合成路线1

Hydrogenolysis of the benzyloxycarbonyl protecting group in N-Cbz-L-cyclohexylglycyl-L-tert-leucine methyl ester (I) in the presence of Pearlman’s catalyst in MeOH gives the free dipeptide ester (II), which is acylated with pyrazinecarboxylic acid (III) by means of DCC in dichloromethane/THF to yield the N-acyl dipeptide (IV) (1). Alkaline hydrolysis of the methyl ester (IV) followed by coupling of the resulting carboxylic acid (V) with ethyl cis-perhydrocyclopenta[c]pyrrole-1-carboxylate (VI) by means of DCC provides the acyl tripeptide ester (VII), which is then hydrolyzed to the corresponding carboxylic acid (VIII) upon treatment with NaOH in EtOH (1, 2). Coupling of L-norvaline (IX) with cyclopropylamine (X) in the presence of EDC and N-hydroxysuccinimide followed by catalytic hydrogenolysis of the N-Cbz group provides N-cyclopropyl-norvalinamide (XI) (3). Subsequent condensation of aminoamide (XI) with the N-acyl tripeptide (VIII) using either PyBOP or EDC/HOBt gives the tetrapeptide derivative (XII). Finally, oxidation of the secondary alcohol (XII) by means of Dess-Martin periodinane or NaOCl and a catalytic amount of TEMPO furnishes the title α-ketoamide (1-3). Scheme 1.