T. Vantruong et H. Rapoport, CHIROSPECIFIC SYNTHESIS OF THE TETRAHYDROIMIDAZODIAZEPINOL AGLYCON OFPENTOSTATIN AND ITS ANALOGS, Journal of organic chemistry, 58(22), 1993, pp. 6090-6096
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.