Synthesis of Arylethylamines via C(sp3)-C(sp3) Palladium-Catalyzed Cross-Coupling.

Substituted arylethylamines represent a key structural motif in natural, pharmaceutical, and agrochemical compounds. Access to such scaffolds has been the subject of long-standing synthetic interest. Herein, we report the synthesis of such scaffolds via a palladium-catalyzed C(sp3)-C(sp3) coupling between (chloromethyl)aryls and air-/moisture-stable N,N-dialkylaminomethyltrifluoroborate salts. Rapid hit identification was achieved using microscale high-throughput experimentation and was followed by millimolar-scale reaction parameter optimization. A range of structurally and electronically varied arylethylamine products were obtained in moderate to excellent yields (27-96%, >60 examples). The reaction mechanism is proposed to proceed via formation of a trialkylbenzylammonium species prior to oxidative addition.

Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner-Wadsworth-Emmons-based approach.

Integrin inhibitors based on the tripeptide sequence Arg-Gly-Asp (RGD) are potential therapeutics for the treatment of idiopathic pulmonary fibrosis (IPF). Herein, we describe an expeditious three-step synthetic sequence of Horner-Wadsworth-Emmons olefination, diimide reduction, and global deprotection to synthesise cores for these compounds in high yields (63-83% over 3 steps) with no need for chromatography. Key to this transformation is the phosphoramidate protecting group, which is stable to metalation steps.

ß-Keto-dioxinones and ß,δ-diketo-dioxinones in biomimetic resorcylate total synthesis.

Resorcylates are a large group of bioactive natural products that are biosynthesized from acetate and malonate units via the intermediacy of polyketides. These polyketides undergo cyclization reactions to introduce the aromatic core. The bioactivities of the resorcylates including resorcylate macrocyclic lactones include anticancer, antimalarial, mycotoxicity, antifungal, and antibiotic properties, and several compounds in the series are already in use in medicine. Examples are prodrugs derived from mycophenolic acid as immunosuppressants and the Hsp-90 inhibitor, AT13387, which is in phase-II clinical trials for the treatment of small cell lung cancer and melanoma. In consequence of these biological activities, methods for the concise synthesis of diverse resorcylates are of considerable importance. In natural product chemistry, biomimetic total synthesis can have significant advantages including functional group tolerance in key steps, the minimization of the use of protection and deprotection reactions and the shortening of the total number of synthetic steps. This Account provides a description of our adaption of the dioxinone chemistry of Hyatt, Clemens, and Feldman for the synthesis and retro-Diels-Alder reactions of diketo-dioxinones. Such dioxinones, which were synthesized by a range of C-acylation reactions, were found to undergo retro-Diels-Alder reactions on heating to provide the corresponding triketo-ketenes with the loss of acetone. The ketene reactive intermediates were rapidly trapped both inter- and intramolecularly with alcohols to provide the corresponding ß,δ,ζ-triketo-esters. These compounds, which consist of keto-enol mixtures, readily undergo cycloaromatization to produce resorcylate esters and macrocyclic lactones. We have established the use of diketo-dioxinones as key general intermediates for the synthesis of diverse resorcylate natural products and for the synthesis of new classes of compounds for the generation of medicinal chemistry lead structures. Many of the methods used were found to be tolerant of multiple sensitive functional groups. These include enolate C-acylations with acyl chlorides, 1-acyl-benzotriazoles, acyl imidazolides, or Weinreb amides to prepare diketo-dioxinones and their subsequent use to prepare ß,δ,ζ-triketo-esters and lactones and hence resorcylates. In addition, in most cases, phenol protection was avoided. As an alternative to the synthesis of ß,δ,ζ-triketo-esters, diketo-dioxinones were also found to undergo cycloaromatization with retention of the ketal entity via a nonketene pathway. Finally, diketo-dioxinones with an allyl, prenyl, geranyl, or other 2-alkenyl carboxylate esters at the γ-carbon underwent decarboxylative rearrangement with tetrakis(triphenylphosphine)palladium catalysis to produce α-substituted diketo-dioxinones and resorcylates with 3-allyl, prenyl, geranyl, or other 2-alkenyl groups. Such diketo-dioxinone chemistry was used in the total synthesis of natural products including aigialomycin, cruentaren A, and the oligomeric resorcylate antibiotics ent-W1278 A, B, and C. Additionally, tandem use of the decarboxylative rearrangement process and cycloaromatization was used in the total synthesis of natural products including the methyl ester of cristatic acid, mycophenolic acid, and hongoquercin B. The methodology was also applied to the synthesis of 9,10-anthraquinones, o-aminoalkyl resorcylates, dihydroxyisoindolinones, oligomers, and resorcinamides. The development of this methodology is described in this Account, showcasing its applicability and versatility for the synthesis of complex resorcylate products.

