A synthetic route from digitoxigenin to 20(22)-dihydro-23-deoxodigitoxigenin (10a) has been developed. Digitoxigenin was aeetylated, dehydrated, and selectively hydrogenated to give 3/3-acetoxy-5/3,20i~card-14-enolide (4). Reduction with lithium aluminum hydride gave diol 5 which was cyclized to yield 3/3-hydroxy-23-deoxo-5/3,20£-card-14-enolide (6). Introduction of the 14/3-hydroxyl (10a) group was achieved by successive formation of the 14/3-hydroxy-15a-bromo ( 7) and /3-epoxide (8) derivatives followed by a reduction step.(1) This investigation was supported by Public Health Service Research Grants CA-10612-03 and CA-10612-04 from the National Cancer Institute and was abstracted in part from the Ph.D. dissertation of F.
A Tautomeric Nitrile-Thiol Iminothiolactone System 607 agent.19 Nitrogen was bubbled through the reaction mixture. After 1 hr. at room temperature, the chromate color had disappeared and 0.2 ml. more of standard chromate reagent was added.with that of a compound previously prepared 16 The melting point of this compound was 205-207°. A mixture of this compound and an authentic sample of VHb8 melted at 203-207°.
In earlier communications1'2 we reported our investigations to find a potent inhibitor of phenylalanine hydroxylase for the purpose of creating a condition of phenylketonuria. As a continuation of this work we have continued to seek potent irreversible inhibitors of the enzyme. Previous results2 showed that introduction of large groups in the 4 position of phenylalanine drastically lowered activity.3-Chloroacetamidophenylalanine was also ineffective as an inhibitor. However, it can be hypothesized that an extended 3 side chain, containing an alkylating function, may achieve alkylation at a location distant from the active site of the enzyme.3
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