Natural Products

I. Tether-mediated Approaches to the Total Synthesis of Natural Products

The facile generation of biologically important small molecules and their analogues via step-, atom-, and redox-economical methods has held the attention of medicinal and organic synthetic chemists for decades. Within this realm, the tethering of two advanced intermediates has emerged as a powerful approach to streamline asymmetric synthesis of complex biologically active targets. While silicon has been the most widely used tether, the investigation of other tether systems in the synthesis of complex bioactive compounds has gathered considerable interest over the past several years.

Our approach utilizes the potential of phosphorus tethers to mediate both di- and tripodal coupling of key structural fragments and provide multivalent activation within the phosphate ester appendages to allow for further two-directional synthetic transformations. Manipulating the innate chemistry of phosphate triesters, our approach involves the use of phosphate-tethers in desymmetrization and orthogonal protection, in addition to their use as latent leaving groups. Current studies seek to probe the scope of phosphate-tether technology through its application to the total synthesis of several complex, small molecule targets, and in the hopes of generating a suite of practical synthetic tools, studies will also include the development of a variety of new tether systems for potential use in the synthesis of biologically relevant molecules.

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Recent Reported Highlights

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II. Natural Product Synthesis

Inspired by the stereochemical and biological complexity of polyketide and polyketide-like natural products, our group has focused on the development of tether-mediated processes that allow for the easy formation of 1,3-diol—in particular, 1,3-anti-diol—subunits and the subsequent, two-directional functionalization of this extremely common motif. Using phosphate tether technology developed in our laboratory, we have successfully synthesized dolabelide C, (-)-tetrahydrolipstatin, and salicylihalamide A and continue efforts toward the total synthesis of other polyketide natural products and their analogs.

 

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Recent Reported Highlights

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