Johannes Lehmann’s research while affiliated with Simon Fraser University and other places

Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. However, the structural and stereochemical complexity inherent to glycomimetics often challenges medicinal chemistry efforts and is incompatible with diversity-oriented synthesis approaches. Here, we describe a one-pot proline-catalyzed aldehyde α-functionalization/aldol reaction that produces an array of stereochemically well-defined glycomimetic building blocks containing fluoro, chloro, bromo, trifluoromethylthio and azodicarboxylate functional groups. Using density functional theory calculations, we demonstrate both steric and electrostatic interactions play key diastereodiscriminating roles in the dynamic kinetic resolution. The utility of this simple process for generating large and diverse libraries of glycomimetics is demonstrated in the rapid production of iminosugars, nucleoside analogues, carbasugars and carbohydrates from common intermediates. Glycomimetics are structural mimics of carbohydrates that can replicate their biological activity but have improved drug-like properties. Here, using proline-catalysed α-halogenation/aldol cascades, carbohydrate building blocks are readily assembled and then diversified into glycomimetics including imino- and carbasugars.

Short path to a complex ring Nucleotide analogs are valuable tools and therapeutics because of their ability to interfere with processes such as DNA synthesis, which are vital to rapidly dividing cells and replicating viruses. These molecules are challenging to synthesize chemically. Meanwell et al. developed a “ribose last” synthetic strategy in which a fluorinated acyclic nucleic acid is formed by an l - or d -proline–catalyzed aldol reaction (see the Perspective by Miller). This intermediate can then be cyclized to yield the nucleic acid analog in one pot with control of anomeric conformation based on cyclization conditions. Nucleotide analogs accessible by this strategy include those with modifications at C2′ and C4′, purines and pyrimidines, and locked and protected products. Science , this issue p. 725 ; see also p. 623

Acyl fluorides are versatile acylating agents owing to their unique stability. Their synthesis, however, can present challenges and is typically accomplished through deoxyfluorination of carboxylic acids. Here, we demonstrate that acyl fluorides can be prepared directly from aldehydes via a C(sp²)–H fluorination reaction involving the inexpensive photocatalyst sodium decatungstate and electrophilic fluorinating agent N-fluorobenzenesulfonimide. This convenient fluorination strategy enables direct conversion of aliphatic and aromatic aldehydes into acylating agents.

A series of cyclopenta[c]pyridine aldosterone synthase (AS) inhibitors were conveniently accessed using batch or continuous flow Kondrat'eva reactions. Preparation of the analogous cyclohexa[c]pyridines led to the identification of a potent and more selective AS inhibitor. The structure-activity-relationship (SAR) in this new series was rationalized using binding mode models in the crystal structure of AS.

We report the optimization of a neglected reaction for the rapid and direct conversion of oxazoles into N-substituted imidazoles. The utility of this microwave-promoted reaction for diversity-oriented synthesis is demonstrated in the preparation of >40 N-substituted imidazoles, including α-imidazolyl esters.

The direct synthesis of cycloalka[c]pyridines via the title reaction by using continuous flow reaction conditions is developed.

A continuous flow inverse-electron-demand Kondrat'eva reaction has been developed that provides direct access to cycloalka[c]pyridines from unactivated oxazoles and cycloalkenes. Annulated pyridines obtained by this one-step process are valuable scaffolds for medicinal chemistry.