Flow chemistry syntheses of natural products.

The development and application of continuous flow chemistry methods for synthesis is a rapidly growing area of research. In particular, natural products provide demanding challenges to this developing technology. This review highlights successes in the area with an emphasis on new opportunities and technological advances.

[1]  Steven V Ley,et al.  Preparation of arylsulfonyl chlorides by chlorosulfonylation of in situ generated diazonium salts using a continuous flow reactor. , 2010, Organic & biomolecular chemistry.

[2]  Yuta Murai,et al.  Highly (Z)-Selective Synthesis of β-Monosubstituted α,β-Unsaturated Cyanides Using the Peterson Reaction , 2004 .

[3]  The changing face of organic synthesis , 2010 .

[4]  L. Marion,et al.  The structure of sedamine. , 1951, Canadian journal of chemistry.

[5]  Steven V Ley,et al.  Flow synthesis of organic azides and the multistep synthesis of imines and amines using a new monolithic triphenylphosphine reagent. , 2011, Organic & biomolecular chemistry.

[6]  J. Yoshida,et al.  Grignard Exchange Reaction Using a Microflow System: From Bench to Pilot Plant , 2005 .

[7]  Steven V Ley,et al.  A fully automated, multistep flow synthesis of 5-amino-4-cyano-1,2,3-triazoles. , 2011, Organic & biomolecular chemistry.

[8]  Hayato Yoshida,et al.  Continuous-flow synthesis of vitamin D3. , 2010, Chemical communications.

[9]  P. Scheuer,et al.  Hennoxazoles, bioactive bisoxazoles from a marine sponge , 1991 .

[10]  Steven V. Ley,et al.  A breakthrough method for the accurate addition of reagents in multi-step segmented flow processing† , 2011 .

[11]  Jun-ichi Yoshida,et al.  Green and sustainable chemical synthesis using flow microreactors. , 2011, ChemSusChem.

[12]  N. Zhu,et al.  Syntheses of dihydroartemisinic acid and dihydro-epi-deoxyarteannuin B incorporating a stable isotope label at the 15-position for studies into the biosynthesis of artemisinin , 2001 .

[13]  Richard J Ingham,et al.  Camera-enabled techniques for organic synthesis , 2013, Beilstein journal of organic chemistry.

[14]  Markus Hager,et al.  Application of metal-based reagents and catalysts in microstructured flow devices. , 2012, ChemSusChem.

[15]  S. Ley,et al.  A modular flow reactor for performing Curtius rearrangements as a continuous flow process. , 2008, Organic & biomolecular chemistry.

[16]  Pedro Fernandes,et al.  Microfluidic Devices: Useful Tools for Bioprocess Intensification , 2011, Molecules.

[17]  Jeremy L. Steinbacher,et al.  Greener approaches to organic synthesis using microreactor technology. , 2007, Chemical reviews.

[18]  Peter Gilligan,et al.  A bacterial cell to cell signal in the lungs of cystic fibrosis patients. , 2002, FEMS microbiology letters.

[19]  J. F. Stevens,et al.  Alkaloids of some Asian Sedum species , 1996 .

[20]  Steven V Ley,et al.  Continuous flow reaction monitoring using an on-line miniature mass spectrometer. , 2012, Rapid communications in mass spectrometry : RCM.

[21]  D. Spring,et al.  Structure-Activity Analysis of the Pseudomonas Quinolone Signal Molecule , 2010, Journal of bacteriology.

[22]  Geoffrey D. Brown,et al.  The mechanism of the spontaneous autoxidation of dihydroartemisinic acid , 2002 .

[23]  T. Bieringer,et al.  Future Production Concepts in the Chemical Industry: Modular – Small‐Scale – Continuous , 2013 .

[24]  Steven V. Ley,et al.  Flow ozonolysis using a semipermeable Teflon AF-2400 membrane to effect gas-liquid contact. , 2010, Organic letters.

[25]  Steven V Ley,et al.  The oxygen-mediated synthesis of 1,3-butadiynes in continuous flow: using Teflon AF-2400 to effect gas/liquid contact. , 2012, ChemSusChem.

[26]  Bernd Nidetzky,et al.  Biotransformations in microstructured reactors: more than flowing with the stream? , 2011, Trends in biotechnology.

[27]  David M J S Bowman,et al.  Flammable biomes dominated by eucalypts originated at the Cretaceous-Palaeogene boundary. , 2011, Nature communications.

