John T. Welch

Organofluorine Chemistry


Organopentafluorosulfonyl Chemistry

The pentafluorosulfanyl (SF5) group is one of only a very few truly new functional groups to be introduced to the armentarium of the synthetic organic chemist in the last 100 years. The pseudooctahedral symmetry of the SF5 group, presenting a square pyramid of electron density, as defined by the fluorine ligands, is not otherwise known to the medicinal or pharmaceutical chemist. However only with the recent availability of the necessary reagents and building blocks has this functional group found applications as an aromatic substituent in agrochemicals, pharmaceuticals and liquid crystals. In aliphatic chemistry, pentafluorosulfanylated materials are even more rarely encountered with applications largely limited to polymer or oligomer preparations. The SF5 group is profoundly electron withdrawing but with the highly polarizable carbon-sulfur bond may directly influence reactivity in a manner different from that associated with the trifluoromethyl group.


Treflan Analogs

The synthesis of 2,6-dinitro-4-pentafluorosulfanyl-N,N-dipropylaniline, 2, was achieved in a straightforward manner from commercially available 1-nitro-4-pentafluorosulfanylbenzene. In post-emergence screening 2 was found to be approximately twice as potent as trifluralin with the same general spectrum of activity. In contrast, in pre-emergence tests, 2 was nearly 5 fold more potent against quackgrass and crabgrass.

References
  • Synthesis and Herbicidal Activity of a Pentafluorosulfanyl Analog of Trifluralin
    D.S. Lim, J.-S. Choi, C. S. Pak and J. T. Welch, J. Pesticide Science, 2007, in press

Serotonin Analogs

The trifluoromethyl group of fluoxetine and fenfluramine and norfenfluramine was substituted by the pentafluorosulfanyl group. On examination of the efficacy of the pentafluorosulfanyl containing compounds as inhibitors of 5-hydroxytryptamine receptors, it was found that substitution could lead to enhanced selectivity and in the case of the pentafluorosulfanyl analog of fenfluramine, led to significantly enhanced potency against the 5-HT2b, 5-HT2c and 5-HT6 receptors.

References
  • The synthesis and biological activity of pentafluorosulfanyl analogs of fluoxetine, fenfluramine and norfenfluramine.
    D.S. Lim and J.T. Welch, 2007, under review

Fluoroolefin Peptidomimetics

The fluoroolefin dipeptide isostere (peptidomimetic) has been found to be a superior isoelectronic and isosteric replacement for the peptide amide bond on the basis of its planar geometry and direction of polarization. The fluoroolefin isoster not only possesses similar steric demand, bond lengths and bond angles to those of the amide bond but also a fixed conformation. The high electronegativity of fluorine can introduce a pronounced polarity in an olefin unit, in a direction similar to that created by the carbonyl oxygen of the amide bond. Fluoroolefin can efficiently mimic the electronic features of the amide bond. We have described the synthesis of a series of fluoroolefin containing dipeptide isosteres, as inhibitors of Dipeptidyl peptidase IV (DPP IV, CD26), with Ki in the submicromolar range and as components of tetrapeptide substrates for the cyclosporin binding protein cyclophilin.

References
  • Fluoroolefin Peptide Isosteres
    J.T. Welch in Fluorine and Health, ed. A. Tressaud and G. Haufe, Elsevier-Science, Amsterdam, 2007 in press.
  • Fluoroolefin Peptide Isosteres
    J. T. Welch and T. Allmendinger in Peptidomimetic Protocols ed. W. M. Kazmierski, Humana Press, New Jersey, 1999, pp. 375-384.
  • Fluoroolefin Isosteres as Peptidomimetics
    J. T. Welch, J. Lin, L. G. Boros, B. DeCorte, K. Bergmann, and R. Gimi in Biomedical Frontiers of Fluorine Chemistry ed. I. Ojima, J. R. McCarthy, J. T. Welch, ACS Books, Washington, D.C., 1996, pp. 129-142.

