The impact of earth-abundant metals as a replacement for Pd in cross coupling reactions.

Substitution of one metal catalyst for another is not as straightforward as simply justifying this change based on the availability and/or cost of the metals. Methodologies to properly assess options for reaction design, including multiple factors like a metal's availability, cost, or environmental indicators have not advanced at the pace needed, leaving decisions to be made along these lines more challenging. Isolated indicators can lead to conclusions being made in too hasty a fashion. Therefore, an extensive life cycle-like assessment was performed documenting that the commonly held view that methods using earth-abundant metals (and in this case study, Ni) are inherently green replacements for methods using palladium in cross-coupling reactions, and Suzuki-Miyaura couplings, in particular, is an incomplete analysis of the entire picture. This notion can be misleading, and unfortunately derives mainly from the standpoint of price, and to some degree, relative natural abundance associated with the impact of mining of each metal. A more accurate picture emerges when several additional reaction parameters involved in the compared couplings are considered. The analysis points to the major impact that use of organic solvents has in these couplings, while the metals themselves actually play subordinate roles in terms of CO2-release into the environment and hence, the overall carbon footprint (i.e., climate change). The conclusion is that a far more detailed analysis is required than that typically being utilized.

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

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.

Inside the human gut there are trillions of bacteria. These microbes are critical for breaking down and modifying molecules that the body consumes (such as nutrients and drugs) and produces (such as hormones). Although metabolizing these molecules is known to impact health and disease, little is known about the specific components, such as the genes and enzymes, involved in these reactions. A prominent microbial reaction in the gut metabolizes molecules by removing a hydroxyl group from an aromatic ring and replacing it with a hydrogen atom. This chemical reaction influences the fate of dietary compounds, clinically used drugs and chemicals which transmit signals between nerves (neurotransmitters). But even though this reaction was discovered over 50 years ago, it remained unknown which microbial enzymes are directly responsible for this metabolism. In 2019, researchers discovered the human gut bacteria Eggerthella lenta produces an enzyme named Dadh that can remove a hydroxyl group from the neurotransmitter dopamine. Now, Maini Rekdal et al. ­ including many of the researchers involved in the 2019 study ­ have used a range of different experiments to further characterize this enzyme and see if it can break down molecules other than dopamine. This revealed that Dadh specifically degrades dopamine, and this process promotes E. lenta growth. Next, Maini Rekdal et al. uncovered a group of enzymes that had similar characteristics to Dadh and could metabolize molecules other than dopamine, including molecules derived from plants and nutrients in food. These Dadh-like enzymes were found not only in the guts of humans, but in other organisms and environments, including the soil, ocean and plants. Plant-derived molecules are associated with human health, and the discovery of the enzymes that break down these products could provide new insights into the health effects of plant-based foods. In addition, the finding that gut bacteria harbor a dopamine metabolizing enzyme has implications for the interaction between the gut microbiome and the nervous system, which has been linked to human health and disease. These newly discovered enzymes are also involved in metabolic reactions outside the human body. Future work investigating the mechanisms and outputs of these reactions could improve current strategies for degrading pollutants and producing medically useful molecules.

Biocatalytic Friedel-Crafts Alkylation Using a Promiscuous Biosynthetic Enzyme.

The Friedel-Crafts alkylation is commonly used in organic synthesis to form aryl-alkyl C-C linkages. However, this reaction lacks the stereospecificity and regiocontrol of enzymatic catalysis. Here, we describe a stereospecific, biocatalytic Friedel-Crafts alkylation of the 2-position of resorcinol rings using the cylindrocyclophane biosynthetic enzyme CylK. This regioselectivity is distinct from that of the classical Friedel-Crafts reaction. Numerous secondary alkyl halides are accepted by this enzyme, as are resorcinol rings with a variety of substitution patterns. Finally, we have been able to use this transformation to access novel analogues of the clinical drug candidate benvitimod that are challenging to construct with existing synthetic methods. These findings highlight the promise of enzymatic catalysis for enabling mild and selective C-C bond-forming synthetic methodology.

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

SnAP-eX (tin amine protocol, exocyclic heteroatoms) reagents allow the single-step transformation of aldehydes and ketones into 2,3-disubstituted pyrrolidines and piperidines containing exocyclic amine or alkoxy groups. These saturated N-heterocycles are of importance in modern drug discovery approaches and are prepared in moderate yields using an operationally simple protocol that is compatible with a range of functional groups and heterocyclic aldehydes.

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

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.

Synthesis of maculalactone A and derivatives for environmental fate tracking studies.

Maculalactone A (1) constitutes a promising antifouling agent, inhibiting the formation of biofilms in marine and freshwater systems. In this study, we developed a new route, based on a late-stage formation of the butenolide core, leading to the total synthesis of maculalactone A (three steps, overall yield of 45%) and delivering material on a gram scale. In addition, analogues of the title compound were assayed concerning their biological activity, utilizing Artemia franciscana and Thamnocephalus platyurus. The most active analogue was functionalized with a rhodamine B fluorophore and was utilized in an in vivo staining experiment in Artemia salina. Two different tissues were found to accumulate this maculalactone A derivative.

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

Interest in saturated N-heterocycles as scaffolds for the synthesis of bioactive molecules is increasing. Reliable and predictable synthetic methods for the preparation of these compounds, especially medium-sized rings, are limited. We describe the development of SnAP (Sn amino protocol) reagents for the transformation of aldehydes into seven-, eight- and nine-membered saturated N-heterocycles. This process occurs under mild, room-temperature conditions and offers exceptional substrate scope and functional-group tolerance. Air- and moisture-stable SnAP reagents are prepared on a multigram scale from inexpensive starting materials by simple reaction sequences. These new reagents and processes allow widely available aryl, heteroaryl and aliphatic aldehydes to be converted into diverse N-heterocycles, including diazepanes, oxazepanes, diazocanes, oxazocanes and hexahydrobenzoxazonines, by a single synthetic operation.

SnAP reagents for the synthesis of piperazines and morpholines.

Substituted piperazines and morpholines are valuable structural motifs in biologically active compounds, but are not easily prepared by contemporary cross-coupling approaches. In this report, we introduce SnAP reagents for the transformation of aldehydes into N-unprotected piperazines and morpholines. This approach offers simple, mild conditions compatible with aromatic, heteroaromatic, aliphatic, and glyoxylic aldehydes and provides mono- and disubstituted N-heterocycles in a single step.