Automated, Accelerated Nanoscale Synthesis of Iminopyrrolidines

Abstract

Miniaturization and acceleration of synthetic chemistry is an emerging area in pharmaceutical, agrochemical, and materials research and development. Herein, we describe the synthesis of iminopyrrolidine-2-carboxylic acid derivatives using chiral glutamine, oxo components, and isocyanide building blocks in an unprecedented Ugi-3-component reaction. We used I-DOT, a positive-pressure-based low-volume and non-contact dispensing technology to prepare more than 1000 different derivatives in a fully automated fashion. In general, the reaction is stereoselective, proceeds in good yields, and tolerates a wide variety of functional groups. We exemplify a pipeline of fast and efficient nanomole-scale scouting to millimole-scale synthesis for the discovery of a useful novel reaction with great scope.

Keywords: automation; miniaturization; multicomponent reactions; nanoscale synthesis; sustainable chemistry.

Figure 1

Evolution of iminopyrrolidines. A) The Ugi‐type reaction of l‐Gln with oxo components and isocyanides yields iminopyrrolidines (P) and not glutarimides. B) Biologically active compounds based on the iminopyrrolidine pharmacophore. C) Crystal structure of compound I‐D18, proving the structural outcome of the U‐3CR.20

Scheme 1

Optimized condition for the U‐5C‐3CR.

Figure 2

Diversity‐oriented nanoscale synthesis of iminopyrrolidines. A) Reaction condition for nanoscale synthesis. B) Oxo component building blocks. C) Isocyanide building blocks.

Figure 3

A 384‐well synthesis plate, direct MS‐based quality control, and resynthesized compounds on a mmol scale with isolated yields. I‐E21 and I‐H18 are shown blue because of I‐DOT reagent transfer failure, however their synthesis showed medium product formation.

Scheme 2

Proposed reaction mechanism.