Over the past 30 years, enantioselective catalysis has become one of the most important frontiers in exploratory organic synthetic research. During this time, remarkable advances have been made in the development of organometallic asymmetric catalysts that in turn have provided a wealth of enantioselective oxidation, reduction, π-bond activation, and Lewis acid-catalyzed processes. 1 Surprisingly, however, relatively few asymmetric transformations have been reported which employ organic molecules as reaction catalysts, 2 despite the widespread availability of organic chemicals in enantiopure form and the accordant potential for academic, industrial, and economic benefit. Herein, we introduce a new strategy for organocatalysis that we expect will be amenable to a range of asymmetric transformations. In this context, we document the first highly enantioselective organocatalytic Diels-Alder reaction. 3 We recently embarked upon the development of a general strategy for organocatalytic reactions based upon design features derived from the arena of Lewis acid catalysis. Specifically, we reasoned that (i) LUMO-lowering activation and (ii) the kinetic lability toward ligand substitution that enables Lewis acid-catalyst turnover (eq 1) might also be available with a carbogenic system that exists as a rapid equilibrium between an electron-deficient and a relatively electron-rich state. With this in mind, we hypothesized that the reversible formation of iminium ions from R,β-unsaturated aldehydes and amines (eq 2) might emulate the equilibrium dynamics and π-orbital electronics that are inherent to Lewis acid catalysis, thereby providing a new platform for the design of organocatalytic processes. Significantly, this analysis reveals the attractive prospect that chiral amines might function as enantioselective catalysts for a range of transformations that traditionally utilize metal salts.

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Class II fructose 1,6-bisphosphate aldolase (FBA) is an enzyme critical for bacterial, fungal, and protozoan glycolysis/gluconeogenesis. Importantly, humans lack this type of aldolase, having instead a class I FBA that is structurally and mechanistically distinct from class II FBAs. As such, class II FBA is considered a putative pharmacological target for the development of novel antibiotics against pathogenic bacteria such as Mycobacterium tuberculosis, the causative agent for tuberculosis (TB). To date, several competitive class II FBA substrate mimic-styled inhibitors have been developed; however, they lack either specificity, potency, or properties that limit their potential as possible therapeutics. Recently, through the use of enzymatic and structure-based assisted screening, we identified 8-hydroxyquinoline carboxylic acid (HCA) that has an IC50 of 10 ± 1 μM for the class II FBA present in M. tuberculosis (MtFBA). As opposed to previous inhibitors, HCA behaves in a noncompetitive manner, shows no inhibitory properties toward human and rabbit class I FBAs, and possesses anti-TB properties. Furthermore, we were able to determine the crystal structure of HCA bound to MtFBA to 2.1 Å. HCA also demonstrates inhibitory effects for other class II FBAs, including pathogenic bacteria such as methicillin-resistant Staphylococcus aureus. With its broad-spectrum potential, unique inhibitory characteristics, and flexibility of functionalization, the HCA scaffold likely represents an important advancement in the development of class II FBA inhibitors that can serve as viable preclinical candidates.

The V600E mutation of B-Raf kinase results in constitutive activation of the MAPK signaling pathway and is present in approximately 7% of all cancers. Using structure-based design, a novel series of pyrazolopyridine inhibitors of B-Raf(V600E) was developed. Optimization led to the identification of 3-methoxy pyrazolopyridines 17 and 19, potent, selective, and orally bioavailable agents that inhibited tumor growth in a mouse xenograft model driven by B-Raf(V600E) with no effect on body weight. On the basis of their in vivo efficacy and preliminary safety profiles, 17 and 19 were selected for further preclinical evaluation.

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