Enantiopure Trisubstituted Tetrahydrofurans with Appendage Diversity: Vinyl Sulfone- and Vinyl Sulfoxide-Modified Furans Derived from Carbohydrates as Synthons for Diversity Oriented Synthesis

Enantiomerically pure 2-substituted-2,5-dihydro-3-(aryl) sulfonyl/sulfinyl furans have been prepared from the easily accessible carbohydrate derivatives. The orientation of the substituents attached at the C-2 position of furans is sufficient to control the diastereoselectivity of the addition of various nucleophiles to the vinyl sulfone/sulfoxide-modified tetrahydrofurans, irrespective of the size of the group. The orientation of the substituents at the C-2 center also suppresses the influence of sulfoxides on the diastereoselectivity of the addition of various nucleophiles. The strategy leads to the creation of appendage diversity, affording a plethora of enantiomerically pure trisubstituted furanics for the first time.


Introduction
In order to increase the efficiency of a synthetic strategy for creating appendage, stereochemical, and scaffold diversities, explosive growth has taken place in the area of diversity-oriented synthesis (DOS) [1][2][3][4][5][6][7][8][9][10][11][12]. However, the imposition of stereocontrol in DOS remains a most difficult task. The asymmetric version of multicomponent reactions, considered as the cornerstone of DOS [4,7], has started emerging only recently [13]. It would be logical to use enantiopure substrates for the generation of new appendage or skeletal diversities with defined stereogenic centers in DOS, but in reality only a limited number of enantiopure "chiral pool" substrates such as carbohydrates have been utilized [2,3,7,8,13].
Carbohydrates as the source of chirality carbons are thoroughly underutilized and understudied in DOS [13], although carbohydrates are by far the most abundant organic compounds on earth. Carbohydrates represent the major portion of the annually renewable biomass [14,15], and it is estimated that, in 2025, up to 30% of raw materials for the chemical industry will be produced from renewable sources such as biomass [16]. As a result of continued efforts, 2,5-dimethylfuran (DMF) [17], a molecule with the potential of an alternative fuel, is now generated from the easily available biomass precursor D-fructose via 5-hydroxymethylfurfural (HMF). However, the conversion of biomass is not restricted to use as an alternative fuel alone. Recent research in this area is generating new tetrahydrofuran derivatives (furanics) such as 2,5-dimethyltetrahydrofuran (DMTHF), 2-methylfuran  Since substituted tetrahydrofuran moiety occurs extensively in natural and synthetic compounds, synthetic approaches to access this class of oxaheterocycles, especially in an enantiopure form, has proliferated during last several decades, and the overall work has been reviewed [19,20]. As part of a program for the generation of enantiomerically pure non-carbohydrate chemicals from easily available carbohydrates, we developed a DOS-based strategy for the construction of enantiopure furofurans from vinyl sulfone-modified mono-as well as bicylic-carbohydrates [21][22][23]. In such a synthesis, our tool was to use highly reactive vinyl sulfone [24][25][26][27][28][29] and vinyl sulfoxide [30][31][32] functional groups that are known as powerful Michael acceptors and efficient partners in Diels-Alder reactions.

Result and Discussion
2-benzyloxymethyl-2,5-dihydro-3-(p-tolyl sulfonyl)-and 2-benzyloxymethylene-2,5-dihydro-3-(p-tolyl sulfinyl)-furans 3 and 4 ( Figure 2) undergoes nucleophilic attack at C-4 position from the -side of the tetrahydrofuran ring in such a fashion that all substituents attached to the furan ring occupy anti-orientations [23]. In order to broaden the scope of converting carbohydrates to furanics, we examined whether the steric bulk at C-2 position of furans would play the deciding role in determining the diastereoselectivity of the addition of nucleophiles to vinyl sulfones and vinyl sulfoxides structurally close to 3 and 4. Therefore, two vinyl sulfone-modified tetrahydrofurans, one with a "small" methyl group at the C-2 position of the furan ring and another with the "large" -CH 2 OTr group at the same position, were prepared and subjected to addition reactions.
