Jakob Schneider

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Planar-Chiral Hydrogen-Bond Donor Catalysts
Synthesis, Application and Structural Analysis
Literature Seminar
Montréal, 11.04.2011

• Jakob Schneider

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Planar-Chiral Hydrogen-Bond Donor Catalysts
Synthesis, Application and Structural Analysis
Outlook

• Hydrogen-Bond Catalysis
• 2.2Paracyclophane Chemistry
• Synthesis of planar-chiral H-bond donor
  catalysts
• Organocatalytic applications
• Experimental and computational structural
  analysis
• Synthesis and Application of amino acid-based
  organocatalysts

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Organocatalysis Structural motivs
Takemoto, 2003
Rawal, 2002
L-proline-mediated enamine-catalysis 1970
Wang, 2005
Akiyama, 2004
Jacobsen, 2004
MacMillan, 2003
Fu, 2002
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Hydrogen-Bond catalysis

• Properties of hydrogen bonds

Strong Moderate Weak
Type of bonding Mostly covalent Mostly electrostatic Electrostatic
Length of H-Bond (Å) 1.2-1.5 1.5-2.2 2.2-3.2
Bond angles () 175-180 130-180 90-150
Bond energy (kcal/mol) 14-40 4-15 lt4

• Hydrogen-bond vs. Brønsted acid catalysis

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Broensted acid catalysis

• BINOL-derived phosphoric acid-catalyzed addition
  of silyl ketene acetales to
• aldimines.

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Hydrogen Bond catalysis Chiral Diols

• TADDOL-catalyzed hetero-Diels Alder reaction

• H-Bond-promoted H-Bond

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Hydrogen-Bond catalysis Development of
(thio)urea compounds

• Activation of epoxides and unsaturated ketones

• Schreiners electron-deficient N,N-diphenyl
  thiourea

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Hydrogen-Bond catalysis

• Strecker reaction of N-alkyl imines, catalyzed
  by
• Jacobsens Schiff-base thiourea

• Takemotos thiourea catalyst
• asymmetric Michael reaction

• Bifunctional mode of action

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Hydrogen-bond catalysis

• Wang, 2005 Asymmetric MBH reaction.

• Asymmetric Michael reaction

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Hydrogen-bond catalysis

• Mono- and bidentate interaction of thiourea
  derivatives with
• anionic substrates

• Role of the thiourea
• - preorganizing the arrangement of substrates
• - activating substrates through polarization
• - stabilizing charges, transition states or
  intermediates

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Proposed mechanisms

• Mechanistic controversies

• Ternary complexes in the thiourea-catalyzed
  Michael reaction a) Takemotos proposal and b)
  results calculated by Pápai et al

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2.2Paracyclophane

• Ar-ring distance 3.083.09 Å

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2.2Paracyclophane

Light-weight Parylene functions under rugged
vacuum conditions and extreme temperatures, and
has been proven in multiple spaceflight
applications Parylene meets MIL-I-46058C, Army
Regulation 70-71, NAV.INST. 3400.2, and
USAF-80-30 regs

• Applications of 2.2Paracyclophane-based
• polymers

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2.2Paracyclophane

• Transannular substitution Pseudo-geminally
  directing effect of acetyl, carbomethoxy,
  carboxy, nitro and sulfone substitutents

• Selective ortho-functionalization of
  4-hydroxy2.2paracyclophane
• derivatives via Friedel-Crafts acylation or
  directed metalation

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2.2Paracyclophanes - Applications

• Catalytic enantioselective cyclopropanation of
  styrenes

• Enantioselective diethylzinc addition to
  benzaldehyde

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2.2Paracyclophanes - Applications

• a) 1,2-addition of diethylzinc to
  isobutyraldehyde
• b) 1,4-addition of
• diethylzinc to cinnamylaldehyde

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2.2Paracyclophanes - Applications

• Application of the Phanephos ligand in the
  enantioselective
• hydrogenation of ß-ketoesters

