Copper Reactivity Can Be Tuned to Catalyze the Stereoselective Synthesis of 2-Deoxyglycosides from Glycals

Article abstract of DOI:10.1021/acs.orglett.9b04525

We demonstrate that tuning the reactivity of Cu by the choice of oxidation state and counterion leads to the activation of both "armed" and "disarmed" type glycals toward direct glycosylation leading to the α-stereoselective synthesis of deoxyglycosides in good to excellent yields. Mechanistic studies show that Cu^I is essential for effective catalysis and stereocontrol and that the reaction proceeds through dual activation of both the enol ether as well as the OH nucleophile.

Full text of DOI:10.1021/acs.orglett.9b04525

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Letter
Copper Reactivity Can Be Tuned to Catalyze the Stereoselective
Synthesis of 2‑Deoxyglycosides from Glycals
∥
∥
́
Carlos Palo-Nieto, Abhijit Sau, Robin Jeanneret, Pierre-Adrien Payard, Aude Salame,
Maristela Braga Martins-Teixeira, Ivone Carvalho, Laurence Grimaud,* and M. Carmen Galan*
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ABSTRACT: We demonstrate that tuning the reactivity of Cu by the choice of
oxidation state and counterion leads to the activation of both “armed” and “disarmed”
type glycals toward direct glycosylation leading to the α-stereoselective synthesis of
deoxyglycosides in good to excellent yields. Mechanistic studies show that CuI is
essential for effective catalysis and stereocontrol and that the reaction proceeds
through dual activation of both the enol ether as well as the OH nucleophile.
general harsher conditions used to activate such glycals often
lead to donor hydrolysis and/or Ferrier type products.26
These findings prompted us to explore the utility of copper
in the activation of glycals to yield 2-deoxyglycosides. To that
end, a series of Cu(I) [Cu(MeCN)4(NTf2) and (CuOTf)2·
C6H6] and Cu(II) [Cu(NTf)2·H2O and Cu(OTf)2] salts at
different catalyst loadings, reaction temperatures, and solvents
arbohydrates play significant roles in a wide range of
1
Cbiological events, and efficient catalytic and asymmetric
methods to access this class of chiral molecules are needed to
further our understanding of their various roles and functions
in health and disease.2,3
First row transition metals have recently attracted attention
as alternatives to precious metals in catalysis.4 Among those,
copper is a cost-effective, earth-abundant, and sustainable
metal and Cu-complexes can display unique and versatile
reactivity and good functional group tolerance.4 The chemistry
exhibited by Cu can be very diverse depending on its oxidation
state, as this metal can efficiently catalyze reactions involving
one or two-electron mechanisms.4−7 In the context of O-linked
glycosylation reactions, a few examples of Cu(II) as a mild
oxophilic Lewis acid catalyst for the activation of oxygen-
containing leaving groups have been reported.8−11 More
recently, the use of CuII(OTf)2 as an in situ oxidant in the
photoinduced-activation of thioglycosides was also exempli-
fied.12 However, despite copper catalysts being relatively cheap
and widely available, we were surprised by the overall under
exploration of this metal in glycosylation chemistry.13−17
Our group is interested in the development of sustainable
and catalytic methods for the synthesis of oligosacchar-
ides.18−21 2-Deoxyhexoses are prominent components of
natural products which due to the lack of substituents at C-2
to direct the nucleophile approach present significant synthetic
challenges, and stereoselective protocols for their assembly
have been of great interest.5,18,22−38
Scheme 1. CuI-Catalyzed Direct Synthesis of
Deoxyglycosides from Glycals
Previous work from our group and others has shown that
activation of glycals to yield glycosides can be achieved using
transition metals such as Pd(II),39,40 Au(I),41 or Re(V)42
catalysts; however, activation of sensitive enol ethers bearing
electron-withdrawing groups at the C-3 position of the glycal
was not possible under those conditions (Scheme 1), and in
Received: January 23, 2020
https://dx.doi.org/10.1021/acs.orglett.9b04525
© XXXX American Chemical Society
