The role of the methoxy group in approved drugs.

The methoxy substituent is prevalent in natural products and, consequently, is present in many natural product-derived drugs. It has also been installed in modern drug molecules with no remnant of natural product features because medicinal chemists have been taking advantage of the benefits that this small functional group can bestow on ligand-target binding, physicochemical properties, and ADME parameters. Herein, over 230 methoxy-containing small-molecule drugs, as well as several fluoromethoxy-containing drugs, are presented from the vantage point of the methoxy group. Biochemical mechanisms of action, medicinal chemistry SAR studies, and numerous X-ray cocrystal structures are analyzed to identify the precise role of the methoxy group for many of the drugs and drug classes. Although the methoxy substituent can be considered as the hybridization of a hydroxy and a methyl group, the combination of these functionalities often results in unique effects that can amount to more than the sum of the individual parts.

Total Synthesis of Dynobactin A.

The first total synthesis of the potent antimicrobial agent dynobactin A is disclosed. This synthesis enlists a singular aziridine ring opening strategy to access the two disparate ß-aryl-branched amino acids present within this complex decapeptide. Featuring a number of unique maneuvers to navigate inherently sensitive and epimerizable functional groups, this convergent approach proceeds in only 16 steps (LLS) from commercial materials and should facilitate the synthesis of numerous analogues for medicinal chemistry studies.

"Magic Chloro": Profound Effects of the Chlorine Atom in Drug Discovery.

Chlorine is one of the most common atoms present in small-molecule drugs beyond carbon, hydrogen, nitrogen, and oxygen. There are currently more than 250 FDA-approved chlorine-containing drugs, yet the beneficial effect of the chloro substituent has not yet been reviewed. The seemingly simple substitution of a hydrogen atom (R = H) with a chlorine atom (R = Cl) can result in remarkable improvements in potency of up to 100,000-fold and can lead to profound effects on pharmacokinetic parameters including clearance, half-life, and drug exposure in vivo. Following the literature terminology of the "magic methyl effect" in drugs, the term "magic chloro effect" has been coined herein. Although reports of 500-fold or 1000-fold potency improvements are often serendipitous discoveries that can be considered "magical" rather than planned, hypotheses made to explain the magic chloro effect can lead to lessons that accelerate the cycle of drug discovery.

Atroposelective Total Synthesis of Darobactin A.

A concise, modular synthesis of the novel antibiotic darobactin A is disclosed. The synthesis successfully forges the hallmark strained macrocyclic ring systems in a sequential fashion. Key transformations include two atroposelective Larock-based macrocyclizations, one of which proceeds with exquisite regioselectivity despite bearing an unprotected alkyne. The synthesis is designed with medicinal chemistry considerations in mind, appending key portions of the molecule at a late stage. Requisite unnatural amino acid building blocks are easily prepared in an enantiopure form using C-H activation and decarboxylative cross-coupling tactics.

Highly Stereoselective Glycosylation Reactions of Furanoside Derivatives via Rhenium (V) Catalysis.

A novel approach for the formation of anomeric carbon-functionalized furanoside systems was accomplished through the employment of an oxo-rhenium catalyst. The transformation boasts a broad range of nucleophiles including allylsilanes, enol ethers, and aromatics in addition to sulfur, nitrogen, and hydride donors, able to react with an oxocarbenium ion intermediate derived from furanosidic structures. The excellent stereoselectivities observed followed the Woerpel model, ultimately providing 1,3-cis-1,4-trans systems. In the case of electron-rich aromatic nucleophiles, an equilibration occurs at the anomeric center with the selective formation of 1,3-trans-1,4-cis systems. This anomalous result was rationalized through density functional theory calculations. Different oxocarbenium ions such as those derived from dihydroisobenzofuran, pyrrolidine, and oxazolidine heterocycles can also be used as a substrate for the oxo-Re-mediated allylation reaction.

N-Ammonium Ylide Mediators for Electrochemical C-H Oxidation.

The site-specific oxidation of strong C(sp3)-H bonds is of uncontested utility in organic synthesis. From simplifying access to metabolites and late-stage diversification of lead compounds to truncating retrosynthetic plans, there is a growing need for new reagents and methods for achieving such a transformation in both academic and industrial circles. One main drawback of current chemical reagents is the lack of diversity with regard to structure and reactivity that prevents a combinatorial approach for rapid screening to be employed. In that regard, directed evolution still holds the greatest promise for achieving complex C-H oxidations in a variety of complex settings. Herein we present a rationally designed platform that provides a step toward this challenge using N-ammonium ylides as electrochemically driven oxidants for site-specific, chemoselective C(sp3)-H oxidation. By taking a first-principles approach guided by computation, these new mediators were identified and rapidly expanded into a library using ubiquitous building blocks and trivial synthesis techniques. The ylide-based approach to C-H oxidation exhibits tunable selectivity that is often exclusive to this class of oxidants and can be applied to real-world problems in the agricultural and pharmaceutical sectors.