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Khalid Baig Mirza Advisor : Prof. Jean-Claude Bradley Drexel University Prof Frank Ji  (Chair)  , Prof. Susan A. Varnum, P...
Introduction <ul><ul><li>“ Open Notebook Science” is a term used to indicate that the primary record of a research in its ...
<ul><li>Why Open Note Book Science? </li></ul>
Justification for the Open Notebook Science approach  Oxidation of benzylic alcohols using sodium hydride <ul><ul><li>NaH ...
Sodium hydride as an oxidizing agent <ul><li>In a JACS publication last year, Wang, et. al. reported that benzylic type </...
Wang’s ketones...
Experiments repeated by the scientific community from the blogosphere <ul><li>Totally synthetic a  : </li></ul><ul><li>Use...
Green: 1-phenylethanol Blue: acetophenone Red: product HNMR Overlay PPM
Green: acetophenone Blue:1-phenylethanol Red: product IR Overlay
<ul><li>After 19h no conversion to acetophenone was observed, paper mentioned 75% GC yield </li></ul><ul><li>However, tota...
Lewis E., G.;  J. Org. Chem ; 30; 7; 2433–2436 (1965)  Scientific communication through social networks- Blog
<ul><li>Wang’s paper withdrawn from JACS </li></ul><ul><li>Social networking can/has played an important role in the devel...
<ul><li>The UsefulChem Project </li></ul>
Malaria – Some Facts <ul><li>Reported cases: 190-311m  [ 2008, CDC] </li></ul><ul><li>Deaths: 708,000 - 1,003,000 [2008, W...
<ul><li>Collaboration with Find-a-Drug </li></ul><ul><li>Obtained a small library of diketopiperazines designed to inhibit...
Reterosynthesis of the target diketopiperazine <ul><li>All starting materials except 3, 4-dihydrophenyl acetaldehyde  (6) ...
Proposed mechanism for the dehydration of adrenaline to DOPAL
Ugi reaction The reaction did not produce the desired Ugi product
<ul><li>Monitored the reaction with similar simpler reactants such as phenylacetaldehyde and boc-glycine </li></ul><ul><li...
A Mechanistic Insight
Imine kinetics a- Alicia Holsey, b- James Giammarco, c- Sean Gardner 0.1043  c CD3OD 5-methylfurfurylamine 3,4,-dihydroxyb...
Ugi reaction
<ul><li>Fufuryl Cleavage </li></ul>
Attempt at 2,5-diketopiperazine synthesis <ul><li>The UDC strategy- Ugi deboc cyclization 4 </li></ul>4 Hulme, C.; Morriss...
Furfuryl Cleavage The unusual elimination was seen in Ugi products containing the N-furfuryl group.
Reactivity of furan derivatives acidic media Butin, A.,V; Stroganova, T.; Lodina, I., V.; Krapivin, G., D.;  Tet. Lett; 42...
Furan ring opening with lewis acid Piancatelli, G.; Scettri, A.; David, G.; D’Auria, M.; Tetrahedron; 34; 18;  2775-; (197...
1, 6-Hoffman elimination of quaternary amines Appropriately substituted quaternary ammonium hydroxides undergo loss of tri...
Furfuryl cleavage in Ugi products <ul><li>Observed 5-methyl-2-furfuryl group on nitrogen of a tertiary amide, in the Ugi p...
k = 0.9x10-3 min-1  k = 0.9x10 -3  min -1
k = 1.2x10 -3  min -1
k = 0.9x10 -3  min -1
Proposed mechanism for furfuryl cleavage
No methyl group- The cleavage is a thousand times slower than the methyl furfuryl analogs cleavage under the same conditio...
Mechanism for the furfuryl cleavage for the non methylated analog
<ul><li>Optimization of the Ugi reaction </li></ul>
Automated optimization of a Ugi reaction*   <ul><li>The reaction is usually carried-out at room temperature while the prod...
<ul><li>Automation performed using the 48-slot Mettler-Toledo MiniBlock quipped with filtration tubes. </li></ul>Automation
<ul><li>Objective: To optimize  the conditions to obtain highest yield </li></ul><ul><li>Concentration (0.4, 0.2, 0.07M) <...
