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

含氟手性结构单元的合成和利用用于新型药物的开发

• 批准号: 07557304
• 负责人: TAKEUCHI Yoshio
• 金额: $ 1.47万
• 依托单位: TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07557304/
• 关键词: alpha-Fluoro-alpha-amino Acid; N-Fluoroproline; Fluorine-containing Peptides; Isostere; Asymmetric Fluorination; Fluorotetralone; Fluoroindanone; Five-membered Sultam; 6員環スルタム; α-フルオロアミノ酸; 2-(1-フルオロエテニル)ピロリジン; タイソスター; TRH類縁体; サリドマイド; フッ化過クロリ

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.

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.尽管α-氟丙二酸二酯的合成是成功的，但所有实现二酯酶促水解以获得光学活性单酯的尝试都没有成功。4.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。

项目成果

Yoshio Takeuchi et al.: "Efficient Synthesis of a New, Highly Versatile Chiral Derivatizing Agent, alpha-Cyano-alpha-fluoro-p-tolylacetic Acid (CFTA)" Chem.Commun.1998. 365-366 (1998)

Yoshio Takeuchi 等人：“高效合成新型、高度通用的手性衍生剂 α-氰基-α-氟-对甲苯基乙酸 (CFTA)”Chem.Commun.1998。

Guenter Haufe et al.: "Synthesis of gamma-Fluoro-alpha-methyl-alpha-amino Acids. New Alkylation Procedure for Ester Imines" Tetrahedron. 54. (1998)

Guenter Haufe 等人：“γ-氟-α-甲基-α-氨基酸的合成。酯亚胺的新烷基化程序”四面体。

Takeuchi, Y.et al.: "Efficient Syuthesis of a new,highly versatile chiral derivatizing agent,α-cyano-αfluor-P-tolylacetic acid(CFTA)" Chem.Commun.1998. 365-366 (1998)

Takeuchi, Y. 等人：“一种新型、高度通用的手性衍生剂 α-氰基-α氟-对甲苯基乙酸 (CFTA) 的高效合成”Chem.Commun.1998 (1998)。

Y.Takeuchi et al.: "Enantioselective Fluorination of Organic Molecules.I.Synthetic Studies of the Agents for Electrophilic,Enantioselective Fluorination of Carbanions" Chem.Pharm.Bull.45(6). 1085-1088 (1997)

Y.Takeuchi 等人：“有机分子的对映选择性氟化。I.碳负离子亲电、对映选择性氟化试剂的合成研究”Chem.Pharm.Bull.45(6)。

Kakuda, H.et al: "X-Ray crystallographic structure determination of some unique chiral suetam derivatives" Chem.Commun.1997. 85-86 (1997)

Kakuda, H.et al：“X 射线晶体结构测定一些独特的手性舒达衍生物”Chem.Commun.1997。