Benjamin A. Chalmers

1,1,3,3‐Tetramethylisoindolin‐2‐yloxyl (TMIO) is a well‐known stable 2,3‐dihydroisoindoline aminoxyl radical, which is thermally generated (at >100 °C) from literature alkoxyamine derivatives. Herein is the synthesis of visible light activated benzimidazolequinone alkoxyamines of TMIO using oxidative methods and the first room temperature nitroxide‐exchange experiments with 2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPO) analogues. For the alkoxyamine TMIO‐Vis dissociation rate constants are provided using TEMPO and oxygen as radical traps.

The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G) and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibarotene). This investigation highlights the scope and limitations of incorporating cubane into bioactive molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was less active in the case of the anticancer agent (tamibarotenne). Application of the cyclooctatetraene (COT) (bio)motif complement was found to optimize benznidazole relative to the benzene parent, and augmented anticancer activity relative to the cubane analogue in the case of tamibarotene. Like all bioisosteres, scaffolds and biomotifs, however, there are limitations (e.g. synthetic implementation), and these have been specifically highlighted herein using failed examples. A summary of all templates prepared to date by our group that were biologically evaluated strongly supports the concept that cubane is a valuable tool in bioactive molecule discovery and COT is a viable complement.

The first enantioselective synthesis of (R)-2-cubylglycine, an analogue of (R)-2-phenylglycine in which the phenyl ring has been replaced by cubane, is disclosed. The key step was a telescoped Strecker reaction using (S)-2-amino-2-phenylethanol as a chiral auxiliary. Exploration of an alternative synthetic approach resulted in unprecedented cubane C–H insertion.

The traditional thermal Mannich reaction is unsuitable for preparing polymerizable N-methylene amino substituted acrylamides and methacrylamides. Herein we provide a facile multi-gram high yield synthesis of these monomeric precursors to stimuli-responsive polymers by the addition of acrylamides and methacrylamides onto in situ generated or freshly isolated methylene Schiff base (iminium) salts. The X-ray crystal structure of the hydrated iminium salt, 1-(hydroxymethyl)azocan-1-ium chloride and monomer·HCl salt (N-[(azocan-1-yl)methyl]prop-2-enamide hydrochloride) is described.