(2R)-3,3-dimethylbutane-1,2,4-triol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-3,3-dimethylbutane-1,2,4-triol (2.7 g, 20 mmol) and 4-methylbenzenesulfonic acid (0.017 g, 0.10 mmol) were added to 25 mL of acetone and catalytic 4-methylbenzenesulfonic acid (0.017 g, 0.10 mmol) and stirred overnight at ambient temperature. The solution was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with aqueous Na2CO3, dried over MgSO4 and filtered. The filtrate was concentrated to provide 1.7 g of the desired product as a clear oil. The solution was evaporated to the residue was added ethyl acetate The organic layer was washed with aqueous Na2CO3 dried over MgSO4 filtered The filtrate was concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (3.21 g, 24.7 mmol) was added to 30 mL THF and cooled to 0° C. Lithium aluminum hydride (24.7 mL, 24.7 mmol) was added slowly and the reaction was warmed to ambient temperature and heated for 6 hours at reflux, during which a heterogeneous mixture of white solids formed. The reaction was cooled to ambient temperature, and 1 mL water was added, followed by the addition of 1 mL of a 15% NaOH aqueous solution (w/v) and 3 mL of water, and the reaction was stirred overnight. The reaction was passed through Celite and filtered, rinsed with copious amounts of ethyl acetate, then dried over Na2SO4. The mixture was filtered, the filtrate was concentrated, and excess water was azeotroped with toluene-DCM (1-1). The residue was dried under high vacuum for 1 hour to yield 2.4 g of the desired product as a clear thick oil. the reaction was warmed to ambient temperature heated for 6 hours at reflux, during which a heterogeneous mixture of white solids formed The reaction was cooled to ambient temperature filtered rinsed with copious amounts of ethyl acetate dried over Na2SO4 The mixture was filtered the filtrate was concentrated excess water was azeotroped with toluene-DCM (1-1) The residue was dried under high vacuum for 1 hour

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (3.21 g, 24.7 mmol) was added to 30 mL THF and cooled to 0° C. Lithium aluminum hydride (24.7 mL, 24.7 mmol) was added slowly and the reaction was warmed to ambient temperature and heated for 6 hours at reflux, during which a heterogeneous mixture of white solids formed. The reaction was cooled to ambient temperature, and 1 mL water was added, followed by the addition of 1 mL of a 15% NaOH aqueous solution (w/v) and 3 mL of water, and the reaction was stirred overnight. The reaction was passed through Celite and filtered, rinsed with copious amounts of ethyl acetate, then dried over Na2SO4. The mixture was filtered, the filtrate was concentrated, and excess water was azeotroped with toluene-DCM (1-1). The residue was dried under high vacuum for 1 hour to yield 2.4 g of the desired product as a clear thick oil. the reaction was warmed to ambient temperature heated for 6 hours at reflux, during which a heterogeneous mixture of white solids formed The reaction was cooled to ambient temperature filtered rinsed with copious amounts of ethyl acetate dried over Na2SO4 The mixture was filtered the filtrate was concentrated excess water was azeotroped with toluene-DCM (1-1) The residue was dried under high vacuum for 1 hour

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-3,3-dimethylbutane-1,2,4-triol (2.7 g, 20 mmol) and 4-methylbenzenesulfonic acid (0.017 g, 0.10 mmol) were added to 25 mL of acetone and catalytic 4-methylbenzenesulfonic acid (0.017 g, 0.10 mmol) and stirred overnight at ambient temperature. The solution was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with aqueous Na2CO3, dried over MgSO4 and filtered. The filtrate was concentrated to provide 1.7 g of the desired product as a clear oil. The solution was evaporated to the residue was added ethyl acetate The organic layer was washed with aqueous Na2CO3 dried over MgSO4 filtered The filtrate was concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (3.21 g, 24.7 mmol) was added to 30 mL THF and cooled to 0° C. Lithium aluminum hydride (24.7 mL, 24.7 mmol) was added slowly and the reaction was warmed to ambient temperature and