CHIROSPECIFIC SYNTHESIS OF THE TETRAHYDROIMIDAZODIAZEPINOL AGLYCON OFPENTOSTATIN AND ITS ANALOGS

A high-yield, versatile method is presented for the stereo- and regios pecific synthesis of the aglycon of pentostatin and its analogues usin g the L-vinylglycine 1 as the chiral educt. From this four-carbon asym metric core, containing the contiguous carbons of the target ring syst em, the synthetic process proceeds with development of the R absolute stereochemistry for the hydroxyl group at C-8 and nitrogen or potentia l nitrogen functions at the other three carbons. Conversion of the alp ha-amino ester to an alpha-amino nitrile is followed by formation of t he 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-sub stituted tetrahydroimidazodiazepinols has been prepared. The protectin g group protocol allows specific deprotection at N-3 for subsequent gl ycosylation and other substitution.