一种高效的氮氧脂肪杂环多取代基修饰策略

Aliphatic nitrogen and oxygen-containing heterocycles widely exist in many listed drugs which can be used to treat various diseases.These heterocycles play important roles in exerting effect on drug's efficacy or physical and chemical properties. So far, almost no concise and systematic method about systhesis of polysubstituted aliphatic heterocycles was reported because little attention was paid to this field by people. This results in the limited applications of polysubstituted aliphatic heterocycles in medicinal chemistry. In this proposal, we design a systematic solution based on some experiments and reasonable inference to solve the problem: 1)Aliphatic heterocycles can be transformed into hemiacetal structures under some oxidative conditions. 2) Hemiacetal has been proved by our initial experiment to be a good nucleophile in organocatalytic reactions, introducing a functional group at α-position of hemiacetal. 3) Hemiacetal itselt can react with suitable nucleophile under catalysis of Lewis acid to introduce the second functional group. 4) Reapting steps 1-3 will introduce the third and the fourth functional groups. Obviously, our protocol can prepare chiral polysubstituted aliphatic heterocycles in a rapid and efficient way. We also need to apply this protocol directly to the derivatization of listed drugs or bioactive compounds and will obtain a lot of potential bioactive compounds quickly. And this provides a very useful method for the construction of active compounds libraries.

含有氮氧的脂肪杂环广泛存在于治疗各种疾病的上市药物中，对药物药效的发挥和药物的物理化学性质有着重要影响。由于人们对氮氧脂肪杂环的研究较少，所以缺少简洁而系统的合成多取代氮氧脂肪杂环的好方法，进而限制了这些脂肪杂环在药物化学中的应用。据此，我们根据一些实验事实和合理的推断设计了一套解决方法：一，氮氧脂肪杂环可以在某些氧化条件下生成半缩醛结构；二，初步的实验证实半缩醛可以代替游离醛基应用于有机催化的各类反应中，在半缩醛邻位对映选择性引入基团；三，邻位取代后的半缩醛可以继续发生半缩醛本身参与的反应，引入第二个取代基；四，重复以上反应可以引入第三、第四个取代基。显然，我们的方案可以快速而高效地合成手性多取代的氮氧脂肪杂环。当把这套方法直接应用于上市药物或者活性化合物的结构改造中时，就可以快速得到大量潜在的活性化合物，为组建活性化合物库提供了一种高效而实用的方法。

以简单的半缩醛2-羟基四氢呋喃/吡喃为原料，在有机催化剂作用下和分别和硝基烯、醛、酮、醌、邻羟基硝基苯乙烯、DEAD、马来酰亚胺反应，得到相应的手性单取代的半缩醛；半缩醛再在Lewis酸的作用下，和亲核试剂反应，得到手性单取代或者双取代的四氢呋喃/吡喃。产物都具有很高的ee和不错的收率，可以作为手性合成的砌块或者用于药物化学研究。例如从半缩醛和硝基烯反应得到的Michael加成产物出发，合成了一系列抗抑郁药物文拉法辛的衍生物，经活性测定，有数个化合物活性和文拉法辛相当。双取代的四氢呋喃/吡喃可以在醚键小位阻的一侧继续氧化生成半缩醛，然后和亲核试剂反应，得到手性三取代的四氢呋喃/吡喃。初步试验的一锅法反应虽然收率较低，但是提供了一种制备多取代四氢呋喃/吡喃的简易方法。

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