Lipid Expansion Microscopy.

Strategies to visualize cellular membranes with light microscopy are restricted by the diffraction limit of light, which far exceeds the dimensions of lipid bilayers. Here, we describe a method for super-resolution imaging of metabolically labeled phospholipids within cellular membranes. Guided by the principles of expansion microscopy, we develop an all-small molecule approach that enables direct chemical anchoring of bioorthogonally labeled phospholipids into a hydrogel network and is capable of super-resolution imaging of cellular membranes. We apply this method, termed lipid expansion microscopy (LExM), to visualize organelle membranes with precision, including a unique class of membrane-bound structures known as nuclear invaginations. Compatible with standard confocal microscopes, LExM will be widely applicable for super-resolution imaging of phospholipids and cellular membranes in numerous physiological contexts.

Lipids: chemical tools for their synthesis, modification, and analysis.

Lipids remain one of the most enigmatic classes of biological molecules. Whereas lipids are well known to form basic units of membrane structure and energy storage, deciphering the exact roles and biological interactions of distinct lipid species has proven elusive. How these building blocks are synthesized, trafficked, and stored are also questions that require closer inspection. This tutorial review covers recent advances on the preparation, derivatization, and analysis of lipids. In particular, we describe several chemical approaches that form part of a powerful toolbox for controlling and characterizing lipid structure. We believe these tools will be helpful in numerous applications, including the study of lipid-protein interactions and the development of novel drug delivery systems.

Nanohoop Rotaxanes from Active Metal Template Syntheses and Their Potential in Sensing Applications.

The unique optoelectronic properties and smooth, rigid pores of macrocycles with radially oriented π systems render them fascinating candidates for the design of novel mechanically interlocked molecules with new properties. Two high-yielding strategies are used to prepare nanohoop [2]rotaxanes, which owing to the π-rich macrocycle are highly emissive. Then, metal coordination, an intrinsic property afforded by the resulting mechanical bond, can lead to molecular shuttling as well as modulate the observed fluorescence in both organic and aqueous conditions. Inspired by these findings, a self-immolative [2]rotaxane was then designed that self-destructs in the presence of an analyte, eliciting a strong fluorescent turn-on response, serving as proof-of-concept for a new type of molecular sensing material. More broadly, this work highlights the conceptual advantages of combining compact π-rich macrocyclic frameworks with mechanical bonds formed via active-template syntheses.

Expanding the Chemical Space of Biocompatible Fluorophores: Nanohoops in Cells.

The design and optimization of fluorescent molecules has driven the ability to interrogate complex biological events in real time. Notably, most advances in bioimaging fluorophores are based on optimization of core structures that have been known for over a century. Recently, new synthetic methods have resulted in an explosion of nonplanar conjugated macrocyclic molecules with unique optical properties yet to be harnessed in a biological context. Herein we report the synthesis of the first aqueous-soluble carbon nanohoop (i.e., a macrocyclic slice of a carbon nanotube prepared via organic synthesis) and demonstrate its bioimaging capabilities in live cells. Moreover, we illustrate that these scaffolds can be easily modified by well-established "click" chemistry to enable targeted live cell imaging. This work establishes the nanohoops as an exciting new class of macrocyclic fluorophores poised for further development as novel bioimaging tools.

An Operationally Simple and Mild Oxidative Homocoupling of Aryl Boronic Esters To Access Conformationally Constrained Macrocycles.

Constrained macrocyclic scaffolds are recognized as challenging synthetic motifs with few general macrocyclization methods capable of accessing these types of systems. Although palladium catalyzed oxidative homocoupling of aryl boronic acids and esters to biphenyls has been recognized as a common byproduct in Suzuki-Miyaura cross-couplings for decades, this reactivity has not been leveraged for the synthesis of challenging molecules. Here we report an oxidative boronic ester homocoupling reaction as a mild method for the synthesis of strained and conformationally restricted macrocycles. Higher yields and better efficiencies are observed for intramolecular diboronic ester homocouplings when directly compared to the analogous intramolecular Suzuki-Miyaura cross-couplings or reductive Yamamoto homocouplings. Substrates included strained polyphenylene macrocycles, strained cycloalkynes, and a key macrocyclic intermediate toward the synthesis of acerogenin A. Notably, this oxidative homocoupling reaction is performed at room temperature, open to atmosphere, and without the need to rigorously exclude water, thus representing an operationally simple alternative to traditional cross-coupling macrocyclizations. The mechanism of the reaction was investigated indicating that 1-5 nm palladium nanoparticles may serve as the active catalyst.

Towards pi-extended cycloparaphenylenes as seeds for CNT growth: investigating strain relieving ring-openings and rearrangements.

Despite significant multidisciplinary effort over many years, the preparation of uniform carbon nanotubes (CNTs) is still an unsolved problem in the scientific community. This inaccessibility hampers the commercial use of CNTs in electronic devices due to the sensitive connection between their electronic properties and molecular structure. The [n]cycloparaphenylenes ([n]CPPs), the smallest horizontal segment of an armchair CNT, hold great promise as "seeds", or templates, for the preparation of homogenous batches of CNTs. Initial reports towards this goal, however, suggest that it would be advantageous to pi-extend these structures through traditional organic synthesis before their use in CNT growth. Towards this, several strategies have been reported attempting to utilize the Scholl reaction on aryl-substituted cycloparaphenylenes to yield a small CNT for use as a template for larger tubes. Prominently used in polyaromatic hydrocarbon chemistry, the Scholl reaction has afforded numerous extraordinary targets, such as graphene nanoribbons and graphene propellors. In this work, both experimental and computational studies are provided to unravel the complex cationic rearrangements and ring-openings associated with the Scholl reaction in the context of the cycloparaphenylenes-systems that are thermodynamically and kinetically different from flat graphene fragments. Additionally, this work demonstrates the unique reactivity of cycloparaphenylenes in the context of cationic or radical cationic intermediates, which are common reaction pathways for numerous transformations.