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Extramural Research

Final Report: Synthetic Methodology "Without Reagents" Tandem Enzymatic and Electrochemical Methods for the Manufacturing of Fine Chemicals

EPA Grant Number: R826113
Title: Synthetic Methodology "Without Reagents" Tandem Enzymatic and Electrochemical Methods for the Manufacturing of Fine Chemicals
Investigators: Hudlicky, Tomas
Institution: University of Florida
EPA Project Officer: Karn, Barbara
Project Period: September 1, 1997 through August 31, 2000
Project Amount: $411,593
RFA: Technology for a Sustainable Environment (1997)
Research Category: Pollution Prevention/Sustainable Development

Description:

Objective:

The overall focus of the project was on the development of alternative synthetic methodology for pollution prevention in chemical manufacturing. Two major techniques were utilized to accomplish this goal:

  • Enzymatic oxidation of aromatic compounds by whole cell fermentation with recombinant organisms expressing toluene dioxygenase. This process removes toxic aromatic compounds, including those containing halogens, from the potential waste pool and renders them into useful chiral synthons for the preparation of pharmaceutical intermediates.
  • Electrochemical methods of oxidation and reduction were examined as alternatives to the use of toxic, metal-based reagents. Reduction of halogens and oxidation of olefins to epoxides were the major areas to be investigated.

The combination of the enzymatic and electrochemical methods with traditional synthetic techniques proved to be a powerful tool that, when applied to synthetic ventures, did result in more efficient and environmentally benign procedures.

Summary/Accomplishments (Outputs/Outcomes):

The project was divided into several major categories: new metabolites for enantioselective synthesis, electrochemical methods of oxidation and reduction, alkaloid synthesis, and inositol and glycoconjugate synthesis. The most important accomplishments in each area are briefly described below.

Several new metabolites have been identified from the oxidation of aromatic compounds containing side-chain chiral centers. The new compounds were committed to existing approaches to the synthesis of morphine alkaloids. During the pursuit of this research, an important discovery was made in the application of direct enzymatic synthesis of functionalized catechols from aromatic precursors. This procedure provides such compounds in one aqueous step and in high yield, completely eliminating the need for traditional methods that use metal-based reagents.

Oxidation of olefins to epoxides and reduction of vinyl halides to olefins have been accomplished electrochemically. These findings have been published and provide cleaner alternatives to the use of m-chlorobenzoic acid and tin hydride reagents, respectively, as previously used methods to achieve these transformations.

In the area of alkaloid synthesis, several novel approaches to morphine and pancratistatin have been pursued. New methods of carbon-carbon bond formation through palladium intermediates have been discovered, and a successful model study toward morphine was published. A regioisomer of 7-deoxypancratistatin along with several truncated derivatives has been synthesized, and the findings were submitted for publication.

In the synthesis of inositols, several advances have been made. These include new and efficient ways to prepare several of the inositols previously unavailable commercially. Six of the inositols prepared by this technology are now catalog items at Aldrich Chemical Company. Oligoinositols have been prepared by coupling of monomers, and their chemical, biological, and structural properties have been studied.

The most significant achievement is probably the synthesis of a conduritol in four steps from bromobenzene by a sequence of reactions that utilize only enzymes and electrochemical methods in benign solvents. This synthesis conforms well to the title of the entire project because it was indeed made "without reagents," at least in the classical meaning of the word.

A new way to measure the efficiency of a chemical process has been advanced and published in Green Chemistry. The "Effective Mass Yield" concept, defined as the percentage of product of all materials used in its preparation, is a more accurate way of representing the overall efficacy in manufacturing.

Overall, the project delivered results consistent with the original propositions. Commercial products resulted from this work and are now listed in the Aldrich catalog. A large review of chemoenzymatic synthesis from aromatic compounds was published in 1999 in a special issue of Aldrichimica Acta?with a circulation of over 100,000.


Journal Articles on this Report : 36 Displayed | Download in RIS Format

Other project views: All 89 publications 42 publications in selected types All 36 journal articles

