Ligand-Enabled C–H Hydroxylation with Aqueous H₂O₂ at Room Temperature

With the large number of Pd(II)-catalyzed C–H activation reactions of native substrates developed in the past decade, the development of catalysts to enable the use of green oxidants under safe and practical conditions has become an increasingly important challenge. Notably, the compatibility of Pd(II) catalysts with sustainable aqueous H2O2 has been a long-standing challenge in catalysis including Wacker-type oxidations. We report herein a bifunctional bidentate carboxyl-pyridone (CarboxPyridone) ligand that enables room-temperature Pd-catalyzed C–H hydroxylation of a broad range of benzoic and phenylacetic acids with an industry-compatible oxidant, aqueous hydrogen peroxide (35% H2O2). The scalability of this methodology is demonstrated by a 1000 mmol scale reaction of ibuprofen (206 g) using only a 1 mol % Pd catalyst loading. The utility of this protocol is further illustrated through derivatization of the products and synthesis of polyfluorinated natural product coumestan and pterocarpene from phenol intermediates prepared using this methodology

Diverse <i>ortho</i>-C(sp²)–H Functionalization of Benzaldehydes Using Transient Directing Groups

Pd-catalyzed C–H functionalizations promoted by transient directing groups remain largely limited to C–H arylation only. Herein, we report a diverse set of <i>ortho</i>-C­(sp²)–H functionalizations of benzaldehyde substrates using the transient directing group strategy. Without installing any auxiliary directing group, Pd­(II)-catalyzed C–H arylation, chlorination, bromination, and Ir­(III)-catalyzed amidation, could be achieved on benzaldehyde substrates. The transient directing groups formed <i>in situ</i> via imine linkage can override other coordinating functional groups capable of directing C–H activation or catalyst poisoning, significantly expanding the scope for metal-catalyzed C–H functionalization of benzaldehydes. The utility of this approach is demonstrated through multiple applications, including late-stage diversification of a drug analogue

Ligand-Enabled β‑C–H Arylation of α‑Amino Acids Using a Simple and Practical Auxiliary

Pd-catalyzed β-C–H functionalizations of carboxylic acid derivatives using an auxiliary as a directing group have been extensively explored in the past decade. In comparison to the most widely used auxiliaries in asymmetric synthesis, the simplicity and practicality of the auxiliaries developed for C–H activation remains to be improved. We previously developed a simple <i>N</i>-methoxyamide auxiliary to direct β-C–H activation, albeit this system was not compatible with carboxylic acids containing α-hydrogen atoms. Herein we report the development of a pyridine-type ligand that overcomes this limitation of the <i>N</i>-methoxyamide auxiliary, leading to a significant improvement of β-arylation of carboxylic acid derivatives, especially α-amino acids. The arylation using this practical auxiliary is applied to the gram-scale syntheses of unnatural amino acids, bioactive molecules, and chiral bis­(oxazoline) ligands

Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Attachment 6. Preclinical and Human Pharmacokinetic Profiling of BMS-663749, a Phosphonooxymethyl Prodrug of the HIV-1 Attachment Inhibitor 2-(4-Benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1<i>H</i>-pyrrolo[2,3-<i>c</i>]pyridin-3-yl)-2-oxoethanone (BMS-488043)

BMS-663749, a phosphonooxymethyl prodrug <b>4</b> of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1<i>H</i>-pyrrolo­[2,3-<i>c</i>]­pyridin-3-yl)-2-oxoethanone (BMS-488043) (<b>2</b>) was prepared and profiled in a variety of preclinical in vitro and in vivo models designed to assess its ability to deliver parent drug following oral administration. The data showed that prodrug <b>4</b> had excellent potential to significantly reduce dissolution rate-limited absorption following oral dosing in humans. Clinical studies in normal healthy subjects confirmed the potential of <b>4</b>, revealing that the prodrug significantly increased both the AUC and <i>C</i>_max of <b>2</b> compared to a solid capsule formulation containing the parent drug upon dose escalation. These data provided guidance for further efforts to obtain an effective HIV-1 attachment inhibitor

Improving Metabolic Stability with Deuterium: The Discovery of BMT-052, a Pan-genotypic HCV NS5B Polymerase Inhibitor

Iterative structure–activity analyses in a class of highly functionalized furo­[2,3-<i>b</i>]­pyridines led to the identification of the second generation pan-genotypic hepatitis C virus NS5B polymerase primer grip inhibitor BMT-052 (<b>14</b>), a potential clinical candidate. The key challenge of poor metabolic stability was overcome by strategic incorporation of deuterium at potential metabolic soft spots. The preclinical profile and status of BMT-052 (<b>14</b>) is described

Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies

The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid <b>4</b>, the known benzofuran analogue <b>5</b>, and the benzothiadiazine derivative <b>6</b>, an optimization process utilizing the simple benzofuran template <b>7</b> as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (<b>37</b>), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of <b>37</b> were better than anticipated and suggest promising potential for QD administration

Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase

Described herein are structure–activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (<b>2</b>) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation