THE JOURNAL OF BIOLOGICAL CHEMISTRY: The Biochemical Behavior of LeadL I. Influence of Calcium, Phosphorus, and Vitamin D on Lead in Blood and Bone

Saturated N-heterocycles are prevalent in biologically active molecules and are increasingly attractive scaffolds in the development of new pharmaceuticals. Unlike their aromatic counterparts, there are limited strategies for facile construction of substituted saturated N-heterocycles by convergent, predictable methods. In this Synopsis, we discuss recent advances in the synthesis of these compounds, focusing on approaches that offer generality and convenience from widely available building blocks.

Synthesis of Saturated N-Heterocycles

The first catalytic formal [5+4] cycloaddition to prepare nine-membered heterocycles is presented. Under palladium catalysis, the reaction of N-tosyl azadienes and substituted vinylethylene carbonates (VECs) proceeds smoothly to produce benzofuran-fused heterocycles in uniformly high efficiency. Highly diastereoselective functionalization of the nine-membered heterocycles through peripheral attack is also demonstrated.

Construction of Nine-Membered Heterocycles through Palladium-Catalyzed Formal [5+4] Cycloaddition

An unprecedented visible-light-induced direct C−H bond difluoroalkylation of aldehyde-derived hydrazones was developed. This reaction represents a new way to synthesize substituted hydrazones. The salient features of this reaction include difluorinated hydrazone synthesis rather than classical amine synthesis, extremely mild reaction conditions, high efficiency, wide substrate scope, ease in further transformations of the products, and one-pot syntheses. Mechanistic analyses and theoretical calculations indicate that this reaction is enabled by a novel aminyl radical/polar crossover mechanism, with the aminyl radical being oxidized into the corresponding aminyl cation through a single electron transfer (SET) process.

Visible-Light Photoredox-Catalyzed C−H Difluoroalkylation of Hydrazones through an Aminyl Radical/Polar Mechanism

We report herein the first enantioselective cycloaddition of vinyl oxetanes, the reaction of which with azadienes provided unprecedented access to ten-membered heterocycles through a [6+4] cycloaddition. By using a commercially available chiral Pd-SIPHOX catalyst, a wide range of benzofuran- as well as indole-fused heterocycles could be accessed in excellent yield and enantioselectivity. A unique Lewis acid induced fragmentation of these ten-membered heterocycles was also discovered.

Pd-Catalyzed Enantioselective [6+4] Cycloaddition of Vinyl Oxetanes with Azadienes to Access Ten-Membered Heterocycles.

The availability of facile cross-coupling protocols is sometimes blamed for the high occurrence of ‘flat’ aromatic molecules in drug-screening collections. Here, reagents are described that make possible the one-step transformation of aldehydes into medium-ring saturated N-heterocycles. The methodology has exceptional substrate scope and functional group tolerance and provides a route to heterocycles not easily prepared by other methods.

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SnAP reagents for the one-step synthesis of medium-ring saturated N-heterocycles from aldehydes

SnAP Reagents for the Synthesis of Piperazines and Morpholines

Commercially available SnAP (stannyl amine protocol) reagents allow the transformation of aldehydes and ketones into a variety of N-unprotected heterocycles. By identifying new ligands and reaction conditions, a robust catalytic variant that expands the substrate scope to previously inaccessible heteroaromatic substrates and new substitution patterns was realized. It also establishes the basis for a catalytic enantioselective process through the use of chiral ligands.

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Catalytic Synthesis of N-Unprotected Piperazines, Morpholines, and Thiomorpholines from Aldehydes and SnAP Reagents.

Catechol dehydroxylation is a central chemical transformation in the gut microbial metabolism of plant- and host-derived small molecules. However, the molecular basis for this transformation and its distribution among gut microorganisms are poorly understood. Here, we characterize a molybdenum-dependent enzyme from the human gut bacterium Eggerthella lenta that dehydroxylates catecholamine neurotransmitters. Our findings suggest that this activity enables E. lenta to use dopamine as an electron acceptor. We also identify candidate dehydroxylases that metabolize additional host- and plant-derived catechols. These dehydroxylases belong to a distinct group of largely uncharacterized molybdenum-dependent enzymes that likely mediate primary and secondary metabolism in multiple environments. Finally, we observe catechol dehydroxylation in the gut microbiotas of diverse mammals, confirming the presence of this chemistry in habitats beyond the human gut. These results suggest that the chemical strategies that mediate metabolism and interactions in the human gut are relevant to a broad range of species and habitats.

https://escholarship.org/content/qt0ps3217c/qt0ps3217c.pdf?t=qafc62

Michael U. Luescher

Papers

SnAP reagents for the one-step synthesis of medium-ring saturated N-heterocycles from aldehydes

SnAP Reagents for the Synthesis of Piperazines and Morpholines

Catalytic Synthesis of N-Unprotected Piperazines, Morpholines, and Thiomorpholines from Aldehydes and SnAP Reagents.

A widely distributed metalloenzyme class enables gut microbial metabolism of host- and diet-derived catechols.

SnAP-eX Reagents for the Synthesis of Exocyclic 3-Amino- and 3-Alkoxypyrrolidines and Piperidines from Aldehydes.