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1 Clark W. Still Career in Review Department of Chemistry, University of Ottawa March 17 th, 2009 By Anik Michelle Chartrand.

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Presentation on theme: "1 Clark W. Still Career in Review Department of Chemistry, University of Ottawa March 17 th, 2009 By Anik Michelle Chartrand."— Presentation transcript:

1 1 Clark W. Still Career in Review Department of Chemistry, University of Ottawa March 17 th, 2009 By Anik Michelle Chartrand

2 Who Is He ?  Born in Augusta, Georgia  Graduated from Winter Haven High School in Polk Country, FL  B.Sc. At Emory University  Ph.D. At Emory University – Advisor was David Goldsmith  Postdoc at Princeton University (computer related)  1974/75- Postdoc at Columbia University with Gilbert Stork  1975/76- Professor at Vanderbilt University in Nashville, TN  1977 to 98 - Professor at Columbia University in NY, NY  1999 – Professor Emeritus, Columbia University in NY, N 2

3 Graduate Studies 3

4 His Graduate Work ( )  Diborane Reductions of Oxygen Heterocycles  Hydroboration-Oxydation Products of Oxygen Heterocycles W. C. Still and D.J. Goldsmith, J. Org. Chem., 1970, 35 (7),

5 His Graduate Work ( )  Bicyclic Intermediate for Trichothecane Synthesis  Exploitation of an Enolate as a Protecting Group  Tandem sequence involving bis alkylation  The decarboxylative elimination reaction of β,γ- epoxyacids to make allylic alcohols Still, W.C.; Lewis, A.J.; Goldsmith D.; Tetrahedron Letters, 1971, 18, 1421 Still, W.C.; Lewis, A.J.; Goldsmith D.; Tetrahedron Letters, 1973, 48,

6 His Graduate Work ( ) Most of his work with Prof. Stork concentrated of the formation of Gibberellic Acids B-C-D ring: Stork, G.; Boeckman, R.K. Jr..; Taber, D.F.; Still W.C. Singh, J.,JACS, 1979, 101 (23) 7107 Stork, G.; Still W.C. Singh, J., Tetrahedron Letters, 1979, 52, 5077  Unusual regiospecificity in the enolization of a ketone as the result of a difference in energy to achieve the best overlap of an alpha hydrogen  Reductive cyclization of Ethynyl ketones 6

7 Independent Researcher 7 Vanderbilt UniversityColumbia University

8 His Work at Vanderbilt University ( )  Organo cuprates and the development of a new highly selective stereoselective alkylation agent to produce axial alcohols  Conjugate Addition of trimetylsilyllithium – Axial addition is highly favoured “ In contrast to the numerous highly stereoselective reducing agents which have been developed, the ability of reagents for the addition of unhindered alkyl nucleophiles to ketones with high stereoselectivity is limited.” Macdonald, T.L.; Still, W.C.; JACS, 1975, 97(18), 5280 & Still, W.C., J. Org. Chem., 1976, 41(18),

9 His Work at Vanderbilt University ( )  Allyloxy Carbanions:  Cyclization to vinyl oxetans via allyloxycarbanions : Selective fomation of the more strained oxetane as long as the addition produces the cis ring juncture Still C.W., Tetrahedron Letters, 1976, 25, 2115 & Still, W.C.; Macdonald, T.L.; J. Org. Chem., 1976, 41(22),

10 His Work at Vanderbilt University ( )  Claisen Variant:  Tin chemistry (stannylation/destannylation)  α-Alkoxy Organolithium Reagents Still, C.W.; Schneider, M.J., JACS, 1977, 99(3), 948 & Still, C.W., JACS, 1978, 100 (5),

11 His Work at Vanderbilt University ( )  Alkylation and oxidation – efficient dialkylative enone transposition  Tri-alkyl tin anions undergo high yield conjugate addition to α,β-enones to give the regiospecific enolate  Alkylstannanes are smoothly oxidized by chromic anhydride/pyridine to the corresponding ketone Still, C.W., JACS, 1977, 99(14),

