Clark W. Still Career in Review

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

2. Who Is He ? • 1946 - Born in Augusta, Georgia • 1964 - Graduated from Winter Haven High School in Polk Country, FL • 1969- B.Sc. At Emory University • 1972- Ph.D. At Emory University – Advisor was David Goldsmith • 1973- 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

3. Graduate Studies

4. His Graduate Work (1969-72) • Diborane Reductions of Oxygen Heterocycles • Hydroboration-Oxydation Products of Oxygen Heterocycles W. C. Still and D.J. Goldsmith, J. Org. Chem., 1970, 35 (7), 2282

5. His Graduate Work (1969-72) • The decarboxylative elimination reaction of β,γ- epoxyacids • to make allylic alcohols • Bicyclic Intermediate for Trichothecane Synthesis • Exploitation of an Enolate as a Protecting Group • Tandem sequence involving bis alkylation 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, 4807

6. His Graduate Work (1974-75) Most of his work with Prof. Stork concentrated of the formation of Gibberellic Acids B-C-D ring: • Reductive cyclization of Ethynylketones • 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 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

7. Independent Researcher Vanderbilt University Columbia University

8. His Work at Vanderbilt University (1975-76) • Organocuprates and the development of a new highly selective stereoselective alkylation agent to produce axial alcohols “ 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.” • Conjugate Addition of trimetylsilyllithium – Axial addition is highly favoured Macdonald, T.L.; Still, W.C.; JACS, 1975, 97(18), 5280 & Still, W.C., J. Org. Chem., 1976, 41(18), 3063

9. His Work at Vanderbilt University (1975-76) • AllyloxyCarbanions: • 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), 3620.

10. His Work at Vanderbilt University (1975-76) • Claisen Variant: • Tin chemistry (stannylation/destannylation) • α-AlkoxyOrganolithium Reagents Still, C.W.; Schneider, M.J., JACS, 1977,99(3), 948 & Still, C.W., JACS, 1978, 100 (5), 1481

11. His Work at Vanderbilt University (1975-76) • Tri-alkyl tin anions undergo high yield conjugate addition to α,β-enones to give • the regiospecificenolate 42 40 41 • Alkylstannanes are smoothly oxidized by chromic anhydride/pyridine to the • corresponding ketone • Alkylation and oxidation – efficient dialkylativeenone transposition Still, C.W., JACS, 1977, 99(14), 4836

12. Columbia University (1977-1998) • 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), 2923

13. Columbia University (1977-1998) • 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.” • Monensin – Polyether antibiotic and naturally occurring ionophore • 17 asymmmetric centers, 26 carbon backbone • Theoretically 131 072 stereoisomers can exist 1) Still, C.W.; Kahn, M.; Mitra, A., J. Org. Chem., 1978, 43(14), 2923 2) Still, W. C.; Dongwei, J. Org. Chem., 1988,53, 4643 3) Still, W.C.; MacDonald, J.H.III; Collum, D.B.; JACS, 1980, 102(6), 2117 4) Still, W.C.; MacDonald, J.H.III; Collum, D.B.; JACS, 1980,102(6), 2118 5)Still, W.C.; MacDonald, J.H.III; Collum, D.B.; JACS, 1980, 102(6), 2120

14. Columbia University (1977-1998) • Direct Synthesis of Z-unsaturated esters; a useful modification of the • Horner-Emmons Olefination Horner-Wadsworth-Emmons Still – Gennari Modification 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

15. Z-trisubstitutedAllylic 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), 226

16. Z-trisubstitutedAllylic Alcohols via the Wittig Reaction • Noβ-oxidoYlide intermediate or n-BuLi required α Counterion effect Phosphoniumfluoroborate Vs Phosphonium halide α ‘ α-santalol Sreekumar, C.; Darst, K.P.; Still, W.C., J. Org. Chem, 1980, 45(21), 4260

17. Columbia University (1977-1998) • Dichlorocarbenecyclopropanation 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), 2094

