Design ＆ Synthesis of Novel Enantioselctive Fluorinationg Agents

新型对映选择性氟化剂的设计与合成

• 批准号: 10557206
• 负责人: TAKEUCHI Yoshio
• 金额: $ 3.2万
• 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: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10557206/
• 关键词: fluorine; asymmetric; fluorinating agents; chiral; 不斉フッ素化; フルオロケトン; フッ素化反応剤; 医薬品; 液晶; フッ素化剤; 生物活性物質; アントラサイクリン; 不斉・合成; ケトン

Several novel chiral N-fluorobenzosultams, BNBT-F, SCBT-F, and MNBT-F, 6), have been developed as efficient, enantioselective electrophilic fluorinating agents.1. Preparation of (R)- and (S)-BNBT-FA novel pathway for the preparation of 3-monosubstituted six-membered benzosultam was developed.N-pivaloyl-o-toluenesulfonamide was treated with 2 equiv of BuLi to produce the cyclized unsaturated sultam, which was hydrogenated and nitrated to yield the corresponding racemic benzosultam. Chemical resolution of the racemic sultam using (+)-10-camphorsulfonyl chloride as derivitazing agent gave the optically pure sultams, which were fluorinated with FClO3, respectively, to afford (R)-and (S)-BNBT-F.2. Synthesis of SCBT-F Two novel cyclization methods mediated by MeSO3H or TMSCl/Nal/MeCN reagent developed for the synthesis of 3,3-disubstituted and spiro six-membered benzosultams. o-Methyl lithiation of N-Boc-o-toluenesulfonamide followed by reaction with (1)-menthone gave the carbinol sulfonamid … More e, which was treated with TMSCl/Nal/MeCN reagent to form the spiro benzosultams as two separable diastereomers that were separately subjected to FClO3 fluorination to give the corresponding diastereomerically pure N-fluorosultams SCBT-F.3. Preparation of (+)- MNBT-FAt first, racemic N-fluorobenzosultam, EMBT-F, was prepared and proved to be a good electrophilic fluorinating agent towards carbanions. Based on this structure, chiral N-fluorobenzosultam, (+)-MNBT-F, was designed for asymmetric fluorination studies. o-Lithiation of N-tert-butyl sulfonamide followed by reaction with the corresponding ester gave the ketone sulfonamide, which was treated with TMSCl/NaI/MeCN reagent to afford the N-sulfonylimine, that underwent bromination and ring expansion to form the racemic benzosultam. Conventional chemical resolution of racemic sultam and followed by fluorination of the optical pure (+)-benzosultam with FClO3 afforded (+)-MNBT-F.4. Enantioselective Fluorination of Prochiral EnolatesBNBT-F, SCBT-F, and (+)-MNBT-F were tested for enantioselective enolate fluorinations. Chiral N-F agents, (R)- and (S)-BNBT-F, make both enantiomers of optically active quaternary a-fluoro carbonyl compounds accessible in modest enantioselectivities. SCBT-F exhibited modest asymmetric inducing abilities with the highest ee, reaching 70% for the enantioselective fluorination of the lithium enolate of 2-methyl-1-tetralone. Chiral N-F agent (+)-MNBT-F exhibited good reactivity towards the corresponding aryl ketone enolates, but showed low enantioselectivities. To demonstrate the potential of this procedure, the fluoro analog of Donepezil was synthesized for biological evaluation employing this "agent-controlled enantioselective fluorination." Less

