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不对称合成6-取代-5,6-二氢菲啶类化合物的研究

发布时间:2018-08-29 16:23
【摘要】:以5,6-二氢菲啶为主要骨架的化合物是一种重要的氮杂环化合物,具有广泛的生物活性,如抗癌、抗菌、消炎等。虽然这一类化合物的合成方法已有很多报道,但是都集中于非手性化合物的合成,有关含手性结构5,6-二氢菲啶的合成方法却鲜有涉及。本论文以手性6-取代-5,6-二氢菲啶类化合物的合成为研究目标,开展有关方法学研究。采用联苯-2-胺和具有较高亲电性的羰基化合物,在手性磷酰亚胺酸催化剂的作用下,通过Pictet-Spengler反应合成出较高产率和高对映选择性的6-取代-5,6-二氢菲啶类化合物。我们首先将10种手性磷酰亚胺酸和手性磷酸的催化剂运用到3’,5’-二甲氧基-[1,1’-联苯]-2-胺和对硝基苯甲醛的不对称Pictet-Spengler反应中。常温下,以甲苯为溶剂,筛选出3,3’位为二萘取代基的(R)-H8-BINOL磷酰亚胺酸作为最佳催化剂。之后依次进行溶剂、催化剂用量、反应温度的筛选,得出了最佳的反应条件,即0℃时,在5mol%3,3’位为2-萘取代基的(R)-H8-BINOL磷酰亚胺酸催化剂的作用下,以氯仿为反应溶剂,5?分子筛为添加剂。最后我们分别对不同取代基的两种底物进行扩展,在最佳反应条件的基础上,得到了20种不同取代基的6-芳基-5,6-二氢菲啶的不对称产物,产率最高达到了95%,ee值更是达到了99%,并通过单晶衍射,确认了产物的最终构型。由此,我们可以看出手性磷酰亚胺酸对此类不对称化合物的合成有着较强的催化活性和手性控制能力。在此基础上,我们继续考察了3’,5’-二甲氧基-[1,1’-联苯]-2-胺和亲电性更强的丙酮酸酯作为起始原料,以手性磷酰亚胺酸为催化剂,通过不对称Pictet-Spengler反应合成手性6-烷氧羰基-5,6-二氢菲啶化合物的反应活性,同样依次考查了催化剂、反应溶剂、催化剂用量以及反应温度对于结果的影响。我们由此得到了最佳的反应条件:-40℃时,仍然在3,3’位为2-萘取代基的(R)-H8-BINOL磷酰亚胺酸催化剂的作用下,以CCl4为反应溶剂,5?分子筛为添加剂,得到了90%的最高产率,以及83%的ee值。综上所述,我们利用手性磷酰亚胺酸做催化剂,通过不对称Pictet-Spengler反应,合成所需要的具有高对映选择性的6-取代-5,6-二氢菲啶类化合物,已经取得了较理想的研究成果,丰富了这类不对称氮杂环化合物的合成方法。
[Abstract]:The compound with 5-dihydrophenanthroline as the main skeleton is an important nitrogen heterocyclic compound, which has a wide range of biological activities, such as anti-cancer, antibacterial, anti-inflammatory and so on. Although there have been many reports on the synthesis of this kind of compounds, they are mainly focused on the synthesis of non-chiral compounds. In this thesis, the synthesis of chiral 6-substituted-5-5-dihydrophenanthroline compounds was studied. The high yield and high enantioselectivity of 6- substituted-5-dihydrophenanthroline compounds were synthesized by Pictet-Spengler reaction with biphenyl-2-amine and carbonyl compounds with high electrophilic activity under the action of chiral phosphoimide acid catalyst. We first applied 10 kinds of chiral phosphoimide and chiral phosphoric acid catalysts to asymmetric Pictet-Spengler reactions of 3H5, dimethoxy-[1hlO- biphenyls] -2-amine with p-nitrobenzaldehyde, and the results were as follows: (1) Chiral phosphoimide and chiral phosphoric acid were used in the asymmetric Pictet-Spengler reaction of p-nitrobenzaldehyde. Using toluene as solvent, (R) H 8 BINOL phosphorimide at 3'3 'position was selected as the best catalyst at room temperature. Then the solvent, catalyst dosage and reaction temperature were screened in turn, and the optimum reaction conditions were obtained, namely, chloroform was used as the reaction solvent at 0 鈩,

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