[28]  Steven V. Ley,et al.  Synthesis of the alkaloids (±)-oxomaritidine and (±)-epimaritidine using an orchestrated multi-step sequence of polymer supported reagents , 1999 .

[29]  Claudio Battilocchio,et al.  A prototype device for evaporation in batch and flow chemical processes , 2013 .

[30]  Steven V Ley,et al.  Synthesis of acetal protected building blocks using flow chemistry with flow I.R. analysis: preparation of butane-2,3-diacetal tartrates. , 2009, Organic & biomolecular chemistry.

[31]  S. Achanta,et al.  The development of a general strategy for the synthesis of tyramine-based natural products by using continuous flow techniques. , 2010, Chemistry.

[32]  Steven V Ley,et al.  A prototype continuous-flow liquid-liquid extraction system using open-source technology. , 2012, Organic & biomolecular chemistry.

[33]  T. Yasumoto,et al.  Isolation and structure of yessotoxin, a novel polyether compound implicated in diarrhetic shellfish poisoning , 1987 .

[34]  S. Ley,et al.  Teflon AF-2400 mediated gas-liquid contact in continuous flow methoxycarbonylations and in-line FTIR measurement of CO concentration. , 2011, Organic & biomolecular chemistry.

[35]  R. Bouillon,et al.  Structure-function relationships in the vitamin D endocrine system. , 1995, Endocrine reviews.

[36]  M. Köck,et al.  Siphonazole, an unusual metabolite from Herpetosiphon sp. , 2006, Angewandte Chemie.

[37]  Robert Ashe,et al.  Continuous Flow Processing of Slurries: Evaluation of an Agitated Cell Reactor , 2011 .

[38]  Tetsuro Ito,et al.  Three new resveratrol oligomers from the stem bark of Vatica pauciflora. , 2004, Journal of natural products.

[39]  John Tsanaktsidis,et al.  Flow synthesis of tricyclic spiropiperidines as building blocks for the histrionicotoxin family of alkaloids , 2010 .

[40]  R. Sarpong,et al.  Concise synthesis of pauciflorol F using a Larock annulation. , 2009, Organic letters.

[41]  Steven V. Ley,et al.  Synthesis of highly substituted nitropyrrolidines, nitropyrrolizines and nitropyrroles via multicomponent-multistep sequences within a flow reactor , 2010 .

[42]  Steven V Ley,et al.  KMnO(4)-Mediated oxidation as a continuous flow process. , 2010, Organic letters.

[43]  Koichi Fukase,et al.  Renaissance of Traditional Organic Reactions under Microfluidic Conditions: A New Paradigm for Natural Products Synthesis , 2009 .

[44]  Steven V Ley,et al.  A new enabling technology for convenient laboratory scale continuous flow processing at low temperatures. , 2011, Organic letters.

[45]  Jun-ichi Yoshida,et al.  Flash chemistry: fast chemical synthesis by using microreactors. , 2008, Chemistry.

[46]  K. Jensen,et al.  Multistep continuous-flow microchemical synthesis involving multiple reactions and separations. , 2007, Angewandte Chemie.

[47]  Steven V. Ley,et al.  ReactIR Flow Cell: A New Analytical Tool for Continuous Flow Chemical Processing , 2010 .

[48]  S. Ley,et al.  Polymer supported perruthenate (PSP): a new oxidant for clean organic synthesis , 1997 .

[49]  M.H.J.M. de Croon,et al.  Novel process windows – Concept, proposition and evaluation methodology, and intensified superheated processing , 2011 .

[50]  C. Oliver Kappe,et al.  Continuous-flow syntheses of heterocycles , 2011 .

[51]  Ryan L. Hartman,et al.  Deciding whether to go with the flow: evaluating the merits of flow reactors for synthesis. , 2011, Angewandte Chemie.

[52]  M. Iwu,et al.  Convulsant alkaloids from Dioscorea dumetorum , 1985 .

[53]  Steven V. Ley,et al.  Multi-step organic synthesis using solid-supported reagents and scavengers: a new paradigm in chemical library generation , 2000 .

[54]  T. Yoshihara,et al.  A new lignan amide, grossamide, from bell pepper (Capsicum annuum var. grossum) , 1981 .

[55]  Andreas Kirschning,et al.  Combining enabling techniques in organic synthesis: continuous flow processes with heterogenized catalysts. , 2006, Chemistry.

