Practical Site-Selective Oxidation of Glycosides with Palladium(II) Acetate/Neocuproine

The palladium-catalyzed oxidation of the secondary C(3) hydroxy group of glycopyranosides has set a mark in the selective modification of unprotected carbohydrates. The preformed catalyst [(neocuproine)PdOAc] 2 (OTf) 2 oxidizes di-and oligosaccharides, as well as monosaccharides. Here, we provide a more convenient protocol for this reaction in which the Pd catalyst is formed in situ from Pd(OAc) 2 and neocuproine in methanol at 50 °C. Together with a simplified product isolation, this protocol was applied to a series of mono-and disac-charides, and has been applied on a 10 gram scale. The protocol is also valuable as a screening method to determine whether more-extensive studies using the preformed catalyst are worthwhile.

2][3][4] To modify carbohydrates, it is therefore of preeminent importance that hydroxy groups in carbohydrates can be oxidized in a site-selective manner to the corresponding carbonyl group.This can be effected by means of protecting-group strategies in which a hydroxy group is singled out and subsequently oxidized.An alternative is the site-selective oxidation of nonprotected carbohydrates.][7][8][9][10] The regioselectivity of this oxidation reaction is clearly based on steric hindrance.

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Other approaches for the selective oxidation of 1,2-diols make use of chelating agents such as boronic acids 21,22 or organotin reagents [23][24][25] in combination with an oxidant.Recently, Kaspar and Kudova investigated the use of moreclassical oxidation reagents to achieve selective oxidation of 1,2-diols in steroids. 26Although it was possible to achieve the selective oxidation of hydroxy groups at different positions in the steroid, no selectivity was observed for 1,2-diols.
][30][31] Despite all these illustrations of the versatility and applicability of Waymouth's catalyst in carbohydrate oxidation, its incorporation in the toolbox of the carbohydrate chemist has been slow.The main reason is probably that the catalyst is not commercially available and has to be prepared.This forms a barrier to applying the method to novel substrates without a guarantee of success.It would be highly desirable to have at hand a straightforward protocol to test the palladium-catalyzed oxidation reaction to decide on its suitability for chemical-biology or glycochemistry applications.A second reason is the laborious purification of the highly polar carbohydrates, so a protocol avoiding column chromatography would also be welcomed.
We reasoned that by using commercially available Pd(OAc) 2 and neocuproine (2,9-dimethyl-1,10-phenanthroline), a catalyst might be prepared in situ, and that this system, although potentially less active and selective, would form a versatile screening system to determine whether substrates are suitable and could provide access to ketosaccharides.
Before the advent of [(neocuproine)PdOAc] 2 (OTf) 2 , it had already been shown that secondary alcohols could be oxidized with (neocuproine)Pd(OAc) 2 at high temperatures. 32This bisacetate catalyst has been applied with various solvents and with several oxidants such as O 2 /air 33,34 or a combination of benzoquinone and electrochemistry. 35It had also been shown that ligandless Pd(OAc) 2 was also effective in some cases. 36,37Lemaire's group combined these methods by preparing (neocuproine)Pd(OAc) 2 in situ to selectively oxidize fatty-acid-derived 1,2-diols. 38These approaches, however, required a high temperature, which is problematic for sensitive substrates and, in addition, carbohydrates are deactivated substrates for oxidation.
We therefore decided to prepare (neocuproine)Pd(OAc) 2 catalyst in situ and to study whether, in combination with a suitable solvent and temperature, it could act as a suitable screening catalyst for a variety of carbohydrate substrates.