heated for 6 hours at reflux, during which a heterogeneous mixture of white solids formed. The reaction was cooled to ambient temperature, and 1 mL water was added, followed by the addition of 1 mL of a 15% NaOH aqueous solution (w/v) and 3 mL of water, and the reaction was stirred overnight. The reaction was passed through Celite and filtered, rinsed with copious amounts of ethyl acetate, then dried over Na2SO4. The mixture was filtered, the filtrate was concentrated, and excess water was azeotroped with toluene-DCM (1-1). The residue was dried under high vacuum for 1 hour to yield 2.4 g of the desired product as a clear thick oil. the reaction was warmed to ambient temperature heated for 6 hours at reflux, during which a heterogeneous mixture of white solids formed The reaction was cooled to ambient temperature filtered rinsed with copious amounts of ethyl acetate dried over Na2SO4 The mixture was filtered the filtrate was concentrated excess water was azeotroped with toluene-DCM (1-1) The residue was dried under high vacuum for 1 hour

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the general procedure for the transacetalization reaction of Description 6, 21.4 g (160.0 mmol) of (2R)-3,3-dimethylbutane-1,2,4-triol (6) was reacted in 400 mL of dichloromethane (DCM) in the presence of 932 μL (1.53 g, 10.0 mmol) of phosphorus(V) oxychloride (POCl3) with 45.6 g (250.0 mmol) of para-anisaldehyde dimethyl acetal. Two-fold purification by silica gel column chromatography using tert-butyl methyl ether (MTBE) and hexane (Hxn) mixtures as eluent (MTBE/Hxn=3:7→MTBE/Hxn=2:3→MTBE/Hxn=1:1→MTBE/Hxn=2:1→MTBE/Hxn=3:1) provided 26.7 g (66% yield) of the title compound (8a) as a pale-yellow liquid. Rf=0.26 (MTBE/Hxn=2:3). 1H NMR (400 MHz, CHCl3): δ=0.86 (s, 3H), 1.16 (s, 3H), 2.01-2.05 (m, 1H), 3.59-3.3.63 (m, 1H), 3.66-3.73 (m, 4H), 3.82 (s, 3H), 5.48 (s, 1H), 6.88-6.94 (m, 2H), 7.42-7.46 (m, 2H) ppm. MS (ESI) m/z: 253.1 (M+H)+. The analytical data for the compound was consistent with that given in the literature (Blakemore et al., J. Org. Chem. 2005, 70, 5449-5460; and Shiina et al., Bull. Chem. Soc. Jpn. 2001, 74, 113-122). Similar yields were obtained using camphorsulfonic acid (CSA) as the acidic catalyst. Two-fold purification by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the general procedure for the transacetalization reaction of Description 6, 6.6 g (49.2 mmol) of (2R)-3,3-dimethylbutane-1,2,4-triol (6) was reacted in 120 mL of dichloromethane (DCM) in the presence of 2.51 g (10.0 mmol) of PPTS with 11.3 mL (11.4 g, 75.0 mmol) of benzaldehyde dimethyl acetal. Purification by silica gel column chromatography using diethylether (Et2O) and hexane (Hxn) mixtures as eluent (Et2O/Hxn=2:3→Et2O/Hxn=1:1→Et2O/Hxn=3:2) provided 4.9 g (45% yield) of the title compound (7a) as a colorless liquid. Rf=0.44 (Et2O/Hxn=2:3). 1H NMR (400 MHz, CHCl3): δ=0.86 (s, 3H), 1.16 (s, 3H), 2.02-2.06 (m, 1H), 3.60-3.64 (m, 1H), 3.68-3.72 (m, 4H), 5.52 (s, 1H), 7.33-7.41 (m, 3H), 7.49-7.53 (m, 2H) ppm. MS (ESI) m/z: 223.0 (M+H)+, 245.0 (M+Na)+. The analytical data for the compound was consistent with that given in the literature. Purification by silica gel column chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Adapting a procedure or a variation thereof according to Blakemore et al., J. Org. Chem. 2005, 70, 5449-5460; Mandel et al., Org. Lett. 2004, 6(26), 4801-4803; Lavallée et al., Tetrahedron Lett. 1986, 27, 679-682; Shiina et al., Bull Chem. Soc. Jpn. 2001, 74, 113-122; Ito et al., Synthesis 1993, 137-140; Callant et al., Tetrahedron: Asymmetry 1993, 4(2), 185-188; Dolle et al., J. Am. Chem. Soc. 1985, 107, 1691-1694; and Matsuo et al., Tetrahedron Lett. 1976, 17(23), 1979-1982, a dry 1,000 mL three-necked flask equipped with a magnetic stirring bar, addition funnel, and reflux condenser topped with rubber septa was charged under a nitrogen atmosphere with 7.8 g (60.0 mmol) of commercially available D-pantolactone. The material was dissolved in 100 mL of anhydrous tetrahydrofuran (THF) and the solution cooled to ca. 0° C. (ice bath). Sixty-five (65) mL (38.5 mmol) of a one molar (1.0 M) solution of lithium aluminum