不對稱催化製備螺氧雜吲哚環戊二烯[c] chromen-4-ones和藉由分子內Wittig反應合成多種類雜芳烴

第一部分：本部分以一個章節闡述了有機催化（3 + 2）環加成反應的重要性。以及描述所有碳1,3-偶極反應，特別是通過環加成反應形成的所有碳螺環。第一章：本實驗使用起始物3-高醯基香豆素 (3-homoacyl coumarin) 與亞烷基吲哚酮(alkylidene oxindoles) ，藉由雙功能金雞納鹼催化劑催化逐步的(stepwise) (3+2) 環加成反應去建立具有對掌體選擇性 (enantioselective) 之螺環吲哚酮其架構中含有全碳的五環結構並且有連續五個立體中心，可以得到良好的產率以及立體選擇性，此外我們也更換亞烷基吲哚酮上的取代，包含兩種具有羰基取代的酯基 (ester group)、苯甲醯基 (benzyl group) 以及去除羰基之苯基 (phenyl group) 去比較羰基在氫鍵催化下的影響。放大反應證實此反應即使在克級條件下進行仍然能夠維持良好的產率以及立體選擇性。第二部分：第二部分分為三個章節，闡述了Wittig反應近年來的發展以及在合成各種雜芳烴中的應用。還簡要介紹了一些雜芳烴6/5/5和6/6/5骨架的合成方法及其生物學重要性。此外，本部分探討使用不同方法來形成C–C鍵（例如MBH反應，RC型反應），及其在有機化學中的重要性。第二章：本章節的研究利用本實驗所發表之磷兩性離子 (phosphorus zwitterion) 之合成策略，利用三組分反應(three-component reaction)建構新型磷兩性離子中間體，並在醯氯 (acyl chloride) 以及鹼的作用下，進行Wittig反應建構茚並- [1,2-b]吡咯。藉由反應機構的探討，螺環噁二唑(spiro-indene-1,2'-[1,3,4]oxadiazol)的形成是合成上述雜芳烴的關鍵步驟，出乎意料的是使用不同膦試劑能得到螺環噁二唑衍生物，經由探討發現利用不同親和性的膦試劑能夠影響其脫去與否，進而使得反應導向不同的結果。相比於過去合成茚並- [1,2-b]吡咯的策略，本篇提供一個全新的合成策略，不但能有良好的產率其產物的取代基也相當廣泛。第三章：長期以來，本實驗室一直致力於在不同位置的共軛羰基化合物中添加膦試劑以進行Wittig反應，進而生成磷兩性離子或膦鹽。在延續過去研究的同時，我們對於開發雜環化合物的新方法感興趣。因此，本章節中我們開發了一種通過MBH型/酰基轉移/ Wittig反應構建功能化呋喃[3,2-c]香豆素(furo[3,2-c]coumarins) 的新方法。此方法的特點是兩性離子的O-酰化反應是由PPh3與烷酸酯的MBH型反應形成的，生成了甜菜鹼(betaine)中間體，該中間體通過前所未有的酰基轉移/Wittig反應進一步產生了上述雜芳烴。在無金屬的一鍋化反應中藉由末端鏈烷酸酯(terminal alkynoates)和酰氯的幫助下，成功在呋喃[3,2-c]香豆素的芳香環上建立酮官能基並且同時形成兩個雜環。此外，此方法也可適用於內部鏈烷酸酯(internal alkynoates) /丙酰胺類(propiolamides)化合物，通過MBH型/ Wittig反應生成2,3-二取代的呋喃[3,2-c]香豆素和呋喃[3,2-c]喹啉酮(furo[3,2-c]quinolinones)。第四章：本章節討論了通過RC型/酰基轉移/ Wittig策略合成螺環[環戊達[c]色烯-二氫吲哚]二酮衍生物的方法。螺環產物是在溫和且無金屬的條件下從簡單的帶有羥吲哚的鏈烷酸酯作為起始物所製備而得，具有良好至高的產率。經由RC型/ Wittig反應同時形成兩個雜環，其由末端炔酸酯，PPh3和酰氯形成螺[環戊[c]亞甲基-吲哚]二酮。

關鍵字

逐步（3 + 2）環加成；螺環吲哚；環戊色酮；化學選擇性；茚並[1,2-b]吡咯；酰化；磷兩性離子；威悌反應； MBH反應；呋喃[3,2-c]香豆素；酰基轉移；威悌反應； RC型反應；螺環[環戊[c]亞甲基-吲哚啉]二酮；末端炔酸

