Homogeneous Gold-Catalyzed Glycosylations in Continuous Flow

Article abstract of DOI:10.1021/acs.orglett.5b01584

The use of versatile alkynyl-building blocks that are activated by gold(I)-catalysis is demonstrated to efficiently generate a variety of glycosides in continuous flow. The application of a continuous flow setting to gold(I)-catalyzed glycosylations enables very short reaction times and excellent control of the reaction conditions.

Full text of DOI:10.1021/acs.orglett.5b01584

Letter
pubs.acs.org/OrgLett
Homogeneous Gold-Catalyzed Glycosylations in Continuous Flow
Stefan Matthies,†,‡ D. Tyler McQuade,†,§ and Peter H. Seeberger*,†,‡
†Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Muhlenberg 1, 14476 Potsdam, Germany
̈
‡Institute of Chemistry and Biochemistry, Freie Universitat Berlin, Arnimallee 22, 14195 Berlin, Germany
̈
§Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306, United States
S
* Supporting Information
ABSTRACT: The use of versatile alkynyl-building blocks that are activated by gold(I)-catalysis is demonstrated to efficiently
generate a variety of glycosides in continuous flow. The application of a continuous flow setting to gold(I)-catalyzed
glycosylations enables very short reaction times and excellent control of the reaction conditions.
he efficient and selective formation of O-glycosidic bonds is
Tkey to the synthesis of complex oligosaccharides. So far, no
general approach is available that would address all synthetic
challenges associated with the construction of oligosacchar-
ides.1−6 Most common glycosylation protocols make use of
stoichiometric amounts of promoter and require extensive
cooling or harsh reaction conditions, hence rendering them
incompatible to labile substrates or protecting groups. An ideal
addition to the toolbox of glycosylation procedures would
involve mild reaction conditions combined with the use of
Figure 1. Experimental setup for Au-catalyzed glycosylation in
continuous flow.
catalytic amounts of the activating agent. While transition metal
catalysis for many reactions is far advanced,7−15 glycochemists
only recently adapted this method to O-glycosylation.16−18
passes a 5 bar backpressure regulator. Studies by Yu et al. report
Initially, propargyl glycosides activated by gold(III)-catalysts
were used; yet, they were proven to be unsuitable for complex
oligosaccharide synthesis.19 An improved method allowing for
complex oligosaccharide synthesis replaced the propargylic
leaving group with ortho-hexynylbenzoates via gold(I)-activa-
tion.20−22 Initial results using a gold-catalysis protocol proved to
be both mild and versatile.22 The development of reliable
glycosylating protocol using mild conditions would be beneficial
for oligosaccharide synthesis on solid support23−31 or by flow
chemistry.32−42
the use of 0.1 equiv of PPh3AuOTf with respect to the glycosyl
acceptor to efficiently promote the gold(I)-catalyzed glycosyla-
tion.22
First, the in-flow protocol was optimized for the reaction of
glycosylating agents bearing a C2-ester with selected nucleo-
philes. Activation of C2-O-acetate building block 5 by
PPh3AuOTf furnished the corresponding glycosides; yet, the
formation of orthoester- and other byproducts was also
observed.46 In contrast, the desired glycosides 10−16 were
obtained when glycosyl ortho-hexynylbenzoate 6 (1.3 equiv with
respect to the glycosyl acceptor) was activated by PPh3AuOTf
(0.13 equiv) with a residence time of 20 min at slightly elevated
temperatures (40 °C, Scheme 1). As expected, the exclusive
formation of the trans-glycosides was observed.
Continuous chemical syntheses exhibit many advantages43−45
including high material throughput and improved control over
the reaction conditions. Here, we report on gold(I)-catalyzed
glycosylation protocols developed for a continuous flow setting.
The continuous glycosylation setup is composed of two syringes
containing (a) the solution of the nucleophile (glycosyl
acceptor) and glycosylating agent (donor) and (b) the catalyst
in a suitable solvent and a syringe pump to deliver the solutions
through a T-mixer followed by a check valve into the reactor loop