• Fürstners 2.2Pyridinophane-
• -based NHC ligand

• Epoxide ring-opening and Diels-Alder reaction
• (essentially racemic), catalyzed by RP-PHANOL

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Development of planar-chiral catalysts

• Bifunctional thiourea-catalyst
• H-bond donor
• Planar chirality
• Defined distance between the functionalities
• Flexible catalyst design

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Synthesis

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Synthesis

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2.2Paracyclophanes Synthetic Approaches
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2.2Paracyclophanes Synthetic Approaches
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Synthesis
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Synthesis

• Versatile precursor synthesis

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Synthesis
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Synthesis
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Synthesis

• Variation of the steric environment

• Variation of the H-bond donor functionality

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Organocatalytic applications

• Asymmetric transfer hydrogenation of
• nitro olefins

• possible catalyst-substrate
• complex

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Organocatalytic applications

• Asymmetric transfer hydrogenation of
• nitro olefins

• possible catalyst-substrate
• complex

• 30 24 ee

• 29 21 ee

• 42 lt5 ee

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Structural analysis

• X-Ray structure of the racemic
  2.2Paracyclophane-thiourea
• H-bond-mediated association of the dimer

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Structural analysis - Conformational Analysis
A quick introduction
1. Simple Force Field Approach Rough
classification
gt 130 kJ
2. Best of Energy Optimization simple
method (e.g. B3LYP, B98)
3. Single Point Energy calculation (various
methods and basis sets)
mPW1K, MP2, MP2(FC), QCISD,
Comparison of relative energies
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Structural analysis - Comparison of relative
energies
- Ranking dependent on applied method
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Computational analysis of conformers

• 1. Force-field conformational analysis
• 2. Energy optimization with DFT (B98/6-31G(d))
• 3. Single-point energy calculation with HF
  (MP2(FC)/6-31G(2d,p))
• 4. Comparison of all obtained structures

• 0.0

• 26.76 kJ/mol

• 26.01 kJ/mol

• 38.41 kJ/mol

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Structural analysis NMR-titration
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• Determination of the
• catalyst/substrate stoichiometry

Addition (equiv) of the substrate

• Observing the complexation of substrates

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Structural analysis anion-complexation

• co-crystal structure of a
• thioureaNMe4Cl complex
• double hydrogen bonding

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Structural analysis anion-complexation

• Complexation of DMSO

?d 0.144 ppm
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Structural analysis

• Binding mode of the thiourea catalyst

• weak H-bond-
• interactions

• strong H-bond-
• interactions

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Synthesis of amino acid-based catalysts

• easily accessible library of catalysts

• commercially available
• amino acid esters as
• starting materials

• tertiary alcohols

• secondary alcohols

• primary alcohols

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Application of amino acid-based catalysts

• Asymmetric transfer hydrogenation
• of nitro olefins and nitro acrylates

• optimized conditions

• catalyst-screening

• tertiary alcohols
• 26 81, lt5 16 ee

• secondary alcohols
• 70 90, 20 62 ee

• primary alcohols
• 78 99, 50 70 ee

• 99, 70 ee

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Application of amino acid-based catalysts

• Asymmetric transfer hydrogenation of
• nitro olefins and nitro acrylates

• scope

99, 70 ee
99, 50 ee
97, 67 ee
95, 63 ee
88, 56 ee
95, 68 ee
76, 87 ee
84, 40 ee
95, 60 ee
99, 58 ee
93, 54 ee
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Application of amino acid-based catalysts

• mechanistic considerations

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Conclusion

• Development of planar-chiral organocatalysts

• Organocatalytic applications transfer
• hydrogenation

• Conformational / substrate-binding
• analysis

• Synthesis and application of amino acid-
• based catalysts

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Acknowledgements
Montréal, 11.04.2011

• Dr. Jan Paradies
• Prof. Stefan Bräse

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