Thus, the preparation of vinyl sulfone-modified tetrahydrofuran 10 with a methyl group at C-2 position started from Compound 5 (Scheme 1) [45]. The tosyl compound 5 was heated with p-thiocresol in the presence of NaOMe at 120˝C to afford the sulfide (6). Compound 6 was consecutively treated with trifluoroacetic acid (TFA) and sodium borohydride (NaBH 4 ) to afford the acyclic compound 7. Selective tosylation of Compound 7 afforded the desired enantiomerically pure cyclic compound 8. Oxidation of 8 with magnesium monoperoxyphthalate hexahydrate (MMPP) afforded the sulfone compound 9. The hydroxyl group of 9 was mesylated, and the subsequent elimination of the mesyl group produced the desired vinyl sulfone 10 (Scheme 1). The vinylic proton of 10 at δ 7.17 ( 1 H-NMR) and the corresponding carbon at δ 138.3 ( 13 C-NMR) confirmed the formation of the vinyl sulfone moiety of Compound 10.

Result and Discussion
2-benzyloxymethyl-2,5-dihydro-3-(p-tolyl sulfonyl)-and 2-benzyloxymethylene-2,5-dihydro-3-(p-tolyl sulfinyl)-furans 3 and 4 ( Figure 2) undergoes nucleophilic attack at C-4 position from the -side of the tetrahydrofuran ring in such a fashion that all substituents attached to the furan ring occupy anti-orientations [23]. In order to broaden the scope of converting carbohydrates to furanics, we examined whether the steric bulk at C-2 position of furans would play the deciding role in determining the diastereoselectivity of the addition of nucleophiles to vinyl sulfones and vinyl sulfoxides structurally close to 3 and 4. Therefore, two vinyl sulfone-modified tetrahydrofurans, one with a "small" methyl group at the C-2 position of the furan ring and another with the "large" -CH2OTr group at the same position, were prepared and subjected to addition reactions.
Thus, the preparation of vinyl sulfone-modified tetrahydrofuran 10 with a methyl group at C-2 position started from Compound 5 (Scheme 1) [45]. The tosyl compound 5 was heated with p-thiocresol in the presence of NaOMe at 120 °C to afford the sulfide (6). Compound 6 was consecutively treated with trifluoroacetic acid (TFA) and sodium borohydride (NaBH4) to afford the acyclic compound 7. Selective tosylation of Compound 7 afforded the desired enantiomerically pure cyclic compound 8. The vinyl sulfone-modified tetrahydrofuran 16, having a bulky group like -CH2OTr group at C-2 position, was obtained as follows. α-Anomeric arabino sulfide 11 [48,49] was treated with 70% TFA in water to afford the acyclic aldehyde 12. The aldehyde was directly treated with trityl chloride in pyridine to selectively protect the primary alcohol; the crude material was reduced with NaBH4 in ethanol to produce the trityl protected acyclic sulfide 13 in two steps. Selective tosylation of 13 afforded the cyclic compound 14. Oxidation of 14 produced the corresponding sulfone 15, which, after mesylation, produced the desired tritylated vinyl sulfone 16 (Scheme 2). The vinylic proton of 16 at δ 7.00 and the corresponding carbon at δ 140.8 confirmed the formation of the vinyl sulfone moiety of Compound 16. The vinyl sulfone-modified tetrahydrofuran 16, having a bulky group like -CH 2 OTr group at C-2 position, was obtained as follows. α-Anomeric arabino sulfide 11 [48,49] was treated with 70% TFA in water to afford the acyclic aldehyde 12. The aldehyde was directly treated with trityl chloride in pyridine to selectively protect the primary alcohol; the crude material was reduced with NaBH 4 in ethanol to produce the trityl protected acyclic sulfide 13 in two steps. Selective tosylation of 13 afforded the cyclic compound 14. Oxidation of 14 produced the corresponding sulfone 15, which, after mesylation, produced the desired tritylated vinyl sulfone 16 (Scheme 2). The vinylic proton of 16 at δ 7.00 and the corresponding carbon at δ 140. 