University of Groningen Selective oxidation of glycosides ... · PDF fileSelective alcohol oxidation ... C4 benzyl protected methyl glucopyranoside ... Low reactivity has also been

University of Groningen

Selective oxidation of glycosidesJäger, Manuel

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CHAPTER 3

Discrimination among fewer equals: In order to get more insight into the origin of the selectivity

of the glycoside oxidation described in Chapter 2, the substrate scope was expanded to partially

protected glycosides. Various substrates, either protected on the C4- or the C6-position, were

successfully oxidized at C3, indicating that both the 2,3-diol and the 3,4 diol result in the same

regioselectivity. Although no change in the selectivity was observed, some substrates, especially

C6-tosyl substituted glycosides reacted considerably slower. A thorough NMR study did not reveal

a significant and consistent effect of the electronic nature of the substituent at C6 on the chemical

shift of the C3 carbon and proton. This indicates that either there is no long-range effect or that this

effect is not visible in the chemical shifts.

Catalytic Regioselective Oxidation

of Partially Protected Glycosides

Chapter 3

54

INTRODUCTION The selective oxidation of glucosides as described in Chapter 2 showed a

strong preference for oxidation at C3 in a range of glucosides (mono- and

diglucosides). The origin of this selectivity remains still unclear. In order

to get further insight, a better understanding of the mechanism of the

reaction is required and more in particular a clear picture of the substrate

requirements that lead to this regioselectivity.

Selective alcohol oxidation

The palladium catalyzed alcohol oxidation by catalyst 1 was published by

Waymouth et al.[1,2] Interestingly, in the reported oxidation reactions

vicinal diols were not only more reactive, but showed also higher

selectivities compared to single primary and secondary alcohols. A range

of vicinal diols containing a primary and a secondary alcohol could

therefore be oxidized selectively on the secondary alcohol.[2] The

mechanism for the oxidation of vicinal diols as proposed by Waymouth

is depicted in Figure 1.

Catalytic Regioselective Oxidation of Partially Protected Glycosides

55

Figure 1 Mechanism for the oxidation of vicinal diols as proposed by R. Waymouth[2]

[(Neocuproine)PdOAc]2(OTf)2 1 is in equilibrium with its monomer 1b or

1c in MeCN, H2O or DMSO. Further ligand exchange with the vicinal diol

gives rise to the hydroxyl-alkoxy species 2. Subsequent β-hydride

elimination, which is thought to be the product- and rate-determining

step, and finally the release of hydroxyacetone leads to palladium hydride

species 6. 6 is then re-oxidized by benzoquinone, regenerating 1b or 1c.

Chapter 3

56

Figure 2 DFT- calculated reaction coordinates for the oxidation of the primary vs. the

secondary alcohol in 1,2-propane diol[2]

Waymouth showed by DFT calculations that β-hydride elimination in

case of the secondary alkoxide F is favored compared to that in primary

alkoxide F’. While this explains the selectivity in the oxidation of 1,2-

propanediol and glycerol (secondary vs. primary), it is no explanation for

the observed discrimination of several secondary hydroxyl groups as

described in Chapter 2.

GOAL The goal of the research described in this chapter was to gain more insight

into the origin of the regioselective oxidation of glycosides, which has

been described in Chapter 2.[3] We envisioned getting a better

understanding of this phenomenon by increasing the substrate scope to

partially protected glycosides, in particular at C4 and C6.


57

From the research of the Waymouth group on the selective oxidation of

glycerol and 1,2-propanediol with palladium catalyst 1 it became clear

that vicinal diols are oxidized faster compared to mono-ols and

exclusively at the secondary alcohol. In the oxidation of glycosides two

different vicinal diol motifs, which can lead to oxidation at C3, are

present, the 2,3- and the 3,4 vicinal diol.

Figure 3 Vicinal diol motifs in a glycoside, which can lead to oxidation at C3

Either the 2,3-vicinal diol or the 3,4-vicinal diol could be preferred by the

catalyst and would lead therefore to the observed selectivity. The initial

results in Chapter 2 led us to believe that the 3,4-vicinal diol is the one to

which the catalyst coordinates, since the oxidation of either 2-desoxy

methyl glucopyranoside or 2-acetamido methyl glucopyranoside was

selective towards oxidation at C3 (Scheme 1). Furthermore, the oxidation

of 1,4-disaccharides was selective for the ring connected at the anomeric

carbon (the left ring, Scheme 1). This also could be just a steric effect which

would mean that protection at C4 would diminish the reactivity or

selectivity of the oxidation.

Scheme 1 Previous examples of the selective oxidation at C3

Chapter 3

58

In the first part of the project, several substrates were designed, protected

at the C4 position. If the selectivity is dependent on the 3,4-vicinal diol,

this would be disturbed in these cases. As a second objective, we desired

to increase the substrate scope with variations on the C6 position.

Previously we used already bulky electron donating as well as electron

withdrawing substituents at this position to study whether electronic

effects influence the reaction rate or even the selectivity of the oxidation.

Three compounds were selected to gain more insight into the origin of the

selectivity, C4 benzyl protected methyl glucopyranoside 7, C6 desoxy

methyl glucopyranoside 8 and the combination of both; the C4 benzyl

protected C6 desoxy methyl glucopyranoside 9.

Figure 4 Partial protected and modified substrates for the oxidation

Synthetic approach

The C4 modified glycosides 7 and 9 can be obtained by benzylidene

protection of methyl D-α-glucopyranoside (10). Selective acetal opening

to 7 followed by tosylation and reduction should give 9.