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were initially screened as promoters in the glycosylation of
perbenzylated galactal 1a and glucoside acceptor 2a6 (See
Table S1 in the Supporting Information (SI)). It was found
that 5 mol % (CuIOTf)2·C6H6 in toluene at 45 °C gave the
best results (Table 1, entry 1). The substrate scope was thus
acetate, methoxymethyl acetal, silyl ether, and siloxane
protecting groups were prepared and subjected to the
glycosylation conditions with 2a or 2g as the acceptors
(Table 2). Pleasingly, reactions involving galactal donors 1c−
1h were complete within 2−4 h and in yields of 72−98% and
high α-selectivities (15:1 to 30:1) (entries 2−6). Excitingly,
CuI-activation of galactals bearing acetyl groups at C-3 such as
peracetylated galactal 1b and silyl acetal 1h with 2a gave
glycosylation products 7b and 7h, in 63% and 84% yield,
respectively, with high α-stereocontrol (entries 1 and 7). This
is noteworthy, as most protocols used to activate “disarmed”
glycals tend to give mixtures of glycoside and Ferrier-type
products18,19,40 as we also observe when using Cu(II) (Table
2, entry 1). The reaction was also amenable to glycosylations
with glucal substrates, and reactions with 3,4-O-siloxane-
protected 5a44 or 5b44 afforded the corresponding glycosides
8a, 8b, and 9 in high α-stereocontrol (>30:1α:β) and yields
(72−79%) within 1−4 h (entries 8−10). Under the Cu-
catalyzed reaction, peracetylated glucal 5c could also be
activated; however, it afforded Ferrier type glycoside 10 as the
major product (67%, 78:22 α:β, entry 11).45 Conversely,
activation of peracetylated L-fucal 618 afforded 2,6-dideox-
yglycoside 10 in 71% yield within 2 h and in a > 30:1 α:β ratio
(entry 12).
Table 1. Reaction of Glycal 1a with Glycoside Acceptors
2b−2i
To probe the mechanism of our reaction, a 3:1 α/β-
anomeric disaccharide mixture (4j; see the SI for details) was
subjected to the reaction conditions in the absence and
presence of the OH acceptor and gave no change in the
anomeric ratio, indicating that the high α-selectivity is not the
result of anomerization (Figure S1 in the SI). Reaction with
deuterated galactal 12 yielded disaccharides 13a and 13b in
70% yield as a 2:1 mixture of cis:trans products in favor of
equatorial protonation and axial addition of the OH
nucleophile across the double bond (Scheme 2 and Figure
S2). In the presence of 20 mol % DIPEA, the reaction between
galactal 1a and 2d using either Cu(NTf)2·H2O or Cu(OTf)2
was inhibited, which suggests that the presence of a Brønsted
acid might be involved in the reaction.15 To evaluate this,
reactions between both 1a and 1b and 2a in the presence of
0.1−2 mol % TfOH were carried out in toluene (Table S2 in
the SI). In general, lower conversions (20−60%) and
selectivities (3:1 α:β ratios) were observed in all cases
including inseparable mixtures of other side-products (see
the SI for details). This suggests that although a catalytic
amount of TfOH alone is able to activate both armed and
disarmed glycals, Cu(I) is essential for effective and controlled
catalysis.
a
b
c
1
Isolated yield. Determined by H NMR. Reaction using Cu(II)-
(OTf)2 (5 mol %) and sodium ascorbate (10 mol %) to generate
Cu(I) in situ also afforded 4c in 89% yield and >30:1 α:β.
investigated, and galactal 1a was reacted with a range of
primary and secondary OH nucleophiles 2b−2i43 under the
optimized reaction conditions (Table 1). In all cases, reactions
proceeded smoothly and in good to excellent yields and α-
selectivity, demonstrating that the catalytic system tolerates the
presence of common alcohol and amine protecting groups
such as acetals, ethers, esters, and carbamates. Glycosylations
with primary alcohols such as simple benzyl alcohol 2b,
glycosides 2c and 2d, thioglycoside 2e and Boc-protected
serine 2f afforded the corresponding glycoside products in 79−
88% yield within 2 h and with an >30:1 α:β ratio (Table 1,
entries 2−6). Similarly, reactions with secondary alcohols such
as glycoside 2g, Boc-protected threonine 2h, and cholesterol 2i
also afforded the desired products in good yields (72−75%)
and with high α-selectivity (>30:1 α:β ratio, entries 7−9).
