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Synthesis of many different types of organic small molecules using one automated process.

ABSTRACT: Small-molecule synthesis usually relies on procedures that are highly customized for each target. A broadly applicable automated process could greatly increase the accessibility of this class of compounds to enable investigations of their practical potential. Here we report the synthesis of 14 distinct classes of small molecules using the same fully automated process. This was achieved by strategically expanding the scope of a building block-based synthesis platform to include even C(sp3)-rich polycyclic natural product frameworks and discovering a catch-and-release chromatographic purification protocol applicable to all of the corresponding intermediates. With thousands of compatible building blocks already commercially available, many small molecules are now accessible with this platform. More broadly, these findings illuminate an actionable roadmap to a more general and automated approach for small-molecule synthesis.

SUBMITTER: Li J

PROVIDER: S-EPMC4687482 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Synthesis of many different types of organic small molecules using one automated process.

Li Junqi J Ballmer Steven G SG Gillis Eric P EP Fujii Seiko S Schmidt Michael J MJ Palazzolo Andrea M E AM Lehmann Jonathan W JW Morehouse Greg F GF Burke Martin D MD

Science (New York, N.Y.) 20150301 6227

Small-molecule synthesis usually relies on procedures that are highly customized for each target. A broadly applicable automated process could greatly increase the accessibility of this class of compounds to enable investigations of their practical potential. Here we report the synthesis of 14 distinct classes of small molecules using the same fully automated process. This was achieved by strategically expanding the scope of a building block-based synthesis platform to include even C(sp3)-rich p ...[more]

PMID: 25766227

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Project description:When using nuclear magnetic resonance (NMR) to assist in chemical identification in complex samples, researchers commonly rely on databases for chemical shift spectra. However, authentic standards are typically depended upon to build libraries experimentally. Considering complex biological samples, such as blood and soil, the entirety of NMR spectra required for all possible compounds would be infeasible to ascertain due to limitations of available standards and experimental processing time. As an alternative, we introduce the in silico Chemical Library Engine (ISiCLE) NMR chemical shift module to accurately and automatically calculate NMR chemical shifts of small organic molecules through use of quantum chemical calculations. ISiCLE performs density functional theory (DFT)-based calculations for predicting chemical properties-specifically NMR chemical shifts in this manuscript-via the open source, high-performance computational chemistry software, NWChem. ISiCLE calculates the NMR chemical shifts of sets of molecules using any available combination of DFT method, solvent, and NMR-active nuclei, using both user-selected reference compounds and/or linear regression methods. Calculated NMR chemical shifts are provided to the user for each molecule, along with comparisons with respect to a number of metrics commonly used in the literature. Here, we demonstrate ISiCLE using a set of 312 molecules, ranging in size up to 90 carbon atoms. For each, calculation of NMR chemical shifts have been performed with 8 different levels of DFT theory, and with solvation effects using the implicit solvent Conductor-like Screening Model. The DFT method dependence of the calculated chemical shifts have been systematically investigated through benchmarking and subsequently compared to experimental data available in the literature. Furthermore, ISiCLE has been applied to a set of 80 methylcyclohexane conformers, combined via Boltzmann weighting and compared to experimental values. We demonstrate that our protocol shows promise in the automation of chemical shift calculations and, ultimately, the expansion of chemical shift libraries.

Dataset Information

Synthesis of many different types of organic small molecules using one automated process.

Publications

Synthesis of many different types of organic small molecules using one automated process.

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