合成路线1

A new synthesis of BO-2727 has been described: The condensation of (2S,4R)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-2-carbaldehyde (I) with ethyl acetate (II) by means of butyllithium and hexa-methyldisylazane (HMSA) in THF gives 3-[1-(tert-butoxycarbonyl)-4(R)-(tert-butyldimethylsilyloxy) pyrrolidin-2(S)-yl]-3-hydroxypropionic acid ethyl ester (III), which was submitted to column chromatography over silicagel yielding the pure 3(R)-hydroxypropionic acid (IV). The reduction of (IV) with NaBH4 in THF afforded the expected diol (V), which was treated with tosyl chloride and triethylamine to give the monotosylate (VI). The reaction of (VI) first with methylamine in methanol, and then with p-nitrobenzyloxycarbonyl chloride (PNZ-Cl) in the same solvent yielded (2S,4R)-2-[1(R)-hydroxy-3-[N-methyl-N-(p-nitrobenzyloxycarbonyl)amino]propyl] pyrrolidin-4-ol (VII). The reaction of (VII) first with SOCl2 and then with potassium thioacetate afforded the 4(R)-acetylsulfanyl derivative (VIII), which was hydrolyzed with NaOH in methanol/water to the corresponding thiol (IX). The condensation of (IX) with the carbapenem intermediate (X) by means of diisopropylethylamine (DIEA) in acetonitrile gave the precursor (protected) of BO-2727 (XI), which was finally deprotected by hydrogenation with H2 over Pd/C in THF/ethanol/pH-7 buffer.