8  To synthesize the corresponding vinyl sulfoxides, Compound 8 was oxidized under controlled condition [31] using NaIO4/MeOH-H2O to afford the sulfoxides. Two sulfoxides 17SS and 17RS, formed almost in a 1:1 ratio, were separated. The structure of Sulfoxide 17SS was confirmed by X-ray crystallography (Figure 3), which indirectly confirmed the structure of 17RS. The sulfoxides were separately mesylated to afford 18SS and 18RS, respectively, which were treated with DBU in DCM at room temperature for 3 h to afford desired vinyl sulfoxides 19RS and 19SS, respectively, in excellent yields (Scheme 3). The crystal structure of sulfoxide 17SS (Figure 3) also indirectly confirmed the structure of the corresponding vinyl sulfoxide 19RS. To synthesize the corresponding vinyl sulfoxides, Compound 8 was oxidized under controlled condition [31] using NaIO 4 /MeOH-H 2 O to afford the sulfoxides. Two sulfoxides 17S S and 17R S , formed almost in a 1:1 ratio, were separated. The structure of Sulfoxide 17S S was confirmed by X-ray crystallography ( Figure 3), which indirectly confirmed the structure of 17R S . The sulfoxides were separately mesylated to afford 18S S and 18R S , respectively, which were treated with DBU in DCM at room temperature for 3 h to afford desired vinyl sulfoxides 19R S and 19S S , respectively, in excellent yields (Scheme 3). The crystal structure of sulfoxide 17S S (Figure 3) also indirectly confirmed the structure of the corresponding vinyl sulfoxide 19R S . To synthesize the corresponding vinyl sulfoxides, Compound 8 was oxidized under controlled condition [31] using NaIO4/MeOH-H2O to afford the sulfoxides. Two sulfoxides 17SS and 17RS, formed almost in a 1:1 ratio, were separated. The structure of Sulfoxide 17SS was confirmed by X-ray crystallography ( Figure 3), which indirectly confirmed the structure of 17RS. The sulfoxides were separately mesylated to afford 18SS and 18RS, respectively, which were treated with DBU in DCM at room temperature for 3 h to afford desired vinyl sulfoxides 19RS and 19SS, respectively, in excellent yields (Scheme 3). The crystal structure of sulfoxide 17SS ( Figure 3) also indirectly confirmed the structure of the corresponding vinyl sulfoxide 19RS.  The absolute configuration at the sulfur of vinyl sulfoxides 19RS and 19SS could also be confirmed by comparing the NMR data of 19 with those reported for 2-aryl-3-sulfinyl-2,5-dihydrofuran [23,50]. In the reported data, the vinylic proton was used as a tool for assigning the stereochemistry of sulfur atom because of the highly deshielding effect induced by the sulfinyl oxygen on the vinylic hydrogen [50]. The vinylic proton of Compound 19RS appeared at δ 6.59 in its 1 H-NMR spectrum, whereas that for Compound 19SS appeared at δ 6.52. Thus, it was clear that the chemical shift value of the vinylic proton of 19Rs was much more deshielded than that of 19SS. According to the reported data [50], the higher chemical shift value of the vinylic proton is possible if sulfur oxygen is oriented towards the vinylic proton. It was therefore clear that in Compound 19SS the sulfur oxygen was oriented opposite the vinylic proton. The corresponding trityl protected vinyl sulfoxides were synthesized from the cyclic sulfide (14) via sulfoxides (20). These sulfoxides could not be separated at this stage and therefore were directly converted to vinyl sulfoxides (21) in excellent yields, once again as an inseparable mixture (Scheme 4); two vinylic protons appeared at δ 6.50 and δ 6.81, confirming the formation of the vinyl sulfoxide group. Vinyl sulfone 10 was reacted with sodium methoxide/methanol, dimethylmalonate/KO t Bu, thymine/TMG, benzylamine, cyclohexylamine, and morpholine at room temperature to afford the Michael-adducts 22-27, respectively (Scheme 5). The spectral data of all these compounds were found to be similar to the spectra of compounds obtained from 4 [23]. However, the structures 24 and 25 were confirmed by X-ray crystallography (Figures 4 and 5). Thus, it was clear that all the addition compounds in Scheme 5 were in "arabino" configuration. The tritylated vinyl sulfone-modified tetrahydrofuran 16 was also reacted with sodium methoxide/MeOH, nitromethane/KO t Bu, dimethylmalonate/KO t Bu, thymine/TMG, benzylamine, cyclohexylamine, and morpholine to afford the single diastereomers 28-34, respectively (Scheme 6). Once again, the spectral data established the similarity between the Michael adducts of 4 and Compounds 22-27.
