Faculty Bibliography

The variecolortides are a family of unusual natural products that combine motifs from a variety of biosynthetic streams. Herein, we present the gradual evolution of a convergent synthetic strategy that ultimately culminated in a reaction cascade featuring a hydrogen shift and a cycloaddition followed by a spontaneous air oxidation. Attempts to link an anthrone building block with an exo-methylene diketopiperazine using radical chemistry were ultimately unsuccessful, but led to interesting observations that shaped our successful strategy. The total synthesis of variecolortide C is presented for the first time.

Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are degenerative blinding diseases caused by the death of rods and cones, leaving the remainder of the visual system intact but largely unable to respond to light. Here, we show that AAQ, a synthetic small molecule photoswitch, can restore light sensitivity to the retina and behavioral responses in vivo in mouse models of RP, without exogenous gene delivery. Brief application of AAQ bestows prolonged light sensitivity on multiple types of retinal neurons, resulting in synaptically amplified responses and center-surround antagonism in arrays of retinal ganglion cells (RGCs). Intraocular injection of AAQ restores the pupillary light reflex and locomotory light avoidance behavior in mice lacking retinal photoreceptors, indicating reconstitution of light signaling to brain circuits. AAQ and related photoswitch molecules present a potential drug strategy for restoring retinal function in degenerative blinding diseases.

A synthetic approach to several sesterterpenoids containing an isopropyl trans-hydrindane system is presented. Its most remarkable feature is the stereochemical diversification of a common precursor through the choice of different hydrogenation conditions.

Sesterterpenoids account for many bioactive natural products, often with unusual and complex structural features, which makes them attractive targets for synthetic chemists. This review surveys efforts undertaken toward the synthesis of sesterterpenoids, focusing on completed total syntheses and covering ca. 50 natural products in total.

Better late than never! Two herbicidins, members of an important family of nucleoside antibiotics, have been synthesized for the first time. The route integrates a stereoselective C-glycosylation with several reagent-controlled stereoselective transformations and a surprisingly facile and highly diastereoselective late-stage N-glycosylation.

A concise asymmetric approach to the indeno-tetrahydropyridine core of the unusual alkaloid haouamine B allowed for an investigation of a biomimetic oxidative phenol coupling as a proposed biosynthetic step, and ultimately provided access to the published structure of the natural product. As a consequence of our synthetic studies, the structure of haouamine B has been revised.

The evolution of a total synthesis of the exiguamines, two structurally unusual natural products that are highly active inhibitors of indolamine-2,3-dioxygenase (IDO), is described. The ultimately successful strategy involves advanced cross-coupling methodology and features a potentially biosynthetic tautomerization/electrocyclization cascade reaction that forms two heterocycles and installs a quaternary ammonium ion in a single synthetic operation.

In this paper, we experimentally study the dynamics of slow oscillations in Purkinje neurons in vitro, and derive a strong association with a forced parametric oscillator model. We observed the precise rhythmicity of these oscillations in Purkinje neurons, as well as a dynamic tunability of this oscillation using a photoswitchable compound. We found that this slow oscillation can be induced in every Purkinje neuron measured, having periods ranging between 10 and 25 s. Starting from a Hodgkin-Huxley model, we demonstrate that this oscillation can be externally modulated, and that the neurons will return to their intrinsic firing frequency after the forced oscillation is concluded. These findings signify an additional timing functional role of tunable oscillations within the cerebellum, as well as a dynamic control of a time scale in the brain in the range of seconds.