the shielding of Pd(II) by sterically demanding JackiePhos, whereas smaller ligands, which allow for the formation of a Pd-F complex, predominantly result in a glycal product. Similar steric effects account for the diminished rates of cross-couplings of 1,2-cis C1-stannanes with aryl halides. DFT calculations also revealed that the transmetalation occurs via a cyclic transition state with retention of configuration at the anomeric position. Taken together, facile access to both anomers of various glycoside nucleophiles, a broad reaction scope, and uniformly high transfer of anomeric configuration make the glycosyl cross-coupling reaction a practical tool for the synthesis of bioactive natural products, drug candidates, allowing for late-stage glycodiversification studies with small molecules and biologics.

Full text of DOI:10.1021/jacs.7b08707

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Article
Glycosyl Cross-Coupling of Anomeric Nucleophiles – Scope,
Mechanism and Applications in the Synthesis of Aryl C-glycosides
Feng Zhu, Jacob Rodriguez, Tianyi Yang, Ilia Kevlishvili, Eric Miller, Duk
Yi, Sloane O'Neill, Michael Rourke, Peng Liu, and Maciej A. Walczak
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08707 • Publication Date (Web): 17 Nov 2017
Downloaded from http://pubs.acs.org on November 17, 2017
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Glycosyl Cross-Coupling of Anomeric Nucleophiles – Scope, Mechanism
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Feng Zhu,1 Jacob Rodriguez,1 Tianyi Yang,1 Ilia Kevlishvili,2 Eric Miller,1 Duk Yi,1 Sloane O’Neill,1
Michael J. Rourke,1 Peng Liu,2* and Maciej A. Walczak1*
1Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA; 2Department of Chem-
istry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USA
ABSTRACT: Stereoselective manipulations at the C1 anomeric position of saccharides are one of the central goals of preparative
carbohydrate chemistry. Historically, the majority of reactions forming a bond with anomeric carbon has focused on reactions of
nucleophiles with saccharide donors equipped with a leaving group. Here, we describe a novel approach to stereoselective synthesis
of C-aryl glycosides capitalizing on the highly stereospecific reaction of anomeric nucleophiles. First, methods for the preparation of
anomeric stannanes have been developed and optimized to afford both anomers of common saccharides in high anomeric selectivities.
We established that oligosaccharide stannanes could be prepared from monosaccharide stannanes via O-glycosylation with Schmidt-
type donors, glycal epoxides, or under dehydrative conditions with C1 alcohols. Second, we identified a general set of catalytic
conditions with Pd2(dba)3 (2.5 mol%) and a bulky ligand (JackiePhos, 10 mol%) controlling the b-elimination pathway. We demon-
strated the glycosyl cross-coupling results in consistently high anomeric selectivities for both anomers with mono- and oligosaccha-
rides, deoxysugars, saccharides with free hydroxyl groups, pyranose and furanose substrates. The versatility of the glycosyl cross-
coupling reaction was probed in the total synthesis of salmochelins (siderophores) and commercial anti-diabetic drugs (gliflozins).
Combined experimental and computational studies revealed that the b-elimination pathway is suppressed for biphenyl-type ligands
due to the shielding of Pd(II) by sterically demanding JackiePhos whereas smaller ligands, which allow for the formation of a Pd-F
complex, predominantly result in a glycal product. Similar steric effects account for the diminished rates of cross-couplings of 1,2-
cis C1-stannanes with aryl halides. DFT calculations also revealed that the transmetalation occurs via a cyclic transition state with
retention of configuration at the anomeric position. Taken together, facile access to both anomers of various glycoside nucleophiles,
a broad reaction scope, and uniformly high transfer of anomeric configuration make the glycosyl cross-coupling reaction a practical
tool for the synthesis of bioactive natural products, drug candidates, allowing for late-stage glycodiversification studies with small
molecules and biologics.
INTRODUCTION
Due to the unique position of C-aryl glycosides as
privileged glycomimetics, various methods have been de-
scribed to stereoselectively introduce aryl groups into the ano-
meric position.17-22 The most common approaches focus on (i)
nucleophilic addition of an organometallic reagent (e.g., or-
ganozinc)23-24 to anomeric halides catalyzed by Ni,25-28 Co, Pd,
and Fe29 complexes, (ii) addition of a nucleophile to a lactone
followed by reduction of the resultant acetal, and (iii) Friedel-
Crafts-type alkylation of electron-rich arenes or direct phenol
O-glycosylation followed by a stereoselective O®C rearrange-
ment.30-31 In the context of C(sp2)-C(sp2) cross-couplings, reac-
tions of glycals in the form of a C1-nucleophile32 or a C1-elec-
trophile33-35 have been described. These methods often repre-
sent a viable solution to a particular synthetic problem and the
key limitations such as the control of anomeric configuration
dependent on the identity of the saccharide and the C2 substit-
uents, functional group compatibility of the nucleophilic rea-
gents, and the need for additional manipulations required to es-
tablish a proper carbohydrate core prevent their widespread use.
Although the chemical synthesis of saccharides is considered a
mature branch of organic chemistry dating back to the works of
Michael1 and Fischer,2 stereoselective manipulations at the ano-
meric position continue to present a formidable challenge. A
special class of glycosides containing a C-C bond between C1
carbon of a saccharide ring termed C-glycosides are found in
numerous bioactive natural products such as anti-tumor antibi-
otics3-4 and glycosylated flavonoids5-8 (Figure 1A). Many bio-
active aryl C-glycosides feature different C-glycoside groups
and oligosaccharide chains attached to an aromatic core.9 Other
well-established examples of C-glycosylation include C-man-
nosylation of tryptophan in glycoproteins,10 a posttranslational
modification found in proteins belonging to the TRC family
(Figure 1B), aryl C-nucleosides,11 and C-glycosyl porphyrin
glycoconjugates.12 In the 2010s, aryl C-glycosides derived from
phlorizin, a natural b-D-glucoside, were introduced into the
market in the United States as anti-diabetic drugs inhibiting so-
dium/glucose cotransporter 2 (SGLT2, Figure 1C).13 Because
C-glycosides (unlike O-glycosides) are not stabilized by
(exo)anomeric effect yet show similar conformational prefer-
ences around the exocyclic C-C bond as their natural counter-
parts with a C-O bond, the replacement of a hydrolytically la-
bile C-O bond with a stable C-C linkage is an effective strategy
to improve physiological stability and efficacy.14-16
In order to overcome these challenges, we posited that
a method in which the configuration of the C-glycoside product
could be established based solely on the configuration of the
substrate and controlled by a stereospecific process allowing for
a highly stereoretentive (or stereoinvertive) transformation of
the saccharide substrate would offer a promising solution.36-37
Introduction of glycans with any anomeric configuration with
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has to be taken into account.40 Saccharide C1-organolithium
Figure 1. Representative aryl C-glycosides
reagents have been described41 but have limited scope due to
1
2
o
A. Aryl C-glycoside natural products
poor configurational stablity at temperatures over -30 C and
3
4
5
6
7
8
9
Me
incompatibility with typical protective groups used in
preparative carbohydrate chemistry. Organolithium reagents
derived from C2-protected saccharides (e.g., benzyl ethers)
undergo a facile elimination of the oxygen group and the
formation of a glycal, and only C2-OH or C2-deoxy sugars are
a reliable source of anomeric organolithium reagents.42 An
anomeric boronic ester derived from D-glucose was reported in
a patent,43 and Chirik44 and Molander45-46 described the
preparation of pyranose- and chromanone-based boronic esters
and borate salts, but these systems lack the critical C2 oxygen
substituent present in most saccharides. Anomeric silicon
reagents have been reported only for alkyl- and arylsilyl groups
attached at the C1 position.47-48 Anomeric stannanes described
by Sinaÿ,49 Kessler,50-51 and Vasella52 can be prepared through
the use of electrophilc and nucleophillic tin reagents. Given the
highly stereoretetive nature of reactions with chiral C(sp3)
stannanes,53-61 their configurational stability, and the ease of
preparation, C1 stannanes emerge as the optimal reagents for
the studies on stereospecific glycosyl cross-coupling reactions.
The development of a coupling process utilizing anomeric nu-
cleophiles is a promising alternative to the nucleophilic addi-
tion/displacement methods - provided that the undesired b-
elimination could be controlled or suppressed by a catalyst
and/or a ligand. Here, we describe a full report detailing the de-
velopment of the stereoretentive glycosyl cross-coupling reac-
tion, applications in the synthesis of aryl C-glycosides derived
from mono/oligosaccharides, and mechanistic/computational
studies on the origin of high stereoselectivity and ligand prefer-
ence.
