C3 Epimerization of Glucose, via Regioselective Oxidation and Reduction

Article abstract of DOI:10.1021/acs.joc.6b02074

Palladium-catalyzed oxidation can single out the secondary hydroxyl group at C3 in glucose, circumventing the more readily accessible hydroxyl at C6 and the more reactive anomeric hydroxyl. Oxidation followed by reduction results in either allose or allitol, each a rare sugar that is important in biotechnology. Also, N-acetylglucosamine is selectively oxidized at C3. These results demonstrate that glucose and N-acetylglucosamine, the most readily available chiral building blocks, can be versatile substrates in homogeneous catalysis.

Full text of DOI:10.1021/acs.joc.6b02074

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Note
C-3 Epimerization of glucose, via regioselective oxidation and reduction
Varsha R. Jumde, Niek N. H. M. Eisink, Martin D. Witte, and Adriaan J. Minnaard
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02074 • Publication Date (Web): 18 Oct 2016
Downloaded from http://pubs.acs.org on October 19, 2016
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Cꢀ3 Epimerization of glucose, via regioselective oxidation and reduction
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Varsha R. Jumde‡, Niek N. H. M. Eisink‡, Martin D. Witte*, Adriaan J. Minnaard*
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Stratingh Institute for Chemistry, University of Groningen Nijenborgh 7, 9747 AG, Groningen, The Netherlands
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Palladium catalysed oxidation is able to single out the secondary hydroxyl group at C3 in glucose, circumventing the more readily accessiꢀ
ble hydroxyl at C6 and the more reactive anomeric hydroxyl. Oxidation followed by reduction results in either allose or allitol, rare sugars
that are important in biotechnology. Also Nꢀacetyl glucosamine is selectively oxidized at C3. These results demonstrate that glucose and
Nꢀacetyl glucosamine, the most readily available chiral building blocks, can be versatile substrates in homogeneous catalysis.
Glucose, an aldohexose, is arguably the most important monosaccharide because it is used in respiration to provide energy for cells. Of the
sixteen stereoisomeric aldohexoses, only
Dꢀglucose, Dꢀmannose, and Dꢀgalactose (Figure 1), are readily available. The others, and in parꢀ
ticular most
L
ꢀsugars, are rare or do not occur as such in nature.1 As a consequence, the properties of most of these rare aldohexoses have
not been studied extensively, although these could be of importance in chemical biology and pharmacy, as mimics of the commonly occurꢀ
ring aldohexoses.
Some rare sugars have been obtained by selectively epimerizing asymmetric centers in other monosaccharides. This field, in which readily
available hexoses are interconverted into the desired rare hexose, is largely the realm of enzyme catalysis, applying a highly versatile but
limited set of transformations.2 Important biotechnological processes are for instance the conversion of glucose into fructose, and the conꢀ
version of fructose into psicose (Figure 1).3 The possible enzymatic interconversions of the hexoses have been beautifully represented in
the soꢀcalled Izumoring (see SI), a scheme that relates all aldohexoses, 2ꢀketohexoses and hexitols.4 From this scenario it becomes apparꢀ
ent that many of these hexoses are not readily accessible using the currently known enzymatic transformations.
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Figure 1. Mutarotation in glucose, and the most readily available monosaccharides
Chemical interconversion of hexoses provides a viable alternative to these enzymatic transformations. On lab scale, this has been worked
out for several hexoses using (multiꢀstep) synthetic procedures involving protectionꢀdeprotection strategies.5 Depending on the target
sugar, this approach can be elegant and efficient, as shown by recent work of Fleet, Jenkinson and Kanai.6–8 Surprisingly, however, homoꢀ
geneous catalysis has refrained from this field entirely. This is rather surprising as several of the reactions used by enzymes to interconvert
hexoses, in particular oxidation and reduction, are studied intensively in transition metal catalysis and organocatalysis.9–12
Focusing on oxidation, the main challenge clearly is to single out a particular hydroxyl group, as the number of hydroxyl groups in carboꢀ
hydrates closely equals the number of CꢀH bonds. The selective oxidation of the primary hydroxyl function in pyranoses and furanoses can
often be achieved with reasonable selectivity exploiting the limited steric hindrance compared to the secondary hydroxyl groups.13–15 The
anomeric hydroxyl group on the other hand is readily oxidized selectively in the presence of both primary and secondary hydroxyl groups
due to its lower pKa value, like in the classic oxidation with bromine.16 This leaves in the case of glucopyranosides, the very similar secꢀ
ondary hydroxyl groups.
