Conspectus: Steroids, 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., abeo-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.

Esters are bulk and fine chemicals and ubiquitous in polymers, bioactive compounds, and natural products. Their traditional synthetic approach is the esterification of carboxylic acids or their activated derivatives with alcohols. Herein, a bimetallic relay catalytic protocol was developed for the aerobic esterification of one alcohol in the presence of a slowly oxidizing alcohol, which has been identified as methanol. A concise synthesis of phlomic acid was executed to demonstrate the practicality and potential of this reaction.

Ligand coupling on hypervalent main group elements has emerged as a pivotal methodology for the synthesis of functionalized N-heteroaromatic compounds in recent years due to the avoidance of transition metals and the mildness of the reaction conditions. In this direction, the reaction of N-heteroaryl sulfur(IV) and N-heteroaryl phosphorus(V) compounds has been well studied. However, the ligand coupling of sulfur(VI) is still underdeveloped and the reaction of alkyl N-heteroarylsulfones is still elusive, which does not match the high status of sulfones as the chemical chameleons in organic synthesis. Here we present a ligand coupling-enabled formal SO2 extrusion of fluoroalkyl 2-azaheteroarylsulfones under the promotion of Grignard reagents, which not only enriches the chemistry of sulfones, but also provides a novel and practical synthetic tool towards N-heteroaromatic fluoroalkylation.

Three ionic supramolecular polymers (ISPs) have been assembled from an imidazolium-modified decacationic pillar[5]arene (P5A) and hyaluronic acid (HA, MW = 3000 Da) by controlling their molar ratio at 1 : 0.2, 1 : 0.4 or 1 : 0.6. Dynamic light scattering experiments show that at [P5A] = 16 mu M the ISPs afford nano-scale aggregates with hydrodynamic diameters of 21, 33 and 21 nm, respectively. Fluorescence and zeta potential experiments support that the ISPs include short single- and double-stranded DNA of 21 nucleotides. Fluorescence imaging and flow cytometric analysis demonstrate that the ISPs can deliver the included DNA into both normal and cancer cells, with the percentage of delivered cells reaching up to 99.7%. In vitro and in vivo assays reveal that the second ISP has the highest biocompatibility, and mixing with HA improves the biocompatibility of P5A. A multicationic pillar[5]arene noncovalently crosslinks hyaluronic acid to afford ionic supramolecular polymers for intramolecular delivery of short DNA.