Symmetry-Driven Total Synthesis of Myrioneurinol.

We report a total synthesis of the Myrioneuron alkaloid myrioneurinol enabled by the recognition of hidden symmetry within its polycyclic structure. Our approach traces myrioneurinol's complex framework back to a symmetrical diketone precursor, a double reductive amination of which forges its central piperidine unit. By employing an inexpensive chiral amine in this key desymmetrizing event, four stereocenters of the natural product including the core quaternary stereocenter are set in an absolute sense, providing the first asymmetric entry to this target. Other noteworthy strategic maneuvers include utilizing a bicyclic alkene as a latent cis-1,3-bis(hydroxymethyl) synthon and a topologically controlled alkene hydrogenation. Overall, our synthesis proceeds in 18 steps and ∼1% yield from commercial materials.

Biomimetic Reductive Cleavage of Keto Aryl Ether Bonds by Small-Molecule Thiols.

The nucleophilic and reductive properties of thiolates and thiols make them ideal candidates as redox mediators via the thiol/disulfide couple. One mechanism for biological lignin depolymerization entails reduction of keto aryl ether bonds by an SN 2 mechanism with the thiol redox mediator glutathione. In this study, mimicking this chemistry in a simple protein- and metal-free process, several small organic thiols are surveyed for their ability to cleave aryl keto ethers that model the ß-O-4 linkages found in partially oxidized lignin. In polar aprotic solvents, ß-mercaptoethanol and dithiothreitol yielded up to 100 % formation of phenol and acetophenone products from 2-phenoxyacetophenone, but not from its reduced alcohol congener. The effects of reaction conditions and of substituents on the aryl rings and the keto ether linkage are assessed. These results, together with activation barriers computed by quantum chemical simulations and direct observation of the expected intermediate thioether, point to an SN 2 mechanism. This study confirms that small organic thiols can reductively break down lignin-relevant keto aryl ether linkages.