Faculty Bibliography

Dibefurin is a Ci -symmetric natural product that acts as an inhibitor of calcineurin phosphatase. A six-step synthesis of this compound is reported, which features an oxidative dimerization of the aromatic polyketide epicoccine as the key step. Dibefurin is proposed to be related to epicolactone, a complex yet racemic fungal metabolite that has recently been discovered. Attempts to access epicolactone from epicoccine and epicoccone B resulted in an unusual dimer that is formed through a hetero-Diels-Alder reaction of a para-quinone methide with an ortho-quinone.

Periodic mesoporous organosilica (PMO) materials offer a strategy to position molecular semiconductors within a highly defined, porous network. We developed thin films of a new semiconducting zinc phthalocyanine-bridged PMO exhibiting a face-centered orthorhombic pore structure with an average pore diameter of 11 nm. The exceptional degree of order achieved with this PMO enabled us to create thin films consisting of a single porous domain throughout their entire thickness, thus providing maximal accessibility for subsequent incorporation of a complementary phase. The phthalocyanine building blocks inside the pore walls were found to be well-aggregated, enabling electronic conductivity and extending the light-harvesting capabilities to the near IR region. Ordered 3D heterojunctions capable of promoting photo-induced charge transfer were constructed by impregnation of the PMO with a fullerene derivative. When integrated into a photovoltaic device, the infiltrated PMO is capable of producing a high open-circuit voltage and a considerable photocurrent, which represents a significant step towards potential applications of PMOs in optoelectronics.

The total synthesis of the diterpenoids sandresolide B and amphilectolide from a common furan building block is presented. Key steps include palladium-mediated carbonylation, lanthanide catalyzed ring closure, Myers alkylation, intramolecular Friedel-Crafts acylation, photooxygenation, and a Kornblum-DeLaMare rearrangement.

Nitidasin is a pentacyclic sesterterpenoid with a rare 5-8-6-5 carbon skeleton that was isolated from the Peruvian folk medicine "Hercampuri". It belongs to a small class of sesterterpenoids that feature an isopropyl trans-hydrindane moiety fused to a variety of other ring systems. As a first installment of our general approach toward these natural products, we report the total synthesis of the title compound. Our stereoselective, convergent route involves the addition of a complex alkenyl lithium compound to a trans-hydrindanone, followed by chemoselective epoxidation, ring-closing olefin metathesis, and redox adjustment.

A diastereoselective Frater-Seebach-type alkylation provides access to a highly functionalized pyrrolizidine, which could serve as a key building block for the total synthesis of Daphniphyllum alkaloids, such as oldhamine A.

Sulfonylureas are widely prescribed for the treatment of type 2 diabetes mellitus (T2DM). Through their actions on ATP-sensitive potassium (KATP) channels, sulfonylureas boost insulin release from the pancreatic beta cell mass to restore glucose homeostasis. A limitation of these compounds is the elevated risk of developing hypoglycemia and cardiovascular disease, both potentially fatal complications. Here, we describe the design and development of a photoswitchable sulfonylurea, JB253, which reversibly and repeatedly blocks KATP channel activity following exposure to violet-blue light. Using in situ imaging and hormone assays, we further show that JB253 bestows light sensitivity upon rodent and human pancreatic beta cell function. Thus, JB253 enables the optical control of insulin release and may offer a valuable research tool for the interrogation of KATP channel function in health and T2DM.

A short total synthesis of the published structure of racemic trichodermatide A is reported. Our synthesis involves a Knoevenagel condensation/Michael addition sequence, followed by the formation of tricyclic hexahydroxanthene-dione and a diastereoselective bis-hydroxylation. The final product, the structure of which was confirmed by X-ray crystallography, has NMR spectra that are very similar, but not identical, to those of the isolated natural product. Quantum chemically computed (13)C shifts agree well with the present NMR measurements.

Sunlight is the ultimate driver of biosynthesis but photochemical steps late in biosynthetic pathways are very rare. They appear to play a role in the formation of certain furanocembranoids isolated from Caribbean corals. One of these compounds, intricarene, has been suspected to arise from an intramolecular 1,3-dipolar cycloaddition involving an oxidopyrylium. Here we show, by a combination of experiments and theory, that the oxidopyrylium forms under photochemical conditions and that its cycloaddition occurs via a triplet state. The formation of a complex by-product can be rationalized by another photochemical step that involves a conical intersection. Our work raises the question whether intricarene is biosynthesized in the natural habitat of the corals or is an artefact formed during workup. It also demonstrates that the determination of exact irradiation spectra, in combination with quantum chemical calculations, enables the rationalization of complex reaction pathways that involve multiple excited states.

Twistane, C10H16, is a classic D2-symmetric chiral hydrocarbon that has been studied for decades due to its fascinating stereochemical and thermodynamic properties. Here we propose and analyze in detail the contiguous linear extension of twistane with ethano (ethane-1,2-diyl) bridges to create a new chiral, C2-symmetric hydrocarbon nanotube called polytwistane. Polytwistane, (CH)n, has the same molecular formula as polyacetylene but is composed purely of C(sp(3))-H units, all of which are chemically equivalent. The polytwistane nanotube has the smallest inner diameter (2.6 A) of hydrocarbons considered to date. A rigorous topological analysis of idealized polytwistane and a C236H242 prototype optimized by B3LYP density functional theory reveals that the polymer has a nonrepeating, alternating sigma-helix, with an irrational periodicity parameter and an instantaneous rise (or lead) angle near 15 degrees . A theoretical analysis utilizing homodesmotic equations and explicit computations as high as CCSD(T)/cc-pVQZ yields the enthalpies of formation Delta(f)H(0) degrees (twistane) = -1.7 kcal mol(-1) and Delta(f)H(0) degrees (polytwistane) = +1.28 kcal (mol CH)(-1), demonstrating that the hypothetical formation of polytwistane from acetylene is highly exothermic. Hence, polytwistane is synthetically viable both on thermodynamic grounds and also because no obvious pathways exist for its rearrangement to lower-lying isomers. The present analysis should facilitate the preparation and characterization of this new chiral hydrocarbon nanotube.

Opioid receptors (ORs) are widely distributed in the brain, the spinal cord, and the digestive tract and play an important role in nociception. All known ORs are G-protein-coupled receptors (GPCRs) of family A. Another well-known member of this family, rhodopsin, is activated by light through the cis/trans isomerization of a covalently bound chromophore, retinal. We now show how an OR can be combined with a synthetic azobenzene photoswitch to gain light sensitivity. Our work extends the reach of photopharmacology and outlines a general strategy for converting Family A GPCRs, which account for the majority of drug targets, into photoreceptors.