【摘要】：不對稱反應(yīng)是當今有機合成中的熱點研究領(lǐng)域。目前，關(guān)于不對稱反應(yīng)的研究主要是對手性催化劑的設(shè)計與合成。手性催化劑法通過催化劑的空間結(jié)構(gòu)對底物產(chǎn)生定向誘導最終生成不對稱產(chǎn)物。設(shè)計并合成具有高效活性、穩(wěn)定性好、價格低廉等優(yōu)點的手性催化劑是目前該研究領(lǐng)域中面臨的艱巨挑戰(zhàn)。 目前，對于有機物的不對稱Hosomi-Sakurai的研究主要是在兩方面展開研究工作的。一方面以手性輔基為對象，主要研究烯丙基硼試劑和烯丙基硅試劑。已經(jīng)合成一大批手性烯丙基試劑具有良好的不對稱選擇活性，但由于條件苛刻，因此難以廣泛應(yīng)用。另外則從合成具有空間結(jié)構(gòu)匹配的催化劑著手，對聯(lián)二萘酚類衍生物和手性VA唑啉類衍生物進行研究，產(chǎn)物具有較好的光學活性。 本文是根據(jù)L-脯氨酸衍生物催化Hosomi-Sakurai反應(yīng)為突破點，合成了以苯酚為主要骨架的催化劑51。其中對比三種不同的(S)-α, α′-二苯基-2-吡咯烷甲醇合成路線的反應(yīng)條件、產(chǎn)率、溶劑使用、投料比等方面的分析，確定了最佳的反應(yīng)路線。經(jīng)過L-脯氨酸經(jīng)酯化、氨基保護、格氏反應(yīng)、催化氫解保護等步驟合成(S)-α, α′-二苯基-2-吡咯烷甲醇(47)，四步反應(yīng)綜合產(chǎn)率為57.8%；2,6-二溴甲基-4-甲基苯酚的合成是以對甲基苯酚為原料經(jīng)取代苯酚的羥甲基化、溴取代等反應(yīng)合成2,6-二溴甲基-4-取代基苯酚(50)。羥甲基化反應(yīng)中重點對堿的類型、用量進行研究，溴代反應(yīng)中是從反應(yīng)條件等方面進行研究，最終確定合適的反應(yīng)路線，兩步反應(yīng)綜合產(chǎn)率為63.2~71.0%。對于手性催化劑的合成中的鹵代烴與胺的偶聯(lián)反應(yīng)，重點研究了反應(yīng)的物料配比、反應(yīng)溫度和碳酸鉀的用量對反應(yīng)的影響，經(jīng)過上述的研究最終確定了最佳的合成條件，產(chǎn)率為51.5~61.2%。 在研究中，不對稱Hosomi-Sakuai反應(yīng)條件的優(yōu)化是重點。從路易斯酸催化能力、不同溶劑對反應(yīng)的影響、溫度對于手性催化劑的活性影響，，催化劑的用量等方面進行了研究對比，最終確定了最宜反應(yīng)條件。通過對影響不對稱反應(yīng)的因素后得出最優(yōu)化的反應(yīng)條件是溶劑為甲苯，手性催化劑為51a(10mol%)，路易斯酸為四氯化鈦，反應(yīng)溫度為室溫，反應(yīng)時間為2h，不飽和酮：四氯化鈦：烯丙基硅試劑為1:2:2的物料比。產(chǎn)率為52.7~85.5%，產(chǎn)物的光學純度為10.8~26.1%。實驗同時發(fā)現(xiàn)，底物苯酚對位有無取代基對本催化劑的催化活性影響不大。 最終，我們認為催化劑51a對Hosomi-Sakuai反應(yīng)有一定不對稱誘導能力，為不飽和酮的不對稱烯丙基化反應(yīng)的研究找到了新的合成途徑，并有望應(yīng)用于原料藥的合成中。
[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)-偽, 偽'- diphenyl-2-pyrrolidine methanol synthesis routes. (S)-偽, 偽'- 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

本文編號：2511106