Glycosyl Cross-Coupling with Diaryliodonium Salts: Access to Aryl C -Glycosides of Biomedical Relevance

Article abstract of DOI:10.1021/acs.orglett.8b00475

A stereospecific cross-coupling reaction of anomeric nucleophiles with diaryliodonium triflates resulting in the synthesis of aryl C-glycosides is reported. This process capitalizes on a stereoretentive reaction of configurationally stable C1 stannanes and is promoted by a palladium catalyst in the presence of a bulky phosphine ligand that suppresses the undesired β-elimination. The utility of this reaction has been demonstrated in the preparation of a series of C-glycosides derived from common saccharides resulting in exclusive transfer of anomeric configuration from the anomeric nucleophile to the product, and in the synthesis of empagliflozin, a commercial antidiabetic drug.

Full text of DOI:10.1021/acs.orglett.8b00475

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Glycosyl Cross-Coupling with Diaryliodonium Salts: Access to Aryl
C‑Glycosides of Biomedical Relevance
Duk Yi, Feng Zhu, and Maciej A. Walczak*
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309, United States
S
* Supporting Information
ABSTRACT: A stereospecific cross-coupling reaction of
anomeric nucleophiles with diaryliodonium triflates resulting
in the synthesis of aryl C-glycosides is reported. This process
capitalizes on a stereoretentive reaction of configurationally
stable C1 stannanes and is promoted by a palladium catalyst in
the presence of a bulky phosphine ligand that suppresses the
undesired β-elimination. The utility of this reaction has been
demonstrated in the preparation of a series of C-glycosides
derived from common saccharides resulting in exclusive
transfer of anomeric configuration from the anomeric
nucleophile to the product, and in the synthesis of
empagliflozin, a commercial antidiabetic drug.
tereoselective manipulations at the anomeric carbon
constitute one of the most challenging problems in
Scheme 1. Selected C-Glycosides and Methods for Their
Preparation
S
preparative carbohydrate chemistry.1,2 An overwhelming
majority of chemical methods that form a new bond with the
anomeric carbon are focused on reactions with glycosyl donors
in which the anomeric position is substituted with a heteroatom
or a halide. These methods inevitably result in a loss of
stereochemical integrity because of the formation of an
oxocarbenium intermediate, and sophisticated strategies are
needed to achieve high anomeric control. An alternative
method that focuses on reactions of configurationally stable
anomeric nucleophiles might provide a viable solution to these
problems. Here we report the glycosyl cross-coupling reactions
of diaryliodonium triflates with anomeric stannanes that furnish
C-glycosides with a consistently high transfer of anomeric
configuration from the substrate to the product. This method
furnished both anomers of common saccharides with high
anomeric selectivities through transfer of the anomeric
configuration from the substrate to the product.
Many C-aryl glycosides are a common structural motif found
in bioactive natural products (angucycline antitumor anti-
biotics),3 imaging agents,4 and glycoproteins (C-mannosyla-
tion)5 (Scheme 1A). The most prominent commercial
application of C-glycosides is gliflozins, a class of sodium-
glucose cotransporter (SGLT2) inhibitors used as a treatment
for diabetes mellitus type 2.6 Gliflozins contain a β-D-glucose
residue directly linked to an aromatic ring usually containing a
modification at the para position.
