Synthesis and Utilization of Fluorine-containing Chiral Building Blocks for Development of the New Type of Drugs

以脯氨酸酯为原料，通过对酯基的修饰，成功地合成了脯氨酸酰胺的电子等排体1.2-（1-氟乙烯基）吡咯烷。通过对C-端和N-端进行适当的保护，制备了α-氟脯氨酸衍生物。实现了含乙内酰脲结构的构象受限寡肽的合成。在α-氟代甘氨酸寡肽的合成研究中，发展了一条新的合成α-氨基酸酰胺的保护路线.虽然α-氟丙二酰二酯的合成是成功的，但所有试图实现二酯的酶水解以得到光学活性单酯的尝试都是不成功的.通过将它们转化为非对映体的薄荷氧基乙酰基衍生物，然后水解，成功地解决了五元磺内酰胺衍生物。磺内酰胺易于氟化得到N-氟代衍生物，其有望成为立体选择性取代的有效试剂。这些试剂被用于一些茚满酮和四氢萘酮的不对称手性合成。当手性中心上同时具有甲基和环己基的N-氟磺内酰胺用于2-甲基-1-四氢萘酮的手性拆分时，获得了最好的结果。这得到2-氟-2-甲基-1-四氢萘酮，产率为80%，ee为80%。以N-酰基-邻甲苯磺酰胺为起始原料，用BuLi处理，然后氢化，合成了六元磺酰胺。制备了相应的N-氟代衍生物，它们已被证明具有足够的亲电性。

1.2-(1-Fluoroethenyl) pyrrolidine, designed as a potential isostere of proline amide, was successfully prepared from proline ester by manipulation of the ester moiety. The alpha-fluoroproline derivative was also prepared by suitable protection of both C- and N-terminals.2. The synthesis of conformationally constrained oligopeptides containing the hydantoin structure was achieved. A new route to the suitably protected alpha-amino acid amides was developed during the synthetic studies of alpha-fluoroglycine-containing oligopeptides.3. Although the synthesis of alpha-fluoromaloni diesters was successful, all attempts to achieve the enzymatic hydrolysis of the diesters to get optically active mono-esters were unsuccessful.4. The five-membered sultam derivatives were successfully resolved by converting them to the diastereomeric menthoxyacetyl derivatives followed by hydrolysis. The sultams were readily fluorinated to give the N-fluoro derivatives, which were expected to be potent agents for stereoselective fluorination. These agents were used for asymmetric fluorination of some indanones and tetralones. The best results were obtained when the N-fluorosultam, having both methyl and cyclohexyl groups on the chiral center, was used for fluorination of 2-methyl-1-tetralone. This gave 2-fluoro-2-methyl-1-tetralone in 80% yield with ee of 80%.5. The synthesis of six-membered sultams was also achieved starting with N-acyl-o-toluenesulfonamides by treatment with BuLi followed by hydrogenation. The corresponding N-fluoro derivatives were prepared and they have been shown to posses enough reactivity for electrophilic fluorination.