Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/90588
標題: Development of A New Entry of Highly Nucleophilic and Selective Dibromomethyltitanium and Bromomethyltitanium Complexes and Synthetic studies toward (+)-Valienamine
開發高親核性及高選擇性的二溴甲基鈦錯合物與溴甲基鈦錯合物以及探索不對稱合成(+)-Valienamine
作者: 張書豪
Su-Haur Chang
關鍵字: Dibromomethyltitanium
二溴甲基鈦錯合物
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摘要: We wish to report protocols whereby the direct coupling of CHBr3 with titanium-dibromomethyl-titanium complexes derived from TiCl4-Mg-promoted oxidative additions of CHBr3 can be directed to form dibromomethyl-titanium complexes. With access to this system, we had established the best conditions whereby the direct coupling of CHBr3 with aldehydes and ketones promoted by TiCl4-Mg-THF sysem can be directed to form dibromomethyl alcohols. Not only can these dibromomethyl-titanium complexes be directed to react with simple aldehydes and ketones but they are also suitable for coupling with sterically hindered or enolizable ketones such as 2-indanone and β-tetralone. This novel TiCl4-Mg-THF-promoted CHBr3-tiansfer reaction of CHBr3 provides a new, efficient and practical methology for converting a variety of aldehydes and ketones to dibromomethyl alcohols. The system is highly neuclophilic、highly selective and might become practical dibromomethyl-transfer reagent that is applicable to large-scale synthesis, should prove to be a particular valuable strategy. The direct coupling of CHBr3 with titanium-dibromomethyl-titanium complexes derived from TiCl4-Mg-promoted oxidative additions of CHBr3 can be directed to form dibromomethyl-titanium complexes. With access to this system, we had established the best conditions whereby the direct coupling of CHBr3 with esters promoted by TiCl4-Mg-THF sysem can be directed to form α,α-dibromoketones. The highly neuclophilic systems have good effects in selectivity of intramolecular and intermolecular esters. We wish to report protocols whereby the direct coupling of CH2Br2 with titanium-bromomethyl-titanium complexes derived from TiCl4-Mg-promoted oxidative additions of CH2Br2 can be directed to form bromomethyl-titanium and dibromomethyl-titanium complexes. With access to this system, we had established the best conditions whereby the direct coupling of CH2Br2 with aldehydes and ketones promoted by TiCl4-Mg-THF sysem can be directed to form bromomethyl and dibromomethyl alcohols. (+)-Valienamine, a potent glycosidase, has a cyclohexene framework containing one amino and three hydroxyl groups on four stereogenic carbons. A new strategy toward enantiopure O-isopropylidene-protected Valienamine evolved from controlled construction of a C2 chiral O-isopropylidene-protected cyclohexenediol via ruthenium-catalyzed ring closing metathesis of a C2 chiral O-isopropylidene-protected cyclohexenediol. Regiocontrolled introduction of the hydroxymethyl unit via palladium-promoted carbonylation of vinyl triflate followed by stereocontrolled installation of the amino unit via a displacement of hydroxyl group with net inversion of configuration led efficiently to isopropylidene-protected Valienamine. The requisite C2 chiral octadienediol was readily prepared from the (+)-tartaric acid via a three-step protocol: (a) conventional one-pot elaboration of tartaric acid into O-isopropylidene-protected diamide, (b) coupling of diamide with vinylmagnesium bromide, and (c) stereocontrolled reduction of dienedione.
第一部分 高親核性及高選擇性的二溴甲基鈦錯合物 本實驗室研究由鈦-鎂雙金屬錯合物與溴仿氧化加成後可生成二溴甲基鈦錯合物且應用此錯合物進一步與醛、酮進行反應可得到獨特的二溴甲基醇類化合物。這個藉由氯鈦-鎂誘導溴仿轉移二溴甲基與醛、酮反應以形成二溴甲基醇類化合物的方式與實驗條件,不僅可與一般的醛、酮進行反應,針對低反應性的酮類、易形成enolate的Indanone、tetralone都可得到很好的反應效果。這種與羰基反應以形成二溴甲基醇化合物的方式,不謹具高親核性、高選擇性且在大量的製備上也相當容易同時也有合乎經濟效益的優點。 第二部分 酯進行二溴烯化反應. 製取鄰二溴酮 將鈦-鎂雙金屬錯合物與溴仿氧化加成後所生成二溴甲基鈦錯合物與低反應性的酯類進行二溴甲基化反應,形成二溴乙烯醚,將其水解後可製取少見的鄰二溴酮化合物。此高親核性反應在分子內與分子間的選擇性反應測試中也取得極優的成效。 第三部分 氯鈦-鎂誘導二溴甲烷和醛、酮進行偶合 本實驗室研究由鈦-鎂雙金屬錯合物與低反應性的二溴甲烷氧化加成後可生成溴甲基鈦錯合物且應用此錯合物進一步與醛、酮進行反應可得到獨特的溴甲基醇類化合物。此外,當鈦-鎂雙金屬錯合物與二溴甲烷氧化加成生成的溴甲基鈦錯合物還可與二溴甲烷的作酸鹼平衡反應進而形成二溴甲基醇類化合物,此二溴甲基醇類化合物與第一章所述是相同的,但生產成本與產率均更優於其且還能與立障極大的2,2-Dimethylcyclohexanone反應,是一種全新的反應。 第四部分 探索不對稱合成(+)-Valienamine (+)-Valienamine 具有一個環己烯烷的架構,在其四個立體化學中心的碳上接了一個氨基及三個羥基,是一個有效的α-葡萄糖甘酶抑制劑。在本研究中,本實驗團隊以具有C2對稱的 L-(+)-酒石酸為起始物,在酸性條件下利用DMP將其轉化成 O-isopropylidene-protected diamide,再以 vinylmaganesium bromide 進行偶合反應得到不飽和酮類,接著運用 Luche reduction立體選擇性的還原成diol,最後以Grubbs(II) catalyst進行ring-closing-metathesis,即可合成出具有C2對稱的環己烯烷主體架構。之後再利用分子中C2對稱的特性,可有位置選擇性的引進hydroxymethyl group,合成化合物174,總計11個步驟,產率14.2 %。之後再延伸三個已報導過的步驟,可合成出氨基化合物177。最後若能在適當的酸性條件下將acetonide去保護,理論上應可順利完成(+)-Valienamine的全合成研究。
URI: http://hdl.handle.net/11455/90588
文章公開時間: 2014-02-06
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