Access to d- and l-Psicose Derivatives via Hydroxy Methylation of Ribono Lactone

2,3,5-Tri-O-benzyland 2,3,5-tri-O-methyl-d-ribono-γ-lactone were converted with (methoxyethoxymethoxy)methyl and benzyloxy tributylstannane into the corresponding protected d-psicoses as mixtures of anomers in 31%–72% yield. Treatment of 2,3,5-tri-O-methyl-l-ribono-γ-lactone with benzyloxy tributylstannane afforded the corresponding l-psicose derivative as an anomeric mixture in 72% yield. Both methylated psicoses were further converted into 1,2-O-isopropylidene-3,4,6-tri-O-methyl-dand l-psicofuranosides, the respective αand β-anomers of which could be separated and characterized.


Introduction
Only a few ketoses occur in nature in significant amounts. d-Fructose is the only ketose that occurs in large quantities in nature and can be isolated from plant material [1]. Other ketoses like psicose ( Figure 1) are rare carbohydrates which cannot be isolated in considerable amounts from natural sources. They can be synthesized either by isomerization of the corresponding aldoses in low yields or by multi-step syntheses involving different protection and deprotection steps or by enzymatic methods [2][3][4][5][6][7][8] resulting in a high price for these ketoses. As part of an ongoing research project about the synthesis of carbohydrate derived catalysts for asymmetric syntheses [9][10][11][12] we required considerable amounts of d-and l-psicofuranose derivatives 3. Due to the high price of both enantiomers of psicose [13] we developed a specific synthetic route for the preparation of d-and l-psicose derivatives 3, starting from d-and l-ribose (2). We chose ribose as the starting material because both enantiomers of this sugar are commercially available at decent costs [13] and the stereocenters possess the same configuration as psicose.

Introduction
Only a few ketoses occur in nature in significant amounts. D-Fructose is the only ketose that occurs in large quantities in nature and can be isolated from plant material [1]. Other ketoses like psicose ( Figure 1) are rare carbohydrates which cannot be isolated in considerable amounts from natural sources. They can be synthesized either by isomerization of the corresponding aldoses in low yields or by multi-step syntheses involving different protection and deprotection steps or by enzymatic methods [2][3][4][5][6][7][8] resulting in a high price for these ketoses. As part of an ongoing research project about the synthesis of carbohydrate derived catalysts for asymmetric syntheses [9][10][11][12] we required considerable amounts of D-and L-psicofuranose derivatives 3. Due to the high price of both enantiomers of psicose [13] we developed a specific synthetic route for the preparation of D-and Lpsicose derivatives 3, starting from D-and L-ribose (2). We chose ribose as the starting material because both enantiomers of this sugar are commercially available at decent costs [13] and the stereocenters possess the same configuration as psicose.

