Copper-Catalyzed Asymmetric Sulfonylative Desymmetrization of Glycerol

Glycerol is the main side product in the biodiesel manufacturing process, and the development of glycerol valorization methods would indirectly contribute the sustainable biodiesel production and decarbonization. Transformation of glycerol to optically active C3 units would be one of the attractive routes for glycerol valorization. We herein present the asymmetric sulfonylative desymmetrization of glycerol by using a CuCN/(R,R)-PhBOX catalyst system to provide an optically active monosulfonylated glycerol in high efficiency. A high degree of enantioselectivity was achieved with a commercially available chiral ligand and an inexpensive carbonate base. The optically active monosulfonylated glycerol was successfully transformed into a C3 unit attached with differentially protected three hydroxy moieties. In addition, the synthetic utility of the present reaction was also demonstrated by the transformation of the monosulfonylated glycerol into an optically active synthetic ceramide, sphingolipid E.


Results and Discussion
For the initial attempt to optimize the enantioselective desymmetrization of glycerol, compound 1 was treated with p-toluenesulfonyl chloride (TsCl) in the presence of copper trifluoromethanesulfonate (Cu(OTf)2)/(R,R)-PhBOX and sodium carbonate in acetonitrile. Pleasingly, the desired monotosylated glycerol 2 was obtained in 91% yield with 83% ee ( Table 1, entry 1). Using other carbonate salts, i.e., potassium carbonate and cesium carbonate, resulted in a decrease in both yield and enantioselectivity (entries 2 and 3). Organic bases were not suitable for the present transformation (entries 4 and 5). Next, other copper catalysts were examined to evaluate the catalytic activity in this reaction system. While CuCl provided 2 with a slightly lowered yield and enantioselectivity, CuBr and CuI exhibited a similar reactivity compared with Cu(OTf)2 (entries [6][7][8]. The use of CuCN led to the formation of 2 in 83% yield with higher enantioselectivity, and the reaction concentration was able to be doubled without significant changes regarding both yield and enantioselectivity (entries 9-10). Pleasingly, we found that acetone was a better solvent choice to afford the desired product in an excellent yield and enantioselectivity (96% yield, 94% ee), and the concentration of 0.25 M was found to be suitable for the present reaction (entries [11][12]. The catalyst loading was able to be reduced to 5 mol% without a significant decrease in the yield and enantioselectivity (entry 13). We also examined the feasibility of the gram-scale preparation of 2. The reaction with 6.0 mmol of glycerol successfully provided the desired product 2 in 88% yield (1.30 g) with 93% ee (entry 14). Control

Results and Discussion
For the initial attempt to optimize the enantioselective desymmetrization of glycerol, compound 1 was treated with p-toluenesulfonyl chloride (TsCl) in the presence of copper trifluoromethanesulfonate (Cu(OTf) 2 )/(R,R)-PhBOX and sodium carbonate in acetonitrile. Pleasingly, the desired monotosylated glycerol 2 was obtained in 91% yield with 83% ee (Table 1, entry 1). Using other carbonate salts, i.e., potassium carbonate and cesium carbonate, resulted in a decrease in both yield and enantioselectivity (entries 2 and 3). Organic bases were not suitable for the present transformation (entries 4 and 5). Next, other copper catalysts were examined to evaluate the catalytic activity in this reaction system. While CuCl provided 2 with a slightly lowered yield and enantioselectivity, CuBr and CuI exhibited a similar reactivity compared with Cu(OTf) 2 (entries 6-8). The use of CuCN led to the formation of 2 in 83% yield with higher enantioselectivity, and the reaction concentration was able to be doubled without significant changes regarding both yield and enantioselectivity (entries 9-10). Pleasingly, we found that acetone was a better solvent choice to afford the desired product in an excellent yield and enantioselectivity (96% yield, 94% ee), and the concentration of 0.25 M was found to be suitable for the present reaction (entries 11-12). The catalyst loading was able to be reduced to 5 mol% without a significant decrease in the yield and enantioselectivity (entry 13). We also examined the feasibility of the gram-scale preparation of 2. The reaction with 6.0 mmol of glycerol successfully provided the desired product 2 in 88% yield (1.30 g) with 93% ee (entry 14).
