Volume 93 Issue 11 | p. 3 | News of The Week
Issue Date: March 16, 2015 | Web Date: March 12, 2015

Machine Automates Assembly Of Small Molecules

Synthetic Chemistry: Tool could speed up search for new medicines, research probes, and electronic device components
Department: Science & Technology | Collection: Life Sciences
News Channels: Organic SCENE, Biological SCENE
Keywords: small molecules, synthesis, automation, polyene, drug discovery, MIDA boronates
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MOLECULE MAKER
This tabletop synthesizer builds complex molecules from modular building blocks.This synthesizer builds complex molecules from modular building blocks.
Credit: L. Brian Stauffer
A picture of a synthesizer.
 
MOLECULE MAKER
This tabletop synthesizer builds complex molecules from modular building blocks.This synthesizer builds complex molecules from modular building blocks.
Credit: L. Brian Stauffer

A new automated machine can synthesize a range of small organic molecules with the push of a button. The synthesizer uses a chemical method that pieces together molecules from modular building blocks. With this technique, the machine synthesized 14 classes of molecules, including some complicated ones with multiple rings.

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Researchers used an automated synthesizer to make this secodaphnane core structure from three components (blue, red, and green). Black bonds were formed in coupling and cyclization reactions.
Secodaphnane core structure, highlighting carbons from similar linear building blocks.
 
Researchers used an automated synthesizer to make this secodaphnane core structure from three components (blue, red, and green). Black bonds were formed in coupling and cyclization reactions.

Organic chemist Martin D. Burke of the University of Illinois, Urbana-Champaign, and coworkers developed the synthetic method and the new machine (Science 2015, DOI: 10.1126/science.aaa5414). The biotech company Revolution Medicines, based in Redwood City, Calif., cofounded by Burke and the venture capital firm Third Rock Ventures, plans to use the technology in drug discovery and is designing a second-generation synthesizer. An automated synthesizer cranking out small molecules, the researchers say, could speed up the search for new medications, research probes, and electronic device components.

The work is “a tour de force in chemical synthesis,” comments synthetic chemist Kenichiro Itami of Nagoya University. “The synthesis and purification of small organic molecules are still hard to automate. Almost all synthetic chemists, including myself, have been dreaming to achieve this because it will offer significant opportunities to rapidly identify functional small molecules.”

Last year, Burke and coworkers devised a modular way to make most of the polyene motifs found in natural products (Nat. Chem. 2014, DOI: 10.1038/nchem.1947; C&EN, May 19, 2014, page 7). The chemists conceptually deconstructed polyenes into component parts. They derivatized each component with methyliminodiacetic acid (MIDA) boronate and used cycles of Suzuki-Miyaura cross-coupling, a palladium-catalyzed C–C bond-forming reaction, to add each part to a synthetic intermediate. During each cycle, they deprotected the growing synthetic intermediate by removing the MIDA group from the boronate, activating it for coupling. They showed they could synthesize more than 75% of polyene natural product motifs using just 12 building blocks.

In the new study, they discovered that MIDA boronates can also serve as purification tags. This led them to develop a “catch and release” system, in which intermediates are immobilized on silica gel after each coupling, excess reagents and by-products are washed away, and the intermediate is then released for the next step.

They also designed and built a synthesizer to automate the three basic steps required for each synthetic cycle—deprotection, coupling, and purification. To run a synthesis, chemists place prepacked cartridges containing the necessary building blocks into the machine and then press a start button. Burke’s team demonstrated the approach by using it to produce milligram quantities of 14 classes of small molecules. This included complex large-ring and polycyclic compounds, which are made as linear precursors on the machine and then cyclized.

Synthetic chemist Cathleen M. Crudden of Queen’s University in Kingston, Ontario, points out that off-line reactions will still be needed to access some types of small molecules. “But being able to automate the synthesis of even the key cores of small molecules or their subunits is a huge step forward in organic chemistry.”

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ONE STEP
Each automated synthesis cycle involves deprotection (D), coupling (C), and purification (P) and couples a modular building block—a reagent (red rectangle) derivatized with a halogen (X) and MIDA boronate (line structure)—to a synthetic intermediate or an initial building block (blue rectangle).
Reaction scheme showing iterative automated synthesis with a palladium catalyst and MIDA-boronate-derivatized building blocks.
 
ONE STEP
Each automated synthesis cycle involves deprotection (D), coupling (C), and purification (P) and couples a modular building block—a reagent (red rectangle) derivatized with a halogen (X) and MIDA boronate (line structure)—to a synthetic intermediate or an initial building block (blue rectangle).
 
Chemical & Engineering News
ISSN 0009-2347
Copyright © American Chemical Society
Comments
matt stanton (Thu Mar 12 20:18:09 EDT 2015)
This is one of the most exciting things I have seen in a long time. Sounds like it could lead to molecular 3D printers, or, perhaps, even replicators.
gary wu (Mon Mar 16 14:01:41 EDT 2015)
What a relief we won't need chemists anymore! Just combine this with Corey's LHASA program to do the thinking for us too.

Perhaps next we'll even have robots that can write news articles--or even re-write press releases--for us! I'm sure whoever's left at C&EN will be thrilled by the possibilities.
Robert Buntrock (Sat Apr 11 17:03:37 EDT 2015)
This might cut down on the number of technicians but it still takes good organic chemists to design and program the machines.
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