Highly Regioselective Monoacylation of Unprotected Glucopyranoside Using Transient Directing-Protecting Groups

DOI: 10.1002/ejoc.201601457

Source and publish data:

European Journal of Organic Chemistry p. 646 - 656 (2017)

Update date:2022-07-30

Topics:

Authors:

Rocheleau, Sylvain

Pottel, Joshua

Huski?, Igor

Moitessier, Nicolas

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Article abstract of DOI:10.1002/ejoc.201601457

The regioselective functionalization of monosaccharides is notoriously achieved using metal catalysis, lengthy synthetic strategies requiring protection/deprotection, various enzymes, or other methods that target cis-diols (and thus cannot be used with glucopyranose derivatives), In this paper, we report a new method using selected boronic acids as temporary protecting groups, and describe its application to the regioselective functionalization of methyl α-d-glucopyranoside, the most difficult monosaccharide to functionalize regioselectively. Generally, reactions of glucopyranosides may lead to a plethora of mono- and polyfunctionalized derivatives, yet our method gave the 3-O-acetylated, 2-O-benzoylated, and 2-O-pivaloylated derivatives of methyl α-d-glucopyranoside as major products. We focused on the use of recyclable and green temporary protecting groups (in a one-pot reaction) and on the modulation of the intramolecular hydrogen-bonding network using selected arylboronic acids. A complete scalable procedure leading to a single regioisomer from unprotected methyl α-d-glucopyranoside is presented.

Full text of DOI:10.1002/ejoc.201601457

A Journal of

Accepted Article

Title: Highly Regioselective Monoacylation of Unprotected

Glucopyranoside using Transient Directing-Protecting Groups

Authors: Sylvain Rocheleau, Joshua Pottel, Igor Huskic, and Nicolas

Moitessier

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the VoR from the journal website shown below when it is published

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content of this Accepted Article.

To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601457

Link to VoR: http://dx.doi.org/10.1002/ejoc.201601457

Supported by

10.1002/ejoc.201601457

European Journal of Organic Chemistry

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Highly Regioselective Monoacylation of Unprotected

Glucopyranoside using Transient Directing-Protecting Groups

Sylvain Rocheleau, Joshua Pottel, Igor Huskić, Nicolas Moitessier*^[a]

Abstract: Regioselective functionalization of monosaccharides is

notoriously achieved using metal catalysis, lengthy synthetic

strategies requiring protection/deprotection, various enzymes, or

other methods that target cis-diols—all of which preclude their use

with glucose derivatives. We report herein a new methodology using

selected boronic acids as temporary protecting groups and describe

its application to the regioselective functionalization of methyl α-D-

containing small peptides^[8-9]for regioselective functionalization

of monosccharides even applying one of them to the

regioselective monoacetylation of natural product derivatives.^[9d,

10]

The Aoyama group used arylboronates for the regiospecific

alkylation^[11]and the glycosylation^[12]of monosaccharides with a

focus on fucosides. Taylor used borinic acids as catalysts for

regioselective functionalization of monosaccharidescis-diols.^[13]

Transition metals have also been exploited for regioselective

transformations of carbohydrates. Most notably, organotin

derivatives (e.g. Bu₂SnO, Oct₂SnCl₂^[14]) have found numerous

applications and research is still ongoing today, despite the

toxicity associated with organotin derivatives.^[15]For

regioselective functionalization on monosaccharides, other

glucopyranoside,

the

most

difficult

monosaccharide

regioselectively functionalize. Generally, the reaction of gluco-

pyranosides may lead to a plethora of mono- and polyfunctionalized

derivatives, yet our methodology afforded the 3-O-acetylated, the 2-

O-benzoylated and the 2-O-pivaloylated isomers of methyl α-D-

glucopyranoside as major products. Focus was put on the use of

recyclable and green temporary protecting groups (in a one-pot

reaction) and modulation of the intramolecular hydrogen bond

network using specifically selected arylboronic acids. A complete

scalable procedure leading to a single regioisomer from non-

protected methyl α-D-glucopyranoside is presented.

transition metals have been used, such as copper^[16]and iron^[17]

as well as other additives as reviewed recently.^[18]Most of these

approaches have been successfully applied to carbohydrates

featuring cis-diols (fucose, galactose, mannose), but rarely

provide good regioselectivities for glucose—having only

equatorial hydroxyl groups. An example of such a method has

been reported by Onomura and co-workers using potentially

toxic organotin catalysts.^[14b]

Introduction

A highly regioselective synthesis plan that is rich in atom

economy, is green and is applicable to glucose is an unmet

need.

Polysaccharides are multifunctional in nature, playing crucial

roles they are the major components of cell walls in plants and

We have previously developed directing-protecting groups

(DPGs) which induced regioselective functionalization and

glycosylation (Figure 1) of glucopyranosides.^[19]This approach

relied on the use of a single protecting group, installed on the

primary hydroxyl at position 6, which interacted with the

secondary unprotected hydroxyl groups. Unfortunately, removal

of these DPGs, similarly to most commonly used protecting

groups, yielded an inert protecting fragment that would require

further chemical transformations to be recycled into a useable

chemical. Regrettably, while some protecting groups (e.g.,

benzylidene) can be hydrolyzed (e.g., into benzaldehyde), easily

recycled and reused, they are hardly useable to regioselectively

functionalize positions 2 or 3.

they are involved in energy storage.

number of

polysaccharides have also been reported as effective vaccines^[1]

or drugs (e.g., Fondaparinux^[2]).^[3]However, the complex

structure of these biopolymers stipulates significant effort in their

total synthesis^[4]—a hurdle to large-scale production that can

nonetheless be overcome.^[5]Access to these polymeric

molecules is made possible primarily through the use of

judicious protection strategies that must be devised to prepare

the building blocks (i.e., monosaccharides) leaving a single

unprotected hydroxyl group to be targeted in glycosylation

reactions. These strategies entail exorbitant repeats of

installation and removal of what is ultimately chemical waste—in

addition to the extra solvent, energy, and time—making these

approaches cost-inefficient and environmentally unfriendly.

As a result, strategies emerged to reduce the use of protecting

groups and to regioselectively recognize a specific hydroxyl

group.^[6]For instance, Griswold and Miller identified small

peptides for potential regioselective acylation of partially

protected carbohydrates^[7]while Kawabata and coworkers

designed, chiral 4-pyrrolidinopyridine derivatives^[8]and DMAP-

[a]

Sylvain Rocheleau, Joshua Pottel, Igor Huskić, Nicolas Moitessier

Department of Chemistry

McGill University

Figure 1. Previously reported DPG-induced regioselective glycosylation.^[19]

801, Sherbrooke St. W. Montreal, Canada H3A 0B8

E-mail: nicolas.moitessier@mcgill.ca

Homepage: moitessier-group.mcgill.ca

Results and Discussion

Supporting information for this article is given via a link at the end of

the document.

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Methodology. We planned to address regioselectivity and, in

parallel, preclude any protection/deprotection steps. We opted

for boronic esters due to their promising, labile covalent bonds

(Figure 2).^[20]This strategy is in line with the green chemistry

principles formulated by Anastas and Warner.^[21]Hydrolysis of

such a protecting group would regenerate the boronic acid to be

recycled and reused with no further transformation (atom

economy, reduction of derivatives and somewhat catalysis).

Figure 2. Proposed strategy using arylboronic acids as transient directing-

protecting groups. FG=Ac, Bz, Piv.

Figure 3. Arylboronic acids tested as transient directing-protecting groups

(TDPGs) and carbon-containing analog 6.

Although the use of arylboronic acids as protecting groups was

proposed more than 50 years ago,^[22]their full potential in

regioselective functionalization of carbohydrates has never been

explored. It is not until recently that they were used in

glycosylation reactions. However, the yield or the regioselectivity

with glucopyranosides as the acceptor was low (35-63%, 1:2.5-

7.3) or unmentioned.^[23]Herein, we planned to exploit boronic

acids as the only protecting groups—leaving positions 2 and 3

free to react (Figure 2)—hence fully exploiting the potential of

arylboronic acids as transient directing-protecting groups

(TDPGs).

Selection of boronic acids. We first considered a diverse set of

commercially available boronic acids (Figure 3). We tested the

stability of the corresponding boronate esters, evaluated their

ability to induce regioselective acylation, optimized the reaction

conditions, and then applied the most promising ones on 1-gram

and 10-gram scales to assess their potential in process

chemistry. Preliminary studies in deuterated solvents with

boronic acids 6a-c showed that these boronic esters could be

hydrolyzed in D₂O. It was quickly apparent that acidic conditions

(i.e., silica gel) also led to significant hydrolysis of the boronic

ester and indicated that traces of water may be detrimental to

our strategy.

