CHIROSPECIFIC SYNTHESIS OF THE TETRAHYDROIMIDAZODIAZEPINOL AGLYCON OF PENTOSTATIN AND ITS ANALOGS

A high-yield, versatile method is presented for the stereo- and regiospecific synthesis of the aglycon of pentostatin and its analogues using the L-vinylglycine 1 as the chiral educt. From this four-carbon asymmetric core, containing the contiguous carbons of the target ring system, the synthetic process proceeds with development of the R absolute stereochemistry for the hydroxyl group at C-8 and nitrogen or potential nitrogen functions at the other three carbons. Conversion of the alpha-amino ester to an alpha-amino nitrile is followed by formation of the 1,4,5-trisubstituted aminoimidazole. After generating another amine by reduction of an azide, the diazepine is then annealed by treatment with orthoformate. Using this process, a series of (8R)-8-hydroxy-substituted tetrahydroimidazodiazepinols has been prepared. The protecting group protocol allows specific deprotection at N-3 for subsequent glycosylation and other substitution.