R
O
O
HO
HO
HO
H
D-Glc
O
O
OH
O
O
NH
HO
Me
Me R = H, Cl
OH
Me
HO
Marmycin A, B
(anti-tumor)
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Me
O
O
OH
OH
D-Glc
HO
O
OH
Me
O
OH
HO
Vicenin-2
Me
HO
O
(anti-inflammatory, anti-tumor,
anti-diabetic, antioxidant)
NMe2
Kidamycin
(anti-tumor)
O
O
Me
O
Me
HO
OH
O
OH
Me
O
NMe2
HO
O
Me
O
D-Oli
OH
O
Me
O
HO
HO
L-Rho
Urdamycin B
O
D-Oli
B. C-mannosylation as a post-translational modification of proteins
HO
C-Man
C-Man
HO
HO
AA-Trp-AA-AA-Trp-AA
OH
O
OH
OH
HO
O
α-D-Man
OH
HN
NH
O
R
H
H
N
α-D-Man
N
HN
N
H
RESULTS AND DISCUSSION
O
R
O
protein chain
protein chain
O
O
Synthesis of anomeric stannanes. Our study began with the
synthesis of anomeric stannanes as the substrates for the glyco-
syl C(sp3)-C(sp2) cross-couplings. As an anomeric nucleophile,
the tri-n-butyltin group was selected although smaller groups
such as Me3Sn (but not carbastannatranes)62 could also be intro-
duced into the C1 position with the synthetic sequences de-
scribed below. In order to access both anomers of common
monosaccharides, a series of transformations depicted in
Scheme 1 was developed using glycal intermediate 1. To pre-
pare the 1,2-trans anomers 3, epoxidation of per-O-benzyl
glycals 1 followed by opening with Bu3SnMgMe (Conditions
A) resulted in the synthesis of b-D-glucose (9), b-D-galactose
(10), a-D-arabinose (11), b-L-olivose (12), and b-D-lactose
(13) stannanes although the yield of the disaccharide 13 was
low (18%). The synthesis of the 1,2-cis stannanes also com-
menced from glycal 1, which was converted into thermody-
C. Gliflozin-type SGLT2 inhibitors
OH
O
β-D-Glc
Cl
OEt
F
HO
HO
S
OH
Me
Dapagliflozin
Ipragliflozin
Cl
O
F
S
O
Canagliflozin
Empagliflozin
high selectivity and functional group compatibility and without
the need for additional (de)protection manipulations38 provides
the opportunity to append glycans to a broad range of acceptors
at the end of synthetic sequences and allows for late-stage gly-
codiversification of small molecules and biologics applicable to
high-throughput format and library preparations. Because in-
stallation of a (pseudo)halide or heteroatom-based leaving
group at the anomeric position inevitably leads to scrambling of
anomeric configuration of the C-glycoside products,39 an alter-
native strategy based on umpolung of the anomeric carbon was
pursued. Successful realization of this proposal requires (a) ac-
cess to both anomers (a and b) of stable anomeric nucleophiles
and (b) a highly stereospecific C-C bond forming process.
o
namic a-chlorides 4 with sat. HCl in Et2O/CHCl3 at 0 C. The
chlorides 4 were then exposed to a strong base (n-BuLi) to re-
move the alcoholic or amide (for D-GlcNAc) protons and the
o
resultant lithium alkoxide/amide was treated at -100 C with
lithium naphthalenide Li(C10H8) followed by quenching with
Bu3SnCl. This set of conditions (Conditions B) led to a transfer
of anomeric configuration from the anomeric halides 4 to the
stannanes 5. The removal of the alcoholic proton is a necessary
step to assure high yields of this transformation and under the
When considering a stereoretentive cross-couppling
method of anomeric nucleophiles without anion-stablizing
groups, the identity of the metal at the carbohydrate C1 postions
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Scheme 1. Synthesis of anomeric stannanes
1
2
3
4
5
6
7
8
9
O
O
O
O
O
a
c
d
b
SnBu3
(RO)n
(RO)n
(RO)n
(RO)n
(RO)n
OH
HO
HO
O
SnBu3
Cl
3
2
1
6
5
4
e
O
SnBu3
O
O
g
f
SnBu3
(RO)n
(RO)n
(RO)n
Cl
7
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Conditions A
β-Glcp
β-Galp
α-Arap
β-Quip
β-Lac
BnO
OBn
O
OBn
OBn
OBn
O
BnO
BnO
SnBu3
OBn
O
SnBu3
OH
Me
O
O
O
BnO
BnO
BnO
BnO
O
OBn
SnBu3
SnBu3
BnO
OBn
11, 29%*
BnO
SnBu3
BnO
OH
OH
9, 60%
OH
10, 61%
12, 54%
13, 18%
Conditions B
Conditions C/D
α-Glcp
α-Galp
BnO
α-GlcNAcp
α-dGlcp
β-dGlcp
β-GlcNAcp
OBn
OBn
OBn
OBn
OBn
OBn
O
O
O
O
O
BnO
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
SnBu3
BnO
BnO
SnBu3
HO
HO
NHAc
AcHN
SnBu3
15, 51%
SnBu3
SnBu3
14, 48%
SnBu3
16, 60%
17, 42%
18, 56%
19, 85%
o
o
Reagents and conditions: (a) Oxone® (4.0 equiv), acetone, NaHCO3, CH2Cl2/H2O, 0 C to rt; (b) n-Bu3SnMgMe (1.5 equiv), THF, - 20 C; (c) i. OsO4
(2.5 mol%), NMO (2.5 equiv), acetone/t-BuOH/H2O (21:9:1), 23 oC, ii. HCl(g), Et2O/CHCl3, 0 oC; (d) n-BuLi (1.2 equiv), Li(C10H8) (2.5 equiv), THF, -
100 oC then n-Bu3SnCl (3.5 equiv), THF, -100 oC to rt; (e) i. HBr/HOAc/THF, then Na2CO3, (ii) SOCl2 (2.0 equiv) CHCl3/PhMe (3:1), 0 oC; (f) Li(C10H8)
(3.5 equiv), THF, -78 C then n-Bu3SnCl (3.5 equiv), -78 oC; (g) n-Bu3SnLi, THF. *11 was prepared using conditions A followed by protection of C2-
o
OH with BnBr (2.0 equiv), KHMDS (1.5 equiv), THF, 0 oC to rt, 2.5 h.
Some saccharides (e.g., 28) are crystalline and can be conven-
iently handled as free-flowing solids.
optimized conditions, a-D-glucose (14), a-D-galactose (15),
and a-D-GlcNAc (16) stannanes were prepared in high ano-
meric selectivities (a:b > 99:1).
To access 2-deoxysaccharides, the sequence of reactions de-
scribed above was repeated starting again from glycal substrate
1 which was converted into C1-alcohol (TsOH/H2O) and ano-
meric chloride 6, followed by lithium-chloride exchange with
Li(C10H8) at -78 oC in THF and a reaction with Bu3SnCl (a:b >
95:5). Alternatively, the b-anomer 8 was prepared by a dis-
placement with Bu3SnLi obtained from Bu3SnH and LDA. This
method for the generation of anionic tin reagents was found to
result in consistently higher yields of the b-stannanes than the
reactions with a nucleophile formed from Bu3SnCl and Li.63
Scheme 2. Removal of benzyl groups from anomeric
stannanes
O
O
(BnO)n
(BnO)n
(HO)n
SnBu3
20
or
SnBu3
22
Na/NH3(l), -35 o
then NH4Cl(s)
C
or
O
O
(HO)n
SnBu3
SnBu3
21
23
OH
O
OH
HO
The preparation of the C1 stannanes with free hydroxyl
groups is presented in Scheme 2. Typical hydrogenolysis con-
ditions for the removal of O-benzyl groups with various heter-
ogeneous and homogenous Pd or Rh catalysts failed to provide
a fully deprotected product and only a partial removal of the
benzyl ethers and destannylation were observed under ambient
and elevated pressures and temperatures. Gratifyingly, we
found that the Birch conditions (Na/NH3) followed by a careful
quenching with solid NH4Cl afforded monosaccharides 24-30
in good yields (50-84%) after chromatographic purification on
silica gel. A few observations regarding the stability of ano-
meric stannanes are noteworthy – fully deprotected saccharides
24-30 are stable at room temperature for at least one year and
can be stored indefinitely at -20 oC. All stannanes can be puri-
fied by chromatography on silica gel, are stable against air or
moisture, and retain anomeric configuration even after exten-
sive heating (150 oC, 4 days, sealed tube) or exposure to light.
OH
O
HO
HO
O
HO
HO
SnBu3
SnBu3
HO
SnBu3
R
OH
26, 73%
24, R = OH, 80%
25, R = NHAc, 67%
OH
27, 50%
OH
OH
O
HO
HO
O
O
HO
HO
HO
HO
HO
HO
SnBu3
SnBu3
SnBu3
30, 53%
28, 84%
29, 60%
The anomeric configuration of C1-stannanes was established
based on the analysis of 3J(H1-H2) and 1J(C1-H1) coupling con-
stants. Unlike O-glycosides, the signals of monosaccharide C1
atoms of anomeric stannanes in the 13C NMR spectra are buried
in 70-80 ppm region, which also contains other saccharide sig-
nals and can be difficult to identify unequivocally without the
3
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use of 2D NMR techniques, thus complicating the structural as- Anomeric stannanes are also compatible with strongly basic re-
signment. Analysis of the 13C NMR data revealed an interesting
trend of heteronuclear coupling constants of the C1 position in
the n-butyl group and anomeric 117Sn/119Sn nuclei (Table 1). For
the anomeric stannanes in which the tin group occupies the
equatorial position in a 4C1 pyranose conformer, the 1J(117Sn-C)
coupling constants are above 305 Hz (319 Hz for 1J(119Sn-C)),
whereas the C1-stannanes with the tin group is in the axial po-
agents (KHMDS, LiHMDS, NaH) in O-alkylation reactions of
the C2-OH positions (no Peterson olefination products ob-
served), halogenation conditions, and small nucleophiles (NaI,
NaN3, TBAI, TBABr). Thus, we synthesized 6-deoxy-6-fluoro-
D-glucose 36 in a reaction with DAST (51%), 6-deoxy-6-iodio-
D-glucose 37 in a reaction with Ph3PI2 (71%), and 6-deoxy-6-
azido-D-glucose 38 (65%) suitable for further functionalization
via cycloaddition reactions. However, we found that the reac-
tion of iodide 37 with t-BuOK resulted in migration of the dou-
ble bond yielding dihydropyran 39.