Regioselective acylation. We have previously exploited the

intramolecular hydrogen bond network to modulate the relative

reactivity of secondary hydroxyl groups OH-2 and OH-3.^[19]The

electronic and structural properties of the boronate derivatives

4a-l are expected to affect the network with OH-2 and OH-3. To

test this hypothesis, we used these boronic acids in one-pot

acylation reactions. We optimized the conditions to insert, react,

and remove the TDPGs in a single experiment. Among these

optimizations were the electrophile addition time, the amounts of

electrophile and catalyst, the chemical nature of the electrophile,

the solvent, the concentration of glucopyranoside, and the

reaction time (supporting information). We observed that the

optimal amount of DMAP was in the 10-25 mol% range, excess

of Ac₂O led to increased amount of overreacted product, and

PivCl, a larger reagent, did not produce a significant amount of

doubly reacted products.

Table 1. Functionalizing methyl-α-D-glucopyranoside 4^a

Yield^b

87%

80%

7 : 8 : 9

Entry

TDPG

Electrophile^a

Ac₂O

29 : 64 : 7^d

37 : 54 : 9

Ac₂O

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the introduction of the TDPG was complete and that the stability

of the boronate enabled acylation without significant hydrolysis

of the boronic ester. It is noteworthy that the highest conversion

was observed only when in situ pre-dried methyl α-D-

glucopyranoside was used. From our observations, traces of

water were extremely detrimental, likely affecting the stability of

the boronic esters and/or reacting with the acylating agents. This

BzCl^e

BzCl

PivCl

PivCl^e

Ac₂O

BzCl

PivCl

Ac₂O

BzCl

PivCl

Ac₂O

PivCl

Ac₂O

PivCl

Ac₂O

PivCl

Ac₂O

PivCl

Ac₂O

PivCl

Ac₂O

BzCl

PivCl

Ac₂O

BzCl

PivCl

87%

82%

95%

94%

81%

82%

79%

80%

51%

73%

82%

91%

n/d^g

83 : 4 : 13

79 : 10 : 11

83 : 10 : 7^d

92 : 7 : 1^d

35 : 49 : 16^f

75 : 12 : 13

86 : 13 : 1^f

18 : 66 : 16^d

33 : 53 : 14^f

63 : 36 : 1^e

26 : 55 : 19

82 : 15 : 3

prompted the use of toluene and a Dean-Stark apparatus.

Boronic acid 6a favored reaction at position 2 more than was

6c (Table 1, acetylation: entries 2 vs. 10; benzoylation: entries 4

vs 11; pivaloylation: entries 5 vs. 12). Additionally, a small

electrophile (Ac₂O) reacted preferentially at position 3 while

larger ones (PivCl and BzCl) reacted primarily at position 2. As a

result, 6a with Ac₂O and 6c with PivCl had synergistic effects

(Table 1, entry 2 and entry 12). The ester of 6c is coordinating

with the boron atom and may induce electronic effects

responsible for the observed selectivity. With 6d-6h, a group

adjacent to the boronic acid will coordinate to the boron atom.

The regioselectivities observed with the five boronic acids filled a

spectrum between those obtained with 6a and 6c; 6d provided a

selectivity of 2.4:1 for acetylation at position 3 and 5.7:1 for

pivaloylation at position 2. We evaluated the effect of bulky

groups but observed minimal acylation conversion (6i,6j, data

not shown) or complex mixtures. Conversely, with the cyclic

monoester 6g we observed inverse regioselectivity for the

pivaloylation. Surprisingly, the yield of acetylation was often

lower than pivaloylation as shown with (6d-l).

86%

n/d^g

60 : 24 : 16

96%

n/d^g

75 : 23 : 2

Structural information. We obtained crystal structures of 4a

and 4b to confirm the functionalization, however these structures

were not representative of the hydrogen bonding in solution.

These structures showed that OH-2 interacts with O-1, while

OH-3 does not interact with either O-2 or O-4 but interacts with

neighboring carbohydrates in the crystal (Figure 4). The

crystalline state is therefore not informative on the solution

conformations and hydrogen bond network.

86%

n/d^g

37 : 58 : 5^f

71%

57%

73%

42%

56%

66%

82%

30 : 17 : 51

52 : 45 : 3^f

78 : 12 : 10

74 : 13 : 13^f

34 : 34 : 32^d

52 : 22 : 26

66 : 18 : 16

^aα-GlcOMe 4, toluene, Dean-Stark, 1 h, then ArB(OH)₂1.10 eq., toluene,

Dean-Stark, 1 h, then K₂CO₃10.0 eq., DMAP 20 mol% then acylating agent

1.05 eq. r.t., 2-16 h, 50-100 mg scale. ^bNMR yields. ^cReaction carried out with

4,6-O-benzylidene methyl-α-D-glucopyranoside 7. ^dMedian value of triplicates;

yield and ratio are <5% in most cases. ^eDMAP 50 mol%. Lowest value of

duplicates. ^gComplex mixture.

We applied the optimized conditions to the regioselective

functionalization of methyl α-D-glucopyranoside after coupling

with our set of boronic acids (Table 1). Successfully, we were

able to monoacylate methyl α-D-glucopyranoside in a one-pot

procedure at positions 2 and 3 exclusively with no detectable

amount of the 4 and 6-O-acetylated isomers. Additionally, we

achieved similar overall conversion to that observed using 7

(entry 1 vs. entry 2), however in a one-pot fashion—shortening

the synthetic sequence by 2 steps. This data demonstrated that

Figure 4. ORTEP representations of molecular structures of 5a and 5b

determined by X-ray diffraction. Crystal structure of 5a, dashed lines represent

hydrogen bonds. Ellipsoids shown at 50% probability level.

We then turned our attention to NMR spectroscopy which was

instrumental in determining the hydrogen bond network in our

previous work.^[19a]Interestingly, the ¹H NMR spectrum of 5c

ester in deuterated DCM showed two signals, one at 2.87

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(singlet) and one at 2.37 ppm (doublet) corresponding to OH-2

and OH-3 (Figure 5). Previous work has shown that the

multiplicity of these signals are indicative of intramolecular

hydrogen bonds.^[19a]The doublet with a coupling constant of 9.5

Hz revealed a torsional angle from H-C2-O2-H-2 of ca. 150°

which would result from a hydrogen bond between OH-2 and

OMe already observed in other similar glucopyranoside

derivatives.^[19b]In contrast, the singlet corresponding to OH-3

indicated a H3-C3-O3-H torsional angle of ca. 90° consequent of

a hydrogen bond with either O-4 or O-2.

Figure 6. Energy profiles when rotating C-O3 bond with three different 4,6-O-

protected methyl -D-glucopyranoside.

The computations revealed that the ester carbonyl oxygen

complexed with the boron atom, activating the O-4 and inducing

a stronger hydrogen bond between OH-3 and O-4 (Figure 7).

Figure 5. ¹H NMR of a crude mixture of 5a showing the two hydroxyl groups

as a singlet (2.97 ppm) and a doublet (2.36 ppm).

Figure 7. Minimum energy conformations of 7 (left) and 5c (right) derived from

methyl 4,6-O--D-glucopyranoside, indicating the different preferred hydrogen

bonding networks.

The experimental data agreed with molecular modeling (DFT),

which suggested a slight preference for OH-3 hydrogen bonded

with O-4 over O-2 in 5c. The ester carbonyl oxygen complexed

with the boron atom, activating the O-4 and inducing a stronger

hydrogen bond between OH-3 and O-4 (Figure S3). The lowest-

in-energy conformation was established for 5a, 5c, and the

benzylidene analog 7 for comparison. Upon rotating the C-O3

bond, the hydrogen bond preference in 5c was demonstrated by

the minimum energy at torsion angle ca. 50° (interaction with O-

4) and a difference of 0.65 kcal/mol at torsion angle ca. 190°

(interaction with O-2). Contrastingly, 7 exhibited a flip in the

minima (negligible energy difference) and 5a had energy profile

similar to 7 (Figure 6). The slight energetic preference of 5c

would explain the improved regioselectivity—the energy

difference between a ratio of 1.3:1 (with 5a) and a ratio of 9:1

(with 5c) being ca. 1 kcal/mol. Although the differences are small

between the three energy profiles, computed relative energies

between similar compounds containing only boron, oxygen,

carbon and hydrogens are usually accurate.

Application. The applicability and reproducibility of this

methodology was demonstrated on a larger scale (ca. 1 g),

although the measured yields decreased for the pivaloylation

and benzoylation (Table 2). Boronic acids 6c and 6a maintained

regioselective acetylation and pivaloylation of our test substrate

with regioselectivity significantly higher than with the more

commonly used substrate 7.

