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

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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.