1
2
3
4
5
6
7
8
1
sition have J(Sn-C) coupling constants below these cut-offs.
This general trend was observed for various pyranoses (deter-
mined for Glcp, Galp, Arap, Quip, GlcNAcp) and is independ-
ent of the substitution of the hydroxyl or amide groups at any
position of the monosaccharide. Similar observations were rec-
orded by Vasella who concluded that the values of 1J(Sn-C) be-
tween anomeric carbon and anomeric tin substituent are larger
when the SnR3 group is located in the equatorial position.52
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 3. Conversions of anomeric stannanes
OTBDPS
OH
a
O
O
BnO
BnO
BnO
BnO
SnBu3
SnBu3
OBn
31
OBn
32
1
1
Table 1. Diagnostic J(117Sn-C) and J(119Sn-C) of pyranosyl
C1-stannanes.
b - f
Me
R
C2
1J(117Sn-13C)
1J(119Sn-13C)
BnO
BnO
Saccharide
O
h
Substituent
(Hz)
(Hz)
SnBu3
O
BnO
BnO
SnBu3
a-D-Glcp
a-D-Glcp
a-D-Galp
a-D-Galp
a-D-GlcNAcp
a-D-dGlcp
b-D-Glcp
b-D-Glcp
b-D-Galp
b-D-Galp
OH
OBn
OH
OBn
NHAc
H
OH
OBn
OH
OBn
NHAc
H
OBn
OH
298.2
293.5
294.8
293.8
304.3
284.4
311.9
310.9
311.5
310.1
313.6
306.8
308.1
311.1
312.1
307.0
308.4
307.4
318.3
297.7
326.4
325.3
325.8
324.6
327.3
320.6
322.4
325.6
OBn
OBn
39
33, R = ONap 36, R = F
34, R = OBz 37, R = I
35, R = OLev 38, R = N3
a
b
g
Reagents and conditions: (a) TBAF, THF, 82%; (b) NapBr, KHDMS, THF,
91% (for 33); (c) Bz2O, DMAP, pyridine, 80% (for 34), (d) LevOH, DIC,
DMAP, CH2Cl2, 93% (for 35); (e) DAST, 2,6-lutidine, CH2Cl2, 51% (for
36); (f) PPh3, I2, imidazole, CH2Cl2, 71% (for 37); (g) NaN3, DMF, 65%;
(h) 37 t-BuOK, THF, 62%.
b-D-GlcNAcp
b-D-dGlcp
b-D-Arap
Although disaccharide stannanes can be prepared in a direct
reaction from the corresponding disaccharide glycals (Scheme
1), the diversity of the anomeric nucleophiles was greatly ex-
panded by converting monosaccharide stannanes into oligosac-
charides (Table 2). We established that standard conditions for
the activation of Schmidt donors with TMSOTf (5 mol%) or
PdCl2(MeCN)2 (10 mol%)/AgOTf (20 mol%)64 were efficient
in the synthesis of disaccharide 41 (76%) and trisaccharides 43
(82%) and 45 (80%). We were also pleased to find that even
longer oligomers such as tetrasaccharide 47 (73%) could be pre-
pared from the Schmidt donor 46 without degradation of the
stannane acceptor 32 although this reaction required 8 h to reach
completion most likely due to the size of the glycosyl donor.
We found no impact of the tin substitution on the reactivity of
the glycosyl acceptors, which one might expect to show some-
what reduced reactivity due to the presence of a large group at
C1 and an electropositive (deactivating) element at a remote po-
sition from the reacting 6-OH center. The scope of glycosyl
stannanes was further expanded by converting the acceptor 32
into disaccharides 49-52 in reactions with glycal epoxide 48.
Electrophilic gold catalyst (Ph3PAuCl/AgOTf) described by
Yu65 was found superior (78% of 49) to stoichiometric ZnCl2
(25%)66 or other Lewis acid promoters (BF3, TfOH) that re-
sulted in no reaction. These catalytic conditions were then ap-
plied to the synthesis of (1®6)- and (1®2)-linked disaccha-
rides 49-52 in consistently high anomeric selectivities. Dehy-
drative glycosylation of C1-hemiacetal 53 pre-activated with
DPPBO2/Tf2O furnished a mixture of anomers 54 in a moderate
b-L-Quip
Free saccharides
a-D-Glcp
a-D-Galp
a-D-dGlcp
b-D-Glcp
b-D-Galp
b-D-dGlcp
OH
OH
H
OH
OH
H
292.7
290.5
283.4
311.4
309.9
308.6
305.6
303.9
296.5
325.9
324.5
323.0
a
b
119Sn satellites (Ja < 319 Hz < J )
ꢀ
117Sn satellites (Ja < 305 Hz < Jbb)ꢀ
n-Bu n-Bu
O
Sn
Me
C
H2
Because little is known about the reactivity and stability of
anomeric nucleophiles, we investigated reactions of b-glucosyl
stannane 31 as a model system to probe its compatibility with
common reagents used in preparative carbohydrate chemistry
(Scheme 3). Alcohol 32 was obtained in a reaction of 6-
OTBDPS protected stannanes 31 in which the silicon group was
removed with TBAF (1.1 equiv) without undesired protode-
stannylation. We found that other silicon-based groups (TIPS,
TES) are also compatible with the protocols for the synthesis of
anomeric stannanes (Scheme 1) and can be removed with a flu-
oride anion without a cleavage of the C-Sn bond. These results
demonstrate the stability of anomeric stannanes to anhydrous
fluoride sources allowing for expansion of the scope of protec-
tive groups suitable for the preparation of C1 nucleophiles. C1-
stannanes tolerate standard O-alkylation and O-acylation con-
ditions as demonstrated in the synthesis of protected saccha-
rides 33-35 containing 6-ONap, 6-OBz, and 6-OLev groups.
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Table 2. Scope of O-glycosylation of anomeric stannanes
1
2
3
4
5
6
Entry
Glycosyl donor
Conditions
Product
Yield
OBz
OBz
O
O
BzO
BzO
PdCl2(MeCN)2 (10 mol%),
AgOTf (20 mol%), CH2Cl2,
O
BzO
BzO
41
1
76%
OC(NH)CCl3
BzO
4Å MS, -78 to 23 o
C
O
BnO
BnO
OBz
SnBu3
40
OBn
OAc
7
8
9
AcO
AcO
OAc
OAc
AcO
AcO
OAc
O
O
O
O
O
AcO
TMSOTf (5 mol%),
O
43
SnBu3
2
O
82%
CH2Cl2, 4Å MS, -20 o
C
AcO
OC(NH)CCl3
AcO
AcO
BnO
BnO
AcO
O
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
OAc
42
OBn
OAc
OAc
O
O
AcO
AcO
OAc
AcO
AcO
OAc
O
PdCl2(MeCN)2 (10 mol%),
AgOTf (20 mol%), CH2Cl2,
AcO
AcO
O
O
3
80%
45
O
AcO
4Å MS, -78 to 23 o
C
O
OC(NH)CCl3
AcO
AcO
O
BnO
BnO
OAc
SnBu3
44
OBn
OAc
O
AcO
AcO
OAc
OAc
AcO
AcO
OAc
O
O
O
O
O
AcO
O
AcO
TMSOTf (5 mol%),
O
AcO
AcO
AcO
AcO
4
5
6
73%
78%
56%
CH2Cl2, 4Å MS, -20 o
C
AcO
O
AcO
O
O
AcO
AcO
BnO
BnO
OC(NH)CCl3
AcO
46
O
AcO
SnBu3
47
OBn
OBn
OBn
O
BnO
BnO
AuPPh3Cl (10 mol%),
O
BnO
BnO
O
49
AgOTf (10 mol%), CH2Cl2,
-78 to 23 o
C
O
HOBnO
BnO
SnBu3
O
48
OBn
OBn
O
O
BnO
BnO
OBn
SnBu3
AuPPh3Cl (10 mol%),
O
BnO
BnO
AgOTf (10 mol%), CH2Cl2,
-78 to 23 o
C
O
50
OH
O
BnO
48
OBn
BnO
OTBDPS
O
BnO
BnO
OBn
OBn
SnBu3
51
AuPPh3Cl (10 mol%),
O
O
BnO
BnO
7
AgOTf (10 mol%), CH2Cl2,
52%
-78 to 23 o
C
O
OH
O
BnO
48
48
OBn
BnO
OBn
AuPPh3Cl (10 mol%),
O
BnO
BnO
O
BnO
BnO
O
52
SnBu3
8
9
AgOTf (10 mol%), CH2Cl2,
72%
-78 to 23 o
C
HO
BnO
BnO
O
O
OBn
OBn
O
BnO
BnO
41%
a:b
52:48
DPPBO2, Tf2O,
O
BnO
BnO
BnO
54
2,6-di-t-Bu-4-Me-pyridine,
O
CH2Cl2, 0 o
C
OH
BnO
53
BnO
BnO
O
SnBu3
OBn
OBz
O
OBz
O
Tf2O,
2,6-di-t-Bu-4-Me-pyridine,
CH2Cl2, 4Å MS, -40 to 0 o
BzO
BzO
O
BzO
BzO
41
10
38%
S(O)Ph
C
O
BzOBnO
BnO
OBz
55
SnBu3
OBn
yield (41%) and slight preference for the a-anomer (a:b
52:48).67 Similarly, glycosylation conditions employing sulfox-
ide donor 55 activated with Tf2O furnished 41 in a modest yield
(38%, a:b > 1:99). We also established that anomeric thioethers
(SPh, STol) requiring strong electrophilic reagents (NIS or
NBS/AgOTf) and anomeric fluoride donors activated with
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Cp2Hf(OTf)2 are incompatible with anomeric stannanes leading
Page 6 of 17
1
2
3
4
5
6
7
8
to protodestannylation instead of the formation of a new glyco-
sidic bond. Taken together, we conclude that C1 stannanes are
compatible with standard O-glycosylation conditions and the
extension of an oligosaccharide chain can be readily accom-
plished at the stage of anomeric nucleophiles.