Ultimately, the optimized conditions led to excellent conversion

and good regioselectivity for the acetylation at position 3 (ca.

2.5:1) and pivaloylation at position 2 (12:1) starting from fully

unprotected methyl-α-D-glucopyranoside. Interestingly, when

excess of electrophile was used, the pivaloylation is quantitative

with little dipivaloylated products.

Our main objective is to functionalize glucose derivatives such

as -GlcOMe 4, regioselectively, as the presence of cis-diols in

other monosaccharides enables the use of several other

methods. However, considering the high degree of selectivity of

the acylation reactions, the two most effective boronic acids 6a

and 6c were tested on different substrates: -GlcOOct 11, -

GalOMe 12 and -ManOMe 13 (Table 2, entries 13-18) for

acetylation and pivaloylation on a 1 g scale. Interestingly,

acetylation of -GlcOOct 11 (Table 2, entry 10) and pivaloylation

of -GalOMe 12 (Table 2, entry 16) showed selectivity at

position 2 and 3 respectively in presence of B(OH)₂PhCOOEt

(6c). The absence of intramolecular hydrogen bond between O-

2 and the anomeric position of the -GlcOOct 11, is likely the

cause of the drop and reversal of selectivity when moving from

-GlcOMe (Table 2, Entry 4) to -GlcOOct (Table 2, Entry 10).

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In the case of the -GalOMe 12, the shape of the 4,6-O-

boronate intermediate is very different from the one derived from

-GlcOMe 4, allowing an extra hydrogen bond between the ethyl

ester and O-3.

3-O-Piv 18b (Table 2, entry 16) with excellent yields and good to

excellent regioselectivity.

The other conditions tested without monosaccharides 11-13

showed little regioselectivity.

A complete protocol. At the outset of this project, we planned

to develop a green method that would convert an unprotected

Table 2. Large scale functionalization. 1.0-10.0 g scale.

glucose derivative into

single regioisomer of the

monofunctionalized derivative with optimal atom economy. The

remaining obstacles in our strategy were isolating the major

isomer and recovering the boronic acid. The optimal protocol

shown in Figure 8 was devised after numerous iterations of

reaction condition optimization, crystallization of the major

product, and extraction of the boronic acid. Efforts were also

made to reduce the amount of solvent (toluene) used throughout

the process (ca. 0.1 L per 1 g of starting material).

Applied to 10 g of dry methyl-α-D-glucopyranoside 4 in refluxing

toluene, this protocol yielded up to 6.9 g (49%) of crystallized 2-

O-pivaloyl methyl- α -D-glucopyranoside 8c after

recrystallization while 6.2 g (87%) of the boronic acid was

recovered on a silica gel pad.

a single

NMR

Yield^b

66%

73%

83%

80%^e

61%^e

70%^e

>95%

86%

87%

92%

64%

55%

54%

66%

72%

27%

19%

Electro-

phile^a

Regio-

Entry Sub-strate TDPG

selectivity^c

Ac₂O

BzCl

34 : 46 : 20

59 : 23 : 18

83 : 11 : 6

28 : 71 : 1

90 : 9 : 1

PivCl

Ac₂O

BzCl

PivCl

PivCl^f

PivCl^e,g

PivCl^e,h

Ac₂O

PivCl

93 : 7 : n/d

92 : 3 : 5

92 : 7 : 3

86 : 7 : 7

62 : 32 : 6

17 : 55 : 28

31 : 11 : 58

22 : 40 : 38

0 : 50 : 50

22 : 34 : 44

19 : 76 : 5

100 : n/d : n/d

Figure 8. A single regioisomer (and recovered boronic acid) from unprotected

methyl 4,6-O--D-glucopyranoside.

Conclusions

^aOptimal conditions: dry α-GlcOMe 4, toluene, Dean-Stark, 1 h,

then B(OH)₂PhCOOEt 1.10 eq., toluene, Dean-Stark, 1 h, then

K₂CO₃10.0 eq., Ac₂O/BzCl/PivCl 1.05 eq., 1 h, then DMAP 20

mol%, r.t, 2-16 h. ^bNMR yield. ^c8:9:10. ^dRegioselectivity

measured for 4,6-O-benzylidene methyl-α-D-glucopyranoside 7.

^eMedian value of triplicates; yield and ratio are <5%; ^fUsing 5.0

eq. of PivCl and 0.8 eq. of DMAP. ^g1 g scale, 60 mol% DMAP.

Our approach demonstrated that a judiciously selected boronic

acid can be used to regioselectively functionalize simple

unprotected carbohydrate units on small (50 to 100 mg) to

medium scale (1-10 g) with good reproducibility if care is taken

to ensure the dryness of the chemicals. More specifically,

applied to 10 g of methyl-α-D-glucopyranoside, this unique

methodology enabled the functionalization of position 2 with

good yields and regioselectivities with no need for time-

consuming separation of regioisomers. This single one-pot

procedure is significantly more economical than the use of

protecting groups. The development of this new protocol paves

the way to significantly more efficient and greener

polysaccharide synthesis.

Overall, we obtained four sets of reaction conditions with good

regioselectivity: phenylboronic acid (6a) favors the formation of

the 2-O-Piv product 8b (e.g. Table 2, entry 7) while the use of

B(OH)₂PhCOOEt leads to the syntheses of three compounds: 3-

O-Ac 8c (Table 2, entry 4), 2-O-Ac 14a (Table 2, entry 10) and

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mmol, 0.20 eq.) were reacted. However, the reaction was stirred for 16 h

at room temperature (in I.2. the reaction mixture is stirred for 2 h).

Experimental Section

General Information. All commercially available reagents were used

without further purification unless otherwise stated. Optical rotations were

measured on a JASCO DIP 140 in a 0.5 dm cell at 22°C unless

otherwise stated. FTIR spectra were recorded using a Perkin-Elmer

Spectrum One FT-IR. ¹H and ¹³C NMR spectra were recorded on Varian

Mercury 400 MHz, 300 MHz, or Unity 500 spectrometers. Chemical shifts

are reported in ppm using the residual of deuterated solvents as internal

standard. Thin layer chromatography visualization was performed by UV

or by development using KMnO₄, H₂SO₄/MeOH, Mo/Ce or curcumin

solutions. Chromatography was performed on silica gel 60 (230-40

mesh). Low resolution mass spectrometry was performed by ESI using a

Thermoquest Finnigan LCQ Duo. High resolution mass spectrometry was

performed by EI peak matching (70 eV) on a Kratos MS25 RFA double

focusing mass spectrometer or by ESI on a Ion Spec 7.0 T FTMS at

McGill University.

One-pot pivaloylation on a 1.0 g scale. Following the procedure

described above., methyl -D-glucopyranoside (1.00 g, 5.15 mmol), solid

phenylboronic acid (691 mg, 5.67 mmol, 1.10 eq.), K₂CO₃(7.12 g, 10.0

eq.), neat PivCl (666 µL, 5.41 mmol, 1.05 eq.) and DMAP (126 mg, 1.03

mmol, 0.20 eq.) were reacted. However, the reaction was stirred for 16 h

at room temperature (in I.2. the reaction mixture is stirred for 2 h).

One-pot monoacetylation on a 50 mg scale. Following the procedure

described above., methyl -D-glucopyranoside (50 mg, 0.26 mmol)

suspended in toluene (50 mL), solid 2-ethoxycarbonylphenylboronic acid

(55 mg, 0.28 mmol, 1.10 eq.), K₂CO₃(356 mg, 10.0 eq.), a freshly

prepared (in 5 mL flame-dried round-bottom flask) 0.50 M solution (50 µL

per mL) of Ac₂O (0.51 mL, 2.73 mmol, 1.05 eq.), DMAP (2.52 mL, 0.013

mmol, 0.05 eq.) were reacted.

General procedure. A very detailed procedure is described below as

several features are critical to avoid precipitation of the

carbohydrate/boronic acid mixture and ensure optimal yields. In any case,

a particular attention must be taken to reduce contact between the

reagents/reaction mixture and water/moisture (i.e. when weighting or

adding the reagents). Freshly purchased reagents (GlcOMe, K₂CO₃,

B(OH)₂COOEt, B(OH)₂Ph, Ac₂O, BzCl, PivCl, DMAP) are highly

recommended. All of these reactions are carried out at reflux. Use

extreme caution as the glassware may be hot. Ensure to cool down the

reaction mixture prior to adding any chemicals to reduce the solvent

vapors.