Dipeptidyl Peptidase IV (CD26) Inhibitors

Dipeptidyl-peptidase IV (DPP IV, EC 3.4.14.5, CD26), designated CD26, is an extracellular membrane-bound enzyme expressed on the surface of several cell types, in particular CD4+ T-cells,as well as on kidney, placenta, blood plasma, liver, and intestinal. On T-cells, DPP IV has been shown to be identical to the antigen CD26. CD26 is expressed on a fraction of resting T cells at low density but is strongly upregulated following T-cell activation. Recent results indicate that CD26 is a multifunctional molecule that may have an important functional role in T-cells and in overall immune system modulation. CD26 is associated with other receptors of immunological significance found on the cell suface such as the protein tyrosine phosphatase CD45 and adenosine deaminase (ADA). In our laboratories we have prepared several DPPIV inhibitors as shown below with excellent potency yet retaining sufficient stability for ready investigation.

References
  • Inhibition of dipeptidyl peptidase IV (DPP IV) by 2-(2-amino-1-fluoro-propylidene)-cyclopentanecarbonitrile, a fluoroolefin containing peptidomimetic K. Zhao, D. S. Lim, T. Funaki and J. T. Welch, Bioorg. Med. Chem. 2003, 11, 207-215. abstract
  • Inhibition of Dipeptidyl Peptidase IV (DPP IV) by Fluoroolefin Containing N-Peptidyl-O-hydroxylamine Peptidomimetics
    J. T. Welch and J. Lin, Proc. Nat. Acad. Sci., 1998, 95, 14020-14024. abstract

Pyrazinamide Analogs and the Mechanism of Action of an Antituberculous Agent

The resurgence of tuberculosis (TB) coupled with the emergence of multi-drug resistant strains (MDR-TB) necessitates that novel therapies be developed. One strategy for the discovery of novel drugs is to identify the targets of effective agents. Pyrazinamide (PZA), one such agent, has a unique sterilizing activity. It is the inclusion of PZA with isoniazid and rifampin in current treatment regimens that constitutes the basis for 6-month short course therapy for M. tuberculosis (Mtb). PZA efficacy depends upon conversion of PZA to pyrazinoic acid, (POA) the active agent. The lack of pyrazinamidase, an enzyme that converts PZA to POA, confers resistance to PZA. PZA is effective only against Mtb among the mycobacterial species, and then is effective only at an acidic pH. Although the mechanism of PZA activation and resistance is known the precise mycobacterial function that is inhibited remains unknown. Using 5-Cl-PZA as a selective agent for mycobacteria, we have found that 5-Cl-PZA and PZA inhibit fatty acid synthetase I FASI in Mtb. FASI has been purified from M. smegmatis 2700 mc2, a recombinant strain where the native fas 1 gene has been deleted and replaced with Mtb fas 1 gene. Following purification, FASI enzymatic activity was measured using a spectrometric assay which monitors NADPH oxidation. Both 5-Cl-PZA and PZA showed concentration and substrate dependence consistent with competitive inhibition of FASI. These results were validated by a radiolabeled fatty acid assay. Preliminary studies have shown improved activity of PZA analogs against Mtb in infected human monocyte-derived macrophages and in murine models of infection.

A number of substituted pyrazinoic acid esters (POE) have been prepared providing considerable insight into the effect of structure on activity. These modifications have been very successful in expanding the activity of pyrazinamide to include M. avium and M. kansasii, organisms normally not susceptible to PZA. Several of these compounds (2'-octyl 5-chloropyrazinoate, n-octyl 5-chloropyrazinoate and n-propyl 5-chloropyrazinoate) have activities 100 to 1000 fold greater than that of pyrazinamide against M. tuberculosis. To afford a better comparison between the substituent effects of the POE and PZA, a number of substituted PZA analogs have been prepared (Table 1). Interestingly, some of these compounds not only show an expanded spectrum of antimycobacterial activity, e.g., they are active against M. avium, but they are also active against the PZA-resistant strain of M. tuberculosis, ATCC 35828. Particularly, remarkable was the activity of 5-chloropyrazinamide against the PZA-resistant organisms. Comparison of the activity of 5-chloropyrazinamide, PZA, POA and 5-chloropyrazinoic acid, revealed that 5-chloropyrazinamide is considerably more active than PZA against a number of different isolates. Most significantly the lower activity of 5-chloropyrazinoic acid relative to POA suggests that the activity of the 5-chloropyrazinamide against PZA resistant organisms may not be related to an increase in the potency of the acid formed on amidase action.