並列摘要

PART-I This part contains one chapter, which illustrates the importance of organocatalytic stepwise (3+2) cycloaddition reactions. Also describe about all carbon 1,3-dipoles and its reactions, specifically formation of all carbon spiro-rings via cycloaddition reactions. CHAPTER-1: “Enantioselective Construction of Spirooxindole-Fused Cyclopenta[c]chromen-4-ones Bearing Five Contiguous Stereocenters via a Stepwise (3+2) Cycloaddition.” In this section, we demonstrated bifunctional quinine-catalyzed stepwise (3+2) cycloaddition for the enantioselective construction of spirooxindole-fused cyclopenta[c]chromen-4-one derivatives. The reactions of 3-homoacylcoumarins and alkylidene oxindole electrophiles generate aforementioned spirooxindole-chromenone adducts bearing five contiguous stereocenters, of which one is the spiro all-carbon quaternary stereocenter in high yields (up to 99%) with excellent stereoselectivities (up to >20:1 dr and 99% ee). Different Michael acceptors such as alkylidene oxindole esters, ketones and benzylidene oxindoles were investigated for the substrate scope of this stepwise (3+2) cycloaddition reaction. This methodology was investigated for three different alkylidene oxindole electrophiles and could also be practically demonstrated on a gram scale. Mechanistic investigations revealed that the (3+2) cycloaddition for the enantioselective synthesis of spirooxindole-fused cyclopenta[c]chromen-4-ones is proceeding via a stepwise reaction pathway. Key words: Stepwise (3+2) cycloaddition reaction, spirooxindole, cyclopentachromenones. PART-II This part is subdivided into three chapters, which illustrates the brief history of Wittig reaction, its development throughout these years and its applications toward synthesis of diverse heteroarenes. In addition, the brief introduction about some elegant synthetic methods of 6/5/5 and 6/6/5 framework of heteroarenes and its biological importance is discussed. Moreover, discussion about formation C–C bonds using different protocols such as the MBH reaction , RC type reaction and its importance in organic chemistry. CHAPTER-2: “Construction of Indeno[1,2-b]pyrrole derivatives via Chemoselective Phosphours Zwitterion Formation/N-Acylation/Wittig Reaction.” This section demonstrates an efficient method for the construction of the indeno-[1,2-b]pyrroles is reported from the phosphorus zwitterions and acyl chlorides in the presence of Et3N via an unprecedented chemoselective N-acylation/cyclization/intramolecular Wittig reaction sequence. A series of new type of phosphorus zwitterions are readily prepared from the indane-1,3-dione hydrazone derivatives, aldehydes, and phosphines through a chemoselective tandem three-component reaction. The mechanistic investigations revealed that the formation of spiro-indene-1,2'-[1,3,4]oxadiazol is the key step for the synthesis of aforementioned heteroarenes. Further, these spiro-indene-1,2'-[1,3,4]oxadiazol compounds were prepared in a reaction of phosphorus zwitterion embedded with PPh2Me, acyl chloride and base, thereby realizing a diversity-oriented synthesis. In addition, our protocol allowed to synthesize the rearranged indeno-[1,2-b]pyrroles via an intramolecular acyl group transfer and Wittig reaction. Key words: chemoselectivity; indeno[1,2-b]pyrroles; N‒acylation; phosphorus zwitterions; Wittig reactions. Chapter 3: “Phosphine-Mediated MBH-Type/Acyl Transfer/Wittig Sequence for Construction of Functionalized Furo[3,2-c]coumarins.” Our group has long been devoted toward the in situ generation of phosphorus zwitterions or phosphonium salts by the addition of phosphine to conjugated carbonyl compounds at different positions for their subsequent Wittig reaction. In continuation of the legacy of our research, we were interested in the development of new methods for the synthesis of privileged heterocycle scaffolds. Thus, herein we developed a new method for the construction of functionalized furo[3,2-c]coumarins via MBH-type/acyl transfer/Wittig reaction. This methodology features O-acylation of zwitterions which were formed by the MBH-type reaction of PPh3 to alkynoates, generating the betaine intermediates that further resulted in the aforementioned heteroarenes via an unprecedented acyl transfer/Wittig reaction. The simultaneous formation of two heterocycles with installing a keto functionality on the aryl ring of the furo[3,2-c]coumarin has been realized from the terminal alkynoates and acyl chlorides in a metal-free one-pot reaction. Furthermore, this protocol could also be applicable to the internal alkynoates/propiolamides to generate the 2,3-disubstituted furo[3,2-c]coumarins and furo[3,2-c]quinolinones via MBH-type/Wittig reaction. To investigate the mechanism, we have performed several control experiments and we prove that acyl transfer between O-to C-acylation by using acyl chloride addition sequence and was confirmed by X-ray analysis. Key words: MBH reaction, Furo[3,2-c]coumarin, acyl transfer, Wittig strategy. Chapter 4: “An efficient method for the Construction of spiro[cyclopenta[c]chromene-indoline]dione derivatives via RC-type/acyl transfer/Wittig strategy.” This section discusses an efficient method for the synthesis of spiro[cyclopenta[c]chromene-indoline]dione derivatives via RC-type/acyl transfer/Wittig strategy. The spiro product was obtained under mild and metal-free conditions from simply oxindole bearing alkyonate as starting material with good to high yields. The simultaneous formation of two heterocycles via RC type/Wittig reaction aforementioned spiro[cyclopenta[c]chromene-indoline]diones from the terminal alkynoates, PPh3 and acyl chlorides. Further investigations to access multifarious heteroarenes utilizing this protocol are underway in our laboratory. Key words: RC-type reaction, Spiro[cyclopenta[c]chromene-indoline]dione, terminal alkynoate.

並列關鍵字

Stepwise (3+2) cycloaddition reaction ； spirooxindole ； cyclopentachromenones ； chemoselectivity ； indeno[1,2-b]pyrroles ； N‒acylation ； phosphorus zwitterions ； Wittig reactions ； MBH reaction ； Furo[3,2-c]coumarin ； acyl transfer ； Wittig strategy ； RC-type reaction ； Spiro[cyclopenta[c]chromene-indoline]dione ； terminal alkynoate