有機催化連鎖反應應用於官能基化螺環與雙環化合物之合成
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2016
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有機催化連鎖反應應用於官能基化螺環與雙環化合物之合成
本文包含三部份：第一章說明有機催化劑在不對稱合成反應的應用與發展，其中包含共價鍵－烯胺及亞胺離子催化反應、非共價鍵－相轉移催化劑、氫鍵催化劑及天然生物鹼作為催化劑，應用於不對稱催化反應，成功建立碳－碳鍵結之例子。
第二章描述三大主題：第一部分說明利用有機催化進行[5+1]環化反應，經由Michael-Aldol 連鎖反應合成六員螺環茚滿-1,3- 二酮/ 羥吲哚
（indane-1,3-diones/oxindoles）。此反應成功地以1,3-二酮/羥吲哚/香豆酮作為雙親核試劑（ dinucleophilic components ） 及(E)-5- 硝基-6- 芳基- 己-5- 烯-2- 酮
（(E)-5-nitro-6-aryl-hex-5-en-2-one）為雙親電子試劑（dielectrophile）於DBACO存在之鹼性條件下，有效得到雙螺環結構之產物，並擁有不錯的產率（30-84%）及非鏡像選擇性（>95 : 5 dr）表現。
第二部分主軸是透過掌性方醯胺（squaramide）催化劑，進行Michael/Aldol 反應，獲得連續三個立體中心之螺環己烷二茚-1,3- 二酮（spirocyclohexaneindan-1,3-diones）衍生物，其中非鏡像及鏡像選擇性均表現優異。
第三部分：透過3-甲基-1-芳基-2-吡唑啉-5-酮（3-methyl-1-aryl-2-pyrazolin-5-ones）與(E)-5-硝基-6-芳基-己-5-烯-2-酮（(E)-5-nitro-6-aryl-hex-5-en-2-ones）為起始物，
加入方醯胺催化劑進行不對Michael/Aldol 連鎖反應，建構了連續四個立體中心之螺吡喃酮（spiropyrazolone）衍生物，並控制其立體選擇性（up to >20: 1 dr, 94%ee）。
第三章描述如何透過溫和的反應條件，發展出鹼催化sulfa-Michael/Aldol 反應合成雙環四氫噻吩（biheterocyclic tetrahydrothiophene）衍生物之方法，並兼具官能基忍受度廣及起始物容易製備等優點，提供一個快速且有效率的雙環化合物合成途徑。
The content of this thesis is divided into three chapters. The chapter-I, illustrate overview on asymmetric synthesis and organocatalysis. It includes, terminology, introduction to asymmetric synthesis, some historical aspects of organocatalysts, classification and utilization of covalent catalysis including iminium and enamine, non-covalent catalysis including phase-transfer catalysts, hydrogen bonding catalysts and importance of alkaloids in asymmetric synthesis as organocatalysts. And successful applications on important C-C bond forming asymmetric Michael domino/cascade/tandem reactions are presented. The interesting art of hydrogen bonding, namely, the formation of double hydrogen bonds between organic molecules is also described. II.1. Organocatalytic formal [5+1] annulation: diastereoselective cascade synthesis of functionalized six-membered spirocyclic indane-1,3-diones/oxindoles via Michael-aldol reaction Chapter-II is divided into 3 sections. Section-1, represents the diastereoselective synthesis of functionalized six membered spirocyclic compounds via Michael-aldol cascade reaction. The reaction proceeds smoothly between indane 1,3-diones/oxindoles/coumaranone as the dinucleophilic components and (E)-5-nitro-6-aryl-hex-5-en-2-one as the dielectrophile in presence of DABCO to give the desired spirocyclic products with reasonable to high chemical yields (30- 84%) and high levels of diastereoselectivities (up to >95:5 dr). II.2. Organocatalytic synthesis of spirocyclohexane indan-1, 3-diones via a chiral squaramide-catalyzed Michael/aldol cascade reaction of γ-nitro ketones and 2- arylideneindane-1, 3-diones. This section describes a chiral squaramide catalyzed stereoselective synthesis of spirocyclohexane indan-1, 3-diones via Michael-aldol cascade reaction of 2-arylideneindan-1, 3-diones and γ- nitroketones. The reaction produces three stereogenic centers having spirocyclohexaneindan-1, 3- diones derivatives with excellent diastereo and high enantioselectivity in good to excellent yields. II.3. Organocatalytic one-pot asymmetric synthesis of functionalized spiropyrazolones via a Michaelaldol sequential reaction. In this section an efficient organocatalytic stereoselective method for the synthesis of functionalized spiropyrazolone derivatives with four contiguous stereogenic centers has been developed through a chiral squaramide catalyzed Michael-aldol sequential reaction. The reaction between 3-methyl-1-aryl-2-pyrazolin-5-ones and (E)-5-nitro-6-aryl-hex-5-en-2-ones is catalyzed by a quinine derived squaramide to give the desired spiropyrazolone derivatives in moderate-to-good yields (up to 80%) with good-to-excellent stereoselectivities (up to >20: 1 dr, 94% ee). III. Organocatalytic diastereoselective [3+2] annulation of 1, 4-dithiane-2, 5-diol and nitro allylic amines via sulfa-Michael-aldol cascade reaction. The chapter III, discloses base catalyzed cascade sulfa-Michael-aldol reaction for the synthesis of novel class of biheterocyclic tetrahydrothiophene derivatives in good yield with high diastereoselectivity. The mild reaction conditions, good functional group tolerance, and broad range of nitro allylic compounds are salient features of this protocol. Due to the easy preparation of the starting materials, we believe this methodology provides a simplified route for the synthesis of biheterocyclic thiophene derivatives.