This work is collaborative with M. H. Cynamon, VA Syracuse, NY, O. Zimhony Kaplan Medical Center, The Hebrew University , Rehovot Israel, W. R. Jacobs, Albert Einstein College of Medicine, Bronx, NY and A. Shekhtman of the Chemistry Department, University at Albany.

References
  • Inhibition of M. tuberculosis fatty acid synthetase I isolated from M. smegmatis by pyrazinamide analogs
    S. C. Ngo, O. Zimhony, W. J. Chung, H. Sayahi, W. R. Jacobs, Jr. and J. T. Welch, Antimicrobial Agents Chemother. 2007, in press
  • Pyrazinoic Acid and Its n-Propyl Ester Inhibit Fatty Acid Synthase Type I in Replicating Tubercle Bacilli
    O. Zimhony, C. Vilchèze, M. Arai, J. T. Welch, and W. R. Jacobs Jr., Antimicrobial Agents Chemother., 2007, 51, 752-754.
  • Pyrazinamide inhibits fatty acid synthetase 1 (FAS1) of Mycobacterium tuberculosis
    O. Zimhouny, J. S. Cox, J. T. Welch, C. Vilcheze, and W. R. Jacobs Jr., Nature Med., 2000, 6, 1043-1047.
  • In Vitro Antimycobacterial Activity of 5-Chloropyrazinamide
    R. J. Speirs, J.T. Welch and M. H. Cynamon, Antimicrobial Agents and Chemotherapy, 1998, 42, 462-463.
  • Quantitative Structure-Activity Relationships for the in vitro Antimycobacterial Activity of Pyrazinoic Acid Esters
    K. E. Bergmann, M. H. Cynamon, and J. T. Welch, J. Med. Chem. 1996, 39, 3394-3400.
  • Pyrazinoic Acid Esters with Broad Spectrum In vitro Antimycobacterial Activity
    M. H. Cynamon, R. Gimi, C. A. Sharpe, K. E. Bergmann, F. Gyenes, and J. T. Welch, J. Med. Chem.. 1995, 20, 3902-3907.
  • In Vitro Mycobacterial Activity of n-Propyl Pyrazinoate Against Pyrazinamide Resistant Mycobacterium tuberculosis.
    R.J. Speirs, J.T. Welch, and M.H. Cynamon. Antimicrob. Agents Chemother. 1995, 39, 1269-1271.

Genetically Engineered Peptides

The preparation of genetically engineered protein-based polymers, where the polypeptides can be prepared with precise control of the sequence, molecular weight and stereochemistry, is an exciting and very promising area of polymer chemistry. A unique aspect of genetically engineered polymeric materials is that the preparation of the biochemical polymer template, synthesis of the coding DNA sequence, is required only once. Subsequent biosynthetic processes obviate the need for difficult or complex synthetic manipulations. In particular, modern cloning techniques facilitate the systematic substitution of unique or regular sites in very large polymers.

