Stereoretentive Intramolecular Glycosyl Cross-Coupling: Development, Scope, and Kinetic Isotope Effect Study

Article abstract of DOI:10.1021/acs.orglett.8b01927

A series of cyclic C-glycosides were synthesized using the palladium-catalyzed stereoretentive intramolecular glycosylation of aryl iodides by employing a bulky phosphine ligand. A variety of functional groups are tolerated in the reaction, and enantioenr

Full text of DOI:10.1021/acs.orglett.8b01927

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereoretentive Intramolecular Glycosyl Cross-Coupling:
Development, Scope, and Kinetic Isotope Effect Study
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 series of cyclic C-glycosides were synthesized
using the palladium-catalyzed stereoretentive intramolecular
glycosylation of aryl iodides by employing a bulky phosphine
ligand. A variety of functional groups are tolerated in the
reaction, and enantioenriched anomeric nucleophiles could be
coupled without erosion of optical purity. This study offers a
unified method to access both cis- and trans-fused rings by
capitalizing on the stereoretentive nature of the Stille reaction.
In addition, competition experiments for intermolecular and
intramolecular cross-couplings revealed secondary KIEs of
1.43 and 0.81, respectively, suggesting a profoundly different
steric congestion at the transition state.
accharide mimicry through modifications of the labile
glycosidic C−O bond constitutes one of the most successful
The synthesis of cyclic C-glycosides is often accomplished by
the cyclization of an electron-rich arene group linked via the C2
position (Scheme 1A). Such intramolecular C-glycosylations
S
strategies in medicinal chemistry and chemical biology.1
Although many approaches focus on C−O linkage modification,
functionalization of the anomeric position via a C−C bond has
become a routine process for generating O-glycoside surrogates
due to the enhanced in vivo stabilities and predominance of C-
glycosides in nature.2−4 Internal C-glycosides comprise a major
subset of bioactive natural products that include molecules such
as paecilomycin B (1),5−8 bergenin (2),9 chafuroside A (3),10,11
and the papulacandins12−14 (e.g., 4) (Figure 1). Because of the
Scheme 1. Selected Methods for the Synthesis of Cyclic Aryl
C-Glycosides
exploit the steric constraints imposed by the linked intermediate
6 to exclusively prepare cis-fused systems. Currently, this
strategy holds no viable solution for introducing the five- and
six-membered heterocyclic trans-fused rings commonly found in
many natural products.19−23 Methods to establish the trans
configuration are based on intermolecular O-glycosylation
Figure 1. Selected natural products featuring cyclic aryl C-glycosides.
unique roles and diverse activities of C-glycosides, various
methods for their preparation have been described. Representa-
tive examples include the addition of Grignard or organolithium
reagents to glycolactones followed by stereoselective reduction,
opening of 1,2-anhydro sugars, and intramolecular glycosylation
with electron-rich arenes.8,15−18
Received: June 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01927
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Organic Letters
Letter
followed by an O → C migration and subsequent cyclization
(Scheme 1B).24 Although these methods present a viable
solution to the specific synthetic problem at hand, they often
lack generality and can result in suboptimal selectivities at the
anomeric position. Furthermore, the functional group tolerance
and incompatibility with free amide or hydroxyl groups presents
another major limitation.
We hypothesized that a standardized protocol for the
synthesis of both cis- and trans-fused cyclic C-glycosides could
be developed based on stereospecific glycosyl cross-coupling
that capitalized on the stereoretentive transfer of anomeric
configuration from C1 stannanes into a new C−C bond
(Scheme 1C). Herein, we report a stereospecific intramolecular
glycosyl cross-coupling reaction with anomeric nucleophiles and
aryl halides that proceeds for both anomers of the saccharides
used and results in excellent anomeric selectivities.
Unlike intermolecular cross-couplings, securing high anome-
ric selectivity without compromising yield in an intramolecular
pathway is inherently more challenging. For instance, the steric
constraints imposed on the C−Sn (or C−Cu) to C−Pd
transmetalation and reductive elimination may prevent efficient
C−C bond formation due to the increased likelihood of
competing elimination reactions. Furthermore, steric conges-
tion within the anomeric organopalladium intermediate might
also compromise the stereoretentive nature of the glycosyl cross-
coupling reaction.
To test our proposal, we set out to investigate a reaction of the
glycosyl stannane 13 using Pd2(dba)3 (5 or 7.5 mol %) as the
precatalyst and JackiePhos (20 or 30 mol %) as the ligand to
suppress unwanted glycal formation (Table 1).25−29 We
product. As a result, our optimization studies were aimed at
suppressing the undesired elimination pathway.
