Synthesis of protected glucose derivatives from levoglucosan by development of common carbohydrate protecting group reactions under continuous flow conditions

Article abstract of DOI:10.1016/j.carres.2018.08.002

Common carbohydrate protecting group reactions under continuous flow processes are reported in the context of producing partially-protected glucose building blocks from levoglucosan. Benzyl ether protection was demonstrated without the use of NaH using ba

Full text of DOI:10.1016/j.carres.2018.08.002

Accepted Manuscript
Synthesis of protected glucose derivatives from levoglucosan by development of
common carbohydrate protecting group reactions under continuous flow conditions
Keevan C. Marion, Zachary Wooke, Nicola L.B. Pohl
PII:
S0008-6215(18)30399-9
10.1016/j.carres.2018.08.002
CAR 7588
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 10 July 2018
Revised Date: 3 August 2018
Accepted Date: 3 August 2018
Please cite this article as: K.C. Marion, Z. Wooke, N.L.B. Pohl, Synthesis of protected glucose
derivatives from levoglucosan by development of common carbohydrate protecting group reactions
under continuous flow conditions, Carbohydrate Research (2018), doi: 10.1016/j.carres.2018.08.002.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
O
OH
O
Short Synthetic Steps
Green Solvent
Base-mediated Packed-bed Reactor
Continuous Flow
BnO
OBn
O
OAc
O
Reagents A
Reagents B
Reaction
Zone
Mixer
BPR
BnO
OBn
OH
O
BnO
S
Packed-bed
reactor
HO
Heating coil
BnO
column

ACCEPTED MANUSCRIPT
Synthesis of Protected Glucose Derivatives from Levoglucosan by Development of Common
Carbohydrate Protecting Group Reactions Under Continuous Flow Conditions
Keevan C. Marion, Zachary Wooke, and Nicola L. B. Pohl1*
Corresponding Author
* npohl@indiana.edu
1. Department of Chemistry, Indiana University, 800 E. Kirkwood Ave, Bloomington, Indiana
47405, United States.
ABSTRACT: Common carbohydrate protecting group reactions under continuous flow processes are
reported in the context of producing partially-protected glucose building blocks from levoglucosan.
Benzyl ether protection was demonstrated without the use of NaH using barium oxide, which, however,
pointed to the need for forms of this catalyst not as susceptible to close packing under flow. Acylation
conditions were developed under continuous flow in acetonitrile and avoiding pyridine. Ring-opening
the derivatized levoglucosan with propanethiol was also demonstrated producing S-alkyl 2,4-di-O-
benzyl-glucopyranoside building block in 2 rather than 12 steps in increased overall yield.
KEYWORDS: Continuous flow process, Glucose building blocks, Levoglucosan, Green solvent
1. Introduction
Carbohydrates play an important role in biological systems and the ability to synthesize complex
oligosaccharides in gram quantities amenable for in vivo studies has been challenging[1]. Given the
narrow range of stable glycosyltransferases, chemical synthesis has been one of the predominant ways
to synthesize complex oligosaccharides.[2] Although methods have been developed to automate the
coupling of monosaccharide and nucleoside building blocks in various fashions including continuous
flow,[3-10] new efficient technologies and techniques for the gram to kilogram scale production of these
selectively protected monosaccharide building blocks has become a major obstacle to the widespread
use of automated oligosaccharide synthesis.
Monosaccharides have been traditionally protected in multistep batch processes. However, more
recently, continuous flow processes have found their way into various academic and pharmaceutical labs
to synthesize complex natural products.[11-18] Continuous flow processes are highly adaptable; many
reaction zones (for example UV irradiation, supercritical fluids, and solid reactor beds) can be used to
synthesize compounds under diverse conditions.[19-25] Successful reactions on the milligram scale can
also easily be scaled to the gram or kilogram scale by keeping the parameters of the reaction the same
but increasing the flow time until the desired quantity is met [26, 27] or performing multiple reactions
in parallel. This smart dimensioning and scaling-out is a significant advantage over batch scale
processes, but is still relatively unexplored for fine chemical synthesis such as the production of
carbohydrate derivatives. Herein we report the development of the first continuous flow process for the
production of partially-protected glucose building blocks from levoglucosan—with process evaluations
based on green chemistry considerations—and demonstrate the ability to produce a carbohydrate
building block in 2 rather than 12 steps in increased overall yield.
Levoglucosan is a derivative of glucose in which the 6-OH of the sugar closes onto its anomeric center
to form a second ring structure. Increased efforts to produce levoglucosan from biomass have led to
significant cost decreases,[28-30] thereby making this molecule a more desirable chiral pool material.

ACCEPTED MANUSCRIPT
Past efforts have shown that levoglucosan can be used to produce functionalized glucose analogs in
batch production.[31-33] However, these batch production methods do not readily lend themselves to a
continuous synthesis process and have not been carried out with the use of green solvents in mind. With
green chemistry becoming increasingly common on the industry scale,[15, 16, 34, 35] processes to
modify carbohydrate precursors with protecting groups commonly used in carbohydrate synthesis could
be designed without resorting to halogenated solvents, very long reaction times, and significant waste
production.
2. Results and discussion
One of the widely used protecting groups in carbohydrate chemistry is the benzyl ether protecting
group.[36] The benzyl ether serves as a so-called “permanent” protecting group due to its ability to
withstand a wide range of chemical conditions used in protecting group manipulations and
oligosaccharide construction.[36] The ability to benzylate regioselectively in the early stages of a
monosaccharide building block synthesis is important because it can drastically reduce the number of
synthetic steps.[37, 38] However, common benzylation methods are not readily amenable to flow
chemistry as they require a variety of heterogeneous reagents such as sodium hydride in DMF and can
result in pressure buildup from the release of hydrogen gas resulting in runaway reactions.[39-41] A
benzylation reagent that is safe on large scale and amenable to a continuous flow process is needed. A
batch process to regioselectively benzylate the 2- and 4-positions of levoglucosan has been reported
using the uncommon base barium oxide.[42] Unfortunately, barium oxide has very poor solubility in
standard organic solvents used for alkylation reactions. Due to this solubility problem, a column packed
with solid barium oxide was tested for its ability to sustain a benzylation reaction when benzyl bromide
and the levoglucosan were flowed across the bed (Scheme 1). To that end, a syringe pump containing
two 8-mL stainless steel syringes connected to perfluoroalkoxy (PFA) tubing (I.D. 0.04 in, 1/16 in)
using flangeless fittings (1/16 in) containing a ferrule (1/16 in) was constructed. The PFA tubing was
joined together via a Y connector (0.02 in I.D.) and connected to a PFA tubing reactor coil (12.5 ft, 3
mL, I.D. 0.04) which was placed in a hot bath connected to a stainless steel column (25 cm x 4.6 mm
I.D.). The preparation of 2 was achieved by using 0.2 M of levoglucosan 1 and 0.9 M of BnBr which
were brought together at a flowrate of 0.26 mL/min at 91°C into the barium oxide packed-bed reactor
for 22 min.
Scheme 1. Continuous Synthesis of 1,6-Anhydro-2,4-di-O-benzyl-β-D-glucopyranose (2) Using a
Barium Oxide Packed-bed Reactor.
This process did produce the desired product after flash chromatography in a 59% isolated yield.
However, this process also made clear current limitations in available reagents for column packing. The
moderate yield could be due to material retained in the column, which has been an issue previously
reported[43] with packed-bed approaches. Pressure build up during the continuous flow process was
also problematic despite various attempts to pack columns with this reagent (see Supporting
Information). The morphology of the BaO powder does not have a known porous matrix to allow
liquids to easily flow through. Consistent reaction performance and thereby wide-scale adoption of this
method will require the production of BaO catalysts with a consistent size, shape, and porosity.

