Electrochemical Nickel-Catalyzed C(sp)-C(sp) Cross-Coupling of Alkyl Halides with Alkyl Tosylates.

Formation of new C(sp)-C(sp) bonds is a powerful synthetic tool to increase molecular diversity, which is highly sought after in medicinal chemistry. Traditional generation of carbon nucleophiles and more modern cross-electrophile-coupling methods typically lack sufficient selectivity when cross-coupling of analogous C(sp)-containing reactants is attempted. Herein, we present a nickel-catalyzed, electrochemically driven method for the coupling of alkyl bromides with alkyl tosylates.

Synthesis of Enantiopure Unnatural Amino Acids by Metallaphotoredox Catalysis.

We describe herein a two-step process for the conversion of serine to a wide array of optically pure unnatural amino acids. This method utilizes a photocatalytic cross-electrophile coupling between a bromoalkyl intermediate and a diverse set of aryl halides to produce artificial analogues of phenylalanine, tryptophan, and histidine. The reaction is tolerant of a broad range of functionalities and can be leveraged toward the scalable synthesis of valuable pharmaceutical scaffolds via flow technology.

Self-Optimization of Continuous Flow Electrochemical Synthesis Using Fourier Transform Infrared Spectroscopy and Gas Chromatography.

A continuous-flow electrochemical synthesis platform has been developed to enable self-optimization of reaction conditions of organic electrochemical reactions using attenuated total reflection Fourier transform infrared spectroscopy (ATR FT-IR) and gas chromatography (GC) as online real-time monitoring techniques. We have overcome the challenges in using ATR FT-IR as the downstream analytical methods imposed when a large amount of hydrogen gas is produced from the counter electrode by designing two types of gas-liquid separators (GLS) for analysis of the product mixture flowing from the electrochemical reactor. In particular, we report an integrated GLS with an ATR FT-IR probe at the reactor outlet to give a facile and low-cost solution to determining the concentrations of products in gas-liquid two-phase flow.

Rapid Optimization of Photoredox Reactions for Continuous-Flow Systems Using Microscale Batch Technology.

Photoredox catalysis has emerged as a powerful and versatile platform for the synthesis of complex molecules. While photocatalysis is already broadly used in small-scale batch chemistry across the pharmaceutical sector, recent efforts have focused on performing these transformations in process chemistry due to the inherent challenges of batch photocatalysis on scale. However, translating optimized batch conditions to flow setups is challenging, and a general approach that is rapid, convenient, and inexpensive remains largely elusive.

Photochemical benzylic bromination in continuous flow using BrCCl and its application to telescoped p-methoxybenzyl protection.

BrCCl3 represents a rarely used benzylic brominating reagent with complementary reactivity to other reagents. Its reactivity has been revisited in continuous flow, revealing compatibility with electron-rich aromatic substrates. This has brought about the development of a p-methoxybenzyl bromide generator for PMB protection, which was successfully demonstrated on a pharmaceutically relevant intermediate on 11 g scale, giving 91% yield and a PMB-Br space-time-yield of 1.

Metallaphotoredox-Catalyzed Cross-Electrophile C-C Coupling of Aliphatic Bromides.

A strategy for the installation of small alkyl fragments onto pharmaceutically relevant aliphatic structures has been established via metallaphotoredox catalysis. Herein, we report that tris(trimethylsilyl)silanol can be employed as an effective halogen abstraction reagent that, in combination with photoredox and nickel catalysis, allows a generic approach to C-C cross-electrophile coupling. In this study, we demonstrate that a variety of aliphatic drug-like groups can be successfully coupled with a number of commercially available small alkyl electrophiles, including methyl tosylate and strained cyclic alkyl bromides.

Discovery of chiral dihydropyridopyrimidinones as potent, selective and orally bioavailable inhibitors of AKT.

During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties.

Electrochemical Deprotection of para-Methoxybenzyl Ethers in a Flow Electrolysis Cell.

Electrochemical deprotection of p-methoxybenzyl (PMB) ethers was performed in an undivided electrochemical flow reactor in MeOH solution, leading to the unmasked alcohol and p-methoxybenzaldehyde dimethyl acetal as a byproduct. The electrochemical method removes the need for chemical oxidants, and added electrolyte (BFNEt) can be recovered and reused. The method was applied to 17 substrates with high conversions in a single pass, yields up to 92%, and up to 7.