59

Scheme 2 Synthetic strategy towards the C4 modified glycosides 7 and 9

The synthesis of the C6 modified glycoside 8, although in principle

available via hydrogenolysis of 9, should be accessible by straightforward

tosylation of methyl D–α-glucopyranoside (10) and subsequent

reduction.

Scheme 3 Synthetic strategy towards the C6 modified glycoside 8

Not only the three designed substrates 7, 8 and 9 but the intermediates

are also interesting substrates. 11 has a rigid bicyclic structure, 13 has

another electron withdrawing group on C6 and 12 could give more

insight in the protection on C4 in combination with an electron

withdrawing group on C6. So the intermediates 11, 12 and 13 were also

planned to be tested in the regioselective oxidation.

Chapter 3

60

RESULTS AND DISCUSSION

Substrate synthesis

First, methyl D-α-glucopyranoside (10) was reacted with benzaldehyde

dimethyl acetal and p-toluenesulfonic acid in DMF. 11 was isolated pure

in 94% yield.[4] Selective acetal opening toward 7 was carried out using

Bu2OTf as Lewis acid and borane tetrahydrofuran complex as the

reducing agent at 0 °C. Pure 7 was isolated in 82% yield after

recrystallization.[5] Initial attempts with anhydrous CoCl2 as the Lewis

acid were abandoned because of the lower isolated yield, the formation

of the undesired regio-isomer 6-Bn-glucoside and the time consuming

drying of CoCl2.[6] Tosylation of 7 using standard conditions afforded 12

in 75% isolated yield after purification by column chromatography,

testifying to the difference in steric hindrance between a primary and a

secondary alcohol. Subsequent reduction by lithium aluminium hydride

(LAH) gave 9 in 92% yield.

Scheme 4 Synthesis of substrate 7, 9, 11 and 12

Tosylation of methyl α-D-glucopyranoside (10) using standard conditions

afforded 13 together with di-tosylated products as has been described

earlier.[7,8] Separation by column chromatography resulted in a low

isolated yield of 24%, also because of the polar nature of this compound.

Reduction by lithium aluminum hydride, peracetylation for isolation-


61

and purification-purposes and deprotection using standard Zemplén

conditions[4] gave 8 in 32% yield over three steps.

Scheme 5 Synthesis of substrate 8 and 13

Oxidation

With all substrates in hand, the selective oxidation of 7-9 was studied. A

representative oxidation procedure involved treatment of the glycoside

with 2.5 mol% [(neocuproine)PdOAc]2(OTf)2 and 3 eq of benzoquinone in

DMSO at rt. The regioselectivity of the oxidation was determined from

the crude reaction mixtures by 1H-, 13C-, HSQC- and COSY- NMR

spectroscopy. Surprisingly, all the substrates (7-9) were selectively

oxidized within 2 h at C3 to afford a single oxidation product.

The intermediates 11-13 were also subjected to the same oxidation

conditions and were all selectively oxidized at C3 as well. But whereas

benzyl protected tosylate 12 showed 65% conversion after 1 h, tosylate 13

showed only 40% conversion after this time. Initially benzylidene

protected 11 oxidized slowly and showed a conversion of less than 5%

after 1 h, 60% after 24 h and the reaction was complete after 4 days, upon

addition of another 2.5 mol% of catalyst. Later, the slow oxidation rate

could be assigned to residual sodium bicarbonate in the sample. The

conversion of purified 11 was 60% after 1 h, but did not go to completion

after 24 h. Low reactivity has also been observed in the acetylation of 11

and derivatives thereof.[9]

Chapter 3

62

Table 1 Oxidation of substrates 7-13

Entry Substrate Product Conversion

after 1 h

1

80%

2

85%

3

90%

4

65%

5

40%

6

60%

The reactions were carried out with 0.4 mmol glycoside, 2.5 mol% 1, 3 eq benzoquinone, in DMSO

(0.3 M), at room temperature.

Isolation and purification

The isolation and purification of the keto glucosides turned out to be

problematic. Several attempts to purify the products by crystallization,

titration, precipitation or extractive work-up using a variety of solvents

were unsuccessful. Attempted purification by normal phase column

chromatography using either conventional silica, low-surface silica or

neutralized silica led either to product degradation or failed to provide

pure products. One compound was purified successfully; the oxidation of

12 gave pure 17 after purification by column chromatography in a rather

low isolated yield of 33%.


63

Scheme 6 Oxidation of 12 to 17

Although not successful until now, I foresee that purification of the

products is nevertheless possible, provided a suitable method is found. A

solution might be the use of reversed-phase column chromatography or

chromatography based on charcoal as the stationary phase[3,10] as

described earlier.

On the regioselectivity of the oxidation

To our surprise, all substrates were selectively oxidized at C3 as shown in

Table 1. Our initial studies[3] suggested that the 3,4-vicinal diol-motif was

important for the selectivity since both 2-desoxy methyl D-α-

glucopyranoside and 2-acetamido methyl D-α-glucopyranoside were

rapidly and selectively oxidized at C3. The successful selective oxidation

of 7 showed that this assumption is not correct or at least not the complete

explanation. It seemed that the presence of either the 2,3- or the 3,4- vicinal

diol-motif leads to selective oxidation at C3. A cause of the retained

reactivity of 7 and 12 could be that coordination of the (benzyl)oxy

function to the palladium complex is still possible. The oxidation of C4-

desoxy methyl glucopyranoside would be insightful here, but this

substrate was not prepared in this study.

