Academ Present 022009 001[1]
Upcoming SlideShare
Loading in...5
×
 

Academ Present 022009 001[1]

on

  • 723 views

 

Statistics

Views

Total Views
723
Views on SlideShare
715
Embed Views
8

Actions

Likes
1
Downloads
1
Comments
0

3 Embeds 8

http://www.linkedin.com 6
http://www.slideshare.net 1
https://www.linkedin.com 1

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

Academ Present 022009 001[1] Academ Present 022009 001[1] Presentation Transcript

  • Prolog Overview publications
    • JOURNAL PUBLICATIONS/PATENTS
    • Pieter Otten and Benjamin Littler, “Heat Flow Profiling as a Tool to Assess the Scale-up of Biphasic Reaction”, In Progress for Organic Process Research and Development
    • “ Fluorescent Magnesium Indicators”, Robert E. London, Pieter A. Otten , and Louis A. Levy. US Patent 6,706,528
    • Yu, J.; Otten, P .; Ma, Z.; Cui, W.; Liu, L.; Mason, R. P., “Novel NMR Platform for Detecting Gene Transfection: Synthesis and Evaluation of Fluorinated Phenyl b-D-Galactosides with Potential Application for Assessing LacZ Gene Expression”. Bioconjugate Chemistry, 15(6); 1334: 2004
    • Weina Cui, Pieter Otten , Yingming Li, Kenneth Koeneman, Jianxin Yu, and Ralph P. Mason, “Novel NMR Approach to Assessing Gene Transfection: 4-Fluoro-2-Nitrophenyl-β-D-Galactopyranoside as a Prototype Reporter Molecule for β-Galactosidase”. Magnetic Resonance in Medicine, 51 (3); 616:2004
    • Pieter A. Otten , Robert E. London, and Louis A. Levy, “4-Oxo-4 H -quinolizine-3-carboxylic Acids as Mg2+ Selective, Fluorescent Indicators”. Bioconjugate Chemistry, 12; 203: 2001
    • Pieter A. Otten , Robert E. London, and Louis A. Levy, “A New Approach to the Synthesis of APTRA Indicators”. Bioconjugate Chemistry, 12; 76: 2001
    • Pieter A. Otten , Syb Gorter, and Arne van der Gen, “A Structural Study of Selenobenzamides. Crystal Structures and Dynamic 13C NMR”. Chem. Ber./Recl. Trav. Chim. Pays-Bas, 130; 49: 1997
    • Pieter A. Otten , Honorine M. Davis, Jan Hein van Steenis, Syb Gorter, and Arne van der Gen, “Stereoselective Synthesis of ( Z )-1-Chlorovinyl Sulfoxides”. Tetrahedron, 53; 10527: 1997
    • Pieter A. Otten , Njord Oskam, and Arne van der Gen, “A Horner-Wittig Approach to S,N -Ketene Acetals. Acid-catalyzed Hydrolysis of S,N -Ketene Acetals to ( S )-Thioesters”. Tetrahedron, 52; 11095: 1996
    • Pieter A. Otten , Honorine M. Davis, and Arne van der Gen, “A Horner-Wittig Synthesis of 1-Chlorovinyl Sulfoxides”. Tetrahedron Letters, 36; 781: 1995
    • Pieter A. Otten and Arne van der Gen, “The Reaction of  -Amino-substituted Diphenyl Phosphine Oxide Anions with Elemental Sulfur and Selenium. A New Route to Thio- and Selenoamides”. Recl. Trav. Chim. Pays-Bas, 113; 499: 1994
  • Horner-Wittig Reagents in Sulfur and Selenium Chemistry Pieter Otten and Arne van der Gen Leiden Institute of Chemistry Leiden University, The Netherlands P S Se
  • Advantages of Diphenylphosphine Oxides
    • Crystalline materials
    • Reactive anions
    • Superb anion stability
    • Excellent stereoselectivity
    • Water soluble by-product
    View slide
  • Thioamide Synthesis Aminomethylphosphine oxides, excellent reagents for enamine formation, show a unique reactivity towards chalcogens to form amides R = aryl: reaction at r.t R = alkyl: reaction at 0 o C to quell deprotonation of formed thioalkanamides by the HW reagent View slide
