Stereocontrolled Synthesis of Functionalized <i>cis</i>-Cyclopentapyrazolidines by 1,3-Dipolar Cycloaddition Reactions of Azomethine Imines

The reaction of alkene-tethered α-ketocarboxylic acid derivatives with monosubstituted hydrazines allows highly substituted cis-cyclopentapyrazolidine ring systems 4 to be constructed rapidly. Successful cyclocondensations are realized under thermal reaction conditions; in some cases, protic or Lewis acids accelerate these reactions. α-Methoxy-α,β-unsaturated esters are suitable alkene components, as are alkenes having either electron-withdrawing or electron-donating substituents at the terminal alkene carbon. α-Ketoesters, α-ketoamides, and α-ketothioesters can be employed. Various hydrazines substituted with N-acyl, N-carboalkoxy, or N-carbamothioyl protecting groups are tolerated in these transformations. The rate of intramolecular cycloaddition is found to reflect not only the reactivity and equilibrium concentration of the azomethine imine intermediate, but, also in some cases, the rate at which hydrazone stereoisomers interconvert under the reaction conditions.带有烯烃侧链的α-酮羧酸衍生物与单取代肼的反应，可快速构建高度取代的顺式环戊并吡唑烷环系4。该类环缩合反应可在热反应条件下顺利实现；部分场景中，质子酸或路易斯酸可加速反应进程。α-甲氧基-α,β-不饱和酯可作为合适的烯烃组分，在烯烃末端碳原子带有吸电子或给电子取代基的烯烃同样适用。反应可采用α-酮酯、α-酮酰胺以及α-酮硫代酯作为底物。各类带有N-酰基、N-烷氧羰基或N-氨硫代羰基保护基的肼在该转化反应中均具有良好的耐受性。研究发现，分子内环加成反应的速率不仅取决于偶氮甲碱亚胺（azomethine imine）中间体的反应活性与平衡浓度，在部分情况下还取决于腙立体异构体在反应条件下的相互转化速率。