Faculty Bibliography

Photochromic ligands have been used to control a variety of biological functions, especially in neural systems. Recently, much effort has been invested in the photocontrol of ion channels and G-protein coupled receptors found in the synapse. Herein, we describe the expansion of our photopharmacological approach toward the remote control of an enzyme. Building on hallmark studies dating from the late 1960s, we evaluated photochromic inhibitors of one of the most important enzymes in synaptic transmission, acetylcholinesterase (AChE). Using structure-based design, we synthesized several azobenzene analogues of the well-known AChE inhibitor tacrine (THA) and determined their effects on enzymatic activity. One of our compounds, AzoTHA, is a reversible photochromic blocker of AChE in vitro and ex vivo with high affinity and fast kinetics. As such, AzoTHA can be used to control synaptic transmission on the neuromuscular endplate based on the light-dependent clearance of a neurotransmitter.

A short total synthesis, guided by biosynthetic considerations, of racemic merochlorin B is presented. The formation of its isomer, merochlorin A, was not observed under the conditions. Key steps include a directed ortho-metalation (DoM), a selective demethylation, an ortho-allylation, and an oxidative [3 + 2]-cycloaddition mediated by an iodine(III) reagent.

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.

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.

Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are blinding diseases caused by the degeneration of rods and cones, leaving the remainder of the visual system unable to respond to light. Here, we report a chemical photoswitch named DENAQ that restores retinal responses to white light of intensity similar to ordinary daylight. A single intraocular injection of DENAQ photosensitizes the blind retina for days, restoring electrophysiological and behavioral responses with no toxicity. Experiments on mouse strains with functional, nonfunctional, or degenerated rods and cones show that DENAQ is effective only in retinas with degenerated photoreceptors. DENAQ confers light sensitivity on a hyperpolarization-activated inward current that is enhanced in degenerated retina, enabling optical control of retinal ganglion cell firing. The acceptable light sensitivity, favorable spectral sensitivity, and selective targeting to diseased tissue make DENAQ a prime drug candidate for vision restoration in patients with end-stage RP and AMD.

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.

Twistane is a classic hydrocarbon with fascinating stereochemical properties. Herein we describe a series of oligomers of twistane that converges on a chiral nanorod, which we term polytwistane. A member of this series, C2-symmetric tritwistane, has been synthesized for the first time.

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.