Peptide Macrocyclization Guided by Reversible Covalent Templating.

The creation of complementary products via templating is a hallmark feature of nucleic acid replication. Outside of nucleic acid-like molecules, the templated synthesis of a hetero-complementary copy is still rare. Herein we describe one cycle of templated synthesis that creates homomeric macrocyclic peptides guided by linear instructing strands. This strategy utilizes hydrazone formation to pre-organize peptide oligomeric monomers along the template on a solid support resin, and microwave-assisted peptide synthesis to couple monomers and cyclize the strands. With a flexible templating strand, we can alter the size of the complementary macrocycle products by increasing the length and number of the binding peptide oligomers, showing the potential to precisely tune the size of macrocyclic products. For the smaller macrocyclic peptides, the products can be released via hydrolysis and characterized by ESI-MS.

Computer-designed repurposing of chemical wastes into drugs.

As the chemical industry continues to produce considerable quantities of waste chemicals1,2, it is essential to devise 'circular chemistry'3-8 schemes to productively back-convert at least a portion of these unwanted materials into useful products. Despite substantial progress in the degradation of some classes of harmful chemicals9, work on 'closing the circle'-transforming waste substrates into valuable products-remains fragmented and focused on well known areas10-15. Comprehensive analyses of which valuable products are synthesizable from diverse chemical wastes are difficult because even small sets of waste substrates can, within few steps, generate millions of putative products, each synthesizable by multiple routes forming densely connected networks. Tracing all such syntheses and selecting those that also meet criteria of process and 'green' chemistries is, arguably, beyond the cognition of human chemists. Here we show how computers equipped with broad synthetic knowledge can help address this challenge. Using the forward-synthesis Allchemy platform16, we generate giant synthetic networks emanating from approximately 200 waste chemicals recycled on commercial scales, retrieve from these networks tens of thousands of routes leading to approximately 300 important drugs and agrochemicals, and algorithmically rank these syntheses according to the accepted metrics of sustainable chemistry17-19. Several of these routes we validate by experiment, including an industrially realistic demonstration on a 'pharmacy on demand' flow-chemistry platform20. Wide adoption of computerized waste-to-valuable algorithms can accelerate productive reuse of chemicals that would otherwise incur storage or disposal costs, or even pose environmental hazards.

Large transition state stabilization from a weak hydrogen bond.

A series of molecular rotors was designed to study and measure the rate accelerating effects of an intramolecular hydrogen bond. The rotors form a weak neutral O-H⋯O[double bond, length as m-dash]C hydrogen bond in the planar transition state (TS) of the bond rotation process. The rotational barrier of the hydrogen bonding rotors was dramatically lower (9.9 kcal mol-1) than control rotors which could not form hydrogen bonds. The magnitude of the stabilization was significantly larger than predicted based on the independently measured strength of a similar O-H⋯O[double bond, length as m-dash]C hydrogen bond (1.5 kcal mol-1). The origins of the large transition state stabilization were studied via experimental substituent effect and computational perturbation analyses. Energy decomposition analysis of the hydrogen bonding interaction revealed a significant reduction in the repulsive component of the hydrogen bonding interaction. The rigid framework of the molecular rotors positions and preorganizes the interacting groups in the transition state. This study demonstrates that with proper design a single hydrogen bond can lead to a TS stabilization that is greater than the intrinsic interaction energy, which has applications in catalyst design and in the study of enzyme mechanisms.

Electrostatically Driven CO-π Aromatic Interactions.

A series of N-arylimide molecular balances were developed to study and measure carbonyl-aromatic (CO-π) interactions. Carbonyl oxygens were observed to form repulsive interactions with unsubstituted arenes and attractive interactions with electron-deficient arenes with multiple electron-withdrawing groups. The repulsive and attractive CO-π aromatic interactions were well-correlated to electrostatic parameters, which allowed accurate predictions of the interaction energies based on the electrostatic potentials of the carbonyl and arene surfaces. Due to the pronounced electrostatic polarization of the C═O bond, the CO-π aromatic interaction was stronger than the previously studied oxygen-π and halogen-π aromatic interactions.

Tipping the Balance between S-π and O-π Interactions.

A comprehensive experimental survey consisting of 36 molecular balances was conducted to compare 18 pairs of S-π versus O-π interactions over a wide range of structural, geometric, and solvent parameters. A strong linear correlation was observed between the folding energies of the sulfur and oxygen balances across the entire library of balance pairs. The more stable interaction systematically switched from the O-π to S-π interaction. Computational studies of bimolecular PhSCH3-arene and PhOCH3-arene complexes were able to replicate the experimental trends in the molecular balances. The change in preference for the O-π to S-π interaction was due to the interplay of stabilizing (dispersion and solvophobic) and destabilizing (exchange-repulsion) terms arising from the differences in size and polarizability of the oxygen and sulfur atoms.