One-pot monobenzoylation on a 50 mg scale. Following the procedure

described above., methyl -D-glucopyranoside (50 mg, 0.26 mmol)

suspended in toluene (50 mL), solid phenylboronic acid (35 mg, 0.28

mmol, 1.10 eq.), K₂CO₃(356 mg, 10.0 eq.), a freshly prepared (in 5 mL

flame-dried round-bottom flask) 0.60 M solution (50 µL per mL) of BzCl

(0.53 mL, 2.73 mmol, 1.05 eq.), DMAP (2.52 mL, 0.013 mmol, 0.05 eq.)

were reacted.

One-pot pivaloylation on a 50 mg scale. Following the procedure

described in I.2., methyl -D-glucopyranoside (50 mg, 0.26 mmol)

suspended in toluene (50 mL), solid phenylboronic acid (35 mg, 0.28

mmol, 1.10 eq.), K₂CO₃(356 mg, 10.0 eq.), a freshly prepared (in 5 mL

flame-dried round-bottom flask) 0.50 M solution (60 µL per mL) of PivCl

(0.56 mL, 2.73 mmol, 1.05 eq.), DMAP (2.52 mL, 0.013 mmol, 0.05 eq.)

were reacted.

One-pot monoacetylation on a 1.0 g scale. Overnight oven-dried

(110 °C) methyl -D-glucopyranoside (1.00 g, 5.15 mmol) was weighted

and added quickly (to minimize contact with air moisture from the air) to

toluene (1.0 L) then suspended in toluene (1 L). This low concentration

(ca. 0.005 M, 1.0 g per L), 3 boiling chips and a large stirring bar are

recommended to preclude precipitation. A copper wire/aluminum foil

covered Dean-Stark apparatus (20 mL) was installed on top of the round

bottom flask with a large water condenser and the system was placed

under argon (large balloon of argon). The sidearm of the Dean-Stark

apparatus was fully filled with toluene and the 2 L round bottom flask was

covered with aluminum foil. The reaction mixture was heated to reflux

using a heating mantle (it takes approximately 90 min to heat toluene up

One-pot pivaloylation on a 1.0 g scale - purification. The crude

toluene solution was filtered through a short silica gel pad (30 mL of

silica) then washed with a portion (100 mL) of 10% MeOH/EtOAc. The

MeOH/EtOAc mixture was evaporated under vacuum and the crude

yellow oil was redissolved into EtOAc (100 mL). Then, the EtOAc crude

solution was washed with portions of water (9 × 30 mL). The water layer

was evaporated under vacuum, redissolved into EtOAc (100 mL), dry

with sodium sulfate, filtered, evaporated again under vacuum to collect

the mixture of mono- and di- pivaloylated methylglucoside was collected

as a white syrup (1054-1100 mg, 72-75% crude yield). The white syrup

was hen dissolved into a minimum amount of EtOAc (~10 mL) and

selectively crystallized overnight (16 h) into pentane (100 mL) to obtain

pure methyl 2-O-pivaloyl--D-glucopyranoside as white flaky crystals

(686-703 mg, 47-48% crystallized yield). The EtOAc layer from the

aqueous extraction was evaporated under vacuum and the

phenylboronic acid was collected as a white solid (494-519 mg, 75-79%

recovery). Both water and EtOAc layers were monitored by TLC (50%

EtOAc/Hex).

to the boiling point). After refluxing for

h, solid 2-

ethoxycarbonylphenylboronic acid (1.10 g, 5.67 mmol, 1.10 eq.) was

carefully added into the solution. After another 1 h of reflux, the reaction

mixture was cooled down to ca. 40 °C, capped with a rubber septum and

a balloon of argon then cooled down to room temperature. Overnight

oven-dried (110 °C) solid K₂CO₃(7.12 g, 10.0 eq.) was added to the

reaction mixture and suspended. Then neat Ac₂O (511 µL, 5.41 mmol,

1.05 eq.) was added to the reaction flask, stir for 1 h at room temperature,

then 4 h oven-dried (110 °C) recrystallized DMAP (126 mg, 1.03 mmol,

0.20 eq.) was added to the reaction flask. Stirring should be such that

any material aggregated on the glassware surface is suspended. The

reaction mixture was stirred for 2 h at room temperature under argon

atmosphere then filtrated under vacuum through Büchner funnel to

remove the excess of solid K₂CO₃. Toluene was evaporated under

vacuum, and the ¹H NMR spectrum of the crude colorless syrup was

taken in MeOH-d⁴.

One-pot pivaloylation on a 10.0 g scale – purification. The crude

toluene solution was filtered through a short silica gel pad (300 mL of

silica) then washed with a portion (1 L) of 10% MeOH/EtOAc. The

MeOH/EtOAc mixture was evaporated under vacuum and the crude

yellow oil was redissolved into EtOAc (1 L). Then, the EtOAc crude

solution was washed with portions of water (9 × 300 mL). Only the first

three washings (3 × 300 mL) of the water layer were evaporated under

vacuum (the rest was discarded), redissolved into EtOAc (1 L), dry with

sodium sulfate, filtered, evaporated again under vacuum to collect the

mixture of mono- and di- pivaloylated methylglucoside was collected as a

One-pot monobenzoylation on a 1.0 g scale. Following the procedure

described above., methyl -D-glucopyranoside (1.00 g, 5.15 mmol), solid

phenylboronic acid (691 mg, 5.67 mmol, 1.10 eq.), K₂CO₃(7.12 g, 10.00

eq.), neat BzCl (628 µL, 5.41 mmol, 1.05 eq.) and DMAP (126 mg, 1.03

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European Journal of Organic Chemistry

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white syrup (9.0 g - 9.3 g, 63-65% crude yield). The white syrup was hen

dissolved into a minimum amount of EtOAc (~100 mL) and selectively

crystallized overnight (16 h) into pentane (1 L) to obtain pure methyl 2-O-

pivaloyl--D-glucopyranoside as white flaky crystals (6393-7376 mg, 45-

51% crystallized yield). The EtOAc layer from the aqueous extraction

was evaporated under vacuum and the phenylboronic acid was collected

as a white solid (6019-6260 mg, 86-90% recovery). Both water and

EtOAc layers were monitored by TLC (50% EtOAc/Hex).

101.3, 75.1, 73.6, 73.5, 71.8, 62.7, 62.6, 55.5, 14.5; ¹¹B NMR (160 MHz,

CD₂Cl₂)  = 29.3; HRMS (APCI+) calcd for [C_{16 h21}BO₈+ H]⁺: 353.14077,

found: 353.1392.

Methyl 2-O-acetyl-α-D-glucopyranoside (8a),^[25]methyl 3-O-acetyl-α-

D-glucopyranoside

(9a),^[25]

methyl

2,3-di-O-acetyl-α-D-

glucopyranoside (10a)^[26]and methyl 2,3,4,6-tetra-O-acetyl-α-D-

[27]

glucopyranoside.

To a suspension of methyl -D-glucopyranoside

(503 mg, 2.59 mmol) in toluene (500 mL), was added 2-

ethoxycarbonylphenylboronic acid (554 mg, 2.86 mmol, 1.10 equiv.) and

the reaction mixture was refluxed for 2 h using a Dean-Stark apparatus.

The solution was then cooled down to room temperature and the solution

was divided in 8 portions of 50 mL and used as it is for 8 reactions with

different conditions. Solid K₂CO₃was suspended in the previous solution

(357 mg, 2.58 mmol, 10.03 equiv.) and a 0.05 M solution of DMAP in dry

toluene (0.30 mL, 0.015 mmol, 0.05 equiv. or 0.60 mL, 0.030 mmol, 0.10

equiv.) was added dropwise followed by a 0.5 M solution of acetic

anhydride in dry toluene (0.6 mL, 0.30 mmol, 1.17 equiv. or 1.20 mL,

0.60 mmol, 2.35 equiv.). The reaction mixture was stirred for either 2 h or

16 h at room temperature under an argon atmosphere. Toluene was

removed under vacuum and the crude materials from the 8 reactions

combined were purified by silica gel column chromatography using a

gradient eluent system (1-10% MeOH/DCM) to obtain:

Methyl

4,6-phenylboronate-α-D-glucopyranoside

(5a).^[24]

suspension of methyl -D-glucopyranoside (501 mg, 2.58 mmol) in

toluene (25 mL) was refluxed for 1 h using a Dean-Stark apparatus. Then

phenylboronic acid (345 mg, 3.26 mmol, 1.27 eq.) was added and the

reaction mixture was refluxed for 1 h using a Dean-Stark apparatus. The

solution was cooled down to room temperature and the solvent

evaporated under vacuum. The crude material was dissolved in DCM,

filtrated and concentrated under vacuum. The remaining solid was

dissolved in a minimum of boiling toluene and allowed to cool down to

room temperature to obtain methyl 4,6-phenylboronate--D-

glucopyranoside 5a as small white needles crystals (683 mg, 95% yield).