Table 3. Ligand optimization for the cross-coupling of b-glu-
cose stannane 56 and 3-iodotoluene
3-iodotoluene (1 equiv),
Pd2(dba)3 (2.5 mol%),
Ligand (5/10 mol%),
Me
OBn
OBn
O
OBn
O
O
+
BnO
BnO
BnO
BnO
BnO
BnO
CuCl (3 equiv),
KF (2 equiv),
SnBu3
OBn
56
OBn
57
PhMe (0.03 M), 110 o
C
58
Reaction Development
Having access to a series of anomeric stannanes, the next task
toward successful realization of the glycosyl coupling reaction
was the identification of a set of conditions that would allow for
stereospecific reactions at the C1 position. The following key
challenges were addressed from the outset of this study: (a) high
stereospecificity of cross-couplings with both carbohydrate
anomers regardless of steric and electronic environment of the
stannane and (b) competitive b-elimination of the oxygen-based
groups at C2 or b-hydride elimination. We hypothesized that
the b-elimination pathway could be controlled by a judicious
selection of a ligand that could: (i) prevent the elimination of
the C2 group (i.e., from the stannane substrate prior to
transmetalation to Pd, thus facilitating the transmetalation step
C-Sn®C-Pd), and (ii) control the glycal formation by prevent-
ing the elimination of a C2 substituent from anomeric palladium
intermediate and/or facilitate reductive elimination resulting in
the formation of C(sp3)-C(sp2) bonds. The undesired glycal syn-
thesis could also be initiated by the reaction additives them-
selves. For example, a leaving group at C2 (OBn) and the Bu3Sn
moiety in b-D-arabinose 11 and other protected 1,2-trans pyra-
nose stannanes are locked in a 4C1 conformation, which, after a
ring flip, leads to a 1C4 conformer poised for a facile b-elimina-
tion. Similarly, the 1,2-cis stannanes (e.g., 14) with free 2-OH
groups can engage in a Peterson-type reaction leading to a
glycal product. It was discovered early in this study that amine
additives known to exert positive effect on the Stille reaction
(Et3N, Hünig’s base, pyridine, DMAP) are not compatible with
the anomeric stannanes and a rapid glucal formation was ob-
served when b-D-glucose stannane was used. These additives
were thus excluded from the optimization studies. Based on our
success with the deprotection of the 6-OH group in 31 (Scheme
3) and literature precedent that fluoride facilitates the Stille re-
action,68 KF was selected as an additive for the ligand optimi-
zation studies (vide infra). Furthermore, given the accelerating
role of Cu additives, CuCl (3 equiv) in a combination with
Pd2(dba)3 as a pre-catalyst were employed. This general set of
conditions was used to test the hypothesis that a phosphine lig-
and can control the rate of b-elimination and C-C coupling in
reactions with C1 nucleophiles. In search of effective ligands
for Pd-catalyzed glycosyl Stille cross-coupling reactions, the
electronic nature and steric hindrance of the ligands are partic-
ularly important. Therefore, biaryl phosphines were selected
because their electronic and steric properties can be finely tuned
by introducing modifications on the phosphorus atom and aro-
matic rings. The cross-coupling reaction of (2,3,4,6-tetra-O-
benzyl-β-D-glucopyranosyl)tri-n-butylstannane 56 with 3-io-
dotoluene was selected as a model system (Table 3).
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
L
Name
AdBrettPhos
BrettPhos
R1
Ad
Cy
R2
R3
R4
L1
L2
L3
OMe
OMe
OMe
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
tBuBrettPhos
t-Bu
3,5-(CF3)2
C6H3
Cy
t-Bu
t-Bu
Cy
L4
JackiePhos
OMe
i-Pr
i-Pr
L5
L6
L7
L8
L9
XPhos
tBuXPhos
JohnPhos
CyJohnPhos
RuPhos
H
H
H
H
H
H
i-Pr
i-Pr
H
H
Oi-Pr
OMe
i-Pr
i-Pr
H
H
H
Cy
Cy
L10
SPhos
H
PPh2
PPh2
PCy2
NMe2
Fe
Pt-Bu3
L15
PCy2
O
NMe2
L12
PPh2
PPh2
DPPF
L13
Xantphos
L14
Davephos
L11
From the initial optimization studies BrettPhos-type
ligands (L1-L3) reported by Buchwald69-70 emerged as promis-
ing hits and afforded 57 in modest but comparable yields (19-
28%). These three ligands contain a methoxy group on the up-
per “A” ring of the biphenyl group in 59, which, we hypothe-
sized, directly interacts with Pd.71 Furthermore, L1 (Ad-
BrettPhos) with a large adamantyl substituent showed dimin-
ished propensity for the formation of the elimination product
58, indicating that further modifications of this position may be
beneficial for controlling the b-elimination pathway.72 Indeed,
phosphine L4 (JackiePhos)73 with a large substituent modified
with a strongly electron-withdrawing 2,6-bis-(trifluorome-
thyl)phenyl group gave the best result of all ligands tested fur-
nishing b-glucoside 57 in 62% yield and trace amounts (2%) of
the elimination product 58. To fine-tune the above conditions,
a solvent screen (PhMe, m-xylene, THF, DMF, 1,4-dioxane) re-
vealed that the yield of 57 could be improved to 94% if the re-
action was conducted in 1,4-dioxane (0.03 M) instead of PhMe.
This protocol is also scalable and a reaction of 1.0 g of 56 with
3-iodotoluene afforded a single anomer of 57 in 88% isolated
yield. A subtle balance between the electron-withdrawing prop-
erties of L4 resulting in a more-electrophilic character of Pd(II)
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Journal of the American Chemical Society
stabilized by OMe necessary to promote the transmetalation likely: (i) they act as a scavenger for free neutral ligand to avoid
1
2
3
4
5
6
7
8
step with anomeric stannanes is balanced by the sterics of the
3,5-substituted group. Consistent with this hypothesis is the re-
action with L7 (JohnPhos)74 in which t-Bu group occupies the
R1 position and afforded almost equal amounts of 57 and 58.
autoretardation of the rate-determining associative transmeta-
lation and (ii) the combination of fluoride and Cu facilitates the
transmetalation from the anomeric stannane to generate a more
reactive organocopper intermediate, which then enters the cata-
lytic cycle with Pd. 68, 81-82 The formation of a more reactive or-
ganocopper species is favorable when the tin group is converted
into insoluble Bu3SnF resulting in the improvement of the effi-
ciency of the reaction.
The role of the OMe group in the ortho position of the
“A” ring was further investigated, and replacement of OMe
with H (L5, Xphos and L6, tBuXphos)75 or Me (L10, SPhos)76
caused a drastic decrease of the yield and overall conversion.