Control experiments revealed that both the copper salt and the BOX ligand were essential to promote the tosylation of 1 (entries 15-16). experiments revealed that both the copper salt and the BOX ligand were essential to promote the tosylation of 1 (entries 15-16).  9 The reaction was carried out in the absence of (R,R)-PhBOX.
In order to gain insight into the chemoselectivity of the present reaction, we performed competition studies with alcohol additives ( Table 2). The addition of n-propanol (1.0 eq) led to a slight decrease in both yield and enantioselectivity, but the formation of n-propyl tosylate was not detected (entry 1 vs. entry 2). Moreover, selective sulfonylation of glycerol (1) over 1,2-and 1,3-diols was observed under the present reaction conditions, and the desired monosulfonylated glycerol 2 was obtained without a significant loss of enantioselectivity (entry 1 vs. entries [3][4]. In addition, the reaction of 2-O-benzylglycerol (4) provided the corresponding monotosylated product 5 in a low yield with poor enantioselectivity (Scheme 2). These results indicated that the present reaction system would be highly selective for the glycerol transformation even in the presence of other alcohols, and the presence of a free 2-hydroxy moiety would play a crucial role in accelerating the tosylation with high asymmetric induction.  5 CuCN Na 2 CO 3 acetone 96 94 12 6 CuCN Na 2 CO 3 acetone 93 89 13 5,7 CuCN Na 2 CO 3 acetone 83 91 14 5,8 CuCN Na 2 CO 3 acetone 88 93 15 5 -Na 2 CO 3 acetone trace -16 5,9 CuCN Na 2 CO 3 acetone 3 rac  9 The reaction was carried out in the absence of (R,R)-PhBOX.
In order to gain insight into the chemoselectivity of the present reaction, we performed competition studies with alcohol additives ( Table 2). The addition of n-propanol (1.0 eq) led to a slight decrease in both yield and enantioselectivity, but the formation of n-propyl tosylate was not detected (entry 1 vs. entry 2). Moreover, selective sulfonylation of glycerol (1) over 1,2-and 1,3-diols was observed under the present reaction conditions, and the desired monosulfonylated glycerol 2 was obtained without a significant loss of enantioselectivity (entry 1 vs. entries [3][4]. In addition, the reaction of 2-O-benzylglycerol (4) provided the corresponding monotosylated product 5 in a low yield with poor enantioselectivity (Scheme 2). These results indicated that the present reaction system would be highly selective for the glycerol transformation even in the presence of other alcohols, and the presence of a free 2-hydroxy moiety would play a crucial role in accelerating the tosylation with high asymmetric induction. With successful asymmetric desymmetrization of glycerol achieved, we the tigated the synthetic applications of the obtained optically active glycerol. First, selective protection of the remained hydroxy groups in (R)-2 was examined (Sch The primary hydroxy moiety was selectively protected by using tert-butyldimet chloride (TBSCl) with imidazole, affording the corresponding product (R)-6. Ace  and the desired monosulfonylated glycerol 2 was obtained without a significant loss of enantioselectivity (entry 1 vs. entries [3][4]. In addition, the reaction of 2-O-benzylglycerol (4) provided the corresponding monotosylated product 5 in a low yield with poor enantioselectivity (Scheme 2). These results indicated that the present reaction system would be highly selective for the glycerol transformation even in the presence of other alcohols, and the presence of a free 2-hydroxy moiety would play a crucial role in accelerating the tosylation with high asymmetric induction.  With successful asymmetric desymmetrization of glycerol achieved, we then investigated the synthetic applications of the obtained optically active glycerol. First, the siteselective protection of the remained hydroxy groups in (R)-2 was examined (Scheme 3). The primary hydroxy moiety was selectively protected by using tert-butyldimethylsilyl chloride (TBSCl) with imidazole, affording the corresponding product (R)-6. Acetylation of the secondary hydroxy group with Ac2O in the presence of a DMAP catalyst provided (R)-7 in an excellent yield. Since each protective group would be removed by different deprotecting protocols, (R)-7 would be potentially useful as a versatile chiral C3 building block. Next, we turned our attention to the application of the present transformation in the synthesis of an optically active synthetic ceramide. Ceramides are major components of the lamellar structure in stratum corneum lipids which protect the epidermis from excess transepidermal water loss and from the permeation of pathogens [64]. Interestingly, optically active natural ceramides showed different thermotropic behavior from racemic variants, and the lamellar liquid crystalline system containing optically