mp 166-168 °C (toluene); [α]_D²²= +95.3° (c 0.5, CHCl₃); IR (film, CHCl₃)

 max: 3354, 2940, 2906, 1602, 1441, 1409, 1313, 1297, 1254, 1029,

909, 697 cm^-1; ¹H NMR (300 MHz, CDCl₃)  = 7.47-7.35 (m, 5H), 4.84 (d,

1H, J = 3.9 Hz), 4.25 (dd, 1H, J = 4.4, 9.3 Hz), 3.97 (t, 1H, J = 9.7 Hz),

3.93-3.65 (m, 4H), 3.48 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)  = 134.1

Methyl 2-O-acetyl--D-glucopyranoside 8a from a mixture as a colourless

oil (57 mg, 9% yield). R_f= 0.22 (1:9 MeOH/DCM); IR (film, CHCl₃)  max:

3339, 2918, 2842, 2506, 1647, 1263, 1193, 1020, 899, 841, 752, 708,

668 cm^-1; ¹H NMR (300 MHz, CD₃OD)  = 4.83 (d, 1H, J = 3.7 Hz), 4.57

(dd, 1H, J = 3.7, 10.0 Hz), 3.84-3.76 (m, 2H), 3.71-3.65 (m, 1H), 3.53

(ddd, 1H, J = 2.2, 5.6, 9.8 Hz), 3.39-3.32 (m, 1H), 3.36 (s, 3H), 2.08 (s,

3H); ¹³C NMR (75 MHz, CD₃OD)  = 172.4, 98.3, 75.0, 73.5, 72.4, 71.8,

62.5, 55.4, 20.8; HRMS (ESI+) calcd for [C₉H₁₆O₇+ Na]⁺: 259.07937,

found: 259.07883.

(2C), 131.1 (2C), 127.6 (2C), 99.8, 74.8, 73.4, 72.5, 64.4, 64.3, 55.7; ¹¹

NMR (160 MHz, CDCl₃)  = 27.0; HRMS (APCI+) calcd for [C₁₃H₁₇BO₆+

H]⁺: 281.11964, found: 281.1188. HRMS (ESI-) calcd for [C₁₃H₁₇BO₆

CHO₂]^-: 325.10947, found: 325.11050. HRMS (ESI-) calcd for [C₁₃H₁₇BO₆

+ Cl]^-: 315.08067, found: 315.08200.

Methyl 4,6-(para-fluoro)phenylboronate-α-D-glucopyranoside (5b).

Following the procedure described in II.1, methyl -D-glucopyranoside

(501 mg, 2.58 mmol) in toluene (25 mL) and 4-fluorophenylboronic acid

(398 mg, 3.84 mmol, 1.10 equiv.) afforded methyl 4,6-(para-

fluoro)phenylboronate--D-glucopyranoside 5b as white fluffy cotton-like

crystals (759 mg, 99% yield). mp 183-185°C (toluene); [α]_D²²= +40.3° (c

1.0, CHCl₃); IR (film, CHCl₃)  max: 3353, 2940, 2910, 1597, 1510, 1483,

1405, 1315, 1298, 1221, 1085, 1038, 995, 837, 729 cm^-1; ¹H NMR (300

MHz, CDCl₃)  = 7.82-6.99 (m, 4H), 4.84 (d, 1H, J = 3.9 Hz), 4.24 (dd, 1H,

J = 4.3 Hz, 9.3 Hz), 3.95 (t, 1H, J = 10.2 Hz), 3.90-3.64 (m, 4H), 3.48 (s,

3H);. ¹H NMR (300 MHz, (CD₃)₂CO)  = 7.86-7.79 (m, 2H), 7.12-7.06 (m,

2H), 4.76 (d, 1H, J = 3.8 Hz), 4.59 (d, 1H, J = 3.4 Hz), 4.20 (dd, 1H, J =

4.7 Hz, 9.4 Hz), 3.96 (t, 1H, J = 9.9 Hz), 3.91-3.68 (m 4H), 3.41 (s, 3H);

¹³C NMR (125 MHz, (CD₃)₂CO)  = 167.2, 163.9, 137.3, 137.2, 115.2,

114.9, 101.5, 76.4, 73.6, 73.3, 65.2, 65.1, 55.5; ¹¹B NMR (160 MHz,

CDCl₃)  = 31.7; ¹⁹F NMR (471 MHz, CDCl₃)  = -108.8; HRMS (APCI+)

calcd for [C₁₃H₁₆BFO₆+ H]⁺: 299.1102, found: 299.1100; HRMS (ESI-)

calcd for [C₁₃H₁₆BFO₆+ CHO₂]^-: 343.10005, found: 343.10100.

Methyl 3-O-acetyl--D-glucopyranoside 9a as a white solid (78 mg, 13%

yield). mp 142-145°C (CHCl₃); [α]_D²²= +281.8° (c 0.3, CHCl₃); R_f= 0.22

(1:9 MeOH/DCM); IR (film, CHCl₃)  max: 3400, 2914, 1716, 1430, 1249,

1190, 1152, 1046, 908, 843 cm^-1; ¹H NMR (300 MHz, CDCl₃)  = 5.06 (t,

1H, J = 9.3 Hz), 4.78 (d, 1H, J = 3.8 Hz), 3.91-3.81 (m, 2H), 3.70-3.57 (m,

3H), 3.45 (s, 3H), 2.16 (s, 3H); ¹³C NMR (300 MHz, CD₃OD)  = 173.8,

102.1, 78.1, 74.4, 72.8, 70.7, 63.3, 56.6, 22.1; HRMS (ESI+) calcd for

[C₉H₁₆O₇+ Na]⁺: 259.07937, found: 259.07873.

Methyl 2,3-di-O-acetyl--D-glucopyranoside 10a (262 mg, 36% yield).

[α]_D= +111.1° (c 1.0, CHCl₃); R_f= 0.38 (1:9 MeOH/DCM); IR (film,

CHCl₃)  max: 3426, 2937, 1742, 1436, 1371, 1226, 1032, 919, 755 cm^-1;

¹H NMR (300 MHz, CDCl₃)  = 5.34-5.23 (m, 1H), 4.91 (d, 1H, J = 3.6

Hz), 4.84 (dd, 1H, J = 3.6 Hz, 10.1 Hz), 3.92-3.81 (m, 2H), 3.75-3.67 (m,

2H), 3.40, (s, 3H), 2.11 (s, 3H), 2.09 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

 = 172.0, 170.3, 96.8, 73.5, 71.1, 70.7, 70.0, 62.0, 55.3, 20.9, 20.8;

HRMS (ESI+) calcd for [C₁₁H₁₈O₈+ Na]⁺: 301.08994, found: 301.08957,

literatureFehler! Textmarke nicht definiert.: 301.0941.

Methyl

4,6-(ortho-ethoxycarbonyl)phenylboronate-α-D-

glucopyranoside (5c). Following the procedure described in II.1, methyl

-D-glucopyranoside (246 mg, 1.27 mmol) in toluene (13 mL) and 2-

ethoxycarbonylphenylboronic acid (221 mg, 1.14 mmol, 0.90 equiv.)