The group of Waymouth has shown that certain palladium catalysts can effectively discriminate between primary and secondary hydroxyl
groups, preferentially oxidizing the secondary hydroxyl group.17,18 Based on this, we demonstrated the highly regioselective oxidation of
glucopyranosides, thereby expanding the selectivity to the differentiation among secondary hydroxyl groups.19 Oxidation takes place at the
C3ꢀposition to provide the corresponding 3ꢀketo sugars. The method was shown to be effective as well for the disaccharides maltose and
cellobiose, and recently even for oligomaltoses up to the 7ꢀmer.20 Waymouth and coworkers recently revealed that 6ꢀdeoxyglycosides, like
Lꢀrhamnopyranosides and Lꢀfucopyranosides, and pentoses like Dꢀxylopyranosides and Dꢀarabinopyranosides are selectively oxidized by
these catalysts as well.21 Invariably, glycosides have been used as substrates with the anomeric center as part of an acetal to avoid oxidaꢀ
tion of the anomeric alcohol and to lock the equilibrium in one anomeric form. Glucose itself, being a soꢀcalled reducing sugar, consists of
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a mixture of the α and βꢀanomer in aqueous solution, together with small amounts of furanoses and the inferred open form. In attempts to
selectively oxidize glucose at a secondary hydroxyl position, one therefore has to cope not only with the reactive anomeric hydroxyl group
(C1ꢀOH) and the more accessible primary hydroxyl group (C6ꢀOH), but also with a potentially complex equilibrium. However, we realꢀ
ized that the palladiumꢀcatalyzed selective oxidation of glucose would be worthwhile to pursue as it would silence the common opinion
that unprotected, reducing sugars are unsuitable substrates for homogeneous catalysis.
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Recent studies in our group have revealed that the palladium catalyst chelates preferentially with vicinal bisꢀequatorial hydroxyl groups,
preceding oxidation. This was concluded based on the observation that methyl glucoside oxidizes faster than methyl mannoside (C2ꢀOH
axial) and considerably faster than methyl galactoside (C4ꢀOH axial).22 Glucose preferentially crystallizes as the αꢀanomer (C1ꢀOH axial),
and we reasoned that this readily available isomer would not have an inherent preference for oxidation at the anomeric position because it
lacks a vicinal bisꢀequatorial diol at C1ꢀC2. Equilibration (mutarotation) of αꢀglucose results in the formation of βꢀglucose, which does
possess a vicinal bisꢀequatorial diol at the anomeric center and hence is likely to be oxidized to the corresponding gluconolactone (vide
infra). To successfully oxidize glucose, it is therefore essential to suppress mutarotation during the oxidation reaction. This process is rapid
in protic solvents, including water, and catalyzed by both acid and base.23,24 To our delight, αꢀglucose turned out to be stable in DMSO, not
showing notable mutarotation at room temperature over several hours.25,26 Apparently the hydroxyl groups of the glucose itself are not
sufficient to catalyze mutarotation to an appreciable extent, even up to a glucose concentration of 1.5 M.
