Abstract
The interrogation of complex biological pathways demands diverse small molecule tool compounds, which can often lead to important therapeutics for the treatment of human diseases. Since natural products are the most valuable source for the discovery of therapeutics, the derivatization of natural products has been extensively investigated to generate molecules for biological screenings. However, most previous approaches only modified a limited number of functional groups, which resulted in a limited number of skeleta. Here we show a general strategy for the preparation of a library of complex small molecules by combining state-of-the-art chemistry – the site-selective oxidation of C-H bonds - with reactions that expand rigid, small rings in polycyclic steroids to medium-sized rings. This library occupies a unique chemical space compared to selected diverse reference compounds. The diversification strategy developed herein for steroids can also be expanded to other types of natural products.
Highlights
The interrogation of complex biological pathways demands diverse small molecule tool compounds, which can often lead to important therapeutics for the treatment of human diseases
We envisioned that the diversification of natural product skeleta via C–H functionalization would offer a general strategy for the synthesis of many structurally complex and functionally diverse natural product-like small molecules, while simultaneously preparing compounds in an underexplored chemical space
Inspired by nature’s biosynthesis pathways and Baran’s twophase strategy for the total synthesis of terpenes[31,32,33,34,35,36], we envisioned that oxidation of the most abundant C–H bonds in polycyclic natural products to C–O bonds, followed by ring expansion, may offer a general and efficient strategy for the diversification of natural products and yield a collection of compounds to probe an underexplored chemical space—polycyclic compounds with medium-sized rings (Fig. 1)
Summary
The interrogation of complex biological pathways demands diverse small molecule tool compounds, which can often lead to important therapeutics for the treatment of human diseases. We show a general strategy for the preparation of a library of complex small molecules by combining state-of-the-art chemistry – the site-selective oxidation of C-H bonds - with reactions that expand rigid, small rings in polycyclic steroids to medium-sized rings This library occupies a unique chemical space compared to selected diverse reference compounds. We envisioned that the diversification of natural product skeleta via C–H functionalization would offer a general strategy for the synthesis of many structurally complex and functionally diverse natural product-like small molecules, while simultaneously preparing compounds in an underexplored chemical space. We report our diversification strategy for the synthesis of natural product-like, polycyclic scaffolds containing medium-sized rings (7–11 membered) using ring expansion reactions and C–H functionalization
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