And methyl 2,3,4,6-tetra-O-acetyl--D-glucopyranoside as a colourless oil

afforded

methyl

4,6-(ortho-ethoxycarbonyl)phenylboronate--D-

(247 mg, 26% yield). [α]_D= +90.7° (c 0.5, CHCl₃); R_f= 0.72 (1:9

glucopyranoside 5c as white foam crystals (406 mg, 91% yield). [α]_D

MeOH/DCM); IR (film, CHCl₃)  max: 2947, 1744, 1436, 1368, 1216,

1032, 930, 896, 755 cm^-1; ¹H NMR (300 MHz, CDCl₃)  = 5.47 (dd, 1H, J

= 9.5 Hz, 10.0 Hz), 5.06 (dd, 1H, J = 9.5 Hz, 10.1 Hz), 4.94 (d, 1H, J =

3.7 Hz), 4.89 (dd, 1H, J = 3.7 Hz, 10.1 Hz), 4.26 (dd, 1H, J = 4.6 Hz,

12.3 Hz), 4.10 (dd, 1H, J = 2.3 Hz, 12.3 Hz), 3.98 (ddd, 1H, J = 2.3 Hz,

4.5 Hz, 10.2 Hz), 3.40 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H),

2.00 (s, 3H); ¹H NMR (300 MHz, , CD₃OD)  = 5.40 (t, 1H, J = 9.5 Hz),

5.02 (t, 1H, J = 9.5 Hz,), 4.93 (d, 1H, J = 3.6 Hz), 4.84 (dd, 1H, J = 3.6 Hz,

6.6 Hz), 4.25 (dd, 1H, J = 4.7 Hz, 12.3 Hz), 4.10 (dd, 1H, J = 2.4 Hz, 12.3

+67.3° (c 0.7, MeOH); IR (film, CHCl₃)  max: 3355, 2913, 1680, 1396,

1366, 1262, 1285, 1186, 1111, 1024, 899 843, 754, 710, 670 cm^-1; ¹H

NMR (300 MHz, CD₃OD)  = 8.02-7.99 (m, 1H), 7.59 (td, 1H, J = 7.4 Hz,

12 Hz), 7.46 (td, 1H, J = 7.7 Hz, 14 Hz), 7.48-7.41 (m, 1H), 4.66 (d, 1H, J

= 3.7 Hz), 4.37 (q, 2H, J = 7.1 Hz), 3.80 (dd, 1H, J = 2.4 Hz, 11.8 Hz),

3.69-3.57 (m, 2H), 3.52 (ddd, 1H, J = 2.3 Hz, 5.5 Hz, 9.9 Hz), 3.40 (s,

3H), 3.39-3.35 (m, 1H), 3.27-3.24 (m, 1H), 1.39 (t, 3H, J = 7.1 Hz); ¹³C

NMR (125 MHz, CD₃OD)  = 169.3, 133.7, 133.6, 131.8, 129.8, 129.5,

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European Journal of Organic Chemistry

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Hz), 3.99 (ddd, 1H, J = 2.4 Hz, 4.7 Hz, 10.2 Hz), 3.41 (s, 3H), 2.05 (s,

3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)

 = 170.7, 170.1, 170.0, 169.6, 96.75, 70.8, 70.1, 68.5, 67.1, 61.9, 55.5,

20.7 (2C), 20.7, 20.6; HRMS (ESI+) calcd for [C₁₅H₂₂O₁₀+ Na]⁺:

385.11107, found: 385.11054.

9.6 Hz), 5.53 (s, 1H), 4.86 (d, 1H, J = 3.8 Hz), 4.34 (dd, 1H, J = 4.6 Hz,

10.0 Hz), 3.99-3.91 (m, 1H,), 3.84-3.73 (m, 1H), 3.51 (s, 3H); ¹³C NMR

(75 MHz, CDCl₃)  = 166.6, 136.9, 133.1, 129.9 (2C), 129.0 (2C), 128.3

(2C), 128.2 (2C), 126.1 (2C), 101.5, 100.2, 78.8, 73.0, 72.0, 68.96, 62.8,

55.6; HRMS (ESI+) calcd for [C₂₁H₂₂O₇+ Na]⁺: 409.12632, found:

409.12493.

Methyl 4,6-O-benzylidene-α-D-glucopyranoside (7).^[19a]Methyl -D-

glucopyranoside (1.010 g, 5.20 mmol) was suspended in acetonitrile (20

mL). A catalytic amount of solid (±)-camphorsulfonic acid (60 mg, 0.26

mmol, 0.05 equiv.) was added then benzaldehyde dimethyl acetal (1.4

mL, 9.33 mmol, 2.5 equiv.) was added. The reaction mixture was

refluxed 20 min and monitored by TLC (9:1 EtOAc/Hexanes) until the

majority of the starting material disappeared. The reaction mixture was

cooled down to room temperature, neutralized with 2-3 drops of Et₃N (0.1

mL approx.) and the solvent evaporated under vacuum. The crude white

solid was solubilized using a minimum of DCM (10 mL approx.), poured

in an Erlenmeyer containing hexanes (40 mL approx.), crystallized and

filtrated. The resulting white solid was purified by silica gel column

and methyl 2,3-di-O-benzoyl-4,6-di-O-benzylidene--D-glucopyranoside

(223 mg, 51% yield). mp 150-152°C (CHCl₃); [α]_D= +95.0° (c 1.0,

CHCl₃); R_f= 0.83 (3:7 Et₂O/Toluene); IR (film, CHCl₃)  max: 2934, 2865,

1722, 1602, 1585, 1451, 1376, 1333, 1315, 1274, 1179, 1092, 991, 750,

708 cm^-1; ¹H NMR (300 MHz, CDCl₃)  = 8.01-7.31 (m, 15H), 6.06 (t, 1H,

J = 9.7 Hz), 5.57 (s, 1H), 5.25 (dd, 1H, J = 3.7 Hz, 9.9 Hz), 5.18 (d, 1H,

3.7 Hz), 4.38 (dd, 1H, J = 4.8 Hz, 10.2 Hz), 4.13-4.05 (m, 1H), 3.89 (q,

2H, J = 9.9 Hz, 21.4 Hz), 3.44 (s, 3H); ¹³C NMR (167 MHz, CDCl₃)  =

166.0, 165.6, 136.9 (2C), 133.4, 133.0, 129.9 (2C), 129.7 (2C), 129.0

(2C), 128.4 (2C), 128.3 (2C), 128.2 (2C), 126.1 (2C), 101.6, 97.8, 79.4,

72.5, 69.5, 68.9, 62.5, 55.5; HRMS (ESI+) calcd for [C₂₈H₂₆O₈+ Na]⁺:

513.15254, found: 513.15058.

chromatography using

EtOAc/Hexanes) to

gradient eluent system (10-90%

methyl 4,6-di-O-benzylidene--D-

obtain

Methyl 2-O-benzoyl-α-D-glucopyranoside (8b)^[14b]Methyl 2-O-benzoyl-

4,6-di-O-benzylidene--D-glucopyranoside (242 mg, 0.81 mmol) was

dissolved in methanol/DCM 6:1 (7.0 mL) and 10% w/w Pd/C (25 mg) was

placed. The reaction mixture was bubbled with argon then stirred

overnight (16 h) at room temperature under hydrogen atmosphere. The

solution was filtrated on Celite®, concentrated under vacuum and purified

by silica gel column chromatography using a gradient eluent system (60-

glucopyranoside 7 as a white solid (1.069 g, 73% yield). mp 159-161°C

(CHCl₃); [α]_D²²= +116.7° (c 1.0, CHCl₃); R_f= 0.31 (90% EtOAc/Hexanes);

IR (film, CHCl₃)  max: 3367, 2940, 2869, 1452, 1372, 1335, 1276, 1190,

1072, 1027, 997, 747, 695 cm^-1; ¹H NMR (300 MHz, CDCl₃)  = 7.51-7.34

(m, 5H), 5.52 (s, 1H), 4.77 (d, 1H, J = 3.9 Hz), 4.28 (q, 1H, J = 3.4 Hz,

8.8 Hz), 3.91 (t, 1H, J = 9.2 Hz), 3.84-3.69 (m, 2H), 3.61 (m, 1H), 3.47 (t,

1H, J = 9.2 Hz), 3.44 (s, 3H); ¹³C NMR (167 MHz, CDCl₃)  = 137.0,

129.2, 128.3 (2C), 126.3 (2C), 101.9, 99.8, 80.9, 72.8, 71.6, 68.9, 62.3,

55.; HRMS (ESI+) calcd for [C₁₄H₁₈O₆+ Na]⁺: 305.10011, found:

305.09934.

100%

EtOAc/Hexanes)

obtain

methyl

2-O-benzoyl--D-

glucopyranoside 8b as a white solid (140 mg, 75% yield). mp 161-165°C

(CHCl₃); [α]_D²²= +96.5° (c 1.0, MeOH); R_f= 0.28 (9:1 EtOAc/Hexanes);

IR (film, MeOH)  max: 3488, 2929, 1716, 1602, 1452, 1276, 1094, 1027,

909, 713 cm^-1; ¹H NMR (300 MHz, CDCl₃)  = 8.10-7.44 (m, 5H), 5.03 (d,

1H, J = 3.7 Hz), 4.91 (dd, 1H, J = 3.7 Hz, 10.0 Hz), 4.15 (dd, 1H, J = 8.7

Methyl

2-O-benzoyl-4,6-O-benzylidene-α-D-glucopyranoside,^[28]

methyl 3-O-benzoyl-4,6-O-benzylidene-α-D-glucopyranoside, and

methyl 2,3-di-O-benzoyl-4,6-O-benzylidene-α-D-glucopyranoside^[29]

Methyl 4,6-di-O-benzylidene--D-glucopyranoside (506 mg, 1.79 mmol)

was dissolved in dry toluene (355 mL) then solid K₂CO₃was suspended

(2.46 g, 17.8 mmol, 9.9 equiv.). A 0.05 M solution of DMAP in dry toluene

(1.8 mL, 0.09 mmol, 0.05 equiv.) was added dropwise followed by a 0.5

M solution of benzoyl chloride in dry toluene (2.5 mL, 1.25 mmol, 0.70

equiv.). The reaction mixture was stirred overnight (16 h) at room

temperature under an argon atmosphere and monitored by TLC (3:7

Et₂O/Toluene) until the majority of the starting material disappeared.