To identify the asymmetric induction by the sulfoxide group, if any, vinyl sulfoxide-modified tetrahydrofurans were treated with sodium methoxide/MeOH, dimethylmalonate/NaH, benzylamine, and cyclohexylamine. Thus, 19RS afforded single diastereomers 35SS-38SS, respectively, and 19SS afforded 35RS-38RS, respectively (Scheme 7). All these Michael-adduct pairs, 35SS/35RS, 36SS/36RS, 37SS/37RS, and 38SS/38RS were separately oxidized with MMPP in MeOH to afford 22-26, respectively, (Scheme 7). The oxidation reactions of amino compounds were terminated within 0.5 h to avoid over-oxidation. The tritylated vinyl sulfoxides 21 were also reacted with a selected group of The absolute configuration at the sulfur of vinyl sulfoxides 19R S and 19S S could also be confirmed by comparing the NMR data of 19 with those reported for 2-aryl-3-sulfinyl-2,5-dihydrofuran [23,50]. In the reported data, the vinylic proton was used as a tool for assigning the stereochemistry of sulfur atom because of the highly deshielding effect induced by the sulfinyl oxygen on the vinylic hydrogen [50]. The vinylic proton of Compound 19R S appeared at δ 6.59 in its 1 H-NMR spectrum, whereas that for Compound 19S S appeared at δ 6.52. Thus, it was clear that the chemical shift value of the vinylic proton of 19Rs was much more deshielded than that of 19S S . According to the reported data [50], the higher chemical shift value of the vinylic proton is possible if sulfur oxygen is oriented towards the vinylic proton. It was therefore clear that in Compound 19S S the sulfur oxygen was oriented opposite the vinylic proton. The corresponding trityl protected vinyl sulfoxides were synthesized from the cyclic sulfide (14) via sulfoxides (20). These sulfoxides could not be separated at this stage and therefore were directly converted to vinyl sulfoxides (21) in excellent yields, once again as an inseparable mixture (Scheme 4); two vinylic protons appeared at δ 6.50 and δ 6.81, confirming the formation of the vinyl sulfoxide group. The absolute configuration at the sulfur of vinyl sulfoxides 19RS and 19SS could also be confirmed by comparing the NMR data of 19 with those reported for 2-aryl-3-sulfinyl-2,5-dihydrofuran [23,50]. In the reported data, the vinylic proton was used as a tool for assigning the stereochemistry of sulfur atom because of the highly deshielding effect induced by the sulfinyl oxygen on the vinylic hydrogen [50]. The vinylic proton of Compound 19RS appeared at δ 6.59 in its 1 H-NMR spectrum, whereas that for Compound 19SS appeared at δ 6.52. Thus, it was clear that the chemical shift value of the vinylic proton of 19Rs was much more deshielded than that of 19SS. According to the reported data [50], the higher chemical shift value of the vinylic proton is possible if sulfur oxygen is oriented towards the vinylic proton. It was therefore clear that in Compound 19SS the sulfur oxygen was oriented opposite the vinylic proton. The corresponding trityl protected vinyl sulfoxides were synthesized from the cyclic sulfide (14) via sulfoxides (20). These sulfoxides could not be separated at this stage and therefore were directly converted to vinyl sulfoxides (21) in excellent yields, once again as an inseparable mixture (Scheme 4); two vinylic protons appeared at δ 6.50 and δ 6.81, confirming the formation of the vinyl sulfoxide group.  Vinyl sulfone 10 was reacted with sodium methoxide/methanol, dimethylmalonate/KO t Bu, thymine/TMG, benzylamine, cyclohexylamine, and morpholine at room temperature to afford the Michael-adducts 22-27, respectively (Scheme 5). The spectral data of all these compounds were found to be similar to the spectra of compounds obtained from 4 [23]. However, the structures 24 and 25 were confirmed by X-ray crystallography (Figures 4 and 5). Thus, it was clear that all the addition compounds in Scheme 5 were in "arabino" configuration. The tritylated vinyl sulfone-modified tetrahydrofuran 16 was also reacted with sodium methoxide/MeOH, nitromethane/KO t Bu, dimethylmalonate/KO t Bu, thymine/TMG, benzylamine, cyclohexylamine, and morpholine to afford the single diastereomers 28-34, respectively (Scheme 6). Once again, the spectral data established the similarity between the Michael adducts of 4 and Compounds 22-27.

