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

短句来源以脯氨酸酯为原料，通过对酯段的处理，成功地制备了脯氨酸酰胺的异位异构体——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。合成了含有该结构的构象约束型寡肽。在含α -氟甘氨酸寡肽的合成研究中，开辟了一条获得适当保护的α -氨基酸酰胺的新途径。虽然成功地合成了-氟马洛尼二酯，但所有试图将二酯酶解得到光学活性单酯的尝试都是不成功的。通过将五元硫丹衍生物转化为非对映异构体的薄荷氧乙酰基衍生物，然后水解，成功地分离了五元硫丹衍生物。磺胺类化合物很容易被氟化，得到n -氟衍生物，有望成为立体选择性氟化的有效试剂。这些试剂用于一些吲哚酮和四酮的不对称氟化。用手性中心同时具有甲基和环己基的n -氟舒坦氟化2-甲基-1-四酮的效果最好。2-氟-2-甲基-1-四酮的收率为80%，ee为80%。以n -酰基-邻甲苯磺酰胺为原料，经BuLi处理，再加氢，合成了六元磺胺。制备了相应的n -氟衍生物，并证明它们具有足够的亲电氟化反应活性。

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.