Aldol Reactions of Biorenewable Triacetic Acid Lactone Precursor Evaluated Using Desorption Electrospray Ionization Mass Spectrometry High-Throughput Experimentation and Validated by Continuous Flow Synthesis.

Desorption electrospray ionization-mass spectrometry (DESI-MS) was used as a high-throughput experimentation (HTE) tool to rapidly identify derivatives of the biobased platform molecule triacetic acid lactone (TAL). TAL is a platform molecule capable of conversion to a wide range of useful commodity chemicals, agrochemicals, and advanced pharmaceutical intermediates. In the present study, a diverse family of aldol reaction mixtures were prepared in high-density microtiter plates with a liquid handling robot, then printed with a pin tool onto a PTFE surface for analysis by DESI-MS. Our DESI-MS results indicate that aldol products of TAL were obtained for each substrate tested, in good agreement with previously reported TAL reactivity. These HTE experiments also revealed solvent-dependent reactivity trends that facilitated reaction scale up. Our findings suggest that DESI-MS analysis can rapidly inform the selection of optimal reaction conditions from a wide variety of conditions for scale up using continuous synthesis conditions.

[1]  M. A. Pericàs,et al.  Decarboxylative Hydroalkylation of Alkynes via Dual Copper-Photoredox Catalysis , 2020, ACS Catalysis.

[2]  D. Thompson,et al.  High Throughput Experimentation Using DESI-MS to Guide Continuous-Flow Synthesis , 2019, Scientific Reports.

[3]  D. Thompson,et al.  Multistep Flow Synthesis of Diazepam Guided by Droplet-Accelerated Reaction Screening with Mechanistic Insights from Rapid Mass Spectrometry Analysis , 2017 .

[4]  D. Thompson,et al.  Can Accelerated Reactions in Droplets Guide Chemistry at Scale , 2016 .

[5]  S. Y. Wong,et al.  On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system , 2016, Science.

[6]  George A. Kraus,et al.  Triacetic acid lactone as a common intermediate for the synthesis of 4-hydroxy-2-pyridones and 4-amino-2-pyrones , 2016 .

[7]  George A. Kraus,et al.  An improved aldol protocol for the preparation of 6-styrenylpyrones , 2015 .

[8]  Marcus Baumann,et al.  The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry , 2015, Beilstein journal of organic chemistry.

[9]  G. Kraus,et al.  Selective pyrone functionalization: reductive alkylation of triacetic acid lactone , 2015 .

[10]  Kotaro Kajikawa,et al.  Label and Label-Free Detection Techniques for Protein Microarrays , 2015, Microarrays.

[11]  W. Janzen,et al.  Screening technologies for small molecule discovery: the state of the art. , 2014, Chemistry & biology.

[12]  Thomas O. Ronson,et al.  4-Hydroxy-6-alkyl-2-pyrones as nucleophilic coupling partners in Mitsunobu reactions and oxa-Michael additions , 2014, Beilstein journal of organic chemistry.

[13]  Frank Glorius,et al.  A robustness screen for the rapid assessment of chemical reactions , 2013, Nature Chemistry.

[14]  Prabha Dwivedi,et al.  Mass spectrometry: recent advances in direct open air surface sampling/ionization. , 2013, Chemical reviews.

[15]  P. Walsh,et al.  Palladium-catalyzed C(sp3)-H arylation of diarylmethanes at room temperature: synthesis of triarylmethanes via deprotonative-cross-coupling processes. , 2012, Journal of the American Chemical Society.

[16]  James A. Dumesic,et al.  Triacetic acid lactone as a potential biorenewable platform chemical , 2012 .

[17]  Akos Vertes,et al.  Ambient mass spectrometry for in vivo local analysis and in situ molecular tissue imaging , 2012 .

[18]  Flavien Susanne,et al.  Continuous flow synthesis. A pharma perspective. , 2012, Journal of medicinal chemistry.

[19]  Yefeng Tang,et al.  Enantioselective biomimetic total syntheses of katsumadain and katsumadain C. , 2012, Organic letters.

[20]  Christopher K Prier,et al.  Discovery of an α-Amino C–H Arylation Reaction Using the Strategy of Accelerated Serendipity , 2011, Science.

[21]  John F. Hartwig,et al.  A Simple, Multidimensional Approach to High-Throughput Discovery of Catalytic Reactions , 2011, Science.

[22]  Joseph J. Bozell,et al.  Technology development for the production of biobased products from biorefinery carbohydrates—the US Department of Energy’s “Top 10” revisited , 2010 .

[23]  Lorenz M Mayr,et al.  Novel trends in high-throughput screening. , 2009, Current opinion in pharmacology.

[24]  Frank E Koehn,et al.  High impact technologies for natural products screening. , 2008, Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques.

[25]  M. Pagliaro,et al.  From glycerol to value-added products. , 2007, Angewandte Chemie.

[26]  G. Palmisano,et al.  One-pot electrocatalytic oxidation of glycerol to DHA , 2006 .

[27]  Zheng Ouyang,et al.  Ambient Mass Spectrometry , 2006, Science.

[28]  Huimin Zhao,et al.  Microbial synthesis of triacetic acid lactone , 2006, Biotechnology and bioengineering.

[29]  H. Vogel,et al.  Dehydration of d-fructose to hydroxymethylfurfural in sub- and supercritical fluids , 2005 .

[30]  Johnathan E. Holladay,et al.  Top Value Added Chemicals From Biomass. Volume 1 - Results of Screening for Potential Candidates From Sugars and Synthesis Gas , 2004 .

[31]  J. Lyga.  Convergent syntheses of luteoreticulin and didemethylluteoreticulin , 1995 .