A small molecule synthesizer

Ballmer, Steven

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https://hdl.handle.net/2142/45669 Copy

Description

Title

A small molecule synthesizer

Author(s)

Ballmer, Steven

Issue Date

2013-08-22T16:57:19Z

Director of Research (if dissertation) or Advisor (if thesis)

Burke, Martin D.

Doctoral Committee Chair(s)

Burke, Martin D.

Committee Member(s)

• Denmark, Scott E.
• Moore, Jeffrey S.
• Kenis, Paul J.A.

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• iterative cross-coupling
• automated synthesis
• small molecule synthesis

Abstract

Despite many advances over the last two centuries, small molecule synthesis remains a relatively complex, unsystematized, and time-intensive process practiced almost exclusively by highly trained specialists. Collectively, these limitations represent a major bottleneck in the efforts to study, understand, and harness the vast functional capacity of small molecules. In an effort to shift the rate-limiting step of small molecule science from synthesis to function study, we have designed, constructed, and implemented a fully automated small molecule synthesizer. The synthesizer uses only one C-C bond forming reaction, the Suzuki-Miyaura cross-coupling (SMC) reaction, to assemble off-the-shelf building blocks into many different types of small molecules including organic materials, pharmaceuticals, natural products, and natural product derivatives. Specifically, this automated synthesis platform utilizes the iterative cross-coupling (ICC) strategy enabled by the capacity of N-methyliminodiacetic acid (MIDA) to reversibly attenuate the reactivity of a boronic acid. MIDA boronates are generally crystalline free-flowing solids and are stable to bench-top storage. Furthermore, it has been discovered that they are universally amenable to catch-and-release column chromatography and are universally susceptible to general mild deprotection conditions. Additionally, MIDA boronates can be prepared by a variety of synthetic methods on multi-gram scale and they demonstrate significantly improved reaction yields with slow-addition cross-coupling (SACC). It was understood that these strikingly general features of MIDA boronates made them highly amenable to an automated ICC platform. Fully automated modules for MIDA boronate purification, deprotection, and cross-coupling were developed and with thousands of applicable building blocks commercially available or easily accessible, this now simple, general, and fully automated synthesis platform stands to afford more efficient access to small molecule targets to specialists and non-specialists alike.

Graduation Semester

2013-08

Permalink

http://hdl.handle.net/2142/45669

Copyright and License Information

Copyright 2013 Steven G. Ballmer

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