hydride (LAH) in THF was added dropwise and the reaction mixture stirred overnight with gradual warming to room temperature. (Note: To ensure complete global reduction of the lactone several authors recommend heating the reaction mixture to reflux for ca. two hours after the overnight reaction to complete the reduction.) The reaction mixture was again cooled to ca. 0° C. (ice bath) and 4.23 mL of water, 8.46 mL of an aqueous solution of sodium hydroxide (10 wt-%), and 4.23 mL of water were carefully added (Note: Initially, there is a vigorous evolution of hydrogen gas.) and the resulting colorless precipitate was filtered off. The filter residue was washed with dichloromethane (DCM) and the combined filtrates were dried over anhydrous magnesium sulfate (MgSO4). After filtration and evaporation of the solvents under reduced pressure using a rotary evaporator, 6.6 g (82% yield) of the title compound (6) was obtained as a slightly yellow, viscous liquid that was of sufficient purity to be used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ=0.768 (s, 3H), 0.777 (s, 3H), 3.15 (d, J=10.4 Hz, 1H), 3.21 (d, J=10.0 Hz, 1H), 3.22-32 (m, 2H), 3.44-3.52 (m, 1H), 4.20-4.40 (br. m, 3H) ppm. MS (ESI) m/z: 135.03 (M+H)+, 132.89 (M−H)−. The analytical data for the compound was consistent with the proposed structure and with the data given in the literature. Ito et al., Synthesis 1993, 137-140 1976, 17(23), 1979-1982, a dry 1,000 mL three-necked flask equipped with a magnetic stirring bar, addition funnel reflux condenser with gradual warming to room temperature recommend heating the reaction mixture to reflux for ca. two hours after the overnight reaction were carefully added (Note ) and the resulting colorless precipitate was filtered off The filter residue was washed with dichloromethane (DCM) the combined filtrates were dried over anhydrous magnesium sulfate (MgSO4) After filtration and evaporation of the solvents under reduced pressure a rotary evaporator

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the general procedure for the transacetalization reaction of Description 6, 21.4 g (160.0 mmol) of (2R)-3,3-dimethylbutane-1,2,4-triol (6) was reacted in 400 mL of dichloromethane (DCM) in the presence of 932 μL (1.53 g, 10.0 mmol) of phosphorus(V) oxychloride (POCl3) with 45.6 g (250.0 mmol) of para-anisaldehyde dimethyl acetal. Two-fold purification by silica gel column chromatography using tert-butyl methyl ether (MTBE) and hexane (Hxn) mixtures as eluent (MTBE/Hxn=3:7→MTBE/Hxn=2:3→MTBE/Hxn=1:1→MTBE/Hxn=2:1→MTBE/Hxn=3:1) provided 26.7 g (66% yield) of the title compound (8a) as a pale-yellow liquid. Rf=0.26 (MTBE/Hxn=2:3). 1H NMR (400 MHz, CHCl3): δ=0.86 (s, 3H), 1.16 (s, 3H), 2.01-2.05 (m, 1H), 3.59-3.3.63 (m, 1H), 3.66-3.73 (m, 4H), 3.82 (s, 3H), 5.48 (s, 1H), 6.88-6.94 (m, 2H), 7.42-7.46 (m, 2H) ppm. MS (ESI) m/z: 253.1 (M+H)+. The analytical data for the compound was consistent with that given in the literature (Blakemore, et al., J. Org. Chem. 2005, 70, 5449-5460; and Shiina, et al., Bull. Chem. Soc. Jpn. 2001, 74, 113-122). Similar yields were obtained using camphorsulfonic acid (CSA) as the acidic catalyst. Two-fold purification by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the general procedure for the transacetalization reaction of Description 6, 6.6 g (49.2 mmol) of (2R)-3,3-dimethylbutane-1,2,4-triol (6) was reacted in 120 mL of dichloromethane (DCM) in the presence of 2.51 g (10.0 mmol) of PPTS with 11.3 mL (11.4 g, 75.0 mmol) of benzaldehyde dimethyl acetal. Purification by silica gel column chromatography using diethylether (Et2O) and hexane (Hxn) mixtures as eluent (Et2O/Hxn=2:3→Et2O/Hxn=1:1→Et2O/Hxn=3:2) provided 4.9 g (45% yield) of the title compound (7a) as a colorless liquid. Rf=0.44 (Et2O/Hxn=2:3). 