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

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

Graduate Studies

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

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

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 Ethynyl ketones Add reference for second part. 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

Independent Researcher Vanderbilt University Columbia University

His Work at Vanderbilt University (1975-76) Organo cuprates 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

His Work at Vanderbilt University (1975-76) 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 -First example od allyloxycarbanion cyclisation. High regio and stereoselectivity - one of the first examples of the nonphotochemical oxetane synthesis. Still C.W., Tetrahedron Letters, 1976, 25, 2115 & Still, W.C.; Macdonald, T.L.; J. Org. Chem., 1976, 41(22), 3620.

His Work at Vanderbilt University (1975-76) Claisen Variant: Read paper for claisen variant. Add diagrams for tin. At the time most carbon carbon bond formations were done via a carbonyl group behaving like a hydroxyl0substituted carbocation, but there was almost no examples of the oposite charge affinity pattern because there was alack of regent availability to do so. - Still envisionned that a general preparation of a masked carbinyl carbanion would be the best way to proceed and so he divised a a way to make it via a alpha-alkoxy organostannane. - he found that generating Bu3SNLI was eisier with tributyltin hydride and LDA than with hexabutyl ditin with n-buli or MeLi. - One problem he had envisioned was that anion-destabilizing alkyl substituents R might be expected to bias the equilibrium between SnBu3 and Li. But they report that both alkyl and aryl substituted alpha-alkoxy organolithium reagents produce the desired product in high yields. Ask for equilibrium explanation. 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), 1481

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

Columbia University (1977-1998) Anionic [2,3]-sigmatropic rearrangements Still developped a highly efficient way to synthesize stereoselectively a C18 Cepcropia hormone. Here i will demonstrate how he got the to core of the molecule. Synthesis of X tool 3 steps. From that he was able to do a 2, 3 sigmatroips RR to give the selective Z-homoallylic alcohol product X. The stereoselctivity comes from the transition state that has the speudo axial R group, minimizing the strain and giving the trans product as opposed to the cis product. Here they report a efficient [2,3]-sigmatropic Wittig rearrangement which produces 2-trisubstituted homoallylic alcohols in high yields and with >95% stereoselectivity. This reaction is the first example of a [2,3]-sigmatropic rearrangement having a transition state which prefers pseudoaxial substitution 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

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

Columbia University (1977-1998) Direct Synthesis of Z-unsaturated esters; a useful modification of the Horner-Emmons Olefination Horner-Wadsworth-Emmons Amongs his many total syntheses of natural products one of his most famous was that of Periplanone –B. His work on macrocyclo conformation and reactivity was one of the key concepts demonstrated in the synthesis. For example he demonstrated that the peripheral attack of the double bond would be favores because the anti-periferal attack is shielded by the ring. To elucidate the structure and determine the relative stereochemistry of periplanone –B he synthesiszed 3 of the 4 stereoisomers of this natural product. 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

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), 226

Z-trisubstituted Allylic Alcohols via the Wittig Reaction No β-oxido Ylide intermediate or n-BuLi required α Counterion effect Phosphonium fluoroborate Vs Phosphonium halide α ‘ In general substitution at the alpha position of the ketone tends to improve the stereoselectivity and at he alpha’ it tends to diminish it. Chemical yield are very high provided that the atoms being joined are relatively unhindered. - The ylide may be substituted by various alkyl chains so long as the carbon beta to the phosphorous is not branched. α-santalol Sreekumar, C.; Darst, K.P.; Still, W.C., J. Org. Chem, 1980, 45(21), 4260

Columbia University (1977-1998) 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), 2094

Columbia University (1977-1998) A highly stereoselective synthesis of trans epoxides via arsonium Ylides 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

Columbia University (1977-1998) Synthesis of Macrocyclic Trichothecanoids: 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

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

8-Membered Ring

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

Peripheral vs Antiperipheral 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

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), 2493

Periplanone B – First Diastereomer Except for the geometries of the endocyclic epoxide and olefin (cis and trans, respectively) the relative stereochemistry in periplanone-B was unknown. Therefore a flexible route to i had to be developed which allowed for the stereochemical uncertainties at C-1, C-2, and C-8. The basic plan called for the preparation of an advanced cyclodecanoid intermediat which could be converted in a stereorational fashion to each possible diastereomer of i for spectral and biological evaluation. 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

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

Periplanone B – First Diastereomer Corey-Chaykovsky epoxidation. The Corey–Chaykovsky reagent, dimethylsulfonium methylide 1, generated from a trimethylsulfonium salt and a base is known to react with an aldehyde or a ketone to give an epoxide by an overall methylene insertion.1 Excess reagent could lead to the formation of allylic alcohol by further addition of the ylide on the epoxide.2 Spectral comparison with authentic Periplanone-B concludes they are Unidentical

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

Periplanone B – Second Diastereomer Peterson-Chan olefination and epoxidation didn’t work. The latter was a problem because the double bond 6-7 was more reactive. 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

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), 2495

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

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

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

Complex Synthetic Chemical Libraries Indexed with Molecular Tags Spacially segrated 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

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

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

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

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

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

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

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 This binding interaction induces a change in distance between a fluorophonre attached to one of the macrocyclic arms and a quenching moiety attached to the core. The are engaged in a Forster typer interation. (FRET – fluorescence resonance energy transfer_) 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

New Fluorencent Chemosensors with Improved Photobleaching Resistance Dansyl fluorofore 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

Dansyl vs Acridone Moiety Replacement of the dansyl fluorophore 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

New Fluorencent Chemosensors with Improved Photobleaching Resistance 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 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

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.....

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)

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

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

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

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

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

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

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

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

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

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

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

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