ACCEPTED MANUSCRIPT
With flow conditions established for the production of 2,4-di-O-benzylated levoglucosan 2, we turned
our attention to functionalizing the 3-OH of the resulting compound by incorporating a temporary acyl
protecting group (Scheme 2). Acetyl groups are often used in carbohydrate synthesis as temporary
protecting groups that allow further modification at the site by simple removal of the acyl group under
basic conditions. Unlike benzylation reactions, acylation reactions have been performed as continuous
processes before.[16, 44, 45] To this end, common methods to acylate sugars in batch were explored in
flow. Fortunately, the preparation of known[31] compound 3 proved to be straightforward using 0.1 M
of 2,4-di-O-benzyl levoglucosan with 0.05 M 4-(dimethylamino)pyridine (DMAP) in pyridine and neat
acetic anhydride which was flowed together at a flow rate of 0.26 mL/min for 11.5 min at 23 °C. The
reaction mixture at steady state was worked up with ethyl acetate and water; the resulting organic layer
was then purified to provide 86% of product 3 (Scheme 2A).
Scheme 2. Standard Batch Acylation Conditions Converted to a Continuous Flow Process (A) and
(B).
Although this set of conditions did produce the desired compound, ideally pyridine and DMAP could
be replaced with more environmentally-benign reagents and acetic anhydride could be replaced with a
more atom economical alternative. To this end, acetyl chloride was tested as the acyl source along with
acetonitrile as solvent, which is favored under green standards as compared to pyridine[35] (Scheme
2B). When this acylation was carried out at 80 °C and 0.5 mL/min for 6 min, full conversion of starting
material was not observed at steady state; therefore, higher temperatures were explored. Fortunately,
product 3 was produced in 58% yield utilizing a flow rate of 0.5 mL/min for 6 min at 100 °C with a 250
psi backpressure regulator (BPR) (see Supporting Information). Acylation of compound 2 could also be
performed at higher concentration without a 250 psi BPR (see Supporting Information). The low
isolated yield could be the result of side products from competing reactions formed at the higher
temperature (100 °C). As a result of low yields at higher temperatures, the acylation of compound 2
was explored with a longer residence time and lower temperature. The acylation was conducted with a

ACCEPTED MANUSCRIPT
flowrate of 0.1 mL/min for 30 min at 80 °C producing 74% of the desired product 3 (Scheme 2). When
the original and the modified acylation reactions are compared side by side, condition B avoids the use
of DMAP and pyridine, reagent and solvent that is not environmentally benign. As a result, condition B
holds promise for use in the larger-scale flow-based production of acetylated carbohydrates when a
green process perspective is in mind.
To produce glucose derivatives destined for oligosaccharide synthesis, we turned our attention next to
the formation of a thiol-linked glycoside. Thioglycosides are important anomeric constituents that can
be activated for glycosylation.[46, 47] Their range of stabilities under basic and acidic conditions,[48]
ability to be activated with various promoters such as N-iodosuccinimide (NIS), hypervalent iodine and
pentavalent bismuth (V),[49-53] their orthogonal activation over common glycosyl donors,[54] and
their ability to be preactivated and coupled selectively in the presence of other thioglycosides[55] makes
them ideal for building block production and oligosaccharide synthesis. The stereoselective ring
opening of functionalized levoglucosan with bis(trimethylsilyl) sulfide, trimethylsilyl azide, and
aryl(halo)-alanes under batch conditions has been reported,[31-33] although the production of thiol
substrates requires 4 to 6 hours in CH2Cl2.[31] With the use of trimethylsilyl azide, alpha glycosyl
azides can be produced in roughly 24 minutes for click chemistry applications, but this method is not
ideal for carbohydrate building block production. The synthesis of beta C-arylglucosides using
aryl(halo)-alanes requires anywhere from 2 to 24 hours. Ideally, a flow process could be developed that
avoids such long reaction times and incorporates alkyl thiols.
Acids can promote the nucleophilic ring-opening of the levoglucosan ring. Therefore, a first attempt at
the stereoselective ring-opening of known compound 4[31] employed a DOWEX H+ packed-bed reactor
column produced in lab; this approach resulted in irreproducible performance under multiple attempts
(Supporting Information). As a result, the Lewis acids TMSOTf and BF3•OEt2 were explored next
(Scheme 3). Under these conditions trace amounts of product were obtained with a residence time of 9
minutes and 15 minutes with a flow rate of 0.2 mL/min at 90 °C. Multiple attempts were performed
utilizing the greener solvents acetonitrile and cyclopentyl methyl ether (CPME) solvent. Acylation was
performed to confirm the regioisomer of the alcohol produced by 1H NMR analysis of the neighboring
proton shift (Supporting Information). The poor reaction performance could be due to the sterically-
hindered environment created by the benzyl group at C-3.
Scheme 3. Ring Opening of 1,6-Anhydro-2,3,4-tri-O-benzyl-β-D-glucopyranose (4).
Given the slow reaction of 4, compound 2—which lacks the C-3 benzyl protection—was probed. Our
attention was turned to substrate 2 and with a flow rate of 0.15 mL/min and a residence time of 20
minutes at 90 °C; compound 6 was produced with full conversion of starting material with an alpha/beta
ratio of 1.7:1 for the product (Scheme 4). Removal of the benzyl group clearly has a dramatic effect on
the reaction outcome. Cyclopentyl methyl ether (CPME) showed good solubility of reactants and its
high boiling point (106 °C) makes it ideal for this high temperature reaction. The importance of using
solvents such as CPME that reduce the negative impact on the environment is increasing in both
industrial and academic settings;[56-58] therefore, the development of chemical synthesis/processes
that are green in nature are key for a sustainable chemical industry.[59, 60]
Scheme 4. Ring Opening of 1,6-Anhydro-2,4-di-O-benzyl-β-D-glucopyranose (2).

