Gold(I)‐Catalyzed Cascade Cycloadditions between Allenamides and Carbonyl‐Tethered Alkenes: An Enantioselective Approach to Oxa‐Bridged Medium‐Sized Carbocycles

Trigonelline (TG; methylnicotinate) is a ubiquitous osmolyte. Although it is known that it can be degraded, the enzymes and metabolites have not been described so far. In this work, we challenged the laboratory model soil-borne, gram-negative bacterium ADP1 (ADP1) for its ability to grow on TG and we identified a cluster of catabolic, transporter, and regulatory genes. We dissected the pathway to the level of enzymes and metabolites, and proceeded to in vitro reconstruction of the complete pathway by six purified proteins. The four enzymatic steps that lead from TG to methylamine and succinate are described, and the structures of previously undescribed metabolites are provided. Unlike many aromatic compounds that undergo hydroxylation prior to ring cleavage, the first step of TG catabolism proceeds through direct cleavage of the C5-C6 bound, catalyzed by a flavin-dependent, two-component oxygenase, which yields ()-2-((methylformamido)methylene)-5-hydroxy-butyrolactone (MFMB). MFMB is then oxidized into ()-2-((methylformamido) methylene) succinate (MFMS), which is split up by a hydrolase into carbon dioxide, methylamine, formic acid, and succinate semialdehyde (SSA). SSA eventually fuels up the TCA by means of an SSA dehydrogenase, assisted by a Conserved Hypothetical Protein. The cluster is conserved across marine, soil, and plant-associated bacteria. This emphasizes the role of TG as a ubiquitous nutrient for which an efficient microbial catabolic toolbox is available.

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“…4 E and F). This probably originates from the rare exoenamide moiety, which may be prone to isomerization (34).…”

Section: 6x10mentioning

confidence: 99%

Elucidation of the trigonelline degradation pathway reveals previously undescribed enzymes and metabolites

Perchat

Saaidi

Darii

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Zuschriften found in many bioactive molecules. The practicability of such intermolecular cycloadditions [18][19][20] is demonstrated by the wide scope with respect to both the ynamides and nitriles. We postulate that the reaction mechanism involves initial attack of a p-alkyne on two nitriles followed by a ring closure.…”

Section: Methodsmentioning

confidence: 99%

Regiocontrolled Gold‐Catalyzed [2+2+2] Cycloadditions of Ynamides with Two Discrete Nitriles to Construct 4‐Aminopyrimidine Cores

Karad

Liu

2014

Angewandte Chemie

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“…As part of our ongoing work in gold catalysis, 11 we have recently reported a gold-catalyzed annulation between allenamides and alkene-tethered carbonyl derivatives that allows a straightforward assembly of oxa-bridged medium-sized carbocycles. 12 Additionally, we have developed a fully intermolecular annulation between allenamides, alkenes and carbonyl derivatives, which provides highly substituted tetrahydropyran systems in high yield and with moderate to good diastereo-and enantioselectivities (Scheme 1). 13 These annulations have been proposed to proceed by an initial activation of the allene moiety by the gold(I) complex, which likely generates a zwitterionic intermediate of type I.…”

Section: Figure 1 Some Aza-heterocycles Containing Piperidine Scaffomentioning

confidence: 99%

“…Scheme 1. Previous Au I -catalyzed formal [2 + 2 + 2] Cycloadditions Towards Oxa-heterocycles 12,13 With this conceptual framework at hand, we questioned whether it would be possible to extend this methodology to imine instead of carbonyl partners, and therefore lever a direct, atom-economical entry to densely substituted piperidine-containing scaffolds, including aza-bridged medium sized carbocycles (Scheme 2, products A and B).…”

Section: Figure 1 Some Aza-heterocycles Containing Piperidine Scaffomentioning

confidence: 99%

Gold(I)-Catalyzed Enantioselective Annulations between Allenes and Alkene-Tethered Oxime Ethers: A Straight Entry to Highly Substituted Piperidines and aza-Bridged Medium-Sized Carbocycles

et al. 2018

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Piperidine scaffolds are present in a wide range of bioactive natural products, and are therefore considered as highly valuable, privileged synthetic targets. In this manuscript, we describe a gold-catalyzed annulation strategy that allows a straightforward assembly of piperidines and piperidine-containing azabridged products from readily available alkene-tethered oxime ethers (or esters) and N-allenamides. Importantly, we demonstrate the advantages of using oxime derivatives over imines, something pertinent to the whole area of gold catalysis, and provide relevant mechanistic experiments that shed light into the factors affecting the annulation processes. Moreover, we also describe preliminary experiments demonstrating the viability of enantioselective versions of the above reactions.

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Gold(I)‐Catalyzed Cascade Cycloadditions between Allenamides and Carbonyl‐Tethered Alkenes: An Enantioselective Approach to Oxa‐Bridged Medium‐Sized Carbocycles

Cited by 36 publications

References 75 publications

Elucidation of the trigonelline degradation pathway reveals previously undescribed enzymes and metabolites

Elucidation of the trigonelline degradation pathway reveals previously undescribed enzymes and metabolites

Regiocontrolled Gold‐Catalyzed [2+2+2] Cycloadditions of Ynamides with Two Discrete Nitriles to Construct 4‐Aminopyrimidine Cores

Gold(I)-Catalyzed Enantioselective Annulations between Allenes and Alkene-Tethered Oxime Ethers: A Straight Entry to Highly Substituted Piperidines and aza-Bridged Medium-Sized Carbocycles

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