Next, the scope of the reaction with respect to the glycal
donor was investigated. A series of differentially protected
galactals 1b−1h, glucals 5a and 5b, and fucal 6 bearing benzyl,
1H NMR spectroscopy studies carried out at room
temperature in toluene-d8 of equimolar mixtures of Cu(I)
catalyst and glycoside acceptor 2a showed signal broadening
for 2a, suggesting an interaction between Cu(I) and the
alcohol (Figure S3). NMR mixtures of 1 equiv of (CuIOTf)2·
C6H6 and galactal 1a also showed slight H-shifts and peak
broadening associated with an interaction between the alkene
protons in 1a (from δ 6.22 to 6.21 ppm), while mixtures of 1
equiv of CuII(OTf)2 and 1a led to quick glycal activation and
formation of degradation products (see Figures S4−S6 in the
SI). On the other hand, no interactions between deactivated
1
peracetylated galactal 1b and Cu(I) were observed by H
NMR at room temperature, while slow degradation of 1b in
the presence of Cu(II)OTf2 could be seen over time (Figure
S7 and S8). Moreover, reaction between 1a and 2c using 5 mol
% CuII(OTf)2 and 10 mol % sodium ascorbate (to generate
B
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Table 2. Reaction Scope between Glycals 1b−1h, 5a−5c, and 6 with Acceptors 2a or 2g
a
b
entry
donor
R1
Ac
Bn
TBS
TBS
MOM
MOM
Ac
R2
Ac
Bn
TBS
TBS
MOM
R3
OAc
OAc
OTBS
N3
OMOM
product
time (h)
yield (%)
cd
α:β
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
5a
5b
5b
5c
6
7b
7c
7d
7e
7f
7g
7h
8a
8b
9
2
3
4
4
3
3
3
3
4
1
5
2
63
15:1
25:1
30:1
30:1
30:1
30:1
21:1
30:1
30:1
30:1
78:22
30:1
80
78
98
75
72
84
OSi(tBu)2
OSi(tBu)2
c
O[Si(iPr)2]2
O[Si(iPr)2]2
O[Si(iPr)2]2
OTIPS
OBn
OBn
72
c
9
79
c
10
11
12
75
e
Ac
Ac
Ac
Ac
OAc
10
11
67
c
71
a
b
c
d
Isolated yield. Determined by 1H NMR. Reaction was carried out at 70 °C. Reactions using Cu(NTf)2·H2O or Cu(OTf)2 afforded inseparable
e
anomeric mixtures of Ferrier and glycoside products (13:87 (79%) and 25:75 (67%), respectively). The reaction favored the Ferrier product over
the 2-deoxyglycoside product (the latter obtained in 15%).
Scheme 2. Glycosylation of Deuterated Glycal Donor 12
with 2a
Cu(I) in situ) also afforded 4c in 89% yield and >30:1 α:β
(Table 1, entry 3). This result further indicates that Cu(I) is
important for effective catalysis toward stereoselective
glycosylation.
Figure 1. CV toward oxidation potentials of [CuI(OTf)] (2 mM) in
the presence of benzyl alcohol (158 equiv) with increasing amounts of
1b (0, 1, 2, 5, 14, 50 equiv), recorded at a steady glassy carbon disk
electrode (d = 3 mm) in nitromethane containing n-Bu4NBF4 (0.3 M)
at 20 °C with a scan rate of 0.5 V s−1.
To better understand the interactions between the Cu
catalysts and both donor 1b and the OH nucleophile, cyclic
voltammetry experiments were undertaken. The electro-
chemical behaviors of both Cu(I) and Cu(II) were studied
(Figure 1, [CuI(OTf)]2 data shown).46 The reduction of
Cu(II) to Cu(I) is a quasi-reversible transfer occurring around
E1/2 = +0.8 V vs SCE, while the electrodeposition and
oxidative dissolution of Cu(0) occurred at +0.1 and +0.6 V,
respectively. The interaction with dihydropyran (DHP), as a
model, was first investigated (Figure S13). Based on the shift of
potentials observed for the reduction peak of CuI, we can
conclude that CuI is stabilized compared to Cu0 due to the
formation of a CuI-DHP complex, suggesting that the
complexation of one DHP to CuI through the π system is
possible.47−49
galactal than with DHP due to the possible complexation of
copper by acetates. In the presence of 1b, the reduction peaks
of both Cu(I) and Cu(II) were shifted toward lower potentials.
These observations are consistent with the formation of
different Cu(I)-1b complexes and Cu(II)-1b. The latter is
likely the result from an interaction between Cu(II) and
acetates as expected from the oxophilicity of Cu(II) and also
since no interaction with CC bond was observed in the CV
experiment with cyclohexene (see SI Figures S9−S12).