  • Selenoamide Synthesis “ Red selenium”, Se 8 , more reactive than metallic or gray Se; allows isolation of acidic selenoalkanamides at lower temperatures Reaction is sluggish at ambient.
  • Mechanistic Considerations One eq. of S gives < 50% yield, recover phosphine oxide All intermediates isolated and characterized. Mass balance accounted for. Intermediate trapped at low temperatures with MeI Independently confirmed
  • Crystal Structure Selenobenzamides Amino group reduces dihedral angle  C=Se: 1.840 Å C-N: 1.331 Å  = 53.3º C=Se: 1.824 Å  = 81.1º C(5) is sp 2 -hydrid.
  • Other Selenocarbonyls C=Se of selenoamides close to other N- or C=C-conjugated selenocarbonyls
  • VT 13 C NMR Study: Rotational Barriers C=S and C=Se strongly e-withdrawing groups,  + p fits only More polarizable Se more sensitive to  + p than S o = Se * = S Eyring eq.:  G* rot = 19.5T c x [9.971 + log(T c /  )]
  • Synthesis of (Thiomethyl)- and (Selenomethyl)phosphine Oxides
  • Synthesis of Vinyl Selenides
    • >98% E-selectivity if R 1 , R 3 = aryl
    • Reacts w/ acidic ketones, HW reagent weakly basic
    • E/Z ratio by NMR and GC
  • Mechanistic Considerations (Curtin-Hammett Principle) Trapped HW-adducts (R3 = Ph -60 o C, H 2 O): R1 = n-Pr: pro(E)/pro(Z) = 1/1, quant. R1 = c-Hex: pro(E)/pro(Z) = 1/1+ 22% (E)-vinyl selenide! Sterics facilitate elimination, k E increases R1 = phenyl, pro(E)/pro(Z) = 3/2. quant, pro-(E) and pro(Z) must rapidly equilibrate via reverse to aldehyde and/or epimerization and (E)-isomer is thermodynamic sink pro-(E) Pro-(Z)
  • Do HW adducts equilibrate? No vinyl selenide derived from propionaldehyde observed: no equilibration via reverse reaction with aliphatic aldehydes. Cannot rule out epimerization. Fast equilibration with aromatic aldehydes to explain discrepancy between pro-(E) and pro-(Z) ratio for isolated HW adduct (3/2) and strong E-selectivity for completed HW reaction.
  • Alternate Intermediate Warren proposes this late-stage intermediate to explain high pro-(Z) selectivity for simple alkyl phosphine oxides (R1 = alkyl) Pro-(E) Six-centered transition state. R1 equatorial to avoid 1,3-interaction with equatorial Ph. Low energy difference between SeR3 equatorial or axial, reflected by observed low stereoselectivity In HW-adducts. Pro-(Z)
  • Formation of 1-Chlorovinyl Sulfoxides A New Class of Compounds (1994)
  • >96% Z-selectivity if R 2 = aryl, alkenyl and/or R 1 = aryl
  • Crystal Structure Confirms Z-geometry P -1 , a = 13.3146, b = 11.326, c = 9.395 Å;  = 125.15  = 97.88,  = 96.76; V = 1097.45 Å 3 , Z = 4,  = 1.396 kg/dm 3
  • Mechanistic Considerations Phosphine oxide anion and carbonyl are in equilibrium w/ adduct. Fast when R1 = anion stabilizing aryl Rotation sets up for the oxaphosphetane. Sterics favor pro-(Z) intermediate Thermodynamic sink Elimination fast if R2 stabilizes double bond: aryl, vinyl
  • Mechanistic Considerations: Alternate Approach Surprisingly poor stereochemistry with bulky c-hexanecarboxaldehyde Li + ligated between P=O and S=O. R1 equatorial to avoid axial Ph. Aldehyde approaches with R2 pointing away from axial Ph. Must be an intermediate trough on the energy surface
  • Michael Addition P 2 1 , a = 6.371, b = 7.646, c = 12.364 Å;  = 90.0  = 98.45,  = 90.0; V = 595.7 Å 3 , Z = 2,  = 1.50 kg/dm 3
  • Mechanistic Considerations A compact sodium complex is formed, dictating stereochemistry Malonitrile gives 1:1 mixture of diastereoisomers
