p-Toluenesulfonic acid → (+)-Pantolactone

Participants

Reaction Conditions

Reaction Steps

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.

Provenance & Evidence