Synthesis of benzo[b]furans by intramolecular C–O bond formation using iron and copper catalysis

One-pot processes for the synthesis of benzo[b]furans from 1-aryl- or 1-alkylketones using nonprecious transition metal catalysts have been developed. Regioselective iron(III)-catalyzed halogenation of the aryl ring, followed by iron- or copper-catalyzed O-arylation allowed the synthesis of various structural analogues, including the benzo[b]furan-derived natural products corsifuran C, moracin F, and caleprunin B

Synthesis of functionalized indolines and dihydrobenzofurans by iron and copper catalyzed aryl C-N and C-O bond formation

A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N- or O-arylation step leading to indolines, dihydrobenzofurans and six-membered analogues. The general applicability and functional group tolerance of this method was exemplified by the total synthesis of the neolignan natural product, (+)-obtusafuran. DFT calculations using Fukui functions were also performed, providing a molecular orbital rationale for the highly regioselective arene iodination process

Iron-catalyzed regioselective synthesis of 2-arylbenzoxazoles and 2-arylbenzothiazoles via alternative reaction pathways

A one‐pot regioselective method for the preparation of 2‐arylbenzoxazoles from N‐arylbenzamides has been developed using iron(III)‐catalyzed bromination of the aryl ring, followed by copper(I)‐catalyzed O‐cyclization with the benzamide side chain. In contrast, reaction of N‐arylthiobenzamides with N‐bromosuccinimide and iron triflimide led directly to the isolation of the corresponding 2‐arylbenzothiazoles via intramolecular C–S bond formation. Mechanistic and control experiments suggest that in this case, bromination occurs at the sulfur atom, resulting in a reactive intermediate that can undergo electrophilic aromatic substitution and S‐cyclization. The scope of both processes was explored yielding a range of structural analogues, including a pharmaceutically active compound for the treatment of Duchenne muscular dystrophy and an affinity agent of the amyloid‐beta protein in Alzheimer's disease

Recent advances in transition-metal-catalyzed, directed Aryl C-H/N-H cross coupling reactions

Amination and amidation of aryl compounds using a transition-metal-catalyzed cross-coupling reaction typically involves prefunctionalization or preoxidation of either partner. In recent years, a new class of transition-metal-catalyzed cross-dehydrogenative coupling reaction has been developed for the direct formation of aryl C–N bonds. This short review highlights the substantial progress made for ortho-C–N bond formation via transition-metal-catalyzed chelation-directed aryl C–H activation and gives an overview of the challenges that remain for directed meta- and para-selective reactions

One-pot ortho-amination of aryl C-H bonds using consecutive iron and copper catalysis: late-stage structural diversification of 3,4-dihydroquinolin-2-one

A one-pot approach for ortho-coupling of arenes with non-actived N-nucleophiles has been developed using sequential iron and copper catalysis. Regioselective ortho-activation of anisoles, anilines and phenols was achieved through iron(III) triflimide catalysed iodination, followed by a copper(I)-catalysed, ligand-assisted coupling reaction with N-heterocycle, amide and sulfonamide-based nucleophiles. The synthetic utility of this one-pot, two-step method for the direct amination of ortho-aryl C–H bonds was demonstrated with the late-stage functionalisation of 3,4-dihydroquinolin-2-ones. This allowed the preparation of a TRIM24 bromodomain inhibitor and a series of novel analogues

Five axioms for location functions on median graphs

__Abstract__ In previous work, two axiomatic characterizations were given for the median function on median graphs: one involving the three simple and natural axioms anonymity, betweenness and consistency; the other involving faithfulness, consistency and ½-Condorcet. To date, the independence of these axioms has not been a serious point of study. The aim of this paper is to provide the missing answers. The independent subsets of these five axioms are determined precisely and examples provided in each case on arbitrary median graphs. There are three cases that stand out. Here non-trivial examples and proofs are needed to give a full answer. Extensive use of the structure of median graphs is used throughout

Iron(III)-catalyzed chlorination of activated arenes

A general and regioselective method for the chlorination of activated arenes has been developed. The transformation uses iron(III) triflimide as a powerful Lewis acid for the activation of N-chlorosuccinimide and the subsequent chlorination of a wide range of anisole, aniline, acetanilide and phenol derivatives. The reaction was utilized for the late-stage mono- and di-chlorination of a range of target compounds such as the natural product nitrofungin, the antibacterial agent chloroxylenol and the herbicide chloroxynil. The facile nature of this transformation was demonstrated with the development of one-pot tandem iron-catalyzed dihalogenation processes allowing highly regioselective formation of different carbon-halogen bonds. The synthetic utility of the resulting dihalogenated aryl compounds as building blocks was established with the synthesis of natural products and pharmaceutically relevant targets

A tumor-associated β1 integrin mutation that abrogates epithelial differentiation control

SCC4 human keratinocytes are derived from a squamous cell carcinoma of the tongue and undergo very little spontaneous differentiation. Introduction of a wild-type β1 integrin subunit into SCC4 cells stimulates differentiation, suggesting either that the cells have a defect in the integrin signaling pathways that control differentiation or that the β1 subunit itself is defective. Here we describe a heterozygous mutation in the SCC4 β1 subunit. The mutation, T188I, maps to the I-like domain. It results in constitutive activation of ligand binding, irrespective of the partner α subunit, in solid phase assays with recombinant protein and in living cells. The mutation promotes cell spreading, but not proliferation, motility, or invasiveness. It results in sustained activation of Erk MAPK independent of cell spreading. When introduced into SCC4 keratinocytes, the wild-type β1 integrin stimulates differentiation, whereas the mutant is inactive. Activation of β1 integrins in normal keratinocytes also suppresses differentiation. These results establish, for the first time, mutation as a mechanism by which integrins can contribute to neoplasia, because the degree of differentiation in epithelial cancers is inversely correlated with prognosis. They also provide new insights into how integrins regulate keratinocyte differentiation

Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain

Acknowledgments We thank Craig Irving for his assistance with NMR spectroscopy and Pat Keating, Dr. Jessica Bame, and Dr. Graeme Anderson for their assistance with HRMS.Peer reviewe

Current and emerging approaches to noncompetitive AR inhibition

The Androgen Receptor (AR) has been shown to be a key determinant in the pathogenesis of castration-resistant prostate cancer (CRPC). Current standard of care therapies target the ligand-binding domain of the receptor, and afford improvements to life expectancy often only in the order of months before resistance occurs. Emerging preclinical and clinical compounds that inhibit receptor activity via differentiated mechanisms of action which are orthogonal to current anti-androgens show promise for overcoming treatment resistance. In this review we present an authoritative summary of molecules that non-competitively target the AR. Emerging small molecule strategies for targeting alternative domains of the AR represent a promising area of research that shows significant potential future therapies. The overall quality of lead candidates in the area of non-competitive AR inhibition is discussed, and identifies the key chemotypes and associated properties which are likely to be, or are currently, positioned for first in human applications