(3R)-3-hydroxy-4,4-dimethyloxolan-2-one

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The aqueous phase (21 ml; Na L-pantoate) was adjusted to pH 1 with about 5 ml of 3 M H2SO4, heated at 80° C. for 15 min and mixed with 8 g of anhydrous Na2SO4. The resulting L-pantolactone was analogously extracted 3× with one volume of ethyl acetate, dried with Na2SO4 and evaporated. For recycling to the hydrolysis, the L-pantolactone melt can be racemized by heating after addition of NaOH in the presence of small amounts of Na L-pantoate (180° C., 3 h). The resulting L-pantolactone was analogously extracted 3× with one volume of ethyl acetate dried with Na2SO4 evaporated For recycling to the hydrolysis by heating

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The aqueous phase (21 ml; Na L-pantoate) was adjusted to pH 1 with about 5 ml of 3 M H2SO4, heated at 80° C. for 15 min and mixed with 8 g of anhydrous Na2SO4. The resulting L-pantolactone was analogously extracted 3× with one volume of ethyl acetate, dried with Na2SO4 and evaporated. For recycling to the hydrolysis, the L-pantolactone melt can be racemized by heating after addition of NaOH in the presence of small amounts of Na L-pantoate (180° C., 3 h). The resulting L-pantolactone was analogously extracted 3× with one volume of ethyl acetate dried with Na2SO4 evaporated For recycling to the hydrolysis by heating

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:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.0025 m-mole of rhodium-1,5-cyclooctadienechloride complex and 0.0065 m-mole of one of the asymmetric ligand compounds indicated in Table 2 were dissolved in 10 ml of THF, and 5 m-mole of ketopantolactone was added thereto. Reduction was carried out at a hydrogen atmosphere of 50 atm. The mixture was stirred at 50° C. for 45 hours. The reaction mixture was concentrated under reduced pressure and distilled under reduced pressure to obtain optically active (R)-(-)pantolactone. The results are shown in Table 2. The reaction mixture was concentrated under reduced pressure distilled under reduced pressure

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

Procedure: 390.5 mg of D-pantolactone was dissolved in 30 ml of a 0.1 N aqueous sodium hydroxide solution and reacted at room temperature for 3 hours to form an aqueous pantoic acid sodium salt solution. Separately, 321 mg of cis-dinitrato-diammine platinum (II) was dissolved in 50 ml of water, and thereto was added the previously prepared aqueous pantoic acid sodium salt solution. After 48-hour reaction at room temperature, water was evaporated away under reduced pressure. Methanol was added to the residue and the produced platinum complex was extracted. Then methanol was removed under reduced pressure to obtain a crude powdery product. This product was again dissolved in methanol and added with acetone, causing reprecipitation. The precipitate was filtered out and dried under reduced pressure to obtain 510 mg of the compound No. 1. reacted at room temperature for 3 hours

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

Procedure: 390.5 mg of D-pantolactone was dissolved in 30 ml of a 0.1 N aqueous sodium hydroxide solution and reacted at room temperature for 3 hours to form an aqueous pantoic acid sodium salt solution. Separately, 321 mg of cis-dinitrato-diammine platinum (II) was dissolved in 50 ml of water, and thereto was added the previously prepared aqueous pantoic acid sodium salt solution. After 48-hour reaction at room temperature, water was evaporated away under reduced pressure. Methanol was added to the residue and the produced platinum complex was extracted. Then methanol was removed under reduced pressure to obtain a crude powdery product. This product was again dissolved in methanol and added with acetone, causing reprecipitation. The precipitate was filtered out and dried under reduced pressure to obtain 510 mg of the compound No. 1. reacted at room temperature for 3 hours

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

Procedure: To a stirring solution comprised of (R)-(−)-pantolactone (44.7 g; 336 mmol) in tetrahydrofuran (625 mL) at 0° C. under a nitrogen atmosphere was added a 60% sodium hydride mineral oil dispersion (14.1 g; 352 mmol) directly in portions. Upon the completion of hydrogen gas liberation, 4-fluoro-2-trifluoromethylbenzonitrile solid (59.0 g; 312 mmol) was added directly. The reaction mixture was allowed to warm slowly to ambient temperature overnight. The reaction mixture was neutralized with saturated aqueous ammonium chloride (500 mL.) The mixture was extracted with ethyl acetate (800 mL) and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate and was concentrated in vacuo to afford 99.83 g of a beige solid. The solid was recrystallized from absolute ethanol (300 mL) to afford 81.56 g of an off-white crystalline solid; 1H-NMR (400 MHz; CDCl3) δ 7.78 (dd, 1H, J=8.6, 0.4 Hz), 7.43 (d, 1H, J=2.5 Hz), 7.31 (dd, 1H, J=8.6, 2.7 Hz), 4.67 (s, 3H), 4.17 (d, 1H, J=9.0 Hz), 4.10 (d, 1H, J=9.0 Hz), 1.29 (s, 6H); 19F-NMR (376 MHz; CDCl3) δ-62.70 (s, 3F). was extracted with ethyl acetate (800 mL) the layers were separated The organic layer was dried over anhydrous magnesium sulfate was concentrated in vacuo

