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New Dearomatization Methods for Chemical Synthesis and Synthetic Biology

Final Report Summary - DEAROMATIZATION (New Dearomatization Methods for Chemical Synthesis and Synthetic Biology)

The capacity to generate enantiopure and architecturally complex molecules is pivotal to the realization of new paradigms in chemical synthesis, medicine and functionalized materials. Synthetic chemists can often generate small building block-type molecules, in excellent yield and enantiomeric excess, using asymmetric catalysis. Despite this, the development of catalytic enantioselective cascade reactions that directly form natural product or natural product-like molecules are less common; rapid access to these nonracemic complex structures would greatly facilitate many synthetic campaigns in natural product chemistry and chemical biology. The project undertaken by the researcher over the past twelve months involves the development of new catalytic strategies for chemical synthesis, wherein catalytic cascade processes are designed around transforming a common functional motif to a diversity of enantiopure natural product and natural product-like architectures quickly and efficiently.

We have developed a catalytic enantioselective dearomatization strategy that enables the direct transformation of planar latently functionalized phenols into highly complex enantiopure molecules.

In this transformation, an external nucleophile is added to the para-position of a phenol during the oxidation step, followed by an enantioselective desymmetrizing enamine intramolecular Michael addition. In considering the dearomatization step of the tandem process, it is possible to design reactions wherein an internal π-nucleophile participates in the phenol oxidation to form a structurally complex and symmetrical dienone intermediate that can be intercepted as before through an enantioselective Michael addition. The result would be the direct formation of a highly complex and chiral molecule that is ‘natural product-like’ from a simple linear precursor that is readily assembled. A key aspect of this process is the concomitant formation of quaternary stereocentres embedded within a complex molecular structure that contains valuable orthogonal functionality. Using such a strategy enables synthetic chemists to generate new exciting molecules with novel scaffolds and to design extremely direct strategies to the synthesis of natural products.