合成路线1

The Diels-Alder cyclization of 1-acetoxy-1,3-butadiene (XIV) with maleimide (XV) in toluene at 80 C gives racemic (3aRS,4RS,7aSR)-4-acetoxy-2,3,3a,4,7,7a-hexahydro-1H-isoindole-1,3-dione (XVI), which is reduced with LiAlH4 in THF to the racemic alcohol (XVII). Optical resolution of (XVII) with Di-p-toluoyl-L-tartaric acid in THF/ethanol/ /water yields the (3aS,4S,7aR)-isomer (XVIII), which is N-protected with tert-butoxycarbonyl anhydride to the protected compound (XIX). The Oppenauer oxidation of (XIX) catalized by aluminum isopropoxide affords the unsaturated ketone (XX), which is condensed with cyanacetic acid (XXI) by means of NaOH in toluene/water to afford the substituted cyanacetic derivative (XXII). The decarboxylation of (XXII) catalized by Cu2O in refluxing acetonitrile gives the suitably substituted ketone (XXIII), which is submitted to a Grignard condensation with 2-methoxy-phenylmagnesium bromide (XXIV) in THF yielding the alcohol (XXV) as a single isomer. The deprotection of (XXV) with HCl in THF affords compound (XXVI) with a free NH group, which is finally acylated with 2(S)-(2-methoxyphenyl)propionic acid (II) by means of SOCl2 and K2CO3 to obtain RPR-111905.