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In the event, it turned out that αꢀglucose 2 is rapidly and with excellent selectivity oxidized at C3 with Waymouth’s catalyst 1 and benzoꢀ
quinone as coꢀoxidant in DMSO. By NMR, no gluconolactone (the product resulting from oxidation at the anomeric center) could be
detected. The reaction is exceptionally fast, reaching full conversion within 1 h with catalyst loadings as low as 0.5 mol% (Scheme 1).
Scheme 1. Regioselective oxidation of αꢀglucose and Nꢀacetyl αꢀglucosamine.
Reaction conditions: [(neocuproine)PdOAc]2OTf2 (1) (0.5 mol %), benzoquinone (1.25 eq), 1.5 M in DMSO, r.t., 1 h
Even a catalyst loading of 0.05 mol% resulted in 95% conversion after 1 h (see SI). It is remarkable that the involved chelation control of
the catalyst overrules both the better accessibility of the primary hydroxyl group and the enhanced reactivity of the anomeric hydroxyl
group. Only prolonged reaction times at elevated temperature induced further oxidation of the product at the anomeric center (vide infra).
To determine whether αꢀglucose is unique in this reaction, we applied Nꢀ acetylꢀαꢀDꢀglucosamine 3 in the same reaction and obtained the
same highly selective oxidation at the C3 position.
To confirm our hypothesis that oxidation of αꢀglucose is selective because of the axial hydroxyl group at the anomeric center, we also
studied the oxidation of βꢀglucose 6, which can be obtained by crystallization of glucose from pyridine.27 Since the anomeric hydroxyl
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group is now in equatorial position we predicted oxidation at this center. In the palladiumꢀcatalyzed oxidation reaction we indeed observed
a mixture of products, likely formed by either oxidation at C3 or at C1. In an attempt to drive the reaction to the doubly oxidized product,
the reaction was heated to 40 °C for a prolonged time (~12 h). Although one product was indeed formed, it turned out not to be the exꢀ
pected ketolactone! In addition, prolonged reaction times and elevated temperatures in the oxidation of both αꢀglucose and gluconolactone,
in the presence of excess benzoquinone, led selectively to the same compound (see SI). Initially, extensive NMRꢀstudies did not provide a
conclusive answer, until we realized that glucose is available in its allꢀ13C labeled form. Upon oxidation of glucoseꢀ13C6, the 1Hꢀ and 13Cꢀ
NMR spectra in combination with 2DꢀNMR techniques led unambiguously to compound 11. Apparently, ketolactone 7 is formed, but
rapidly tautomerizes
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Scheme 2. Oxidation of βꢀDꢀglucose leads to rearranged bislactone 11.
Reaction conditions: [(neocuproine)PdOAc]2OTf2 (1) (2.5 mol %), benzoquinone (3 eq), 0.3 M in DMSO, 40 °C, 18 h
to the corresponding enediol 8, which in turn is rapidly oxidized to the diketolactone 9. This intermediate subsequently undergoes intramoꢀ
lecular lactol formation followed by αꢀketol rearrangement leading to 11 (Scheme 2). None of the intermediate stages could be observed by
NMR. Although 11 as such has not been described in literature, products of this αꢀketol rearrangement in pyranoses have been reported
and the skeleton is present in the antibiotic ashimycin A. 28–31
In order to study the implications of this regioselective oxidation of αꢀDꢀglucose on the interconversion of hexoses, we aimed at the reducꢀ
tion of 3ꢀketoglucose with sodium borohydride to
D
ꢀallose. Noteworthy, the synthesis of this rare sugar currently takes several steps.2
Treatment of aqueous solutions of the parent carbohydrate glucose with sodium borohydride is used to produce glucitol (sorbitol), as the
minute amount of the open form, the aldehyde, is rapidly reduced.32 In the reduction of αꢀ
D
ꢀ3ꢀketo glucose to Dꢀallose, this reduction of the
open form has to be effectively suppressed as both the starting material 3ꢀketoglucose and the product allose are vulnerable to the reduction
of the open form. In addition, the axial hydroxyl group at the anomeric center is required to induce the desired stereoselectivity in the
reduction of the keto group by hampering the approach of the borohydride from the bottom face. Any mutarotation to the βꢀanomer would
eradicate this stereoselectivity. We were pleased to see that treatment of the crude 3ꢀketoglucose in DMSO with an aqueous solution of
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sodium borohydride at 0 °C cleanly effected the reduction. The resulting 3:2 mixture of allose and glucose could be effectively separated
by chelation chromatography on a calciumꢀloaded ionꢀexchange resin affording pure ꢀallose in 54% yield from glucose over just two
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steps.33–36 The ratio of allose to glucose was somewhat disappointing as we had shown that this reduction carried out on 3ꢀketo αꢀmethyl
glucoside produces αꢀmethyl alloside with high selectivity.19 Variation in the reducing agent (see scheme 3 and SI) showed that the bulky
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LSꢀselectride produces Dꢀallose in high selectivity, though at the expense of a more complicated work up and purification.
