Synthetic nat- or ent-steroids in as few as five chemical steps from epichlorohydrin

Abstract

Today, more than 100 Food and Drug Administration-approved steroidal agents are prescribed daily for indications including heart failure, inflammation, pain and cancer. While triumphs in organic chemistry have enabled the establishment and sustained growth of the steroid pharmaceutical industry, the production of highly functionalized synthetic steroids of varying substitution and stereochemistry remains challenging, despite the numerous reports of elegant strategies for their de novo synthesis. Here, we describe an advance in chemical synthesis that has established an enantiospecific means to access novel steroids with unprecedented facility and flexibility through the sequential use of two powerful ring-forming reactions: a modern metallacycle-mediated annulative cross-coupling and a new acid-catalysed vinylcyclopropane rearrangement cascade. In addition to accessing synthetic steroids of either enantiomeric series, these steroidal products have been selectively functionalized within each of the four carbocyclic rings, a synthetic ent-steroid has been prepared on a multigram scale, the enantiomer of a selective oestrogen has been synthesized, and a novel ent-steroid with growth inhibitory properties in three cancer cell lines has been discovered.

A synthesis strategy for tetracyclic terpenoids leads to agonists of ERβ

“…2c was conceived. Taking a departure from previous studies aimed at the enantiospecific synthesis of estranes 18 , it was thought that metallacycle-mediated annulative cross-coupling 19 between a readily available enyne ( 2 ) and trimethylsilylpropyne 3 would deliver hydrindane intermediate 4 , possessing the C13 quaternary center common to this large natural product class. Notably, and consistent with previous studies, it was anticipated that 4 would be formed with high levels of regioselectivity, positioning the trimethylsilyl (TMS) group at C11 of the carbocyclic nucleus.

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

“…Steroids are perhaps the most privileged structures in the history of drug development. In fact, more than 100 different steroid molecules have been approved by the U.S. Food and Drug Administration (FDA) as therapeutics for a wide range of symptoms and diseases, such as inflammation, pain, cancers, and bacterial infections 37 . Not surprisingly, a variety of methods have been developed for the modification of steroids.…”

“…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 .…”

Asymmetric Organocatalysis Revisited: Taming Hydrindanes with Jørgensen–Hayashi Catalyst

“…8 Interesting targets for organocatalysis are substituted hydrindanes 1, that is, bicyclo [4.3.0]nonanes, which are important scaffolds of natural products and synthetic bioactive compounds. Selected ex-amples are amaminol A (2), 9 the tricyclic unit of ikarugamycin (3), 10 or the CD ring unit of deoxycholic acid (4) 11 (Figure 1). Various synthetic methods have been developed to access the bicyclo [4.3.0]nonane core, 12 most notably Diels-Alder reactions, [13][14][15][16][17] Pauson-Khand reactions of alkenes and alkynes or enynes with carbon monoxide, 18 radical cyclizations, 19 titanacycle-mediated annulations, 20 intramolecular aldol and Michael reactions, 21 Morita-Baylis-Hillman reactions, [22][23][24] sequential ring-opening/ring-closing metathesis, [25][26][27] and enyne metathesis, 28 or one-pot consecutive Pdcatalyzed Overman rearrangement, Ru-catalyzed ring closing enyne metathesis, and hydrogen bond-directed Diels-Alder reaction.…”