However, Cu(I)-1b has a lower stoichiometry than the
Cu(I)-cyclohexene one, in agreement with the formation of
aggregates (see SI Figure S15).
The interaction of Cu(II) and Cu(I) with deactivated
triacetyl galactal 1b was next considered (see SI Figure S14).
Interestingly, the pattern observed is somehow different with
The interaction between the OH nucleophile and copper
was also studied and BnOH was chosen as a model substrate,
C
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Scheme 3. Proposed Mechanism and 3D Structures of Mixed Complexes [CuI(1b)(ROH)]+ Optimized at the DFT B3LYP/
def2-SVP Level
as it was the simplest alcohol used in our scope. In the
presence of BnOH, the reduction peak of Cu(II) was shifted
toward lower potentials, as was the reduction peak of Cu(I)
(see SI Figure S16). These observations are consistent with the
formation of complexes between BnOH and both Cu(I) and
Cu(II) with a higher stoichiometry for the Cu(II) complex
(Figure S17). Finally, in order to study the nature of the
catalyst under conditions close to the catalytic ones, increasing
amounts of galactal 1b were added to a mixture of CuI(OTf) in
the presence of an excess of BnOH (158 equiv).50 The
reduction peak of Cu(I) was shifted toward lower potentials
(Figures 1, S20, and S21). This is consistent with the
formation of a complex between Cu(I) and 1b even in the
presence of a large excess of BnOH.
From our initial mechanistic studies, we concluded that (i)
Cu(I)OTf leads to activation of the glycal double bond and
that in the case of electron-deficient enol ethers Cu(I)
interactions with the acyl groups facilitate the activation;51
(ii) the active form of the catalyst is likely a complex involving
both the glycal and the OH nucleophile [Cu(Glycal)(ROH)]+.
Two possible isomers of [Cu(1b)(ROH)]+ were optimized
using DFT at the B3LYP/def2-SVP level to help us provide
some insights with regard to the active species (see the SI for
computational details): one featuring a copper-acetate
interaction (“up”) and one with the copper in the position
opposite to the acetate moieties (“down”). Upon coordination
to the CC bond, copper induces a modification of the
electronic structure (Figure S22 and Table S3, SI). The
electronic density on the carbon C2 increases (−0.063 for up
and −0.161 for down), while the one on O1 and C1 (+0.075
for up and +0.104 for down) decreases. In the meantime, the
CC bond length increases (+0.032 for up and +0.040 for
down) while the CO bond shortens (−0.008 for up and
−0.019 for down). All these observations suggest that these
complexes have a carbocation-like behavior. A mechanism can
thus be proposed involving two [Cu(1b)(ROH)]+ complexes
“up” or “down” (A) which can form two different
oxocarbenium intermediates (B) that are quickly trapped by
the OH nucleophile to yield the glycoside products (Scheme
3). Two alternative pathways can be invoked for the
nucleophile addition, an outer sphere attack of the OH
nucleophile (not coordinated to Cu) on the carbocation ((B)
pink arrow) and a second one with an inner sphere addition
involving the ROH coordinated to Cu ((B) red arrow). Based
on the labelling experiments (Scheme 2), it seems that a
bottom face attack of the nucleophile is preferred.
In summary, we have shown that adjusting the oxidation
state and counterion of Cu can be exploited to control its
reactivity profile. We demonstrate for the first time the CuI-
catalyzed direct α-stereoselective glycosylation of glycals to
give 2-deoxyglycosides in high yields and α-stereocontrol. The
reaction is tolerant of most common protecting groups in both
the glycal donor and nucleophile acceptor, including electron-
deficient galactals. Initital investigations indicate that the Cu-
catalyzed enol ether activation/functionalization may proceed
through dual activation of both the enol ether and nucleophile,
whereby the Cu catalyst plays a key role in effective
glycosylation and stereocontrol. Understanding the reactivity
of these type of catalytic systems is of fundamental importance
to be able to exploit the repertoire of transition metal catalysis
in synthesis.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04525.