Toluene was removed under vacuum and the crude material was

dissolved in DCM then filtrated and concentrated in vacuum. The crude

material was purified by silica gel column chromatography using a

gradient eluent system (5-20% Et₂O/Toluene) to obtain methyl 2-O-

benzoyl-4,6-di-O-benzylidene--D-glucopyranoside as a white solid (38

mg, 5% yield). mp 160-165°C (CHCl₃); [α]_D²²= +113.1° (c 1.0, CHCl₃); R_f

= 0.57 (3:7 Et₂O/Toluene); IR (film, CHCl₃)  max: 3477, 2935, 2867,

1717, 1602, 1585, 1451, 1377, 1334, 1316, 1272, 1177, 1092, 988, 750,

711 cm^-1; ¹H NMR (300 MHz, CDCl₃)  = 8.12-7.38 (m, 10H), 5.59 (s, 1H),

5.08 (t, 1H, J = 3.5 Hz), 5.03 (q, 1H, J = 5.5 Hz), 4.40-4.31 (m, 2H), 3.97-

3.89 (m, 1H), 3.81 (1, 1H, J = 10.1 Hz), 3.65 (t, 1H, J = 9.3 Hz), 3.40 (s,

3H); ¹³C NMR (167 MHz, CDCl₃)  = 166.2, 137.0, 133.3, 129.9 (2C),

129.5, 129.3, 128.4 (2C), 128.3 (2C), 126.3 (2C), 102.0, 97.7, 81.4, 74.1,

68.9, 68.8, 62.0, 55.5; HRMS (ESI+) calcd for [C₂₁H₂₂O₇+ Na]⁺:

409.12632, found: 409.12528.

Hz, 9.9 Hz), 3.96-3.85 (m, 2H), 3.78-3.68 (m, 2H), 3.40 (s, 3H); H NMR

(300 MHz, CD₃OD)  = 8.09-7.45 (m, 5H), 4.99 (d, 1H, J = 3.7 Hz), 4.83

(dd, 1H, J = 3.7 Hz, 10.0 Hz), 3.98 (dd, 1H, J = 8.9 Hz, 9.9 Hz), 3.86 (dd,

1H, J = 2.3 Hz, 11.8 Hz), 3.73 (dd, 1H, J = 5.5 Hz, 11.8 Hz), 3.65-3.59 (m,

1H), 3.44 (dd, 1H, J = 9.0 Hz, 9.8 Hz), 3.38 (s, 3H); ¹³C NMR (125 MHz,

CD₃OD)  = 168.6, 135.3 (2C), 131.7 (2C), 130.3 (2C), 99.4, 76.4, 74.4,

73.3, 72.8, 63.4, 56.4; HRMS (ESI+) calcd for [C₁₄H₁₈O₇+ Na]⁺:

321.09502, found: 321.09401.

Methyl 3-O-benzoyl-α-D-glucopyranoside (9b)^[30]Methyl 3-O-benzoyl-

4,6-di-O-benzylidene--D-glucopyranoside (131 mg, 0.44 mmol) was

dissolved in methanol/DCM 6:1 (5.0 mL) and 10% w/w Pd/C (14 mg) was

placed. The reaction mixture was bubbled with argon then stirred

overnight (16 h) at room temperature under hydrogen atmosphere. The

solution was filtrated on Celite®, concentrated under vacuum and purified

by silica gel column chromatography using a gradient eluent system (60-

100%

EtOAc/Hexanes)

obtain

methyl

3-O-benzoyl--D-

glucopyranoside 9b as a white solid (73 mg, 72% yield). mp 151-155°C

(CHCl₃); [α]_D²²= +98.9° (c 1.0, MeOH); R_f= 0.33 (9:1 EtOAc/Hexanes);

IR (film, CHCl₃)  max: 3420, 2931, 1706, 1603, 1451, 1272, 1125, 1042,

908, 710 cm^-1; ¹H NMR (300 MHz, CDCl₃)  = 8.09-7.42 (m, 5H), 5.31

(dd, 1H, J = 8.9 Hz, 9.6 Hz), 4.84 (d, 1H, J = 3.8 Hz), 3.94-3.71 (m, 5H),

3.48 (s, 3H); ¹H NMR (300 MHz, CD₃OD)  = 8.10-7.45 (m, 5H), 5.43 (dd,

1H, J = 8.8 Hz, 9.9 Hz), 4.77 (d, 1H, J = 3.7 Hz), 3.87-3.60 (m, 5H), 3.47

(s, 3H); ¹³C NMR (125 MHz, CDCl₃)  = 168.1, 133.5, 129.9 (2C), 129.5,

128.4 (2C), 99.4, 77.7, 71.4, 70.9, 69.4, 62.2, 55.5; HRMS (ESI+) calcd

for [C₁₄H₁₈O₇+ Na]⁺: 321.09502, found: 321.09418.

as well as methyl 3-O-benzoyl-4,6-di-O-benzylidene--D-glucopyranoside

in a mixture of mono- and disubstitued carbohydrates as a white solid (56

mg, 8% yield). mp 203-204°C (CHCl₃); [α]_D²²= +47.6° (c 1.0, CHCl₃); R_f=

0.41 (3:7 Et₂O/Toluene); IR (film, CHCl₃)  max: 3478, 2935, 2866, 1717,

1602, 1584, 1451, 1377, 1334, 1316, 1272, 1177, 1092, 988, 750, 711

cm^-1; ¹H NMR (300 MHz, CDCl₃)  = 8.09-7.30 (m, 10H), 5.59 (t, 1H, J =

Methyl 2,3-di-O-benzoyl-α-D-glucopyranoside (10b)^[29]Methyl 2,3-O-

benzoyl-4,6-di-O-benzylidene--D-glucopyranoside (315 mg, 0.78 mmol)

was dissolved in methanol/DCM 3:1 (8.0 mL) and 10% w/w Pd/C (33 mg)

10.1002/ejoc.201601457

European Journal of Organic Chemistry

FULL PAPER

was placed. The reaction mixture was bubbled with argon then stirred

overnight (16 h) at room temperature under hydrogen atmosphere. The

solution was filtrated on Celite®, concentrated under vacuum and purified

by silica gel column chromatography using a gradient eluent system (30-

70% EtOAc/Hexanes) to obtain methyl 2,3-di-O-benzoyl--D-

glucopyranoside 10b as a white solid (185 mg, 72% yield). mp 69-73°C

(CHCl₃); [α]_D²²= +114.1° (c 1.0, MeOH); R_f= 0.71 (9:1 EtOAc/Hexanes);

IR (film, CHCl₃)  max: 3446, 2936, 1721, 1602, 1452, 1277, 1096, 1027,

915, 709 cm^-1; ¹H NMR (300 MHz, CDCl₃)  = 7.99-7.34 (m, 10H), 5.73

(dd, 1H, J = 8.9 Hz, 10.1 Hz), 5.23 (dd, 1H, J = 3.6 Hz, 10.1 Hz), 5.12 (d,

1H J = 3.6 Hz), 3.99-3.83 (m, 4H), 3.43 (s, 3H); ¹H NMR (300 MHz,

CD₃OD)  = 7.98-7.35 (m, 10H), 5.81-5.74 (m, 1H), 5.14-5.09 (m, 2H),

3.92-3.74 (m, 4H), 3.46 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)  = 167.5,

166.0, 133.5 (2C), 133.4 (2C), 129.9 (2C), 129.2 (2C), 129.1 (2C), 128.4

(2C), 97.1, 74.4, 71.4, 71.3, 70.0, 62.13, 55.4; HRMS (ESI+) calcd for

[C₂₁H₂₂O₈+ Na]⁺: 425.12124, found: 425.12005.

