– Planar-Chiral Hydrogen-Bond Donor Catalysts –
Synthesis, Application and Structural Analysis
Literature Seminar
Jakob Schneider
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Montréal, 11.04.2011
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– Planar-Chiral Hydrogen-Bond Donor Catalysts –
Synthesis, Application and Structural Analysis
Outlook:
Hydrogen-Bond Catalysis
[2.2]Paracyclophane 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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Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743; Dalko, P. I.; Moisan, L. Angew. Chem. 2004,
116, 5248-5286; Angew. Chem., Int. Ed. 2004, 43, 5138–5175; Fu, G. C. Acc. Chem. Res. 2000, 33, 412–420.
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
<4
Hydrogen-bond vs. Brønsted acid catalysis
Pihko, P. M. Hydrogen Bonding in Organic Synthesis, 2009, Wiley-VCH, Weinheim.
5
Broensted acid catalysis
BINOL-derived phosphoric acid-catalyzed addition of silyl ketene acetales to
aldimines.
6
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566-1568; Angew. Chem. 2004,
116, 1592-1594. Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. Adv. Synth. Catal. 2005, 347, 1523-1526.
Hydrogen Bond catalysis – Chiral Diols
TADDOL-catalyzed hetero-Diels Alder reaction
H-Bond-promoted H-Bond
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Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146. Unni, A. K.; Takenaka, N.;
Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 1336-1337.
Hydrogen-Bond catalysis – Development of (thio)urea compounds
Activation of epoxides and unsaturated ketones
Schreiner´s electron-deficient N,N`-diphenyl thiourea
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Hine, J.; Ahn, K.; Gallucci, J. C.; Linden, S.-M. J. Am. Chem. Soc. 1984, 106, 7980-7981; Hine, J.; Ahn, K. J. Org.
Chem. 1987, 52, 2083-2086; Etter, M. C.; Panunto, T. W. J. Am. Chem. Soc. 1988, 110, 5896-5897 ; Schreiner,
P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217-220.
Hydrogen-Bond catalysis
Strecker reaction of N-alkyl imines, catalyzed by
Jacobsen´s Schiff-base thiourea
Takemoto´s thiourea catalyst:
asymmetric Michael reaction
Bifunctional mode of action
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Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2000, 39, 1279-1281; Angew. Chem. 2000,
112, 1336-1338.; Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672-12673.
Hydrogen-bond catalysis
Wang, 2005: Asymmetric MBH reaction.
Asymmetric Michael reaction
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Wang, J.; Li, H.; Duan, W.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293-4296.; Sibi, M. P.; Itoh, K. J. Am. Chem.
Soc. 2007, 129, 8064-8065.
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
Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187-1198.
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Proposed mechanisms
Mechanistic controversies
Ternary complexes in the thiourea-catalyzed Michael reaction :
a) Takemoto’s proposal and b) results calculated by Pápai et al
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Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672-12673; Hamza A; Schubert, G.; Soo´ s,
T.; Papai, I. J. Am. Chem. Soc. 2006, 128, 13151-13160.
[2.2]Paracyclophane
C11
C1
C10
C9
C2
C3
C4
Ar-ring distance: 3.08–3.09 Å
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Winberg, H. E.; Fawcett, F. S.; Mochel, W. E.; Theobald, C. W. J. Am. Chem. Soc. 1960, 82, 1428-1435; Reich,
H.; Cram, D. J. J. Am. Chem. Soc. 1967, 89, 3078-3080.
[2.2]Paracyclophane
„Light-weight Parylene functions under rugged vacuum
conditions and extreme temperatures, and has been proven in
multiple spaceflight applications”
Applications of [2.2]Paracyclophane-based
polymers:
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“Parylene meets MIL-I-46058C, Army Regulation 70-71,
NAV.INST. 3400.2, and USAF-80-30 regs”
Chen, H.-Y.; Hirtz, M.; Deng, X.; Laue, T.; Fuchs, H.; Lahann, J. J. Am. Chem. Soc. 2010, 132, 18023–18025.;
http://www.parylene.com/applications/parylene-applications.html
[2.2]Paracyclophane
Transannular substitution: Pseudo-geminally directing effect of:
acetyl, carbomethoxy, carboxy, nitro and sulfone substitutents
Selective ortho-functionalization of 4-hydroxy[2.2]paracyclophane
derivatives via Friedel-Crafts acylation or directed metalation
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Reich, H.; Cram, D. J. J. Am. Chem. Soc. 1967, 89, 3078-3080; Reich, H. J.; Yelm, K. E. J. Org. Chem. 1991, 56,
5672-5679.
[2.2]Paracyclophanes - Applications
Catalytic enantioselective cyclopropanation of styrenes
Enantioselective diethylzinc addition to benzaldehyde
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Masterson, D. S.; Hobbs, T. L.; Glatzhofer, D. T. J. Mol. Cat. A: Chem. 1999, 145, 75-81; Danilova, T. I.; Rozenberg, V. I.; Vorontsov, E.
V.; Starikova, Z. A.; Hopf, H. Tetrahedron: Asymmetry 2003, 14, 1375-1383; Danilova, T. I.; Rozenberg, V. I.; Sergeeva, E. V.; Starikova,
Z. A.; Bräse, S. Tetrahedron: Asymmetry 2003, 14, 2013-2019.
[2.2]Paracyclophanes - Applications
a) 1,2-addition of diethylzinc to isobutyraldehyde
b) 1,4-addition of
diethylzinc to cinnamylaldehyde
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Hermanns, N.; Dahmen, S.; Bolm, C.; Bräse, S. Angew. Chem., Int. Ed. 2002, 41, 3692-3694; Angew. Chem.
