Total Synthesis of (-)-Rauvomine B via a Strain-Promoted Intramolecular Cyclopropanation.

We describe the first total synthesis of the unusual cyclopropane-containing indole alkaloid (-)-rauvomine B via a strategy centered upon intramolecular cyclopropanation of a tetracyclic N-sulfonyltriazole. Preparation of this precursor evolved through two generations of synthesis, with the ultimately successful route involving a palladium-catalyzed stereospecific allylic amination, a cis-selective Pictet-Spengler reaction, and ring-closing metathesis as important bond-forming reactions. The key cyclopropanation step was found to be highly dependent on the structure and conformational strain of the indoloquinolizidine N-sulfonyltriazole precursor, the origins of which are explored computationally through DFT studies. Overall, our synthesis proceeds in 11 total steps and 2.4% yield from commercial materials.

Synthetic Studies toward the Myrioneuron Alkaloids.

The Myrioneuron alkaloids are a relatively small family of plant-derived alkaloids that present an intriguing array of structural intricacy and biological properties. As such, these natural products have drawn interest from the synthetic community, resulting in creative total syntheses of several family members. This review showcases recent synthetic efforts towards these polycyclic alkaloids.

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.

Synthesis of Mitomycin C and decarbamoylmitomycin C N6 deoxyadenosine-adducts.

Mitomycin C (MC), an anti-cancer drug, and its analog, decarbamoylmitomycin C (DMC), are DNA-alkylating agents. MC is currently used in the clinics and its cytotoxicity is mainly due to its ability to form Interstrand Crosslinks (ICLs) which impede DNA replication and, thereby, block cancer cells proliferation. However, both MC and DMC are also able to generate monoadducts with DNA. In particular, we recently discovered that DMC, like MC, can form deoxyadenosine (dA) monoadducts with DNA. The biological role played by these monoadducts is worthy of investigation. To probe the role of these adducts and to detect them in enzymatic digests of DNA extracted from culture cells treated by both drugs, we need access to reference compounds i.e. MC and DMC dA-mononucleoside adducts. Previous biomimetic methods used to generate MC and DMC mononucleoside adducts are cumbersome and very low yielding. Here, we describe the diastereospecific chemical synthesis of both C-1 epimers of MC and DMC deoxyadenosine adducts. The key step of the synthesis involves an aromatic substitution reaction between a 6-fluoropurine 2'-deoxyribonucleoside and appropriately protected stereoisomeric triaminomitosenes to form protected-MC-dA adducts with either an S or R stereochemical configuration at the adenine-mitosene linkage. Fluoride-based deprotection methods generated the final four reference compounds: the two stereoisomeric MC-dA adducts and the two stereoisomeric DMC-dA adducts. The MC and DMC-dA adducts synthesized here will serve as standards for the detection and identification of such adducts formed in the DNA of culture cells treated with both drugs.

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.