合成路线1

In a further process, the proline analogue (XI) is prepared starting from ethyl chrysanthemate (LV). Oxidative cleavage of the isobutenyl side-chain of compound (LV) with KMnO4 followed by alkaline hydrolysis of the ethyl ester group provides caronic acid (XLV) as a mixture of cis- and trans-isomers. Diacid (XLV) is then converted to the bicyclic anhydride (XLVI) using either trifluoroacetic anhydride or acetic anhydride as dehydrating reagents. Ring opening opening of anhydride (XLVI) with allyl alcohol and quinidine, followed by resolution with (R)-(+)-α-methylbenzylamine gives the chiral monoallyl ester (LVI), which is subsequently coupled with ammonium bicarbonate by means of di-tert-butyl dicarbonate and pyridine to afford the amide ester (LVII). After reduction of compound (LVII) with LiAlH4, the resulting amino alcohol (LVIII) is protected as the benzyl carbamate (LIX) by treatment with benzyl chloroformate and K2CO3. The primary alcohol (LIX) is then oxidized to aldehyde (LX) by means of sodium hypochlorite and a catalytic amount of TEMPO. Cyclization of aldehyde (LX) with AcOH in EtOH followed by replacement of the EtOH solvent with THF gives a mixture of the bicyclic hemiaminal (LXI) and its O-ethyl derivative (LXII), which, without separation, is treated with cyanotrimethylsilane and boron trifluoride etherate to afford nitrile (LXIII). Addition of NaOMe to the nitrile (LXIII) followed by aqueous hydrolysis of the obtained imidate (LXIV) provides ester (LXV), which can be alternatively obtained by treatment of nitrile (LXIII) with acetyl chloride in MeOH, followed by addition of water. Finally, the benzyl carbamate (LXV) is then deprotected by hydrogenation over Pd/C to yield the cyclopropanefused prolinate ester (XI) .