Experimental procedures, full characterization data and
copies of NMR data (PDF)
D
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Letter
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AUTHOR INFORMATION
■
Corresponding Authors
́
Laurence Grimaud − Laboratoire des biomolecules (LBM),
́
́
Sorbonne Universite − Ecole Normale Superieure − CNRS,
75005 Paris, France; orcid.org/0000-0003-3904-1822;
Email: Laurence.grimaud@ens.fr
M. Carmen Galan − School of Chemistry, University of Bristol,
Bristol BS8 3TS, United Kingdom; orcid.org/0000-0001-
7307-2871; Email: M.C.Galan@bristol.ac.uk
Authors
Carlos Palo-Nieto − School of Chemistry, University of Bristol,
Bristol BS8 3TS, United Kingdom
Abhijit Sau − School of Chemistry, University of Bristol, Bristol
BS8 3TS, United Kingdom
Robin Jeanneret − School of Chemistry, University of Bristol,
Bristol BS8 3TS, United Kingdom
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ylation and glycosylation: effective and convenient approaches for the
stereoselective synthesis of 2-deoxy-2-iodo glycosides. Tetrahedron
Lett. 2016, 57 (7), 811−814. (b) Frem, D.; Urban, D.; Norsikian, S.;
Beau, J. M. From Chitin to alpha-Glycosides of N-Acetylglucosamine
Using Catalytic Copper Triflate in a Heated Sealed-Vessel Reactor.
Eur. J. Org. Chem. 2017, 2017, 5094−5101. (c) Kusunuru, A. K.;
Tatina, M.; Yousuf, S. K.; Mukherjee, D. Copper mediated
stereoselective synthesis of C-glycosides from unactivated alkynes.
Chem. Commun. 2013, 49, 10154−10156.
́
Pierre-Adrien Payard − Laboratoire des biomolecules (LBM),
́
́
Sorbonne Universite − Ecole Normale Superieure − CNRS,
75005 Paris, France
́
́
Aude Salame − Laboratoire des biomolecules (LBM), Sorbonne
́
́
Universite − Ecole Normale Superieure − CNRS, 75005 Paris,
France
(12) Mao, R. Z.; Guo, F.; Xiong, D. C.; Li, Q.; Duan, J. Y.; Ye, X. S.
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Maristela Braga Martins-Teixeira − School of Pharmaceutical
̃ ̃
Sciences of Ribeirao Preto, University of Sao Paulo, Monte
Alegre CEP 14040-903, Brazil
Ivone Carvalho − School of Pharmaceutical Sciences of Ribeirao
Preto, University of Sao Paulo, Monte Alegre CEP 14040-903,
Brazil
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Catalysis: Challenges and Opportunities. Eur. J. Org. Chem. 2016,
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Complete contact information is available at:
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(15) Sletten, E. T.; Tu, Y. J.; Schlegel, H. B.; Nguyen, H. M. Are
Bronsted Acids the True Promoter of Metal-Triflate-Catalyzed
Glycosylations? A Mechanistic Probe into 1,2-cis-Aminoglycoside
Formation by Nickel Triflate. ACS Catal. 2019, 9 (3), 2110−2123.
(16) McKay, M. J.; Nguyen, H. M. Recent Advances in Transition
Metal-Catalyzed Glycosylation. ACS Catal. 2012, 2 (8), 1563−1595.
(17) Ling, J.; Bennett, C. S. Recent Developments in Stereoselective
Chemical Glycosylation. Asian J. Org. Chem. 2019, 8 (6), 802−813.
(18) Sau, A.; Palo-Nieto, C.; Galan, M. C. Substrate-Controlled
Direct alpha-Stereoselective Synthesis of Deoxyglycosides from
Glycals Using B(C6F5)3 as Catalyst. J. Org. Chem. 2019, 84, 2415.
(19) Palo-Nieto, C.; Sau, A.; Williams, R.; Galan, M. C. Cooperative
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(20) Beattie, R. J.; Hornsby, T. W.; Craig, G.; Galan, M. C.; Willis,
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Author Contributions
∥C.P.-N. and A.S.: Equal contribution.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.C.G., R.J., and A.S. thank the European Research Council
(ERC−COG: 648239), and C.P.-N. is thankful for a RS
Newton Fellowship. L.G. thanks the CNRS, the ENS/PSL, and
the ENS Paris Saclay (Ph.D. scholarship to P.-A.P.) for
financial support. I.C. and M.B.M.-M. thank Fundaca
̧
o
̃
de
̀
Amparo a Pesquisa do Estado de Sao
2016/21194-6
̃
Paulo -FAPESP Proc no.
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stereoselective synthesis of deoxy glycosides. Carbohydr. Chem.
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F
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