Given the special role of C-glycosides in medicinal chemistry
and drug discovery, methods that enable the introduction of the
glycosyl group with high and predictable stereochemical
outcome are desired.7−10 The most common methods for
establishing the C-glycosyl bond rely on the reduction of
glycals, and the nucleophilic addition to lactones followed by
reduction or nucleophilic substitution with electron-rich arenes
(Scheme 1B).5 These methods often present a viable solution
to a specific synthetic problem, and the stereochemical
Received: February 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00475
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Letter
a
outcome is often dependent on subtle structural features of the
substrate. We recently described the synthesis and cross-
coupling reactions of anomeric stannanes.11−13 These reagents
are configurationally stable anomeric nucleophiles14 and can be
engaged in cross-coupling reactions with various aryl halides
with retention of anomeric configuration. During our studies
we established that electron-rich arenes resulted in lower yields
of the cross-coupling product. The impact of electronic
substitution on the rate of cross-couplings with C(sp2)
nucleophiles such as boronic acids or esters and Grignard
reagents has been reported.15−17 However, the role of
electronic substitution has an even more dramatic effect for
C(sp3) nucleophiles, especially in the case of anomeric
nucleophiles where the competing β-elimination can become
a dominant pathway. The glycosyl cross-coupling is a special
case because, in addition to a potentially problematic β-hydride
elimination, the β-oxygen group can be removed under the
reaction conditions. The subtle balance between the reductive
elimination leading to a new C−C bond and β-elimination can
be shifted in favor of the former by the judicious selection of a
bulky phosphine ligand. In order to overcome the difficulties
with aromatic substrates, we hypothesized that more reactive
iodonium salts18−20 would be suitable candidates for this
transformation. We speculated that the transfer of an aryl group
to Pd would be facilitated by a reduction of the iodine to
iodine(I) and that it could have a beneficial effect on the overall
efficiency of the process. Diaryliodonium salts have recently
become useful reagents for C(sp3)−H activation21−28 and the
preparation of sterically congested alkyl aryl ethers.29
Furthermore, unlike the reactions of aryl halides, cross-
couplings of C(sp3) nucleophiles (e.g., organozinc, organo-
stannanes, organocuprates) with iodonium reagents are far less
known and only a handful of examples have been reported with
activated substrates such as allylic,30 benzylic,31 and strained32
reagents. To the best of our knowledge, the formation of
C(sp2)−C(sp3) bonds using unactivated substrates remains
unknown, yet the synthetic potential of such transformation is
clear.
Table 1. Optimization of Glycosyl Cross-Coupling
In order to identify the conditions for glycosyl cross-coupling
with anomeric stannanes, we used β-D-glucose nucleophile 13
and diphenyliodonium salts 14 (Table 1). Our initial catalyst
identification studies focused on control of the undesired β-
elimination of the C2 benzyloxy group using a biaryl phosphine
ligand. These reactions were conducted in the presence of a
stoichiometric amount of a copper additive which often exerts
positive effects on the Stille reaction.33 We also hypothesized
that an inorganic fluoride source might facilitate the trans-
metalation step and quench the tin byproduct. Thus, 2 equiv of
KF were added. From the optimization studies, BrettPhos34
ligands resulted in no detectable amounts (entries 1 and 2) or
low yields (entry 3) of the desired C-glycoside 7 and resulted in
full consumption of 13 to D-glucal.
a
General conditions: 13 (1.5 equiv), iodonium salt (1 equiv),
Pd2(dba)3 (5 mol %), ligand (20 mol %), CuCl (3 equiv), KF (2
equiv), 1,4-dioxane (0.05 M). NMR yield. Isolated yield. N.D. = not
detected.
b
c
14d salts and engaged them in the cross-couplings under the
previously optimized conditions (entries 11−13). We found
that the triflate salt 14a was the optimal reagent for the glycosyl
C(sp2)−C(sp3) coupling resulting in the best yield. This
observation is consistent with previous reports on the reactions
of iodonium tosylates which state that they are sluggish in the
C(sp2)−C(sp2) cross-couplings due to the coordination of the
tosyl ion with the electrophilic iodine center.36,37 Also, to rule
out the possibility that Cu alone catalyzes glycosyl cross-
coupling, a control reaction was conducted in the absence of Pd
(entry 14). The desired product 15 was detected in 8% yield,
which substantiates the need for a Pd catalyst. The optimized
conditions are user-friendly, and no special precautions are
needed; the glycosyl cross-coupling can be conducted using
commercially available 1,4-dioxane without additional purifica-
tions and on a 1 mmol scale with no impact on yield (85%) or
selectivity.
Gratifyingly, JackiePhos L435 was found to result in an
excellent yield of the product 15 (93%) and exclusive (1H
NMR) β-selectivity was observed. Further optimization studies
revealed that no other ligand tested, regardless of their size or
electronic nature, could compare to L4 (entries 5−10). For the
cross-couplings described in Table 1 to reach full consumption
of 13, reaction times up to 72 h were required. However, for all
ligands tested only the β-anomer was detected. We also
wondered if the counterion in the iodonium salt 14 exerted any
impact on the yield of this process. To this end, we prepared
tetrafluoroborate 14b, tosylate 14c, and hexafluorophosphate
Having established a set of conditions that resulted in a
transfer of anomeric configuration from the anomeric
B
DOI: 10.1021/acs.orglett.8b00475
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nucleophiles, we next investigated the substrate scope (Scheme
2). First, we tested the scope of iodonium partners that could
Scheme 3. Scope of C-Glycosylation with Anomeric
Stannanes
Scheme 2. Scope of C-Glycosylation with Symmetrical (A)
and Unsymmetrical (B) Iodonium Triflates
be engaged in the cross-couplings.38,39 Scheme 2A lists
examples of reactions with various symmetrical iodonium
salts that were engaged in reactions with β-D-glucose 13. For all
examples reported, not only good to excellent yields could be
obtained but also uniformly high levels of retention were40,41
detected in favor of the β-anomer (1H NMR). One of the main
limitations of symmetrical iodonium salts is the loss of one aryl
group that cannot participate in the cross-coupling reaction.