ACCEPTED MANUSCRIPT
The new continuous flow processes developed for the di-O-benzylation and alkythiol installation
represents a significant improvement to the previously reported[61] batch synthesis of ethyl 2,4-di-O-
benzyl-1-thio-β-D-glucopyranoside, an advanced monosaccharide intermediate used in the total
synthesis of Kaempferol 3-O-(3’’,6’’-di-O-E-p-coumaroyl)-β-D-glucopyranoside. That synthesis
required 12 synthetic steps for an overall yield of 1.6% (Scheme 5).[61] With the use of levoglucosan
and the described continuous flow processes, functionally equivalent compound 6 could be produced in
2 synthetic steps with an overall yield of 34% (Scheme 5) even without further optimization.
Scheme 5. Comparison of Synthetic Routes to the n-Alkyl-2,4-di-O-benzyl-1-thio-β-D-
glucopyranoside Building Block.
3. Conclusions
Several continuous flow processes that define key steps in the protection of carbohydrate building
blocks—namely O-benzylation and O-acetylation—have been investigated. Through these experiments,
we have demonstrated the first continuous flow process for O-benzylation by the use of BaO in a
packed-bed reactor column and highlighted the problems with using this reagent in its current
availability under flow conditions. The chemistries have also been adapted to eliminate the use of very
common toxic reagents and solvents traditionally used in carbohydrate acylation processes.
Incorporation of n-propanethiol with the use of the green solvent CPME at high temperature results in
the production of an advanced carbohydrate building block in a much shorter synthetic sequence than
previously published and avoids the use of hazardous CH2Cl2. This work sets the foundation for future
work in developing catalysts and reagents for continuous flow processes for the efficient production of
the many different carbohydrate building blocks needed to feed automated oligosaccharide synthesizers.
The very recent report of a high-throughput experimentation (HTE) and high-throughput analytics[62]

ACCEPTED MANUSCRIPT
platform to accelerate reaction optimization in flow should further aid efforts to screen reaction
conditions to optimize carbohydrate building block production.
4. Experimental
4.1. General Experimental Information
All solvents used for air- and moisture-sensitive reactions were high purity reagent grade. Solvent was
collected from a solvent tower followed by the addition of oven-dried room temperature (~23 °C) 4 Å
molecular sieves and placed under argon gas via a syringe, balloon and septum contained in an
Erlenmeyer flask or glass bottle and stored for 12 hours before use. Compounds were dissolved in
anhydrous solvent prior to loading into stainless steel 8-mL VWR syringes. Thin layer chromatography
(TLC) was performed using Sorbent Technologies silica gel TLC plates, glass-backed and pre-coated
with a thickness of 0.25 mm. After TLC development, TLC plates were visualized using UV light
followed by p-anisaldehyde solution containing absolute ethanol and sulfuric acid (1:18:1, p-
anisaldehyde:ethanol:sulfuric acid). Flash silica gel chromatography was carried out using the
Teledyne ISCO CombiFlash® purification system (Combi flash Rf 200 and 200i) with preloaded silica
columns and operated under the conditions stated for the column used.
Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) were
performed on either 1) a Varian 500 MHz NMR containing a dual pulsed field gradient (PFG) probe
with proton (1H) signal to noise ratio 390 to 1, carbon (13C) signal to noise ratio 290 to 1, and
temperature range from -80 to 120 °C or 2) a Varian 400 MHz NMR containing a pulsed field gradient
(PFG) probe with proton (1H) signal to noise ratio 175 to 1, carbon (13C) signal to noise ratio 160 to 1,
and temperature range from -80 to 130 °C. Proton, carbon, and 2D analyses (dqCOSY, HMBC, HSQC)
were performed and recorded in parts per million (ppm) and the residual signal of chloroform (CDCl3)
(δ 7.26 ppm 1H NMR; δ 77.0 ppm 13C NMR) was used as reference. ESI-MS Agilent 1200 HPLC-6130
MSD was used for mass analysis of synthesized compounds.
BaO Packed-bed Reactor Column Construction
The stainless steel column (25 cm x 4.6 mm I.D.) was end-capped and position end up. BaO was added
to the column and packed by tapping on the bench as well as inserting a boiling stick to remove any
BaO that might stick on the side of the column. The column was capped and further packed by flowing
the solvent used for the reaction through the column to remove any air bubbles. The column was then
capped closed at both ends and weighed. The difference between the dry and wet column divided by
the density of the solvent was used to determine the void volume.
BaO/Al2CO3, DOWEX and Amberlite Packed-bed Reactor Column Construction
The same packing procedure as above was used but with Amberlite, Dowex or BaO and Al2CO3 in a 3:2
ratio. BaO and Al2CO3 were premixed by placing the two in a vial and agitating until both powders
were observed to be well mixed.
4.2. Design and Construction of Flow Apparatus
See supporting information for figures.
Continuous flow equipment:
Perfluoroalkoxy (PFA) tubing (I.D. 0.04 in, 1/16 in)
Flangeless fittings (1/16 in)
Ferrule (1/16 in)
Y connector (0.02 in I.D.)
250 psi back pressure regulator

