Rapid automated iterative small-molecule synthesis

Automated iterative small-molecule synthesis has the potential to advance and democratize the discovery of new medicines, materials and many other classes of functional chemical matter. To date, however, this approach has been limited because each carbon–carbon bond-forming step takes about a day. Here we report a next-generation small-molecule synthesizer that operates an order of magnitude faster than previous systems through improvements in both chemistry and engineering. Key advances include the discovery that rapid Suzuki–Miyaura cross-couplings under homogeneous conditions, although not tolerated by N-methyliminodiacetic acid boronates, are fully compatible with their more stable tetramethyl-N-methyliminodiacetic acid boronate counterparts, and the development of optimized cartridges for rapid catch-and-release purification. These findings move the field of small-molecule synthesis a step closer to democratizing its core discovery engine. (Figure presented.)