Alternatively, increasing the steric bulk on the oxygen substit-
uent (L9, RuPhos)77 led to similarly low conversion and prefer-
ential formation of 59. However, N,N-dimethylamine group in
the ortho position (L11, DavePhos78 and L12) favored the for-
mation of D-glucal 58 in high yields. The origin of this effect
can be attributed to the interactions of the nitrogen atom with
Pd(II) center which becomes more electron-rich and susceptible
to b-elimination. Alternatively, a moderately basic aniline sub-
stituent can directly cause b-elimination from the C1-stannane
by a mechanism analogous to the one observed with amine/pyr-
idine additives (vide supra). Other phosphines afforded pre-
dominantly D-glucal 58, although the efficiency of this process
was dependent on the phosphine itself. For example, a modifi-
cation of the bottom “B” ring of the biaryl ligand by replacing
the isopropyl group with a proton (L7-L10) resulted in reaction
yields of 57 below 30% but high yields of 58 (23-55%). Con-
sistent with the above trend are the results with other ligands
such as L13 (DPPF), L14 (Xantphos),79 or L15 (t-Bu3P)80
providing low yields of 58. Taken together, the biphenyl phos-
phines emerge as the optimal ligands for the glycosyl C(sp3)-
C(sp2) cross-coupling reactions and the OMe group in the “A”
ring of the scaffold 59 located in the ortho position to phospho-
rus is of critical importance to maintain catalyst stability
through coordination to the Pd center. For all phosphines tested,
the formation of only one diastereoisomer was observed (based
on the analysis of 1H NMR of unpurified reaction mixtures).
Lastly, to better understand the relative reactivities of
aryl halides or pseudohalides in the glycosyl Stille cross-cou-
pling reactions, we compared the reactions of 3-chlorotoluene,
3-bromotoluene, 3-iodotoluene and 3-tolyl triflate with b-D-
glucose stannane 56 (Table 4). Consistent with the previous re-
sults regarding the reactivity of aryl halides in the Stille reac-
tion,83-84 3-chlorotoluene resulted in only 14% of the product 57
whereas 3-bromotoluene and 3-tolyl triflate furnished the C-
glycoside 57 in 53% and 21%, respectively.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scope and Applications
Monosaccharide cross-coupling reactions. The optimized gly-
cosyl cross-coupling conditions were tested in reactions with
various monosaccharides (Figure 2). We found that the general
set of conditions using Pd2(dba)3 and JackiePhos L4 is opera-
tional for D-glucose (61, 62), D-galactose (63, 64), modified D-
glucose containing a fluoride (68), an azide (69) and a benzyli-
dene group (70), unsaturated glycosides (71), D-olivose (72),
and D-arabinose (73). Hydroxyl protective groups commonly
employed in carbohydrate synthesis such as Nap, Bz, and Lev
are also tolerated under the cross-coupling conditions (65-67).
2-Deoxysaccharides are frequently found in angucycline anti-
tumor antibiotics and present a synthetic challenge because they
lack a controlling substituent at C2 for stereoselective C-glyco-
sylation.85 We found that 2-deoxy-D-glucose glycosides 74 and
75 were efficiently prepared from PhI with retention of ano-
meric configuration for both anomers. An additional powerful
example of glycosyl cross-coupling is the reaction of saccha-
rides containing free hydroxyl groups (Figure 2B). Standard-
ized conditions using 1,4-dioxane as a solvent cleanly afforded
C-glycosides 78-83. The triol and tetraol substrates (see
Scheme 2) and the products 78-83 are readily soluble in 1,4-
dioxane and one can anticipate that the cross-coupling protocol
can be further extended to more complex polyols. To accom-
modate polar reagents with multiple hydroxyl groups, the solu-
bility of the substrates and products in organic solvents needs
to be taken into account. To address these potential challenges,
we examined a series of protic solvents as additives together
with 1,4-dioxane, and a 9:1 mixture of 1,4-dioxane and MeOH
in the cross-coupling of 56 and 3-iodotoluene under otherwise
identical conditions resulted in 79% of 57. Comparable results
(86% of 57) were obtained in a 9:1 mixture of 1,4-dioxane and
t-BuOH.
Table 4. Cross-couplings of b-D-glucose stannane 60
56 (1.5 equiv),
Pd2(dba)3 (2.5 mol%),
Me
X
OBn
O
L4 (5 mol%),
BnO
BnO
CuCl (3 equiv),
KF (2 equiv),
Me
OBn
PhMe (0.03 M), 110 o
C
60
57
Entry
X
Yield
1
2
3
Cl
Br
OTf
14%
53%
21%
To better understand the effects of the fluoride source,
copper and other transition-metal additives were investigated
(for details, see the SI). These results can be summarized as fol-
lows: (a) KF, NaF, and LiF (but not CsF and TBAF) resulted in
good overall yields of C-glycoside 57 (58-62%), (b) the yield
of the reaction is dependent on the identity of the Cu(I) salt –
CuCl (2 equiv) is superior to all other counterions tested (CuBr
and CuTC resulted in the formation of the product 57 in modest
yields (18-28%) whereas CuI and CuOTf were not suitable for
this transformation), (c) other transition-metal additives
(MgCl2, AgBF4, AuCl3, ZnCl2) have no beneficial effect on the
reaction yield although Ag(I) salts generated a yield comparable
to the optimized conditions with CuCl (60%). Based on these
data, we conclude that CuCl and KF exert a synergic effect that
accelerates the Stille reaction. Two roles of Cu(I) salts are
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Figure 2. Scope of glycosyl cross-coupling reaction of anomeric stannanes with PhI
1
2
3
4
5
6
7
8
A. Protected saccharides
OBn
O
OH
OH
O
OBn
O
OR
R
BnO
BnO
BnO
BnO
Ph
O
O
O
O
O
O
Ph
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
Ph
Ph
Ph
Ph
Ph
Ph
OH
HO
OBn
61, 90%
only β
OH
62, 92%
only β
OH
63, 81%
only β
OBn
OBn
Ph
70, 92%
only β
68, R = F, 92%, only β
69, R = N3, 86%, only β
64, 85%
only α
65, R = Nap, 84%, only β
66, R = Bz, 82%, only β
67, R = Lev, 85%, only β
OAc
9
OAc
OBn
O
Me
O
OAc
O
AcO
BnO
Ph
OBn
Ph
O
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
Me
BnO
O
BnO
BnO
O
OH
O
AcO
AcO
AcO
AcO
Ph
Ph
Ph
OBn
AcO
AcO
BnO
BnO
Ph
OBn
71, 89%
only β
NHAc
76, 88%
only β
OBn
77, 70%
only β
Ph
72, 93%
only β
73, 86%
only α
74, 82%
only β
75, 79%
only α
B. Deprotected saccharides
OH
OH
HO
OH
O
OH
OH
O
HO
HO
OH
O
O
O
O
HO
HO
HO
HO
HO
HO
Ph
HO
HO
HO
Ph
Ph
HO
HO
OH
OH
Ph
Ph
Ph
78, 84%
only β
79, 82%
only β
80, 92%
only β
81, 88%
only α
82, 91%
only α
83, 89%
only α
Reagents and conditions: (a) PhI (2.0 equiv), anomeric nucleophile (1.0 equiv), Pd2(dba)3 (5 mol%), L4 (20 mol%), CuI (3 equiv), KF (2 equiv), 1,4-dioxane,
110 oC; (b) PhI (1.0 equiv), anomeric nucleophile (2.0 equiv), Pd2(dba)3 (5 mol%), L4 (20 mol%), CuI (3 equiv), KF (2 equiv), 1,4-dioxane, 110 oC. Compounds
61, 62, 68-72 were prepared with conditions a, compounds 63-67, 73-83 with conditions b.
The hydroxyl groups in majority of carbohydrate examples
presented in Figure 2 are protected with electron-donating sub-
stituents (benzyl ethers). These reagents in the carbohydrate ter-
minology would be considered as “armed” (activated).86 We
found little impact of the protective groups on the reaction yield
and no impact on selectivity, as exemplified by reactions with
2-deoxy-D-glucose (74 and 75) and per-O-acetyl-D-GlcNAc.
Ester groups known to deactivate glycosyl acceptor in classical
O-glycosylation reaction have no effect on the reaction yields
when it comes to anomeric stannanes (products 74-77) do not
have any impact on anomeric selectivity. For example, an ester
group at the 4-O position in galactose can direct the delivery of
a nucleophile through a transannular participation.87 However,
in the case of b-D-galactose stannanes, such remote participa-
tion was not observed event and starting from b-stannane, the
corresponding C-b-glycoside 77 was prepared without erosion
of anomeric configuration. Analogous results were observed in
reactions with both anomers of D-GlcNAc.37 The substitution
at C2 carbon in monosaccharides is well-tolerated although we
observed a slight decrease of the reaction yield caused by a
competing elimination of the OBn group. In general, 1,2-cis
anomers require longer reaction times (48-72 h) for full con-
sumption of the aryl halide and produce consistently ca. 20%
more of the glycal by-products. Careful analysis of the crude
reaction mixture revealed that b-hydride elimination accounts
for <1% of the material for reactions with protected saccharides
and with free hydroxyl groups.
4), we envisioned that the installation of two different glycans
could be accomplished by a judicious selection of a reactive io-
dide with either bromide or chloride. These types of C-glyco-
sylations selectively delivered only one C-glycoside group in a
synthetically acceptable yield (70%). However, after some ex-
perimentation we found that 1,4-diiodobenzene cleanly af-
forded the mono-glycosylated product 84 by simply adjusting
the equivalency of halide electrophile (3 equiv) and 56 (1
equiv). This intermediate was then coupled with a and b
anomers 17 and 18 to afford asymmetric glycoconjugates 85
and 87.