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Scheme 3. Selective reduction of 3ꢀketoglucose to allose and allitol.
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Reaction conditions: A: NaBH4 (0.75 eq), DMSO/H2O (1:1), 0 °C B: LSꢀSelectride (3 eq), DMSO/THF (2:1), 0 °C. C: NaBH4 (6 eq),
DMSO/H2O (1:1), r.t. 12 h
With these results established, a twoꢀstepsꢀoneꢀpot conversion of glucose to allitol, was envisioned. Allitol and galactitol (dulcitol), being
meso compounds, play a central role in Izumoring as the bridges between Dꢀ and Lꢀhexoses. Currently, allitol is produced by a combination
of enzymatic transformations (Figure 2). 37,38 The envisioned chemical method to interconvert glucose to allitol would not only be a drastic
shortcut in the Izumoring scheme, but would also demonstrate that homogeneous catalysis is complementary to the existing biotechnologiꢀ
cal methods and that can be used to fill blank spots in the Izumoring. Treatment of the crude 3ꢀketo glucose with aqueous sodium borohyꢀ
dride at room temperature led smoothly to a mixture of allitol and glucitol (3:2) (scheme 3) from which allitol was readily purified by
calcium chelation chromatography. This synthesis of allitol from glucose in a twoꢀstepsꢀoneꢀpot sequence is more efficient than the current
enzymatic route. Furthermore, with LSꢀselectride as the reducing agent, up to 90% selectivity to allitol would be obtained.
Apart from the conversion into platform chemicals, the field of transition metal catalysis has kept a distance to unprotected carbohydrates
as substrates for selective transformations. We show that in addition to biotechnology, also homogeneous catalysis can make an important
contribution to the selective conversion and interconversion of unprotected carbohydrates. This is demonstrated in the palladiumꢀcatalyzed
regioselective oxidation of glucose and Nꢀacetyl glucosamine. Chelationꢀcontrol overrules in this case both steric hindrance and the reacꢀ
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tivity of the anomeric hydroxyl group. Subsequent reduction under controlled conditions leads directly to either allose or allitol. This stratꢀ
egy provides not only ground for the straightforward synthesis of rare sugars but also for their potential applications in chemical biology.
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Figure 2. Chemical conversion of Dꢀglucose to Dꢀallose and allitol, complementary to the current enzymatic conversions.
EXPERIMENTAL SECTION
General Information
All solvents used for reaction, extraction, filtration and chromatography were of commercial grade, and used without further purification.