18. Columbia University (1977-1998) • A highly stereoselective synthesis of trans epoxides via arsoniumYlides High stereoselectivity for trans epoxide ≥ 50:1 • Remote 1,3-, 1,4-,and 1,5- asymmetric induction. A stereoselective approach to acyclic • diols via Cyclic Hydroboration Still, W.C.; Novack, V. J., JACS,1981, 103(5), 1283 & Still , W.C..; Darst, K.P., JACS,1980, 1021(24), 7385

19. Columbia University (1977-1998) • Synthesis of MacrocyclicTrichothecanoids: Baccharin B5 and Roridin E 85 86 87 88 • 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), 3981

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. Conformations – Transannular non bonded repulsions and high-energy torsional arrangements must be minimized Still, W.C.; Galynker, I., Tetrahedron,1981, 37(23), 3981

21. 8-Membered Ring

22. 9-Membered Rings Still, W.C.; Galynker, I., Tetrahedron, 1981, 37 (23), 3981

23. Peripheral vsAntiperipheral Attack • 3D Structure – sp2 centers are perpendicular to the plane of the ring Cis-cyclohexene Cis- cyclooctene Cis- cyclodecene • 2 faces of π-system are sterically different • Peripheral attack preferred Still, W.C.; Galynker, I., Tetrahedron, 1981, 37 (23), 3981

24. Periplanone B- Total synthesis and structure of the Sex Excitant Pheromone of the American Cockroach • Female species of Periplanetaamericana, 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), 2493

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), 2495

26. Periplanone B – Stereocontrol Approach X Peripheral Attack • 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

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

28. Periplanone B – First Diastereomer First Disatereomer • 300-MHz NMR strongly suggest : • Only difference is the configuration of the isopropyl group. • Pseudo-axial in X: (J7-8 = 5, J8-9a = 7.5, J8-9b= 2 Hz) • Pseudo-equatorial (Periplanone B) : (J7-8 = 10, J8-9a = 10, J8-9b= 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

29. Periplanone B – Second Diastereomer • NMR of 116 is very different than Periplanone B • Transannular -O- interaction is replaced by a more severe -CH2- 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

30. Periplanone B -Third Diastereomer • Construction of the stereoisomeric C-2 – C-3 cisepoxide: • 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), 2495

31. Periplanone B -Third Diastereomer • 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

32. Columbia University (1977-1998) • 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), 3075

33. Columbia University (1977-1998) • Complex Synthetic chemical libraries indexed with molecular tags • A new generation of Fluorescent chemosensors demonstrate improved analyte detection • sensitivity and photobleaching resistance. 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), 10922 & 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

34. Complex Synthetic Chemical Libraries Indexed with Molecular Tags • Spaciallysegrated arrays • Only small libraries • 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. 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), 10922

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 = 1 048 576 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), 10922

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), 10922

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), 4723

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: • Receptor – site that selectively binds an analyte • Redout mechanism – signals binding. • Chemosensor for tripeptides in CHCl3. • 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, 279 5352), 851

39. Chemosensors Chemosensor A Chemosensor B Dabcyl N-hydrosuccinamide ester Q = COC6H4N=NC6H4NMe2 F = (CH2)2NH-SO2C10H6NMe2 Dansylsulfonamide of ethanolamine

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), 851

41. New FluorencentChemosensors 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. 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. New FluorencentChemosensors with Improved Photobleaching Resistance Dansylfluorofore moiety Known to undergo photobleaching 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. DansylvsAcridone Moiety • Replacement of the dansylfluorophore moiety with an acridone derivative 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. New FluorencentChemosensors with Improved Photobleaching Resistance Receptor binding saturation experiment. • Receptor is now more resistant to fluorophorephotobleaching. • No significant change in binding saturation characteristics • Acridone exhibits increased fluorescence upon binding 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 • Still was clearly ahead of his time • - Total synthesis - Methodology • - Computational chemistry - Chemical biology etc.. • 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: 7419 • 2) 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: 2788 • 3) 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 • Retired at 53 years old – Emeritus professor at Columbia University • Never got an NIH grant • Now building planes as a hobby.....

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

47. Monensine • 17 asymmmetric centers, 26 carbon backbone • theoretically 131 072 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), 2117

48. Retrosynthetic Pathway Collum, D.B.; McDonald, J.H. III; Still, W. C., JACS, 1980, 102(2), 2117

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, 4641

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