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

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Science  13 Mar 2015:
Vol. 347, Issue 6227, pp. 1221-1226
DOI: 10.1126/science.aaa5414
  • Fig. 1 Common building block–based approach for making many different types of small molecules.

    (A) A collection of compounds representing the structural and functional diversity of small molecules. tBu, tert-butyl. (B) Analogous building block–based strategies for the synthesis of peptides and small molecules. R, amino acid side chains. (C) Synthesis of the Csp3-rich pentacyclic secodaphnane core (±)-14 via iterative Csp3 couplings to yield a linear precursor followed by biosynthesis-inspired cascade polycyclization. An x-ray crystallographic study of the N-bromoacyl derivative of 14 unambiguously confirmed the structure of 14. TIPS, triisopropylsilyl; Ph, phenyl; DMSO, dimethyl sulfoxide.

  • Fig. 2 General purification process to enable automation.

    (A) MIDA boronates uniformly show binary elution properties on silica gel thin-layer chromatography. (B) Photograph of the small-molecule synthesizer, which comprises three modules that execute the deprotection, coupling, and purification steps. (C) Automated synthesis of natural products, materials, pharmaceuticals, and biological probes via iterative coupling of building blocks indicated by different colors (24). TBDPSE, tert-butyldiphenylsilylethyl; TMSE, trimethylsilylethyl.

  • Fig. 3 Automated synthesis of ratanhine derivatives.

    Conditions: Deprotection – NaOH, THF:H2O. Coupling – cycle 1: Pd(OAc)2, SPhos, K2CO3, THF, 55°C, 16 hours; cycle 2: Pd(OAc)2, XPhos, K3PO4, THF, 55°C, 14 hours; cycle 3: Pd(OAc)2, SPhos, K3PO4, THF, 55°C, 24 hours. Purification – SiO2, MeOH:Et2O; THF. All protecting groups other than MIDA [R: TIPS, TBDPSE, TMSE, or Bz (benzoyl)] were successfully removed in a separate step (24). OAc, acetate.

  • Fig. 4 Synthesis of Csp3-rich macro- and polycyclic natural products and natural product–like cores.

    Modular linear precursors assembled via automated Csp2 and Csp3 couplings are diastereo- and/or enantioselectively cyclized. TBAF, tetra-n-butylammonium fluoride; DEAD, diethyl azodicarboxylate; OTf, trifluoromethanesulfonate; DIBAl-H, diisobutylaluminum hydride. e.r., enantiomeric ratio; d.r., diastereomeric ratio.

Supplementary Materials

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

    Junqi Li, Steven G. Ballmer, Eric P. Gillis, Seiko Fujii, Michael J. Schmidt, Andrea M. E. Palazzolo, Jonathan W. Lehmann, Greg F. Morehouse, Martin D. Burke

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Materials and Methods
    • Supplementary Text
    • Figs. S1 to S14
    • Tables S1 to S3
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