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The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (

A practical reduction of carboxylic acids (no Schlenk apparatus) using inexpensive and readily available catalysts.

The total synthesis of (+/-)-powelline (13 linear steps in an overall yield of 6%) and (+/-)-buphanidrine (14 linear steps and a 6% overall yield) and has been achieved using a novel approach to the crinane skeleton. An organocatalytic oxidative coupling allowed direct construction of the key quaternary carbon-to-aryl bond in high yield allowing rapid access to the target alkaloids.

For the first time, the title reaction is used to transform difluorinated silylenol ethers to difluorinated cycloalkenones under mild conditions.

In this paper we present a study into the direct formation of five plant-derived natural products via intramolecular Diels-Alder cycloaddition of a series of 1,7,9-decatriene precursors. Methods for the preparation of the trienes are also discussed.

(R)-3-Amino-2-[1-(2-hydroxyethoxy)ethyl]quinazolin-4(3H)-one 10 was prepared in 62% yield without the need for chromatography and O-cinnamoylated; reaction with lead tetra-acetate gave aziridine 12 as a single diastereoisomer in quantitative yield which was converted into the β-amino acid ester 15 corresponding to overall enantioselective addition of ammonia to the double bond of cinnamic acid.

In the presence of a base, ortho-quinones such as (I) can act as Michael acceptors towards carbon-centered nucleophiles to give a series of compounds with arylated quaternary carbon centers such as (IV).

In this paper we report the development of a stereoselective IMDA approach to the phytotoxic polyketides (±)-solanapyrones A and B. The stereoselectivity of the key IMDA cycloaddition was optimized by investigating a range of 2,8,10-dodecatrienoic acid derivatives. This established that use of the Weinreb amide led to the desired exo -selectivity and also facilitated construction of the pyrone moiety. A novel approach to the installation of the C-3 formyl group in solanapyrone A is also described.