Research Article

Mapping the dark space of chemical reactions with extended nanomole synthesis and MALDI-TOF MS

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Science  10 Aug 2018:
Vol. 361, Issue 6402, eaar6236
DOI: 10.1126/science.aar6236
  • Extended nanomole chemistry and MALDI-TOF MS for systematic reaction profiling.

    Nanomole-scale chemistry tools that can execute a wide variety of synthetic protocols are combined with rapid MALDI-TOF MS analysis to enable broad reaction profiling to map the dark space of chemical reactivity. DMSO, dimethyl sulfoxide; DABCO, 1,4-diazabicyclo[2.2.2]octane.

  • Fig. 1 uHT MALDI-MS approach to screening potential reaction poisons.

    (A) 1536 reactions were run with four leading C–N coupling methods to evaluate the impact of 383 single and polyfunctional fragments on one simple coupling reaction, requiring 11 min of MALDI acquisition time. Ph, phenyl; DiF, difluoro; RuPhos, 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl; ppy, 2-phenyl pyridinyl; dtbbpy, di-tert-butyl di-pyridyl; DABCO, 1,4-diazabicyclo[2.2.2]octane; bpy, bipyridinyl. (B) Raw MALDI product response is not well correlated with UPLC-MS or UPLC-UV measures, but normalization using an internal standard reveals very good correlation. (C) Ranked, normalized MALDI product response data with corresponding UPLC-MS (EIC) data below for comparison.

  • Fig. 2 Fragment additives poisoning study.

    Comparative rates of poisoning determined by MALDI analysis for single functional fragments and polyfunctional fragments for the four tested methods are displayed. This study reveals that Cu is well-suited to managing diverse functionality. Polyfunctional fragments that are composed of linked, single functional fragments that are not poisons themselves often lead to differential poisoning.

  • Fig. 3 Whole-molecule simplest-partner evaluation with MALDI analysis.

    (A) Bromides and amines (192 of each) are each crossed with a simple, mass-active coupling partner under the four previously described (Fig. 1A) catalytic methods. (B) Using a single internal standard, the normalized MALDI data show poor correlation with UPLC-MS and UPLC-UV metrics.

  • Fig. 4 Whole-molecule reactivity trends from binary thresholding analysis.

    (A) Failure percentage for different clustered parameters determined by pass-fail binary binning using thresholded MALDI data correlates very well with similarly binned UPLC-MS EIC and UPLC-UV TWC data. Each point on the graph represents the failure rate of different specific aggregated structural parameters, such as NH heterocycles or H-bond donors, for each synthetic method. Circles and crosses denote whether the trend is for amines (circles) or bromides (crosses). The symbol color of each circle or cross indicates which synthetic method was used for the data point. (B) The average failure rate for clustered parameters for all four methods reveals the functionality that is problematic across methods. The color of each data point reveals which method has the lowest failure rate. (C and D) The most problematic parameters for aryl bromides (blue shaded area from Fig. 4B) and amines (red shaded area in Fig. 4B) are listed in descending order of failure rates across methods, along with the number of examples in the test set. In nearly all cases, Cu is the preferred method. However, several very specific structural types in amines are found to be problematic for Cu and show greater reactivity with Pd. MR, membered ring; TPSA, total polar surface area; NHR, nitrogen with an alkyl group and a hydrogen; MW, molecular weight; clogP, calculated logP (logarithm of the partition coefficient between n-octanol and water); Bn, benzyl.

Supplementary Materials

  • Mapping the dark space of chemical reactions with extended nanomole synthesis and MALDI-TOF MS

    Shishi Lin, Sergei Dikler, William D. Blincoe, Ronald D. Ferguson, Robert P. Sheridan, Zhengwei Peng, Donald V. Conway, Kerstin Zawatzky, Heather Wang, Tim Cernak, Ian W. Davies, Daniel A. DiRocco, Huaming Sheng, Christopher J. Welch, Spencer D. Dreher

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

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    • Materials and Methods
    • Figs. S1 to S55
    • Tables S1 to S8
    • References
    Data S1 to S5

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