酵母催化还原制备手性双羟基苊及其应用开发
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摘要
双羟基苊及其衍生物广泛存在于生理活性物质中,同时作为中间体用于功能材料的合成。由于没有有效的合成方法,几乎没有手性双羟基苊的应用研究。与在手性荧光探针和手性催化剂配体中常用的联萘化合物相比，手性双羟基苊的刚性更好,其在这些领域具有非常高的潜在的应用价值。由于苊醌羰基两侧的立体结构和电子排布的相似性,常规化学还原方法制备手性双羟基苊还是较大的难题。因此,开发手性双羟基苊的合成方法及其应用是一个新颖并且具有挑战性的课题。
本文以苊醌和取代苊醌为底物,用面包酵母作为生物催化剂,探索并实现了生物催化高立体选择性的还原苊醌制备相应的手性双羟基苊。通过筛选搅拌设备和有机助溶剂等方法,对反应过程进行了系统的研究和优化。采用高效液相色谱手性柱实现了ee值的测定,用激子手性圆二色谱(ECCD)成功对反式手性双羟基苊及取代的手性双羟基苊的绝对构型进行了确定。对手性双羟基苊及其衍生物在生理活性方面的应用做了初步探索。
以苊醌为起始原料,经溴化、硝化、取代、还原等多步反应合成取代苊醌。使用DMSO作为底物助溶剂,在强烈搅拌下,面包酵母催化还原苊醌和5-取代苊醌制备了具有ee.为>97-100%的trans-5-取代-1,2-二羟基苊。采用激子手性圆二色谱(ECCD)方法确定了制备的(-)-trans-双羟基苊为(S,S)构型,(-)-trans-5-甲氧基-双羟基苊为(S,S)构型, (+)-trans-5-溴-双羟基苊为(S,S)构型, (-)-trans-5-硫代吗啉-双羟基苊为(R,R)构型。
以Bcl-2为靶向的抗肿瘤活性测试中,发现cis-双羟基苊及其衍生物比trans-构型的相应化合物的活性高出近10倍。这部分研究还有待于进一步对这类化合物进行优化改造。
以反式手性双羟基苊为手性源,对相应手性探针设计、合成做了一些尝试,还有待于进一步优化。
本论文研究,是建立在面包酵母制备手性芴醇的基础上,作为第二个实例,扩展了生物转化法还原刚性、稠环芳香酮反应的底物适用范围。进一步证明了在克服质量传递限制的反应条件下,面包酵母有能力还原具有高度空间位阻的芳香酮。
Acenaphthene-1,2-diol derivatives are widely exsited in many biologically active compounds and also widely used as synthetic intermediates for functional materials. However, the applying of enantiomerically pure substituted acenaphthene-1,2-diol have been scarcely reported due to lacking of efficient preparation procedure to obtain them. Compared with binanaphthalenes, which are widely used in chiral recognition or as ligands of chiral catalyst, dihydroxyacenaphthenes have better rigid structures. So, dihydroxyacenaphthenes may have more potential value in these two aspects. Because of the structural and electronic symmetry of the two sides, it was difficult to obtain the enantiopure dioxyacenaphthenes from the usual chemical methods. Finding an efficient method to synthesize the chiral dihydroxyacenaphthene and developing its applying has still been a novel challenging.
In this paper, we explored and achieved to obtain the enantiomerically pure acenaphthene-1,2-diols and 5-substitued-acenaphthene-1,2-diols using baker's yeast as reducing reagent. To optimize the reacting condition a series of reacts were carried out to find the proper mass-transfer driver and co-solvent. The anantiomeric excess was determined by HPLC with a chiral AD-H column and the absolute configuration was assignment by the exciton chirality circular dichroism method (ECCD). To some degree, we also made some exploring in applying of the acenaphthene-1,2-diols and its derivatives in physiologically active aspect.
The 5-substitued-acenaphthylene-1,2-diones were prepared by nitration, substitution, diazotization and reduction using acenaphthylene-1,2-diones as the crude material. A series of highly enantioselective trans-5-subsitituded-acenaphthene-1,2-diols in 21～72% yield with 97～100% ee could be obtained by baker's yeast mediated reduction of corresponding 5-substituted-acenaphthylene-1,2-dione, in the presence of DMSO as co-solvent and under vigorous agitation. The absolute configuration of (-)-trans-5-methoxy-acenaphthene-1,2-diol, (-)-trans-5-methoxy-acenaphthene-1,2-diol, (-)-trans-5-bromo-acenaphthene-1,2-diol were assigned as (S,S), and (-)-trans-5-thiomorpholin-acenaphthene-1,2-diol was established as (R,R) by the exciton chirality circular dichroism method.
In the measurement of Bcl-2 targeted antitumor drugs, we found the efficiency of the cis-5 thiomorpholin-dihydroxyacenathenes and these derivatives were nearly 10 times toward the corresponding trans-congiguration. On base of this result, the object products could be further modified.
In the resesrch of chrial recognition, we found another dihydroxyacenaphthene derivatives could recognize L-glutamic acid to some extent, in spite of needing more identification.