12 Columbia University ( )  Anionic [2,3]-sigmatropic rearrangements Still, C.W.; McDonald J.H. III; Collum, D.B.; Mitra, A., Tetrahedron Letters, 1979, 7, 593 & Still, C.W.; Kahn, M.; Mitra, A., J. Org. Chem., 1978, 43(14),

13 13  Rapid Chromatographic Technique for Preparative Separation of moderate resolution “ We have recently developed a substantially faster technique for the routine purification of a products which we call flash chromatography.” 1) Still, C.W.; Kahn, M.; Mitra, A., J. Org. Chem., 1978, 43(14), ) Still, W. C.; Dongwei, J. Org. Chem., 1988, 53, ) Still, W.C.; MacDonald, J.H.III; Collum, D.B.; JACS, 1980, 102(6), ) Still, W.C.; MacDonald, J.H.III; Collum, D.B.; JACS, 1980, 102(6), )Still, W.C.; MacDonald, J.H.III; Collum, D.B.; JACS, 1980, 102(6), 2120 Columbia University ( )  17 asymmmetric centers, 26 carbon backbone  Theoretically stereoisomers can exist  Monensin – Polyether antibiotic and naturally occurring ionophore

14 Columbia University ( )  Direct Synthesis of Z-unsaturated esters; a useful modification of the Horner-Emmons Olefination Still, W.C., JACS, 1979, 101(9), 2493 & Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9), Still – Gennari Modification Horner-Wadsworth-Emmons

15 Z-trisubstituted Allylic Alcohols via the Wittig Reaction Schlosser, M; Christmann, K.F. Angew. Chem. Intl, Ed., 1966, 5(1), 126 & Schlosser, M; Christmann, K.F,; Muller, G., Angew. Chem. Intl, Ed., 1966, 5 (17), 667 & Corey, E.J.; Yamamoto, H.; JACS, 1970, 92(1),

16 Z-trisubstituted Allylic Alcohols via the Wittig Reaction  No β-oxido Ylide intermediate or n-BuLi required Counterion effect Phosphonium fluoroborate Vs Phosphonium halide Sreekumar, C.; Darst, K.P.; Still, W.C., J. Org. Chem, 1980, 45(21), α-santalol α α ‘

17 Columbia University ( )  Dichlorocarbene cyclopropanation of allylic alcohols: This is a Simmons-Smith equivalent that works well in acyclic systems  Synthesis of Alternating Hydroxy- and Methyl-Substituted Hydrocarbons by Oxymercuration of Cyclopropylcarbinols. Mohamadi, F.; Still, W.C., Tetrahedron Letters, 1986, 27(8), 893 & Collum, D.B.; Still, W.C., Mohamadi, F., JACS, 1986, 108(8),

18 Columbia University ( )  A highly stereoselective synthesis of trans epoxides via arsonium Ylides  Remote 1,3-, 1,4-,and 1,5- asymmetric induction. A stereoselective approach to acyclic diols via Cyclic Hydroboration High stereoselectivity for trans epoxide ≥ 50:1 Still, W.C.; Novack, V. J., JACS, 1981, 103(5), 1283 & Still, W.C..; Darst, K.P., JACS, 1980, 1021(24),

19 Columbia University ( )  Synthesis of Macrocyclic Trichothecanoids: Baccharin B5 and Roridin E  Chemical consequence of conformation in macrocyclic compounds. An effective approach to remote asymmetric induction. Still, W.C.; Gennari, C.; Noguez, J.A..; Pearson, D.A., JACS, 1984, 106(1), 260 & Still, W.C.; Galynker, I., Tetrahedron, 1981, 37 (23),

20 Macrocycles  Stereochemical control - acyclic and macrocyclic natural products rely on some form of absolute stereochemical control to set up remote diastereometric relationship  Readily available enantiomerically pure S.M.  Resolution of an intermediate  Asymetric induction by enantiomerically pure reagent  Still’s alternative – pre-existing substrate chirality, which may be quite distant from the reaction site, to direct the stereoselectivity of the reaction. A.Conformations – Transannular non bonded repulsions and high-energy torsional arrangements must be minimized Still, W.C.; Galynker, I., Tetrahedron, 1981, 37(23),