active natural ceramides improved recovering effects of a water-holding ability and a barrier function of the skin [65]. Sphingolipid E (SLE) was a synthetic ceramide designed and synthesized by Kao Corporation as a structural analog of natural type 2 ceramide and was found to form a stable lamellar structure that exhibits a high water-holding ability [66]. Although SLE has been utilized as a racemic form, optically active SLE might affect the physicochemical property to form a lamellar structure and the interaction mode with water molecules. The synthesis of optically active SLE commenced with the introduction of nitrogen functionality to (R)-2 (Scheme 4). The nucleophilic azide substitution of the tosyloxy group in (R)-2 with sodium azide provided azide diol (S)-8 in an excellent yield in the With successful asymmetric desymmetrization of glycerol achieved, we then investigated the synthetic applications of the obtained optically active glycerol. First, the siteselective protection of the remained hydroxy groups in (R)-2 was examined (Scheme 3). The primary hydroxy moiety was selectively protected by using tert-butyldimethylsilyl chloride (TBSCl) with imidazole, affording the corresponding product (R)-6. Acetylation of the secondary hydroxy group with Ac2O in the presence of a DMAP catalyst provided (R)-7 in an excellent yield. Since each protective group would be removed by different deprotecting protocols, (R)-7 would be potentially useful as a versatile chiral C3 building block. Next, we turned our attention to the application of the present transformation in the synthesis of an optically active synthetic ceramide. Ceramides are major components of the lamellar structure in stratum corneum lipids which protect the epidermis from excess transepidermal water loss and from the permeation of pathogens [64]. Interestingly, optically active natural ceramides showed different thermotropic behavior from racemic variants, and the lamellar liquid crystalline system containing optically active natural ceramides improved recovering effects of a water-holding ability and a barrier function of the skin [65]. Sphingolipid E (SLE) was a synthetic ceramide designed and synthesized by Kao Corporation as a structural analog of natural type 2 ceramide and was found to form a stable lamellar structure that exhibits a high water-holding ability [66]. Although SLE has been utilized as a racemic form, optically active SLE might affect the physicochemical property to form a lamellar structure and the interaction mode with water molecules. The synthesis of optically active SLE commenced with the introduction of nitrogen functionality to (R)-2 (Scheme 4). The nucleophilic azide substitution of the tosyloxy group in (R)-2 with sodium azide provided azide diol (S)-8 in an excellent yield in the With successful asymmetric desymmetrization of glycerol achieved, we then investigated the synthetic applications of the obtained optically active glycerol. First, the siteselective protection of the remained hydroxy groups in (R)-2 was examined (Scheme 3). The primary hydroxy moiety was selectively protected by using tert-butyldimethylsilyl chloride (TBSCl) with imidazole, affording the corresponding product (R)-6. Acetylation of the secondary hydroxy group with Ac2O in the presence of a DMAP catalyst provided (R)-7 in an excellent yield. Since each protective group would be removed by different deprotecting protocols, (R)-7 would be potentially useful as a versatile chiral C3 building block. Next, we turned our attention to the application of the present transformation in the synthesis of an optically active synthetic ceramide. Ceramides are major components of the lamellar structure in stratum corneum lipids which protect the epidermis from excess transepidermal water loss and from the permeation of pathogens [64]. Interestingly, optically active natural ceramides showed different thermotropic behavior from racemic variants, and the lamellar liquid crystalline system containing optically active natural ceramides improved recovering effects of a water-holding ability and a barrier function of the skin [65]. Sphingolipid E (SLE) was a synthetic ceramide designed and synthesized by Kao Corporation as a structural analog of natural type 2 ceramide and was found to form a stable lamellar structure that exhibits a high water-holding ability [66]. Although SLE has been utilized as a racemic form, optically active SLE might affect the physicochemical property to form a lamellar structure and the interaction mode with water molecules. The synthesis of optically active SLE commenced with the introduction of nitrogen functionality to (R)-2 (Scheme 4). The nucleophilic azide substitution of the tosyloxy group in (R)-2 with sodium azide provided azide diol (S)-8 in an excellent yield in the 91 95 n.d.
