Miniaturization of Popular Reactions from the Medicinal Chemists’ Toolbox for Ultrahigh-Throughput Experimentation

Abstract

Miniaturization is a tactic employed in many technologies to accelerate discovery and enable new applications such as systems-level evaluation. The miniaturization of chemical synthesis to the limits of chemoanalytical and bioanalytical limits of detection could accelerate drug discovery by increasing the amount of experimental data collected per milligram of material consumed. Here we demonstrate the miniaturization of popular reactions used in drug discovery such as reductive amination, N-alkylation, N-Boc deprotection and Suzuki coupling for utilization in 1.2 μL reaction droplets. Reaction methods were evolved to perform in high boiling solvents at room temperature, enabling the diversification of precious starting materials, such as the complex natural product staurosporine.

Integrated Direct-to-Biology Platform for the Nanoscale Synthesis and Biological Evaluation of PROTACs

“…LCMS (HpH): R t = 1.13 min, [M + H] + 299.1, 100% purity. Methyl (16). Methyl 4-((1,3-dimethoxypropan-2-yl)amino)-3-nitrobenzoate (2.10 g, 6.48 mmol) was dissolved in ethanol (12 mL) with heating.…”

“…Methyl 1- (1,3-dimethoxypropan-2-yl)-2-(1,5-dimethyl-6-oxo-1,6dihydropyridin-3-yl)-1H-benzo[d]imidazole-5-carboxylate (16). amino)-3-nitrobenzoate (2.10 g, 6.48 mmol) was dissolved in ethanol (12 mL) with heating.…”

Organopalladium Catalysis as a Proving Ground for Data-Rich Approaches to Reaction Development and Quantitative Predictions

“…88 In academia, the Cernak group is continuing to push the envelope of ultra-high throughput methods in array design and execution. [89][90][91] In the area of laboratory automation, the Hein group, in collaboration with Merck and the Aspuru-Guzik and Sigman groups, demonstrated the power of data-dense experimentation in an autonomous optimization of a Pd-catalyzed Suzuki-Miyaura reaction. 18 The Newman group published a user-centered "how-to-HTE" guide on multiwell screening, using a Pd-catalyzed C-N coupling as the prototype reaction.…”

A Mild Synthesis of Aryl Triflates Enabling the Late‐Stage Modification of Drug Analogs and Complex Peptides

“…[1b,3] Moreover, the increased use of robotic systems to set up, work up, and purify chemical reactions without human intervention (automated chemistry) [4] requires reactions which ideally are convenient to set up, air-tolerant, have short reaction times, a straightforward purification, and importantly avoid the use of corrosive reagents which can harm the robotic machinery. [5] Aryl triflates are key intermediates in synthetic organic chemistry, used for example in Suzuki-Miyaura cross-couplings, Buchwald-Hartwig aminations, and aminocarbonylations. [6] The use of aryl triflates instead of aryl halides can have several advantages as for example shown by the Buchwald group with higher yields and less racemization for the N-arylation of amino acid esters when using aryl triflates instead of aryl bromides.…”