Synthesis and Hydrogenation Activity of Iron Dialkyl Complexes with Chiral Bidentate Phosphines

The activity of bis­(phosphine) iron dialkyl complexes for the asymmetric hydrogenation of alkenes has been evaluated. High-throughput experimentation was used to identify suitable iron–phosphine combinations using the displacement of pyridine from py₂Fe­(CH₂SiMe₃)₂ for precatalyst formation. Preparative-scale synthesis of a family of bis­(phosphine) iron dialkyl complexes was also achieved using both ligand substitution and salt metathesis methods. Each of the isolated organometallic iron complexes was established as a tetrahedral and hence high-spin ferrous compound, as determined by Mössbauer spectroscopy, magnetic measurements, and, in many cases, X-ray diffraction. One example containing a Josiphos-type ligand, (SL-J212-1)­Fe­(CH₂SiMe₃)₂, proved more active than other isolated iron dialkyl precatalysts. Filtration experiments and the lack of observed enantioselectivity support dissociation of the phosphine ligand upon activation with dihydrogen and formation of catalytically active heterogeneous iron. The larger six-membered chelate is believed to reduce the coordination affinity of the phosphine for the iron center, enabling metal particle formation

Heterocyclic Regioisomer Enumeration (HREMS): A Cheminformatics Design Tool

We report the development and implementation of a cheminformatics tool which aids in the design of compounds during exploratory chemistry and lead optimization. The Heterocyclic Regioisomer Enumeration and MDDR Search (HREMS) tool allows medicinal chemists to build greater structural diversity into their synthetic planning by enabling a systematic, automated enumeration of heterocyclic regioisomers of target structures. To help chemists overcome biases arising from past experience or synthetic accessibility, the HREMS tool further provides statistics on clinical testing for each enumerated regioisomer substructure using an automated search of a commercial database. Ready access to this type of information can help chemists make informed choices on the targets they will pursue being mindful of past experience with these structures in drug development. This tool and its components can be incorporated into other cheminformatics workflows to leverage their capabilities in triaging and in silico compound enumeration

Heterocyclic Regioisomer Enumeration (HREMS): A Cheminformatics Design Tool

We report the development and implementation of a cheminformatics tool which aids in the design of compounds during exploratory chemistry and lead optimization. The Heterocyclic Regioisomer Enumeration and MDDR Search (HREMS) tool allows medicinal chemists to build greater structural diversity into their synthetic planning by enabling a systematic, automated enumeration of heterocyclic regioisomers of target structures. To help chemists overcome biases arising from past experience or synthetic accessibility, the HREMS tool further provides statistics on clinical testing for each enumerated regioisomer substructure using an automated search of a commercial database. Ready access to this type of information can help chemists make informed choices on the targets they will pursue being mindful of past experience with these structures in drug development. This tool and its components can be incorporated into other cheminformatics workflows to leverage their capabilities in triaging and in silico compound enumeration

High-Throughput Optimization of Ir-Catalyzed C–H Borylation: A Tutorial for Practical Applications

With the aid of high-throughput screening, the efficiency of Ir-catalyzed C–H borylations has been assessed as functions of precatalyst, boron reagent, ligand, order of addition, temperature, solvent, and substrate. This study not only validated some accepted practices but also uncovered unconventional conditions that were key to substrate performance. We anticipate that insights drawn from these findings will be used to design reaction conditions for substrates whose borylations are difficult to impossible using standard catalytic conditions

Photoredox-Catalyzed Hydroxymethylation of Heteroaromatic Bases

We report the development of a method for room-temperature C–H hydroxymethylation of heteroarenes. A key enabling advance in this work was achieved by implementing visible light photoredox catalysis that proved to be applicable to many classes of heteroarenes and tolerant of diverse functional groups found in druglike molecules

Cu-Mediated C–H ¹⁸F‑Fluorination of Electron-Rich (Hetero)arenes

This communication describes a method for the nucleophilic radiofluorination of electron-rich arenes. The reaction involves the initial C­(sp²)–H functionalization of an electron-rich arene with MesI­(OH)­OTs to form a (mesityl)­(aryl)­iodonium salt. This salt is then used in situ in a Cu-mediated radiofluorination with [¹⁸F]­KF. This approach leverages the stability and availability of electron-rich arene starting materials to enable mild late-stage radiofluorination of toluene, anisole, aniline, pyrrole, and thiophene derivatives. The radiofluorination has been automated to access a 41 mCi dose of an ¹⁸F-labeled nimesulide derivative in high (2800 ± 700 Ci/mmol) specific activity

Silyl Phosphorus and Nitrogen Donor Chelates for Homogeneous Ortho Borylation Catalysis

Ir catalysts supported by bidentate silyl ligands that contain P- or N-donors are shown to effect ortho borylations for a range of substituted aromatics. The substrate scope is broad, and the modular ligand synthesis allows for flexible catalyst design

Synthesis of Antifungal Glucan Synthase Inhibitors from Enfumafungin

An efficient, new, and scalable semisynthesis of glucan synthase inhibitors <b>1</b> and <b>2</b> from the fermentation product enfumafungin <b>3</b> is described. The highlights of the synthesis include a high-yielding ether bond-forming reaction between a bulky sulfamidate <b>17</b> and alcohol <b>4</b> and a remarkably chemoselective, improved palladium­(II)-mediated Corey-Yu allylic oxidation at the highly congested C-12 position of the enfumafungin core. Multi-hundred gram quantities of the target drug candidates <b>1</b> and <b>2</b> were prepared, in 12 linear steps with 25% isolated yield and 13 linear steps with 22% isolated yield, respectively