Performing the reaction in a more concentrated system led to
a decrease in overall yield by 10% with minimal reduction of
elimination product (entry 3), whereas a more diluted condition
(entry 5) gave a comparable result to entry 1. During this time,
we observed a unique effect of the solvent on the rate of C2
elimination: introduction of an aromatic solvent (o-xylene)
resulted in complete suppression of the competing pathway
(entry 2). We reasoned that, similar to the role of a bulky
phosphine ligand, the aromatic solvent serves to stabilize the C1-
organopalladium intermediate in addition to removing the
insoluble Bu3SnF byproduct. After analyzing the varying
stoichiometric systems of cosolvents, we determined that a 5:1
ratio of dioxane and o-xylene (entry 8) was the condition of
choice for the cross-coupling. The presence of a polar solvent in
the mixture ensures that optimal concentrations of fluoride ion
are available to carry out efficient activation of the tin group. In
addition, stoichiometric amounts of copper chloride are
necessary for the reaction to take place. The copper additive
likely affects a preliminary transmetalation reaction from the
organostannane to generate a more reactive organocopper
intermediate; alternatively, copper could also facilitate activation
of the organopalladium intermediate (Pd−F).26,30,31 The
optimized conditions could be conducted without additional
precautions and are scalable (1 mmol) without a detrimental
impact on the yield (63%) or selectivity. In all entries reported in
Table 1, the formation of a single anomer (β) was detected using
1H NMR of unpurified reaction mixtures.
Having established the optimal set of reaction conditions for
affecting these reactions, we next investigated the scope of the
cross-coupling. First, we wanted to better understand the
relative reactivities of the different aryl halides in the
intramolecular glycosyl cross-coupling manifold (Table 2).
Table 1. Optimization of Intramolecular Glycosyl Cross-
a
Coupling with 13
a
Table 2. Cross-Coupling of β-D-Glucose Stannane 15
1,4-
D-
CuCl
T
dioxane: o- concentration
glucal
b
b
entry (equiv) (°C)
xylene
(M)
yield (%)
(%)
1
2
3
4
5
6
7
8
3
3
3
2
3
3
3
3
110
110
110
110
110
110
125
110
1:0
1:1
1:0
1:0
1:0
2:1
2:1
5:1
0.05
0.05
0.1
0.05
0.03
0.03
0.03
0.03
60
37
50
60
61
52
18
N.D.
14
13
18
6
9
11
entry
X
yield (%)
b
1
2
Br (15a)
I (15b)
9
52
a
b
Conditions from Table 1, entry 8. NMR yield.
During our studies, we established that electron-poor arenes
resulted in higher yields of the intermolecular cross-coupling
product compared to those of electron-rich arenes. This result
prompted us to test whether an activated electron-poor arene
such as 15 could easily cross-couple with bromine as the halide
source. Thus, bromoarene 15a was subjected to glycosylation
under the standard conditions and resulted in 9% conversion to
C-glycoside 16, whereas iodoarene 15b furnished 16 in 52%.
These results are consistent with previous findings regarding the
reactivity of aryl halides in the Stille coupling. The striking
difference in yield between the two halides suggested the need
for iodoarene substrates, and thus, bromoarenes were not
pursued further.
53
c
61 (60)
a
General conditions: 13 (0.1 mmol), Pd2(dba)3 (5 mol %),
JackiePhos (20 mol %). NMR yield. Isolated yield. N.D. = not
detected.
b
c
attributed these observations to the sterics and electronic nature
of the phosphine that stabilizes the anomeric organopalladium
species and promotes the reductive elimination leading to the
formation of a C−C bond.26 Under these conditions, desired
product 14 was obtained in 60% yield with exclusive β-selectivity
(entry 1). Despite the encouraging initial results, a significant
amount of D-glucal was also detected as a competitive side-
Scheme 2 lists examples of reactions with variously
substituted iodoarenes that were engaged in cross-coupling
B
DOI: 10.1021/acs.orglett.8b01927
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Organic Letters
Letter
a
Scheme 2. Scope of C-Glycosylation with Iodoarenes 17
Scheme 3. Scope of C-Glycosylation with Anomeric
Stannanes
a
General conditions: 17 (0.1 mmol), Pd2(dba)3 (5 mol %),
JackiePhos (20 mol %), CuCl (3 equiv), KF (2 equiv), 1,4-dioxane,
b
o-xylene, 110 °C. Pd2(dba)3 (7.5 mol %), JackiePhos (30 mol %).
with glycosyl stannanes of structure 17. Substrates bearing an
electron-donating methoxy group para to the iodide are often
difficult substrates for these palladium-catalyzed reactions;32,33
however, cyclization proceeded in good yield to give desired
product 18a in 51%. Alkyl-substituted substrates bearing a
methyl group meta and para to the iodide also furnished their
respective C-glycosides with the meta-alkylated substrate 18c
giving a slightly lower yield than the para-alkylated substrate
18b. Halogenated anomeric nucleophiles were also well-
tolerated under the standardized conditions and provided C-
glycosides 18d, 18f, and 18g in 49−65% yield. Dialkyl C-
glycoside 18e was also formed, but the yield was lower than for
the monoalkyl substrates. It appears that electronic modifica-
tions of the aromatic ring play only a small role in comparison to
the steric effects imposed by various substitutions (e.g., 18a and
18e).
