Faculty Bibliography

Highly unsaturated pyrone polyketides ('HUPPs') are a growing family of natural products derived from polyene precursors, often through pericyclic or ionic reaction cascades. We describe our extensive studies on this class of compounds, which have so far resulted in the total synthesis of 17 of its members. 1 Introduction. 2 Initial Studies toward (-)-SNF4435 C and (+)-SNF4435 D. 3 Intramolecular Diels-Alder Cycloadditions of Vinylcyclohexadienes. 4 Lewis Acid Catalyzed Cycloisomerization of Trienoates to Bicyclo[3.1.0]hex-2-enes. 4.1 Total Synthesis of Photodeoxytridachione. 4.2 Total Synthesis of (-)-Crispatene. 5 Total Synthesis of Cyercene A and the Placidenes. 6 Total Synthesis of Aureothin, N-Acetylaureothamine and Aureonitrile. 7 Total Synthesis of Deoxytridachione and Serendipitous Total Synthesis of Ocellapyrone A. 8 Rational Total Synthesis of Ocellapyrone A, Ocellapyrone B, Elysiapyrone A and Elysiapyrone B. 9 Completion of the Total Synthesis of (-)-SNF4435 C and (+)-SNF4435 D. 10 The Polyene Manifold. 11 Outlook.

A unified approach toward the taiwaniaquinoids that has yielded four natural products is described. A new variant of the Nazarov reaction with concomitant formation of an enol triflate serves as one of the key steps, considerably shortening the synthetic scheme and providing a general entry into this class of bioactive natural products.

[reaction: see text] A nine-step, stereoselective synthesis of bipinnatin J is described, which features a ruthenium-catalyzed Alder-ene reaction, a Stille cross coupling, and an intramolecular Nozaki-Hiyama-Kishi allylation as key steps. The biosynthetic relationship between bipinnatin J and complex polycyclic diterpenes isolated from gorgonian corals is discussed.

[reaction: see text] A concise synthetic approach toward the haouamines based on Stork-Danheiser alkylation and Friedel-Crafts chemistry is described. A novel electrophilic aromatic substitution with concomitant formation of an enol triflate is reported.

The precise regulation of protein activity is fundamental to life. The allosteric control of an active site by a remote regulatory binding site is a mechanism of regulation found across protein classes, from enzymes to motors to signaling proteins. We describe a general approach for manipulating allosteric control using synthetic optical switches. Our strategy is exemplified by a ligand-gated ion channel of central importance in neuroscience, the ionotropic glutamate receptor (iGluR). Using structure-based design, we have modified its ubiquitous clamshell-type ligand-binding domain to develop a light-activated channel, which we call LiGluR. An agonist is covalently tethered to the protein through an azobenzene moiety, which functions as the optical switch. The agonist is reversibly presented to the binding site upon photoisomerization, initiating clamshell domain closure and concomitant channel gating. Photoswitching occurs on a millisecond timescale, with channel conductances that reflect the photostationary state of the azobenzene at a given wavelength. Our device has potential uses not only in biology but also in bioelectronics and nanotechnology.

[reaction: see text] A total synthesis of the bioactive naphthohydroquinone mollugin and the related naphthoquinone dimer microphyllaquinone is described. Both syntheses exploit the propensity of prenylated quinones to undergo tautomerization/oxa 6pi-electrocyclizations.