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: The optically active bases (+)- and (-)-3-aminomethylpinane prove astonishingly stable in the course of the various stages of the process. In none of them are measurable quantities of by-products produced, so that when recycling the (+)- or (-)-3-aminomethylpinane and L-pantolactone for re-use, neither the 3-aminomethylpinane nor the racemized pantolactone has to be subjected to special purification treatments. The optical purity of the D-pantolactone obtained in accordance with the process corresponds, within the limits of analytical error, to the data given in Example 3 for the product obtained from a first separation, even after the optically active base used, the racemized pantolactone left in each case, and the solvent used, have been recycled 20 times; this shows that special purification treatments are not necessary. The new process gives optically pure D-(-)-pantolactone in an overall yield of 90%, based on the DL-pantolactone employed. produced, so that when to be subjected to special purification treatments

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

Procedure: Adapting procedures or variations thereof according to O'Brien et al., Tetrahedron Lett. 2002, 43, 5491-5494; Weinges et al., Chem. Ber. 1994, 127, 1305-1309; Johnston et al., J. Chem. Soc. Perkin Trans. I, 2000, 5, 681-695; Iversen et al, J. Chem. Soc. Chem. Commun. 1981, 1240-1241; Wessel et al. J. Chem. Soc. Perkin Trans. I, 1985, 2247-2250; Enders et al., Org. Syntheses 2002, 78, 177-183; and Rai et al., Tetrahedron Lett. 2003, 44, 2267-2269, in a representative example, an oven-dried three necked 3,000 mL round bottomed flask equipped with a Tallboys 138 over-head mechanical stirrer was charged under a nitrogen atmosphere with 97.6-117.1 g (750-900 mmol, 1.25-1.5 mol-eq.) of D-pantolactone. The lactone was dissolved in a mixture of 700 mL of anhydrous cyclohexane (Chx) and 300 mL of anhydrous dichloromethane (DCM). One-hundred twelve (112) mL (151.5 g, 600 mmol) of commercially available O-benzyl 2,2,2-trichloroacetimidate or suitable derivative thereof such as O-(4-methoxybenzyl) 2,2,2-trichloroacetimidate was added and the solution cooled to ca. 0° C. (ice bath). Ca. 2.65 mL (ca. 4.50 g, ca. 30 mmol, ca. 5 mol-%) of anhydrous trifluoromethanesulfonic acid (triflic acid) was added dropwise to the stirred reaction mixture. (Caution: The O-benzylation reaction is exothermic!) Other useful catalyst systems include Brønstedt-acids such as para-toluenesulfonic acid (TsOH), camphorsulphonic acid (CSA), trifluoroacetic acid (TFA), and Lewis-acids such as trifluoroborane diethyl ether complex (BF3.Et2O), trityl tetrafluoroborate (TrBF4), trityl perchlorate (TrClO4), trimethylsilyl trifluoromethanesulfonate (TMSOTf), or tin- and lanthanide triflates (Sn(OTf)2, Ln(OTf)3 in similar or other suitable solvents such as toluene or acetonitrile. The reaction was stirred with gradual warming to room temperature for approximately 24 hours. The reaction was then quenched by addition of water and the reaction mixture was diluted with hexane (Hxn). The reaction mixture was stirred for an additional three hours to ensure hydrolysis of unreacted O-benzyl or (4-methoxybenzyl) 2,2,2-trichloroacetimidate. The reaction mixture was filtered to remove part of the precipitated 2,2,2-trichloroacetamide. After phase separation, the aqueous phase was extracted three more times with hexanes (Hxn), diethyl ether (Et2O), or other suitable solvent. The combined organic extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate (NaHCO3), brine, and dried over anhydrous magnesium sulfate (MgSO4). After filtration and evaporation of the solvents under reduced pressure using a rotary evaporator, the O-protected D- or D/L-pantolactone was obtained as a yellow-brown to colorless, clear oil, typically of high chemical purity as determined by TLC and/or 1H NMR spectroscopy, that solidified upon refrigeration (4° C.). The material thus prepared was generally of sufficient purity to be used directly in the next step without further isolation or purification. Optionally, the isolated material was further purified by silica gel column chromatography using ethyl acetate (EtOAc) and hexane (Hxn) or n-heptane (Hptn) mixtures and/or gradients as eluent to provide O-protected D-pantolactone as a colorless, viscous oil or solid. O-protected D-pantolactone was also further purified by crystallization from pentane (Pnt), hexanes (Hxn), or n-heptane (Hptn) to provide colorless crystals. equipped with a Tallboys 138 over-head mechanical stirrer (Caution: The O-benzylation reaction with gradual warming to room temperature for approximately 24 hours The reaction was then quenched by addition of water the reaction mixture was diluted with hexane (Hxn) The reaction mixture was stirred for an additional three hours hydrolysis of unreacted O-benzyl or (4-methoxybenzyl) 2,2,2-trichloroacetimidate The reaction mixture was filtered to remove part of the precipitated 2,2,2-trichloroacetamide After phase separation the aqueous phase was extracted three more times with hexanes (Hxn), diethyl ether (Et2O), or other suitable solvent The combined organic extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate (NaHCO3), brine dried over anhydrous magnesium sulfate (MgSO4) After filtration and evaporation of the solvents under reduced pressure a rotary evaporator