Asymmetric N‑Heterocyclic Carbene Catalyzed Addition of Enals to Nitroalkenes: Controlling Stereochemistry via the Homoenolate Reactivity Pathway To Access δ‑Lactams

An asymmetric intermolecular reaction between enals and nitroalkenes to yield δ-nitroesters has been developed, catalyzed by a novel chiral N-heterocyclic carbene. Key to this work was the development of a catalyst that favors the δ-nitroester pathway over the established Stetter pathway. The reaction proceeds in high stereoselectivity and affords the previously unreported <i>syn</i> diastereomer. We also report an operationally facile two-step, one-pot procedure for the synthesis of δ-lactams

Facile Quantum Yield Determination via NMR Actinometry

A simplified approach to quantum yield (ϕ) measurement using in situ LED NMR spectroscopy has been developed. The utility and performance of NMR actinometry has been demonstrated for the well-known chemical actinometers potassium ferrioxalate and <i>o</i>-nitrobenzaldehyde. A novel NMR-friendly actinometer, 2,4-dinitrobenzaldehyde, has been introduced for both 365 and 440 nm wavelengths. The method has been utilized successfully to measure the quantum yield of several recently published photochemical reactions

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

Development of a Direct Photocatalytic C–H Fluorination for the Preparative Synthesis of Odanacatib

Late-stage C–H fluorination is an appealing reaction for medicinal chemistry. However, the application of this strategy to process research appears less attractive due to the formation and necessary purification of mixtures of organofluorines. Here we demonstrate that γ-fluoroleucine methyl ester, an intermediate critical to the large-scale synthesis of odanacatib, can be accessed directly from leucine methyl ester using a combination of the decatungstate photocatalyst and <i>N</i>-fluorobenzene­sulfonimide in flow. This efficient C–H fluorination reaction compares favorably with several generations of classical γ-fluoroleucine process syntheses

Asymmetric Hydrogen Bonding Catalysis for the Synthesis of Dihydroquinazoline-Containing Antiviral, Letermovir

A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C₂-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,β-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues

Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 1Process History and Development Strategy

An improved synthesis has been developed for belzutifan, a novel HIF-2α inhibitor for the treatment of Von Hippel–Lindau (VHL) disease-associated renal cell carcinoma (RCC). The efficiency of previous supply and commercial routes was encumbered by a lengthy 5-step sequence, needed to install a chiral benzylic alcohol by traditional methods. Identification and directed evolution of FoPip4H, an iron/α-ketoglutarate dependent hydroxylase, enabled a direct enantioselective C–H hydroxylation of a simple indanone starting material. While this enabling transformation set the stage for a greatly improved synthesis, several other key innovations were made including the development of a base-metal-catalyzed sulfonylation, a KRED-catalyzed dynamic kinetic resolution, and a facile SNAr reaction in water. Together, these improvements resulted in a significantly shorter synthesis (9 steps) versus the supply route (16 steps) and a 75% reduction in process mass intensity (PMI), while also removing the reliance on third-row transition metals and toxic solvents