On the basis of baker's yeast-catalyzed reduction of fluorenones, the substrate of the baker's yeast reductions was extended in the research. It further proved that if the obstacle of mass-transfer was overcomed, rigid and polycyclic aromatic ketones could be reduced by baker's yeast.
本文以苊醌和取代苊醌为底物,用面包酵母作为生物催化剂,探索并实现了生物催化高立体选择性的还原苊醌制备相应的手性双羟基苊。通过筛选搅拌设备和有机助溶剂等方法,对反应过程进行了系统的研究和优化。采用高效液相色谱手性柱实现了ee值的测定,用激子手性圆二色谱(ECCD)成功对反式手性双羟基苊及取代的手性双羟基苊的绝对构型进行了确定。对手性双羟基苊及其衍生物在生理活性方面的应用做了初步探索。
以苊醌为起始原料,经溴化、硝化、取代、还原等多步反应合成取代苊醌。使用DMSO作为底物助溶剂,在强烈搅拌下,面包酵母催化还原苊醌和5-取代苊醌制备了具有ee.为>97-100%的trans-5-取代-1,2-二羟基苊。采用激子手性圆二色谱(ECCD)方法确定了制备的(-)-trans-双羟基苊为(S,S)构型,(-)-trans-5-甲氧基-双羟基苊为(S,S)构型, (+)-trans-5-溴-双羟基苊为(S,S)构型, (-)-trans-5-硫代吗啉-双羟基苊为(R,R)构型。
以Bcl-2为靶向的抗肿瘤活性测试中,发现cis-双羟基苊及其衍生物比trans-构型的相应化合物的活性高出近10倍。这部分研究还有待于进一步对这类化合物进行优化改造。
以反式手性双羟基苊为手性源,对相应手性探针设计、合成做了一些尝试,还有待于进一步优化。
本论文研究,是建立在面包酵母制备手性芴醇的基础上,作为第二个实例,扩展了生物转化法还原刚性、稠环芳香酮反应的底物适用范围。进一步证明了在克服质量传递限制的反应条件下,面包酵母有能力还原具有高度空间位阻的芳香酮。
Acenaphthene-1,2-diol derivatives are widely exsited in many biologically active compounds and also widely used as synthetic intermediates for functional materials. However, the applying of enantiomerically pure substituted acenaphthene-1,2-diol have been scarcely reported due to lacking of efficient preparation procedure to obtain them. Compared with binanaphthalenes, which are widely used in chiral recognition or as ligands of chiral catalyst, dihydroxyacenaphthenes have better rigid structures. So, dihydroxyacenaphthenes may have more potential value in these two aspects. Because of the structural and electronic symmetry of the two sides, it was difficult to obtain the enantiopure dioxyacenaphthenes from the usual chemical methods. Finding an efficient method to synthesize the chiral dihydroxyacenaphthene and developing its applying has still been a novel challenging.
In this paper, we explored and achieved to obtain the enantiomerically pure acenaphthene-1,2-diols and 5-substitued-acenaphthene-1,2-diols using baker's yeast as reducing reagent. To optimize the reacting condition a series of reacts were carried out to find the proper mass-transfer driver and co-solvent. The anantiomeric excess was determined by HPLC with a chiral AD-H column and the absolute configuration was assignment by the exciton chirality circular dichroism method (ECCD). To some degree, we also made some exploring in applying of the acenaphthene-1,2-diols and its derivatives in physiologically active aspect.
The 5-substitued-acenaphthylene-1,2-diones were prepared by nitration, substitution, diazotization and reduction using acenaphthylene-1,2-diones as the crude material. A series of highly enantioselective trans-5-subsitituded-acenaphthene-1,2-diols in 21～72% yield with 97～100% ee could be obtained by baker's yeast mediated reduction of corresponding 5-substituted-acenaphthylene-1,2-dione, in the presence of DMSO as co-solvent and under vigorous agitation. The absolute configuration of (-)-trans-5-methoxy-acenaphthene-1,2-diol, (-)-trans-5-methoxy-acenaphthene-1,2-diol, (-)-trans-5-bromo-acenaphthene-1,2-diol were assigned as (S,S), and (-)-trans-5-thiomorpholin-acenaphthene-1,2-diol was established as (R,R) by the exciton chirality circular dichroism method.
In the measurement of Bcl-2 targeted antitumor drugs, we found the efficiency of the cis-5 thiomorpholin-dihydroxyacenathenes and these derivatives were nearly 10 times toward the corresponding trans-congiguration. On base of this result, the object products could be further modified.
In the resesrch of chrial recognition, we found another dihydroxyacenaphthene derivatives could recognize L-glutamic acid to some extent, in spite of needing more identification.
On the basis of baker's yeast-catalyzed reduction of fluorenones, the substrate of the baker's yeast reductions was extended in the research. It further proved that if the obstacle of mass-transfer was overcomed, rigid and polycyclic aromatic ketones could be reduced by baker's yeast.
引文
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