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yl -?-glucopyranoside (1) in 9:1 v/v acetonitrile-water and in methanol (Table 1). 40,41In line with previous studies on the oxidation of 2-heptanol and glycerol, 33,39 3 showed higher turnover frequencies, and it turned out to be the more active in methanol.Although the oxidation reaction with the bisacetate catalyst 4 was considerably slower than that with 3, the TOF almost doubled when methanol was used instead of acetonitrile-water, indicating that oxidation of glucosides with the bisacetate catalyst 4 is facilitated by a protic polar solvent (Table 1).The origin of the higher activity of catalyst 4 in methanol was not studied in detail, but we hypothesize that it is caused by differences in the dissociation constant of the acetate ligand.The pKa of acetic acid is considerably higher in acetonitrile (pK a = 23.5) 42than in methanol (pK a = 9.63). 43We reason that the acetate anion dissociates much more readily in methanol than in acetonitrile and, after dissociation of acetate, the substrate or the solvent can coordinate to the vacant site. 32Methanol thus facilitates a rapid equilibrium between the inactive palladium acetate complex and the active substrate-bound catalyst.
Having identified methanol as a solvent and preprepared (neocuproine)Pd(OAc) 2 (4) as a suitable catalyst system for the oxidation of 1, we subsequently focused our attention on the in-situ-prepared catalyst 4. We were pleased to note that overnight reaction at room temperature, provided partial conversion of glucoside 1 (SI, Table S3).
A simplified product-purification method was designed to ensure the general applicability of the procedure.After concentrating the reaction mixture in vacuo and adding water, the hydroquinone and neocuproine were removed by washing with diethyl ether.Filtration of the aqueous layer through syringe filters of 0.45 m (twice) and 0.1 m (once) removed palladium black and polymerized benzoquinone/hydroquinone. Subsequent lyophilization provided the product in >90% purity.With these optimized oxidation and purification methods in hand, 1 was oxidized on a 10-gram scale and produced the 3-ketoglucoside 2 in quantitative yield.
To explore the scope of this procedure, various glucoconfigured glycosides were oxidized, including a thioglucopyranoside, various protected glucopyranosides, a xylopyranoside, and glucuronopyranoside (Figure 1). 44The corresponding ketosaccharides 6-13 [45][46][47][48] were isolated in high yields, with the exception of 7. Some products contained trace amounts of starting material, which was not removed by filtration.The moderate yield of 7 was due to its greater solubility in diethyl ether.For the synthesis of 10-12, 1.5 equivalents of benzoquinone were used, because 1.05 equivalents led to incomplete conversion.Compound 13 was purified by column chromatography because of its low solubility in water.
Our study continued with the disaccharides cellobiose and maltose.Regioselective oxidation of methyl -cellobioside proceeded smoothly, and 14 was isolated in 62% yield, which was slightly higher than the previously reported yield. 15The tert-butylbenzyl -maltoside 15, on the other hand, proved to be a more challenging substrate: NMR analysis showed that several byproducts were formed, and purification by column chromatography gave 15 in only 27% yield.Oxidation of the Type 2 diabetes drug dapagliflozin 50,51 completed our study on gluco-configured substrates, and the 3-ketosaccharide 16 52 was obtained in 62% yield.
The scope was expanded with substrates possessing a non-glucose configuration.As shown previously, substrates such as mannose and galactose are prone to overoxidation and rearrangements, and provide moderate yields with 3. 49 Indeed, attempts to oxidize methyl L-rhamnopyranoside, methyl D-mannopyranoside, and methyl D-galactopyranoside, as well as TIPS-protected methyl D-mannopyranoside (17; Scheme 2) led to complex mixtures of compounds, precluding the isolation of the desired ketosaccharides (see SI).We conclude, therefore, that for these and related compounds, the in-situ-formed catalyst in methanol is suitable to determine whether oxidation occurs, whereas catalyst 3 should subsequently be employed to prepare the desired products. 19,49t was noticed that next that the products of non-glucoconfigured monosaccharides, as well as several oxidized Cglycosides, can be quite sensitive to overoxidation and rearrangement (Scheme 2).The oxidation of puerarin (19) with Pd-catalyst 3 has been reported by Nakamura et al. to give 3-ketopuerarin in 70% yield. 53With the current in-situ-prepared catalyst, a mixture of 20 54 and 21 was obtained in-

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stead of the desired C(3)-keto saccharide.These products are probably formed by migration of the keto functionality from C(3) to C(2), followed by a rearrangement reaction, because a migration of 3-ketopuerarin was observed by Nakamura et al., and the formation of such rearranged products from -glycosides has been observed before by us. 49xidation of glycoside 22 provided the desired product 23 55 in 32% yield together with the 2-keto saccharide 24 56 in 9% yield.The latter is probably formed through an intramolecular deprotonation of the C(2) position by adventitiously formed phenolate.
In conclusion, the catalyst prepared in situ from Pd(OAc) 2 and neocuproine in methanol proved to be a suitable catalyst system for rapid screening of the C(3)-selective oxidation of carbohydrates.A straightforward purification protocol that avoids column chromatography permits rapid isolation of the products.For gluco-configured substrates, high yields are obtained and the reaction can be readily scaled up.The sensitivity of some substrates to overoxidation gives lower yields or mixtures of products.Nevertheless, even for these substrates, the protocol functions as a suitable and rapid screening method to determine whether it is worth preparing the Waymouth catalyst for the oxidation of a particular substrate.This protocol should lead to more-widespread application of the site-selective modification of unprotected carbohydrates and, in addition, is not limited to this substrate class, as shown by the oxidation of C-glycosides.

aC
The turnover number (TON) was calculated by dividing the conversion after 24 h by the mol% of [Pd].bThe turnover frequency (TOF) was calculated by dividing the conversion after 0.5 h by the mol% of [Pd] and the reaction time.See the Supporting Information (SI) TablesS1 and S2for the results at all time points.c MeCN-H 2 O (9:1 v/v) was used to completely dissolve 1.Synlett 2023, 34, A-E N. R. M. Reintjens et al.

Table 1
Oxidation of Glucoside 1 in 9:1 Acetonitrile-H 2 O or Methanol with Catalysts 3 and 4