<ul><li>Reactions performed in little tube with filters at the tip </li></ul><ul><li>Robot added the four components and s...
Results of the Optimization study Statistical analysis: Prof. Kevin Owens
Results of the Optimization study <ul><li>Methanol and ethanol best solvents at 0.2M reagent concentration </li></ul><ul><...
<ul><li>Best yield was 66% at 0.4M in methanol with imine excess (1.2eq).  </li></ul><ul><li>This was significantly higher...
<ul><li>Library Synthesis </li></ul>
Library synthesis <ul><li>Most reactions were performed for the products which were predicted to possess some biological a...
Ugi product precipitation <ul><li>Very few Ugi reactions yielded solid products </li></ul><ul><li>Empirical modeling studi...
Ugi reaction precipitation trends Correlation in terms of isocyanide Carboxylic acid – boc-glycine 35 % 0 0 107 tosylmethy...
Tosylmethyl isocyanide (TOSMIC).. <ul><li>TOSMIC was used in 107 Ugi reactions due to its odor-free nature </li></ul><ul><...
Anti-malarial activity results
Anti-malarial activity <ul><li>Ugi products show inhibition of falcipain-2,  cystein protease inhibitor used by the malari...
<ul><li>Solubility </li></ul>
Polyaromatic components in Ugi reactions <ul><li>1-pyrenebutyric acid  </li></ul>
Solubility issues 0.14 toluene 17 0.104 methanol 16 0.07 hexane 15 0.44 ethyl acetate 14 0.1 ethanol 13 0.1 diethyl ether ...
Solubility.. <ul><li>Poor solubility of reactants resulted in decreased reagent concentration </li></ul><ul><li>Reduced li...
Methods for solubility assessment <ul><li>The shake flask method to saturate a solution </li></ul><ul><li>UV-VIS, HPLC, GC...
Methods we used <ul><li>Speed-Vac method </li></ul>
Hemiacetal of 4-nitrobenzaldehyde in methanol (3:1 aldehyde: hemiacetal ratio) Solute- Solvent reaction
2-chloro-5-nitrobenzaldehyde in methanol (2:3 aldehyde: hemiacetal ratio) Solute- Solvent reaction
NMR method and Semi Automated Measurement of Solubility (SAMS) <ul><li>Web-service created by Prof. Bradley and Prof. Lang...
SAMS.. <ul><li>Spreadsheet calculates the molar ratio of solute to solvent </li></ul><ul><li>Molarity calculation is then ...
Problem.. <ul><li>Inconsistent integration of aromatic and non aromatic protons observed </li></ul><ul><li>Increasing the ...
Conclusions <ul><li>An open, collaborative and more transparent approach to scientific research has been established </li>...
Future work <ul><li>Convenient web services for solubility measurement and prediction </li></ul><ul><li>Virtual library ge...
 
Books published..
Acknowledgements <ul><li>A very patient advisor –  Prof. Jean-Claude Bradley </li></ul><ul><li>My Parents and families sup...
<ul><li>Questions ? </li></ul>Thank You
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Mirza PhD defense on the Ugi reaction for anti-malarial screening

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Khalid Baig Mirza defends his Ph.D. thesis at Drexel University on December 6, 2010 (advisor JC Bradley). He first discusses Open Notebook Science and his contribution to the sodium hydride oxidation controversy. Then he describes the UsefulChem project, involving the use of the Ugi reaction as an approach to synthesizing new anti-malarial agents, including a few unexpected side reactions and challenges. Finally he presents an overview of the ONS Solubility Challenge and its application to organic synthesis.