Type Citation Project Document Sources
Journal Article Abboud KA, Butora G, Fearnley SP, Gum AG, Stabile MR, Hudlicky T. (7R,8S,10bR)-7,8-Dihydroxy-1,5,6,7,8,9,10,10b-octahydro-3H-1,3-oxazolo[4,3-a]isoquinolin-3-one. Acta Crystallographica C-Crystal Structure Communications 1998;54(Pt 8):1162-1164. R826113 (Final)
  • Abstract: International Union of Crystallography-Abstract
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  • Journal Article Akgun H, Hudlicky T. Total syntheses of ert-conduramine A and ent-7-deoxypancratistatin. Tetrahedron Letters 1999;40(16):3081-3084. R826113 (Final)
  • Full-text: ScienceDirect-Full Text PDF
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  • Abstract: ScienceDirect-Abstract
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  • Journal Article Bottari P, Endoma MA, Hudlicky T, Ghiviriga I, Abboud KA. Intramolecular N-acyliminium ion-olefin cyclization in the synthesis of optically pure isoquinoline derivatives: control of stereochemistry and application to synthesis of morphine alkaloids. Collection of Czechoslovak Chemical Communications 1999;64(2):203-216. R826113 (Final)
  • Abstract: CCCC-Abstract
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  • Journal Article Brammer Jr. LE, Hudlicky T. Inositol synthesis: concise preparation of L-chiro-inositol and muco-inositol from a common intermediate. Tetrahedron-Asymmetry 1998;9(12):2011-2014. R826113 (Final)
  • Abstract: ScienceDirect-Abstract
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  • Journal Article Bui VP, Hansen TV, Stenstrom Y, Hudlicky T. Direct biocatalytic synthesis of functionalized catechols: a green alternative to traditional methods with high effective mass yield. Green Chemistry 2000;2(6):263-265. R826113 (Final)
  • Full-text: Brock University-Full Text PDF
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  • Abstract: RSC-Abstract
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  • Other: RSC-Full Text PDF
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  • Journal Article Bui VP, Hansen TV, Stenstrom Y, Hudlicky T, Ribbons DW. A study of substrate specificity of toluene dioxygenase in processing aromatic compounds containing benzylic and/or remote chiral centers. New Journal of Chemistry 2001;25(1):116-124. R826113 (Final)
  • Full-text: RSC-Full Text PDF
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  • Abstract: RSC-Abstract
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  • Journal Article Bui V, Hansen TV, Stenstrom Y, Ribbons DW, Hudlicky T. Toluene dioxygenase-mediated oxidation of aromatic substrates with remote chiral centers. Journal of the Chemical Society, Perkin Transactions 1 2000;(11):1669-1672. R826113 (Final)
  • Full-text: Brock University-Full Text PDF
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  • Abstract: RSC-Abstract
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  • Other: RSC-Full Text PDF
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  • Journal Article Butora G, Hudlicky T, Fearnley SP, Stabile MR, Gum AG, Gonzalez D. Toward a practical synthesis of morphine. The first several generations of a radical cyclization approach. Synthesis-Stuttgart 1998;52(Suppl 1):665-681. R826113 (Final)
  • Full-text: Brock University - Full Text PDF
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  • Abstract: Thieme-Abstract
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  • Other: ResearchGate-Abstract
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  • Journal Article Butora G, Gum AG, Hudlicky T, Abboud KA. Advanced intramolecular Diels-Alder study toward the synthesis of (-)-morphine: structure correction of a previously reported Diels-Alder product. Synthesis-Stuttgart 1998;52(3):275-278. R826113 (Final)
  • Full-text: Brock University-Full Text PDF
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  • Abstract: Thieme-Abstract
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  • Journal Article Cheng M, De B, Almstead NG, Pikul S, Dowty ME, Dietsch CR, Dunaway CM, Gu F, Hsieh LC, Janusz MJ, Taiwo YO, Natchus MG, Hudlicky T, Mandel M. Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold. Journal of Medicinal Chemistry 1999;42(26):5426-5436. R826113 (Final)
  • Abstract from PubMed
  • Full-text: Brock University-Full Text PDF
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  • Abstract: ACS-Abstract
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  • Journal Article Desjardins M, Lallemand MC, Freeman S, Hudlicky T, Abboud KA. Synthesis and biological evaluation of conduritol and conduramine analogs. Journal of the Chemical Society, Perkin Transactions 1 1999;(5):621-628. R826113 (Final)
  • Full-text: RSC-Full Text PDF
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  • Abstract: RSC-Abstract
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  • Other: Brock University-Full Text PDF
