Design ＆ Synthesis of Novel Enantioselctive Fluorinationg Agents

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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