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Transcript of "Mirza PhD defense on the Ugi reaction for anti-malarial screening"

  1. 1. Khalid Baig Mirza Advisor : Prof. Jean-Claude Bradley Drexel University Prof Frank Ji (Chair) , Prof. Susan A. Varnum, Prof. Sally Solomon, Prof Peter Wade, Prof. Louis Scerbo, Prof. Jun Xi
  2. 2. Introduction <ul><ul><li>“ Open Notebook Science” is a term used to indicate that the primary record of a research in its entirety is made public over the internet as soon as it is conducted </li></ul></ul><ul><ul><ul><li>Achieves and advocates complete transparency of research being performed </li></ul></ul></ul><ul><ul><ul><li>Serve as an open invitation to collaborate with like minded researchers / scientists who are capable and willing to participate in the project </li></ul></ul></ul><ul><ul><ul><li>The planned experimental procedure, the log, raw data, and a discussion of the analysis of the data, the assumptions and the conclusions drawn from the specific experiment and the project in general made public in real time. </li></ul></ul></ul><ul><ul><li>The UsefulChem project – A collaborative effort to find a treatment/cure to malaria </li></ul></ul><ul><ul><li>Tools used – Wikis, blogs, YouTube, FriendFeed, Google Docs, JSpecView, ChemSpider, Mendeley, Online repositories, etc </li></ul></ul>
  3. 3. <ul><li>Why Open Note Book Science? </li></ul>
  4. 4. Justification for the Open Notebook Science approach Oxidation of benzylic alcohols using sodium hydride <ul><ul><li>NaH is commonly used as a base, eg. enolate chemistry 1 </li></ul></ul>References 1 Hudrlik,P., F.; Takacs, J., M.; J. Org. Chem; 43; 20; 3861-3865 (1978) 2 McConaghy Jr. J., S.; Bloomfield, J., J,; J. Org. Chem; 33; 9; 3425-3428 (1968) To a lesser extent it has also been used as a reducing agent 2
  5. 5. Sodium hydride as an oxidizing agent <ul><li>In a JACS publication last year, Wang, et. al. reported that benzylic type </li></ul><ul><li>secondary alcohols under go oxidation when treated with NaH (2eq) in THF at </li></ul><ul><li>room temperature. Several examples were given 3 . </li></ul><ul><li>Well picked-up in the blogosphere community, facilitated by social networking </li></ul><ul><li>websites like Friendfeed and others. </li></ul>References 3 Wang, X., Zhang, B., Wang, D., Z.; J Amer. Chem Soc ; DOI: 10.1021/ja904224y; (2009)
  6. 6. Wang’s ketones...
  7. 7. Experiments repeated by the scientific community from the blogosphere <ul><li>Totally synthetic a : </li></ul><ul><li>UsefulChem b : </li></ul><ul><li>Experimental details were comprehensively documented with </li></ul><ul><li>photos and videos </li></ul>a) Paul Docherty- totallysynthetic.com/blog/?p=1903; (12/05/2010) b) Khalid Mirza, Marshall Moritz, Jean-Claude Bradley; UsefulChem.wikispaces.com/Exp243. Reaction monitored before quenching; (12/05/2010)
  8. 8. Green: 1-phenylethanol Blue: acetophenone Red: product HNMR Overlay PPM
  9. 9. Green: acetophenone Blue:1-phenylethanol Red: product IR Overlay