ACCEPTED MANUSCRIPT
PFA tubing reactor coil (0.04 I.D., 381 cm (12.5 ft), 3 mL)
PFA tubing reactor coil (0.03 I.D., 670.56 cm (22 ft), 3 mL)
PFA tubing reactor coil (0.02 I.D., 1524 cm (50 ft), 3 mL)
Stainless steel column (25 cm x 4.6 mm I.D.)
Stainless steel column (50 mm x 4.6 mm I.D.)
Genie Touch Dual Syringe Pump
Hitachi (Model L-7100) HPLC Pump
4.3. Synthetic Procedures
4.4. 1,6-Anhydro-2,4-di-O-benzyl-β-D-glucopyranose (2)
Levoglucosan 1 (200 mg, 1.2 mmol) was dissolved in anhydrous N,N-dimethylformamide (7 mL) and
loaded into an 8-mL stainless steel syringe. Benzyl bromide (0.75 mL, 6.3 mmol) was dissolved in N,N-
dimethylformamide (6.25 mL) and loaded into a separate 8-mL stainless steel syringe. A reactor coil
high purity PFA tubing (0.04 I.D., 381 cm (12.5 ft), 3 mL) was placed in a hot bath at 91 °C to warm the
reaction solution. The levoglucosan and benzyl bromide solutions were flowed together at a flowrate of
0.26 mL/min through the PFA tubing into the packed barium oxide column (3.0 g, 2.7 mL void volume,
25 cm x 4.6 mm I.D.) with a residence time of 22 min. The reaction solution was collected at steady
state in a flask containing methanol (0.5 mL) to quench the reaction. The reaction mixture was diluted
with dichloromethane (10 mL) and washed with water (10 mL), brine (10 mL), and lithium chloride
solution (10 mL). The organic layer was collected, dried over anhydrous sodium sulfate and
concentrated under vacuum via rotary evaporation. The residue was subjected to column purification via
Teledyne ISCO CombiFlash® Rf 200i in hexane/ethyl acetate in a stepwise gradient with elution of
compound in 15% ethyl acetate to provide 2 as a white solid (0.25 g, 0.73 mmol, 59%). See Figure S4
1
in supporting information. Rf 0.46 (1:1 hexane: ethyl acetate); H NMR (500 MHz, chloroform-d) δ
= 7.44 - 7.29 (m, 10 H, Ph), 5.47 (s, 1 H, H-1), 4.77 - 4.67 (m, 5 H, CH2 Ph), 4.59 (d, J = 4.9 Hz, 1 H,
H-5), 3.89 (t, J = 4.1 Hz, 1 H, H-3), 3.83 (d, J = 7.3 Hz, 1 H, H-6), 3.68 (dd, J = 5.4, 7.3 Hz, 1 H, H-6),
3.36 (d, J = 3.4 Hz, 1 H, H-2), 3.28 (d, J = 3.9 Hz, 1 H, H-4), 2.20 (bs, 1 H, OH).
1H NMR matches a previously reported spectrum: Iversen, T; Bundle, D. R. Can. J. Chem. 1982, 60,
299.
Void volume = 2.7 mL BaO column
4.5. 1,6-Anhydro-2,4-di-O-benzyl-3-O-acyl-β-D-glucopyranose (3)
With acetic anhydride
Compound 2 (155.8 mg, 0.45 mmol) and 4-(dimethylamino)pyridine (27.8 mg, 0.23 mmol) were
dissolved in anhydrous pyridine (4.25 mL) and uploaded into an 8-mL stainless steel syringe. Acetic
anhydride (4.25 mL) was uploaded into an 8-mL stainless steel syringe and the solutions were flowed
together via syringe pump at a flowrate of 0.26 mL/min through high purity PFA tubing [0.02 I.D., 1524
cm (50 ft), 3 mL] with a residence time of 11.5 min at 23 °C. The reaction solution was collected in test
tubes containing ethyl acetate and water (0.2 mL each) to quench the reaction and TLC monitoring was
performed on small aliquots of the reaction. Reaction at steady state was collected with ethyl acetate (2
mL, 1.8 g) and water (2 mL, 2 g) total quenching solution. The reaction solution was diluted with ethyl
acetate (12 mL, 10.8 g) and extraction was performed on the reaction mixture with water (10 mL, 10 g).
The organic solution was collected and dried over anhydrous sodium sulfate (10 g). The organic
solution was decanted and ethyl acetate (18 mL, 16.2 g) was used to rinse the sodium sulfate. The

ACCEPTED MANUSCRIPT
organic solution was concentrated via rotary evaporation with 2.9 g of silica and the residue was
subjected to column purification via Teledyne ISCO CombiFlash® Rf 200i using 12 g ISCO column in
hexane ethyl acetate in a stepwise gradient with elution of compound in 15% ethyl acetate. A total of
1042.5 mL (687 g) of hexane was used for purification along with 157.5 mL (142 g) ethyl acetate to
give a total volume of 1200 mL for purification and 89.9 mL (81.2 g) of ethyl acetate used to rinse test
tubes to provide 3 as an oil (0.15 g, 0.39 mmol, 86%). See Figure S5 in supporting information for
details of the setup. Rf 0.6 (1:1 hexane: ethyl acetate).
With acetyl chloride and back pressure regulator
Compound 2 (250.1 mg, 0.73 mmol) was dissolved in anhydrous acetonitrile (7 mL). Acetyl chloride
(0.25 mL, 3.7 mmol) was diluted with acetonitrile (7 mL) and the two solutions were streamed together
via HPLC pump at a flowrate of 0.5 mL/min through high purity PFA tubing [0.03 I.D., 670.56 cm (22
ft), 3 mL] with a residence time of 6 min at 100 °C with an inline 250 psi back pressure regulator.
Additional acetonitrile was passed through the flow system to collect the remaining reaction solution (8
mL, 6.3 g). The reaction solution was collected in test tubes containing ethyl acetate (0.2 mL) and
water (0.2 mL) to quench the reaction and TLC performed. Reaction at steady state was collected with
ethyl acetate (2 mL, 1.8 g) and water (2 mL, 2 g) total quenching solution. The reaction solution was
diluted with ethyl acetate (15 mL, 11.8 g) extraction was performed on the reaction mixture with water
(10 mL, 10 g), and brine (10 mL, 11.8 g). The organic solution was collected, dried with anhydrous
sodium sulfate (10 g) and concentrated via rotary evaporation with 3 g silica. The residue was subjected
to column purification via Teledyne ISCO CombiFlash® Rf 200i using 12 g Isco column in hexane ethyl
acetate in a stepwise gradient with elution of compound in 15% ethyl acetate. A total of 1202.2 mL
(792.24 g) of hexane was used for purification along with 213.8 mL (192.8 g) ethyl acetate to give a
total volume of 1416 mL for purification and 55.4 mL (49.9 g) of ethyl acetate used to rinse test tubes to
provide 3 as an oil (0.162 g, 0.42 mmol, 58%). See Figure S3 in supporting information for details of
the setup. Rf 0.6 (1:1 hexane: ethyl acetate).
With acetyl chloride without back pressure regulator
Compound 2 (395 mg, 1.2 mmol) was dissolved in anhydrous acetonitrile (2.7 mL). Acetyl chloride
(0.4 mL, 5.8 mmol) diluted with acetonitrile (2.7 mL) and each of the two solutions were streamed
together via HPLC pump at a flowrate of 0.7 mL/min through high purity PFA tubing [0.02 I.D., 1524
cm (50 ft), 3 mL] with a residence time of 4 min at 100 °C. Additional acetonitrile was passed through
the flow system to collect the remaining reaction solution (8 mL). The reaction solution was collected
in test tubes containing ethyl acetate (0.5 mL) and water (0.5 mL) to quench the reaction and TLC
performed. Samples at steady state were collected. The reaction solution was diluted with ethyl acetate
(15 mL) extraction was performed on the reaction mixture with water (10 mL), and brine (10 mL). The
organic solution for both steady state and non-steady state were collected, dried with anhydrous sodium
sulfate (10 g) and concentrated via rotary evaporation. The steady state and non-steady state were
evaluated by HPLC and a standard curve was produce to determine yield of product, how much starting
material reacted at steady state and how much starting material was in non-steady state. At steady state,
the flow system provided 3 as an oil (0.248 g, 0.65 mmol, 56%). See Figure S2 in supporting
information for details of the setup. Rf 0.6 (1:1 hexane: ethyl acetate)
With increased residence time and lower temperature
Compound 2 (155.8 mg, 0.45 mmol) was dissolved in anhydrous acetonitrile (4.25 mL) and uploaded
into an 8 mL stainless steel syringe. Acetyl chloride (0.16 mL, 2.3 mmol) diluted with acetonitrile (4.09
mL) and placed in a separate 8 mL stainless steel syringe and the two solutions were streamed together
via syringe pump at a flowrate of 0.1 mL/min through high purity PFA tubing [0.02 I.D., 1524 cm (50
ft), 3 mL] with a residence time of 30 min at 80 °C. The reaction solution was collected in test tubes
containing ethyl acetate (0.2 mL) and water (0.2 mL) to quench the reaction and TLC performed.
Samples at steady state were collected with ethyl acetate (2 mL, 1.8 g) and water (2 mL, 2 g) total
quenching solution. The reaction solution was diluted with ethyl acetate (12 mL, 11 g) extraction was

