An integrated console for capsule-based, automated organic synthesis

Abstract

The current laboratory practices of organic synthesis are labor intensive, impose safety and environmental hazards, and hamper the implementation of artificial intelligence guided drug discovery. Using a combination of reagent design, hardware engineering, and a simple operating system we provide an instrument capable of executing complex organic reactions with prepacked capsules. The machine conducts coupling reactions and delivers the purified products with minimal user involvement. Two desirable reaction classes - the synthesis of saturated N-heterocycles and reductive amination - were implemented, along with multi-step sequences that provide drug-like organic molecules in a fully automated manner. We envision that this system will serve as a console for developers to provide synthetic methods as integrated, user-friendly packages for conducting organic synthesis in a safe and convenient fashion.

Fig. 1. Approaches towards automatic organic synthesis with specially developed instruments.

Fig. 2. Fluidics setup of the automated console. The setup is composed of two valves, two syringe pumps and the heatable capsule holder. Through different valve settings solvents can be pumped from the solvent reservoirs or sample vial into the individual compartments of the capsule or into the waste. The connected nitrogen supply facilitates preserving an inert environment.

Fig. 3. The user adds the starting material to the reaction vial, which is loaded together with the cartridge into the console. The automated reaction is started on the touchscreen. After completion the user can pick up the product in the reaction vial.

Fig. 4. The capsule consists of four compartments that are prefilled with the necessary reagents. A chemically resistant seal on top and luer connections at the bottom interface with the console. After the capsule is inserted into the capsule holder, the fluidic lines connected automatically via motorized sledge.

Scheme 1. Automated formation of saturated N-heterocycles. A broad scope of aldehydes are transformed to various saturated N-heterocycle using SnAP reagent capsules. In most cases a purity of >90% was obtained. See ESI for detailed evaluation of the reaction product after automated sequence (a) quantity of the desired product directly after the automated sequence, calculated from H-NMR using 0.25 mmol (0.5 equiv.) of mesitylene as internal standard is given (b) quantity of isolated product after column chromatography is given.

Scheme 2. Reductive amination process and products. Aldehydes and ketones are coupled with primary or secondary amines with a capsule for reductive amination. Yields of the reaction product (purity >95%) directly after the automated synthesis are given.

Scheme 3. Automated, multistep, capsule-based organic synthesis. The SnAP capsule and reductive amination capsule can be combined in two consecutive machine runs to generate more complex structures. Yields were calculated from isolated material after purification by chromatography; diastereomers -where present-were resolved in a later step by preparative HPLC for characterization; see ESI for details.