General Methods
All reactions were conducted in a N2 atmosphere. Melting points were determined in open-end capillary tubes and are uncorrected. Carbohydrates and other fine chemicals were obtained from commercial suppliers and are used without purification. Solvents were dried and distilled following the standard procedures. TLC was carried out on pre-coated plates (Merck silica gel 60, f254, Merck, Darmstadt, Germany), and the spots were visualized with UV light or by charring the plate dipped in a 5% H2SO4-MeOH solution. Column chromatography was performed on silica gel (230-400 mesh). 1 H-and 13 C-NMR for new compounds were recorded at 200/400 and 50/100 MHz, respectively, using CDCl3 as the solvent in Bruker (Massachusetts, MA, USA) NMR instrument DEPT experiments had been carried out to identify the methylene carbons. Optical rotations were recorded at 589 nm. Mass spectroscopy data were obtained from a mass analyzer (Xevo G2 QTof) consisting of TOF and quadrupole in either ESI + or ESI − mode. The electronic information of compounds is available in the Supplementary Materials.

Compound 6:
A solution of p-thiocresol (2.83 g, 22.85 mmol) and NaOMe (0.98 g, 18.28 mmol) in anhyd DMF (10 mL) was stirred at room temperature for 0.5 h in a nitrogen atmosphere. A solution of Compound 5 (1.5 g, 4.57 mmol) in anhyd DMF (5 mL) was added, and the final solution was heated at 120 °C After 5 h (tlc), the reaction mixture was cooled to room temperature, poured into cold satd. aqueous solution of NaHCO3, and the product was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhyd Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified over silica gel to afford 6 (0.99 g, 78%). Eluent Compound 7: A mixture of Compound 6 (1.0 g, 3.57 mmol) and 70% trifluoroacetic acid in water (10 mL) was stirred at room temperature. After 3 h, (tlc) the reaction mixture was poured into ice-cold satd. Aqueous solution of NaHCO3, and the product was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhyd Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to get a residue. The residue was dissolved in EtOH (15 mL), and NaBH4 (0.55 g, 14.28 mmol) was added at 0 °C. After 4 h at room temperature, the reaction mixture was concentrated under reduced pressure to get a residue. The residue was poured into satd. Aqueous solution of NaHCO3, and the product was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhyd Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified over silica gel to get 7 (0.42 g, 49%). Eluent

General Methods
All reactions were conducted in a N 2 atmosphere. Melting points were determined in open-end capillary tubes and are uncorrected. Carbohydrates and other fine chemicals were obtained from commercial suppliers and are used without purification. Solvents were dried and distilled following the standard procedures. TLC was carried out on pre-coated plates (Merck silica gel 60, f 254 , Merck, Darmstadt, Germany), and the spots were visualized with UV light or by charring the plate dipped in a 5% H 2 SO 4 -MeOH solution. Column chromatography was performed on silica gel (230-400 mesh). 1 H-and 13 C-NMR for new compounds were recorded at 200/400 and 50/100 MHz, respectively, using CDCl 3 as the solvent in Bruker (Massachusetts, MA, USA) NMR instrument DEPT experiments had been carried out to identify the methylene carbons. Optical rotations were recorded at 589 nm. Mass spectroscopy data were obtained from a mass analyzer (Xevo G2 QTof) consisting of TOF and quadrupole in either ESI + or ESI´mode. The electronic information of compounds is available in the Supplementary Materials. Compound 6: A solution of p-thiocresol (2.83 g, 22.85 mmol) and NaOMe (0.98 g, 18.28 mmol) in anhyd DMF (10 mL) was stirred at room temperature for 0.5 h in a nitrogen atmosphere. A solution of Compound 5 (1.5 g, 4.57 mmol) in anhyd DMF (5 mL) was added, and the final solution was heated at 120˝C After 5 h (tlc), the reaction mixture was cooled to room temperature, poured into cold satd. aqueous solution of NaHCO 3 , and the product was extracted with EtOAc (3ˆ10 mL). The combined organic layers were dried over anhyd Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified over silica gel to afford 6 (0.99 g, 78%). Eluent Compound 7: A mixture of Compound 6 (1.0 g, 3.57 mmol) and 70% trifluoroacetic acid in water (10 mL) was stirred at room temperature. After 3 h, (tlc) the reaction mixture was poured into ice-cold satd. Aqueous solution of NaHCO 3 , and the product was extracted with