With successful asymmetric desymmetrization of glycerol achieved, we then investigated the synthetic applications of the obtained optically active glycerol. First, the siteselective protection of the remained hydroxy groups in (R)-2 was examined (Scheme 3). The primary hydroxy moiety was selectively protected by using tert-butyldimethylsilyl chloride (TBSCl) with imidazole, affording the corresponding product (R)-6. Acetylation of the secondary hydroxy group with Ac 2 O in the presence of a DMAP catalyst provided (R)-7 in an excellent yield. Since each protective group would be removed by different deprotecting protocols, (R)-7 would be potentially useful as a versatile chiral C3 building block. With successful asymmetric desymmetrization of glycerol achieved, we then investigated the synthetic applications of the obtained optically active glycerol. First, the siteselective protection of the remained hydroxy groups in (R)-2 was examined (Scheme 3). The primary hydroxy moiety was selectively protected by using tert-butyldimethylsilyl chloride (TBSCl) with imidazole, affording the corresponding product (R)-6. Acetylation of the secondary hydroxy group with Ac2O in the presence of a DMAP catalyst provided (R)-7 in an excellent yield. Since each protective group would be removed by different deprotecting protocols, (R)-7 would be potentially useful as a versatile chiral C3 building block. Next, we turned our attention to the application of the present transformation in the synthesis of an optically active synthetic ceramide. Ceramides are major components of the lamellar structure in stratum corneum lipids which protect the epidermis from excess transepidermal water loss and from the permeation of pathogens [64]. Interestingly, optically active natural ceramides showed different thermotropic behavior from racemic variants, and the lamellar liquid crystalline system containing optically active natural ceramides improved recovering effects of a water-holding ability and a barrier function of the skin [65]. Sphingolipid E (SLE) was a synthetic ceramide designed and synthesized by Kao Corporation as a structural analog of natural type 2 ceramide and was found to form a stable lamellar structure that exhibits a high water-holding ability [66]. Although SLE has been utilized as a racemic form, optically active SLE might affect the physicochemical property to form a lamellar structure and the interaction mode with water molecules. The synthesis of optically active SLE commenced with the introduction of nitrogen functionality to (R)-2 (Scheme 4). The nucleophilic azide substitution of the tosyloxy group in (R)-2 with sodium azide provided azide diol (S)-8 in an excellent yield in the presence of 15-crown-5. The enantiomeric excess of (S)-8 was determined after the tosylation of the primary hydroxy group, and no obvious racemization was observed in the azide substitution step. The boronic acid-catalyzed site-selective alkylation [67] of (S)-8 with cetyl bromide followed by the Pd/C-catalyzed reduction of the azide group afforded the corresponding aminoalcohol (S)-10. N-Alkylated product (S)-11 was successfully Scheme 3. Synthesis of optically active glycerol derivatives.