Rational design of polypeptide-based polymers, that fold via established rubrics to form specific secondary structures, enables the programming of those mechanical or physical properties1,2 into the sequence that may be desirable for drug delivery or protein purification. The construction of β-sheet forming polypeptides with utility as constructs for the study of β-sheet folding, aggregation or amyloid formation is possible. Ultimately the self-assembly of such molecular building blocks may also find applications in modern nanotechnology where precise dimensional control and selective functionalization are crucial

β-Sheet forming polypeptides

The design and rapid construction of libraries of genes coding β-sheet forming repetitive and block-copolymerized polypeptides bearing various C- and N-terminal sequences was based on the assembly of DNA cassettes coding for the (GA)3GX amino acid sequence where the (GAGAGA) sequences would constitute the β-strand units of a larger β-sheet assembly. The edges of this β-sheet would be functionalized by the turn-inducing amino acids (GX). The polypeptides were expressed in E. coli using conventional vectors and were purified by Ni-NTA chromatography

References
  • Design and preparation of β-sheet forming repetitive and block-copolymerized polypeptides
    S. Higashiya, N. I. Topilina, S. C. Ngo, D. Zagorevskii, and J. T. Welch Biomacromolecules, 2007, in press

The YEHK family of polypeptides.

A de novo, genetically engineered 687 residue polypeptide consisting of repetitive polypeptides with 32 amino acid repeats, (GA)3GY(GA)3GE(GA)3GH(GA)3GK (32YEHK) expressed in E. coli has been found to form highly rectilinear, β-sheet containing fibrillar structures. Tapping-mode atomic force microscopy, deep-UV Raman spectroscopy and transmission electron microscopy definitively established the tendency of the fibrils to predominantly display an apparently planar bilayer or ribbon assemblage.

References
  • Bilayer Fibril Formation by Genetically Engineered Polypeptides. Preparation and Characterization
    N. I. Topilina, S. Higashiya, N. Rana, V. V. Ermolenkov, C. Kossow, A. Carlsen, S. C. Ngo, C. C. Wells, E. T. Eisenbraun, K. A. Dunn, I. K. Lednev, R. E. Geer, A. E. Kaloyeros and J. T. Welch Biomacromolecules, 2006, 7, 1104-1111
  • Reversible Thermal Denaturation of a 60-kDa Genetically Engineered β-sheet Polypeptide
    I. K. Lednev, V. V. Ermolenkov, S. Higashiya, L. Popova, N. I. Topilina, and J. T. Welch, Biophysical Journal, 2006, 91, 3805-3818

The YE family of polypeptides

The de novo polypeptide GH6[(GA)3GY(GA)3GE]8GAH6 (YE8) was designed and genetically engineered to form antiparallel β-strands of GAGAGA repeats. Modulation of pH enables control of solubility, folding and aggregation of YE8 by control of the overall polypeptide charge, a consequence of the protonation or deprotonation of the glutamic acid and histidine residues. YE8 exhibits all the major properties of a fibrillogenic protein providing an excellent model for detailed study of the fibrillation. At neutral pH, YE8 is soluble in disordered form, yet at pH 3.5 folds into a predominantly β-sheet conformation that is fibrillogenic. Atomic force microscopy and transmission electron microscopy indicated the formation of fibrilar aggregates on well-defined, hydrophobic surfaces. The β-sheet folding of YE8 exhibited a lag phase that could be eliminated by seeding or stirring. The strong dependence of lag time on polypeptide concentration established the limiting step in aggregation as initiation of β-sheet folding.

References
  • β-Sheet Folding of 11-kDa Fibrillogenic Polypeptide is Completely Aggregation Driven
    Natalya I. Topilina, Vladimir V. Ermolenkov, Seiichiro Higashiya, John T. Welch and Igor K. Lednev Biopolymers, 2007, in press.

Transition Metal Complex Chemistry

Precursor Design for the Chemical Vapor Deposition of Metals

The semiconductor industry knows the advantages of copper diketonates for chemical vapor deposition to produce uniform thin films of copper on substrates such as TiN, TaN, TiSiN or SiO2. To increase their volatility currently all widely used precursors contain fluorine, which has been shown to have a potential to contaminate the resulting copper films. But not only fluorine is known to increase the volatility, but also silicon containing functional groups. We developed a wide range of silicon containing metal diketonates and also developed a corresponding chemical vapor deposition process.

