2) The reaction of tert-butoxycarbonyl-L-proline (XI) with diazomethane and triethylamine in ether gives the diazoketone (XII), which by treatment with acetic acid at 100 C yields the acetoxyketone (XIII). The deprotection of (XIII) with trifluoroacetic acid affords the unprotected alpha-hydroxyketone (XIV), which is condensed with N-(benzylaminecarbonyl)-L-proline (VI) by means of 1-hydroxybenzotriazole (HOBT) giving the acetylated dipeptide analogue (XV). Finally, this compound is deacetylated with K2CO3 in methanol/water.
1) The reaction of tert-butoxycarbonyl-L-prolinal (I) with trimethylsulfonium iodide (II) and potassium tert-butoxide gives the epoxide (III), which is treated with benzyl alcohol and NaH to perform epoxide ring opening and simultaneous cyclization to yield the oxazolidinone (IV). The hydrolysis of (IV) with KOH affords compound (V), which is condensed with N-(benzylaminocarbonyl)-L-proline (VI) (prepared in situ with benzyl isocyanate (VII) and L-proline (VIII) in the presence of triethylamine) by means of diphenyl phosphoryl azide (DPPA) giving the dipeptide analogue (IX). The oxidation of (IX) with P2O5 in DMSO yields the benzylated JTP-4819 product (X), which is finally deprotected by hydrogenolysis with H2 over Pd/C.