Furthermore, the regioselectivity is independent of the electronic and

steric properties of the C6 substituent. The electron withdrawing

substituents on C6 of 13 and of the earlier described 20 (Table 2), and the

electron donating substituents of 8 and the earlier described 21 (Table 2)

all did not interfere with the regioselective oxidation on C3. Also

substrates with bulky and small substituents as in 21 and 10, respectively,

showed the same regioselective oxidation on C3 as well.

Chapter 3

64

On the reaction rate of the oxidation

In contrast to the earlier described examples (Table 2), which all were

completely oxidized within 1 h, the oxidation of compounds 7-13 took

longer reaction times for all of the substrates.

Table 2 Conversion after 1 h of earlier oxidized methyl glucosides

Entry Substrate Product Conversion

after 1h

1

full

2

full

3

full

5

full

Method: 2.5 mol% 1, 3 eq benzoquinone, DMSO, 0.3 M

To minimize the error in the rate of the reaction, all oxidations were

performed with the same batch of catalyst within a two weeks period.

Compounds 7, 8 and 9 showed a rather fast reaction (all complete within

2 h), which is expected to be within the margin of error and therefore

comparable to the previously described examples depicted in Table 2 (all

complete within 1 h). 11, 12 and 13 showed a somewhat attenuated

reaction rate of 60%, 65% and 40% conversion within 1 h, respectively,

and needed 5-6 h and 24 h (or more) respectively, to reach >90%

conversion. The increase in reaction time is at least 3 fold and should be

significant. The exact reason for the lower reaction rate of both tosyl

substituted substrates remains unclear, although the fact that the tosyl

group is more electron withdrawing than the earlier described benzoyl

substituent might be important in this respect. The rigid bicyclic structure


65

of 11 probably makes the transformation to the more planar oxidation

product more difficult, which would explain the longer reaction time.

Chemical shifts in NMR as indication for electron

density

We wondered whether the electron withdrawing effect of the tosyl group

at C6 could be the cause of the lower reaction rate for the oxidation of

substrates 12 and 13. Long range orbital interactions, either through-bond

or to a lesser extent through-space (hyperconjugation), are well-known

stereo-electronic effects in particular in (rigid) cyclic molecules.[11,12] The

application of stereo-electronic effects, in particular in glycosidic bond

formation via the “armed and disarmed” concept,[13,14] belongs to the

forefront of carbohydrate chemistry.

Long range effects involving tosylates have been described by

Bastiaansen et al..[15] It was shown that the rate of desilylation of norbornyl

silyl ethers with TBAF was dependent on the configuration and electronic

nature of the substituent located opposite on the ring (OMe vs. OTs,

Figure 5). Given that the C6 protected methyl-α-D-glucopyranoside 23,

has the same W-type conformation as in the fastest reacting norbornyl

substrate, an influence of the substituent at C6 on the oxidation of the

C3OH is expected. Unfortunately, although the norbornyl system with a

primary tosylate and secondary silyl ether (and therefore more similar to

23) was used in the same study, comparison with the corresponding

primary methyl ether is lacking.

Chapter 3

66

Figure 5 Long range effects on the desilylation of silyl ethers in norbornyl systems

In an attempt to get more insight into the electronic effects of the used

substituents on the carbohydrate ring, the 1H and 13C-NMR shifts of all

the positions in 12 substrates were identified by 1H-, 13C-, COSY-, and

HMQC-NMR spectroscopy. The complete list is given in the experimental

section.

13C-chemical shifts as indicator for reactivity

First we focused on the chemical shifts of the carbon atoms since these

form the skeleton of the molecule and are less influenced by solvent

effects, concentration etc.. Table 3 and Figure 6 show the 13C-chemical

NMR shifts of 4 selected substrates that vary in the substituent on C6 from

electron donating (TBDPS) to electron withdrawing (Ts).


67

Table 3 Overview of the 13C-NMR chemical shifts (in ppm) of selected substrates in

MeOD-d3

R =

TBDPS

R =

H

R =

Bz

R =

Ts

C2 73.8 73.6 73.6 72.4

C3 75.5 75.2 75.2 75.1

C4 71.9 71.9 72.1 71.5

C5 74.0 73.6 71.1 71.1

C6 64.9 62.8 65.5 71.2 EDG: electron donating group, EWG: electron withdrawing group, TBDPS: tert-butyl-diphenylsilyl,

Bz: benzoyl, Ts: tosyl

The chemical shifts for C2, C3, and C4 are very similar throughout the

series of compounds and do not show any correlation with the electronic

nature of the substituent on C6. The C5 carbon has an increased chemical

shift (higher ppm-value) in case of the more electron donating

substituents (TBDPS and H). The C6-position shows a high ppm-value for

the tosyl-derivative and, except for the methyl glucopyranoside (R = H),

a correlation with the electronic nature of the substituent.

EDG EWG

Chapter 3

68

Figure 6 13C-NMR chemical shifts of selected substrates in MeOD-d3

1H-Chemical shifts as indicator for chemical reactivity

In analogy with the 13C-values, the 1H-NMR chemical shifts are

summarized in Table 4 and Figure 7.

