No abstract

We have developed a strategy for synthesizing passively permeable peptidomimetic macrocycles. The cyclization chemistry centers on using aziridine aldehydes in a multicomponent reaction with peptides and isocyanides. The linker region in the resulting product contains an exocyclic amide positioned α to the peptide backbone, an arrangement that is not found among natural amino acids. This amide provides structural rigidity within the cyclic peptidomimetic and promotes the creation of a stabilizing intramolecular hydrogen bonding network. This exocyclic control element also contributes to the increased membrane permeability exhibited by multicomponent-derived macrocycles with respect to their homodetic counterparts. The exocyclic control element is employed along with a strategic placement of N-methyl and d-amino acids to produce passively permeable peptides, which contain multiple polar residues. This strategy should be applicable in the pursuit of synthesizing therapeutically relevant macrocycles.

Modification of a peptide: The combination of aziridine aldehyde based peptide cyclization and aziridine ring‐opening chemistry furnishes peptides with well‐defined secondary structure. An exocyclic amide, which is a product of the cyclization reaction, forms a number of intramolecular hydrogen bonds, thereby leading to increased scaffold rigidity and cellular permeability (see scheme).

An intramolecular arene alkylation reaction has been developed using the organic photocatalyst 4CzIPN, visible light, and N-(acyloxy)­phthalimides as radical precursors. Reaction conditions were optimized via high-throughput experimentation, and electron-rich and electron-deficient arenes and heteroarenes are viable reaction substrates. This reaction enables access to a diverse set of fused, partially saturated cores which are of high interest in synthetic and medicinal chemistry.

Using light to drive a chemical transformation introduces challenges for ensuring the robust transferability of photochemical reactions across different platforms and scales. We demonstrate a modeling tool to predict the performance of a photochemical reaction as a function of the reactor geometry, concentration of the photoactive species, irradiance of the light source, and residence time. High-throughput experimentation is utilized to optimize reaction conditions and to determine kinetic parameters and quantum yield. Optical characterization of the photoactive reaction species and the reactor is performed to determine the photon absorption rate. The experimental data is combined with computational modeling to predict photochemical conversion for different vial or flow reactors across multiple scales for a [2 + 2] photocycloaddition reaction and a photoredoxmediated decarboxylative intramolecular arene alkylation reaction. The method developed in this work facilitates the transferability of the photochemical processes between different photoreactors without the need for an intensive experimental optimization for each and enables a robust and efficient scale-up.