[(neocuproine)PdOAc]2OTf2 Was prepared according to the literature procedure.39. TLC was performed on silica gel TLC plates and visuꢀ
alization was done by staining with anisaldehyde reagent (a mixture of acetic acid (300 ml), H2SO4 (6 ml), anisaldehyde (3 ml)) or potassiꢀ
um permanganate stain (a mixture of KMnO4 (3 g), K2CO3 (10 g), water (300 mL)).1Hꢀ, 13Cꢀ, APTꢀ, COSYꢀ, HMBCꢀ and HMQCꢀNMR
were performed on at 400, 100 MHz, respectively) using D2O or DMSOꢀd6 as solvent. Chemical shift values are reported in ppm with the
solvent resonance as the internal standard (DMSOꢀd6: δ 2.50 for 1H, δ 39.5 for 13C; D2O: δ 4.80 for 1H)). Data are reported as follows:
chemical shifts (δ), multiplicity (s = singlet, d = doublet, dd = double doublet, ddd = double double doublet, t = triplet, appt = apparent
triplet, q = quartet, m = multiplet), coupling constants J (Hz), and integration.
Exchange of the resin to Ca2+
Dowex 50WX8 (200ꢀ400 mesh) resin in either the H+ or the Na+ form was exchanged to the Ca2+ form by stirring the resin with 4 M aqueꢀ
ous CaCl2 (3 ml : 1 g resin) for at least 3 h. The aqueous layer was decanted, the resin washed with water and decanted once more. This
washing step was repeated till there was a negative result for chlorides in the aqueous layer with AgNO3 (1 M).
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General procedure Ion exchange column
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Dowex 50WX8 (200ꢀ400 mesh) in the Ca2+ form was loaded into a thin and long cylindrical glass column (column diameter 3.2 cm, filled
to 24 cm). The crude material was loaded in 1ꢀ2 ml of water on top of the column and was eluted with water. The effluent was fractionated
every 1.5–2.0 ml with a FRACꢀ100 fraction collector maintaining the flow rate between 0.6 to 0.8 ml/min.
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For separation of glucose and allose
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Glucose elutes first, followed by allose. Fractions were collected roughly on the basis of intensity of the spots on the TLC stained with
anisaldehyde.
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For separation of sorbitol and allitol
Allitol elutes first followed by sorbitol. TLC separation is visible between allitol and sorbitol (20% H2O/acetonitrile as TLC eluens)
3ꢀketoꢀαꢀDꢀglucose (4)
To a mixture of αꢀDꢀglucose 2 (35 mg, 0.19 mmol, 1 eq) and benzoquinone (60 mg, 0.58 mmol, 3 eq) in DMSOꢀd6 (650 µL, 0.3 M) was
added [(2,9ꢀdimethylꢀ1,10ꢀphenanthroline)ꢀPd(ꢁꢀOAc)]2(OTf)2 (5 mg, 45 µmol, 2.5 mol%). The reaction mixture was left at r.t. for 30
min. The product was left crude and characterized by NMR.
1H NMR (400 MHz, DMSOꢀd6) δ 5.30 (d, J = 4.1 Hz, 1H), 4.21 (dd, J = 4.2, 1.5 Hz, 1H), 4.06 (dd, J = 9.7, 1.6 Hz, 1H), 3.74 (ddd, J =
9.6, 4.7, 1.9 Hz, 1H), 3.68 (dd, J = 11.8, 2.0 Hz, 1H), 3.61 (dd, J = 11.9, 4.7 Hz, 1H) 13C NMR (101 MHz, DMSOꢀd6) δ 207.2, 95.3, 75.3,
75.1, 72.2, 61.0.
