Synthesis of the β₃‑Adrenergic Receptor Agonist Solabegron and Analogous <i>N</i>‑(2-Ethylamino)-β-amino Alcohols from <i>O</i>‑Acylated Cyanohydrins – Expanding the Scope of Minor Enantiomer Recycling

A novel methodology to produce highly enantioenriched <i>N</i>-(2-ethylamino)-β-amino alcohols was developed. These compounds were obtained from <i>O</i>-(α-bromoacyl) cyanohydrins, which were synthesized by the minor enantiomer methodology employing a Lewis acid and a biocatalyst, followed by nucleophilic substitution with amines and reduction. The importance of the developed methodology was demonstrated by completing a highly enantioselective total synthesis of the β₃-adrenergic receptor agonist Solabegron

Redox Control over Acyl Hydrazone Photoswitches

Photoisomerization provides a clean and efficient way of reversibly altering physical properties of chemical systems and injecting energy into them. These effects have been applied in development of systems such as photoresponsive materials, molecular motors, and photoactivated drugs. Typically, switching from more to less stable isomer(s) is performed by irradiation with UV or visible light, while the reverse process proceeds thermally or by irradiation using another wavelength. In this work we developed a method of rapid and tunable <i>Z</i>→<i>E</i> isomerization of CN bond in acyl hydrazones, using aromatic thiols as nucleophilic catalysts. As thiols can be oxidized into catalytically inactive disulfides, the isomerization rates can be controlled via the oxidation state of the catalyst, which, together with the UV irradiation, provides orthogonal means to control the <i>E</i>/<i>Z</i> state of the system. As a proof of this concept, we have applied this method to control the diversity of acyl hydrazone based dynamic combinatorial libraries

Self-Assembly Can Direct Dynamic Covalent Bond Formation toward Diversity or Specificity

With the advent of reversible covalent chemistry the study of the interplay between covalent bond formation and noncovalent interactions has become increasingly relevant. Here we report that the interplay between reversible disulfide chemistry and self-assembly can give rise either to molecular diversity, i.e., the emergence of a unprecedentedly large range of macrocycles or to molecular specificity, i.e., the autocatalytic emergence of a single species. The two phenomena are the result of two different modes of self-assembly, demonstrating that control over self-assembly pathways can enable control over covalent bond formation