title: Organic chemistry. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules.
abstract: At the forefront of new synthetic endeavors, such as drug discovery or natural product synthesis, large quantities of material are rarely available and timelines are tight. A miniaturized automation platform enabling high-throughput experimentation for synthetic route scouting to identify conditions for preparative reaction scale-up would be a transformative advance. Because automated, miniaturized chemistry is difficult to carry out in the presence of solids or volatile organic solvents, most of the synthetic "toolkit" cannot be readily miniaturized. Using palladium-catalyzed cross-coupling reactions as a test case, we developed automation-friendly reactions to run in dimethyl sulfoxide at room temperature. This advance enabled us to couple the robotics used in biotechnology with emerging mass spectrometry-based high-throughput analysis techniques. More than 1500 chemistry experiments were carried out in less than a day, using as little as 0.02 milligrams of material per reaction.
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories, Merck and Co. Inc., Rahway, NJ 07065, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Buitrago Santanilla
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories, Merck and Co. Inc., Rahway, NJ 07065, USA.
authors.forename: Erik L
authors.initials: EL
authors.lastname: Regalado
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Merck and Co. Inc., West Point, PA 19486, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Pereira
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories, Merck and Co. Inc., Rahway, NJ 07065, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Shevlin
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, Merck and Co. Inc., West Point, PA 19486, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bateman
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories, Merck and Co. Inc., Rahway, NJ 07065, USA.
authors.forename: Louis-Charles
authors.initials: LC
authors.lastname: Campeau
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schneeweis
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories, Merck and Co. Inc., Rahway, NJ 07065, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Berritt
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, Merck and Co. Inc., Kenilworth, NJ 07033, USA.
authors.forename: Zhi-Cai
authors.initials: ZC
authors.lastname: Shi
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, Merck and Co. Inc., West Point, PA 19486, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Nantermet
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories, Merck and Co. Inc., Rahway, NJ 07065, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories, Merck and Co. Inc., Rahway, NJ 07065, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Helmy
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories, Merck and Co. Inc., Rahway, NJ 07065, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Welch
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, Merck and Co. Inc., Rahway, NJ 07065, USA.
authors.forename: Petr
authors.initials: P
authors.lastname: Vachal
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories, Merck and Co. Inc., Rahway, NJ 07065, USA.
authors.forename: Ian W
authors.initials: IW
authors.lastname: Davies
authors.affiliation: Department of Discovery Chemistry, Merck Research Laboratories, Merck and Co. Inc., Boston, MA 02115, USA. timothy_cernak@merck.com spencer_dreher@merck.com.
authors.forename: Tim
authors.initials: T
authors.lastname: Cernak
authors.affiliation: Department of Process and Analytical Chemistry, Merck Research Laboratories, Merck and Co. Inc., Rahway, NJ 07065, USA. timothy_cernak@merck.com spencer_dreher@merck.com.
authors.forename: Spencer D
authors.initials: SD
authors.lastname: Dreher
mesh_terms: D001709:Biotechnology; D002384:Catalysis; D057166:High-Throughput Screening Assays / Q000379:methods*; D013058:Mass Spectrometry; D053758:Nanoparticles; D036103:Nanotechnology / Q000379:methods*; D010165:Palladium / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis*; D012371:Robotics / Q000379:methods
chemical_list: D004364:Pharmaceutical Preparations; D010165:Palladium