Table 4 Overview of the 1H-NMR chemical shifts (in ppm) of selected substrates in

MeOD-d3

R =

TBDPS

R =

H

R =

Bz

R =

Ts

C2 3.40 3.39 3.45 3.32

C3 3.62 3.62 3.66 3.57

C4 3.36 3.29 3.41 3.21

C5 3.62 3.35 3.67 3.51

C6 3.86

3.94

3.67

3.80

4.44

4.64

4.18

4.33 EDG: electron donating group, EWG: electron withdrawing group, TBDPS: tert-butyl-diphenylsilyl,

Bz: benzoyl, Ts: tosyl

62

64

66

68

70

72

74

76

C2 C3 C4 C5 C6

13C

-ch

em

ical

sh

ift

(pp

m)

Position

TBDPSMGlc

MGlc

BzMGlc

TsMGlc

EDG EWG


69

Again, the chemical shifts of C2, C3, and C4 are similar throughout the

series of compounds and no correlation between the chemical shift and

the electronic properties of the substituent on C6 was observed. For C5

and C6 the methyl glucopyranoside (R = H) has the lowest ppm values of

the series and benzoyl in all cases has a higher ppm value than tosyl. The

latter is caused by a different shielding by the benzoyl compared to the

tosyl substituent as in methyl 4-methylbenzenesulfonate (Me-Ts chemical

shift: 1H: 3.74 ppm, 13C: 56.1 ppm)[16] and methyl 4-methylbenzoate (Me-

OOCTol chemical shift: 1H: 3.83 ppm, 13C: 52.6 ppm).[17]

Figure 7 1H-NMR chemical shifts of selected substrates in MeOD-d3

General observations

The 1H- and 13C-chemical shifts of the above mentioned series of

compounds for the C3 position are similar throughout the series. I

conclude therefore, that there is no correlation between the electronic

properties of the substituent on C6 and the chemical shift of C3 and C3H.

This indicates that there is no long-range effect. Another observation

3,0

3,2

3,4

3,6

3,8

4,0

4,2

4,4

4,6

C2 C3 C4 C5 C6-1 C6-2

1H

-ch

em

ical

sh

ift

(pp

m)

Position

TBDPSMGlc

MGlc

BzMGlc

TsMGlc

Chapter 3

70

throughout the series is that C3 and C3H have the highest ppm values

among the secondary alcohols, and this holds for nearly the complete

series (see Table 5 - Table 7, experimental section). The reason for this is

unclear, but it points at a higher deshielding, that is, a lower electron

density at C3/C3H. This would contradict the mechanism proposed by

Waymouth, in which the rate-determining step is β-hydride elimination

(that should be more difficult from an electron poor carbon).

General concerns

Based on the observations above it cannot be concluded from the chemical

shifts in NMR spectroscopy whether there is an electronic effect of the

substituents on C6 position on the C3 position. The chemical shift is of

course not only dependent on the electron density of the proton or carbon,

but also on other effects such as anisotropy or conformation of the ring,

which also determine the overall chemical shift. Therefore it is difficult to

correlate the chemical shift and the electronic properties on the various

positions.

CONCLUSION In conclusion, the substrate scope of the selective oxidation of glycosides

was successfully expanded to partially protected glycosides. All

substrates were regioselectively oxidized at C3 as before, indicating that

both the 2,3-diol and the 3,4-diol-motif lead to selective oxidation at C3.

In contrast to earlier examples, some of the new substrates showed a

lower reaction rate. Especially 11, with its rigid conformation, and the C6

tosyl-derivatives 12 and 13 required longer reaction times. An NMR study

of the correlation between the electronic nature of the substituent on C6

and the chemical shift of C3 and C3H did not confirm a long-range effect.

Remarkably, the C3 position has the highest chemical shift of the


71

secondary alcohols (in 1H- and 13C-NMR), which could indicate that C3 is

the most electron deficient position.

Based on the study presented here, additional substrates can be designed

in order to get further insight into the origin of the selectivity in the

oxidation and their influence on the reaction rate. Some of them are

depicted in Figure 8. To increase the substrate scope on the C4-position,

compounds 18-20 could be studied; 18 ensures that no coordination with

a C4 substituent is possible, 19 is a mimic of a disaccharide (e.g.,

cellobiose), which has shown to be selectively oxidized on the terminal

ring, and 20 carries an electron withdrawing benzoyl substituent on C4.

Substrates 21 and 22 increase the substrate scope further with regard to

the C6-position and it is interesting whether 21 and 22 still are oxidized at

C3 and what the influence on the reaction rate is. The azido glycoside 23

is easily accessible from glucosamine and, as an azide is an electron

withdrawing substituent, could give insight in the inductive effects of the

C2-position.

Figure 8 Proposed substrates for an increased insight into the regioselectivity of the

oxidation

To further elucidate the origin of the selectivity, detailed mechanistic

studies are necessary. Up to now it is not clear what could be the rate

limiting step of the oxidation. Although the β-hydride elimination seems

likely, analogous to the mechanistic studies of the selective diol

oxidation,[2] the kinetic product formation via coordination of the

substrate could be a reasonable explanation for the selectivity.[3]

Chapter 3

72

EXPERIMENTAL SECTION

General Information

All solvents used for extraction, filtration and chromatography were of

commercial grade, and used without further purification. Reagents were

purchased from Sigma-Aldrich, Acros and ABCR and were used without further

purification unless otherwise noted. For purification via column

chromatography silica gel from either Silicycle (Sila Flash 40-63 µm, 230-400

mesh) or from Sigma Aldrich (Silica Amorphous, precipitated, Davisil grade 62,

pore size 150 Å, 60-200 mesh, noted as low surface silica) was used.

[(Neocuproine)PdOAc]2OTf2 was prepared according to the literature

procedure.[18]

Analysis by TLC was performed on Merck silica gel 60, 0.25 mm plates and

visualization was done by UV and staining with potassium permanganate stain

(a mixture of KMnO4 (3 g), K2CO3 (10 g), water (300 mL)) or vanillin stain (a

mixture of vanillin (6 g), sulfuric acid (1.5 mL) and ethanol (95 mL).

