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.

Combining High‐Throughput Synthesis and High‐Throughput Protein Crystallography for Accelerated Hit Identification

“…We produced a total of four 384‐well‐plates. The quality of the reactions on the nanomole scale was evaluated by direct injection into the mass spectrometer as recently described by us (Figure 5, S67) [14f] . Accordingly, in 79 % of the reactions, product formation was observed, while for 21 % no product could be observed (Figure S6, S7, S8).…”

“…Due to the shear infinite scaffold and building block diversity applicable in MCRs, combined with the high throughput miniaturized synthesis format, many more structural opportunities can be realized [31] . With continuing technological advances in speed and scale of chemical synthesis [14a–d,f, 32] and macromolecular crystallography, [29a, 33] it is conceivable that a seamless process of in situ HT synthesis and HT PX can be performed in a cyclic fashion to truly guide compound optimization and complement the “design‐make‐test‐analyze” cycle (DMTA) in drug discovery. Assuming sufficient access to a synchrotron beamline and optimization of all working blocks, a cycle time of 1–2 weeks seems feasible which is comparable to current cycle times in the DMTA cycle but without crystallographic information.…”

Combining High‐Throughput Synthesis and High‐Throughput Protein Crystallography for Accelerated Hit Identification

“…The quality of the reactions on the nanomole scale was evaluated by direct injection into the mass spectrometer as recently described by us (Figure 5 , S67). [14f] Accordingly, in 79 % of the reactions, product formation was observed, while for 21 % no product could be observed (Figure S6, S7, S8). To support our fast qualitative analysis of the nano synthesis, we reproduced 28 compounds on a 0.5 mmol scale, including full NMR and HRMS characterization (Figure 5 , S88, S112).…”

The Ugi Three‐Component Reaction; a Valuable Tool in Modern Organic Synthesis

“…Reactions of a very similar fashion can also be obtained by employing tryptamine-derived isocyanides. [154,155] Dömling et al [156] used L-glutamine (Gln), as a primary amine, cyclic ketones, aliphatic and aromatic aldehydes and isocyanides to synthesize iminopyrrolidines 72, via an U-3CR type using nanoscale synthesis. A nano dispensing instrument was employed, based on the immediate drop-on-demand technology (I-DOT, a non-contact, pressure-based dispensing technology) in ethanol/H 2 O (1:1) at room temperature for 16 h (Scheme 43).…”