Characterization matches literature40
Dꢀallose (12) from 3ꢀketoꢀαꢀDꢀglucose (4)
To a mixture of αꢀDꢀglucose 2 (120 mg, 0.67 mmol, 1 eq) and benzoquinone (90 mg, 0.83 mmol, 1.25 eq) in DMSO (450 µL, 1.5 M) was
added [(2,9ꢀdimethylꢀ1,10ꢀphenanthroline)ꢀPd(ꢁꢀOAc)]2(OTf)2 (3.5 mg, 3.33 µmol, 0.5 mol%). The reaction mixture was stirred at r.t. for
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1.5 h. Upon complete conversion (monitored by TLC 20% H2O/acetonitrile or HꢀNMR), the reaction mixture was directly used for the
successive reduction step. The reaction mixture was diluted with water (DMSO/H2O 2:1). A cold solution of NaBH4 (19 mg, 0.5 mmol,
0.75 eq) in water (225 µL) was added dropwise to the reaction at 0 ° C and stirred for 1.5 h. When the reaction showed complete converꢀ
sion as indicated by TLC, methanol and acetone (1 : 1, 2 ml) were added to quench the reaction. The reaction mixture was concentrated in
vacuo, and the remaining DMSO was diluted with dichloromethane to the point of precipitation. To this suspension, activated carbon (1 g)
was added, the solution was filtered and the charcoal washed multiple times with dichloromethane till TLC indicated complete elution of
the DMSO. Upon complete elution of DMSO, the charcoal was dried with a stream of air, and water was added to elute off the products.
Concentration in vacuo resulted in a mixture of 12 and 2. The mixture was further purified on an ion exchange column Dowex DVB WX8
Ca2+ (180 g of dry resin) and resulted in pure allose (65 mg, 0.36 mmol, 54%).
1H NMR (400 MHz, D2O) (assignment of the major configuration: βꢀ
Dꢀallose) δ 4.89 (d, J = 8.2 Hz, 1H), 4.17 (t, J = 3.0 Hz, 1H), 3.89 (dd,
J = 12.1, 2.0 Hz, 1H), 3.83 – 3.76 (m, 1H), 3.70 (dd, J = 12.0, 5.9 Hz, 1H), 3.64 (dd, J = 10.0, 2.9 Hz, 1H), 3.42 (dd, J = 8.3, 3.0 Hz, 1H).
13C NMR (101 MHz, D2O) (assignment of the major configuration: βꢀDꢀallose) δ 94.2, 74.4, 72.0, 71.9, 67.5, 61.9.
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Characterization matches literature.41
Allitol (13) from 3ꢀketoꢀαꢀ ꢀglucose (4)
To a mixture of αꢀ ꢀglucose 2 (120 mg, 0.666 mmol, 1 eq) and benzoquinone (90 mg, 0.833 mmol, 1.25 eq.) in DMSO (450 µL, 1.5 M)
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D
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was added [(2,9ꢀdimethylꢀ1,10ꢀphenanthroline)ꢀPd(ꢁꢀOAc)]2(OTf)2 (3.5 mg, 3.33 µmol, 0.5 mol%). The reaction mixture was stirred at rt
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for 1.5 h. Upon complete conversion (monitored by TLC, 20% H2O/ACN, or HꢀNMR), the reaction mixture was directly used for the
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successive reduction step. To this end, the reaction mixture was diluted with water (DMSO/H2O 2:1). A cold solution of NaBH4 (150 mg,
4 mmol 6 eq) in water (1 ml) was added dropwise to the reaction at 0 °C and stirred for 18 h. When the reaction showed complete converꢀ
sion as indicated by TLC, methanol and acetone (1 : 1, 2 ml) were added to quench the reaction. The reaction mixture was concentrated in
vacuo. The residue in DMSO was diluted with dichloromethane to the point of precipitation. To this suspension, activated carbon (1 g) was
added, the solution was filtered and the charcoal washed multiple times with dichloromethane till TLC (20% H2O/ACN) indicated comꢀ
plete elution of the DMSO. Upon complete elution of DMSO, the charcoal was dried with a stream of air, and water was added to elute the
product. Concentration in vacuo resulted in a mixture of 13 and 14. The mixture was separated on an ion exchange column Dowex DVB
WX8 Ca2+ (180 g of dry resin) and resulted in pure allitol 13 (76 mg, 0.419 mmol, 62%) (contains ~40% DMSO by NMR integration,
isolated yield corrected for the presence of DMSO). 1H NMR (400 MHz, D2O) δ 3.92 – 3.84 (m, 2H), 3.82 – 3.73 (m, 4H), 3.69 – 3.58 (m,
2H). 13C NMR (101 MHz, D2O) δ 73.0, 72.8, 63.0.
