ethyl 8-fluoro-1,4-dioxaspiro[4.5]decane-8-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of crude ethyl 8-fluoro-1,4-dioxaspiro[4.5]decane-8-carboxylate, Intermediate 30, (16.26 g, 70 mmol calculated based on previous reaction, 1 equiv) in THF (100 mL) was added LiBH4 (45.5 mL of a 2 M solution in THF, 91 mmol, 1.3 equiv) followed by MeOH (3.68 mL, 91 mmol, 1.3 equiv). Significant warming was observed following MeOH addition. The reaction was stirred 30 min at which time TLC showed no ester remaining. The reaction was poured into a saturated aqueous solution of NaHCO3 and the aqueous solution was extracted with ether (×3). The combined ether layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (30-90% ethyl acetate/hexane) to provide the title compound (7.50 g, 56% yield for 2 steps) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.90-4.03 (m, 4H), 3.64 (d, J=6.78 Hz, 1H), 3.59 (d, J=6.78 Hz, 1H), 1.97-2.09 (m, 2H), 1.84-1.95 (m, 2H), 1.62-1.80 (m, 4H); 19F NMR (376 MHz, CDCl3) δ ppm −171.25 (br. s., 1F). Significant warming the aqueous solution was extracted with ether (×3) The combined ether layers were dried (MgSO4) concentrated in vacuo The crude product was purified by silica gel chromatography (30-90% ethyl acetate/hexane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (15 g, 70.0 mmol, 1 equiv) in THF (200 mL) at 0° C. (ice water bath), was added LiHMDS (98 mL of a 1 M solution in THF, 98 mmol, 1.4 equiv) in 4 portions over ˜2 min. After stirring 1 h, N-fluoro-di(benzenesulfonyl)-amine (26.5 g, 84 mmol, 1.2 equiv) was added. The reaction was stirred 20 min then poured into a saturated aqueous solution of NaHCO3. The aqueous solution was extracted with ether (×3). The combined ether layers were dried (MgSO4) and concentrated in vacuo. Crude residue was stirred with hexane (˜600 mL) and filtered. The filtrate was concentrated in vacuo to give 16.68 g of the crude product as a yellow oil. ˜4:1 product:sm. Taken on as is to the ester reduction. 1H NMR (400 MHz, CDCl3) δ ppm 4.25 (q, J=7.11 Hz, 2H), 3.94-4.00 (m, 4H), 2.02-2.26 (m, 4H), 1.92 (td, J=13.30, 4.77 Hz, 2H), 1.66-1.77 (m, 2H), 1.31 (t, J=7.03 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ ppm −168.50 (br. s., 1F). The reaction was stirred 20 min The aqueous solution was extracted with ether (×3) The combined ether layers were dried (MgSO4) concentrated in vacuo Crude residue was stirred with hexane (˜600 mL) filtered The filtrate was concentrated in vacuo