Next, we turned our attention to the application of the present transformation in the synthesis of an optically active synthetic ceramide. Ceramides are major components of the lamellar structure in stratum corneum lipids which protect the epidermis from excess transepidermal water loss and from the permeation of pathogens [64]. Interestingly, optically active natural ceramides showed different thermotropic behavior from racemic variants, and the lamellar liquid crystalline system containing optically active natural ceramides improved recovering effects of a water-holding ability and a barrier function of the skin [65]. Sphingolipid E (SLE) was a synthetic ceramide designed and synthesized by Kao Corporation as a structural analog of natural type 2 ceramide and was found to form a stable lamellar structure that exhibits a high water-holding ability [66]. Although SLE has been utilized as a racemic form, optically active SLE might affect the physicochemical property to form a lamellar structure and the interaction mode with water molecules. The synthesis of optically active SLE commenced with the introduction of nitrogen functionality to (R)-2 (Scheme 4). The nucleophilic azide substitution of the tosyloxy group in (R)-2 with sodium azide provided azide diol (S)-8 in an excellent yield in the presence of 15-crown-5. The enantiomeric excess of (S)-8 was determined after the tosylation of the primary hydroxy group, and no obvious racemization was observed in the azide substitution step. The boronic acid-catalyzed site-selective alkylation [67] of (S)-8 with cetyl bromide followed by the Pd/C-catalyzed reduction of the azide group afforded the corresponding aminoalcohol (S)-10. N-Alkylated product (S)-11 was successfully obtained by the reductive amination of (S)-10 with TBS-protected glycolaldehyde using 2-picoline borane as a reductant. Finally, obtained by the reductive amination of (S)-10 with TBS-protected glycolaldehyde using 2picoline borane as a reductant. Finally, (S)-11 was transformed into the optically active synthetic ceramide (S)-12 via the amidation with palmitoyl chloride followed by the removal of the TBS group.

Scheme 4.
Synthesis of an optically active synthetic ceramide.
In conclusion, we have developed the copper-catalyzed asymmetric sulfonylative desymmetrization of glycerol. The reaction smoothly proceeded under mild reaction conditions with a commercially available (R,R)-PhBOX ligand and an inexpensive inorganic base, providing the optically active monotosylated glycerol derivative in a high yield with high enantiomeric excess. The synthetic utility of the present transformation was demonstrated by the preparation of an enantio-enriched C3 building block with three different types of protective groups. Moreover, the synthesis of the optically active synthetic ceramide was also achieved from the monotosylated glycerol in six steps without a notable loss of enantiopurity.

General
Unless otherwise noted, all reactions were performed under an argon atmosphere, and all reagents and solvents were used as received without further purification. Column chromatography was performed on Fuji silysia Chromatorex 60B silica gel. Melting points (mp) were measured with a Yanako Micro Melting Point Apparatus MP-J3 and reported without correction. Infrared (IR) spectra were recorded on a Shimadzu IRAffinity-1 spectrometer and expressed as frequency of absorption (cm −1 ). Optical rotations were measured with JASCO DIP-1000 or P-2200 spectrometers. 1   In conclusion, we have developed the copper-catalyzed asymmetric sulfonylative desymmetrization of glycerol. The reaction smoothly proceeded under mild reaction conditions with a commercially available (R,R)-PhBOX ligand and an inexpensive inorganic base, providing the optically active monotosylated glycerol derivative in a high yield with high enantiomeric excess. The synthetic utility of the present transformation was demonstrated by the preparation of an enantio-enriched C3 building block with three different types of protective groups. Moreover, the synthesis of the optically active synthetic ceramide was also achieved from the monotosylated glycerol in six steps without a notable loss of enantiopurity.

General
Unless otherwise noted, all reactions were performed under an argon atmosphere, and all reagents and solvents were used as received without further purification. Column chromatography was performed on

Copper-Catalyzed Asymmetric Desymmetrization of Glycerol
A solution of (R,R)-PhBOX (33.4 mg, 0.10 mmol) and CuCN (8.96 mg, 0.10 mmol) in CH 2 Cl 2 (4.0 mL) was stirred for 3 h at 40 • C. The reaction mixture was allowed to cool to room temperature and filtered into a round bottom flask using a cotton plug. After removal of the solvent under reduced pressure, the resulting solid was dried in vacuo for 30 min. To the round-bottom flask containing CuCN/(R,R)-PhBOX was added a solution of glycerol (92.1 mg, 1.0 mmol) in acetone (4.0 mL), and the resulting mixture was stirred for 10 min at room temperature. To the mixture was successively added Na 2 CO 3 (159 mg, 1.5 mmol) and TsCl (229 mg, 1.2 mmol), and the mixture was stirred for 3 h at room temperature. The reaction was quenched with saturated aqueous NH 4 Cl, and the resulting mixture was extracted with AcOEt. Combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/AcOEt = 1/2) to afford (R)-2 (236 mg, 0.96 mmol, 96% yield).

