合成路线1

Condensation of the (3R)-3-pyrrolidinol (I) and the phenylglyoxylate (II) using a procedure described by Bittner gave the (3S)-alpha-keto-ester (III). Wittig reaction of the (3S)-alpha-keto-ester (III) and the phosphonium salts (IV) using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base, followed by catalytic hydrogenation gave the ethyl propanoate derivatives (VI) as an equivalent mixture of two diastereoisomers. The mixture (VI) gave the pure (2S,3'S)-isomer (VII) by means of crystallization in ethanol. Pinner synthesis was applied for the single isomer (VII) to give the amidine (VIII). Treatment of the amidine (VIII) with ethyl acetimidate hydrochloride yielded the N-acetimidoyl derivative (IX). Conversion of (IX) to the final product, DX-9065a, was accomplished by acidic hydrolysis followed by crystallization. The absolute configuration of DX-9065a was assigned as (2S,3'S) based on X-ray crystallographic analysis and the (3'S) configuration of the 3 position on the pyrrolidine ring.