1H NMR (400 MHz, CHCl3): δ=0.86 (s, 3H), 1.16 (s, 3H), 2.02-2.06 (m, 1H), 3.60-3.64 (m, 1H), 3.68-3.72 (m, 4H), 5.52 (s, 1H), 7.33-7.41 (m, 3H), 7.49-7.53 (m, 2H) ppm. MS (ESI) m/z: 223.0 (M+H)+, 245.0 (M+Na)+. The analytical data for the compound was consistent with that given in the literature. Purification by silica gel column chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Adapting a procedure or a variation thereof according to Blakemore et al., J. Org. Chem. 2005, 70, 5449-5460; Mandel et al., Org. Lett. 2004, 6(26), 4801-4803; Lavallée et al., Tetrahedron Lett. 1986, 27, 679-682; Shiina et al., Bull. Chem. Soc. Jpn. 2001, 74, 113-122; Ito et al., Synthesis 1993, 137-140; Callant et al., Tetrahedron: Asymmetry 1993, 4(2), 185-188; Dolle et al., J. Am. Chem. Soc. 1985, 107, 1691-1694; and Matsuo et al., Tetrahedron Lett. 1976, 17(23), 1979-1982, a dry 1,000 mL three-necked flask equipped with a magnetic stirring bar, addition funnel, and reflux condenser topped with rubber septa was charged under a nitrogen atmosphere with 7.8 g (60.0 mmol) of commercially available D-pantolactone. The material was dissolved in 100 mL of anhydrous tetrahydrofuran (THF) and the solution cooled to ca. 0° C. (ice bath). Sixty-five (65) mL (38.5 mmol) of a one molar (1.0 M) solution of lithium aluminum hydride (LAH) in THF was added dropwise and the reaction mixture stirred overnight with gradual warming to room temperature. (Note: To ensure complete global reduction of the lactone several authors recommend heating the reaction mixture to reflux for ca. two hours after the overnight reaction to complete the reduction.) The reaction mixture was again cooled to ca. 0° C. (ice bath) and 4.23 mL of water, 8.46 mL of an aqueous solution of sodium hydroxide (10 wt-%), and 4.23 mL of water were carefully added (Note: Initially, there is a vigorous evolution of hydrogen gas.) and the resulting colorless precipitate was filtered off The filter residue was washed with dichloromethane (DCM) and the combined filtrates were dried over anhydrous magnesium sulfate (MgSO4). After filtration and evaporation of the solvents under reduced pressure using a rotary evaporator, 6.6 g (82% yield) of the title compound (6) was obtained as a slightly yellow, viscous liquid that was of sufficient purity to be used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ=0.768 (s, 3H), 0.777 (s, 3H), 3.15 (d, J=10.4 Hz, 1H), 3.21 (d, J=10.0 Hz, 1H), 3.22-32 (m, 2H), 3.44-3.52 (m, 1H), 4.20-4.40 (br. m, 3H) ppm. MS (ESI) m/z: 135.03 (M+H)+, 132.89 (M−H)−. The analytical data for the compound was consistent with the proposed structure and the data given in the literature. Ito et al., Synthesis 1993, 137-140 1976, 17(23), 1979-1982, a dry 1,000 mL three-necked flask equipped with a magnetic stirring bar, addition funnel reflux condenser with gradual warming to room temperature recommend heating the reaction mixture to reflux for ca. two hours after the overnight reaction were carefully added (Note ) and the resulting colorless precipitate was filtered off The filter residue was washed with dichloromethane (DCM) the combined filtrates were dried over anhydrous magnesium sulfate (MgSO4) After filtration and evaporation of the solvents under reduced pressure a rotary evaporator

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of compound obtained in Step A (5.6 g, 41.76 mmol) in dry CH2Cl2 (115 mL) was added p-methoxybenzaldehyde dimethyl acetal (11.42 g, 62.64 mmol) and pyridinium p-toluenesulfonate (2.1 g, 8.35 mmol). The mixture was heated at reflux for 18 h, then was cooled to room temperature and the reaction was quenched with saturated aqueous NaHCO3 solution (50 mL). The separated aqueous layer was extracted with Et2O (3×75 mL) and the combined extracts were washed with saturated aqueous NaCl solution (100 mL) and dried (MgSO4). Filtration and concentration of the filtrate in vacuo left a residue which was purified by flash chromatography (silica gel, gradient elution from 20% Et2O in hexanes to 40% Et2O in hexanes) to give the title compound as a colorless oil. The mixture was heated at reflux for 18 h the reaction was quenched with saturated aqueous NaHCO3 solution (50 mL) The separated aqueous layer was extracted with Et2O (3×75 mL) the combined extracts were washed with saturated aqueous NaCl solution (100 mL) dried (MgSO4) Filtration and concentration of the filtrate in vacuo left a residue which was purified by flash chromatography (silica gel, gradient elution from 20% Et2O in hexanes to 40% Et2O in hexanes)