Sustainability by design: automated nanoscale 2,3,4-trisubstituted quinazoline diversity

Abstract

Automated, one step, nanoscale synthesis of 2,3,4-trisubstituted quinazoline derivatives using positive pressure facilitated dispensing to access a very large chemical space exemplified by more than 1000 compounds.

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

“… [30] 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 , 14b , 14c , 14d , 14f , 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

“…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.…”

Isocyanide 2.0

“…In our laboratory, the access to a large number of isocyanides with high structural diversity is crucial for example to explore the structure-activity relationship (SAR) and to prepare large libraries of IMCRs on a nanoscale or in the DEL format. [38][39][40][41][42] Thus, we revisited the formamide to isocyanide dehydration and came up with a completely revised procedure avoiding any type of aqueous workup. The advantages of our very general isocyanide syntheses are increased synthesis speeds and thus decreased exposure of the chemist to badly smelling fumes, very mild conditions giving access to hitherto unknown classes of isocyanides, rapid access to large numbers of functionalized isocyanides, increased yields, high purity, exemplified scalability over 5 orders of magnitude, and less reaction waste resulting in a highly reduced environmental footprint.…”