The atomistic change of C(sp3)–H to C(sp3)–O can have a profound impact on the physical and biological properties of small molecules. Traditionally, chemical synthesis has relied on pre-existing functionality to install new functionality, and directed approaches to C–H oxidation are an extension of this logic. The impact of developing undirected C–H oxidation reactions with controlled site-selectivity is that scientists gain the ability to diversify complex structures at sites remote from existing functionality, without having to carry out individual de novo syntheses. This Perspective offers a historical view of why, as recently as 2007, it was thought that the differences between aliphatic C–H bonds of the same bond type (for example, 2° aliphatic) were not large enough to distinguish them preparatively with small-molecule catalysis in the absence of directing groups or molecular recognition elements. We give an account of the discovery of Fe(PDP)-catalyzed non-directed aliphatic C–H hydroxylations and ...

Aliphatic C-H Oxidations for Late-Stage Functionalization.

The Cu-catalyzed novel aerobic oxidative esterification reaction of 1,3-diones for the synthesis of α-ketoesters has been developed. This method combines C–C σ-bond cleavage, dioxygen activation and oxidative C–H bond functionalization, as well as provides a practical, neutral, and mild synthetic approach to α-ketoesters which are important units in many biologically active compounds and useful precursors in a variety of functional group transformations. A plausible radical process is proposed on the basis of mechanistic studies.

Cu-catalyzed esterification reaction via aerobic oxygenation and C-C bond cleavage: an approach to α-ketoesters.

A visible-light-promoted photoredox/nickel protocol for the enantioselective three-component carboarylation of alkenes with tertiary and secondary alkyltrifluoroborates and aryl bromides is described. This redox-neutral protocol allows for facile and divergent access to a wide array of enantioenriched β-alkyl-α-arylated carbonyls, phosphonates, and sulfones in high yields and excellent enantioselectivities from readily available starting materials. We also report a modular and enantioselective synthesis of flurbiprofen analogs and piragliatin lead compound to demonstrate synthetic utility. Experimental and computational mechanistic studies were performed to gain insights into the mechanism and origin of chemo- and enantioselectivity.

General Method for Enantioselective Three-Component Carboarylation of Alkenes Enabled by Visible-Light Dual Photoredox/Nickel Catalysis.

Cumulative research over several decades has implicated the involvement of reactive metabolites in many idiosyncratic adverse drug reactions (IADRs). Consequently, "avoidance" strategies have been inserted into drug discovery paradigms, which include the exclusion of structural alerts and possible termination of reactive metabolite-positive compounds. Several noteworthy examples where reactive metabolite-related liabilities have been resolved through structure-metabolism studies are presented herein. Considerable progress has also been made in addressing the limitations of the avoidance strategy and further refining the process of managing reactive metabolite issues in drug development. These efforts primarily stemmed from the observation that numerous drugs, which contain structural alerts and/or form reactive metabolites, are devoid of ADRs. The Perspective also dwells into an analysis of the structural alert/reactive metabolite concept with a discussion of risk mitigation tactics to support the progression of reactive metabolite-positive drug candidates.

Designing around Structural Alerts in Drug Discovery

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(12)00199-X.pdf

GKAs for diabetes therapy: why no clinically useful drug after two decades of trying?

Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase β-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.

Discovery of piragliatin--first glucokinase activator studied in type 2 diabetic patients.

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Discovery of piragliatin--first glucokinase activator studied in type 2 diabetic patients.