Reagent-controlled regiodivergent ring expansions of steroids

Abstract

Ring expansion provides a powerful way of introducing a heteroatom substituent into a carbocyclic framework. However, such reactions are often limited by the tendency of a given substrate to afford only one of the two rearrangement products or fail to achieve high selectivity at all. These limitations are particularly acute when seeking to carry out late-stage functionalization of natural products as starting points in drug discovery. In this work, we present a stereoelectronically controlled ring expansion sequence towards selective and flexible access to complementary ring systems derived from common steroidal substrates. Chemical diversification of the reaction intermediate affords over 100 isomerically pure analogs with spatial and functional diversity. This regiodivergent rearrangement, and the concept of using chiral reagents to affect regiocontrol in chiral natural products, should be broadly applicable to late-stage natural product diversification programs.

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…As a result, a 49‐compound set with unprecedented diversity and good average physicochemical descriptors ( c log P =2.9, Fsp 3 =0.59, number of stereocenters=5.17) was synthesized (Figure ). Similar examples of such reagent‐controlled regiodivergent ring expansion were published recently: starting from 4 steroids, a set of 114 analogues with high stereochemical and functional diversity were prepared …”

“…Similar examples of such reagent-controlled regiodivergent ring expansion were publishedr ecently:s tarting from 4s teroids, as et of 114a nalogues with high stereochemical and functional diversity were prepared. [88] The substrate-based approach can be illustratedb ythe work of Mortonand co-workers. [89] In this case, librarysynthesis commenced from the attachment of capping reagents to the propagating building blocks on af luoroust ag ( Figure 16).…”

Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis

“…Several strategies for the rapid and efficient synthesis of value-added complex compounds have been developed, including those that construct complex scaffolds from diverse collections of simple building blocks, 3,4 and those that begin with complexity and build in diversity. 5 For this later approach, natural products offer a rich and varied source of starting materials, and collections of compounds have been assembled using the Complexity-to-Diversity (CtD) strategy from the natural products adrenosterone, 6 gibberellic acid, 6 quinine, 6,7 abietic acid, 8 sinomenine, 9 lycorine, 10 yohimbine, 11 haemanthamine, 12 nitrogenous steroids of dutasteride and abiraterone acetate, 13 ilimaquinone, 14 and others. The resulting collections have been used to discover small molecules with anticancer and antimicrobial activities, 11,15 autophagy inhibitors, 16 and to identify predictive guidelines for broad-spectrum antibiotic discovery.…”

A general strategy for diversifying complex natural products to polycyclic scaffolds with medium-sized rings

“…However, most of these methods focused on simple modifications repeatedly using the same core skeleta and FGs 38,39 . Examples of significant diversification are rare 37,40 .…”