However, it is important to highlight that aryl iodoniums
bearing chlorine and bromine were tolerated with excellent
halogen regioselectivity (17 and 18). Unsymmetrical iodonium
triflates containing hindered (e.g., 2,4,6-trimethylphenyl,
mesityl) groups have been reported to transfer the sterically
more accessible group.42−45 Thus, we used a series of
unsymmetrical reagents (Scheme 2B) that contained a mesityl
group and an aryl moiety. As expected, the smaller aryl group
was exclusively transferred into the anomeric position for
electron-poor (21−26), electron-rich (27), and disubstituted
aryls (28 and 29). For comparison, unsymmetrical phenyl
mesityl iodonium triflate furnished the C-phenyl glycoside 15 in
a yield lower (78%) than the symmetrical salt 14a.
Next, we tested the scope of the cross-coupling reaction
using various anomeric nucleophiles (Scheme 3). We were
pleased to find that configurationally stable 1,2-trans anomeric
stannanes derived from D-glucose (32−34), D-galactose (35−
37), D-arabinose (39), L-fucose (40), and even disaccharides
(D-lactose, 41) underwent clean conversion into the corre-
sponding C-aryl glycosides with retention of anomeric
configuration. Similarly, the high transfer of anomeric
configuration from the α-stannane resulted in the synthesis of
C-galactoside 36. 2-Deoxy sugars known for their difficult
control of the anomeric configuration were easily prepared
under the optimized conditions without any detectable erosion
of anomeric configuration (38). The unique feature of our
method is its tolerance and compatibility with free hydroxyl
groups, unlike other technologies that rely on the nucleophilic
addition to glycosyl acceptors. Thus, partially protected
anomeric stannanes with free hydroxyl groups at C6 (33)
and C2 (34, 36, 37) were successfully converted into the C-
glycosides with consistently high anomeric control. Also, other
protecting groups such as 2-methylnaphthyl (42) and acetyl
(43) were tolerated. Our method is also characterized by high
chemoselectivity; we were unable to detect any O-arylation
products for substrates that contain free hydroxyl groups.46,47
Because the cross-coupling with complex saccharides
proceeded with excellent selectivities, we wondered if our
general reaction conditions could be extended to simple α-
alkoxy substrates (Scheme 4). Diaryliodonium substrates have
been engaged in reactions with allyl stannanes, but to the best
of our knowledge, reactions with simple alkoxy stannanes have
not been reported. To this end, tetrahydropyranosyl stannane
44 and symmetrical iodonium triflate 45 were exposed to the
Scheme 4. Cross-Coupling of Stannane 44
C
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Letter
optimized reaction conditions and furnished the expected
product 46 in 52% yield.
Finally, to demonstrate the utility of the cross-coupling
reaction with iodonium salts, we prepared protected empagli-
flozin 49 (Scheme 5). Empagliflozin is a commercial
for late-stage diversification and applications in drug discovery
campaigns, as glycans can be introduced in a predictable and
programmed fashion.
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 5. Synthesis of Empagliflozin
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00475.
Experimental details and copies of NMR spectra for all
new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: maciej.walczak@colorado.edu.
ORCID
Maciej A. Walczak: 0000-0002-8049-0817
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the University of Colorado at
Boulder. Mass spectral analyses were recorded at the University
of Colorado Boulder Central Analytical Laboratory Mass
Spectrometry Core Facility (partially funded by the NIH,
RR026641).
antidiabetic drug that acts as an inhibitor of sodium-glucose
cotransporter 2.48 This compound was prepared via addition of
a Grignard reagent to gluconolactone followed by a silane
reduction.49 The optimized conditions were used in a reaction
between mesityl iodonium 47 and furnished 49 in 79% yield as
a single anomer. The same conditions applied to aromatic
iodide 48 furnished 49 in 7% lower yield but with exclusive β-
selectivity. These results demonstrate the utility of the
iodonium triflates in the cross-coupling reactions even in the
case of complex substrates and present a viable alternative to
the current methodologies for the preparation of bioactive C-
aryl glycosides.
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