1-(3-isopropoxybenzyl)-2-vinylpiperidin-4-one (7.00 g, 25.6 mmol) in methanol (14 ml) was added cyclohexyl isocyanide (3.17 ml, 25.6 mmol) then potassium cyanate (2.08 g, 25.6 mmol) in water (5 ml) was added. 3-Fluoroaniline hydrochloride (3.78 g, 25.6 mmol) was then added at 0° C. The mixture was stirred at rt for 12 hrs. The reaction was incomplete and another half equivalent of cyclohexyl isocyanide (1.59 ml, 12.8 mmol), potassium cyanate (1.04 g, 12.8 mmol), and 3-fluoroaniline hydrochloride (1.89 g, 12.8 mmol) was added. The mixture stirred for an additional twelve hours. The solution was concentrated and purified on silica gel 7% methanol/chloroform with 0.1% triethylamine. The impure product was purified a second time by flash chromatography on silica gel starting with 50% ethyl acetate/hexanes to 100% ethyl acetate. The diastereomers were resolved on a Chiral AD column 10% ethanol/hexanes with 0.3% diethylamine 250 ml/min at 250 nm.