21 8-Membered Ring

22 Still, W.C.; Galynker, I., Tetrahedron, 1981, 37 (23), Membered Rings 22

23 Peripheral vs Antiperipheral Attack  3D Structure – sp 2 centers are perpendicular to the plane of the ring Cis-cyclohexene Cis- cycloocteneCis- cyclodecene  2 faces of π-system are sterically different  Peripheral attack preferred Still, W.C.; Galynker, I., Tetrahedron, 1981, 37 (23),

24 Periplanone B- Total synthesis and structure of the Sex Excitant Pheromone of the American Cockroach  Female species of Periplaneta americana, the American Cockroach.  In the early 70’s Persoons et al. Isolated two extremely active compounds, periplanones-A (-20 pg) and -B (-200 pg).  Periplanone-B was characterized spectrally and tentatively assigned a germacranoid structure.  Still reported highly stereoselective syntheses of three of the four possible diastereomers. Still, W.C., JACS, 1979, 101(9),

25 Periplanone B – First Diastereomer C-5 and C-6 Diaxial coupling (10Hz); C-7 and C-8 trans coupling (16 Hz) Still, W.C., JACS, 1979, 101(9), 2493 & Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9),

26 Peripheral Attack X  Diastereomers synthesis:  1-5 Cyclodecadienes have a well defined conformation  Olefinic linkage perpendicular to plane of ring.  Attack from less hindered peripheral face of the π system Still, W.C., JACS, 1979, 101(9), 2493 & Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9), 2495 Periplanone B – Stereocontrol Approach 26

27 Spectral comparison with authentic Periplanone-B concludes they are Unidentical Periplanone B – First Diastereomer 27

28 300-MHz NMR strongly suggest :  Only difference is the configuration of the isopropyl group.  Pseudo-axial in X: (J 7-8 = 5, J 8-9a = 7.5, J 8-9b = 2 Hz)  Pseudo-equatorial (Periplanone B) : (J 7-8 = 10, J 8-9a = 10, J 8-9b = 5.5 Hz Still, W.C., JACS, 1979, 101(9), 2493 & Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9), 2495 Periplanone B – First Diastereomer 28 First Disatereomer

29  NMR of 116 is very different than Periplanone B  Transannular -O- interaction is replaced by a more severe -CH 2 - interaction Still, W.C., JACS, 1979, 101(9), 2493 & Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9), 2495 Periplanone B – Second Diastereomer 29

30 Periplanone B -Third Diastereomer  Construction of the stereoisomeric C-2 – C-3 cis epoxide:  Desired epoxide is the more hindered one. Disfavoured Antiperipheral attack needed favoured peripheral attack NOT WANTED  Alternate tactic was chosen – construction of the C-5 – C-7 conjugated diene : New conformation exposes opposite face to peripheral attack Still, W.C., JACS, 1979, 101(9), 2493 & Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9),

31  Comparison of (±) – 121 with Periplanone–B showed they were identical Still, W.C., JACS, 1979, 101(9), 2493 & Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9), 2495 Periplanone B -Third Diastereomer 31

32 Columbia University ( )  An internal Coordinate Monte Carlo method for searching conformational Space Random Search for finding the low-energy conformations of molecules Was the first to create a software available and and fairly easy to use for the general public Chang, G.; Guida, W.C.; Still, W.C., JACS, 1989, 111 (8),

33  Complex Synthetic chemical libraries indexed with molecular tags  A new generation of Fluorescent chemosensors demonstrate improved analyte detection sensitivity and photobleaching resistance. Columbia University ( ) Nestler, H.P.; Barlett, P.A.; Still, W.C., J. Org. Chem., 1994, 59(17), 4723 & Ohlmeyer, M.H.J.; Swanson, R.N.; Dillard, L.W.; Reader, J.C.;Asouline, G.;Kobayashi, R.; Wigler, M.;Still, W.C., Proc. Natl. Acad. Sci. USA, 1993, 90(23), & Rothman, J.H.; Still, W.C., Bioorg.& Med. Chem. Letters, 1999, 9(4), 509 & Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, 279 (5352),