Scheme 4. Double glycosylation with 1,4-diiodobenzene
BnO
BnO
OBn
O
OBn
OBn
O
O
BnO
BnO
OBn
BnO
BnO
85
b
SnBu3
17
OBn
O
OBn
a
I
O
BnO
BnO
BnO
BnO
SnBu3
OBn
OBn
84
56
OBn
O
BnO
BnO
c
Orthogonal C-glycosylations. Further studies were focused on
the applications of the glycosyl cross-coupling method in the
synthesis of glycoconjugates containing two different saccha-
rides attached to the aromatic core (Scheme 4). When combined
with the increased metabolic stability, these structures may
serve as mimetics of oligosaccharides.88 Because of the substan-
tial rate differences for cross-coupling with aryl halides (Table
SnBu3
18
OBn
OBn
OBn
O
O
BnO
BnO
BnO
OBn
86
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OBn
Reagents and conditions: (a) 1,4-diiodobenzene (3 equiv), Pd2(dba)3 (5
mol%), L4 (20 mol%), CuCl (3 equiv), KF (2 equiv), 1,4-dioxane, 110 oC,
72 h, 60%; (b) 17 (2 equiv), Pd2(dba)3 (5 mol%), L4 (20 mol%), CuCl (3
equiv), KF (2 equiv), 1,4-dioxane, 110 oC, 72 h, 58%; (c) 18 (2 equiv),
Pd2(dba)3 (5 mol%), L4 (20 mol%), CuCl (3 equiv), KF (2 equiv), 1,4-di-
oxane, 110 oC, 72 h, 63%.
1
2
3
4
5
6
7
8
O
O
OBn
O
BnO
BnO
SnBu3
BnO
BnO
89
O
Pd2(dba)3 (20 mol%),
L4 (40 mol%),
CuCl (300 mol%),
I
91
50%
only β
C-glycosylation on solid-support. In order to adapt the glycosyl
cross-coupling method to high-throughput synthesis format, we
demonstrated a reaction of an aryl halide directly attached to a
solid-support resin (Scheme 5).89 The Merrifield resin 87 was
exposed to the conditions previously optimized using 2 equiv
of anomeric stannane 56. After completion of the reaction (72
h), the excess of reagents was washed off and the acid 88 was
obtained in 78% yield and >95% purity (1H NMR).
OBn
KF (200 mol%),
1,4-dioxane, 110 °C
OBn
O
O
BnO
BnO
92
35%
only α
9
BnO
BnO
O
SnBu3
I
O
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
90
Scheme 5. Glycosyl cross-coupling on solid support
C-Oligosaccharides. To further demonstrate the generality of
the method, a direct reaction of oligosaccharide nucleophiles
with aryl halide was studied (Figure 3). Extensive literature on
the formation of C-aryl glycosides is limited to the reactions
with monosaccharides and a direct C-glycosylation with oligo-
saccharide donors and aromatic acceptors is not known.17 Oli-
gosaccharide stannanes prepared by glycosylation reactions
with monosaccharide stannanes (Table 2) were engaged in
cross-coupling reactions with PhI without any modifications of
the general conditions, allowing for the formation of C-disac-
charides derived from D-lactose (93), D-gentiobiose (94, 95)
and 2-deoxy-D-gentiobiose (96) in excellent yields with 1 equiv
of the anomeric stannane substrate and 2 equiv of PhI. To test
if a bulky group at C2 impacts the reaction efficiency, D-
sophorose disaccharides containing a (1®2) glycosidic bond
(97, 98) and disaccharides with unnatural (2®6) ether bonds
between two D-glucose residues (99, 100) were also prepared
in good yields and consistently high selectivities. Extreme ex-
amples of the generality of the glycosyl cross-coupling method
are the reactions forming phenyl C-trisaccharides (101, 102)
and a tetrasaccharide 103 from the corresponding oligosaccha-
ride stannanes in yields exceeding 80% for all substrates tested.
One can envision that the scope of the cross-coupling method
can be further extended to longer linear and branched oligosac-
charides which can be fused with aromatic acceptors at the end
of the synthetic sequence.
56, Pd2(dba)3 (5 mol%),
L4 (20 mol%),
CuCl (3 equiv), KF (2 equiv),
1,4-dioxane (0.03 M),
110 oC, 72 h
O
OBn
O
CO2H
O
BnO
BnO
Washing:
NH4Cl (aq); H2O/DMF; MeOH
Cleavage:
LiOH/THF/H2O, reflux, 24 h
then HCl (aq)
OBn
I
88, 78%
>95% purity (NMR)
87
Merrifield resin
loading 1.1 mmol/g
Intramolecular C-glycosylations. Internal C-glycosides are pre-
sent in bioactive natural products with potent immunomodula-
tory activities (e.g., bergenin).90 The synthesis of tricyclic C-
glycosides has been reported by intramolecular Friedel-Crafts
reaction with electron-rich arenes linked through a C2 substitu-
ent resulting in cis products.91-93 Because the intermolecular
glycosyl cross-couplings proceed with high levels of stereore-
tention, we examined the feasibility of intramolecular cross-
couplings with 2-iodobenzene electrophiles attached as a ben-
zyl ether to the equatorial alcohol at C2 in D-glucose substrate
(Scheme 6). Both anomers 89 and 90 were converted into the
corresponding cyclic ethers 91 and 92 under the standard con-
ditions with the retention of anomeric configuration. The reac-
tion with a-anomer 90 resulted in a lower yield (35%) of the cis
product 92, and the remainder of the material for both reactions
was tri-O-benzyl glucal 58 originating from the b-elimination
of the C2-benzyloxyl group (full consumption of 89 and 90).
These results demonstrate high stereospecificity of the cross-
coupling reaction even in systems where strained products are
difficult to form and can pose a challenge when attempted with
other synthetic methods.
Cross-coupling with unsubstituted furanosyl/pyranosyl stanan-
nes. Although the conditions for the installation of the aryl
groups at the anomeric position were optimized for the reactions
with carbohydrate substrates, we wondered if simple pyranose
and furanose nucleophiles could be merged with aryl electro-
philes. Curiously, reactions of acyclic stannanes such as a-
acyloxyl- and a-amidostannanes are known,94-95 yet cyclic ox-
ygen-containing heterocycles have not been investigated as
substrates in the Stille C(sp3)-C(sp2) reaction. To this end, we
prepared racemic tetrahydropyranosyl (104) and tetrahydro-
furanosyl stannanes (105)96-97 and cross-coupled them with aryl
iodides decorated with electron-withdrawing (107-110, 111-
114), electron-rich (110, 115) and heterocyclic iodides (116,
Scheme 7).
Scheme 6. Stereoretentive intramolecular glycosyl cross-cou-
pling of 2-iodobenzyl-D-glucose.
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Figure 3. Scope of glycosyl cross-coupling reaction with oligosaccharide stannanes
1
2
3
4
5
6
7
A. Disaccharides
OBn
O
OBn
O
OBn
O
OBn
BnO
OBn
O
BnO
BnO
BnO
BnO
O
BnO
BnO
O
O
O
O
BnO
HO
BnO
BnO
BnO
BnO
O
Ph
O
HO
BnO
O
OBn
Ph
BnO
Ph
BnO
OBn
Ph
BnO
OBn
OBn
β-D-Galp-(1→4)-β-D-Glcp
β-D-Glcp-(1→6)-β-D-Glcp
β-D-Glcp-(1→6)-β-D-Glcp
β-D-Glcp-(1→6)-β-D-Glcp
8
9
93, 90%
only β
94, 91%
only β
95, 88%
only β
96, 85%
only β
OBn
OH
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
OBn
OBn
O
O
BnO
Ph
BnO
Ph
O
O
O
BnO
BnO
BnO
BnO
BnO
BnO
Ph
O
O
O
Ph
OH
O
OH
O
BnO
BnO
O
O
BnO
BnO
BnO
BnO
BnO
BnO
OBn
BnO
β-D-Glcp-(1→2)-β-D-Glcp
OBn
BnO
β-D-Glcp-(1→2)-β-D-Glcp
OMe
OMe
β-D-Glcp-(2→6)-α-D-Glcp
α-D-Glcp-(2→6)-α-D-Glcp
97, 56 %
only β
98, 62%
only β
99, 62%
only β
100, 60%
only α
OAc
B. Tri/tetrasaccharides
OAc
AcO
OAc
O
O
OAc
AcO
AcO
AcO
AcO
OAc
O
OAc
O
O
AcO
AcO
O
AcO
O
O
O
O
OAc
AcO
O
O
AcO
AcO
O
OAc
AcO
AcO
AcO
O
AcO
O
O
BnO
BnO
AcO
BnO
Ph
Ph
BnO
BnO
O
Ph
OBn
OBn
BnO
OBn
β-D-Glcp-(1→4)-β-D-Glcp-(1→6)-β-D-Glcp
β-D-Galp-(1→4)-β-D-Glcp-(1→6)-β-D-Glcp-(1→6)-β-D-Glcp
β-D-Galp-(1→4)-β-D-Glcp-(1→6)-β-D-Glcp
101, 90%
only β
102, 93%
only β
103, 82%
only β
General reaction conditions: PhI (2.0 equiv), anomeric nucleophile (1.0 equiv), Pd2(dba)3 (5 mol%), L4 (20 mol%), CuI (3 equiv), KF (2 equiv), 1,4-
dioxane, 110 oC.