Large-Scale Experiment
A solution of (R,R)-PhBOX (200 mg, 0.60 mmol) and CuCN (53.7 mg, 0.60 mmol) in CH 2 Cl 2 (24 mL) was stirred for 3 h at 40 • C. The reaction mixture was allowed to cool to room temperature and filtered into a round bottom flask using a cotton plug. After removal of the solvent under reduced pressure, the resulting solid was dried in vacuo for 1 h. To the round-bottom flask containing CuCN/(R,R)-PhBOX was added a solution of glycerol (553 mg, 6.0 mmol) in acetone (24 mL), and the resulting mixture was stirred for 10 min at room temperature. To the mixture was successively added Na 2 CO 3 (950 mg, 9.0 mmol) and TsCl (1.37 g, 7.2 mmol), and the mixture was stirred for 9 h at room temperature. The reaction was quenched with saturated aqueous NH 4 Cl, and the resulting mixture was extracted with AcOEt. Combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/AcOEt = 1/2) to afford (R)-2 (1.30 g, 5.28 mmol, 88% yield, 93% ee).
After stirring for 24 h at 95 • C, the reaction mixture was diluted with H 2 O and extracted with AcOEt. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/Et 2 O = 8/2) to afford (S)-9 (87. 3  (S)-1-Amino-3-(hexadecyloxy)propan-2-ol ((S)-10). To a reaction vessel charged with 10% Pd/C (24.9 mg, 10% w/w) was added a solution of (S)-9 (249 mg, 0.73 mmol) in MeOH (7.3 mL) at room temperature under argon atmosphere. The reaction vessel was charged with H 2 gas, and then the mixture was stirred for 4 h at room temperature. The reaction mixture was filtered using celite, and then the filtrate was concentrated under reduced pressure. The residue was dissolved in 10% aqueous HCl and washed with AcOEt. The aqueous layer was basified with saturated aqueous NaHCO 3 and then extracted with CHCl 3 . The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford (S)-10 (211 mg, 0. 67  (S)-2,2,3,3-Tetramethyl-4,11-dioxa-7-aza-3-silaheptacosan-9-ol ((S)-11). To a solution of 2-(tert-butyldimethylsilyloxy)acetaldehyde (34.9 mg, 0.20 mmol) [72] in MeOH/CH 2 Cl 2 (5:2, 1.4 mL) was added (S)-10 (69.4 mg, 0.22 mmol) at room temperature. After stirring for 10 min at the same temperature, 2-picoline borane (256 mg, 0.24 mmol) was added, and then the reaction mixture was stirred for an additional 10 h. The reaction mixture was diluted with H 2 O and extracted with CH 2 Cl 2 . The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH 2 Cl 2 /MeOH = 12/1) to afford (S)-11 (  . To a solution of (S)-11 (135 mg, 0.28 mmol) and i-Pr 2 NEt (77.0 mg, 0.60 mmol) in CH 2 Cl 2 (1.4 mL) was added palmitoyl chloride (81.9 mg, 0.30 mmol) at room temperature. After stirring for 1 h at the same temperature, all volatile was removed under reduced pressure. The residue was dissolved in THF (2.8 mL), and then a 1.0 M solution of TBAF in THF (0.57 mL) was added at room temperature. After stirring for 30 min at the same temperature, the reaction mixture was diluted with H 2 O and extracted with CHCl 3 . The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.  13   and TsCl (57.2 mg, 0.30 mmol) at room temperature. After stirring for 10 h at the same temperature, the reaction was quenched with H 2 O, and the resulting mixture was extracted with AcOEt. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt = 2/1) to afford (S)-8 (