Synthesis of Alkaloid (−)-205B via Stereoselective Reductive Cross-Coupling and Intramolecular [3+2] Cycloaddition

An asymmetric synthesis of alkaloid (−)-205B, a tricyclic member of the architecturally diverse family of natural products isolated from the skin of neotropical poison frogs, is described that proceeds through two recently developed stereoselective synthetic methods: (1) Ti-mediated allylic alcohol–imine reductive cross-coupling and (2) intramolecular [3+2] cycloaddition of a glyoxylate-based homoallylic nitrone. The utility of this latter cycloaddition process for the assembly of the stereochemically dense piperidine core of 205B is noteworthy, as this method enables direct [3+2] cycloaddition of an intermediate homoallylic (<i>E</i>)-nitrone via a pathway that is stereochemically unscathed by competitive [3,3]-sigmatropic rearrangement processes. Overall, the synthesis is asymmetric, concise, and highly stereoselectivefeatures which point to the potential future utility of these chemical methods in natural product synthesis and medicinal chemistry

Birch Reductive Alkylation of Methyl <i>m</i>‑(Hydroxymethyl)benzoate Derivatives and the Behavior of <i>o</i>- and <i>p</i>‑(Hydroxymethyl)benzoates under Reductive Alkylation Conditions

Birch reductive alkylation of methyl <i>m</i>-(hydroxymethyl)­benzoate derivatives, using lithium in ammonia–tetrahydrofuran in the presence of <i>tert</i>-butyl alcohol, can be achieved without significant loss of benzylic oxygen substituents. Similar treatment of <i>o</i>- and <i>p</i>-(hydroxymethyl)­benzoate derivatives results largely in loss of benzylic oxygen substituents. The results are rationalized by computations describing electron density patterns in the putative radical anion intermediate involved in these reactions

Birch Reductive Alkylation of Methyl <i>m</i>‑(Hydroxymethyl)benzoate Derivatives and the Behavior of <i>o</i>- and <i>p</i>‑(Hydroxymethyl)benzoates under Reductive Alkylation Conditions

Birch reductive alkylation of methyl <i>m</i>-(hydroxymethyl)­benzoate derivatives, using lithium in ammonia–tetrahydrofuran in the presence of <i>tert</i>-butyl alcohol, can be achieved without significant loss of benzylic oxygen substituents. Similar treatment of <i>o</i>- and <i>p</i>-(hydroxymethyl)­benzoate derivatives results largely in loss of benzylic oxygen substituents. The results are rationalized by computations describing electron density patterns in the putative radical anion intermediate involved in these reactions

Birch Reductive Alkylation of Methyl <i>m</i>‑(Hydroxymethyl)benzoate Derivatives and the Behavior of <i>o</i>- and <i>p</i>‑(Hydroxymethyl)benzoates under Reductive Alkylation Conditions

Birch reductive alkylation of methyl <i>m</i>-(hydroxymethyl)­benzoate derivatives, using lithium in ammonia–tetrahydrofuran in the presence of <i>tert</i>-butyl alcohol, can be achieved without significant loss of benzylic oxygen substituents. Similar treatment of <i>o</i>- and <i>p</i>-(hydroxymethyl)­benzoate derivatives results largely in loss of benzylic oxygen substituents. The results are rationalized by computations describing electron density patterns in the putative radical anion intermediate involved in these reactions

Structure Guided Discovery of Novel Pan Metallo-β-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration

The use of β-lactam (BL) and β-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-β-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM. Herein, we describe our work to improve the GN coverage spectrum in combination with imipenem and relebactam. This was achieved through structure- and property-based optimization to tackle the GN cell penetration and efflux challenges. A significant discovery was made that inhibition of both VIM alleles, VIM-1 and VIM-2, is essential for broad GN coverage, especially against VIM-producing P. aeruginosa. In addition, pharmacokinetics and nonclinical safety profiles were investigated for select compounds. Key findings from this drug discovery campaign laid the foundation for further lead optimization toward identification of preclinical candidates

Structure Guided Discovery of Novel Pan Metallo-β-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration

The use of β-lactam (BL) and β-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-β-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM. Herein, we describe our work to improve the GN coverage spectrum in combination with imipenem and relebactam. This was achieved through structure- and property-based optimization to tackle the GN cell penetration and efflux challenges. A significant discovery was made that inhibition of both VIM alleles, VIM-1 and VIM-2, is essential for broad GN coverage, especially against VIM-producing P. aeruginosa. In addition, pharmacokinetics and nonclinical safety profiles were investigated for select compounds. Key findings from this drug discovery campaign laid the foundation for further lead optimization toward identification of preclinical candidates