[56]  Steven V. Ley,et al.  Hydrogenation in flow: Homogeneous and heterogeneous catalysis using Teflon AF-2400 to effect gas-liquid contact at elevated pressure†‡ , 2011 .

[57]  Shū Kobayashi,et al.  Asymmetric carbon-carbon bond formation under continuous-flow conditions with chiral heterogeneous catalysts. , 2013, Angewandte Chemie.

[58]  Daiki Sakai,et al.  Diastereoselective chain-elongation reactions using microreactors for applications in complex molecule assembly. , 2011, Chemistry.

[59]  S. Ley,et al.  Continuous Cold without Cryogenic Consumables: Development of a Convenient Laboratory Tool for Low-Temperature Flow Processes , 2013 .

[60]  Ian R. Baxendale,et al.  The integration of flow reactors into synthetic organic chemistry , 2013 .

[61]  Steven V Ley,et al.  Microwave reactions under continuous flow conditions. , 2007, Combinatorial chemistry & high throughput screening.

[62]  N. White,et al.  Qinghaosu (Artemisinin): The Price of Success , 2008, Science.

[63]  Timothy F. Jamison,et al.  Continuous flow multi-step organic synthesis , 2010 .

[64]  Steven V Ley,et al.  Flow synthesis using gaseous ammonia in a Teflon AF-2400 tube-in-tube reactor: Paal-Knorr pyrrole formation and gas concentration measurement by inline flow titration. , 2012, Organic & biomolecular chemistry.

[65]  Yunqing Lin,et al.  Total synthesis of diverse carbogenic complexity within the resveratrol class from a common building block. , 2009, Journal of the American Chemical Society.

[66]  Steven V Ley,et al.  Continuous multiple liquid-liquid separation: diazotization of amino acids in flow. , 2012, Organic letters.

[67]  Simon Saubern,et al.  A gram-scale batch and flow total synthesis of perhydrohistrionicotoxin. , 2010, Chemistry.

[68]  Peter H Seeberger,et al.  Continuous-flow synthesis of the anti-malaria drug artemisinin. , 2012, Angewandte Chemie.

[69]  Steven V. Ley,et al.  Flow Chemistry Syntheses of Styrenes, Unsymmetrical Stilbenes and Branched Aldehydes , 2013 .

[70]  Katsunori Tanaka,et al.  Synthesis of a sialic acid containing complex-type N-glycan on a solid support. , 2009, Chemistry, an Asian journal.

[71]  T. Wirth,et al.  Flow chemistry: enabling technology in drug discovery and process research. , 2012, ChemSusChem.

[72]  Shin-ichi Tanaka,et al.  Large-scale synthesis of immunoactivating natural product, pristane, by continuous microfluidic dehydration as the key step. , 2007, Organic letters.

[73]  Andreas Seidel-Morgenstern,et al.  Continuous synthesis and purification by direct coupling of a flow reactor with simulated moving-bed chromatography. , 2012, Angewandte Chemie.

[74]  D. Passarella,et al.  Synthesis of (+)-dumetorine and congeners by using flow chemistry technologies. , 2011, Chemistry.

[75]  Katsunori Tanaka,et al.  Reinvestigation of the C5-acetamide sialic acid donor for α-selective sialylation: practical procedure under microfluidic conditions. , 2011, Organic & biomolecular chemistry.

[76]  S. Diggle,et al.  Quorum sensing by 2-alkyl-4-quinolones in Pseudomonas aeruginosa and other bacterial species. , 2008, Molecular bioSystems.

[77]  Peter H Seeberger,et al.  Microreactors as tools for synthetic chemists-the chemists' round-bottomed flask of the 21st century? , 2006, Chemistry.

[78]  Steven V Ley,et al.  On being green: can flow chemistry help? , 2012, Chemical record.

[79]  Christian H. Hornung,et al.  A Microcapillary Flow Disc Reactor for Organic Synthesis , 2007 .

[80]  Steven V. Ley,et al.  The flow synthesis of heterocycles for natural product and medicinal chemistry applications , 2011, Molecular Diversity.

[81]  J. Wegner,et al.  Flow Chemistry – A Key Enabling Technology for (Multistep) Organic Synthesis , 2012 .

[82]  Neal G. Anderson,et al.  Using Continuous Processes to Increase Production , 2012 .