Scheme 7. Stille cross-coupling of pyranosyl and furanosyl stanan-
nes
Finally, the utility of the glycosyl cross-coupling reaction was
demonstrated in the context of target-oriented synthesis of TGE
(natural product) and dapagliflozin (anti-diabetic drug).
Ar-I
Pd2(dba)3 (5 mol%),
L4 (20 mol%),
Application I: Glucosylated enterobactins (salmochelins)98-99
are siderophores (Fe3+ scavengers) produced by Salmonella
species as a means to evade the host’s defense system.100 Salmo-
chelins contain up to three b-C-glucoside residues attached to
2,3-dihydroxybenzoic acid and TGE (121) is a triply glycosyl-
ated salmochelin. Given the interest in enterobactins as a plat-
form for the delivery of antibacterial cargo,101 TGE is an ideal
target to apply the glycosyl Stille reaction (Scheme 8). To this
end, 5-bromobenzoate 117 was coupled with b-D-glucose stan-
nane 56 in 77% and a:b > 1:99 and, after a few straightforward
manipulations on the ester group, the product 118 was con-
verted into macrolactone 120 in a reaction with amine salt 119.
Removal of the benzyl groups under standard conditions fur-
nished TGE 121 in 51%.
CuCl (3 equiv),
O
Ar
O
SnBu3
or
O
SnBu3
KF (2 equiv),
1,4-dioxane, 110 °C
104
105
106
A. Tetrahydrofurans
F
OMe
COMe
Ph
O
O
O
O
107, 85%
108, 89%
109, 93%
110, 56%
B. Tetrahydropyrans
CO2Me
NO2
COMe
O
O
O
Scheme 8. Total synthesis of salmochelin TGE
111, 88%
112, 72%
113, 65%
CN
OH
O
O
O
N
Me
114, 83%
115, 82%
116, 80%
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OBn
the highly stereospecific nature of the cross-coupling reactions
OBn
OBn
O
1
2
3
OBn
and no effect of potentially participating groups at C2 on the
anomeric selectivity, we excluded the possibility of a radical
mechanism. This assumption was further corroborated in exper-
iments with 1.0 equiv of 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) and 1,1-diphenylethylene, established radical scav-
engers, which had no effect on the reaction yield and stereo-
specificity (for details, see the SI).
a, b, c
OBn
BnO
BnO
COCl
Br
CO2Me
OBn
117
118
4
5
6
7
+
NH3
RO
RO
R1
O
3 Cl-
O
O
O
8
9
OR
O
R1
=
d
Scheme 10. Proposed catalytic cycle of Pd-catalyzed Stille cou-
pling with anomeric stannanes
O
O
NH
+H3N
NH3
+
RO
RO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
119
OR
O
O
O
O
O
O
Ar
Ar-X(Br or I)
(RO)n
R1
O
R1
Pd0
L
N
H
N
H
reductive
elimination
A
O
OR
RO
oxidative
addition
120, R = Bn
121, R = H
(TGE)
OR
OR
e
Ar
PdII
O
(RO)n
PdII Ar
L
L
F
X
B
Reagents and conditions: (a) 56, Pd2(dba)3 (20 mol%), L4 (20 mol%), CuCl
(3 equiv), KF (2 equiv), 1,4-dioxane, 110 oC, 72 h, 77%; (b) LiOH,
MeOH/THF/H2O (2:1:1), 23 oC, 12 h, 84%; (c) SOCl2, DMF (cat.), CH2Cl2,
Bu3SnF
KF
23 C, 2 h, 99%; (d) Et3N, CH2Cl2, 0 C then 23 oC, 10 h, 33%; (e) H2,
o
o
halogen
exchange
Pd(OH)2, MeOH/EtOAc (1:1), 24 h, 23 oC, 51%.
KX
Bu3Sn
O
F
Application II. Dapagliflozin 124 (Farxiga/Forxiga) is a com-
mercial SGLT2 inhibitor approved worldwide and used to treat
diabetes mellitus type 2.102-104 Because of the generality of the
cross-coupling reaction, we envisioned that the synthesis of this
drug can be streamlined by applying the cross-coupling method.
Thus, the union of protected stannane 56 with iodide 122 pro-
vided protected dapagliflozin 123 in 83% yield (Scheme 9). Al-
ternatively, a reaction of C1-nucleophile 24 and 122 afforded
dapagliflozin 124 in 82% isolated yield as a single diastereoiso-
mer. This direct method for the preparation of gliflozins shows
excellent chemoselectivity and only the more reactive iodide in
122 was coupled with the carbohydrate stannane.
PdII
Ar
L
PdII Ar
L
transmetalation
F
C
(RO)n
D
closed
SE2
(retentive)
O
SnBu3
(RO)n
Bu3Sn
O
L
PdII
F
Ar
E
open
(RO)n
Scheme 9. One-step synthesis of dapagliflozin
OR
OEt
Cl
OEt
Cl
a or b
O
RO
RO
I
OR
122
123, R = Bn, 83%, only β
124, R = H, 82%, only β
(dapagliflozin)
*Reagents and conditions: (a) 56 (2 equiv), Pd2(dba)3 (5 mol%), L4 (20
mol%), CuCl (3 equiv), KF (2 equiv), 1,4-dioxane, 110 oC, 72 h. (b) 24 (2
equiv), Pd2(dba)3 (5 mol%), L4 (20 mol%), CuCl (3 equiv), KF (2 equiv),
1,4-dioxane, 110 oC, 72 h.
Mechanistic and Computational Studies
Broad substrate scope, excellent functional group
compatibly and consistently high stereospecificity in the cross-
coupling reactions for both anomers prompted us to undertake
mechanistic investigations. There is a substantial body of com-
putational105-110 and experimental111-118 data on the mechanism
of the Stille C(sp2)-C(sp2) cross-coupling reactions119 but very
little is known about the Stille C(sp3)-C(sp2) reactions with op-
tically active stannanes. The key questions pertaining to the out-
come of these reactions are (a) the origin of high stereospecific-
ity, (b) the special ligand effect of JackiePhos and the control of
C-C cross-coupling vs. b-elimination pathways, and (c) more
facile cross-coupling of 1,2-trans anomeric stannanes. Based on
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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
Figure 4. Reaction energy profile of the Pd-catalyzed Stille coupling of bromobenzene and tetrahydropyranyl stannane 127 using
JackiePhos ligand. All energies are with respect to the reactant complex 125. Calculations were performed at the M06/SDD−6-
311+G(d,p)/SMD(dioxane)//B3LYP/SDD−6-31G(d) level of theory.
Computational investigations of reaction mechanisms. We per-
formed density functional theory (DFT) calculations to eluci-
date the mechanisms of Pd-catalyzed coupling of bromoben-
zene and organostannane 127 as a model substrate. Three major
points of interest were examined in the computational investi-
gations. First, although the mechanisms of C(sp2)−C(sp2) Stille
coupling has been extensively studied computationally, there
125 undergoes oxidative addition with a barrier of 5.4 kcal/mol
(TS1) leading to phenyl palladium(II) bromide complex 126.
The JackiePhos ligand in the three-coordinate palladium com-
plex 126 adopts the conformation where the biaryl group shields
the remaining open site of the palladium (see the SI for 3D
structures). From 126, the stereoretentive transmetalation via a
four-membered cyclic transition state (TS2’) requires an acti-
vation energy of 24.2 kcal/mol with respect to 126. This
transmetalation is facilitated in the presence of F−. Halide ex-
change with 126 forms a more stable palladium(II) fluoride spe-
cies 128, which then undergoes transmetalation via TS2 and re-
quires a barrier of 23.0 kcal/mol to form intermediate 129. The
fluoride effects are consistent with the Yates study that the
transmetalation with palladium fluoride is faster due to the for-
mation of the stronger Sn−F bond. In both TS2 and TS2’, the
palladium approaches the stannane from the same side of the
C1 hydrogen. The transition state isomer of TS2 in which the
palladium approaches from the opposite side of the C1 hydro-
gen is less stable by 5.2 kcal/mol due to unfavorable steric re-
pulsions of the palladium catalyst with the six-membered ring
(see the SI for details). Attempts to locate the open-form
transmetalation transition state that leads to stereoinversion
were unsuccessful. Constrained geometry optimization of such
transition state suggested a significantly higher energy com-
pared to the closed form transition state (see the SI for details).
Intermediate 129 undergoes reductive elimination to form the
aryl C-glycoside product 130 with a relatively low barrier of
only 10.0 kcal/mol (TS3). Here, the reductive elimination is
promoted by a bulky JackiePhos L4 ligand.73
were no existent studies involving C(sp3)−C(sp2) bond for-
120-124
mation in the Stille coupling.105-106,
Stereoretentive
transmetalation with vinyl stannanes is known to occur via the
“closed” pathway involving a four-membered cyclic transition
state (D in Scheme 10). It was of interest to investigate whether
such cyclic transmetalation transition state with sterically en-
cumbered alkyl stannanes is energetically accessible. A previ-
ous computational study from Yates indicated that the addition
of F− led to increased reactivity of vinyl stannane reagents to-
wards transmetalation.117 Here, we investigate the potentially
more challenging transmetalation with alkyl stannanes pro-
moted by F−.117 Furthermore, efficient C(sp3)−C(sp2) reductive
elimination is the key to prevent the competing b-elimination of
the oxygen-based groups at C2. The effects of JackiePhos lig-
and on the rates of reductive elimination and b-alkoxy elimina-
tion was elucidated by computational methods. Lastly, the
origin of the difference in reactivity between a and b anomeric
stannanes was studied computationally.
