Broad Survey of Selectivity in the Heterogeneous Hydrogenation of Heterocycles.

A broad survey of heterogeneous hydrogenation catalysts has been conducted for the reduction of heterocycles commonly found in pharmaceuticals. The comparative reactivity of these substrates is reported as a function of catalyst, temperature, and hydrogen pressure. This analysis provided several catalysts with complementary reactivity between substrates. We then explored a series of bisheterocyclic substrates that provided an intramolecular competition of heterocycle hydrogenation reactivity. In several cases, complete selectivity could be achieved for reduction of one heterocycle and isolated yields are reported. A general trend in reactivity is inferred in which quinoline is the most reactive, followed by pyrazine, then pyrrole and with pyridine being the least reactive.

Intramolecular Hydrogen Transfer Reactions Catalyzed by Pentamethylcyclopentadienyl Rhodium and Cobalt Olefin Complexes: Mechanistic Studies.

The mechanism of intramolecular transfer dehydrogenation catalyzed by [Cp*M(VTMS)2] (1, M=Rh, 2, M=Co, Cp* = C5Me5, VTMS = vinyltrimethylsilane) complexes has been studied using vinyl silane protected alcohols as substrates. Deuterium-labeled substrates have been synthesized and the regioselectivity of H/D transfers investigated using 1H and 2H NMR spectroscopy. The labeling studies establish a regioselective pathway consisting of alkene directed α C-H activation, 2,1 alkene insertion, and finally ß-hydride elimination to give silyl enol ether products.

Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRASG12C Inhibitor.

Oncogenic mutations in the RAS gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRASG12C covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.

Cobalt-catalyzed hydrosilation/hydrogen-transfer cascade reaction: a new route to silyl enol ethers.

Capitalizing on cobalt: A new route to silyl enol ethers employing a Co-catalyzed cascade reaction featuring a tandem hydrosilation/hydrogen-transfer reaction is reported. The low catalyst loading, mild reaction conditions, and unique η(2)-silane resting state showcase the impressive utility of this seldom used transition-metal catalyst in C-H activation reactions (see scheme; VTMS = vinyltrimethylsilane; Cp* = 1,2,3,4,5-pentamethylcyclopentadiene).

Synthesis of p-xylene from ethylene.

As oil supplies dwindle, there is a growing need to develop new routes to chemical intermediates that utilize alternative feedstocks. We report here a synthesis of para-xylene, one of the highest volume chemicals derived from petroleum, using only ethylene as a feedstock. Ethylene is an attractive alternative feedstock, as it can be derived from renewable biomass resources or harnessed from large domestic shale gas deposits. The synthesis relies on the conversion of hexene (from trimerization of ethylene) to 2,4-hexadiene followed by a Diels-Alder reaction with ethylene to form 3,6-dimethylcyclohexene. This monoene is readily dehydrogenated to para-xylene uncontaminated by the ortho and meta isomers. We report here a selective synthesis of para-xylene, uncontaminated by the ortho or meta isomers, using ethylene as the sole feedstock.

Controlling site selectivity in Pd-catalyzed oxidative cross-coupling reactions.

This paper presents a detailed investigation of the factors controlling site selectivity in the Pd-mediated oxidative coupling of 1,3-disubstituted and 1,2,3-trisubstituted arenes (aryl-H) with cyclometalating substrates (L~C-H). The influence of both the concentration and the steric/electronic properties of the quinone promoter are studied in detail. In addition, the effect of steric/electronic modulation of the carboxylate ligand is discussed. Finally, we demonstrate that substitution of the carboxylate for a carbonate X-type ligand leads to a complete reversal in site selectivity for many arene substrates. The origins of these trends in site selectivity are discussed in the context of the mechanism of Pd-catalyzed oxidative cross-coupling.

Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for Immuno-Oncology.

Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a, 18, and 27, demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model.

Comprehensive Strategies to Bicyclic Prolines: Applications in the Synthesis of Potent Arginase Inhibitors.

Comprehensive synthetic strategies afforded a diverse set of structurally unique bicyclic proline-containing arginase inhibitors with a high degree of three-dimensionality. The analogs that favored the Cγ-exo conformation of the proline improved the arginase potency over the initial lead. The novel synthetic strategies reported here not only enable access to previously unknown stereochemically complex proline derivatives but also provide a foundation for the future synthesis of bicyclic proline analogs, which incorporate inherent three-dimensional character into building blocks, medicine, and catalysts and could have a profound impact on the conformation of proline-containing peptides and macrocycles.

Discovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy.

The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme-inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3, when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored.

Palladium (II/IV) catalyzed cyclopropanation reactions: scope and mechanism.

This report describes detailed studies of the scope and mechanism of a new Pd-catalyzed oxidation reaction for the stereospecific conversion of enynes into cyclopropyl ketones. Unlike related Pd(II/0), Au, and Pt-catalyzed cyclopropane-forming reactions, these transformations proceed with net inversion of geometry with respect to the starting alkene. This result, along with other mechanistic data, is consistent with a Pd(II/IV) mechanism in which the key cyclopropane-forming step involves nucleophilic attack of a tethered olefin onto the Pd(IV)-C bond.

A Next Generation Synthesis of BACE1 Inhibitor Verubecestat (MK-8931).

The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights of which include the application of a continuous processing step to outcompete fast proton transfer in a Mannich-type ketimine addition, a copper-catalyzed amidation reaction, and an optimized guanidinylation procedure to form the key iminothiadiazine dioxide core.