Cascade polyketide and polyene cyclizations: biomimetic total synthesis of hongoquercin B.

The total synthesis of hongoquercin B was carried out in 9 steps from trans,trans-farnesyl acetate using a palladium catalyzed decarboxylative π-farnesyl rearrangement of a diketo-dioxinone ester, aromatization and cationic diene-epoxide cyclization as key steps. This cascade tetracyclization simplifies the synthesis of terpenoid resorcylate natural products.

Structure-Based Design of a Novel Class of Autotaxin Inhibitors Based on Endogenous Allosteric Modulators.

Autotaxin (ATX) facilitates the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA), a bioactive phospholipid, which facilitates a diverse range of cellular effects in multiple tissue types. Abnormal LPA expression can lead to the progression of diseases such as cancer and fibrosis. Previously, we identified a potent ATX steroid-derived hybrid (partially orthosteric and allosteric) inhibitor which did not form interactions with the catalytic site. Herein, we describe the design, synthesis, and biological evaluation of a focused library of novel steroid-derived analogues targeting the bimetallic catalytic site, representing an entirely unique class of ATX inhibitors of type V designation, which demonstrate significant pathway-relevant biochemical and phenotypic biological effects. The current compounds modulated LPA-mediated ATX allostery and achieved indirect blockage of LPA1 internalization, in line with the observed reduction in downstream signaling cascades and chemotaxis induction. These novel type V ATX inhibitors represent a promising tool to inactivate the ATX-LPA signaling axis.

Total synthesis of the marine metabolite (±)-polysiphenol via highly regioselective intramolecular oxidative coupling.

(±)-Polysiphenol (1), an atropisomerically stable 4,5-dibrominated 9,10-dihydrophenanthrene from Polysiphonia ferulacea, was prepared by a biomimetically inspired highly regioselective intramolecular oxidative coupling of a dibrominated dihydrostilbene. The installation of the two bromine atoms prior to oxidative coupling prevents further oxidation to a planar aromatized phenanthrene. By this strategy, the synthesis of (±)-polysiphenol was achieved in four steps in 70% overall yield. Synthesis of the naturally occurring 5,5'-(ethane-1,2-diyl)bis(3-bromobenzene-1,2-diol) (2) (the likely biogenetic precursor of polysiphenol) and 5,5'-(ethane-1,2-diyl)bis(3,4,6-tribromobenzene-1,2-diol) (9) are also reported. The origins of the regioselectivity in the oxidative coupling are explored.

Pharmacological characterisation of GSK3335103, an oral αvß6 integrin small molecule RGD-mimetic inhibitor for the treatment of fibrotic disease.