The calculated reaction energy profile of the Pd-catalyzed
coupling of bromobenzene and stannane 127 using JackiePhos
ligand is shown in Figure 4. The Pd(0)-bromobenzene complex
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rate-determining. Thus, we calculated the transmetalation tran-
We computed the energy profile of the b-methoxy elimina-
1
tion from 129 to investigate the origin of the ability of the Jack-
iePhos ligand to suppress this undesired pathway (Figure 5).
The elimination of trans-b-methoxy group most likely occurs
via the antiperiplanar elimination from the ring flip isomer
(131). Under the reaction conditions, this elimination could be
promoted by the stabilization of the methoxide leaving group
by a Lewis acid (e.g., Cu(I)) and the stabilization of the cationic
Pd(II) by coordination with an F−. Due to the diaxial repulsion
with the phenyl and the JackiePhos ligand on the Pd, the ring
flip isomer 131 is 5.7 kcal/mol less stable than 129. However,
it should be noted that this energy difference would be further
amplified with the real experimental substrate, due to additional
diaxial interactions. Coordination of CuCl and F− to 131 re-
quires 7.4 kcal/mol in terms of Gibbs free energy. The relatively
unfavorable binding of F− is again attributed to the steric hin-
drance of the JackiePhos ligand, which partially blocked the re-
maining binding site on Pd in 131. With the assistance of CuCl
and F−, the E2-type elimination from 133 is relatively facile,
requiring an activation barrier of 10.0 kcal/mol. Nonetheless,
the overall barrier of the b-methoxy elimination from 129 to
TS4, which includes the energies required for ring flip and CuCl
and F− coordination, is 23.1 kcal/mol, significantly higher than
the C−C reductive elimination from 129, which requires only
10.0 kcal/mol. These computational results suggest that bulky
phosphine ligands, such as JackiePhos, not only promote reduc-
tive elimination, but also increase the barrier to b-alkoxy elim-
ination by preventing ring flip and F− coordination to the Pd
center.
sition states with stannanes 127 and 134 as models of the b and
a anomers, respectively (Figure 6). Both transmetalation occur
via the stereoretentive four-membered cyclic transition state.
However, unlike TS2, the six-membered ring in TS2A changes
to a twist-boat-like conformation, leading to the diminished re-
activity of the α anomer. Transition state TS2A is 1 kcal/mol
higher in energy than the transmetalation involving the b
anomer (TS2). This twist-boat conformation in TS2A is
achieved in order to relieve the amplified 1,3-diaxial interac-
tions between tin and the two axial hydrogens in the chair like-
transition state structure (TS2A’).
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
Figure 6. Transition states of transmetalation of the α and β
anomers (134 and 127). All energies are with respect to com-
plex 128. The JackiePhos ligand is not shown in the 3D struc-
tures for clarity.
The preferential reactivity of equatorial stannanes 127
computed at the DFT level was also confirmed experimentally.
A direct competition reaction of a and b anomers of D-glucose
stannanes (57:135, 1:1) with 3-iodotoluene revealed that the
coupling of the b-anomer 57 is 3.2 times faster than the reaction
leading to the a anomer 136 (Scheme 11).
Figure 5. Reaction energy profile of the b-methoxy elimination
pathway. All energies are with respect to complex 129.
We then performed computational analysis to understand the
origin of the reactivity differences between the two anomers of
pyranosyl stannanes. Based on the computationally predicted
reaction mechanism, the transmetalation step is irreversible and
13
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mL) were heated under N2 at 110 ºC for 72 h. The reaction mix-
1
2
3
4
5
6
7
8
ture was filtered through a pad of SiO2, concentrated, and puri-
fied by chromatography on SiO2 (Hexanes:EtOAc, 10:1) to af-
ford 66 (30.7 mg, 82%) as a colorless oil: [ꢀ]ꢂꢁꢃ = +13.3 (c =
0.50, CHCl3); IR (ATR) ν = 3032, 2903, 1720, 1496, 1453,
1273, 1066, 1027, 751 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.10
- 8.01 (m, 2H), 7.66 - 7.54 (m, 1H), 7.50 - 7.16 (m, 20H), 7.02
- 6.91 (m, 2H), 5.01 (d, J = 10.9 Hz, 1H), 4.94 (d, J = 10.7 Hz,
1H), 4.93 (d, J = 10.9 Hz, 1H), 4.67 (d, J = 10.7 Hz, 1H), 4.64
- 4.53 (m, 2H), 4.40 (d, J = 10.1 Hz, 1H), 4.32 (d, J = 9.5 Hz,
1H), 3.94 - 3.68 (m, 4H), 3.61 - 3.53 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 166.4, 139.1, 138.6, 137.8, 137.7, 133.2, 130.2,
129.8, 128.7, 128.5 (2), 128.4 (2), 128.3, 128.1, 128.0, 127.9,
127.7, 86.8, 84.7, 81.8, 78.1, 77.4, 76.0, 75.4, 75.1, 63.8;
HRMS (ESI) m/z calcd for C40H38O6Na [M + Na]+ 637.2561,
found 637.2566.
Scheme 11. Competition experiment of a and b anomers of D-
glucose
Me
OBn
O
OBn
O
BnO
BnO
BnO
BnO
SnBu3
56
BnO
BnO
57
a
+
+
OBn
OBn
9
O
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
BnO
BnO
O
BnO
BnO
BnO
136
BnO
SnBu3
135
Me
Reagents and conditions: (a) 56:135 (1.0:1.0), Pd2(dba)3 (2.5 mol%), L4
(10 mol%), CuCl (3 equiv), KF (2 equiv), 1,4-dioxane, 110 oC; 57:136
(3.2:1.0).
ASSOCIATED CONTENT
CONCLUSIONS
Supporting Information.
To summarize, we have demonstrated that anomeric stannanes
undergo a highly stereoretentive cross-coupling reaction with
aryl halides. First, we have developed a general approach for
the synthesis of both anomers of C1-stannanes derived from
common monosaccharides. We have also demonstrated that
anomeric stannanes are compatible with a range of methods
used in preparative carbohydrate chemistry, including protec-
tive group manipulations and O-glycosylation conditions. Next,
we identified a general set of conditions for a Pd-catalyzed
cross-coupling reaction of aryl halides with C1-nucleophiles.
Under the optimized conditions, the b-elimination pathway us-
ing a bulky phosphine ligand (JackiePhos) was suppressed re-
sulting in a transfer of anomeric configuration from the C1-stan-
nane to aryl C-glycoside. Experimental and computational stud-
ies support a mechanistic proposal that (a) the stereoretentive
transmetalation step in the glycosyl Stille coupling occurs via a
cyclic transition state for both anomers and is independent of
the steric and electronic environment of the saccharide, (b)
JackiePhos facilitates reductive elimination leading to the for-
mation of C-C bond and prevents elimination of the C2 substit-
uents by “locking” the saccharide ring in the anomeric palla-
dium intermediate. We have demonstrated the generality of the
glycosyl cross-coupling method in over 50 examples featuring
both anomers of various monosaccharides, deoxysugars, oligo-
saccharides, and saccharides with free hydroxyl groups. For
each substrate described here, consistently high selectivities
were observed, opening up opportunities to incorporate glyco-
syl groups with exclusive control of anomeric configuration
into a myriad of aryl electrophiles. The precision and selectivity
of our method is thus far unattainable by other chemical ap-
proaches. This powerful tool allows for the glycodiversification
studies and synthesis of a library of glycans to be conducted
with minimal protective group manipulations in a highly pre-
dictable manner.
Experimental and computational details, energies and Carte-
sian coordinates, copies of NMR spectra of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*pengliu@pitt.edu
*maciej.walczak@colorado.edu
ACKNOWLEDGMENT
This work was supported by the University of Colorado Boul-
der, the University of Pittsburgh, and the National Institutes of
Health (GM125284). Mass spectra analyses were performed at
the University of Colorado Boulder Central Analytical Labora-
tory Mass Spectrometry Core Facility (partially funded by the
NIH S10 RR026641). DFT calculations were performed at the
Center for Research Computing at the University of Pittsburgh.
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Page 17 of 17
Journal of the American Chemical Society
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TOC
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L
O
Pd
Ar
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anomeric
nucleophiles
C-glycosides
O
Ar
O
SnBu3
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stereoretentive
glycosyl
cross-coupling
α and β
anomers
L
Pd
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⚬ mono- and oligosaccharides ⚬ pyranoses and furanoses ⚬ free saccharides
⚬ intramolecular cross-couplings ⚬ exclusive anomeric control ⚬ over 50 examples
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