Next, we tested the scope of the glycosyl cross-coupling
reaction using various anomeric nucleophiles 19 (Scheme 3).
We were pleased to find that all of the stannanes tested gave rise
to retention of anomeric configuration (>99:1 dr) without any
detectable erosion of stereochemistry at the anomeric carbon for
both anomers. α-Stannanes derived from D-glucose successfully
cyclized to give the cis ring (20a) in 48% yield. Interestingly, a
silyl ether protected 1,2-trans glucosyl stannane was also well-
tolerated in this system despite the presence of a fluoride source;
it gave the protected C-glycoside 20b in 56% yield with no
detectable amounts of deprotected 6′-OH counterpart.
Furthermore, a benzylidene acetal group (20c) was compatible
with the standard conditions. Other configurationally stable 1,2-
trans anomeric stannanes derived from D-galactose (20d, 20e),
D-glucosamine (20f), L-fucose (20g), and D-quinovose (20h)
underwent conversion to the corresponding C-glycosides. To
our delight, even a disaccharide such as the D-lactose stannane
(20i) was cleanly cyclized.
a
General conditions: 19 (0.1 mmol), Pd2(dba)3 (5 mol %),
JackiePhos (20 mol %), CuCl (3 equiv), KF (2 equiv), 1,4-dioxane,
o-xylene, 110 °C. Pd2(dba)3 (7.5 mol %), JackiePhos (30 mol %).
b
stable by ΔG298 4.9 kcal/mol. Reverse stability preferences were
observed for D-glucose C-glycosides 14 and 20a for which the
trans isomer is more stable by ΔG298 2.8 kcal/mol. However, in
the case of 1,2-cis anomer, the formation of glycals accounts for
∼15% more of the material. These observations indicate that the
rate of the cyclization is heavily influenced by the rate of
transmetalation from sterically congested stannanes.
Further mechanistic studies were focused on the analysis of
secondary kinetic isotope effects (SKIEs). First, the preparation
of labeled stannanes 26 and 27 is presented in Scheme 4. D-
Glucal 21 was converted to labeled compound with excess t-
BuLi and quenched with D2O, resulting in 22 with >99.9%
incorporation of deuterium at C1. The silicon protective groups
in 22 were removed, and the triol was first converted to ester 23
because of the ease of purification and then into ether 24. This
intermediate served as the precursor for the subsequent steps
that introduced the Bu3Sn group in the anomeric carbon. Thus,
epoxidation of D-glucal 24 with DMDO/Oxone34 followed by
opening with a nucleophilic tin reagent (Bu3SnMgMe) afforded
alcohol 25 in 30% yield (over two steps). We elected to protect
the C2-OH position as benzyl and 2-iodobenzyl ethers 26 and
27.
The kinetic isotope effects were studied in competition
experiments for both inter- and intramolecular cross-couplings
and secondary KIEs of 1.43 and 0.81 were observed for reactions
with 26 and 27, respectively (Scheme 4). On the basis of these
experimental results, we propose that the intramolecular cross-
coupling is more sensitive toward steric hindrance than the
intermolecular variant. The vibrational amplitude of a C-D bond
is smaller than that of C-H bond, which in turn makes deuterium
appear to be smaller than a protium atom in some contexts.35,36
Mechanistically, the oxidative addition of Pd(0) occurs on the
aryl iodide followed by a transmetalation step of the anomeric
stannane or the anomeric copper. We believe that, at this stage,
To better understand the structural constraints of the
cyclization reactions with 1,2-cis and 1,2-trans isomers, we
performed in silico studies. DFT calculations (B3LYP/6-311+
+G**//B3LYP/6-31G*) performed for the most stable con-
formers of GlcNAc amides revealed that cis product to be more
C
DOI: 10.1021/acs.orglett.8b01927
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Letter
Author Contributions
Scheme 4. Synthesis of C1-Deuterated Anomeric Stannane
†D.Y. and F.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the University of Colorado at
Boulder and the National Science Foundation (CAREER Award
No. CHE-1753225). Mass spectral analyses were recorded at
the University of Colorado Boulder Central Analytical
Laboratory Mass Spectrometry Core Facility (partially funded
by the NIH, RR026641). Eric Miller (University of Colorado at
Boulder) is acknowledged for the preliminary results.
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