【作者】 李静；

【导师】 刘德龙； 杨熔勇；

【作者基本信息】 上海交通大学 ， 药物化学， 2016， 硕士

【摘要】 手性α-取代丙酸及其衍生物是一类重要的有机合成彻块和关键中间体,被广泛地应用于手性药物的合成之中。如临床正在大量使用的非甾体类抗炎药布洛芬、萘普生和酮洛芬等。众所周知的抗疟药-青蒿素,其合成关键中间体二氢青蒿酸同样属于此种结构。所以,手性α-取代丙酸及其衍生物的不对称合成成为研究的热点。我们课题组开发了一类高效的面手性Ru PHOX-Ru催化剂,其在简单酮类以及氨基酮类化合物的不对称氢化反应中都能使底物完全转化,产物高达99.9%ee的对映选择性。本文就是以Ru PHOX-Ru为催化剂,实现Ru催化α-取代丙酸及其衍生物温和高效的不对称氢化合成。论文首先以α-苯基丙烯酸为基准底物,Ru PHOX-Ru为催化剂,对反应溶剂、碱及其用量及氢气压力等反应条件进行非常详细的优化。结果显示,以价格便宜的甲醇为溶剂、碳酸氢钠为碱,仅在5 bar氢气压力下,反应即可得到定量的收率及高达99.9%ee的对映选择性。接着,论文以该优化的反应条件,对20多种不同取代的底物进行研究,基本都可获定量的收率及最高99.9%ee的对映选择性。最后,论文对催化剂的活性进行了考察。在克级底物的量及5000/1 S/C的比例时,反应也可达到高效的结果。值得一提的是,该反应可用于青蒿素合成关键中间体-二氢青蒿酸的不对称催化氢化合成之中。反应也可以得到>99%的收率及99.7/0.3的立体选择性。更多还原

【Abstract】 Optically pureα-substituted propanic acids and its derivatives represent as a large scope of biologically active compounds,chiral drugs and their key intermediates.Some of them have been used directly as nonsteroidal anti-inflammatory drugs（NSAIDs）,such as ibuprofen,naproxen,ketoprofen and flurbiprofen.Dihydroartemisinic acid（DHAA）is a key intermedia for the synthesis of artemisinin,the most effective and current used anti-malarial drug.Transition-metal catalyzed asymmetric hydrogenation of prochiral acrylic acids is of the most powerful strategies for the synthesis of the corresponding propanic acids.We have developed aruthenocenylphosphino-oxazolineruthenium-complex（Ru PHOX-Ru）which has shown promising catalytic activity in many asymmetric reactions due to its dual reaction sites and large steric hindrance.Recently,Ru PHOX-Ru has been used as chiral catalyst in the asymmetric hydrogenations of simple ketonesandβ-amino ketones,providing the corresponding products in quantitative conversions and with up to 99.9%ee.This dissertation will disclose the asymmetric synthesis ofα-substituted propanic acids using Ru PHOX-Ru as a chiral catalyst.We first carried out the ^tBu-Ru PHOX-Ru-catalyzed asymmetric hydrogenation of 2-phenylacrylic acid under different reaction conditions.Therefore,the optimal reaction conditions were found to be the following:using Na HCO₃ as a base in Me OH under 5 bar hydrogen pressure at room temperature.With the optimal reaction conditions in hand,substrates bearing different 2-position substituents were then investigated.The Ru PHOX-Ru catalyzed asymmetric hydrogenation of acrylic acids with various substituted groups could be achieved successfully,affording the corresponding chiralα-substituted propanic acids in up to 99%yield and 99.9%ee.To examine the efficiency of the catalyst system,a gram-scale hydrogenation of2-phenylacrylic acid was carried out with a low catalyst loading of 0.1 mol%（S/C=5,000）under 50 bar H₂ pressure at RT for 48 h.The desired product was obtained in97%yield and with 99.3%ee.The asymmetric hydrogenation of AA acid has also been achieved with（R）-DHAA being obtained in almost quantitative yield and99.7:0.3 dr,using the above catalytic system.更多还原