Anion-enhanced solvophobic effects in organic solvent.

The influence of salts on the solvophobic interactions of two non-polar surfaces in organic solvent was examined using a series of molecular balances. Specific anion effects were observed that followed the Hofmeister series and enhanced the solvophobic effect up to two-fold.

Stabilizing Fluorine-π Interactions.

A series of N-arylimide molecular balances were designed to study and measure fluorine-aromatic (F-π) interactions. Fluorine substituents gave rise to increasingly more stabilizing interactions with more electron-deficient aromatic surfaces. The attractive F-π interaction is electrostatically driven and is stronger than other halogen-π interactions.

Measurement of Solvent OH-π Interactions Using a Molecular Balance.

A molecular torsion balance was designed to study and measure OH-π interactions between protic solvents and aromatic surfaces. These specific solvent-solute interactions were measured via their influence on the folded-unfolded equilibrium of an N-arylimide rotor. Protic solvents displayed systematically weaker solvophobic interactions than aprotic solvents with similar solvent cohesion parameters. This was attributed to the formation of OH-π interactions between the protic solvents and the exposed aromatic surfaces in the unfolded conformer that offset the stronger solvophobic effects for protic solvents.

Solvent-induced reversible solid-state colour change of an intramolecular charge-transfer complex.

A dynamic intramolecular charge-transfer (CT) complex was designed that displayed reversible colour changes in the solid-state when treated with different organic solvents. The origins of the dichromatism were shown to be due to solvent-inclusion, which induced changes in the relative orientations of the donor pyrene and acceptor naphthalenediimide units.

Measurement of Silver-π Interactions in Solution Using Molecular Torsion Balances.

A new series of molecular torsion balances were designed to measure the strength of individual Ag-π interactions in solution for an Ag(I) coordinated to a pyridine nitrogen. The formation of a well-defined intramolecular Ag-π interaction in these model systems was verified by X-ray crystallography and (1)H NMR. The strength of the intramolecular Ag-π interaction in solution was found to be stabilizing in nature and quantified to be -1.34 to -2.63 kcal/mol using a double mutant cycle analysis. The Ag-π interaction was also found to be very sensitive to changes in geometry or solvent environment.

Mimic of the green fluorescent protein ß-barrel: photophysics and dynamics of confined chromophores defined by a rigid porous scaffold.

Chromophores with a benzylidene imidazolidinone core define the emission profile of commonly used biomarkers such as the green fluorescent protein (GFP) and its analogues. In this communication, artificially engineered porous scaffolds have been shown to mimic the protein ß-barrel structure, maintaining green fluorescence response and conformational rigidity of GFP-like chromophores. In particular, we demonstrated that the emission maximum in our artificial scaffolds is similar to those observed in the spectra of the natural GFP-based systems. To correlate the fluorescence response with a structure and perform a comprehensive analysis of the prepared photoluminescent scaffolds, (13)C cross-polarization magic angle spinning solid-state (CP-MAS) NMR spectroscopy, powder and single-crystal X-ray diffraction, and time-resolved fluorescence spectroscopy were employed. Quadrupolar spin-echo solid-state (2)H NMR spectroscopy, in combination with theoretical calculations, was implemented to probe low-frequency vibrational dynamics of the confined chromophores, demonstrating conformational restrictions imposed on the coordinatively trapped chromophores. Because of possible tunability of the introduced scaffolds, these studies could foreshadow utilization of the presented approach toward directing a fluorescence response in artificial GFP mimics, modulating a protein microenvironment, and controlling nonradiative pathways through chromophore dynamics.

Energy transfer on demand: photoswitch-directed behavior of metal-porphyrin frameworks.

In this paper, a photochromic diarylethene-based derivative that is coordinatively immobilized within an extended porphyrin framework is shown to maintain its photoswitchable behavior and to direct the photophysical properties of the host. In particular, emission of a framework composed of bis(5-pyridyl-2-methyl-3-thienyl)cyclopentene (BPMTC) and tetrakis(4-carboxyphenyl)porphyrin (H4TCPP) ligands anchored by Zn(2+) ions can be altered as a function of incident light. We attribute the observed cyclic fluorescence behavior of the synthesized porphyrin-BPMTC array to activation of energy transfer (ET) pathways through BPMTC photoisomerization. Time-resolved photoluminescence measurements show a decrease in average porphyrin emission lifetime upon BPMTC insertion, consistent with an ET-based mechanism. These studies portend the possible utilization of photochromic ligands to direct chromophore behavior in large light-harvesting ensembles.