Results and Discussion
We first established a synthetic route starting with the cheap d-enantiomer of ribose and applied our findings later to the more expensive l-enantiomer. Since ribose is a pentose and psicose a hexose, the carbohydrate chain of the ribose had to be elongated by one carbon atom. Our strategy for accomplishing this was to first convert ribose to the corresponding lactone 6 and then elongate its carbon chain at C-1 via addition of the organometallic reagent 5 (Scheme 1). The latter could be obtained from tributylstannyl methanol 4 by transmetallation with butyl lithium and had already been used for the elongation of other carbohydrate derivatives [14][15][16][17]. We first established a synthetic route starting with the cheap D-enantiomer of ribose and applied our findings later to the more expensive L-enantiomer. Since ribose is a pentose and psicose a hexose, the carbohydrate chain of the ribose had to be elongated by one carbon atom. Our strategy for accomplishing this was to first convert ribose to the corresponding lactone 6 and then elongate its carbon chain at C-1 via addition of the organometallic reagent 5 (Scheme 1). The latter could be obtained from tributylstannyl methanol 4 by transmetallation with butyl lithium and had already been used for the elongation of other carbohydrate derivatives [14][15][16][17]. Scheme 1. Planned elongation of the carbohydrate chain in order to derive hexose from a pentose.
At first we attempted to react known tri-O-benzyl ribono lactone (8) [18] with unprotected 4 (4a, R = H) [19] since this approach would have led directly to the target molecules without the need of any additional protecting group manipulations. Unfortunately, treatment of D-8 with 4a only resulted in decomposition of the starting materials. Next, we decided to use a suitably protected stannyl reagent 4 since such reagents had previously been used successfully for the elongation of other aldose derivatives. As a protecting group we chose the methoxyethoxmethyl group (MEM) due to its orthogonality to benzyl protecting groups and its facile removal [20]. In fact, treatment of lactone D-8 with MEM-protected 4b afforded the corresponding elongated sugar D-9, however in rather poor yield (Scheme 2). It is known that stannyl reagents of the type 4 may rearrange upon transmetallation, with butyl lithium. Most likely this was the reason for the observed low yield. Such rearrangements may depend on the nature of the protecting group in 4. [19] Therefore, we decided to use a supposedly more stable benzyl group instead of the MEM protective group for reagent 4. In order to keep orthogonality between the protective groups at the ribono lactone and the stannyl reagent we also changed the substituents at the lactone accordingly. Here, we chose methyl groups as they can be introduced easily and are stable to broad range of reaction conditions. Thus known ribose derivative D-10 [21] was first oxidized to D-11 in excellent yield using iodine as the oxidant (Scheme 3). Addition of D-11 to a solution of the benzylated organotin reagent 4c and n-BuLi finally provided D-12 in good yield as an inseparable mixture of anomers.
Next, the benzyl group at position 1 of psicose derivative D-12 was reductively removed in very high yield using palladium on charcoal as the catalyst. Deprotected compound D-13 again emerges as a mixture of inseparable anomers. In order to obtain an anomerically pure substance we further  At first we attempted to react known tri-O-benzyl ribono lactone (8) [18] with unprotected 4 (4a, R = H) [19] since this approach would have led directly to the target molecules without the need of any additional protecting group manipulations. Unfortunately, treatment of d-8 with 4a only resulted in decomposition of the starting materials. Next, we decided to use a suitably protected stannyl reagent 4 since such reagents had previously been used successfully for the elongation of other aldose derivatives. As a protecting group we chose the methoxyethoxmethyl group (MEM) due to its orthogonality to benzyl protecting groups and its facile removal [20]. In fact, treatment of lactone d-8 with MEM-protected 4b afforded the corresponding elongated sugar d-9, however in rather poor yield (Scheme 2). We first established a synthetic route starting with the cheap D-enantiomer of ribose and applied our findings later to the more expensive L-enantiomer. Since ribose is a pentose and psicose a hexose, the carbohydrate chain of the ribose had to be elongated by one carbon atom. Our strategy for accomplishing this was to first convert ribose to the corresponding lactone 6 and then elongate its carbon chain at C-1 via addition of the organometallic reagent 5 (Scheme 1). The latter could be obtained from tributylstannyl methanol 4 by transmetallation with butyl lithium and had already been used for the elongation of other carbohydrate derivatives [14][15][16][17]. Scheme 1. Planned elongation of the carbohydrate chain in order to derive hexose from a pentose.
At first we attempted to react known tri-O-benzyl ribono lactone (8) [18] with unprotected 4 (4a, R = H) [19] since this approach would have led directly to the target molecules without the need of any additional protecting group manipulations. Unfortunately, treatment of D-8 with 4a only resulted in decomposition of the starting materials. Next, we decided to use a suitably protected stannyl reagent 4 since such reagents had previously been used successfully for the elongation of other aldose derivatives. As a protecting group we chose the methoxyethoxmethyl group (MEM) due to its orthogonality to benzyl protecting groups and its facile removal [20]. In fact, treatment of lactone D-8 with MEM-protected 4b afforded the corresponding elongated sugar D-9, however in rather poor yield (Scheme 2). It is known that stannyl reagents of the type 4 may rearrange upon transmetallation, with butyl lithium. Most likely this was the reason for the observed low yield. Such rearrangements may depend on the nature of the protecting group in 4. [19] Therefore, we decided to use a supposedly more stable benzyl group instead of the MEM protective group for reagent 4. In order to keep orthogonality between the protective groups at the ribono lactone and the stannyl reagent we also changed the substituents at the lactone accordingly. Here, we chose methyl groups as they can be introduced easily and are stable to broad range of reaction conditions. Thus known ribose derivative D-10 [21] was first oxidized to D-11 in excellent yield using iodine as the oxidant (Scheme 3). Addition of D-11 to a solution of the benzylated organotin reagent 4c and n-BuLi finally provided D-12 in good yield as an inseparable mixture of anomers.
Next, the benzyl group at position 1 of psicose derivative D-12 was reductively removed in very high yield using palladium on charcoal as the catalyst. Deprotected compound D-13 again emerges as a mixture of inseparable anomers. In order to obtain an anomerically pure substance we further  It is known that stannyl reagents of the type 4 may rearrange upon transmetallation, with butyl lithium. Most likely this was the reason for the observed low yield. Such rearrangements may depend on the nature of the protecting group in 4. [19] Therefore, we decided to use a supposedly more stable benzyl group instead of the MEM protective group for reagent 4. In order to keep orthogonality between the protective groups at the ribono lactone and the stannyl reagent we also changed the substituents at the lactone accordingly. Here, we chose methyl groups as they can be introduced easily and are stable to broad range of reaction conditions. Thus known ribose derivative d-10 [21] was first oxidized to d-11 in excellent yield using iodine as the oxidant (Scheme 3). Addition of d-11 to a solution of the benzylated organotin reagent 4c and n-BuLi finally provided d-12 in good yield as an inseparable mixture of anomers. With a working synthetic sequence for the D-enantiomers in hand, we applied it to the L-enantiomer L-10 as well (Scheme 4). L-10 was prepared as described in the literature for the preparation of D-10. [21] As was expected, the synthetic route worked smoothly with yields nearly identical yields to those obtained for the D-enantiomers in all steps of the reaction sequence.