1H-, 13C-, APT-, COSY-, HSQC-, NOESY spectra were recorded on a Varian

AMX400 (400, 100.59 MHz, respectively) using DMSO-d6, MeOD-d4, CDCl3 or

D2O as solvent. Chemical shift values are reported in ppm with the solvent

resonance as the internal standard (DMSO-d6: 2.50 for 1H, δ 39.51 for 13C; MeOD-

d4: δ3.31 for 1H, δ 49.15 for 13C; CDCl3: δ 7.26 for 1H, δ 77.16 for 13C D2O: δ 4.80 for

1H). Data are reported as follows: chemical shifts (δ), multiplicity (s = singlet, d =

doublet, t = triplet, q =quartet, br = broad, m = multiplet), coupling constants J

(Hz), integration and to which ring carbon (C1 – C6) the signal corresponds. High

Resolution Mass Spectrometry measurements were performed using a

ThermoScientific LTQ OrbitrapXL spectrometer.


73

Substrate synthesis

4,6-Benzylidene-methyl-α-D-glucopyranoside (11)

Methyl-α-D-glucopyranoside (20.0 g, 103 mmol, 1.0 eq),

dimethoxymethylbenzene (15.7 mL, 15.7 g, 103 mmol, 1.0 eq)

and p-toluenesulfonic acid (52 mg, 0.52 mmol, 0.05 eq) were

dissolved in dry DMF (40 mL). The reaction flask was connected to a rotary

evaporator in a 60 °C water bath at 300 mbar. The temperature of the water bath

was increased to approximately 100 °C after 3 h and the mixture was

concentrated in vacuo. After disconnection, saturated aq. NaHCO3 (100 mL) was

added and the flask was heated to reflux by a sand bath to give a homogenous

mixture. The mixture was allowed to cool to rt and the solids were filtered,

washed with water and dried in vacuo to obtain 4,6-benzylidene-methyl-α-D-

glucopyranoside 11 (27.4 g, 97.0 mmol, 94% yield) as a white fluffy solid. A small

amount of residual NaHCO3, which potential inhibits the catalyst for the

oxidation, could be removed by dissolution in DCM and filtration of the

precipitating NaHCO3. 1H-NMR (400 MHz, CD3OD): δ = 7.54 – 7.46 (m, 2H, Ar),

7.35 (dd, J=9.1, 5.4, 3H, Ar), 5.56 (s, 1H, ArCH), 4.72 (d, J=3.7, 1H, C1), 4.22 (d,

J=5.0, 1H, C6), 3.82 (t, J=9.3, 1H, C3), 3.78 – 3.68 (m, 2H, C5+C6), 3.52 (dd, J=9.3,

3.8, 1H, C2), 3.46 (t, J=9.0, 1H, C4), 3.43 (s, 3H, OCH3). 13C-NMR (100 MHz,

CD3OD): δ = 139.3, 130.0, 129.2, 127.7, 103.1 (ArCH), 102.2 (C1), 83.0 (C4), 74.2

(C2), 72.1 (C3), 70.1 (C6), 64.0 (C5), 55.9 (OCH3). HRMS (APCI) m/z calcd for

C14H19O6+ ([M + H+]): 283.118, found: 283.118. Characterization matches

literature.[19]

4-Benzyl-methyl-α-D-glucopyranoside (7)

1 M BH3∙THF (130 mL, 130 mmol, 7.3 eq) was added to a Schlenk

flask containing dry 4,6-benzylidene-methyl-α-D-

glucopyranoside 11 (5.0 g, 17.7 mmol, 1.0 eq) at 0 °C and the

mixture was stirred for 5 min. 1 M Bu2BOTf in DCM (18.5 mL, 18.5 mmol, 1.05 eq)

was added drop wise within 30 min. Additional 1 M Bu2BOTf in DCM (2.0 mL,

2.0 mmol, 0.11 eq) was added drop wise after 1 h and after 2.5 h. The reaction

was quenched after 4 h by addition of triethylamine (9 mL) followed by careful

addition of methanol until (hydrogen) gas formation ceased. The reaction

mixture was co-evaporated with methanol (3x) to give crude 4-benzyl-methyl-α-

Chapter 3

74

D-glucopyranoside (17 g). The crude was subjected to column chromatography

(EtOAc) which did not result in pure product. Recrystallization in MeCN (20 mL,

reduced to 7.5 mL) resulted in 4-benzyl-methyl-α-D-glucopyranoside 7 (4.1 g,

14.4 mmol, 82% yield) as a colorless to white solid which was sufficiently pure to

use in subsequent synthesis.

Part of the obtained 4-benzyl-methyl-α-D-glucopyranoside 7 (3.5 g) was

dissolved in 1 M HCl (20 mL) and stirred for 2 h. The solution was subsequently

extracted with EtOAc (3 x 15 mL), dried with anhydrous magnesium sulfate,

filtered and concentrated in vacuo to increase the purity, but according to NMR

some triethylamine salts still remained. Subsequent treatment with 1 M NaOH

(20 mL), concentration in vacuo to 5 mL and addition of EtOAc (15 mL) gave a

solid that was isolated by filtration to obtain 4-benzyl-methyl-α-D-

glucopyranoside 7 (2.4 g) sufficiently pure for use in the oxidation experiments.