34 Complex Synthetic Chemical Libraries Indexed with Molecular Tags  Spacially segrated arrays  Only small libraries Ohlmeyer, M.H.J.; Swanson, R.N.; Dillard, L.W.; Reader, J.C.;Asouline, G.;Kobayashi, R.; Wigler, M.;Still, W.C., Proc. Natl. Acad. Sci. USA, 1993, 90(23),  Multivalent synthesis methods  Moderate complexity library is produced  Pooling of multiple reagents during synthesis  Pool is identified to have interesting properties  Resynthesized with lower and lower complexity till one compound is identified  NOT practical for construction of massive libraries.  Split synthesis  On solid particles (ex. Beads)  Each bead has a product from a single reaction sequence bound to it  Selection of a bead with desirable property followed by ID of substrate by analytic method.  Only for compounds that can be readily elucidated by micro scale sequencing.  Co-synthesis method  Co-synthesis of a sequencable tag encoding the steps and reagents used in each step.  Oligonucleotide and oligopeptide tags are used  Problem = tag is labile, can associate selectively with biological receptors.

35 Complex Synthetic chemical libraries indexed with molecular tags  Chemically encoded combinatorial library  Synthesis on microsphere beads (like in split method)  Each step tagging molecules are attached to the beads  Encodes both the step number and reagent used in that step = Binary record  No co-synthesis required (tags not connected)  20 tags = different syntheses Ohlmeyer, M.H.J.; Swanson, R.N.; Dillard, L.W.; Reader, J.C.;Asouline, G.;Kobayashi, R.; Wigler, M.;Still, W.C., Proc. Natl. Acad. Sci. USA, 1993, 90(23),

36 Result Analysis Peptide library beads stained with mAb 9E10.GC of tags from EQKLISEEDLGGGG-Bead Ohlmeyer, M.H.J.; Swanson, R.N.; Dillard, L.W.; Reader, J.C.;Asouline, G.;Kobayashi, R.; Wigler, M.;Still, W.C., Proc. Natl. Acad. Sci. USA, 1993, 90(23),

37 General Method for Molecular Tagging of Encoded Combinatorial Libraries  Requires no particular tag-attaching functional group other than what already makes up the polymer matrix  New tagging reagent = tag plus linker Nestler, H.P.; Barlett, P.A.; Still, W.C., J. Org. Chem., 1994, 59(17),

38 Fluorescent, Sequence-Selective Peptide Detection by Synthetic Small molecules  Chemosensors are small molecules that signal the presence of analytes, and typically have two components: o Receptor – site that selectively binds an analyte o Redout mechanism – signals binding. Chemosensor for tripeptides in CHCl 3. Function as synthetic analogs of the antigen-binding site of immunoglobulins FET signal transduction system Rothman, J.H.; Still, W.C., Bioorg.& Med. Chem. Letters, 1999, 9(4), 509 & Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, ),

39 Chemosensors Chemosensor A Chemosensor B Q = COC 6 H 4 N=NC 6 H 4 NMe 2 F = (CH 2 ) 2 NH-SO 2 C 10 H 6 NMe 2 Dabcyl N-hydrosuccinamide ester Dansyl sulfonamide of ethanolamine 39

40 Fluorescent, Sequence-Selective Peptide Detection by Synthetic Small molecules Fluorescence spectra of chemosensor A and B with Peptides P1 and P2  Demonstrate the sequence selective optical detection of peptides  By small molecules chemosensor  Can be extended to solid state libraries Rothman, J.H.; Still, W.C., Bioorg.& Med. Chem. Letters, 1999, 9(4), 509 & Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, 279 (5352),