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  • Journal Article Eger II EI, Halsey MJ, Koblin DD, Laster MJ, Ionescu P, Konigsberger K, Fan R, Nguyen BV, Hudlicky T. The convulsant and anesthetic properties of cis-trans isomers of 1,2-dichlorohexafluorocyclobutane and 1,2-dichloroethylene. Anesthesia and Analgesia 2001;93(4):922-927. R826113 (Final)
  • Abstract from PubMed
  • Full-text: Brock University-Full Text PDF
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  • Abstract: LWW-Abstract
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  • Journal Article Frey DA, Duan C, Hudlicky T. Model study for a general approach to morphine and noroxymorphone via a rare Heck cyclization. Organic Letters 1999;1(13):2085-2087. R826113 (Final)
  • Abstract: ACS-Abstract
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  • Journal Article Frey DA, Duan C, Ghiviriga I, Hudlicky T. Comparison of approaches to ent-morphine via radical, cationic, and Heck-type cyclizations. Collection of Czechoslovak Chemical Communications 2000;65(4):561-569. R826113 (Final)
  • Abstract: CCCC-Abstract
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  • Journal Article Ghiviriga I, Bottari PQ, Hudlicky T. Elucidation of the stereochemistry of octahydroisoquinoline derivatives by NMR spectroscopy. Magnetic Resonance in Chemistry 1999;37(9):653-661. R826113 (Final)
  • Abstract: Wiley-Abstract
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  • Journal Article Gonzalez D, Martinot TA, Hudlicky T. A short chemoenzymatic synthesis of (+)-narciclasine. Tetrahedron Letters 1999;40(16):3077-3080. R826113 (Final)
  • Full-text: ScienceDirect-Full Text PDF
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  • Abstract: ScienceDirect-Abstract
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  • Journal Article Hudlicky T, Gonzalez D, Stabile M, Endoma MA, Deluca M, Parker D, Gibson DT, Resnick SM, Whited GM. New metabolites from the microbial oxidation of fluorinated aromatic compounds. Journal of Fluorine Chemistry 1998;89(1):23-30. R826113 (Final)
  • Abstract: ScienceDirect-Abstract
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  • Journal Article Hudlicky T. Natural product synthesis via biocatalysis: an essay on the merits of multidisciplinary ventures. Journal of the Brazilian Chemical Society 1998;9(4):313-318. R826113 (Final)
  • Full-text: Journal of the Brazilian Chemical Society-Full Text HTML
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  • Abstract: Journal of the Brazilian Chemical Society-Abstract
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  • Other: Journal of the Brazilian Chemical Society-Full Text PDF
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  • Journal Article Hudlicky T, Frey DA, Koroniak L, Claeboe CD, Brammer Jr. LE. Toward a 'reagent-free' synthesis. Green Chemistry 1999;1(2):57-59. R826113 (Final)
  • Full-text: BrockUniversity-Full Text PDF
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  • Abstract: RSC-Abstract
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  • Other: RSC-Full Text PDF
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  • Journal Article Hudlicky T, Claeboe CD, Brammer Jr. LE, Koroniak L, Butora G, Ghiviriga I. Use of electrochemical methods as an alternative to tin reagents for the reduction of vinyl halides in inositol synthons. Journal of Organic Chemistry 1999;64(13):4909-4913. R826113 (Final)
  • Abstract from PubMed
  • Abstract: ACS-Abstract
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  • Journal Article Hudlicky T, Stabile MR, Gibson DT, Whited GM. 1-Chloro-(2S,3S)-dihydroxycyclohexa-4,6-diene. Organic Syntheses 1999;76:77-85. R826113 (Final)
  • Full-text: OrgSyn-Full Text HTML
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  • Other: OrgSyn-Full Text PDF
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  • Journal Article Hudlicky T, Gonzalez D, Gibson DT. Enzymatic dihydroxylation of aromatics in enantioselective synthesis: expanding asymmetric methodology. Aldrichimica Acta 1999;32(2):35-62. R826113 (Final)
  • Full-text: Sigma Aldrich-Full Text PDF
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  • Abstract: Sigma Aldrich-Abstract
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  • Other: ResearchGate - Abstract & Full Text PDF
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  • Journal Article Hudlicky T, Restrepo-Sanchez NE, Kary PD, Jaramillo-Gomez LM. A short, stereoselective synthesis of neo-inositol. Carbohydrate Research 2000;324(3):200-203. R826113 (Final)
  • Abstract from PubMed
  • Abstract: ScienceDirect-Abstract
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  • Journal Article Hudlicky T. Asymmetric synthesis-preface. Current Organic Chemistry 2000;4(3):i-ii. R826113 (Final)
  • Abstract: EBSCO-Abstract
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  • Journal Article Hudlicky T. Recent progress in efficient syntheses of amaryllidaceae and morphine alkaloids. Journal of Heterocyclic Chemistry 2000;37(3):535-539. R826113 (Final)
    not available