  • Synthesis of S , N -ketene Acetals and Thioesters R2=aryl: pure ketene acetale after extractive work-up only. R2=alkyl, contaminated w/ condensation products. Carry thru to thioester for good use
  • Goals Achieved
    • User-friendly access to thio- and selenoamides
    • Proved role of substitution on aryl ring in
    • conjugation in selenobenzamides
    • Stereoselective formation of 1-chlorovinyl sulfoxides
    • Demonstrated diastereoselective Michael addition
    • on 1-chlorovinyl sulfoxides
    • General synthesis of vinyl selenides
    • Facile synthesis of S , N -ketene acetals
    • Homologation of aldehydes to (S)-thioesters
  • Fluorescent Magnesium Indicators Pieter Otten, Louis Levy, and Robert London, National Institute of Environmental Health Sciences, RTP, NC
  • Physiological Importance of Mg 2+
    • Mg 2+ , most abundant divalent cation:
    • 300 enzymatic reactions
    • Energy production
    • Hormone regulation
    • DNA synthesis
    • Muscle contraction
    • Mg-deficiency linked to:
    • Atherosclerosis
    • Hypertension
    • Kidney stones
    • Migraines
    • Psychiatric problems
  • Ideal, Fluorescent Mg 2+ Indicator However, fluoresc. behavior of difficult to predict
    • Selective for Mg
    • Ratioable
    • Polycarboxylate
    • Excitation > 340 nm
    • Emission > 500 nm
    • Photostable
    • Non-toxic
  • Why APTRA (Aminophenol Triacetic Acid)? At physiol. Mg 2+ , BAPTA binds two ions. Cut BAPTA in half to get to APTRA.
  • Pd coupling: fast, one step approach to quickly invest structural diversity
  • Suzuki Coupling K D, Mg = 2.3 mM K D, Ca = 70  M K D, Mg = 2.1 mM K D, Ca = 28  M K D, Mg = 1.8 mM K D, Ca = 17  M
  • Fluorescence Excitation Titration Response to Mg and Ca is not identical, which was often assumed to correct for Ca-spikes
  • Synthesis of 4-Oxo-4 H -quinolizine-3-carboxylates Known complexers of Mg 2+ to shut down bacterial DNA-gyrase w/ K D = 1 mM Explore reactivity to diversify quickly
  • Electrophilic Aromatic Substitution
  • 4-Oxo-4 H -quinolizine-3-carboxylic Acids Compare:
  • Representative Examples; Tri-acids
  • Synthesis Bromo-substituted Triacid Introduce 3 rd ester, as decarboxylation could not be prevented
  • Fluorescence Emission Spectrum The first Mg-selective, ratioable fluorophore!
  • Selected Fluorophores Emission > 500 nm Ratioable
  • Suzuki Coupling
    • Poor aq solubility
    • Future exploration:
    • Buchwald
    • Libraries of boronic acids anno 2009
  • Goals Achieved:
    • Developed a general synthesis of fluorescent APTRA indicators for intra-cellular Mg 2+ and Ca 2+
    • Showed that their response to Mg 2+ and Ca 2+ are not identical
    • Designed, synthesized, and evaluated new, ion-selective ratioable, fluorescent indicators for Mg 2+ based on 4-oxo-4H-quinolizine-3-carboxylic acids
  • NMR-active, Fluorinated Reporter Molecules Pieter Otten and Ralph P. Mason Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX
  • 6-FPOL pK a = 8.2
  • 6-FPAM pK a = 7.05
  • CF 3 -POL Triple the fluorines, triple the signal Does not penetrate rbc membrane
  • Fluorinated Gene Reporter Saline at 30 o C (♦) Plasma at 30 o C (□) Plasma at 37 o C (Δ) Top: pH = 4.5; t = 30 o C; β-gal ( Aspergillus Oryzae ) Bottom: pH = 7.3 -> 6.8; t = 37 o C; β-gal ( E. Coli ) pK a = 6.85