1H-NMR (400 MHz, CD3OD): δ = 7.40 – 7.22 (m, 5H), 4.95 (d, J=11.0, 1H, ArCH2),

4.67 (d, J=3.6, 1H, C1), 4.64 (d, J=11.1, 1H, ArCH2), 3.80 (t, J=8.0, 1H, C3), 3.77 (d,

J=10.1, 1H, C6), 3.66 (dd, J=11.8, 4.8, 1H, C6), 3.57 (dd, J=10.0, 3.5, 1H, C5), 3.42

(dd, J=9.8, 3.7, 1H, C2), 3.39 (s, 3H, OCH3), 3.37 (t, J=9.4, 1H, C4). 13C-NMR (100

MHz, CD3OD): δ = 140.2, 129.4, 129.2, 128.8, 101.3 (C1), 79.6 (C4), 75.9 (ArCH2),

75.7 (C3), 73.9 (C2), 72.8 (C5), 62.4 (C6), 55.7(OCH3). HRMS (APCI) m/z calcd for

C13H20O5+ ([M - -OCH3]): 253.108, found: 253.107. Characterization matches

literature.[20] Impurity (Et3NOTf) 1H-NMR (400 MHz, CD3OD): δ = 3.20 (q, J=7.3,

2H), 1.31 (t, J=7.3, 3H). 13C-NMR (100 MHz, CD3OD): δ = 48.1, 9.4.

6-Tosyl-methyl-α-D-glucopyranoside (13)

Methyl-α-D-glucopyranoside (5.0 g, 25.7 mmol, 1.0 eq) was

dissolved in pyridine (30 mL) and cooled to 0 °C.

p-Toluenesulfonyl chloride (5.9 g, 30.9 mmol, 1.2 eq) was added

portionwise over 30 min. The reaction was stirred at 0 °C for 3.5 h

and subsequently diluted with EtOAc (80 mL). The organic layer was washed

with 1 M HCl (30 mL), saturated aq. NaHCO3 (3 x 30 mL) and brine (20 mL). The

organic layer was dried with anhydrous magnesium sulfate, filtered and

concentrated in vacuo to afford the crude tosylate 13 (5.5 g). Column

chromatography (120 g low surface silica, EtOAc) resulted in pure 6-tosyl-

methyl-α-D-glucopyranoside (2.15 g, 5.78 mmol, 23% yield) as a white solid. 1H-


75

NMR (400 MHz, CD3OD): δ = 7.83 (d, J=8.3, 2H), 7.47 (d, J=8.0, 2H), 4.60 (d, J=3.7,

1H, C1), 4.35 (dd, J=10.7, 1.9, 1H, C6), 4.20 (dd, J=10.8, 6.0, 1H, C6), 3.69 (ddd,

J=10.0, 5.9, 1.8, 1H, C5), 3.59 (t, J=9.3, 1H, C3), 3.36 (s, 3H, OCH3), 3.33 (d, J=3.9,

1H, C2), 3.21 (dd, J=19.1, 9.2, 1H, C4), 2.49 (s, 3H). 13C-NMR (100 MHz, CD3OD):

δ = 146.6, 134.6, 131.1, 129.2, 101.4 (C1), 75.1 (C3), 73.4 (C2), 71.5 (C4), 71.2 (C6),

71.1 (C5), 55.8 (OCH3), 21.7. HRMS (ESI) m/z calcd for C14H20NaO8S+ ([M + Na+]):

371.077, found: 371.077. Characterization matches literature.[21]

6-Deoxy-methyl-α-D-glucopyranoside (8)

6-Tosyl-methyl-α-D-glucopyranoside (590 mg, 1.69 mmol, 1 eq)

was co-evaporated with toluene (3 x) and dry THF (10 mL) was

added. The solution was cooled to 0 °C, placed under N2 atm. and

lithium aluminium hydride (384 mg, 10.2 mmol, 6 eq) in THF (10 mL) was added

drop wise. The temperature was subsequently increased to 45 °C. Additional

lithium aluminium hydride (384 mg, 10.2 mmol, 6 eq) in THF (10 mL) was added

after 4 days. Gas formation was observed during the addition. After 7 days, the

reaction mixture was cooled to 0 °C, and quenching was conducted by careful

addition of water (0.19 mL), 15% NaOH solution (0.19 mL) and additional water

(0.57 mL). The mixture was stirred for 30 min, filtered over celite which was

rinsed 3-times with methanol (10 mL) and the solvents were removed to obtain

crude 8 (425 mg). The crude product was co-evaporated with toluene (3 x),

dissolved in pyridine (4 mL) and acetic anhydride (732 mg, 7.17 mmol, 4 eq) was

added. The reaction was stirred at rt for 4 days. Co-evaporation with toluene (3 x)

gave crude peracetylated 8 (437 mg) which was purified by column

chromatography (20 g low surface silica, 5% to 50% EtOAC in pentane, followed

by pure DCM) to give pure peracetylated 8 (152 mg). Peracetylated 8 was co-

evaporated with toluene (3 x) and dissolved in dry MeOH (5 mL). A small

amount of sodium was added and the mixture was stirred for 19 h. The reaction

was quenched by the addition of Amberlite resin (H+ form) and filtered over

celite to obtain after evaporation 6-deoxy-methyl-α-D-glucopyranoside 8 (96 mg,

0.54 mmol, 32% yield) as a brownish oil. 1H-NMR (400 MHz, CD3OD): δ = 4.59

(d, J=3.8, 1H, C1), 3.59 (dq, J=9.7, 6.3, 1H, C5), 3.55 (t, J=9.3, 1H, C3), 3.40 (dd, J=9.5,

