Our long-range research objective is to demonstrate the effective use of a benzannulation reaction in the synthesis of complex natural products containing biaryl ethers as an important structural feature. The relevance of biaryl ethers to health is illustrated by vancomycin which, in the clinic, is used to treat methicillin-resistant Staphylococcus aureus and other gram-positive bacteria. The emerging bacterial strains resistant to vancomycin justifies the search for new efficient synthetic methodologies toward the biaryl ether moiety of these molecules. Oligomeric ellagitannins, such as sanguiin H-6 which demonstrates an in vitro potency 100-200 times the clinically useful DNA topoisomerase II inhibitor etoposide (VP-16), are characterized by an digalloyl biaryl ether linker between the monomeric units. Our research will explore the utility of a [3+2+1] cycloaddition reaction (the Dotz reaction) to construct an aromatic ring in the syntheses of functionalized biaryl ethers. Key to this methodology is the reaction of O-aryl- Fischer chromium carbene complexes with alkynes to give diversely substituted biaryl ethers. The traditional Dotz reaction uses O-alkyl- unsaturated carbene complexes to form alkyl-aryl ethers. The use of O-aryl-unsaturated carbenes will lead to biaryl ethers which constitutes an unprecedented application of the Dotz reaction in organic synthesis. This approach is particularly advantageous due to the mild neutral reaction conditions required for cyclization and the availability of highly substituted electron-rich aromatic systems that are currently difficult to obtain using existing technology for the synthesis biaryl ethers.
| Qu, Chunrong; Tang, Erqing; Loeppky, Richard et al. (2015) Studies towards the synthesis of medermycin via Dötz benzannulation. Chirality 27:18-22 |
| Gupta, Anuradha; Sen, Subhabrata; Harmata, Michael et al. (2005) Synthesis of (S,S)-isodityrosine by Dotz benzannulation. J Org Chem 70:7422-5 |
| Pulley, S R; Sen, S; Vorogushin, A et al. (1999) Diaryl ethers using Fischer chromium carbene mediated benzannulation. Org Lett 1:1721-3 |