The ligands were synthesized via coupling of a dithiane with a bromoketone or by Claisen type condensation. The ligands were characterized by NMR, UV/VIS, IR, MS and elemental analysis. The complexes were characterized by crystallography, DSC, TGA, UV/VIS and MS. Thin films of copper were deposited using a standalone CVD stainless steel CVD reactor equipped with mass flow controllers, a resistive heater and vacuum gauges. Usual deposition parameters included a hydrogen flow of 20 sccm and a deposition temperature of a 300 °C. The copper films were characterized by four point probe, AES, XRD, RBS, SEM, FIB, TEM and XPS.
This work was collaborative with the NYS Center for Advanced Thin Film Technology.

References
  • R. U. Claessen, A. M. Kornilov, K. K. Banger, S. C. Ngo, S. Higashiya, C. C. Wells, E. V. Dikarev, P. J. Toscano, J. T. Welch, "Investigations into the Preparation of Sila-β-diketones via 2-Trimethylsilyl-1,3-dithianes: Structural Characterization of a Second Polymorph of Bis(2,2,6,6-tetramethyl-2-sila-3,5-heptanedionato)copper(II)." J. Organomet. Chem. 2004, 689, 71-81.
  • K. S. Bousman, P. J. Toscano,* and J. T. Welch, "The Effect of Sulfur on CVD Performance of Pd(II) Beta-diketonate Precursors and the Completion of a Structural trans-Influence Series: Synthesis and Structural Characterization of Pd(S,S-tmhd)2 Inorg. Chim. Acta, 2004, 357(13), 3871-3876.
  • Mark J. DelaRosa, Kulbinder K. Banger, Seiichiro Higashiya, Silvana C. Ngo, Daniel H. Hunt, Kenneth S. Bousman, Paul J. Toscano*, John T. Welch* "Structural investigations of copper(II) complexes containing fluorine-substituted β-diketonate ligands." J. Fluorine Chem. 2003, 123, 109-117.
  • M. J. DelaRosa, K. S. Bousman, J. T. Welch*, and P. J. Toscano, "Structural Investigations of Copper(II) Complexes Containing Unsymmetrical β-diketonate and Monothio-β-diketonate Ligands," J. Coord. Chem. 2003, 56, 1339-1349.
  • Synthesis of fluorinated α-sila-β-diketones and their Cu (II) complexes
    S. Higashiya, K. K. Banger, S. C. Ngo, P. N. Lim, P. J. Toscano, and J. T. Welch, Inorg. Chim. Acta, 2003, 351, 291-304.
  • MOCVD precursor engineering: The preparation and physical and structural characterization of novel non-fluorinated α-sila-β-diketonate copper(II) complexes, Cu[R'C(O)CHC(O)SiR3]2, via the facile synthesis of the α-sila-β-diketones, R'C(O)CH2C(O)SiR3
    K. K. Banger, S. C. Ngo, S. Higashiya, R. U. Claessen, C. Birringer, K. S. Bousman, P. Lim, P. J. Toscano and J. T. Welch, J. Organomet. Chem., 2005, 678, 15-32.
  • Thermal and structural characterization of a series of homoleptic Cu(II) dialkyldithiocarbamate complexes: bigger is only marginally better for potential MOCVD performance
    S. C. Ngo, K. K. Banger, M. J. DelaRosa, P. J. Toscano and J. T. Welch, Polyhedron, 2005, 22, 1575-1583.
  • Physical and structural characterization of Ce(IV) β-diketonate complexes: Evidence for geometrical isomers in the solid state
    M. J. DelaRosa, K. S. Bousman, J. T. Welch, and P. J. Toscano, J. Coord. Chem. 2002, 55, 781-793. abstract
  • Synthesis and physical and structural characterization of Ag(I) complexes supported by non-fluorinated β-diketonate and related ancillary ligands
    S. C. Ngo, K. K. Banger, P. J. Toscano and J. T. Welch, Polyhedron, 2002, 21, 1289-1297. abstract
  • MOCVD Precursors Based on Organomettalloid Ligands
    U.S. Patent 6,340,768. 22 January 2002. PCT Int. Appl. WO 0246200. J. T. Welch, S. Higashiya, K. K. Banger, S. C. Ngo. Research Foundation of the State University of New York.
  • MOCVD Precursors Based on Organomettalloid Ligands
    U.S. Patent 6,184,403. 6 February 2001. PCT Int. Appl. WO 0069863. J. T. Welch, P. J. Toscano, A. M. Kornilov, R. U. Claessen, K. K. Banger, Research Foundation of the State University of New York.
  • MOCVD Processes Using Organomettalloid Ligands
    U.S. Patent 6,099,903, 8 August 2000. PCT Int. Appl. WO 070119. J. T. Welch, P. J. Toscano, A. M. Kornilov, R. U. Claessen, K. K. Banger and A. E. Kaloyeros. Research Foundation of the State University of New York.
  • The 2,2,6,6-tetramethyl-2-sila-3,5-heptanedione route to the chemical vapor deposition of copper for gigascale interconnect applications
    R. U. Claessen, J. T. Welch, P. J. Toscano, K. K. Banger, A. M. Kornilov, E. T. Eisenbraun, and A. E. Kaloyeros, Mater. Res. Soc., Symp. Proc. (Materials, Technology and Reliability for Advanced Interconnects and Low-k Dielectrics), 2000, 612, D6.8.1 - D6.8.6.
  • K.K. Banger, A. Kornilov, R. U. Claessen, E.T. Eisenbraun, A. Kaloyeros, P.J. Toscano, and J. T. Welch. "Facile Preparation and Isolation of the Sila-β-diketone, 2,2,6,6-Tetramethyl-2-sila-3,5-heptanedione: The Influence of Silicon Substitution on the Volatility and Chemical Vapor Deposition Properties of the Cu (II) Complex." Inorg. Chem. Commun. 2001, 4, 496-500.
  • K.K. Banger, P. Lim, P.J. Toscano, and J.T. Welch, "A Facile Synthesis of 2,2,6,6-Tetramethyl-2-germa-3,5-heptandione: The Preparation and Characterization of the First Germa-β-diketonate Copper(II) Complex. Organometallics, 2001, 20, 4745-4748.

