基于alfa-紫罗兰酮不对称共轭加成反应的新型香料合成研究

It’s an ideal way to develop new aroma compounds via modification on structures of nature aroma compounds by organic synthetic methodology with retention of their main skeletons. On the other side, alfa,beta-unsaturated carbonyls are widely found in many flavor compounds. The double bonds present could readily accept attacks of nucleophilic reagents due to the present of conjugate carbonyl group. This project is supposed to utilize organometallic reagents of high reactivity as nucleophiles, to undergo conjugate addition with alfa-ionone, an nature aroma compound containing alfa,beta-unstaturated carbonyl skeleton, and introduce functionalities such as alkyl, phenyl, vinyl, and allyl groups to the beta position of carbonyl group. Meanwhile, the use of electrophiles trapping the reaction intermediates would further allow the carbonyl, ester, hydroxyl, allyl, and benzyl groups to be attached to the alfa position of the carbonyl group, affording a series of addition products with potential fragrant application. Next, the odor characteristics and thresholds of these products would be evaluated and the effect of substituent on the result would be analyzed. Furthermore, products with good odor quility would be screened and asymmetric synthesis of these compounds could be realized with the addition of chiral ligands.

以天然香料化合物为模板，保留其主要结构骨架并采用有机合成的方法进行结构上的修饰，是一种较为理想的发展新型香料化合物的方法。另一方面，alfa,beta-不饱和羰基是一类在香料化合物中广泛存在的结构单元。由于共轭羰基的存在，其双键容易接受外来亲核试剂的进攻发生共轭加成反应。本项目尝试从含有此类结构的天然香料alfa-紫罗兰酮出发，采用高反应活性有机金属试剂作为亲核试剂对其进行共轭加成反应，将亲核试剂取代基如烷基、芳基、烯基、烯丙基等引入羰基的beta位；同时采用亲电试剂对加成中间体进行捕捉，将羰基、酯基、羟基、烯丙基、苄基等官能团引入羰基的alfa位，从而得到一系列具有潜在应用前景的加成衍生物。对这些加成衍生物的香味特征及阈值进行评价，归纳讨论取代基对于香气特征的影响；从中筛选出具有开发价值的香料产物，并通过添加手性配体的方式实现此方法的不对称合成，得到手性香料化合物。

本研究从香料ɑ-紫罗兰酮出发，建立了一条方便快捷的获得新型合成香料的途径，具体取得了以下研究成果：(1) 发展了铁催化下格氏试剂同ɑ-紫罗兰酮的共轭加成反应，将不同的取代基引入到了ɑ-紫罗兰酮羰基的β位，反应的区域及立体选择性高，并基于此反应合成了一系列有潜在香料应用价值的加合物；(2) 采用不同亲电试剂对加成反应中间体进行了捕捉，首次将羟基、乙酰基、酯基、烯丙基等官能团引入到了ɑ-紫罗兰酮羰基的ɑ位；(3) 采用不同手性配体对铁和铜催化下格氏试剂对ɑ-紫罗兰酮的不对称共轭加成反应进行了探索，反应最高ee值50%；(4) 对所得潜在香料化合物进行了香气评价和嗅觉阈值测定，明确了取代基对香气特征的影响，从所得加合物中筛选出了2种效果较好的香料化合物；并采用气相色谱手性柱分离/GC-O评价的方式对他们不同立体构型的香气特征和阈值进行了表征。(5) 发展了一种从氨基酸出发一步法合成4-氨基四氢喹啉的方法，并通过手性配体的引入实现了不对称合成路径。