Triflic Anhydride Promoted Decarboxylative Functionalization of α-Amino Acids.

The decarboxylation of naturally abundant amino acids, followed by subsequent inter- or intramolecular reaction cascades, enables the rapid synthesis of a variety of diverse and high-value amine derivatives. Previous methods have relied heavily on transition metals, involved tedious procedures, or required harsh conditions. Herein, we present a novel reaction cascade for the decarboxylation and nucleophilic functionalization of α-amino acids.

Total synthesis of (±)-3-demethoxyerythratidinone TfO-promoted cascade reaction of enaminone.

The tetracyclic rings with chiral quaternary center represent a formidable synthetic challenge for alkaloids. We present a 6-step synthesis of the alkaloid 3-demethoxyerythratidinone with a 16% overall yield. Our synthesis highlights a cascade reaction initiated by TfO-induced activation of an enaminone substrate, yielding an iminium species and an enol triflate, followed by a Pictet-Spengler reaction.

Total Synthesis of Tetracyclic Spirooxindole Alkaloids via a Double Oxidative Rearrangement/Cyclization Cascade.

Skeleton rearrangement could rapidly transfer simple molecules to complex structures and has significant potential in the total synthesis of natural products. We developed a one-pot reaction cascade of double oxidative rearrangement of furan and indole followed by a nucleophilic cyclization that was successfully applied for the formal synthesis of rhynchophylline/isorhynchophylline and the first total synthesis of (±)-7()-geissoschizol oxindole/(±)-7()-geissoschizol oxindole. In addition, the geissoschizol oxindoles were revised to their C3 epimers, and the mechanism for the reversed stereochemistry through the retro-Mannich/Mannich cascade was proposed and supported by density functional theory calculations.

Asymmetric Total Syntheses of Alkaloids via Selective Fischer Indolization.

The complex structures and important biological functions of alkaloids have attracted a great deal of attention from synthetic chemists. Herein, we describe the concise asymmetric total syntheses of the alkaloids, (-)-dehydrotubifoline, (-)-tubifoline, and (-)-tubifolidine, as well as the formal total synthesis of (-)-strychnine. Our strategy features the construction of the common tetracyclic pyrrolo[2,3-]carbazole structure using regioselective Fischer indolization on unsymmetrical cyclic ketones and late-stage functionalization for divergent synthesis.

5-IP is a GPCR messenger mediating neural control of synaptotagmin-dependent insulin exocytosis and glucose homeostasis.

5-diphosphoinositol pentakisphosphate (5-IP) is a signalling metabolite linked to various cellular processes. How extracellular stimuli elicit 5-IP signalling remains unclear. Here we show that 5-IP in β cells mediates parasympathetic stimulation of synaptotagmin-7 (Syt7)-dependent insulin release.

A novel inhibitor of pyruvate dehydrogenase kinase stimulates myocardial carbohydrate oxidation in diet-induced obesity.

The pyruvate dehydrogenase complex (PDC) is a key control point of energy metabolism and is subject to regulation by multiple mechanisms, including posttranslational phosphorylation by pyruvate dehydrogenase kinase (PDK). Pharmacological modulation of PDC activity could provide a new treatment for diabetic cardiomyopathy, as dysregulated substrate selection is concomitant with decreased heart function. Dichloroacetate (DCA), a classic PDK inhibitor, has been used to treat diabetic cardiomyopathy, but the lack of specificity and side effects of DCA indicate a more specific inhibitor of PDK is needed.

Targeting hepatic pyruvate dehydrogenase kinases restores insulin signaling and mitigates ChREBP-mediated lipogenesis in diet-induced obese mice.

Objective: Mitochondrial pyruvate dehydrogenase kinases 1-4 (PDKs1-4) negatively regulate activity of the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation. PDKs play a pivotal role in maintaining energy homeostasis and contribute to metabolic flexibility by attenuating PDC activity in various mammalian tissues. Cumulative evidence has shown that the up-regulation of PDK4 expression is tightly associated with obesity and diabetes.

Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors.

Pyruvate dehydrogenase kinases 1-4 (PDK1-4) negatively control activity of the pyruvate dehydrogenase complex (PDC) and are up-regulated in obesity, diabetes, heart failure, and cancer. We reported earlier two novel pan-PDK inhibitors PS8 [4-((5-hydroxyisoindolin-2-yl)sulfonyl)benzene-1,3-diol] (1) and PS10 [2-((2,4-dihydroxyphenyl)sulfonyl)isoindoline-4,6-diol] (2) that targeted the ATP-binding pocket in PDKs. Here, we developed a new generation of PDK inhibitors by extending the dihydroxyphenyl sulfonylisoindoline scaffold in 1 and 2 to the entrance region of the ATP-binding pocket in PDK2.