  10. 10. <ul><li>After 19h no conversion to acetophenone was observed, paper mentioned 75% GC yield </li></ul><ul><li>However, totallysynthetic.com reported at 15% conversion to the ketone. Wang reported 85% isolated yield </li></ul><ul><li>A comment made by a reader on another blog Carbon based curiosities a mentions a JOC paper from 1968 which address the issue. </li></ul>a http://www.coronene.com/blog/?p=842 Results
  11. 11. Lewis E., G.; J. Org. Chem ; 30; 7; 2433–2436 (1965) Scientific communication through social networks- Blog
  12. 12. <ul><li>Wang’s paper withdrawn from JACS </li></ul><ul><li>Social networking can/has played an important role in the development of science </li></ul><ul><li>Social networking + collaborative effort => unforeseen innovations (Chemistry, Medicine, Engineering, .. data curation as well. </li></ul>Consequences
  13. 13. <ul><li>The UsefulChem Project </li></ul>
  14. 14. Malaria – Some Facts <ul><li>Reported cases: 190-311m [ 2008, CDC] </li></ul><ul><li>Deaths: 708,000 - 1,003,000 [2008, WHO] </li></ul><ul><li>Half the worlds population (3.3 billion) susceptible to malaria.[CDC] </li></ul><ul><li>Second leading cause of deaths from infectious diseases in Africa after HIV/AIDS [CDC] </li></ul><ul><li>Approximately 1500 cases of malaria are reported in the US annually [CDC] </li></ul><ul><li>Drug resistance of Plasmodium falciparum to chloroquin, sufladoxine-pyrimethamine are well known. [WHO] </li></ul><ul><li>New anti-malarial agents needed. </li></ul>
  15. 15. <ul><li>Collaboration with Find-a-Drug </li></ul><ul><li>Obtained a small library of diketopiperazines designed to inhibit enoyl-reducatase, an essential enzyme for the fatty-acid metabolism of Plasmodium falciparium. </li></ul>Target diketopiperazine Diketopiperazine library
  16. 16. Reterosynthesis of the target diketopiperazine <ul><li>All starting materials except 3, 4-dihydrophenyl acetaldehyde (6) were commercially available. </li></ul><ul><li>Therefore a synthetic procedure had to be designed. </li></ul>
  17. 17. Proposed mechanism for the dehydration of adrenaline to DOPAL
  18. 18. Ugi reaction The reaction did not produce the desired Ugi product
  19. 19. <ul><li>Monitored the reaction with similar simpler reactants such as phenylacetaldehyde and boc-glycine </li></ul><ul><li>Mechanistic understanding of the reaction using NMR monitoring </li></ul><ul><li>Reactivity of the alpha protons on phenylacetaldehyde was one of the main reasons for the failure of reaction. </li></ul>Monitoring the Ugi reaction
  20. 20. A Mechanistic Insight
  21. 21. Imine kinetics a- Alicia Holsey, b- James Giammarco, c- Sean Gardner 0.1043 c CD3OD 5-methylfurfurylamine 3,4,-dihydroxybenzaldehyde 0.008 b CD3OD t-butyl amine piperonal 0.1552 a CD3OD 5-methylfurfurylamine piperonal 0.07 a CDCl3 5-methylfurfurylamine piperonal 0.106 CD3OD 5-methylfurfurylamine veratraldehyde 0.01 CDCl3 5-methylfurfurylamine veratraldehyde Imine formation rate constant 1/(M*min) solvent amine aldehyde
  22. 22. Ugi reaction
  23. 23. <ul><li>Fufuryl Cleavage </li></ul>
  24. 24. Attempt at 2,5-diketopiperazine synthesis <ul><li>The UDC strategy- Ugi deboc cyclization 4 </li></ul>4 Hulme, C.; Morrissette, M.; Volz, F., A.; Burns, C.; Tett. Lett. 39; 10; 1113-1116; (1998)
  25. 25. Furfuryl Cleavage The unusual elimination was seen in Ugi products containing the N-furfuryl group.