ACCEPTED MANUSCRIPT
performed on the reaction mixture with water (10 mL, 10 g). The organic solution was dried with
anhydrous sodium sulfate (6.6 g). The organic solution was decanted and ethyl acetate (18 mL, 16.2 g)
was used to rinse the sodium sulfate. The organic solution was concentrated via rotary evaporation with
3.0 g of silica and the residue was subjected to column purification via Teledyne ISCO CombiFlash® Rf
200i using 12 g ISCO column in hexane ethyl acetate in a stepwise gradient with elution of compound
in 15% ethyl acetate. A total of 1042.5 mL (687 g) of hexane was used for purification along with
157.5 mL (142 g) ethyl acetate to give a total volume of 1200 mL for purification and 89.9 mL (81.2 g)
of ethyl acetate used to rinse test tubes to provided 3 as an oil (0.13 g, 0.33 mmol, 74%). See Figure S5
in supporting information for details of the setup.
1
Rf 0.6 (1:1 hexane: ethyl acetate); H NMR (500 MHz, chloroform-d) δ = 7.43 - 7.29 (m, 10 H, Ph),
5.43 (s, 1 H, H-3), 5.08 (t, J = 1.5 Hz, 1 H, H-1 ), 4.82 (d, J = 12.7 Hz, 2 H, CH2Ph), 4.70 (dd, J = 12.7,
15.1 Hz, 2 H, CH2Ph), 4.62 (d, J = 4.9 Hz, 1 H, H-5), 3.90 (d, J = 7.3 Hz, 1 H, H-6), 3.77 - 3.70 (m, 1 H,
H-6), 3.27 (d, J = 12.9 Hz, 2 H, H-2,H-4), 2.08 (s, 3 H, CH3); 13C NMR (126 MHz, chloroform-d) δ =
169.7, 137.8, 137.7, 128.5, 128.4, 128.0, 127.9, 127.8, 127.8, 100.4, 74.8, 74.3, 74.1, 71.7, 71.1, 68.7,
65.0, 21.2; HRMS (ESI): [M + Na]+ m/z calc. for C22H24O6Na+ 407.1465; found 407.1469.
4.6. n-Propyl-2,3,4-tri-O-benzyl-1-thio-α-D-glucopyranoside (5)
Compound 4 (100 mg, 0.29 mmol) was dissolved in cyclopentyl methyl ether (2 mL). 1-Propanethiol
(0.03 mL, 0.32 mmol) and trimethylsilyl trifluoromethanesulfonate (0.2 mL, 1.1 mmol) was diluted with
cyclopentyl methyl ether (2 mL) and each of the two solutions were streamed together via HPLC pump
at a flowrate of 0.2 mL/min through high purity PFA tubing [0.02 I.D., 1524 cm (50 ft), 3 mL] with a
residence time of 15 min at 90 °C. Additional cyclopentyl methyl ether was passed through the flow
system to collect the remaining reaction solution (8 mL). The reaction solution was collected in test
tubes containing triethylamine (0.2 mL) to quench the reaction. Samples at steady state were collected
and the reaction solution was concentrated under reduced pressure via rotary evaporation. The residue
was subjected to column purification via Teledyne ISCO CombiFlash® Rf 200i in hexane/ethyl acetate
in a linear gradient with elution of compound in 10% ethyl acetate to provide 5 as an oil (0.0155 g, 0.03
mmol, 13%). See Figure S2 for details of the setup. Rf 0.6 (1:1 hexane: ethyl acetate); 1H NMR (500
MHz, chloroform-d) δ = 7.43 - 7.29 (m, 15 H, Ph), 5.33 (d, J = 5.4 Hz, 1 H, H-1), 4.99 (d, J = 10.7 Hz,
1 H, CH2Ph), 4.91 (d, J = 11.2 Hz, 1 H, CH2Ph), 4.83 - 4.73 (m, 2 H, CH2Ph), 4.71 - 4.65 (m, 2 H,
CH2Ph), 4.10 (td, J = 3.1, 10.0 Hz, 1 H, H-5), 3.94 - 3.88 (t, J = 9.3 Hz, 1 H, H-3), 3.82 - 3.75 (m, 3 H,
H-2, H-6), 3.55 (t, J = 9.3 Hz, 1 H, H-4), 2.59 - 2.43 (m, 2 H, SCH2CH2CH3), 1.65 (ddd, J = 4.1, 7.3,
14.4 Hz, 2 H, SCH2CH2CH3), 1.03 (t, J = 7.3 Hz, 3 H, SCH2CH2CH3); 13C NMR (126 MHz,
chloroform-d) δ = 138.7, 138.2, 137.6, 128.5, 128.4, 128.4, 128.1, 128.1, 128.0, 127.9, 127.9, 127.6,
83.5, 82.4, 79.7, 75.7, 75.0, 72.4, 71.1, 62.0, 31.9, 22.8, 13.5; HRMS (ESI): [M + Na]+ m/z calc. for
C30H36O5SNa+ 531.2176 ; found 531.2176
4.7. n-Propyl-2,3,4-tri-O-benzyl-6-acyl-1-thio-α-D-glucopyranoside
Note: Compound 5 was acylated to confirm the position of its free hydroxyl via NMR.
Compound 5 (48 mg, 0.09 mmol) was dissolved in acetic anhydride (0.4 mL, 4.6 mmol) and
supplemented with 1,4-diazabicyclo[2.2.2]octane (DABCO) (10.5 mg, 0.09 mmol) in a round-bottomed
flask. The reaction solution was stirred for 2 h at 23 °C. Upon completion, the reaction was quenched
with water and diluted with dichloromethane. The organic layer was extracted with brine, dried over
anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was
subjected to column purification via Teledyne ISCO CombiFlash® Rf 200i in hexane/ethyl acetate in a

