【作者】 陈平；

【导师】 万谦宏； 唐宇；

【作者基本信息】 天津大学 ， 应用化学， 2017， 博士

【摘要】 炔酰胺化学是炔类化学的一个重要分支,具有氮原子直接与炔键相连特殊结构,使其在化学反应中的区域选择性,立体选择性等方面有着独特的功能,近年来逐渐引起广大化学科研小组的研究热情。本论文首先对炔酰胺的制备,各类反应以及在天然产物全合成中的应用进行全面简介,基于酸催化炔酰胺合成含氮杂环方法学研究及天然产物（-）-Actinophyllic acid全合成的探索性工作,主要分为以下几个方面:首先,本论文发展了一种通过TfOH介导的酸催化炔酰胺与两分子腈类化合物进行[2+2+2]环加成高效制备一系列多取代4-氨基嘧啶类化合物的新方法,此方法对各种官能团比如:卤素,酯基,硝基,醚类等均具有较好的耐受性,同时具有反应条件温和,收率较高,底物适用性强等特点。基于实验结果,我们推测反应机理,首先炔酰胺经过酸活化得到高活性烯酮亚胺中间体,再与腈类化合物发生环合反应,碱化得到目标产物。我们为了拓展产物结构多样性,尝试炔酰胺与两分子不同腈类化合物反应,成功以较高总收率及中等选择性得到其中一种目标产物,丰富了此方法的适用性。在上述研究过程中我们发现芳香胺类炔酰胺化合物与等当量腈类化合物在TfOH介导过程中发生[4+2]环加成反应,得到一类新型苯并含氮杂环化合物,通过对反应条件的筛选得到了一种合成这类新颖的喹唑啉衍生物的新方法,目前这部分工作仍在进行中。在酸催化合成含氮杂环的研究基础上,我们也尝试将这种方法应用到天然产物（-）-Actinophyllic acid全合成研究中。我们通过二乙基碘化铝介导手性环丙烷化合物与吲哚亚胺化合物进行不对称卤素-曼尼希等反应,成功得到手性吡咯环结构关键中间体,并通过¹H NMR,¹³C NMR,NOE,HRMS,X-单晶衍射等表征方法确定其结构以及绝对构型与天然产物相同。但是在接下来酰化与氧化反应中遇到很大困难,多次尝试均未获得目标产物,后续工作主要集中在氮原子对低活性环丙烷的加成以及Dieckmann缩合串联反应新方法的研究,简洁、高效合成复杂含氮杂环生物碱天然产物,目前此部分全合成工作仍在进行中。更多还原

【Abstract】 Ynamides,which can be considered as nitrogen atom-substituted alkynes,have a unique structure with a nitrogen directly attached to the triple bond.The most important feature of the ynamides leads to a special performance at regioselectivity and stereoselectivity.Recent the development of these substrates have stimulated the enthusiasm of research of many scholars.The thesis summarizes the major development of ynamide chemistry contained the preparation methods,various types of reactions and an application in natural product total synthesis recently.The main content of this thesis include the acid-mediated synthesis methodology of nitrogen heterocycles via ynamides and synthetic studies towards precursor of（-）-actinophyllic acid.Firstly,the thesis describes an efficient and atom-economical[2+2+2]cycloaddition of ynamides with two discrete nitriles catalyzed by TfOH to form multi-substituted 4-aminopyrimidine.Various functional groups,such as halides,ester,nitro,and ether,are tolerated.This transformation employs mild conditions,good to excellent yields,and a broad range of substrate scopes.On the basis of the reaction results,a possible mechanism is illustrated,ynamide was activated with acid yielding a highly reactive keteniminium ion intermediate,followed by nitriles attack,cyclization and alkalization to obtained the desired products.Furthermore,we synthesized the correspongding products with different nitriles in good total yield with moderate regioselectivity via a diversity oriented approach for structural optimization.Secondly,[4+2]cycloaddition reaction mediated by TfOH proceeds smoothly to afford quinazoline derivatives in good yield when the equivalent amounts of the nitrile and ynamide was used in the optimized reaction conditions.This part work is ongoing in our laboratories currently.Finally,during our research on（-）-Actinophyllic acid,the key intermediate pyrrolidine derivative was obtained by a Et₂AlI-mediated halo-mannich-type reaction using cyclopropyl carbonyl-derived enolates and sulfonyl-protected imines,which structure and absolute configuration the same as natural product confirmed by ¹H NMR,¹³C NMR,NOE,HRMS and X-ray diffraction.But we have a lot of trouble in consequent acylation and oxidation,numerous attempts to stop the leak had failed or not yielded the desired results.Our further synthetic stratigies involve activated/non-activated cyclopropane ring-opening by nitrogen nucleophiles and Dieckmann cascade reactions.This part work is ongoing in our laboratories currently.更多还原