  26. 26. Reactivity of furan derivatives acidic media Butin, A.,V; Stroganova, T.; Lodina, I., V.; Krapivin, G., D.; Tet. Lett; 42; 10; 2031-2033; (2001) Reissert modification-indole synthesis
  27. 27. Furan ring opening with lewis acid Piancatelli, G.; Scettri, A.; David, G.; D’Auria, M.; Tetrahedron; 34; 18; 2775-; (1978)
  28. 28. 1, 6-Hoffman elimination of quaternary amines Appropriately substituted quaternary ammonium hydroxides undergo loss of trimethyl amine across a furan or thiophene to unusual cyclic conjugated trienes, there dimmers and polymers Winberg, H., E.; Fawcett, F., S.; Mochel, W.,E.; Thebald, W., C.; J. Amer. Chem .Soc ; 82; 6; 1428-1435; (1959)
  29. 29. Furfuryl cleavage in Ugi products <ul><li>Observed 5-methyl-2-furfuryl group on nitrogen of a tertiary amide, in the Ugi products. </li></ul><ul><li>Undergo a 1-6- elimination to yield a secondary amide when treated with trifluoroacetic acid in CDCl 3 or CD 3 OD </li></ul>
  30. 30. k = 0.9x10-3 min-1 k = 0.9x10 -3 min -1
  31. 31. k = 1.2x10 -3 min -1
  32. 32. k = 0.9x10 -3 min -1
  33. 33. Proposed mechanism for furfuryl cleavage
  34. 34. No methyl group- The cleavage is a thousand times slower than the methyl furfuryl analogs cleavage under the same conditions k= 4x10 -6 min -1 A different mechanism needed... Non-methylated furfuryl analog cleavage
  35. 35. Mechanism for the furfuryl cleavage for the non methylated analog
  36. 36. <ul><li>Optimization of the Ugi reaction </li></ul>
  37. 37. Automated optimization of a Ugi reaction* <ul><li>The reaction is usually carried-out at room temperature while the product sometimes precipitates out from the reaction mixture. </li></ul><ul><li>When it precipitates out, the product is then just filtered and washed with the solvent. </li></ul><ul><li>The product precipitation although not consistent is very desirable when performing a scale-up, essentially eliminating an expensive chromatographic purification process. </li></ul><ul><li>In order to obtain high yield and purity of the product optimization studies were performed on a Ugi reaction, where the product was filtered directly and washed with the solvent. </li></ul>Performed in collaboration with Prof. Kevin Owens, Drexel University
  38. 38. <ul><li>Automation performed using the 48-slot Mettler-Toledo MiniBlock quipped with filtration tubes. </li></ul>Automation
  39. 39. <ul><li>Objective: To optimize the conditions to obtain highest yield </li></ul><ul><li>Concentration (0.4, 0.2, 0.07M) </li></ul><ul><li>Solvent (methanol, ethanol, acetonitrile and THF) </li></ul><ul><li>Excess of some reagents (1.2eq) </li></ul>Parameters under consideration
  40. 40. <ul><li>Reactions performed in little tube with filters at the tip </li></ul><ul><li>Robot added the four components and solvent </li></ul><ul><li>Precipitated product then washed, weighed and NMR analyzed to confirm </li></ul>Mettler-Toledo MiniBlock System
  41. 41. Results of the Optimization study Statistical analysis: Prof. Kevin Owens
  42. 42. Results of the Optimization study <ul><li>Methanol and ethanol best solvents at 0.2M reagent concentration </li></ul><ul><li>Yields decreased from 0.2M to 0.07M in MeOH, EtOH & AcCN. Similar yields at 0.2M and 0.4M concentrations in methanol </li></ul><ul><li>In EtOH and MeOH higher yields resulted with imine or isonitrile excess. In AcCN amine, aldehyde or isonitrile excess gave better result. In THF imine excess resulted in higher yields. Over yields significantly lower for THF than other solvents </li></ul><ul><li>Significant interactions between the solvent choice, reagent concentration and identity of the reagent in excess found </li></ul>
  43. 43. <ul><li>Best yield was 66% at 0.4M in methanol with imine excess (1.2eq). </li></ul><ul><li>This was significantly higher than the initial reaction under equimolar conditions (49%) </li></ul>