2002, 114, 3844-3846; Ay, S.; Ziegert, R.; Zhang, H.; Nieger, M.; Rissanen, K.; Fink, K.; Kubas, A.; Gschwind, R.
M.; Bräse, S.J. Am. Chem. Soc. 2010, 132, 12899-12905
[2.2]Paracyclophanes - Applications
Application of the Phanephos ligand in the enantioselective
hydrogenation of β-ketoesters
Fürstner´s [2.2]Pyridinophane-based NHC ligand
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Epoxide ring-opening and Diels-Alder reaction
(essentially racemic), catalyzed by RP-PHANOL
Pye, P. J.; Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider, P. J. Tetrahedron Letters, 1998, 39, 4441-4444;
Focken, T.; Rudolph, J.; Bolm, C. Synthesis, 2005, 3, 429-436; Fürstner, A.; Alcarazo, M.; Krause, H.; Lehmann,
C. W. J. Am. Chem. Soc. 2007, 129, 12676-12677.
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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Schneider, J. F.; Falk, F. C.; Fröhlich, R.; Paradies, J. Eur. J. Org. Chem. 2010, 2265–2269.
Synthesis
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Schneider, J. F.; Falk, F. C.; Fröhlich, R.; Paradies, J. Eur. J. Org. Chem. 2010, 2265–2269.
[2.2]Paracyclophanes – Synthetic Approaches
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[2.2]Paracyclophanes – Synthetic Approaches
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Synthesis
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Synthesis
Br
N
Br
Versatile precursor synthesis
N
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O
Synthesis
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Schneider, J. F.; Fröhlich, R.; Paradies, J. Synthesis 2010, 20, 3486–3492.
Synthesis
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Schneider, J. F.; Fröhlich, R.; Paradies, J. Synthesis 2010, 20, 3486–3492.
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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Schneider, J. F.; Falk, F. C.; Fröhlich, R.; Paradies, J. Eur. J. Org. Chem. 2010, 2265–2269.
Organocatalytic applications
Asymmetric transfer hydrogenation of
nitro olefins
possible catalyst-substrate
complex
42%; <5% ee
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30%; 24% ee
Schneider, J. F.; Falk, F. C.; Fröhlich, R.; Paradies, J. Eur. J. Org. Chem. 2010, 2265–2269.
29%; 21% ee
Structural analysis
2.54 Å
2.67 Å
X-Ray structure of the racemic [2.2]Paracyclophane-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
> +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)/6-31+G(2d,p))
4. Comparison of all obtained structures
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0.0
+26.76 kJ/mol
+26.01 kJ/mol
+38.41 kJ/mol
8.135
0
8.142
1
8.146
2
8.00
7.50
7.00
6.50
Observing the complexation of substrates
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8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
0.00
0.20
0.40
0.60
0.80
Mole fraction χ (nitroolefin)
3
ppm (t1)
χ(thiourea)•δΔ
8.120
Structural analysis – NMR-titration
Addition (equiv)
of the substrate
Determination of the
catalyst/substrate stoichiometry
Structural analysis – anion-complexation
co-crystal structure of a
thiourea–NMe4Cl complex
double hydrogen bonding
2.41 Å
2.49 Å
NMe4+
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Cl–
Structural analysis – anion-complexation
δ = 2.581 ppm
δ = 2.466 ppm
9.0
ppm (t1)
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8.0
7.0
6.0
5.0
4.0
3.0
2.606
2.599
δ = 2.599 ppm
2.581
δ = 2.606 ppm
DMSO
2.466
δ (DMSO) = 2.610 ppm
2.610
Complexation of DMSO
Δδ = 0.144 ppm
2.0
1.0
0.0
Structural analysis
Binding mode of the thiourea catalyst:
weak H-bondinteractions
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strong H-bondinteractions
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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Schneider, J. F.; Lauber, M. B.; Muhr, V.; Kratzer, D.; Paradies, J. Org. Biomol. Chem. 2011, asap.
Application of amino acid-based catalysts
Asymmetric transfer hydrogenation
of nitro olefins and nitro acrylates
optimized conditions
catalyst-screening:
tertiary alcohols:
26 – 81%, <5 – 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
95%, 68% ee
95%, 60% ee
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97%, 67% ee
95%, 63% ee
76%, 87% ee
84%, 40% ee
99%, 58% ee
93%, 54% ee
88%, 56% ee
Application of amino acid-based catalysts
mechanistic considerations
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Schneider, J. F.; Lauber, M. B.; Muhr, V.; Kratzer, D.; Paradies, J. Org. Biomol. Chem. 2011, asap.
Conclusion
Development of planar-chiral organocatalysts
Organocatalytic applications: transfer
hydrogenation
Conformational / substrate-binding
analysis
Synthesis and application of amino acidbased catalysts
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Acknowledgements
Montréal, 11.04.2011
Dr. Jan Paradies
Prof. Stefan Bräse
German Chemical Industry Association
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Landesgraduiertenförderung Baden-Württemberg