To a 50 mL round bottomed flask equipped with a reflux condenser was charged successively (1R,3S)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate hydrochloride salt (0.500 g, 1.494 mmol), trans-bis(benzonitrile)dichloropalladium(II) (0.029 g, 0.075 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.107 g, 0.224 mmol), and cesium carbonate (1.947 g, 5.98 mmol). The flask was evacuated and back-filled with nitrogen for three cycles. Then 7-methoxyhept-1-yne (1.16 g, 9.19 mmol) as a solution in acetonitrile (7.0 ml) was added via syringe. The reaction mixture was heated to about 90° C. After about 4 hours the reaction mixture was cooled to ambient temperature and partitioned into water (50 mL) and ethyl acetate (50 mL). The organic phase was separated, washed with saturated sodium bicarbonate solution (50 mL), brine (50 mL), then dried (MgSO4) and concentrated to yield 1.98 g of crude yellow oil. The crude material was purified via Analogix flash chromatography system using RediSep RS 12 g column, with a gradient of 0-5% methanol in ethyl acetate over 25 min. at 15 mL/min. Fractions containing product were combined and concentrated to yield 0.5 g of greenish yellow oil of (1R,3S)-methyl 1-amino-3-(4-(7-methoxyhept-1-ynyl)phenyl)cyclopentanecarboxylate which was used in the next step without further purification.
