Development and Synthetic Application of Metalative Reppe Reaction

本研究开发了新型的Reppe反应，它从三种不同的不对称乙炔得到单一的芳香族化合物。或者，用腈代替上述一个或两个乙炔，我们还开发了氮杂-雷佩反应，产生金属化吡啶或吡咯作为单一异构体。此外，通过这些新的反应还可以制备一些具有生物活性或药用价值的化合物。结果表明：（1）由炔酸酯、末端炔、二价钛醇盐试剂（Ti（O-i-Pr）_4/2 i-PrMgCl（1））和炔丙基溴反应得到苄基钛化合物。该反应被应用于alcyopterosin A的首次合成和抗癌剂pradimicin的芳族部分的有效合成。2）α-吡啶基钛化合物是由炔酰胺、末端炔、钛试剂1和磺酰腈合成的单一异构体。该反应已应用于抗过敏物质苯并环庚吡啶的合成。3)吡啶甲醛作为单一异构体从炔酰胺、末端炔、钛试剂1和腈得到。4）α-吡啶基钛化合物是由乙炔、腈、钛试剂1和磺酰基乙炔合成的单一异构体。以光学活性腈为起始原料，有效地合成了环噻唑霉素的光学活性吡啶单元。5)氨基吡啶是由乙炔、（磺酰氨基）乙炔、钛试剂1和腈得到的单一异构体。6)由不对称乙炔、钛试剂1和两种不同的腈得到单一异构体的吡咯甲醛。

This research has developed new styles of the Reppe reaction, which afford single aromatic compounds as a titanated form from three different, unsymmetrical acetylenes. Alternatively, replacing one or two acetylene(s) above with nitriles, we also developed an aza-Reppe reaction, producing metalated pyridines or pyrroles as a single isomer. Moreover, some biologically active compounds or medicinally important compounds were prepared by these new reactions. Thus, 1)benzyltitanium compounds were obtained as a single isomer from acetylenic esters, terminal acetylenes, a divalent titanium alkoxide reagent (Ti(O-i-Pr)_4/2 i-PrMgCl (1)), and propargyl bromides. This reaction was applied to the first synthesis of alcyopterosin A and an efficient synthesis of an aromatic moiety of an anti-cancer agent, pradimicin. 2)α-Pyridyltitanium compounds were obtained as a single isomer from acetylenic amides, terminal acetylenes, the titanium reagent 1, and a sulfonylnitrile. This reaction was applied to the synthesis of an antiallergic substance, benzocycloheptapyridine. 3)Pyridinecarbaldehydes were obtained as a single isomer from acetylenic amides, terminal acetylenes, the titanium reagent 1, and nitriles. 4)α-Pyridyltitanium compounds were obtained as a single isomer from acetylenes, nitriles, the titanium reagent 1, and a sulfonylacetylene. Starting this reaction with optically active nitriles, we attained an efficient preparation of an optically active pyridine unit of cyclothiazomycin. 5)Aminopyridines were obtained as a single isomer from acetylenes, (sulfonylamino)acetylenes, the titanium reagent 1, and nitriles. 6)Pyrrolecarbaldehydes were obtained as a single isomer from unsymmetrical acetylenes, the titanium reagent 1, and two different nitriles.