  44. 44. <ul><li>Library Synthesis </li></ul>
  45. 45. Library synthesis <ul><li>Most reactions were performed for the products which were predicted to possess some biological activity. </li></ul><ul><li>Docking and modeling studies were conducted by collaborators, Dr. Rajarshi Guha and Prof. Andrew Lang </li></ul><ul><li>Results of the ranked virtual library of Ugi products were provided in the form of smiles </li></ul><ul><li>Based on the ranking Ugi products were synthesized </li></ul><ul><li>The compounds were then sent for testing against facipain-2, an enzyme used by the malarial parasite to break down hemoglobin. This was done in collaboration with the Rosenthal group at UCSF </li></ul>
  46. 46. Ugi product precipitation <ul><li>Very few Ugi reactions yielded solid products </li></ul><ul><li>Empirical modeling studies were performed by Prof. Andy Lang (ORU) to predict the likelihood of Ugi product precipitation. </li></ul><ul><li>Reactions were performed and the results were incorporated to further improve the model. </li></ul>Ugi reactions performed – 511 Ugi reactions that precipitated a product – 104 (20%) Precipitate confirmed to be Ugi products – 65 (13%) Precipitate not a Ugi product – 8
  47. 47. Ugi reaction precipitation trends Correlation in terms of isocyanide Carboxylic acid – boc-glycine 35 % 0 0 107 tosylmethyl isocyanide 11 23 215 t-butyl isocyanide 4 5 120 n-butyl isocyanide 13 10 77 cyclohexyl isocyanide 7 3 43 benzyl isocyanide 0 0 13 2-morpholinoethyl isocyanide 0 0 4 2-chloro-6-methyl phenyl isocyanide 0 0 38 1-pentyl isocyanide 0 0 32 1,1,3,3-tetramethylbutyl isocyanide Percent precipitation number of product precipitations Number of reaction Isocyanide
  48. 48. Tosylmethyl isocyanide (TOSMIC).. <ul><li>TOSMIC was used in 107 Ugi reactions due to its odor-free nature </li></ul><ul><li>No solid Ugi products were obtained. </li></ul><ul><li>Poor solubility of TOSMIC in most organic solvents </li></ul><ul><li>Reactions had to be performed at lower concentrations </li></ul><ul><li>Reactivity towards aldimine in basic conditions </li></ul>
  49. 49. Anti-malarial activity results
  50. 50. Anti-malarial activity <ul><li>Ugi products show inhibition of falcipain-2, cystein protease inhibitor used by the malarial parasite, Plasmodium falciparum to degrade erythrocytic proteins especially hemoglobin. </li></ul><ul><li>Show inhibition of the Plasmodium falciparum. </li></ul>UsefulChem top inhibitor IC 50 8.4uM
  51. 51. <ul><li>Solubility </li></ul>
  52. 52. Polyaromatic components in Ugi reactions <ul><li>1-pyrenebutyric acid </li></ul>
  53. 53. Solubility issues 0.14 toluene 17 0.104 methanol 16 0.07 hexane 15 0.44 ethyl acetate 14 0.1 ethanol 13 0.1 diethyl ether 12 0 dichloromethane 11 0.03 cyclopentane 10 0.07 cyclohexane 9 0.04 chloroform 8 0.66 benzene 7 0.153 acetonitrile 6 1.29 THF 5 0.77 DMSO 4 1.25 DMF 3 0.07 2-propanol 2 0.02 1,1,2-trichlorotrifluoroethane 1 Ave. (M) Solvent Solubility of phenanthrene-9-carboxaldehyde 0 toluene 16 0.014 methanol 15 0 hexane 14 0.06 ethanol 13 0.02 diethyl ether 12 0.07 dichloromethane 11 0 cyclopentane 10 0 cyclohexane 9 0.03 chloroform 8 0 carbon tetrachloride 7 0 benzene 6 0 acetonitrile 5 0.55 THF 4 2.067 DMSO 3 1.88 DMF 2 0.06 2-propanol 1 Ave. (M) Solvent Solubility of 1-pyrenebutyric acid
  54. 54. Solubility.. <ul><li>Poor solubility of reactants resulted in decreased reagent concentration </li></ul><ul><li>Reduced likelihood of product precipitation </li></ul><ul><li>Need for a solubility model, to predict selective product precipitation </li></ul><ul><li>Need to measure solubility of several reactants and Ugi products in different organic solvents at room temperature </li></ul><ul><li>ONSChallenge a collaborative effort with Prof. Andew Lang (ORU) and Dr. Rajarshi Guha </li></ul>