几种新型的手性N-氟苯磺内酰胺BNBT-F、SCBT-F和MNBT-F（6）已被开发为高效的、对映选择性的亲电氟化剂。以N-新戊酰基-邻甲苯磺酰胺为原料，与2当量BuLi反应生成环化的不饱和磺内酰胺，再经氢化、硝化得到相应的外消旋苯并磺内酰胺。外消旋磺内酰胺用（+）-10-氯代磺酰氯进行化学拆分，得到光学纯的磺内酰胺，再分别用三氯氟甲烷氟化，得到（R）-和（S）-BNBT-F。SCBT-F的合成以MeSO_3H或TMSCl/NaI/MeCN为催化剂，采用两种新的环化方法合成了3，3-二取代和螺环六元苯并磺内酰胺类化合物。N-叔丁氧羰基-邻甲苯磺酰胺经邻甲基锂化，再与（1）-薄荷酮反应，得到甲醇磺酰胺 ...更多信息 e，将其用TMSCl/NaI/MeCN试剂处理以形成作为两种可分离的非对映体的螺苯并磺内酰胺，将其分别进行FClO 3重结晶以得到相应的非对映体纯的N-氟磺内酰胺SCBT-F。（+）-MNBT-F的合成首先合成了外消旋的N-氟苯磺内酰胺（EMBT-F），证明它是一种良好的碳负离子亲电氟化试剂。基于此结构，设计了手性N-氟苯磺内酰胺，（+）-MNBT-F，用于不对称手性研究。N-叔丁基磺酰胺经邻位锂化后与相应的酯反应得到酮磺酰胺，酮磺酰胺经TMSCl/NaI/MeCN试剂处理得到N-磺酰亚胺，N-磺酰亚胺经溴化和扩环得到外消旋苯并磺内酰胺。对外消旋磺内酰胺进行常规化学拆分，然后将光学纯的（+）-苯并磺内酰胺用FClO 3重结晶，得到（+）-MNBT-F。前手性烯醇化物的对映选择性氟化测试了BNBT-F、SCBT-F和（+）-MNBT-F的对映选择性烯醇化物氟化。手性N-F试剂（R）-和（S）-BNBT-F使得光学活性季α-氟羰基化合物的两种对映体以适度的对映选择性可接近。SCBT-F对2-甲基-1-四氢萘酮烯醇锂的不对称诱导能力最强，ee值达到70%。手性N-F试剂（+）-MNBT-F对相应的芳基酮烯醇化物表现出良好的反应性，但表现出较低的对映选择性。为了证明这种方法的潜力，多奈哌齐的氟类似物的合成用于生物学评价，采用这种“试剂控制的对映选择性双链反应”。“减

项目成果

Liu, Z. ; Shibata, N. ; Takeuchi, Y.: "Novel methods for the facile construction of 3,3-disubstituted and 3,3-spiro-2H,4H-benzo [e] 1,2-thiazine-1,1-diones : synthesis of (11S,12R,14R)-2-fluoro-14-methl-11-(methylethyl) spiro [4H-benzo [e]-1,2-thiazine-3,

刘，Z.；

Yoshio Takeuchi,Zhaopeng Liu,Akira Satoh,Tomoki Shiragami,Norio Shibata: "Expeditious Synthesis of 3,4-Dihydro-2H-1λ^6-benzo[e][1,2] thiazine 1,1-Dioxides"Chem.Pharm.Bull.. 47(12). 1730-1733 (1999)

Yoshio Takeuchi、Zhaopeng Liu、Akira Satoh、Tomoki Shiragami、Norio Shibata：“快速合成 3,4-二氢-2H-1λ^6-苯并[e][1,2]噻嗪 1,1-二氧化物”Chem.Pharm .公牛.. 47(12)。1730-1733 (1999)

Takeuchi, Y. ; Liu, Z. ; Akira, S. ; Suzuki, E. ; Shibata, N. ; Kirk, K.L.: "N-Fluoro-3-ethyl-3-methyl-1,1-dioxo-2,3-dihydro-1H-116-benzo [e]1,2-thiazin-4-one, a new and efficient agent for electrophilic fluorination of carbanions."Journal of Fluorine Che

竹内，Y.；

Y. Takeuchi, et al.: "N-Fluoro 3-cyclohexyl-3-methyl-2.3-dihydrobenzo[1.2-d] isothiazole 1・1-Dioxide: An Efficient Agent for Electrophilic Asymmetric Fluorination of Enolates"J. Org. Chem.. 64・15. 5708-5711 (1999)

Y. Takeuchi等人：“N-氟3-环己基-3-甲基-2.3-二氢苯并[1.2-d]异噻唑1·1-二氧化物：烯醇化物亲电不对称氟化的有效试剂”J. .. 64・15. 5708-5711 (1999)

Y.Takeuchi et al: "N-Fluoro-3・ethyl-3-methyl-1,1-dioxo-2,3-dihydro-1H-1λ^6-bemo〔e〕1,2-thiazin-4-one,a new and efficient agent for electrophilicfluorination of carbanions" Journal of Fluorine Chemistry. (未定).

Y.Takeuchi 等人：“N-氟-3·乙基-3-甲基-1,1-二氧代-2,3-二氢-1H-1λ^6-bemo[e]1,2-噻嗪-4-酮，一种新型高效的碳负离子亲电氟化剂”《氟化学杂志》。（待定）。