(5 mL, PFA coil reactor, Figure 1). The reaction is allowed to
proceed at the given temperature before the reaction mixture
The reaction of the nucleophiles N-Cbz-L-serine methyl ester,
N-Cbz-5-aminopentanol, and cholesterol with glycosyl o-
hexynyl-benzoate 6 in the presence of 13 mol % catalyst gave
access to the desired β-glycosides 10, 11, and 12 in good to
Received: May 30, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b01584
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Scheme 1. Glycosylations Using C2-Ester Building Blocks
Scheme 2. Glycosylations Using Perbenzylated Building
Block 17
a
1
The anomeric ratio was determined by H NMR.
block 17 with galactose derivative 8 afforded glycoside 20 in high
to good yield depending on the solvent used (92%, α/β = 1.25:1
in DCM, 48% α/β = 5:1 in Et2O, entries 4 and 5). Lower
efficiency for the formation of diglucoside 21 was observed due
to a lower conversion (entry 6). Longer reaction time (1 h) did
not significantly increase the yield because the formation of
byproducts was observed.
a
b
Not reproducible. Not isolated, yield estimated using the character-
1
istic H NMR signal of 4 as internal standard.
Starting from protected glucosamine building block 22,
excellent yields of the corresponding hexenol- and cholesterol
β-glucosides 23 and 24 were obtained (87% and 86%, Scheme 3).
It is noteworthy that 22 in contrast to perbenzoylated glucose
building block 6 reacted efficiently with 1-hexenol to form linker-
derivative 23 (cf. Scheme 1).
excellent yields (71%−87%, entries 1−3). Trials to attach
glucoside 6 to a hexenol-linker, however, proved irreproducible
(entry 4). Coupling methylglycoside 7 to donor 6 resulted in the
formation of the desired disaccharide 14 in good yield (51%,
entry 5). Entry 6 shows the construction of disaccharide 15 from
galactose acceptor 8 in 50%, while the formation of unidentified
byproducts was observed. Due to the comparatively low
nucleophilicity of glucoside 9, attempts to form disaccharide
16 did not afford the desired product without optimization
(entry 7).
When tri-O-acetyl-2-deoxy donors 25 and 26 were glycosy-
lated to galactose acceptor 8, high yields of the respective
Scheme 3. Glycosylations Using Glucosamine Building Block
22
Next, benzylated building blocks without C2-anchimeric
assistance were examined for their potential in gold(I)-catalyzed
in-flow glycosylations (Scheme 2). These highly armed
glycosylating agents are more reactive than the disarmed
representatives applied previously.47 Higher reactivity in
glycosylation reactions often leads to high conversion and yet
also to the formation of anomeric mixtures. When tetra-O-
benzyl-gluco-pyranoside 17 was used as the donor for the
coupling with hex-5-en-1-ol, glycoside 18 was obtained in good
yield (73%, α/β = 1:2, entry 1, Scheme 2). The reaction of
cholesterol with ortho-hexynylbenzoate 17 furnished glycoside
19 in high yields (84−88%) in both ether and DCM. As
expected, the anomeric ratio was altered toward the preferential
formation of the α-anomer in the presence of ether as the solvent
(1:1 to 4:1, entries 2 and 3). The union of perbenzylated building
B
DOI: 10.1021/acs.orglett.5b01584
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disaccharides 27 and 28 were obtained (75% and 98%, Scheme
4).
of Colloids and Interfaces, Potsdam) for initial experiments and
for providing some staring materials. Dr. S. Gotze and Dr. P.
̈
Stallforth (both Leibniz Institute for Natural Product Research
and Infection Biology, Jena) are acknowledged for critical
comments to the manuscript and the authors are thankful to Dr.
K. Gilmore (Max Planck Institute of Colloids and Interfaces,
Potsdam) for helpful discussions.
Scheme 4. Glycosylations Using Deoxy Glucosides 25 and 26
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ASSOCIATED CONTENT
■
S
* Supporting Information
Schematic representation of the reactor setup, experimental
procedures, and spectroscopic data of new compounds. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01584.
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*E-mail: peter.seeberger@mpikg.mpg.de.
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