反应详情

In a dry 1 L flask was combined tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (6.53 g, 30.9 mmol) and 5-bromoindanone (7.00 g, 30.9 mmol) in 200 mL dichloroethane. Titanium (IV) isopropoxide (18.3 mL, 61.8 mmol) was added and the reaction was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (26.2 g, 123.6 mmol) was added and the reaction was stirred at room temperature for an additional 16 hours. The reaction was quenched with 400 mL saturated sodium bicarbonate and was stirred for 15 minutes. The mixture was passed through a thin layer of Celite®, resulting in a clear bi-phasic mixture. The two layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 17 g of a crude product as a brown oil. This material was purified via Analogix (Analogix Inc., Burlington, Wis.) chromatography eluting with 100:0→85:15 dichloromethane/methanol over 30 minutes to afford the desired product (9.82 g, 76%) as a brown foam. The enantiomers were separated via preparative chiral HPLC (Column chiralcel OJ-H, 250 mm×4.6 mm, flow-rate 2.5 ml/min, CO2/MeOH (80/20/) mobile phase with 0.1% isopropylamine) to afford the desired product (3-1a, 4.6 g, 36%). MS (ES+) 422.3 (M+H)+. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.67 (dd, 4H), 1.84-1.93 (m, 1H), 2.07-2.16 (m, 1H), 2.72-2.81 (m, 1H), 2.95-3.15 (m, 5H), 3.31 (dd, 4H), 3.85 (br s, 1H), 7.12 (d, 1H), 7.28 (br s, 1H), 7.35 (br s, 1H).

1. customIn a dry 1 L flask was combined
2. stirringthe reaction was stirred at room temperature for an additional 16 hours
3. customThe reaction was quenched with 400 mL saturated sodium bicarbonate
4. stirringwas stirred for 15 minutes
5. customresulting in a clear bi-phasic mixture
6. customThe two layers were separated
7. extractionthe aqueous layer was extracted twice with dichloromethane
8. washThe combined organic layers were washed with brine
9. dry with materialdried over anhydrous sodium sulfate
10. filtrationfiltered
11. concentrationconcentrated
12. customto afford 17 g of a crude product as a brown oil
13. customThis material was purified via Analogix (Analogix Inc., Burlington, Wis.) chromatography
14. washeluting with 100:0→85:15 dichloromethane/methanol over 30 minutes