Due to their ready availability and low cost, reactions of aromatic compounds have garnered significant interest in the field of organic synthesis, especially transformations that result in dearomatization. However, most modern dearomatization reactions do not introduce additional functionality into the aromatic cores. Therefore, a strategy which simultaneously dearomatizes and functionalizes an aromatic substrate would permit rapid access to important unsaturated cyclic building blocks for total synthesis without the need for additional transformations. We have recently described a process in which we are able to selectively functionalize one double bond of an arene utilizing molecules we have termed “arenophiles”. This approach is based on the ability of small, unsaturated molecules to undergo para-photocycloaddition with a variety of arenes under visible light irradiation. The arene-arenophile cycloadduct can then be trapped by osmium-catalyzed Upjohn or Narasaka-Sharpless dihydroxylation to produce highly-functionalized bicyclic diols or protected boronic esters. These compounds can then be transformed into dihydrodiol or diaminodiol derivatives of the parent arene through cycloreversion or fragmentation of the arenophile, respectively. Through this process, we are able to access diols that are complementary to the products acquired via microbial arene oxidation and that have no alternative direct chemical synthesis. Furthermore, we have extended this methodology to the selective synthesis of dihydroxylated biphenyl compounds. Conducting the Narasaka-Sharpless variant of our dearomative dihydroxylation process on bromobenzene affords functionalized bicyclic boronic esters. From there, transpositional Suzuki coupling and cycloreversion of the arenophile affords the dihydrodiol biphenyl derivative. Finally, this approach permits rapid synthesis of the anti-cancer alkaloid lycoricidine, representing the first synthesis of this molecule through chemical dearomatization of bromobenzene.

Development and synthetic application of arenophile-mediated dihydroxylation reactions

254th National Meeting (2017)

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