Anodic Cyclizations, Densely Functionalized Synthetic Building Blocks, and the Importance of Recent Mechanistic Observations.

Anodic cyclization reactions can provide a versatile method for converting newly obtained chiral lactols to densely functionalized cyclic building blocks. The method works by first converting the lactol into an electron-rich olefin and then oxidatively generating a radical cation that is trapped by a nucleophile. Historically, such reactions have benefited from the use of less polar radical cations when the trapping nucleophile is a heteroatom and more polar radical cations when the reaction forms C-C bonds. This forced one to optimize underperforming reactions by resynthesizing the substrate. Here, we show that by taking advantage of methods that serve to drive a reversible initial cyclization reaction toward the product, this dichotomy and need to manipulate the substrate can be avoided. Two such methods were utilized: a faster second oxidation step and a mediated electrolysis. Both led to successful cyclizations using a polar radical cation and heteroatom nucleophiles.

Capitalizing on Mediated Electrolyses for the Construction of Complex, Addressable Molecular Surfaces.

Synthetic organic chemists are beginning to exploit electrochemical methods in increasingly creative ways. This is leading to a surge in productivity that is only now starting to take advantage of the full-potential of electrochemistry for accessing new structures in novel, more efficient ways. In this perspective, we provide insight into the potential of electrochemistry as a synthetic tool gained through studies of both direct anodic oxidation reactions and more recent indirect methods, and highlight how the development of new electrochemical methods can expand the nature of synthetic problems our community can tackle.

Cell-Permeable Esterase-Activated Ca(II)-Sensitive MRI Contrast Agent.

Calcium [Ca(II)] is a fundamental transducer of electrical activity in the central nervous system (CNS). Influx of Ca(II) into the cytosol is responsible for action potential initiation and propagation, and initiates interneuronal communication via release of neurotransmitters and activation of gene expression. Despite the importance of Ca(II) in physiology, it remains a challenge to visualize Ca(II) flux in the central nervous system (CNS) in vivo. To address these challenges, we have developed a new generation, Ca(II)-activated MRI contrast agent that utilizes ethyl esters to increase cell labeling and prevent extracellular divalent Ca(II) binding. Following labeling, the ethyl esters can be cleaved, thus allowing the agent to bind Ca(II), increasing relaxivity and resulting in enhanced positive MR image contrast. The ability of this probe to discriminate between extra- and intracellular Ca(II) may allow for spatiotemporal in vivo imaging of Ca(II) flux during seizures or ischemia where large Ca(II) fluxes (1-10 µM) can result in cell death.

Microelectrode Arrays, Electrocatalysis, and the Need for Proper Characterization.

Indirect electrochemical methods are a powerful tool for synthetic chemistry because they allow for the optimization of chemical selectivity in a reaction while maintaining the advantages of electrochemistry in terms of sustainability. Recently, we have found that such methods provide a handle for not only the synthesis of complex molecules, but also the construction of complex, addressable molecular surfaces. In this effort, the indirect electrochemical methods enable the placement or synthesis of molecules by any electrode or set of electrodes in a microelectrode array. The success of these surface-based reactions are typically evaluated with the use of fluorescence labelling studies. However, these fluorescence-based evaluations can be misleading. While they are excellent for determining that a reaction has occurred in a site-selective fashion on an array, they do not provide information on whether that reaction is the one desired or how well it worked. We describe here how the use of a "safety-catch" linker strategy allows for a more accurate assessment of reaction quality on an array, and then use that capability to illustrate how the use of transition metal mediated cross-coupling reactions on an array prevent unwanted background reactions that can occur on a polymer-coated electrode surface. The method enables a unique level of quality control for array-based transformations.

Building Chemical Probes Based on the Natural Products YM-254890 and FR900359: Advances toward Scalability.

The biological activity of natural products YM-254890 (YM) and FR900359 (FR) has led to significant interest in both their synthesis and the construction of more simplified analogs. While the simplified analogs lose much of the potency of the natural products, they are of interest in their own right, and their synthesis has revealed synthetic barriers to the family of molecules that need to be addressed if a scalable synthesis of YM and FR analogs is to be constructed. In the work described here, a synthetic route to simplified analogs of YM is examined and strategies for circumventing some of the challenges inherent to constructing the molecules are forwarded.

Microelectrode Arrays, Dihydroxylation, and the Development of an Orthogonal Safety-Catch Linker.

Construction of larger molecular libraries on an addressable microelectrode array requires a method for recovering and characterizing molecules from the surface of any electrode in the array. This method must be orthogonal to the synthetic strategies needed to build the array. We report here a method for achieving this goal that employs the site-selective dihydroxylation reaction of a simple olefin.

A Multimodal Ca(II) Responsive Near IR-MR Contrast Agent Exhibiting High Cellular Uptake.

Ca(II) ions are critical for the proper function of neurons by contributing to synaptic signaling and regulating neuronal plasticity. Dysregulation of Ca(II) is associated with a number of pathologies that cause neurodegeneration; therefore the ability to monitor Ca(II) intracellularly is an important target for molecular imaging. Contrast-enhanced MR imaging is a promising modality for imaging changes in Ca(II) concentrations. However, the majority of Ca(II) responsive MR agents are limited to the extracellular space or hindered by poor cellular uptake. Here, we describe a new class of multimodal, bioresponsive Ca(II) magnetic resonance agents that are coupled to the NIR probe IR-783. This new design is based on previous generations of our Ca(II) MR agents but overcomes two significant challenges: (1) the presence of the NIR probe dramatically increases cellular uptake of the agent and (2) provides histological validation of the MR signal using NIR fluorescence imaging. IR-783 targets organic anion transporter polypeptides, and we demonstrate that the agents are not toxic in HT-22 or U-87 MG cells up to 20 µM. The cellular uptake of complex 1 was measured to be greater than 16 femtomoles per cell (where ∼1 femtomole/cell is detectable in acquired MR images). Complex 1 is simultaneously detectable by both MR and NIR fluorescence imaging in vitro and is activated (turned on) by intracellular Ca(II) at concentrations between 1 and 10 µM.