The content of this thesis is divided into three chapters. The chapter-I, illustrate overview on asymmetric synthesis and organocatalysis. It includes, terminology, introduction to asymmetric synthesis, some historical aspects of organocatalysts, classification and utilization of covalent catalysis including iminium and enamine, non-covalent catalysis including phase-transfer catalysts, hydrogen bonding catalysts and importance of alkaloids in asymmetric synthesis as organocatalysts. And successful applications on important C-C bond forming asymmetric Michael domino/cascade/tandem reactions are presented. The interesting art of hydrogen bonding, namely, the formation of double hydrogen bonds between organic molecules is also described. II.1. Organocatalytic formal [5+1] annulation: diastereoselective cascade synthesis of functionalized six-membered spirocyclic indane-1,3-diones/oxindoles via Michael-aldol reaction Chapter-II is divided into 3 sections. Section-1, represents the diastereoselective synthesis of functionalized six membered spirocyclic compounds via Michael-aldol cascade reaction. The reaction proceeds smoothly between indane 1,3-diones/oxindoles/coumaranone as the dinucleophilic components and (E)-5-nitro-6-aryl-hex-5-en-2-one as the dielectrophile in presence of DABCO to give the desired spirocyclic products with reasonable to high chemical yields (30- 84%) and high levels of diastereoselectivities (up to >95:5 dr). II.2. Organocatalytic synthesis of spirocyclohexane indan-1, 3-diones via a chiral squaramide-catalyzed Michael/aldol cascade reaction of γ-nitro ketones and 2- arylideneindane-1, 3-diones. This section describes a chiral squaramide catalyzed stereoselective synthesis of spirocyclohexane indan-1, 3-diones via Michael-aldol cascade reaction of 2-arylideneindan-1, 3-diones and γ- nitroketones. The reaction produces three stereogenic centers having spirocyclohexaneindan-1, 3- diones derivatives with excellent diastereo and high enantioselectivity in good to excellent yields. II.3. Organocatalytic one-pot asymmetric synthesis of functionalized spiropyrazolones via a Michaelaldol sequential reaction. In this section an efficient organocatalytic stereoselective method for the synthesis of functionalized spiropyrazolone derivatives with four contiguous stereogenic centers has been developed through a chiral squaramide catalyzed Michael-aldol sequential reaction. The reaction between 3-methyl-1-aryl-2-pyrazolin-5-ones and (E)-5-nitro-6-aryl-hex-5-en-2-ones is catalyzed by a quinine derived squaramide to give the desired spiropyrazolone derivatives in moderate-to-good yields (up to 80%) with good-to-excellent stereoselectivities (up to >20: 1 dr, 94% ee). III. Organocatalytic diastereoselective [3+2] annulation of 1, 4-dithiane-2, 5-diol and nitro allylic amines via sulfa-Michael-aldol cascade reaction. The chapter III, discloses base catalyzed cascade sulfa-Michael-aldol reaction for the synthesis of novel class of biheterocyclic tetrahydrothiophene derivatives in good yield with high diastereoselectivity. The mild reaction conditions, good functional group tolerance, and broad range of nitro allylic compounds are salient features of this protocol. Due to the easy preparation of the starting materials, we believe this methodology provides a simplified route for the synthesis of biheterocyclic thiophene derivatives.
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Keywords
不對稱合成, 有機催化, 螺環化合物, 雙環化合物, 連鎖/一鍋化反應, Asymmetric synthesis, Organocatalysis, Spirocycles, Bicycles, Cascade/one-pot reaction