Discovery of the First α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist Dependent upon Transmembrane AMPA Receptor Regulatory Protein (TARP) γ-8.

Transmembrane AMPA receptor regulatory proteins (TARPs) are a family of scaffolding proteins that regulate AMPA receptor trafficking and function. TARP γ-8 is one member of this family and is highly expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative approach to modulate AMPA receptors in specific brain regions to potentially increase the therapeutic index relative to known non-TARP-dependent AMPA antagonists.

Light-Induced C-H Arylation of (Hetero)arenes by In Situ Generated Diazo Anhydrides.

Diazo anhydrides (Ar-N=N-O-N=N-Ar) have been known since 1896 but have rarely been used in synthesis. This communication describes the development of a photochemical catalyst-free C-H arylation methodology for the preparation of bi(hetero)aryls by the one-pot reaction of anilines with tert-butyl nitrite and (hetero)arenes under neutral conditions. The key step in this procedure is the in situ formation and subsequent photochemical (>300 nm) homolytic cleavage of a transient diazo anhydride intermediate.

A continuous-flow protocol for light-induced benzylic fluorinations.

A continuous-flow protocol for the light-induced fluorination of benzylic compounds is presented. The procedure uses Selectfluor as the fluorine source and xanthone as an inexpensive and commercially available photoorganocatalyst. The flow photoreactor is based on transparent fluorinated ethylene propylene tubing and a household compact fluorescent lamp.

Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.

The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior.

Continuous flow α-trifluoromethylation of ketones by metal-free visible light photoredox catalysis.

A continuous-flow, two-step procedure for the preparation of α-CF3-substituted carbonyl compounds has been developed. The carbonyl substrates were converted in situ into the corresponding silyl enol ethers, mixed with the CF3 radical source, and then irradiated with visible light using a flow reactor based on transparent tubing and a household compact fluorescent lamp. The continuous protocol uses Eosin Y as an inexpensive photoredox catalyst and requires only 20 min to complete the two reaction steps.

A scalable procedure for light-induced benzylic brominations in continuous flow.

A continuous-flow protocol for the bromination of benzylic compounds with N-bromosuccinimide (NBS) is presented. The radical reactions were activated with a readily available household compact fluorescent lamp (CFL) using a simple flow reactor design based on transparent fluorinated ethylene polymer (FEP) tubing. All of the reactions were carried out using acetonitrile as the solvent, thus avoiding hazardous chlorinated solvents such as CCl4.

Privileged structure based ligands for melanocortin-4 receptors--aliphatic piperazine derivatives.

Aliphatic carbocyclic replacement of the benzyl group of compound 1 yielded compounds with high affinity for the melanocortin-4 receptor (MC4R). Compounds with a cyclohexyl group showed a consistent high affinity, while different polar groups with less basicity were good replacements for the original diethyl amines. Substitution of the polar group found in these privileged structures with an aliphatic moiety produced compounds with high affinity for MC4R.

Privileged structure based ligands for melanocortin receptors--substituted benzylic piperazine derivatives.

Replacement of the aryl piperazine moiety in compound 1 with a variety of substituted benzylic piperazines (6) yields compounds that afford melanocortin receptor 4 (MCR4) activity. Analogs with ortho substitution on the aromatic ring afforded the highest affinity. Resolution of the stereocenter of the benzylic piperazine based privileged structure revealed that the R-enantiomer was more active.

Synthesis of C3 benzo[1,2-e:3,4-e':5,6-e"]tribenzo[l]acephenanthrylenes ("crushed fullerene" derivatives) by intramolecular palladium-catalyzed arylation.

The C60 polyarenes 4, 5, 18 a, and 18 b have been synthesized from truxene by triple alkylation at C5, C10, and C15 followed by a palladium-catalyzed intramolecular arylation. The synthesis of "crushed fullerene" C60H30 (2) is the most efficient reported to date and proceeds in 33% overall yield.

Synthesis and self-association of syn-5,10,15-trialkylated truxenes.

syn-Trialkylated truxenes have been synthesized by alkylation of the truxene trianion followed by base-catalyzed isomerization of the anti isomers. 1H NMR studies, including a determination of diffusion coefficients, as well as molecular mechanics calculations, demonstrate that these derivatives self-associate in solution through arene-arene interactions. The benzyl derivatives show the strongest associations, which are a result of both benzyl-benzyl and truxene-truxene interactions.