Continuous-Flow Synthesis of (R)-Tamsulosin Utilizing Sequential Heterogeneous Catalysis.

We describe the continuous-flow synthesis of (R)-tamsulosin, a blockbuster therapeutic drug employed for dysuria associated with urinary stones and benign prostatic hyperplasia, by utilizing sequential heterogeneous catalysis. Two heterogeneous catalysts have been developed for the synthesis, and the key step involves reductive amination of nitriles using dimethylpolysilane-modified Pd on activated carbon/calcium phosphate. Overall, (R)-tamsulosin was obtained in 60 % yield and 64 % ee (99 % ee after recrystallization) in a flow stream through four catalytic transformations without the need for the isolation or purification of any intermediates or byproduct.

Reworking Organic Synthesis for the Modern Age: Synthetic Strategies Based on Continuous-Flow Addition and Condensation Reactions with Heterogeneous Catalysts.

While organic synthesis carried out in most laboratories uses batch methods, there is growing interest in modernizing fine chemical synthesis through continuous-flow processes. As a synthetic method, flow processes have several advantages over batch systems in terms of environmental compatibility, efficiency, and safety, and recent advances have allowed for the synthesis of several complex molecules, including active pharmaceutical ingredients (APIs). Nevertheless, due to several reasons related to the difficulties arising from byproduct formation during the flow process, such as lower yields, poor selectivities, clogging of columns due to poor solubility, catalyst poisoning, etc., successful examples of continuous-flow synthesis of complex organic molecules are still limited. In order to solve this bottleneck, the development of selective and atom-economical continuous-flow organic transformations are needed. This perspective highlights examples of atom-economical addition and condensation reactions with heterogeneous catalysts under continuous-flow conditions and their applications for the synthesis of complex organic molecules such as natural products and APIs. In order to realize new continuous-flow methodologies, based on addition and condensation reactions, in place of substitution reactions, the development of novel reactions and heterogeneous catalysts is required.

Diversity-oriented synthesis of 17-spirosteroids.

A diversity-oriented synthesis (DOS) approach has been used to functionalize 17-ethynyl-17-hydroxysteroids through a one-pot procedure involving a ring-closing enyne metathesis (RCEYM) and a Diels-Alder reaction on the resulting diene, under microwave irradiations. Taking advantage of the propargyl alcohol moiety present on commercially available steroids, this classical strategy was applied to mestranol and lynestrenol, giving a collection of new complex 17-spirosteroids.

Ring-closing enyne metathesis of terminal alkynes with propargylic hindrance.

The ring closing enyne metathesis of substrates with propargylic hindrance was investigated, revealing the successful combination of the Stewart-Grubbs catalysts and microwave heating sometimes up to 170 °C for oxacycles. Medium-sized rings were obtained from terminal alkynes previously reputed as reluctant substrates. This unmatched combination was applied to the synthesis of carbocycles and oxacycles. In addition, this is the first report on the use of the Stewart Grubbs catalyst in ring closing enyne metatheses.

Synthesis of a Biomimetic Tetracyclic Precursor of Aspochalasins and Formal Synthesis of Trichoderone A.

Aspochalasins are leucine-derived cytochalasins. Their complexity is associated with a high degree of biosynthetic oxidation, herein inspiring a two-phase strategy in total synthesis. We thus describe the synthesis of a putative biomimetic tetracyclic intermediate. The constructive steps are an intramolecular Diels-Alder reaction to install the isoindolone core of cytochalasins, whose branched precursor was obtained from a stereoselective Ireland-Claisen rearrangement performed from a highly unsaturated substrate. This also constitutes a formal synthesis of trichoderone A.

Photochemical Chemoselective Alkylation of Tryptophan-Containing Peptides.

We report a photochemical method for the chemoselective radical functionalization of tryptophan (Trp)-containing peptides. The method exploits the photoactivity of an electron donor-acceptor complex generated between the tryptophan unit and pyridinium salts. Irradiation with weak light (390 nm) generates radical intermediates right next to the targeted Trp amino acid, facilitating a proximity-driven radical functionalization. This protocol exhibits high chemoselectivity for Trp residues over other amino acids and tolerates biocompatible conditions.