CD₃OD)  = 179.2, 179.1, 98.2, 73.6, 73.5, 72.7, 69.7, 62.1, 55.7, 39.8,

39.7, 27.6 (3C), 27.4 (3C); HRMS (ESI-) calcd for [C₁₇H₃₀O₈+ Cl]^-_:

397.16292, found: 397.16306. HRMS (ESI-) calcd for [C₁₇H₃₀O₈

HCOO]^-_:407.19172, found: 407.19151.

and methyl 2,3,4,6-O-tetra-pivaloyl--D-glucopyranoside 10d as a white

solid (22 mg, 6% yield). mp 87-89°C (CDCl₃); [α]_D= +80.0° (c 1.0,

CHCl₃); R_f= 0.89 (1:1 EtOAc/Hexanes); IR (film, CHCl₃)  max: 3364,

2974, 2493, 2070, 1737, 1481, 1282, 1124, 1036, 976, 922, 895, 762

cm^-1; ¹H NMR (300 MHz, CD₃OD)  = 5.49 (t, 1H, J = 9.8 Hz), 5.12 (t, 1H,

J = 10.0 Hz), 4.93 (d, 1H, J = 3.7), 4.80 (dd, 1H, J = 3.7, 10.1 Hz), 4.14 (s,

1H), 4.13 (s,1H), 4.03 (m, 1H), 3.42 (s, 3H), 1.11 (s, 9H), 1.15 (s, 18H),

1.12 (s, 9H); ¹³C NMR (75 MHz, CD₃OD)  = 178.0, 179.1, 177.0, 176.4,

96.6, 71.0, 69.7, 67.7, 67.4, 61.6, 54.7, 38.5, 38.4 (2C), 38.3, 26.3 (3C),

26.2 (3C), 26.1 (3C), 26.0 (3C); HRMS (ESI+) calcd for [C₂₇H₄₆O₁₀

Na]⁺_:553.29887, found: 553.29760.

Methyl 2-O-pivaloyl-α-D-glucopyranoside (8c),^[31]methyl 3-O-

pivaloyl-α-D-glucopyranoside (9c) and methyl 2,3-O-di-pivaloyl-α-D-

glucopyranoside (10c). Methyl -D-glucopyranoside (253 mg, 1.30

mmol) was dissolved in dry toluene (250 mL) then solid K₂CO₃was

suspended (173 mg, 1.42 mmol, 1.09 equiv.). Four portions 0.05 M

solution of DMAP in dry toluene (1.3 mL, 0.07 mmol, 0.05 equiv.) were

added dropwise (over 4 days) then four portions of 0.5 M solution of

benzoyl chloride in dry toluene (2.8 mL, 1.40 mmol, 1.07 equiv.) were

also added dropwise (over four days). The reaction mixture was stirred

for 4 days at room temperature under argon atmosphere and monitored

by TLC (1:9 MeOH/DCM) until the majority of the starting material

disappeared. Toluene was removed under vacuum and the crude

material was purified by silica gel column chromatography using a

gradient eluent system (1-20% MeOH/DCM) to obtain methyl 2-O-

pivaloyl--D-glucopyranoside 8c as a white solid (257 mg, 60% yield) mp

n-Octyl 2-O-pivaloyl-β-D-glucopyranoside (14b). Two different

experiments (A and B) where ran in two different round bottom flasks

where n-octyl β-D-glucopyranoside (Experiment A: 1503 mg, 5.14 mmol;

Experiment B: 1502 mg, 5.14 mmol) was suspended in toluene (100 mL)

and was refluxed 1 h using a Dean-Stark apparatus. Then phenylboronic

acid (Experiment A: 693 mg, 5.68 mmol, 1.11 eq.) or 2-

ethoxycarbonylphenylboronic acid (Experiment B: 1109 mg, 5.72 mmol,

1.11 eq.) was added and the reaction mixture was again refluxed 1h

using a Dean-Stark apparatus. The solution was cooled down to room

temperature then oven-dried K₂CO₃(Experiment A: 7130 mg, 51.59

mmol, 10.04 eq.; Experiment B: 7119 mg, 51.51 mmol, 10.02 eq.) then

PivCl (700 µL, 5.68 mmol, 1.11 eq.) were added. The reaction mixture

was let stir 1 h at room temperature the oven-dried DMAP (Experiment A:

383 mg, 3.14 mmol, 0.61 eq.; Experiment B: 379 mg, 3.10 mmol, 0.60

eq.) was added and the reaction mixture was stirred 16 h at room

temperature under argon atmosphere. The crude solution was filtered to

remove K₂CO₃, toluene evaporated under vacuum and the combined

crude materials (Experiment A and B) were purified by silica gel column

chromatography using a gradient eluent system (1-10% MeOH/DCM) to

obtain n-octyl 2-O-pivaloyl-β-D-glucopyranoside 14b as a colorless oil

125-127°C (CDCl₃); [α]_D= +150.3° (c 1.0, CHCl₃); R_f= 0.34 (1:9

MeOH/DCM); . IR (film, CHCl₃)  max: 3388, 2961, 2934, 1729, 1288,

1153, 1035, 912, 773, 707cm^-1; ¹H NMR (300 MHz, CDCl₃)  = 4.87 (d,

1H, J =3.6 Hz), 4.64 (dd, 1H, J = 3.6 Hz, 9.9 Hz), 3.97-3.80 (m, 3H),

3.71-3.59 (m, 2H), 3.35 (s, 3H), 1.22 (s, 9H); ¹H NMR (300 MHz, CD₃OD)

 = 4.81 (d, 1H, J = 3.7 Hz), 4.53 (dd, 1H, J = 3.7 Hz, 10.1 Hz), 3.85-3.77

(m, 2H), 3.68 (dd, 1H, J = 5.6 Hz, 11.9 Hz), 3.55 (ddd, 1H, J = 2.2 Hz, 5.5

Hz, 9.7 Hz), 3.39 (d, 1H, J = 4.8 Hz), 3.36 (s, 3H), 1.21 (s, 9H); ¹³C NMR

(125 MHz, CDCl₃)  = 178.7, 97.2, 73.1, 71.7, 70.9, 70.1, 61.5, 55.4, 38.9,

27.0 (3C); HRMS (ESI+) calcd for [C₁₂H₂₂O₇+ Na]⁺: 301.12631, found:

301.12591, literatureFehler! Textmarke nicht definiert.: 301.1277

(106 mg, 3% yield). [α]_D= -24.2 (c=1.1, MeOH); R_f= = 0.38 (1:9

MeOH/DCM); IR (film, CHCl₃) ν max: 3386, 2927, 1732, 1281, 1175,

1151, 1076, 1031, 755 cm^-1; ¹H NMR (500 MHz, CD₃OD) δ = 4.67 (at, 1H,

J = 8.1 Hz, 9.6 Hz), 4.42 (d, 1H, J = 8.0 Hz), 3.85-3.89 (m, 2H), 3.68 (dd,

1H, J = 5.6 Hz, 12.0 Hz), 3.49 (t, 1H, J = 8.7 Hz), 3.42-3.46 (m, 1H), 3.35

(t, 1H, J = 9.7 Hz), 3.31-3.27 (m, 2H), 1.55-1.48 (m, 2H), 1.34-1.28 (m,

9H), 1.21 (s, 9H), 0.90-0.88 (m, 3H); ¹³C NMR (125 MHz, CD₃OD)

and methyl 3-O-pivaloyl--D-glucopyranoside 9c as a white solid (32 mg,

9% yield). mp 58-63°C (CDCl₃); [α]_D²²= +198.2° (c 0.2, CHCl₃); R_f= 0.41

(1:9 MeOH/DCM); IR (film, CHCl₃)  max: 3421, 2962, 2933, 1716, 1286,

179.0, 102.4, 78.0, 76.2, 75.0, 71.9, 70.6, 62.6, 39.9, 33.0, 30.8, 30.5.

30.4, 27.6, 27.2 (3C), 23.7, 14.4; HRMS (ESI+) calculated for [C₁₉H₃₆O₇

+ Na]⁺: 399.23587, found: 399.23565.

1168, 1046, 909, 769 cm^-1; H NMR (300 MHz, CDCl₃)  = 5.02 (s, 1H),

4.79 (d, 1H, J = 3.8 Hz), 3.92-3.81 (m, 2H), 3.71-3.60 (m, 3H), 3.45 (s,

3H), 1.25 (s, 9H); ¹H NMR (300 MHz, CD₃OD)  = 5.13 (t, 1H, J = 9.6 Hz),

4.69 (d, 1H, J = 3.7 Hz), 3.80 (dd, 1H, J = 2.3 Hz, 11.8 Hz), 3.68 (dd, 1H,

J = 5.1 Hz, 11.8 Hz), 3.59 (ddd, 1H, J = 2.2 Hz, 5.2 Hz, 9.8 Hz), 3.52 (dd,

1H, J = 3.7 Hz, 10.0 Hz), 3.44-3.41 (m, 1H), 3.43 (s, 3H), 1.22 (s, 9H);

¹³C NMR (125 MHz, CDCl₃)  = 180.6, 99.3, 76.9, 71.4, 70.8, 69.4, 62.1,

n-Octyl 3-O-pivaloyl-β-D-glucopyranoside (15b). Two different