α,β-不饱和酮的不对称Hosomi-Sakurai反应研究

发布时间：2019-07-06 15:07

【摘要】：不对称反应是当今有机合成中的热点研究领域。目前，关于不对称反应的研究主要是对手性催化剂的设计与合成。手性催化剂法通过催化剂的空间结构对底物产生定向诱导最终生成不对称产物。设计并合成具有高效活性、稳定性好、价格低廉等优点的手性催化剂是目前该研究领域中面临的艰巨挑战。 目前，对于有机物的不对称Hosomi-Sakurai的研究主要是在两方面展开研究工作的。一方面以手性辅基为对象，主要研究烯丙基硼试剂和烯丙基硅试剂。已经合成一大批手性烯丙基试剂具有良好的不对称选择活性，但由于条件苛刻，因此难以广泛应用。另外则从合成具有空间结构匹配的催化剂着手，对联二萘酚类衍生物和手性VA唑啉类衍生物进行研究，产物具有较好的光学活性。 本文是根据L-脯氨酸衍生物催化Hosomi-Sakurai反应为突破点，合成了以苯酚为主要骨架的催化剂51。其中对比三种不同的(S)-α, α′-二苯基-2-吡咯烷甲醇合成路线的反应条件、产率、溶剂使用、投料比等方面的分析，确定了最佳的反应路线。经过L-脯氨酸经酯化、氨基保护、格氏反应、催化氢解保护等步骤合成(S)-α, α′-二苯基-2-吡咯烷甲醇(47)，四步反应综合产率为57.8%；2,6-二溴甲基-4-甲基苯酚的合成是以对甲基苯酚为原料经取代苯酚的羟甲基化、溴取代等反应合成2,6-二溴甲基-4-取代基苯酚(50)。羟甲基化反应中重点对碱的类型、用量进行研究，溴代反应中是从反应条件等方面进行研究，最终确定合适的反应路线，两步反应综合产率为63.2~71.0%。对于手性催化剂的合成中的卤代烃与胺的偶联反应，重点研究了反应的物料配比、反应温度和碳酸钾的用量对反应的影响，经过上述的研究最终确定了最佳的合成条件，产率为51.5~61.2%。 在研究中，不对称Hosomi-Sakuai反应条件的优化是重点。从路易斯酸催化能力、不同溶剂对反应的影响、温度对于手性催化剂的活性影响，，催化剂的用量等方面进行了研究对比，最终确定了最宜反应条件。通过对影响不对称反应的因素后得出最优化的反应条件是溶剂为甲苯，手性催化剂为51a(10mol%)，路易斯酸为四氯化钛，反应温度为室温，反应时间为2h，不饱和酮：四氯化钛：烯丙基硅试剂为1:2:2的物料比。产率为52.7~85.5%，产物的光学纯度为10.8~26.1%。实验同时发现，底物苯酚对位有无取代基对本催化剂的催化活性影响不大。 最终，我们认为催化剂51a对Hosomi-Sakuai反应有一定不对称诱导能力，为不饱和酮的不对称烯丙基化反应的研究找到了新的合成途径，并有望应用于原料药的合成中。
[Abstract]:Asymmetric reaction is a hot research field in organic synthesis. At present, the research on asymmetric reaction is mainly about the design and synthesis of chiral catalysts. The chiral catalyst method induced the substrate to produce asymmetric products through the spatial structure of the catalyst. The design and synthesis of chiral catalysts with the advantages of high efficiency, good stability and low price are difficult challenges in this field at present. At present, the research on asymmetric Hosomi-Sakurai of organic compounds is mainly carried out in two aspects. On the one hand, the chiral auxiliary group was taken as the object, and the allyl boron reagent and allyl silicon reagent were mainly studied. A large number of chiral allyl reagents have been synthesized with good asymmetric selection activity, but because of the harsh conditions, it is difficult to be widely used. In addition, binaphthol derivatives and chiral VA azolin derivatives were studied from the synthesis of catalysts with spatial structure matching, and the products had good optical activity. In this paper, according to the breakthrough point of Hosomi-Sakurai reaction catalyzed by L-proline derivatives, the catalyst with phenol as the main skeleton was synthesized. The optimum reaction route was determined by comparing the reaction conditions, yield, solvent use and feed ratio of three different (S)-伪, 伪'- diphenyl-2-pyrrolidine methanol synthesis routes. (S)-伪, 伪'- diphenyl-2-pyrrolidine methanol (47) was synthesized by esterification, amino protection, Grignard reaction and catalytic hydrogenolysis protection of L-proline. The comprehensive yield of four-step reaction was 57.8%. The synthesis of 2, 6-dibromomethyl-4-methylphenol is 2, 6-dibromomethyl-4-substituted phenol (50) from p-methylphenol by hydroxymethylation and bromine substitution of p-methylphenol. The type and dosage of alkali were studied in hydroxymethylation reaction, and the reaction conditions were studied in bromination reaction. The suitable reaction route was finally determined, and the comprehensive yield of two-step reaction was 63.2 鈮

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