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Characterization matches literature.42
Oxidation of
D
ꢀglucoseꢀ13C6
ꢀglucoseꢀ13C6 (34 mg, 0.18 mmol, 1 eq) and benzoquinone (58 mg, 0.54 mmol, 3 eq) in DMSOꢀd6 (600 µL, 0.3 M) was
To a mixture of
D
added [(2,9ꢀdimethylꢀ1,10ꢀphenanthroline)ꢀPd(ꢁꢀOAc)]2(OTf)2 (4.7 mg, 45 µmol, 2.5 mol%). The reaction mixture was left at 40 °C for 4
h. The product was left crude and the structure was elucidated by NMR. 1H NMR (400 MHz, DMSOꢀd6) (decoupled for 13C) δ 4.97 (d, J
=5.2 Hz, 1H, H5), 4.66 – 4.58 (m, 2H,H6a + H4), 4.44 (d, J =12.2 Hz, 1H, H6b). 13C NMR (101 MHz, DMSOꢀd6) δ 171.2 (dd, J = 55.0,
1.6 Hz, C1), 166.2 (d, J = 51.4 Hz, C3), 79.9 (ddd, J = 54.9, 51.5, 36.5 Hz, C2), 78.9 (appt, J = 35.0 Hz, C5), 71.6 (appt, J = 35.9 Hz, C4),
70.2 (d, J = 35.0 Hz, C6). HRMS (ESI) calculated for C6H7O6 ([M+H]+): 175.024, found: 175.024
Oxidation of NꢀacetylꢀαꢀDꢀglucosamine (3)
To a mixture of NꢀacetylꢀαꢀDꢀglucosamine (40 mg, 0.18 mmol, 1 eq) and benzoquinone (58 mg, 0.54 mmol, 3 eq) in DMSOꢀd6 (600 µL,
0.3 M) was added [(2,9ꢀdimethylꢀ1,10ꢀphenanthroline)ꢀPd(ꢁꢀOAc)]2(OTf)2 (4.7 mg, 45 µmol, 2.5 mol%). The reaction mixture was left at
1
r.t. for 1.5 h. The crude product was characterized by NMR. H NMR (400 MHz, DMSOꢀd6) δ 7.92 (d, J = 8.2 Hz, 1H), 5.34 (d, J = 4.0
Hz, 1H), 4.69 (ddd, J = 8.2, 4.0, 1.3 Hz, 1H), 4.15 (dd, J = 9.7, 1.3 Hz, 1H), 3.82 (ddd, J = 9.6, 4.7, 2.0 Hz, 1H), 3.70 (dd, J = 11.9, 2.1 Hz,
1H), 3.64 (dd, J = 11.9, 4.7 Hz, 1H), 1.92 (s, 3H). 13C NMR (101 MHz, DMSOꢀd6) δ 204.0, 169.8, 93.8, 75.3, 72.5, 61.0, 59.5, 22.4.
Characterization matches literature.43
ASSOCIATED CONTENT
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The associated analytical data (1HꢀNMR, 13CꢀNMR and APT spectra for all compounds) can be found in the supporting inꢀ
formation. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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* Correspondence can be addressed to Prof. Dr. Ir. Adriaan J. Minnaard – a.j.minnaard@rug.nl and/or Dr. Martin Witte –
m.d.witte@rug.nl
Author Contributions
All authors have given approval to the final version of the manuscript.
‡ Varsha R. Jumde and Niek N. H. M. Eisink contributed equally.
Notes
The authors hereby declare no competing financial interests.
ACKNOWLEDGMENTS
Financial support from The Netherlands Organization for Scientific Research (NWOꢀCW, grant numbers 714.014.004 and
718.016.001) is acknowledged. P. van der Meulen is acknowledged for NMRꢀassistance.
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