General Remarks
Reactions in dry solvents were carried out under an atmosphere of nitrogen. Dry THF was distilled from sodium/benzophenone, dry CH2Cl2 was distilled from P4O10, dry acetone was prepared from HPLC grade acetone by the addition of molecular sieves (4 Å). Tert-butanol and ethanol were HPLC grade and used without further purification. Solvents used for column chromatography were techniqual grade and distilled prior to their use. Petroleum ether (PE) refers to the fraction boiling at 60-90 °C. Silica gel "60 M" from Machery-Nagel was used for column chromatography. For reaction monitoring, TLC plates "Polygram Sil G/U254" from Machery-Nagel were used. Optical rotations were measured with a Perkin Elmer "Polarimeter 341". NMR spectra were measured at a Bruker "Avance Next, the benzyl group at position 1 of psicose derivative d-12 was reductively removed in very high yield using palladium on charcoal as the catalyst. Deprotected compound d-13 again emerges as a mixture of inseparable anomers. In order to obtain an anomerically pure substance we further With a working synthetic sequence for the d-enantiomers in hand, we applied it to the l-enantiomer l-10 as well (Scheme 4). l-10 was prepared as described in the literature for the preparation of d-10. [21] As was expected, the synthetic route worked smoothly with yields nearly identical yields to those obtained for the d-enantiomers in all steps of the reaction sequence. With a working synthetic sequence for the D-enantiomers in hand, we applied it to the L-enantiomer L-10 as well (Scheme 4). L-10 was prepared as described in the literature for the preparation of D-10. [21] As was expected, the synthetic route worked smoothly with yields nearly identical yields to those obtained for the D-enantiomers in all steps of the reaction sequence.

General Remarks
Reactions in dry solvents were carried out under an atmosphere of nitrogen. Dry THF was distilled from sodium/benzophenone, dry CH2Cl2 was distilled from P4O10, dry acetone was prepared from HPLC grade acetone by the addition of molecular sieves (4 Å). Tert-butanol and ethanol were HPLC grade and used without further purification. Solvents used for column chromatography were

General Remarks
Reactions in dry solvents were carried out under an atmosphere of nitrogen. Dry THF was distilled from sodium/benzophenone, dry CH 2 Cl 2 was distilled from P 4 O 10 , dry acetone was prepared from HPLC grade acetone by the addition of molecular sieves (4 Å). Tert-butanol and ethanol were HPLC grade and used without further purification. Solvents used for column chromatography were techniqual grade and distilled prior to their use. Petroleum ether (PE) refers to the fraction boiling at 60-90 • C. Silica gel "60 M" from Machery-Nagel was used for column chromatography. For reaction monitoring, TLC plates "Polygram Sil G/U 254 " from Machery-Nagel were used. Optical rotations were measured with a Perkin Elmer "Polarimeter 341". NMR spectra were measured at a Bruker "Avance III HD 400" or a Bruker "Avance HD 300 NanoBay" and are calibrated to the solvent signal. For peak assignment additional spectra (DEPT, COSY, HMBC, HSQC) were recorded. The atoms are numbered in accordance with the carbohydrate nomenclature. High resolution mass spectra were measured at a Bruker "maXis 4G". Elemental analysis was performed using a HEKAtech "Euro 3000 CHN".

Conclusions
In summary, we describe a method to prepare derivatives of both enantiomers of rare ketoses (i.e., psicose) from inexpensively ribose. The ketoses have the protecting groups necessary for the synthesis of ligands for asymmetric catalysis. With other inexpensive commercially available pentoses like for instance l-arabinose (100 g, 144 €) or d-xylose (1 kg, 57 €) derivatives of other rare ketoses like l-fructose (50 mg, 126 €), or d-sorbose (100 mg, 224 €) are accessible [24]. By using the benzylated lactone 8 in the sequence shown in Schemes 3 and 4, the completely deprotected psicose should be obtained after the reduction under an atmosphere of hydrogen. Since the methyl groups are hard to remove, other protective groups like MEM or TIPS at the carbohydrate may be used if an easily removable to benzyl orthogonal protective group is needed.