ACCEPTED MANUSCRIPT
linear gradient with elution of compound in 5 to 10% ethyl acetate to provide product in quantitative
1
yield as an oil. Rf 0.8 (1:1 hexane: ethyl acetate); H NMR (400 MHz, chloroform-d) δ = 7.43 - 7.21
(m, 15 H, Ph), 5.32 (d, J = 5.5 Hz, 1 H, H-1), 4.96 (d, J = 10.5 Hz, 1 H, CH2Ph ), 4.86 (d, J = 10.9 Hz, 1
H, CH2Ph), 4.78 - 4.60 (m, 3 H, CH2Ph), 4.54 (d, J = 10.9 Hz, 1 H, CH2Ph), 4.33 - 4.17 (m, 3 H, H-5,
H-6), 3.92 - 3.76 (m, 2 H, H-2, H-3), 3.45 (t, J = 9.2 Hz, 1 H, H-4), 2.59 - 2.39 (m, 2 H, SCH2CH2CH3),
2.00 (s, 3 H, CH3), 1.68 - 1.56 (m, 2 H, SCH2CH2CH3), 1.03 - 0.95 (m, 3 H, SCH2CH2CH3); 13C NMR
(101 MHz, chloroform-d) δ = 170.7, 138.5, 137.8, 137.7, 128.4, 128.4, 128.4, 128.1, 128.0, 128.0,
127.9, 127.9, 127.7, 83.4, 82.4, 79.5, 77.1, 75.7, 75.0, 72.3, 68.9, 63.2, 31.9, 22.9, 20.8, 13.5; HRMS
+
(APCI): [M + NH4]+ m/z calc. for C32H38O6SNH4 568.2727 ; found 568.2726
4.8. n-Propyl-2,4-di-O-benzyl-1-thio-α-D-glucopyranoside (6)
Compound 2 (140 mg, 0.41 mmol) was dissolved in cyclopentyl methyl ether (3.5 mL) and loaded into
an 8 mL stainless steel syringe. 1-Propanethiol (0.053 mL, 0.57 mmol) and trimethylsilyl
trifluoromethanesulfonate (0.4 mL, 2.2 mmol) was diluted with cyclopentyl methyl ether (3.1 mL) and
loaded into an 8 mL stainless steel syringe and the two solutions were streamed together via syringe
pump at a flowrate of 0.15 mL/min through high purity PFA tubing (0.02 I.D., 1524 cm (50 ft), 3 mL)
with a residence time of 20 min at 90 °C. The reaction solution was monitored by TLC until steady
state and reaction was collected in a vial containing saturated sodium bicarbonate solution (1.0 mL) to
quench the reaction. The reaction solution was extracted with sodium bicarbonate (8 mL) followed by
water (8 mL, 8 g). The organic solution was dried with sodium sulfate (2.0 g). The organic solution
was decanted and 8 mL (6.9 g) of cyclopentyl methyl ether was used to rinse the sodium sulfate. The
organic solution was concentrated via rotary evaporation with 2.8 g of silica and the residue was
subjected to column purification via Teledyne ISCO CombiFlash® Rf 200i using 4 g ISCO column in
hexane ethyl acetate in a stepwise gradient with elution of compound in 20% ethyl acetate. A total of
450 mL (297 g) of hexane was used for purification a long with 90 mL (81 g) ethyl acetate and 40.2 mL
(36.3 g) of ethyl acetate used to rinse test tubes to give a total volume of 540 mL for purification to
provide 6 as a white solid (0.100 g, 0.24 mmol, 58%). See Figure S5 for details of the setup. Rf 0.6
and 0.7 (1:1 hexane: ethyl acetate), 1.7:1 α/β
Alpha anomer:
1H NMR (500 MHz, chloroform-d) δ = 7.46 - 7.29 (m, 10 H, Ph), 5.37 (d, J = 5.4 Hz, 1 H, H-1), 4.94
(d, J = 11.2 Hz, 1 H, CH2Ph), 4.80 - 4.69 (m, 2 H, CH2Ph), 4.58 (d, J = 11.2 Hz, 1 H, CH2Ph), 4.12 -
3.98 (m, 2 H, H-3, H-5), 3.80 (br. s., 2 H, H-6), 3.63 (dd, J = 5.4, 9.8 Hz, 1 H, H-2), 3.50 (t, J = 9.3 Hz,
1 H, H-4), 2.59 - 2.42 (m, 2 H, SCH2CH2CH3), 1.72 - 1.60 (m, 2 H, SCH2CH2CH3), 1.01 (t, J = 7.3 Hz,
3 H, SCH2CH2CH3); 13C NMR (126 MHz, chloroform-d) δ = 138.3, 137.4, 128.6, 128.5, 128.5, 128.5,
128.2, 128.2, 128.1, 127.9, 127.9, 82.9, 79.0, 74.5, 74.2, 72.1, 70.6, 62.0, 32.1, 22.9, 13.5; HRMS
(ESI): [M + Na]+ m/z calc. for C18H22Cl3NO5SNa+ 441.1706; found 441.1707.
Beta anomer:
1H NMR (500 MHz, chloroform-d) δ = 7.47 - 7.29 (m, 10 H, Ph), 5.01 (d, J = 10.7 Hz, 1 H, CH2Ph),
4.87 (d, J = 11.2 Hz, 1 H, CH2Ph), 4.71 (dd, J = 7.8, 11.2 Hz, 2 H, CH2Ph), 4.48 (d, J = 9.8 Hz, 1 H, H-
1), 3.91 (dd, J = 2.7, 12.0 Hz, 1 H, H-6), 3.82 - 3.70 (m, 2 H, H-3, H-6), 3.49 (t, J = 9.5 Hz, 1 H, H-4),
3.42 - 3.35 (m, 1 H, H-5), 3.27 (t, J = 9.8 Hz, 1 H, H-2), 2.80 - 2.67 (m, 2 H, SCH2CH2CH3), 1.78 - 1.64
(m, 3 H, SCH2CH2CH3), 1.08 - 1.01 (m, 3 H, SCH2CH2CH3); 13C NMR (126 MHz, chloroform-d) δ =
128.6, 128.6, 128.3, 128.1, 128.1, 85.2, 81.6, 78.9, 78.5, 75.3, 74.7, 62.3, 33.3, 23.3, 13.5; HRMS
(ESI): [M + Na]+ m/z calc. for C18H22Cl3NO5SNa+ 441.1706; found 441.1707.