3.8, 1H, C2), 3.38 (s, 3H, OCH3), 2.97 (t, J=9.2, 1H, C4), 1.23 (d, J=6.3, 3H, C6). 13C-

NMR (100 MHz, CD3OD): δ = 101.4 (C1), 77.5 (C4), 75.0 (C3), 73.9 (C2), 68.8 (C5),

Chapter 3

76

55.6 (OCH3), 18.2 (C6). HRMS (ESI) m/z calcd for C7H13O5- ([M - H+]): 177.077,

found: 177.077. Characterization matches literature.[22]

4-Benzyl-6-tosyl-methyl-α-D-glucopyranoside (12)

4-Benzyl-methyl-α-D-glucopyranoside (552 mg, 1.48 mmol,

1.0 eq, containing 131 mg of Et3NHOTf as an impurity) was

dissolved in pyridine (10 mL) and cooled to 0 °C. p-

Toluenesulfonyl chloride (403 mg, 2.11 mmol, 1.4 eq) was added

batch wise over 30 min. After 4.5 h, EtOAc (25 mL) was added. The mixture was

washed with 1 M HCl (15 mL), saturated NaHCO3 (3 x 15 mL) and brine

(10 mL),dried with anhydrous magnesium sulfate, filtered and concentrated in

vacuo to afford crude 12 (572 mg as a mixture of 12 and a di-tosyl, 3 : 1). Column

chromatography (23 g silica, 50% EtOAc in pentane) afforded pure 4-benzyl-6-

tosyl-methyl-α-D-glucopyranoside 12 (315 mg, 1.11 mmol, 75% yield) as white

crystals. 1H-NMR (400 MHz, CD3OD): δ = 7.75 (d, J=8.2, 2H), 7.38 (d, J=8.2, 2H),

7.28 (t, J=5.8, 3H), 7.24 – 7.17 (m, 2H), 4.90 (d, J=10.9, 1H, ArCH2), 4.60 (d, J=3.6,

1H, C1)), 4.41 (d, J=11.0, 1H, ArCH2), 4.18 (dd, J=10.6, 1.6, 1H, C6), 4.11 (dd, J=10.6,

4.7, 1H, C6), 3.74 (t, J=9.2, 1H, C3), 3.68 (dd, J=10.1, 2.7, 1H, C5), 3.36 (dd, J=9.7,

3.7, 1H, C2), 3.33 (s, 3H, OCH3), 3.26 (t, J=9.4, 1H, C4), 2.41 (s, 3H). 13C-NMR (100

MHz, CD3OD): δ = 146.7, 139.8, 134.3, 131.2, 129.4, 129.3, 129.2, 128.9, 101.3 (C1),

78.9 (C4), 75.8 (ArCH2), 75.6 (C3), 73.6 (C2), 70.8 (C6), 70.0 (C5), 55.9 (OCH3), 21.8.

HRMS (ESI) m/z calcd for C21H26NaO8S+ ([M + Na+]): 461.124, found: 461. 124.

[α]D20 +109 (c 0.99, MeOH).

4-Benzyl-6-deoxy-methyl-α-D-glucopyranoside (9)

4-Benzyl-6-tosyl-methyl-α-D-glucopyranoside (12) (250 mg,

0.57 mmol, 1.0 eq) was co-evaporated with toluene (3 x),

dissolved in dry THF (8 mL), cooled to 0 °C and placed under

N2 atm. A 1 M lithium aluminium hydride (65 mg, 1.71 mmol, 3.0 eq) solution in

dry THF (1.7 mL) was added drop wise, and the temperature was increased to 45

°C and the mixture was stirred for 18 h. The mixture was subsequently cooled to

0 °C and quenched by the addition of water (0.06 mL), 15% NaOH solution

(0.06 mL) and additional water (0.13 mL). The mixture was stirred for 1 h and

filtered over celite, which was rinsed 3 times with EtOAc (10 mL) and


77

concentrated in vacuo to obtain pure 9 (102 mg). The celite filter was triturated

with EtOAc, the organic phase filtered and concentrated in vacuo to afford an

additional 38 mg of pure 4-benzyl-6-deoxy-methyl-α-D-glucopyranoside (to give

in total 140 mg, 0.52 mmol, 92% yield) as a white solid. 1H-NMR (400 MHz,

CD3OD): δ = 7.45 – 7.16 (m, 5H), 4.94 (d, J=11.1, 1H, ArCH2), 4.65 (d, J=11.1, 1H,

ArCH2), 4.59 (d, J=3.7, 1H, C1), 3.75 (t, J=9.3, 1H, C3), 3.65 (dq, J=9.6, 6.3, 1H, C5),

3.42 (dd, J=9.7, 3.8, 1H, C2), 3.37 (s, 3H, OCH3), 3.00 (t, J=9.2, 1H, C4), 1.20 (d, J=6.3,

3H, C6). 13C-NMR (100 MHz, CD3OD): δ = 140.2, 129.4, 129.3, 128.8, 101.3 (C1),

85.5 (C4), 76.1 (ArCH2), 75.5 (C3), 74.2 (C2), 67.8 (C5), 55.6 (OCH3), 18.5 (C6).

HRMS (ESI) m/z calcd for C14H20NaO5+ ([M + Na+]): 291.120, found: 291.120.