EtOAc (3ˆ10 mL). The combined organic layers were dried over anhyd Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure to get a residue. The residue was dissolved in EtOH (15 mL), and NaBH 4 (0.55 g, 14.28 mmol) was added at 0˝C. After 4 h at room temperature, the reaction mixture was concentrated under reduced pressure to get a residue. The residue was poured into satd. Aqueous solution of NaHCO 3 , and the product was extracted with EtOAc (3ˆ10 mL). The combined organic layers were dried over anhyd Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure. Compound 8: A solution of tosylchloride (0.6 g, 3.09 mmol) in anhyd tolune (5 mL) was dropwise added to a solution of 7 (0.5 g, 2.06 mmol) in a mixture of anhyd pyridine and toluene (1:1; 5 mL) at 0˝C. The mixture was stirred for 0.5 h at 0˝C, and the reaction mixture was stored at +4˝C for 96 h. The mixture was filtered through celite, and the filtrate was evaporated to dryness. Residual pyridine was co-evaporated with toluene. The residue was purified over silica gel to afford 8 (0.28 g, 60%). Eluent Compound 9: MMPP (3.3 g, 6.69 mmol) was added to a solution of 8 (0.5 g, 2.23 mmol) in MeOH (8 mL), and the mixture was stirred at room temperature. After 6 h (tlc), the mixture was evaporated under reduced pressure. The solid residue was stirred in a mixture of EtOAc and satd. aqueous NaHCO 3 solution for 1 h. The organic part was separated, dried over anhyd Na 2 SO 4 , and filtered, and the filtrate was evaporated to dryness. The residue was purified over silica gel to afford 9 (0.51 g, 90%). Eluent Compound 10: A solution of mesylchloride (0.5 mL, 5.85 mmol) in anhyd pyridine (3 mL) was added dropwise to a solution of 9 (0.5g, 1.95 mmol) in anhyd pyridine (5 mL). The mixture was stirred for 0.5 h and stored at +4˝C. After 24 h (tlc), the reaction mixture was poured into ice-cold water, and the product was extracted with EtOAc. The organic layer was dried over anhyd Na 2 SO 4 and filtered, and the filtrate was evaporated to dryness. The residual pyridine was co-evaporated with toluene. The residue was purified over silica gel to afford 10 (0.39 g, 85%). Eluent Compound 13: A mixture of Compound 11 (1.5 g, 1.11 mmol) and aqueous 70% trifluoroacetic acid (10 mL) was stirred at room temperature. After 24 h (tlc), the reaction mixture was poured into the ice-cold satd. aqueous solution of NaHCO 3, and the product was extracted with EtOAc (3ˆ10 mL). The combined organic layers were dried over anhyd Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure to get the residue 12. The residue was dissolved in pyridine, and tritylchloride (0.93 g, 3.33 mmol) was added. The mixture was stirred at room temperature in an inert atmosphere. After 48 h (tlc), the reaction mixture was poured into ice-cold satd. aqueous solution of NaHCO 3, and the product was extracted with EtOAc (3ˆ10 mL). Organic layers were pooled, dried over anhyd Na 2 SO 4 , and filtered, and the filtrate was concentrated under reduced pressure to get a residue. The residue was dissolved in EtOH (40 mL) and NaBH 4 (0.17 g, 4.44 mmol) was added at 0˝C. After 5 h at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was poured into satd. aqueous solution of NaHCO 3 , and the product was extracted with EtOAc (3ˆ10 mL). The combined organic layers were dried over anhyd Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified over silica gel to afford 13 (1.11 g, 40%). Eluent Compounds 17S S and 17R S : A solution of NaIO 4 (2.27 g, 10.7 mmol) in water (3 mL) was added to a well-stirred solution of 8 (2.0 g, 8.92 mmol) in MeOH (25 mL), and the mixture was stirred at room temperature. After 5 h, volatile matters were evaporated to dryness under reduced pressure, and the residue was partitioned between satd. aqueous solution of NaHCO 3 and EtOAc (3ˆ10 mL). The combined organic layer was dried over anhyd Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure to get a residue. The residue was purified over silica gel to afford 17S S and 17R S . Compound  Compound 21: A solution of mesylchloride (0.25 mL, 3.0 mmol) in anhyd pyridine (3 mL) was dropwise added to a stirred solution of 20 (0.5 g, 1.00 mmol) in anhyd pyridine (5 mL) at 0˝C. After 0.5 h, the solution was stored at +4˝C. After 24 h (tlc), the reaction mixture was poured into ice-cold water, and the compound was extracted with EtOAc. The organic layer was separated, dried over anhyd Na 2 SO 4 , and filtered, and the filtrate was evaporated to dryness. Residual pyridine was co-evaporated