Synthesis of Biologically Active Compounds Based on the Regio- and Stereo-Controlled Radical Cyclizations

1.在烷基末端含有硫原子或氰基的ω-卤代烯烃的自由基环化反应仅以表外方式进行。对所得结果进行了机理上的合理解释，并将其应用于(±)-异帕比丁和(±)-Phystigmines关键中间体的合成。建立了5-外自由基环化立体选择性合成(3R^*，3AS^*，7AS^*)-3-芳基二氢吲哚-2-酮的方法，并将该方法应用于(±)-Pancracine的正式合成。N-乙烯基-2-碘苯甲酰胺自由基环化反应生成的6-内环化产物经过连续的5-外芳基环化和新叶素重排反应。在研究N-(ο-溴苯基)烯胺的自由基环化反应过程中，我们发现了第一个6-内环化产物在烯烃上形成的例子，该产物在烷基上没有取代基。我们还发现，末端有两个苯硫基或N-乙烯基键的酰胺类化合物只以5-exo的方式进行自由基环化。将后一种方法应用于合成抗疱疹病毒的模型化合物MAPPICE酮。在卤代化合物的自由基反应中，使用碘原子比使用氯原子能得到更好的结果。令人惊讶的是，在α-卤代酰胺的5-内环化反应中，氯原子的使用高产率地得到了环化产物，而碘原子的使用只得到了有限数量的预期环化产物。建立了Mu(OAc)_3/Cu(OAc)_2催化的α-(甲硫基)酰胺的氧化自由基环化反应，并将该方法用于构建一种简明的二氯乙烷骨架。

1. Radical cyclization of ω-haloalkenes having a sulfur atom or a nitrile group at the terminus of their alkenic bond was found to undergo in an exo manner exclusively. A mechanistic rationalization for the results was proposed and the methods were applied to the syntheses of the key intermediates for (±)-ipalbidine and (±)-physostigmine.2. Stereoselective synthesis of (3R^*, 3aS^*, 7aS^*)-3-aryloctahydroindol-2-ones using 5-exo radical cyclization was developed and the method was applied to a formal synthesis of (±)-pancracine.3. Formation of 6-endo cyclization products by radical reaction of N-vinylic 2-iodobenzamides was found to proceed through a consecutive 5-exo aryl radical cyclization and neophyl rearrangement.4. In the course of the study on the radical cyclization of N-(ο-bromobenzyl) enamides, we found a first example of the formation of 6-endo cyclization product onto alkene having no substituent on the alkenic bond. We also found that the enamides having two phenylthio groups at the terminus or the N-vinylic bond underwent radical cyclization in a 5-exo manner exclusively. The latter method was applied to the synthesis of a model compound of mappicine ketone, an anti-herpesvirus compound.5. The use of an iodine atom is recognized to give a better result than does that of a chlorine atom in the radical reactions of halogeno compounds. We found, surprisingly, that in the 5-endo cyclization of α-halo amides, the use of a chlorine atom gave the cyclization products in high yields, whereas that of an iodine atom gave only a limited amount of the expected cyclization product.6. Mu(OAc)_3/Cu(OAc)_2-mediated oxidative radical cyclization of α-(methylthio) amides was developed and the method was applied to a concise construction of an erythrinane skeleton.