Fibrosis is the formation of scar tissue due to injury or long-term inflammation and is a leading cause of morbidity and mortality. Activation of the pro-fibrotic cytokine transforming growth factor-ß (TGFß) via the alpha-V beta-6 (αvß6) integrin has been identified as playing a key role in the development of fibrosis. Therefore, a drug discovery programme to identify an orally bioavailable small molecule αvß6 arginyl-glycinyl-aspartic acid (RGD)-mimetic was initiated. As part of a medicinal chemistry programme GSK3335103 was identified and profiled in a range of pre-clinical in vitro and in vivo systems. GSK3335103 was shown to bind to the αvß6 with high affinity and demonstrated fast binding kinetics. In primary human lung epithelial cells, GSK3335103-induced concentration- and time-dependent internalisation of αvß6 with a rapid return of integrin to the cell surface observed after washout. Following sustained engagement of the αvß6 integrin in vitro, lysosomal degradation was induced by GSK3335103. GSK3335103 was shown to engage with the αvß6 integrin and inhibit the activation of TGFß in both ex vivo IPF tissue and in a murine model of bleomycin-induced lung fibrosis, as measured by αvß6 engagement, TGFß signalling and collagen deposition, with a prolonged duration of action observed in vivo. In summary, GSK3335103 is a potent αvß6 inhibitor that attenuates TGFß signalling in vitro and in vivo with a well-defined pharmacokinetic/pharmacodynamic relationship. This translates to a significant reduction of collagen deposition in vivo and therefore GSK3335103 represents a potential novel oral therapy for fibrotic disorders.

Discovery of the first potent and selective αvß5 integrin inhibitor based on an amide-containing core.

Integrins αvß5 and αvß3 are closely related, proangiogenic members of the wider RGD-binding integrin family. Due to their high sequence homology, the development of αvß5-selective compounds has remained elusive to synthetic and medicinal chemists. Herein, we describe a survey of SAR around a series of amide-containing 3-aryl-succinamic acid-based RGD mimetics. This resulted in the discovery of α,α,α-trifluorotolyl 12 which exhibits 800 × selectivity for αvß5versus αvß3 with a pyrrolidine amide linker that confers selectivity for αvß5 by positioning a key aryl ring in the SDL of αvß5 with good complementarity; binding in this mode is disfavoured in αvß3 due to clashes with key residues in the ß3-subunit. Compound 12 exhibits selective inhibition by a cell adhesion assay, high passive permeability and solubility which enables potential use of this inhibitor as an αvß5-selective in vitro tool compound.

The Design of Potent, Selective and Drug-Like RGD αvß1 Small-Molecule Inhibitors Derived from non-RGD α4ß1 Antagonists.

Up to 45 % of deaths in developed nations can be attributed to chronic fibroproliferative diseases, highlighting the need for effective therapies. The RGD (Arg-Gly-Asp) integrin αvß1 was recently investigated for its role in fibrotic disease, and thus warrants therapeutic targeting. Herein we describe the identification of non-RGD hit small-molecule αvß1 inhibitors. We show that αvß1 activity is embedded in a range of published α4ß1 (VLA-4) ligands; we also demonstrate how a non-RGD integrin inhibitor (of α4ß1 in this case) was converted into a potent non-zwitterionic RGD integrin inhibitor (of αvß1 in this case). We designed urea ligands with excellent selectivity over α4ß1 and the other αv integrins (αvß3, αvß5, αvß6, αvß8). In silico docking models and density functional theory (DFT) calculations aided the discovery of the lead urea series.

Profile of a Highly Selective Quaternized Pyrrolidine Betaine αvß6 Integrin Inhibitor-(3S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((1S and 1R,3R)-1-methyl-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-ium-1-yl)butanoate Synthesized by Stereoselective Methylation.

A quaternary ammonium betaine 7 is described which shows exceptional potency and selectivity (1.4 to >3 logs) for the αvß6 integrin receptor over the other αv integrins as determined in cell adhesion assays. 7 is prepared by remarkably stereoselective methylation, the origins of which are discussed. The chemical, biological, physicochemical, and pharmacokinetic properties of 7 and its docking into αvß6 are described along with related analogues.

Discovery of ( S)-3-(3-(3,5-Dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic αvß6 Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis.

A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against αvß1, αvß3, αvß5, αvß6, and αvß8 integrins. Numerous analogs with high affinity and selectivity for the αvß6 integrin were identified. The analog ( S)-3-(3-(3,5-dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride salt was found to have very high affinity for αvß6 integrin in a radioligand binding assay (p Ki = 11), a long dissociation half-life (7 h), very high solubility in saline at pH 7 (>71 mg/mL), and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further clinical investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.