【作者】 何卫民；

【导师】 向建南；

【作者基本信息】 湖南大学 ， 有机合成， 2012， 博士

【摘要】 杂环和杂原子化合物是含有一个或一个以上氮、氧、硫和卤素等杂原子的有机化合物,他们不但广泛存在于生物碱、核酸、抗生素等具有生物活性的分子中,还是很多药物分子的重要组成片段。在温和反应条件下,用易得的原料高效、原子经济、选择性的合成它们是有机化学的一个重要任务。均相金催化是当今有机化学领域研究的热点课题之一。金是一种特殊的Lewis酸,Furstner教授将其定义为π-酸。π-酸可以高效活化π-键使其与多种亲核试剂反应,进而发生σ键迁移重排和环异构化反应。含有亲核性氧的氧化剂是均相金催化反应中一类非常重要的亲核试剂；亚砜、硝酮、环氧化物、硝基化合物、氨基氮氧化物和吡啶/喹啉氮氧化物都属于这种氧化剂。在均相金催化反应中,氧化剂的氧原子亲核进攻金活化的炔基产生的α-羰基金卡宾中间体具有非常高的反应活性,可以发生多种宫能团转化反应。本文主要研究金催化分子间氧化炔基生成的α-羰基金卡宾中间体在杂环和杂原子化合物合成中的应用,研究工作包括以下四个部分：1.本文发展了一种金催化分子间氧化炔丙醇化合物合成3-氧杂环丁酮类化合物的通用方法。反应机理包括金催化分子间氧化炔基生成α-羰基金卡宾及卡宾分子内O-H键插入。3-氧杂环丁酮是一种在药物研发领域有着非常重要作用的四元含氧杂环化合物,本文以丙炔醇为初始原料,利用金催化氧化反应以较好的产率一步合成该化合物。该方法利用金催化氧化炔烃形成α-羰基金卡宾中间体代替使用危险的α-重氮羰基化合物生成卡宾,反应过程不需进行无水无氧处理,操作及后处理简便。2.本文探索了一种金催化分子间氧化炔丙基磺酰胺化合物高效合成手性3-氮杂环丁酮类化合物的方法。反应机理包括金催化分子间氧化炔基生成α-羰基金卡宾及卡宾N-H键插入环化。叔丁基亚磺酰基先作为手性试剂,被氧化后生成的叔丁基磺酰基又作为后续反应中氨基的保护基,避免额外的保护基保护／脱保护步骤。叔丁基磺酰胺可以用三氟甲烷磺酸温和脱去。3.本文建立了一种通过金催化氧化末端炔烃生成a-羰基金卡宾中间体与腈反应生成2,5-二取代嗯唑的新方法,首次实现了α-羰基金卡宾中间体参与的分子间反应。总反应是一个末端炔烃,腈,氮氧化物氧原子进行[2+2+1]环加成反应。腈在反应中不仅作为反应物,还作为溶剂。该反应的反应条件极其温和,官能团兼容性强。对于复杂的或昂贵的腈类化合物,以1mol％BrettPhosAuNTf2作为催化剂,仅需要3当量腈在无溶剂条件下反应,以较为理想产率获得目标化合物。4.我们研究了意外发现的金催化分子间氧化末端炔烃生成α-羰基金卡宾中间体捕获溶剂卤原子生成α-氯/溴代甲基酮的反应。该反应可以用于一步合成α-氯/溴代甲基酮。从反应情况,推测α-羰基金卡宾中间体的亲电性和α-羰基银卡宾中间体相当,弱于α-羰基铑卡宾中间体。更多还原

【Abstract】 Heterocycles and heteroatom compounds are the molecules possessing one or more heteroatom(s) such as nitro, oxygen, sulfur, halogen and so on. They are not only found in alkaloids, nucleic acids, antibiotics, and other biologically active molecules but also the essential components of many drugs. Efficient, atom-economic, and selective constructions of heterocyle compounds from readily available starting materials under mild conditions remain an important task in synthetic chemistry.Gold-mediated homogeneous catalysisis is one of the hot topics in the organic chemistry. Gold compounds are rather unique soft Lewis acids which have been termed by Furstner as π-acid. The π-acid can activate π bonds for reactions with arange of nucleophiles, leading to sigmatropic rearrangements, migrations, and cycloisomerizations. A particularly important class of nucleophiles is an oxidant that possesses a nucleophilic oxygen and can formally deliver the oxygen atom during the reaction, and this type of gold-catalyzed alkyne oxidation has been proposed to generate a reactive a-oxo gold carbene intermediate, which would undergo an array of versatile transformations. Studies in this area use tethered oxidants such as sulfoxide, nitrone, epoxide, nitro, amine N-oxide and pyridine/quinoline N-oxides as external oxidants to achieve intermolecular alkyne oxidation.Recent years, we also have some studies in reactive a-oxo gold carbene intermediate, as shown in the following4parts:(1) A general solution for the synthesis of various oxetan-3-ones has been developed. This reaction uses readily available propargylic alcohols as substrates and proceeds without the exclusion of moisture or air ("open flask"). Notably, oxetan-3-one, a highly valuable substrate for drug discovery, can be prepared in one step from propargyl alcohol in a fairly good yield. Mechanistically, reactive a-oxo gold carbenes are generated as intermediates through intermolecular alkyne oxidation and subsequent intramolecular O-H insertion. This safe and efficient generation of gold carbenes offers a potentially general entry into a-oxo metal carbene chemistry without using hazardous diazo ketones. (2) A practical and flexible synthesis of chiral azetidin-3-ones has been developed. The key reaction is a gold-catalyzed oxidative cyclization of chiral N-propargylsulfonamides. Mechanistically, reactive a-oxo gold carbenes are generated as intermediates through intermolecular alkyne oxidation and subsequent intramolecular N-H insertion. The use of tert-butylsulfonyl as the protecting group takes advantage of the chiral tert-butylsulfinimine chemistry and avoids additional unnecessary deprotection and protection steps. Moreover, the Bus group can be easily removed from the azetidine ring under acidic conditions.(3) The first efficient intermolecular reaction of gold carbene intermediates generated via gold-catalyzed alkyne oxidation has been realized using nitriles as both the reacting partner and the reaction solvent, offering a generally efficient synthesis of2,5-disubstituted oxazoles with broad substrate scope. The overall reaction is a [2+2+1] annulation of a terminal alkyne, a nitrile, and an oxygen atom from an oxidant. The reaction conditions are exceptionally mild, and a range of functional groups are easily tolerated. With complex and/or expensive nitriles, only3equiv could be sufficient to achieve serviceable yields in the absence of any solvent and using only1mol%BrettPhosAuNTf2as the catalyst. (4) We have reported a surprising halide abstraction by a-gold carbenes generated via gold-catalyzed intermolecular oxidation of terminal alkynes. Synthetically useful chloro/bromom ethyl ketones can be prepared in one-step from terminal alkynes. The strong electrophilicity of the gold carbene intermediates reveals that gold in general is less effective in back bonding than rhodium but perhaps similar to Ag.更多还原