[83]  Steven V Ley,et al.  The continuous-flow synthesis of carboxylic acids using CO2 in a tube-in-tube gas permeable membrane reactor. , 2011, Angewandte Chemie.

[84]  S. Ley,et al.  A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine: a new paradigm for molecular assembly. , 2006, Chemical communications.

[85]  I. Karle,et al.  Histrionicotoxins: roentgen-ray analysis of the novel allenic and acetylenie spiroalkaloids isolated from a Colombian frog, Dendrobates histrionicus. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[86]  Steven V Ley,et al.  Azide monoliths as convenient flow reactors for efficient Curtius rearrangement reactions. , 2008, Organic & biomolecular chemistry.

[87]  Andreas Kirschning,et al.  Ten key issues in modern flow chemistry. , 2011, Chemical communications.

[88]  H. Koeffler,et al.  The role of the vitamin D endocrine system in health and disease. , 1989, The New England journal of medicine.

[89]  T. Oishi Convergent Method via α-Cyano Ethers: A Powerful Strategy for Synthesizing Ladder-Shaped Polyethers , 2012 .

[90]  Steven V Ley,et al.  A continuous flow process using a sequence of microreactors with in-line IR analysis for the preparation of N,N-diethyl-4-(3-fluorophenylpiperidin-4-ylidenemethyl)benzamide as a potent and highly selective δ-opioid receptor agonist. , 2010, Chemistry.

[91]  Steven V. Ley,et al.  Asymmetric Homogeneous Hydrogenation in Flow using a Tube-in-Tube Reactor , 2012 .

[92]  A. Carroll,et al.  Aplysamine 6, an alkaloidal inhibitor of Isoprenylcysteine carboxyl methyltransferase from the sponge Pseudoceratina sp. , 2008, Journal of natural products.

[93]  D. Spring,et al.  Microwave and flow syntheses of Pseudomonas quinolone signal (PQS) and analogues. , 2011, Organic & biomolecular chemistry.

[94]  R. Haynes,et al.  A novel endoperoxide and related sesquiterpenes from Artemisia annua which are possibly derived from allylic hydroperoxides , 1998 .

[95]  Steven V. Ley,et al.  New tools and concepts for modern organic synthesis , 2002, Nature Reviews Drug Discovery.

[96]  Geoffrey D. Brown,et al.  The role of the 12-carboxylic acid group in the spontaneous autoxidation of dihydroartemisinic acid , 2002 .

[97]  Steven V Ley,et al.  Safe and reliable synthesis of diazoketones and quinoxalines in a continuous flow reactor. , 2011, Organic letters.

[98]  Steven V Ley,et al.  A flow-based synthesis of imatinib: the API of Gleevec. , 2010, Chemical communications.

[99]  Paul Watts,et al.  Recent advances in micro reaction technology. , 2011, Chemical communications.

[100]  Steven V Ley,et al.  An expeditious synthesis of imatinib and analogues utilising flow chemistry methods. , 2013, Organic & biomolecular chemistry.

[101]  E. Greenberg,et al.  Quinolone signaling in the cell-to-cell communication system of Pseudomonas aeruginosa. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[102]  Steven V Ley,et al.  The application of flow microreactors to the preparation of a family of casein kinase I inhibitors. , 2010, Organic & biomolecular chemistry.

[103]  C. Wiles,et al.  Continuous flow reactors: a perspective , 2012 .

[104]  Gary S. Calabrese,et al.  From batch to continuous flow processing in chemicals manufacturing , 2011 .

[105]  C. Codina,et al.  Crinane and lycorane type alkaloids from Zephyranthes citrina. , 2001, Planta medica.

[106]  S. Snyder,et al.  Total synthesis of resveratrol-based natural products: a chemoselective solution. , 2007, Angewandte Chemie.

[107]  Ryan L. Hartman Managing Solids in Microreactors for the Upstream Continuous Processing of Fine Chemicals , 2012 .

[108]  J. Yoshida Flash chemistry using electrochemical method and microsystems. , 2005, Chemical communications.

[109]  W. Okamura,et al.  Synthesis of Vitamin D (Calciferol) , 1995 .

[110]  Volker Hessel,et al.  A View Through Novel Process Windows , 2013 .

[111]  Jun-ichi Yoshida,et al.  Flash chemistry: flow microreactor synthesis based on high-resolution reaction time control. , 2010, Chemical record.