Mechanistic Studies and Synthetic Applications of 5-Endo Radical Cyclization

本文研究了N-乙烯基α-卤代酰胺的5-内自由基环化反应的机理及其在生物活性生物碱合成中的应用。结果如下：1. N-苄基-2，2，2-三氯-N-[2-（苯硫基）环己-1-烯-1-基]乙酰胺在沸腾甲苯中自由基环化得到5-内-外环化产物，而在室温下自由基环化得到4-外-内环化产物。从取代基对自由基中心和氮原子的影响以及反应温度的角度考察了一系列2-卤代-N-（3，4-二氢-2-萘基）乙酰胺在Bu_3SnH介导的自由基环化反应中的区域选择性（4-exo-benzyl和5-endo-benzyl）。当自由基中心上的取代基是氢或氯原子时，在沸腾的甲苯中有利于4-外消旋环化（β-内酰胺的形成）， ...更多信息 而自由基稳定取代基如烷基、苯基和苯硫基主要或唯一地引起5-内-外环化（γ-内酰胺形成）。然而，在沸腾的苯中，观察到甲基取代基的β-内酰胺的主要形成，另一方面，没有观察到在氮原子上的甲基和苄基取代基之间的产物分布的显著差异。3、2-碘-N-[（S）-1-苯乙基]-N-[（S）-1-苯（6-氧代环己-1-烯-1-基）乙酰胺以5-内-外消旋方式进行，具有中等的非对映选择性，得到作为主要产物的（3aS，7aR）-八氢吲哚-2，7-二酮，将其转化为（-）-γ-石蒜烷。以N-（环己-1-烯-1-基）-N-（对甲氧苄基）-2-（3，4-亚甲二氧基苯基）-2-（苯硫基）乙酰胺为原料，经自由基环合得到（3R*，3aS*，7aS*）-3-芳基八氢吲哚-2-酮，并将其转化为合成（*）-潘克拉辛的关键中间体。少

Mechanistic aspects in the 5-endo radical cyclization of N-vinylic alpha-halo amides and its application to the synthesis of biologically active alkaloids were investigated, The results obtained were as follows :1, The radical cyclization of N-benzyl-2,2,2-trichloro-N-[2-(phenylthio) cyclohex-1-en-1-yl] acetamide in boiling toluene gave the 5-e.ndo-trig cyclization product, whereas, at room temperature, it gave the 4-exo-trig cyclization product. The results may be explained in terms of the reversibility of the 4-exo cyclization.2, The regioselectivity in Bu_3SnH-mediated radical cyclizations (4-exo-trig vs 5-endo-trig) of a range of 2-halo-N-(3,4-dihydro-2-naphthyl)acetamides has been examined from the standpoint of the effects of substituents on the radical center and on the nitrogenatom as well as the reaction temperature. When the substituent on the radical center is a hydrogen or chlorine atom, the 4-exo-trig cyclization (the beta-lactam formation) is favored in boiling toluene, w … More hile the radical stabilizing substituents such as alkyl, phenyl, and phenylthio groups bring about the 5-endo-trig cyclization (the gamma-lactam formation) predominantly or exclusiyely. In boiling benzene, however, the predominant formation of the beta-lactams is observed for the methyl substituent, On the other hand, no remarkable difference in the product distributions between the methyl and benzyl substituents on the nitrogen atom is observed. These results are discussed in terms of kinetic or thermodynamic considerations.3, The radical cyclization of 2-iodo-N-[(S)-1-phenylethyl]-N-(6-oxocyclohex-1-en-1-yl)acetamide proceeded in a 5-endo-trig manner with moderate diastereoselectivity to give the (3aS,7aR)-octahydroindole-2,7-dione as the major product, which was converted into (-)-gamma-lycorane.4, The radical cyclization of N-(cyclohex-1-en-1-yl)-N-(p-methoxybenzyl) -2- (3, 4-methylenedioxyphenyl) -2- (phenylthio) acetamide gave (3R*, 3aS*, 7aS*) -3-aryloctahydroindol-2-one, which was transformed into the key intermediate for the synthesis of (*)-pancracine. Less