Development of New Synthetic Methods for Steroid Sleketon Based on Theoretical Calculation

本研究的目的是在理论计算的基础上发展甾体骨架等多环天然产物的合成新方法。在本报告的第一部分中，研究了利用无环中间体的串联自由基环化来制备甾体BCD-环系统的方法。采用自由基环化和氰醇烷基化串联的方法，有效地合成了甾体BCD-环体系。在第二部分中，另一种方法的类固醇BCD环骨架使用串联跨环自由基环化的十元中间体进行了检查。通过十元中间体的串联自由基环化反应，实现了甾体BCD-环体系的立体选择性一锅合成。第三部分研究了自由基环化-氧捕获反应合成维生素D_3 CD环的方法，实现了维生素D_3 CD环的立体选择性合成。第四部分研究了自由基和阴离子中间体顺序环化合成甾体CD环的新方法。从同一个合成中间体出发，通过自由基环化和阴离子环化，构建了两种不同类型的甾体CD环体系。通过1，5-二烯体系的跨环Oxy-Cope重排和随后的羟醛缩合反应，实现了甾体CD环体系的立体选择性合成。构象分析利用“MM 2过渡态模型”预测的立体选择性自由基环化和Oxy-Cope重排。总之，基于MM 2过渡态模型的立体化学控制在关键合成中间体的设计中可能具有预测价值。

Objective of this study is to develop new synthetic methodologies for polycyclic natural products such as steroid skeleton based on theoretical calculations. In the first part of this report, the approach to the steroid BCD-ring system using tandem radical cyclization of the acyclic intermediate was examined. An efficient synthesis of steroid BCD-ring system was accomplished using a tandem radical cyclization and subsequent cyanohydrin alkylation. In the second part, another approach to the steroid BCD-ring skeleton using tandem transannular radical cyclization of the ten-membered intermediate was examined. By the tandem radical cyclization of the ten-membered intermediate, stereoselective synthesis of steroid BCD-ring system was accomplished in a one-pot operation. In the third part, the approach to the CD-ring system of vitamin D_3 using radical cyclization-oxygen trapping reaction was examined and stereoselective synthesis of the vitamin D_3 CD-ring was achieved, In the fourth part, a new synthetic method for steroid CD-ring system using sequential cyclization of radical and anionic intermediates was examined. Construction of two different types of steroid CD ring systems was accomplished by the sequential radical and anionic cyclization from same synthetic intermediate, In the last part, we focused our attention on a transannular Oxy-Cope rearrangement. Stereoselective synthesis of steroid CD-ring system was accomplished using transannular Oxy-Cope rearrangement of ten-membered 1,5-diene systems and subsequent aldol condensation. Conformational analysis utilizing the "MM2 transition-state model" predicts the stereoselectivity in the radical cyclization and Oxy-Cope rearrangement. In general, considerations of stereochemical control based on MM2 transition-state model might have predictive value in the design of key synthetic intermediates.