41 New Fluorencent Chemosensors with Improved Photobleaching Resistance  Photobleaching : is the photochemical destruction of a fluorophore. Major problem with chemosensors that report binding via fluorescence trough UV  FRET ( fluorescence resonance energy transfer) interaction  The level of fluorescence that escapes quenching is proportional to the binding strength  Photobleaching is a significant source of detection error. 41 Rothman, J.H.; Still, W.C., Bioorg.& Med. Chem. Letters, 1999, 9(4), 509 & Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, 279 (5352), 851

42 Dansyl fluorofore moiety Known to undergo photobleaching New Fluorencent Chemosensors with Improved Photobleaching Resistance 42 Rothman, J.H.; Still, W.C., Bioorg.& Med. Chem. Letters, 1999, 9(4), 509 & Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, 279 (5352), 851

43 Dansyl vs Acridone Moiety  Replacement of the dansyl fluorophore moiety with an acridone derivative 43 Rothman, J.H.; Still, W.C., Bioorg.& Med. Chem. Letters, 1999, 9(4), 509 & Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, 279 (5352), 851

44 Receptor binding saturation experiment.  Receptor is now more resistant to fluorophore photobleaching.  No significant change in binding saturation characteristics  Acridone exhibits increased fluorescence upon binding New Fluorencent Chemosensors with Improved Photobleaching Resistance 44 Rothman, J.H.; Still, W.C., Bioorg.& Med. Chem. Letters, 1999, 9(4), 509 & Chen, C.T.; Wagner, H.; Still, W.C., Science, 1998, 279 (5352), 851

45 Conclusion 45  Still was clearly ahead of his time - Total synthesis- Methodology - Computational chemistry - Chemical biology etc..  Retired at 53 years old – Emeritus professor at Columbia University  Never got an NIH grant  Now building planes as a hobby.....  3 most cited papers (from a total of 190 publications): 1) Still W.C.; Kahn M., Mitra A., Rapid Chromatographic Technique for Preparative Separations with Moderate Resolutions, J. Org. Chem., 1978, 43(14), 2923 Times Cited: ) Mohamadi F.; Richards N.G.J; Guida W.C.; Still, W.C., Macromodel -an Intergrated Software System for Modeling Organic and bioorganic Molecules Using Molecular Mechanics, J. Comp. Chem., 1990, 11(4), 440 Times Cited: ) Still, W.C.; Tempczyka, A.; Hawley R.C. Semianalytical Treatment of Solvation for Molecular Mechanics and Dynamics, JACS, 1991, 112(16), 6127 Times Cited: 1511

46 Prof. Louis Barriault Graduate students Jason Poulin Minaruzaman Kassandra Lepack Francis Barabé Christiane Grisé-Bard Eric Beaulieu (Past) Marie-Christine Brochu (Past) Steve Arns (Past) Undergrads Anne-Catherine Bédard Grabriel Bellavance Jean-Francois Vincent-Rocan Olivier Gagné Patrick Lévesque (Past) 46

47 Monensine  17 asymmmetric centers, 26 carbon backbone  theoretically stereoisomers can exist  Polyether antibiotics constitute a growing class of naturally occurring ionophores. Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2),

48 Retrosynthetic Pathway Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2),

49 Monensin- Chromic Acid Degradation Why degradation ? :  Called relay synthesis  Structure proof of advanced synthetic intermediates  Ex: Stereochemistry Dongwei, C.;Still, W.C.; J.Org. Chem., 1988, 53,

50 Monensin – Further Degradation Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2),

51 Monensin- Retrosynthetic Scheme Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2),

52 Monensin- Further Degradation Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2),

53 Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117 Monensin- Further Degradation 53

54 Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117 Monensin- Retrosynthetic Scheme 54

55 Forward Synthesis Collum, D.B.; McDonald, J.H.III; Still, W.C., JACS, 1980, 102(6),

56 Collum, D.B.; McDonald, J.H.III; Still, W.C., JACS, 1980, 102(6), 2118 Forward Synthesis 56

57 Collum, D.B.; McDonald, J.H.III; Still, W.C., JACS, 1980, 102(6), 2118 Forward Synthesis 57

58 Collum, D.B.; McDonald, J.H.III; Still, W.C., JACS, 1980, 102(6), 2120 Forward Synthesis 58


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