Characterization matches literature.[23]

Substrate Oxidation

Oxidation of glycosides (general method)

The glycoside (0.40 mmol, 1 eq) and benzoquinone (129 mg, 1.19 mmol, 3.0 eq)

were dissolved in DMSO (1.33 mL, 0.3 M in substrate) and

[neocuproinePd(OAc)]2(OTf)2 (10.7 mg, 0.010 mmol, 0.025 eq) was added. The

conversion was followed by 1H-NMR at regular intervals to determine the

reaction rate and selectivity.

3-Keto-4-benzyl-6-tosyl-methyl-α-D-glucopyranoside (17)

4-Benzyl-6-tosyl-methyl-α-D-glucopyranoside (12) (176 mg,

0.40 mmol, 1 eq) and benzoquinone (129 mg, 1.19 mmol, 3.0 eq)

were dissolved in DMSO (1.33 mL, 0.3 M in substrate) and

[neocuproinePdOAc]2(OTf)2 (10.7 mg, 10 µmol, 2.5 mol%) was added. The

reaction was stirred for 6.5 h and water (2 mL) was added to quench the reaction.

More water (10 mL) was added and the aqueous layer was extracted with EtOAc

(3x 10 mL), the combined organic layers were washed with brine, dried with

anhydrous magnesium sulfate, filtered and concentrated in vacuo to obtain crude

ketone 17 (163 mg). Purification by column chromatography (low surface silica,

30% EtOAc in pentane) afforded pure ketone 17 (55 mg, 0.13 mmol, 33% yield) as

a white solid. 1H NMR (400 MHz, CD3OD): δ = 7.82 – 7.72 (m, 2H), 7.45 – 7.35 (m,

2H), 7.35 – 7.21 (m, 5H), 4.95 (d, J=4.2, 1H, C1), 4.80 (d, J=10.9, 1H, ArCH), 4.35 –

4.32 (m, 1H, C2), 4.32 (d, J=11.0, 1H, ArCH), 4.27 – 4.23 (m, 2H, C6), 4.14 (dd, J=9.9,

Chapter 3

78

1.3, 1H, C4), 3.91 – 3.83 (m, 1H, C5), 3.33 (s, 3H, OCH3), 2.40 (s, 3H, TsCH3). 13C

NMR (100 MHz, CD3OD): δ = 205.0 (C3), 146.84, 138.86, 134.2, 131.3, 129.5, 129.4,

129.3, 129.1, 103.7 (C1), 79.3 (C4), 76.4 (C2), 74.4 (ArCH2), 72.3 (C5), 70.3 (C6), 56.2

(OCH3), 21.8 (TsCH3). [α]D20 +128 (c 0.98, MeOH).

Table 5 NMR-shifts of substrate 7, 10, 24 and 25

1H-

NMR

shift

13C-

NMR

shift

1H-

NMR

shift

13C-

NMR

shift

1H-

NMR

shift

13C-

NMR

shift

1H-

NMR

shift

13C-

NMR

shift

C1 4.68 101.3 4.67 101.3 4.69 101.6 4.71 101.6

C2 3.39 73.6 3.42 73.9 3.60 69.6 3.77 72.4

C3 3.62 75.2 3.80 75.7 3.98 73.6 3.74 70.4

or

71.6

C4 3.29 71.9 3.36 79.6 3.47 68.4 3.88 71.2

C5 3.35 73.6 3.57 72.8 3.70 69.1 3.70-

3.77

70.4 or

71.6

C6 3.67

3.80

62.8 3.77

3.66

62.4 3.70

3.84

62.9 3.66-

3.74

62.9

OMe 3.41 55.7 3.39 55.7 3.43 56.2 3.40 55.8


79

Table 6 NMR-shifts of substrate 8, 9, 12 and 13

1H-

NMR

shift

13C-

NMR

shift

1H-

NMR

shift

13C-

NMR

shift

1H-

NMR

shift

13C-

NMR

shift

1H-

NMR

shift

13C-

NMR

shift

C1 4.59 101.4 4.59 101.3 4.58 101.3 4.60 99.8

C2 3.40 73.9 3.42 74.2 3.32 72.4 3.36 72.0

C3 3.55 75.0 3.75 75.5 3.57 75.1 3.74 74.1

C4 2.97 77.5 3.00 85.5 3.21 71.5 3.26 77.3

C5 3.58 68.8 3.64 67.8 3.67 71.1 3.68 68.4

C6 1.23 18.2 1.20 18.5 4.18 4.33

71.2 4.11 4.18

69.2

OMe 3.38 55.6 3.37 55.6 3.33 55.8 3.33 54.3

Chapter 3

80

Table 7 NMR-shifts of substrate 11, 20, 21, and 26

1H-

NMR

shift

13C-

NMR

shift

1H-

NMR

shift

13C-

NMR

shift

1H-

NMR

shift

13C-

NMR

shift

1H-

NMR

shift

13C-

NMR

shift

C1 4.69 101.4 4.70 101.3 4.65 101.4 4.72 102.2

C2 3.45 73.6 3.40 73.8 3.37 73.7 3.52 74.2

C3 3.66 75.2 3.62 74.0 or 75.5

3.78 75.4 3.82 72.1

C4 3.41 72.1 3.36 71.9 3.29 71.8 3.44 83.0

C5 3.85 71.3 3.62 74.0 or 75.5

3.51 74.0 3.74 64.0

C6 4.44 4.64

65.5 3.86 3.94

64.9 3.78 3.91

64.2 3.74 4.22

70.1

OMe 3.41 55.7 3.42 55.6 3.39 55.6 3.43 55.9

ACKNOWLEDGEMENTS Jonas Albada is acknowledged for his contribution for this chapter as part

of his master study.


81

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Chapter 3

82

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