ACCEPTED MANUSCRIPT
Acknowledgment
This work was supported by the U.S. National Institutes of Health Common Fund Glycosciences
Program [1U01 GM116248]. N.P. wishes to also thank the Joan and Marvin Carmack Fund at Indiana
University and the Radcliffe Institute for Advanced Study for the Edward, Frances, and Shirley B.
Daniels Fellow position. K.M. wishes to thank Indiana University for a Theodore C. Mays Chemistry
Fellowship. We also want to thank Frank Gao director of Indiana University Nuclear Magnetic
Resonance Facility and staff. As well as Jonathan Karty, facility manager of Indiana University Mass
Spectrometry Facility and all staff associated. We want to thank John Poehlman of Electronic
Instrument Services at Indiana University for very fruitful discussions on continuous flow chemistry and
assistance with devices related to continuous flow, as well as all the staff in Electronic Instrument
Services. We also want to thank Jeremy Boshears and his team in Mechanical Instrument Services at
Indiana University.
References
[1] Z. Xiao, Y. Guo, Y. Liu, L. Li, Q. Zhang, L. Wen, X. Wang, S.M. Kondengaden, Z. Wu, J. Zhou, X.
Cao, X. Li, C. Ma, P.G. Wang, J. Org. Chem., 81 (2016) 5851-5865.
[2] P. Pornsuriyasak, X.G. Jia, S. Kaeothip, A.V. Demchenko, Org. Lett., 18 (2016) 2316-2319.
[3] S.L. Tang, N.L. Pohl, Org. Lett., 17 (2015) 2642-2645.
[4] S.L. Tang, N.L.B. Pohl, Carbohydr. Res., 430 (2016) 8-15.
[5] N.V. Ganesh, K. Fujikawa, Y.H. Tan, K.J. Stine, A.V. Demchenko, Org. Lett., 14 (2012) 3036-
3039.
[6] C.S. Bennett, Org. Biomol. Chem., 12 (2014) 1686-1698.
[7] P.H. Seeberger, D.B. Werz, Nat. Rev. Drug Discov., 4 (2005) 751-763.
[8] L. Lay, D. Cancogni, Synlett, 25 (2014) 2873-2878.
[9] A. Sniady, M.W. Bedore, T.F. Jamison, Angew. Chem. Int. Ed., 50 (2011) 2155-2158.
[10] B. Shen, T.F. Jamison, Org. Lett., 14 (2012) 3348-3351.
[11] J. Sedelmeier, F. Lima, A. Litzler, B. Martin, F. Venturoni, Org. Lett., 15 (2013) 5546-5549.
[12] F. Levesque, P.H. Seeberger, Angew. Chem. Int. Ed., 51 (2012) 1706-1709.
[13] P. Zhang, M.G. Russell, T.F. Jamison, Org. Process Res. Dev., 18 (2014) 1567-1570.
[14] T. Broom, M. Hughes, B.G. Szczepankiewicz, K. Ace, B. Hagger, G. Lacking, R. Chima, G.
Marchbank, G. Alford, P. Evans, C. Cunningham, J.C. Roberts, R.B. Perni, M. Berry, A. Rutter, S.A.
Watson, Org. Process Res. Dev., 18 (2014) 1354-1359.
[15] K.P. Cole, J.M. Groh, M.D. Johnson, C.L. Burcham, B.M. Campbell, W.D. Diseroad, M.R.
Heller, J.R. Howell, N.J. Kallman, T.M. Koenig, S.A. May, R.D. Miller, D. Mitchell, D.P. Myers, S.S.
Myers, J.L. Phillips, C.S. Polster, T.D. White, J. Cashman, D. Hurley, R. Moylan, P. Sheehan, R.D.
Spencer, P. Desmond, O. Gowran, Science, 356 (2017) 1144-1150.
[16] A. Adamo, R.L. Beingessner, M. Behnam, J. Chen, T.F. Jamison, K.F. Jensen, J.M. Monbaliu,
A.S. Myerson, E.M. Revalor, D.R. Snead, T. Stelzer, N. Weeranoppanant, S.Y. Wong, P. Zhang,
Science, 352 (2016) 61-67.
[17] A.R. Bogdan, K. James, Org. Lett., 13 (2011) 4060-4063.
[18] D. Dallinger, C.O. Kappe, Current Opinion in Green and Sustainable Chemistry, 7 (2017) 6-12.
[19] J. Wu, X. Yang, Z. He, X. Mao, T.A. Hatton, T.F. Jamison, Angew. Chem. Int. Ed., 53 (2014)
8416-8420.
[20] B. Gutmann, J.P. Roduit, D. Roberge, C.O. Kappe, Chem. Eur. J., 17 (2011) 13146-13150.
[21] I.R. Baxendale, S.V. Ley, A.C. Mansfield, C.D. Smith, Angew. Chem. Int. Ed., 48 (2009) 4017-
4021.
[22] T.P. Petersen, A. Polyzos, M. O'Brien, T. Ulven, I.R. Baxendale, S.V. Ley, ChemSusChem, 5
(2012) 274-277.
[23] P. Clark, M. Poliakoff, A. Wells, Adv. Synth. Catal, 349 (2007) 2655-2659.