with toluene. The residue was treated with DBU (0.4 mL, 2.5 mmol) in DCM (8 mL) at ambient temperature for 2 h. Solvent was evaporated under reduced pressure, and the resulting residue was purified over silica gel to afford the diastereomeric mixture of vinyl sulfoxides 21 (0.44 g, 92%). Compound 22: Sodium methoxide (0.02 g, 0.36 mmol) was added to an anhyd methanolic solution (5 mL) of vinyl sulfone 10 (0.043 g, 0.18 mmol), and the mixture was stirred at room temperature. After 4 h (tlc), volatile matters were removed under reduced pressure. The solid residue was stirred in a mixture of EtOAc and satd. aqueous NaHCO 3 solution for 1 h. Organic layers were pooled together, dried over anhyd Na 2 SO 4 , and filtered, and the filtrate was evaporated. The residue thus obtained was purified over silica gel to afford 22 (0.04 g, 89%). Eluent   (5 mL) was stirred at room temperature in a N 2 atmosphere. After 0.5 h, a solution of 10 (0.2 g, 0.84 mmol) in THF (4 mL) was added to the reaction mixture. After stirring for 6 h (tlc), the mixture was evaporated under reduced pressure. The residue was partitioned between a mixture of EtOAc and satd. aqueous NH 4 Cl. The organic part was separated, dried over anhyd Na 2 SO 4 , and filtered, and the filtrate was evaporated to dryness. The residue thus obtained was purified over silica gel coloumn to afford 23 (0.23 g, 78%). Eluent Compound 24: A well-stirred solution of thymine (0.16 g, 1.26 mmol) and TMG (0.11 mL, 0.9 mmol) in DMF (10 mL) was added to 10 (0.043 g, 0.18 mmol), and the mixture was stirred at ambient temperature in a nitrogen atmosphere. After 5 h, the reaction mixture was diluted with EtOAc (20 mL), and the precipitated solid was filtered off. The filtrate was washed with an aqueous satd. aqueous solution of NaHCO 3 , and the aqueous part was extracted with EtOAc (3ˆ10 mL). The combined organic layer was dried over anhyd Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified over silica gel to get 24 (0.05 g, 88%). Eluent Compound 25: Benzylamine (0.2 mL, 1.8 mmol) was added to an anhyd methanolic solution (5 mL) of 10 (0.043 g, 0.18 mmol), and the mixture was stirred at room temperature. After 4 h (tlc), volatile matters were removed under reduced pressure. The residue was partitioned between EtOAc and satd. aqueous NH 4 Cl solution. Then, the organic part was dried over anhyd Na 2 SO 4 and filtered, and the filtrate was evaporated to dryness. The residue thus obtained was purified over silica gel to afford 25 (0.05 g, 88%). Eluent   Compound 30 from 21: Compound 21 (0.3 g, 0.62 mmol) was converted to 40 following the procedure described under the preparation of 36S S . The inseparable mixture 40 was converted to 30 following the procedure described for the preparation of 9.
Compound 33 from 21: Compound 21 (0.3 g, 0.62 mmol) was converted to 41 following the procedure described for the preparation of Compound 37S S . The inseparable mixture 41 was converted to 33 following the procedure described for the preparation of 9. The oxidation of 41 was quenched within 0.5 h to avoid over-oxidation.

Conclusions
A simple strategy was devised for the synthesis of enantiomerically pure 2-substituted 2,5-dihydro-3-(arylsulfonyl)-and 2-substituted-2,5-dihydro-3-(arylsulfinyl)-furans from easily accessible carbohydrate derivatives. Since appendage diversity is one of the three major components of DOS [9], each of the four pure, and a diastereomeric mixture of, Michael acceptors were reacted with a variety of nucleophiles. The reactions were highly efficient, and each of 10, 16, 19R S , and 19S S afforded single diastereomers with varied appendages. The mixture of diastereomers 21 also afforded a pair of diastereomers from the Michael addition. Although the varying steric bulk at C-2 in combination with different nucleophiles could not alter the diastereoselectivity of addition, this strategy opens up a novel route for the synthesis of new enantiopure furanics with appendage diversity. In addition to the synthetic utility of this strategy, the other major observation is that the group, attached to a single chirality carbon (i.e., C-2) originating from carbohydrate irrespective of its size, dictated the formation of all products in anti-anti configurations. Moreover, the group at C-2 suppressed the effect of chiral sulfoxides in the case of vinyl sulfoxide-modified tetrahydrofurans. This strategy is now currently pursued to generate different sets of densely functionalized tetrahydrofurans using a DOS strategy.