  55. 55. Methods for solubility assessment <ul><li>The shake flask method to saturate a solution </li></ul><ul><li>UV-VIS, HPLC, GC </li></ul><ul><li>Turbidimetry and nephlometry </li></ul><ul><li>Differential Scanning Calorimetry </li></ul>
  56. 56. Methods we used <ul><li>Speed-Vac method </li></ul>
  57. 57. Hemiacetal of 4-nitrobenzaldehyde in methanol (3:1 aldehyde: hemiacetal ratio) Solute- Solvent reaction
  58. 58. 2-chloro-5-nitrobenzaldehyde in methanol (2:3 aldehyde: hemiacetal ratio) Solute- Solvent reaction
  59. 59. NMR method and Semi Automated Measurement of Solubility (SAMS) <ul><li>Web-service created by Prof. Bradley and Prof. Lang using Google spreadsheet. </li></ul><ul><li>Based on HNMR of a very small volume of the supernatant in deuterated solvent </li></ul><ul><li>JCAMP dx file of the spectrum is uploaded to the server </li></ul><ul><li>Density and molar mass of the solute and solvent is incorporated </li></ul><ul><li>Predicted densities from ChemSpider.com used for solids </li></ul><ul><li>A range in the solute to integrate with the number of corresponding H </li></ul><ul><li>A range in the solvent to integrate with the number of corresponding H </li></ul>
  60. 60. SAMS.. <ul><li>Spreadsheet calculates the molar ratio of solute to solvent </li></ul><ul><li>Molarity calculation is then done by assuming that the volumes of the two components are additive. </li></ul>
  61. 61. Problem.. <ul><li>Inconsistent integration of aromatic and non aromatic protons observed </li></ul><ul><li>Increasing the relaxation delay d1 from 0.3s to 50s resulted in uniform peak integrations per proton over the entire spectrum </li></ul>
  62. 62. Conclusions <ul><li>An open, collaborative and more transparent approach to scientific research has been established </li></ul><ul><li>A mechanistic understanding in to the ‘furfuryl cleavage’ has been achieved </li></ul><ul><li>Conditions necessary for the Ugi reaction has been optimized </li></ul><ul><li>Library of Ugi reactions have been performed </li></ul><ul><li>Synthesis of potential anti-malarial agents accomplished </li></ul><ul><li>Solubility of the reagents and Ugi products determined to facilitate the successful construction of a model to predict the selective precipitation of the Ugi products from a reaction </li></ul>
  63. 63. Future work <ul><li>Convenient web services for solubility measurement and prediction </li></ul><ul><li>Virtual library generator </li></ul><ul><li>Predictive Toxicology </li></ul><ul><li>Virtual docking </li></ul><ul><li>Integration of Multiple Web Services to expedite the process of drug discover. </li></ul>
  64. 65. Books published..
  65. 66. Acknowledgements <ul><li>A very patient advisor – Prof. Jean-Claude Bradley </li></ul><ul><li>My Parents and families support </li></ul><ul><li>Committee members- Prof Frank Ji, Prof. Susan Jansen Varnum, Prof. Sally Solomon, Prof Peter Wade, Prof. Louis Scerbo and Prof. Jun Xi, Prof. Robert Hutchins (Late) </li></ul><ul><li>Collaborators – Prof. Kevin Owens, Dr. Rajarshi Guha, Prof. Andrew Lang, ONSChallenge Judges & Tom Osborne. </li></ul><ul><li>Prof. Lynn Penn, Prof. Anthony Wambsgans </li></ul><ul><li>Ed Doherty, Virginia Nesmith, Tina Lewinski, Ed Thorne, Tim Wade </li></ul><ul><li>Co-workers - Alicia Holsey, James Giammarco, Sean Gardner, Emily Messner, Shannon Oseback, Tim Bohinski, Cedric Tschakounte, Marshall Moritz. </li></ul><ul><li>Renata Szyszka, Neil Mukherjee, Sudipto Das, David Berke-Schlessel , Kerry Drake, Jonathan Soffer, Addy Kojtari, April Holcomb, Bill Erb, Jim Reiben, Molly O’connor, Tyson Reeves, Christopher Castillo, Nick Paparoidamis, Hung Le, Tom Measy, Andrew Haggarman, Joseph Depasquale, Natalie Dixon, Mukesh Kumar, Ismael Nieto, Marcela Garcia, KimChi Nguyen, Kyle Hess, William Hunt, Arben Kojtari, Michelle Livings, Chi Nguyen, Siobhan Toal and others I missed.. </li></ul>
  66. 67. <ul><li>Questions ? </li></ul>Thank You
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