Rapid synthesis of the core scaffold of crinane and haemanthamine through a multi-component approach.

A rapid synthesis of the core structures of crinane and haemanthamine has been developed, enabled by a multicomponent approach. This work constitutes a formal synthesis of crinane and sets the stage for access to both families of natural products and key analogues. A key highlight of the approach is the modularity of the core synthesis, overcoming existing challenges for these scaffolds and providing a path to explore site-selective oxidation to expand the scope of molecules accessible from common intermediates.

Leveraging Marine Natural Products as a Platform to Tackle Bacterial Resistance and Persistence.

Antimicrobial resistance to existing antibiotics represents one of the greatest threats to human health and is growing at an alarming rate. To further complicate treatment of bacterial infections, many chronic infections are the result of bacterial biofilms that are tolerant to treatment with antibiotics because of the presence of metabolically dormant persister cell populations. Together these threats are creating an increasing burden on the healthcare system, and a "preantibiotic" age is on the horizon if significant action is not taken by the scientific and medical communities.

Stereoselective, Multicomponent Approach to Quaternary Substituted Hydroindole Scaffolds.

The Amaryllidaceae alkaloids have been a target of synthesis for decades due to their complex architectures and biological activity. A central feature of these natural product cores is a quaternary substituted hydroindole heterocycle. Building off the foundation of our previous multicomponent approach to highly functionalized pyrrolidinones, herein we report a highly convergent, diastereoselective, multicomponent approach to access the hydroindole cores present within crinine, haemanthamine, pretazettine, and various other bioactive alkaloids.

Three-Component Approach to Pyridine-Stabilized Ketenimines for the Synthesis of Diverse Heterocycles.

Ketenimines are versatile synthetic intermediates capable of performing novel transformations in organic synthesis. They are normally generated in situ due to their inherent instability and high level of reactivity. Herein, we report pyridine-stabilized ketenimine zwitterionic salts, which are prepared through click chemistry from readily accessible alkynes and sulfonyl azides.

Stereoselective Synthesis of Diverse Lactones through a Cascade Reaction of Rhodium Carbenoids with Ketoacids.

A convergent cascade approach for the stereoselective synthesis of diverse lactones is described. The Rh(TFA)-catalyzed cascade reaction proceeds via a carboxylic acid O-H insertion/aldol cyclization with high chemo-, regio-, and diastereoselectivity. The cascade reaction provides quick access to highly functionalized γ-butyro- and δ-valerolactones from readily accessible ketoacid and diazo synthons.

A serendipitous cascade of rhodium vinylcarbenoids with aminochalcones for the synthesis of functionalized quinolines.

A serendipitous five-step cascade of rhodium vinylcarbenoids with aminochalcones enables a unique synthetic approach to highly functionalized tri- and tetra-cyclic quinolines. The cascade reaction begins with the insertion of aminochalcone nitrogen into rhodium vinylcarbenoids followed by intramolecular aldol cyclization to provide a substituted indoline intermediate that undergoes an oxy-Cope rearrangement to provide a 9-membered azacycle, which then rearranges to the functionalized quinoline through an intramolecular aldol/dehydration sequence. With a catalyst loading as low as 0.

Rhodium Carbenoid Initiated O-H Insertion/Aldol/Oxy-Cope Cascade for the Stereoselective Synthesis of Functionalized Oxacycles.

A novel diazo-cascade approach has been developed for the synthesis of nine-membered oxacycles utilizing readily accessible β-hydroxy vinyl ketones and vinyl diazo esters. The Rh(II)-catalyzed cascade reaction begins with carbene O-H insertion followed by an intramolecular aldol cyclization to provide a substituted tetrahydrofuran intermediate that undergoes an oxy-Cope rearrangement to provide functionalized nine-membered oxacycles with complete stereoselectivity.

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity.

Among the opioid receptors, the κ-opioid receptor (κOR) has been gaining considerable attention as a potential therapeutic target for the treatment of complex CNS disorders including depression, visceral pain, and cocaine addiction. With an interest in discovering novel ligands targeting κOR, we searched natural products for unusual scaffolds and identified collybolide (Colly), a nonnitrogenous sesquiterpene from the mushroom Collybia maculata. This compound has a furyl-δ-lactone core similar to that of Salvinorin A (Sal A), another natural product from the plant Salvia divinorum Characterization of the molecular pharmacological properties reveals that Colly, like Sal A, is a highly potent and selective κOR agonist.