ACCEPTED MANUSCRIPT
[24] C. Csajági, B. Borcsek, K. Niesz, I. Kovács, Z. Székelyhidi, Z. Bajkó, L. Ürge, F. Darvas, Org.
Lett., 10 (2008) 1589-1592.
[25] A. Caron, A.C. Hernandez-Perez, S.K. Collins, Org. Process Res. Dev., 18 (2014) 1571-1574.
[26] R.J. Ingham, C. Battilocchio, D.E. Fitzpatrick, E. Sliwinski, J.M. Hawkins, S.V. Ley, Angew.
Chem. Int. Ed., 54 (2015) 144-148.
[27] P. Plouffe, A. Macchi, D.M. Roberge, in: F. Darvas, V. Hessel, G. Dorman (Eds.) Flow Chemistry
Fundamentals, De Gruyter, Berlin, 2014, pp. 139.
[28] M.S. Mettler, A.D. Paulsen, D.G. Vlachos, P.J. Dauenhauer, Energy Environ. Sci., 5 (2012) 7864-
7868.
[29] F. Shafizadeh, R.H. Furneaux, T.G. Cochran, J.P. Scholl, Y. Sakai, J. Appl. Polym. Sci., 23 (1979)
3525-3539.
[30] C.M. Lakshmanan, H.E. Hoelscher, Ind. Eng. Chem. Prod. Res. Develop, 9 (1970) 57-59.
[31] X. Zhu, R.T. Dere, J. Jiang, L. Zhang, X. Wang, J. Org. Chem., 76 (2011) 10187-10197.
[32] M.L. Lepage, A. Bodlenner, P. Compain, Eur. J. Org. Chem., 2013 (2013) 1963-1972.
[33] J.P. Henschke, P.Y. Wu, C.W. Lin, S.F. Chen, P.C. Chiang, C.N. Hsiao, J. Org. Chem., 80 (2015)
2295-2309.
[34] D. Prat, J. Hayler, A. Wells, Green Chem., 16 (2014) 4546-4551.
[35] R.K. Henderson, C. Jiménez-González, D.J.C. Constable, S.R. Alston, G.G.A. Inglis, G. Fisher, J.
Sherwood, S.P. Binks, A.D. Curzons, Green Chem., 13 (2011) 854-862.
[36] V. Wittmann, The Organic Chemistry of Sugars, WILEY-VCH Verlag, 2006.
[37] A. Attouche, D. Urban, J.M. Beau, Angew. Chem. Int. Ed., 52 (2013) 9572-9575.
[38] B. Ren, J. Lv, Y. Zhang, J. Tian, H. Dong, ChemCatChem, 9 (2017) 950-953.
[39] P. Wuts, Greene's Protective Groups in Organic Synthesis, 5th ed., John Wiley & Sons, Inc.,
Hoboken, New Jersey, 2014.
[40] J. Buckey, e. al., Chem. Eng. News, 60 (1982).
[41] G.D. Wall, Chem. Eng. News, 60 (1982).
[42] T. Iversen, D.R. Bundle, Can. J. Chem., 60 (1982) 299-303.
[43] S. Glockner, D.N. Tran, R.J. Ingham, S. Fenner, Z.E. Wilson, C. Battilocchio, S.V. Ley, Org.
Biomol. Chem., 13 (2015) 207-214.
[44] F. Van Waes, J. Drabowicz, A. Cukalovic, C. Stevens, Green Chem., 14 (2012) 2776-2779.
[45] H. Sahoo, J. Kralj, K. Jensen, Angew. Chem. Int. Ed., 46 (2007) 5704-5708.
[46] X. Zhu, R.R. Schmidt, Angew. Chem. Int. Ed., 48 (2009) 1900-1934.
[47] G. Lian, X. Zhang, B. Yu, Carbohydr Res, 403 (2015) 13-22.
[48] M. Andersen, I. Boos, C. Ruprecht, W. Willats, F. Pfrengle, M. Clausen, J. Org. Chem., 82 (2017)
12066-12084.
[49] A. Kitowski, E. Jimenez-Moreno, M. Salvado, J. Mestre, S. Castillon, G. Jimenez-Oses, O.
Boutureira, G. Bernardes, Org. Lett., 19 (2017) 5490-5493.
[50] M. Goswami, A. Ellern, N.L.B. Pohl, Angew. Chem. Int. Ed., 52 (2013) 8441-8445.
[51] D.E.K. Kabotso, N.L.B. Pohl, Org. Lett., 19 (2017) 4516-4519.
[52] G. Nagy, T. Peng, D.E. Kabotso, M.V. Novotny, N.L. Pohl, Chem. Commun., 52 (2016) 13253-
13256.
[53] R.C. Saliba, Z.J. Wooke, G.A. Nieves, A.A. Chu, C.S. Bennett, N.L.B. Pohl, Org. Lett., 20 (2018)
800-803.
[54] M.M. Mukherjee, R. Ghosh, J. Org. Chem., 82 (2017) 5751-5760.
[55] J. Gao, Z. Guo, J. Org. Chem., 78 (2013) 12717-12725.
[56] L. Qi, Y. Mui, S. Lo, M. Lui, G. Akien, I. Horváth, ACS Catal., 4 (2014) 1470-1477.
[57] I.T. Horváth, Green Chem., 10 (2008) 1024-1028.
[58] I.T. Horváth, P. Anastas, Chem. Rev., 107 (2007) 2169-2173.
[59] I.T. Horváth, E. Cséfalvay, L. Mika, M. Debreczeni, ACS Sustain Chem Eng, 5 (2017) 2734-
2740.

ACCEPTED MANUSCRIPT
[60] R.A. Sheldon, ACS Sustain Chem Eng, 6 (2017) 32-48.
[61] W. Yang, J. Sun, W. Lu, Y. Li, L. Shan, W. Han, W.D. Zhang, B. Yu, J. Org. Chem., 75 (2010)
6879-6888.
[62] D. Perera, J.W. Tucker, S. Brahmbhatt, C.J. Helal, A. Chong, W. Farrell, P. Richardson, N.W.
Sach, Science, 359 (2018) 429-434.

ACCEPTED MANUSCRIPT
Highlights
•
•
•
A greener approach to carbohydrate acylation under flow conditions was developed with
acetyl chloride and acetonitrile, thereby avoiding the use of a DMAP catalyst and
pyridine.
Benzylation without the use of NaH was achieved in a continuous flow process with the
use of a barium oxide packed-bed reactor; however, other forms of this catalyst amenable
to packing under sustained flow conditions are needed.
The n-propyl-2,4-di-O-benzyl-1-thio-α-D-glucopyranoside building block was
synthesized from levoglucosan in only 2 steps using continuous flow processes.