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To a solution of hydroxy ester 11a (560 mg, 2.27 mmol) in MeOH (3 mL) was added a solution of LiOH.H2O (110 mg, 2.57 mmol) in water (2 mL). The resulting solution was stirred at room temperature for 1 hour. Methanol was removed under reduced pressure and the residue was partitioned between water (50 mL) and ether (50 mL). Organic layer was separated. Aqueous layer was acidified with concentrated H2SO4 (pH=1-2) in order to convert the corresponding carboxylate salt into free acid and exracted with ether three times (3x50 mL). Combined organics were dried over anhyrous Na2SO4 and concentrated in vacuo to give the crude free acid 16a. The product was directly subjected to the lactonization step without characterization. A solution of the crude acid (500 mg), conc. H2SO4 (60 mg, 0.61 mmol) and (65 mg, 0.30 mmol) HgO in MeOH (6 mL) was stirred at room temperature for 24 hours. Methanol was removed carefully under reduced pressure and the residue was partitioned between water (50 mL) and ether (50 mL). Organic layer was separated and sequentially washed with saturated NaHCO3 solution, brine, dried over anhyrous MgSO4 and concentrated in vacuo to give the crude product. Purification by flash column chromatography eluting with the ((EtOAc/hexane) 1:4 gradient) afforded (S)-(+)-Dihydrokavain 1a 396 mg in 75percent yield over two steps. Recrystallization from ether-hexane produced analytical pure (S)-(+)-dihydrokavain 1 as colorless crystals. m.p.:55-57 °C (ether-hexane), Lit.[3], 56-58 °C (ether-hexane); [a]D31= +30.1 (c=1.08, EtOH), Lit.[1], [a]D20= +29 (c=1.21, EtOH); TLC, Rf: 0,25[(EtOAc:hexane) 1:4], IR (nujol) umax/cm-1 :1700 (C=O), 1622 (C=C); 1H NMR dH (400 MHz, CDCl3) (ppm) 1.88-1.97 (1H, m), 2.08-2.18 (1H, m), 2.30 (1H, dd, J=4 and 17.2), 2.50 (1H, ddd, J=1.2,11.6 and 16.8), 2.74-2.81 (1H, m), 2.84-2.91 (1H, m), 3.72 (3H, s), 4.32-4.39 (1H, m), 5.13 (1H,d, J=1.2), 7.17-7.21 (3H, m, ArH), 7.26-7.30 (2H, m, ArH); 13C NMR dC (100 MHz, CDCl3) (ppm) 31.20, 33.25, 36.54, 56.20, 75.01, 90.58, 126.35, 128.68, 128.74, 141.05, 167.43, 172.91.
Example 1 Synthesis of S-(+)-4-Methoxy-6-phenethyl-5,6-dihydro-pyran-2-one. (S-+-Dihydrokawain) To a stirred solution of (S)-(-)-alpha,alpha-diphenyl-2-pyrrolidinemethanol (770 mg, 3 mmol) in dry THF (100 mL) was added 2 M THF solution of borane-dimethylsulfide complex (11 mL, 22 mmol) at rt under N2. After being stirred at rt for 16 h, a solution of 3-Oxo-5-phenyl-pentanoic acid methyl ester (JACS, 1974, 1082-1087) (6.5 g, 31.5 mmol) in dry THF (20 mL) was added dropwise at rt over a period of 1 h. The resultant clear solution was stirred at rt for another 30 min and was then cooled to 0 C. in an ice bath. The reaction was quenched by the addition of MeOH (90 mL) and the reaction pot was concentrated under reduced pressure. The residue was taken up with EtOAc (200 mL) and washed successively with H2O (100 mL), citric acid (100 mL), 5% NaHCO3 (100 mL) and brine (100 mL). After being dried over Na2SO4, the solvent was removed to afford an oil. Flush column chromatography purification on silica gel gave 3-Hydroxy-5-phenyl-pentanoic acid methyl ester as an oil (3.3 g, 51%) with 92% e.e. (judged from the corresponding Mosher's ester). 1H NMR (300 MHz, CDCl3) delta1.6-1.9 (m, 2H), 2.4-2.6 (m, 2H), 2.65-2.9 (m, 2H), 3.05 (d, 1H, J=6), 3.7 (s, 3H), 3.95-4.10 (m, 1H), 7.10-7.35 (m, 5H). ESMS calcd (C12H16O3): 208.1; found: 209.1 (M+H)+.
With sulfuric acid; mercury(II) oxide; at 20℃; for 24h;
To a solution of hydroxy ester 11a (560 mg, 2.27 mmol) in MeOH (3 mL) was added a solution of LiOH.H2O (110 mg, 2.57 mmol) in water (2 mL). The resulting solution was stirred at room temperature for 1 hour. Methanol was removed under reduced pressure and the residue was partitioned between water (50 mL) and ether (50 mL). Organic layer was separated. Aqueous layer was acidified with concentrated H2SO4 (pH=1-2) in order to convert the corresponding carboxylate salt into free acid and exracted with ether three times (3x50 mL). Combined organics were dried over anhyrous Na2SO4 and concentrated in vacuo to give the crude free acid 16a. The product was directly subjected to the lactonization step without characterization. A solution of the crude acid (500 mg), conc. H2SO4 (60 mg, 0.61 mmol) and (65 mg, 0.30 mmol) HgO in MeOH (6 mL) was stirred at room temperature for 24 hours. Methanol was removed carefully under reduced pressure and the residue was partitioned between water (50 mL) and ether (50 mL). Organic layer was separated and sequentially washed with saturated NaHCO3 solution, brine, dried over anhyrous MgSO4 and concentrated in vacuo to give the crude product. Purification by flash column chromatography eluting with the ((EtOAc/hexane) 1:4 gradient) afforded (S)-(+)-Dihydrokavain 1a 396 mg in 75% yield over two steps. Recrystallization from ether-hexane produced analytical pure (S)-(+)-dihydrokavain 1 as colorless crystals. m.p.:55-57 C (ether-hexane), Lit.[3], 56-58 C (ether-hexane); [a]D31= +30.1 (c=1.08, EtOH), Lit.[1], [a]D20= +29 (c=1.21, EtOH); TLC, Rf: 0,25[(EtOAc:hexane) 1:4], IR (nujol) umax/cm-1 :1700 (C=O), 1622 (C=C); 1H NMR dH (400 MHz, CDCl3) (ppm) 1.88-1.97 (1H, m), 2.08-2.18 (1H, m), 2.30 (1H, dd, J=4 and 17.2), 2.50 (1H, ddd, J=1.2,11.6 and 16.8), 2.74-2.81 (1H, m), 2.84-2.91 (1H, m), 3.72 (3H, s), 4.32-4.39 (1H, m), 5.13 (1H,d, J=1.2), 7.17-7.21 (3H, m, ArH), 7.26-7.30 (2H, m, ArH); 13C NMR dC (100 MHz, CDCl3) (ppm) 31.20, 33.25, 36.54, 56.20, 75.01, 90.58, 126.35, 128.68, 128.74, 141.05, 167.43, 172.91.
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