Bioinspired Skeletal Reorganization Approach for the Synthesis of Steroid Natural Products.

ConspectusSteroids, termed "keys to life" by Rupert Witzmann, have a wide variety of biological activities, including anti-inflammatory, antishock, immunosuppressive, stress-response-enhancing, and antifertility activities, and steroid research has made great contributions to drug discovery and development. According to a chart compiled by the Njardarson group at the University of Arizona, 15 of the top 200 small-molecule drugs (by retail sales in 2022) are steroid-related compounds. Therefore, synthetic and medicinal chemists have long pursued the chemical synthesis of steroid natural products (SNPs) with diverse architectures, and vital progress has been achieved, especially in the twentieth century. In fact, several chemists have been rewarded with a Nobel Prize for original contributions to the isolation of steroids, the elucidation of their structures and biosynthetic pathways, and their chemical synthesis. However, in contrast to classical steroids, which have a 6/6/6/5-tetracyclic framework, rearranged steroids (i.e., -steroids and secosteroids), which are derived from classical steroids by reorganization of one or more C-C bonds of the tetracyclic skeleton, have started to gain attention from the synthetic community only in the last two decades. These unique rearranged steroids have complex frameworks with high oxidation states, are rich in stereogenic centers, and have attractive biological activities, rendering them popular yet formidable synthetic targets.Our group has a strong interest in the efficient synthesis of SNPs and, drawing inspiration from nature, we have found that bioinspired skeletal reorganization (BSR) is an efficient strategy for synthesizing challenging rearranged steroids. Using this strategy, we recently achieved concise syntheses of five different kinds of SNPs (cyclocitrinols, propindilactone G, bufospirostenin A, pinnigorgiol B, and sarocladione) with considerably rearranged skeletons; our work also enabled us to reassign the originally proposed structure of sarocladione. In this Account, we summarize the proposed biosyntheses of these SNPs and describe our BSR approach for the rapid construction of their core frameworks. In the work described herein, information gleaned from the proposed biosyntheses allowed us to develop routes for chemical synthesis. However, in several cases, the synthetic precursors that we used for our BSR approach differed substantially from the intermediates in the proposed biosyntheses, indicating the considerable challenges we encountered during this synthetic campaign. It is worth mentioning that during our pursuit of concise and scalable syntheses of these natural products, we developed two methods for accessing synthetically challenging targets: a method for rapid construction of bridged-ring molecules by means of point-to-planar chirality transfer and a method for efficient construction of macrocyclic molecules via a novel ruthenium-catalyzed endoperoxide fragmentation. Our syntheses vividly demonstrate that consideration of natural product biosynthesis can greatly facilitate chemical synthesis, and we expect that the BSR approach will find additional applications in the efficient syntheses of other structurally complex steroid and terpenoid natural products.