Enabling strategies for step efficient syntheses.

The field of natural product total synthesis has reached the point where synthetic efficiency has become more important than merely defining a viable (yet less ideal) route to the target molecule. Synthetic efficiency is best represented by the number of steps it takes to finish the target molecule from readily available starting materials, as by reducing the number of steps, all other factors of synthetic efficiency are influenced positively. By comparing several total syntheses from the recent years, the most successful strategies for step efficient syntheses will be highlighted. Each synthesis will be presented using a color-coded synthetic flowchart, in which each step is categorized by a colored box. Five categories of transformations are defined and rated according to their synthetic value. Each class will be signified by different colors so that the reader can quickly see which parts of the synthesis are productive and those that are not.

A Modular, Argon-Driven Flow Platform for Natural Product Synthesis and Late-Stage Transformations.

A modular flow platform for natural product synthesis was designed. To access different reaction setups with a maximum of flexibility, interchangeable 3D-printed components serve as backbone. By switching from liquid- to gas-driven flow, reagent and solvent waste is minimized, which translates into an advantageous sustainability profile. To enable inert conditions, "Schlenk-in-flow" techniques for the safe handling of oxygen- and moisture sensitive reagents were developed. Adopting these techniques, reproducible transformations in natural product synthesis were achieved.

Five-Step Synthesis of Yaequinolones J1 and J2.

A concise synthesis of yaequinolones J1 and J2 is reported. The route is based on the aryne insertion into the σ-C-N bond of an unsymmetric imide followed by a diastereoselective aldol cyclization of the resulting N-acylated aminobenzophenone. The chromene motif is generated in the first step by an organocatalytic tandem Knoevenagel electrocyclization of citral and 2-bromoresorcinol. The approach adheres to the ideality principle, using almost exclusively strategic bond-forming reactions.

Scalable Synthesis of Functionalized Ferrocenyl Azides and Amines Enabled by Flow Chemistry.

A scalable access to functionalized ferrocenyl azides has been realized in flow. By halogen-lithium exchange of ferrocenyl halides and trapping with tosyl azide, a variety of functionalized ferrocenyl azides were obtained in high yields. To allow a scalable preparation of these potentially explosive compounds, a flow protocol was developed accelerating the reaction time to minutes and circumventing accumulation of potentially hazardous intermediates. The corresponding ferrocenyl amines were then prepared by a reliable reduction process.

Synthesis of Quinolinone Alkaloids via Aryne Insertions into Unsymmetric Imides in Flow.

A general strategy for the synthesis of 3,4-dioxygenated quinolin-2-one natural products is reported. The key step is a regioselective insertion of arynes into unsymmetric imides. When performed in continuous flow, the reaction proceeds within minutes, while lower yields and longer reaction times are observed in batch. The resulting N-acylated 2-aminobenzophenones were transformed to (±)-peniprequinolone, (±)-aflaquinolones E and F, (±)-6-deoxyaflaquinolone E, (±)-quinolinones A and B, and (±)-aniduquinolone C in 1-3 steps.