    Journal Article Hudlicky T, Oppong KA, Duan C, Stanton C, Laufersweiler MJ, Natchus MG. Chemoenzymatic synthesis of functionalized cyclohexylglycines and α-methylcyclohexylglycines via Kazmaier–Claisen rearrangement. Bioorganic & Medicinal Chemistry Letters 2001;11(5):627-629. R826113 (Final)
  • Abstract from PubMed
  • Full-text: Brock University-Full Text PDF
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  • Abstract: ScienceDirect-Abstract
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  • Journal Article Hudlicky T. Asymmetric synthesis-preface. Current Organic Chemistry 1998;2(3):U2-U3. R826113 (Final)
  • Full-text: Google Books-Full Text HTML
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  • Journal Article Novak BH, Hudlicky T. New arene cis-dihydrodiol metabolites from β-bromostyrenes. Tetrahedron-Asymmetry 1999;10(11):2067-2069. R826113 (Final)
  • Full-text: Brock University-Full Text PDF
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  • Abstract: ScienceDirect-Abstract
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  • Journal Article Novak BH, Hudlicky T, Reed JW, Mulzer J, Trauner D. Morphine synthesis and biosynthesis-an update. Current Organic Chemistry 2000;4(3):343-362. R826113 (Final)
  • Full-text: ResearchGate-Full Text HTML
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  • Abstract: Ingenta-Abstract
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  • Journal Article Oppong KA, Hudlicky T, Yan F, York C, Nguyen BV. Chemoenzymatic enantiodivergent synthesis of 1,2-dideoxy-2-amino-1-fluoro-allo-inositol. Tetrahedron 1999;55(10):2875-2880. R826113 (Final)
  • Abstract: ScienceDirect-Abstract
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  • Journal Article Paul BJ, Martinot TA, Willis J, Hudlicky T. Novel O-and N-linked inositol oligomers: a new class of unnatural saccharide mimics. Synthesis-Stuttgart 2001;(6):952-956. R826113 (Final)
  • Full-text: Brock University-Full Text PDF
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  • Abstract: Synthesis-Abstract
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  • Journal Article Reddy GD, Wiest O, Hudlicky T, Schapiro V, Gonzalez D. Electron transfer catalyzed [2 + 2] cycloreversion of benzene dimers. Journal of Organic Chemistry 1999;64(8):2860-2863. R826113 (Final)
  • Abstract from PubMed
  • Abstract: ACS-Abstract
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  • Journal Article Restrepo-Sanchez NE, Gomez FJ, Jaramillo-Gomez LM, Hudlicky T. Free radical cyclizations of trienes with tris(trimethylsilyl)silane. Synthetic Communications 1999;29(16):2795-2806. R826113 (Final)
  • Abstract: Taylor&Francis-Abstract
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  • Journal Article Schilling S, Rinner U, Chan C, Ghiviriga I, Hudlicky T. Structure assignment of aminoconduritols by 15N NMR correlation spectroscopy; synthesis of a positional isomer of 7-deoxypancratistatin. Canadian Journal of Chemistry 2001;79(11):1659-1667. R826113 (Final)
  • Abstract: NRC-Abstract
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  • Journal Article Solis-Oba A, Hudlicky T, Koroniak L, Frey D. Selective electrochemical reduction of cinnamyl ethers in the presence of other allylic C–O bonds. Tetrahedron Letters 2001;42(7):1241-1243. R826113 (Final)
  • Full-text: ScienceDirect-Full Text PDF
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  • Abstract: ScienceDirect-Abstract & Full Text HTML
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  • Other: Brock University-Full Text PDF
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  • Journal Article Zezula J, Hudlicky T, Ghiviriga I. Intramolecular Diels-Alder cycloadditions of cis-cyclohexadienediols derived enzymatically from (2-azidoethyl)benzene. Construction of highly functionalized bridged isoquinoline synthons. Collection of Czechoslovak Chemical Communications 2001;66(8):1269-1286. R826113 (Final)
  • Abstract: CCCC-Abstract
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  • Supplemental Keywords:

    biocatalysis, toluene dioxygenase, catechol synthesis, electrochemical reduction, electrochemical oxidation, green chemistry, environmentally benign synthesis, morphine alkaloids, amaryllidaceae alkaloids, inositols, unnatural oligosaccharides, effective mass yield, efficiency in manufacturing, RFA, Industry Sectors, Scientific Discipline, Toxics, Sustainable Industry/Business, cleaner production/pollution prevention, Environmental Chemistry, Manufacturing - NAIC 31-33, Sustainable Environment, HAPS, Technology for Sustainable Environment, 33/50, Environmental Engineering, cleaner production, environmentally conscious manufacturing, aqueous processing, reagents, environmentally benign solvents, carbon-carbon binding, benzene, green process systems, enzyme transformations, electrochemical techniques, chemical manufacturing, innovative technology, industrial innovations, Methylene chloride (Dichloromethane), pollution prevention, biocatalysis, green chemistry, solvents

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