Catalyst Systems for the Syndiotactic Polymerization of Styrene

The syntheses, characterization and applications of cyclopentadienyltitanium triflate and bistriflimide complexes have been investigated. To pursue these aims the preparation of and structural investigations on a series of titanium triflate derivatives as well as the corresponding bistriflimide complexes of titanium has been explored. Our search for an alternative to the triflate ligand led us to the bistriflimide anion (N(SO2CF3)2 or NTf2). This anion appears to satisfy the criteria for a good, weakly-coordinating anion; i.e., it has a low overall charge of -1, a high degree of charge delocalization, good solubility and kinetic stability. This anion also has the potential for diversity with the use of its homologues or unsymmetrical imides such as the perfluoromethylsulfonyl perfluorobutylsulfonylimide reported by DesMarteau. The application of these complexes as catalysts lead to the efficient syndiotactic polymerization of styrene.

References
  • Preparation and characterization of half-sandwich (pentamethylcyclopentadienyl)(triflato)titanium(IV) complexes: Solid-state structural motifs and catalysis studies
    S. C. Ngo, P. J. Toscano, and J. T. Welch, Helv. Chim. Acta, 2002, 85, 3366-82. abstract
  • Triflimide Containing Catalysts for Polymerization
    U.S. Patent 5,986,120, 16 November 1999. PCT Int. Appl. WO 9940124. European Patent EP 1053259. J. T. Welch, R. U. Claessen, and S. C. Ngo, Research Foundation of the State University of New York.
  • Bistriflate Titanium Complexes for the Polymerization of Styrene
    S. C. Ngo, J. T. Welch, J. Okuda, and P. J. Toscano, Polymer Preprints, 1996, 37, 330-331.