Diisobutylaluminum hydride → Diisopropylamine

Participants

Reaction Conditions

Reaction Steps

Synthesis of Dienes 23 and 24 as illustrated in FIG. 4. EDC Coupling of Alcohol 18a with Keto Acid 21. A solution of keto acid 21 (2.43 g, 14.3 mmol, 1.2 equiv), 4-(dimethylamino)pyridine (4-DMAP, 0.145 g, 1.2 mmol, 0.1 equiv) and alcohol 18a (4.048 g, 11.9 mmol, 1.0 equiv) in methylene chloride (40 mL, 0.3 M) was cooled to 0° C. and then treated with 1-ethyl-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (EDC, 2.74 g, 14.3 mmol, 1.2 equiv). The reaction mixture was stirred at 0° C. for 2 h and then at 25° C. for 12 h. The solution was concentrated to dryness in vacuo, and the residue was taken up in EtOAc (10 mL) and water (10 mL). The organic layer was separated, washed with saturated NH4Cl solution (10 mL) and water (10 mL) and dried (MgSO4). Evaporation of the solvents followed by flash column chromatography (silica gel, 4% EtOAc in hexanes) resulted in pure keto ester 22a (5.037 g, 86%). Step B. Aldol Condensation of Ester 22a with Aldehyde 7. A solution of keto ester 22a (1.79 g, 3.63 mmol, 1.0 equiv) in THF (15 mL) was added via cannula to a freshly prepared solution of lithium diisopropylamide [LDA; formed by addition of n-BuLi (2.83 mL, 1.6 M solution in hexanes, 4.58 mmol, 1.25 equiv) to a solution of diisopropylamine (0.61 mL, 4.36 mmol, 1.2 equiv) in THF (30 mL) at −10° C. and stirring for 30 min] at −78° C. After 15 min the reaction mixture was allowed to warm to −40° C. and was stirred for 45 min. The reaction mixture was cooled to −78° C. and a solution of aldehyde 7 (0.740 g, 5.8 mmol, 1.6 equiv) in THF (15 mL) was added dropwise. The resulting mixture was stirred for 15 min, then warmed to −40° C. for 30 min, cooled back to −78° C. and then quenched by slow addition of saturated aqueous NH4Cl solution (10 mL). The reaction mixture was warmed to 25° C., diluted with EtOAc (10 mL) and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4), concentrated under reduced pressure and subjected to flash chromatographic purification (silica gel, 5 20% EtOAc in hexanes) to afford a mixture of aldol products 23 (926 mg, 42%) and 24 (724 mg, 33%), along with unreacted starting keto ester 22a (178 mg, 10%).

Provenance & Evidence