1. Synthesis, Application and Structural Analysis
– Planar-Chiral Hydrogen-Bond Donor Catalysts –
Synthesis, Application and Structural Analysis
Literature Seminar
Montréal,
Jakob Schneider 1

2. 2

3. – 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 3

4. Organocatalysis: Structural motivs
Takemoto, 2003
Rawal, 2002
L-proline-mediated
enamine-catalysis;
1970
Wang, 2005
Akiyama, 2004
Jacobsen, 2004
MacMillan, 2003
Fu, 2002
Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743; Dalko, P. I.; Moisan, L. Angew. Chem. 2004, 116, ; Angew. Chem., Int. Ed. 2004, 43, 5138–5175; Fu, G. C. Acc. Chem. Res. 2000, 33, 412–420. 4 4

5. Bond energy (kcal/mol)
Hydrogen-Bond catalysis
Properties of hydrogen bonds
Strong
Moderate
Weak
Type of bonding
Mostly covalent
Mostly electrostatic
Electrostatic
Length of H-Bond (Å)
Bond angles (°)
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 5

6. Broensted acid catalysis
BINOL-derived phosphoric acid-catalyzed addition of silyl ketene acetales to
aldimines.
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, ; Angew. Chem. 2004, 116, Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. Adv. Synth. Catal. 2005, 347, 6 6

7. Hydrogen Bond catalysis – Chiral Diols
TADDOL-catalyzed hetero-Diels Alder reaction
H-Bond-promoted H-Bond
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, 7 7

8. Hydrogen-Bond catalysis – Development of (thio)urea compounds
Activation of epoxides and unsaturated ketones
Schreiner´s electron-deficient N,N`-diphenyl thiourea
Hine, J.; Ahn, K.; Gallucci, J. C.; Linden, S.-M. J. Am. Chem. Soc. 1984, 106, ; Hine, J.; Ahn, K. J. Org. Chem. 1987, 52, ; Etter, M. C.; Panunto, T. W. J. Am. Chem. Soc. 1988, 110, ; Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 8 8

9. 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
Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2000, 39, ; Angew. Chem. 2000, 112, ; Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 9 9

10. Hydrogen-bond catalysis
Wang, 2005: Asymmetric MBH reaction.
Asymmetric Michael reaction
Wang, J.; Li, H.; Duan, W.; Zu, L.; Wang, W. Org. Lett. 2005, 7, ; Sibi, M. P.; Itoh, K. J. Am. Chem. Soc. 2007, 129, 10 10

11. 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, 11 11

12. Proposed mechanisms Mechanistic controversies
Ternary complexes in the thiourea-catalyzed Michael reaction : a) Takemoto’s proposal and b) results calculated by Pápai et al
Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, ; Hamza A; Schubert, G.; Soo´ s, T.; Papai, I. J. Am. Chem. Soc. 2006, 128, 12 12

13. [2.2]Paracyclophane Ar-ring distance: 3.08–3.09 Å C2 C1 C9 C10 C3 C4
Winberg, H. E.; Fawcett, F. S.; Mochel, W. E.; Theobald, C. W. J. Am. Chem. Soc. 1960, 82, ; Reich, H.; Cram, D. J. J. Am. Chem. Soc. 1967, 89, 13 13

14. [2.2]Paracyclophane Applications of [2.2]Paracyclophane-based
„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 , and USAF regs”
Applications of [2.2]Paracyclophane-based
polymers:
Chen, H.-Y.; Hirtz, M.; Deng, X.; Laue, T.; Fuchs, H.; Lahann, J. J. Am. Chem. Soc. 2010, 132, 18023–18025.; 14 14

15. [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
Reich, H.; Cram, D. J. J. Am. Chem. Soc. 1967, 89, ; Reich, H. J.; Yelm, K. E. J. Org. Chem. 1991, 56, 15 15

16. [2.2]Paracyclophanes - Applications
Catalytic enantioselective cyclopropanation of styrenes
Enantioselective diethylzinc addition to benzaldehyde
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, ; Danilova, T. I.; Rozenberg, V. I.; Sergeeva, E. V.; Starikova, Z. A.; Bräse, S. Tetrahedron: Asymmetry 2003, 14, 16 16

17. [2.2]Paracyclophanes - Applications
a) 1,2-addition of diethylzinc to isobutyraldehyde
b) 1,4-addition of
diethylzinc to cinnamylaldehyde
Hermanns, N.; Dahmen, S.; Bolm, C.; Bräse, S. Angew. Chem., Int. Ed. 2002, 41, ; Angew. Chem. 2002, 114, ; 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, 17 17

18. [2.2]Paracyclophanes - Applications
Application of the Phanephos ligand in the enantioselective
hydrogenation of β-ketoesters
Fürstner´s [2.2]Pyridinophane-
-based NHC ligand
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, ; Focken, T.; Rudolph, J.; Bolm, C. Synthesis, 2005, 3, ; Fürstner, A.; Alcarazo, M.; Krause, H.; Lehmann, C. W. J. Am. Chem. Soc. 2007, 129, 18 18

19. Development of planar-chiral catalysts
Bifunctional thiourea-catalyst
H-bond donor
Planar chirality
Defined distance between the functionalities
Flexible catalyst design 19 19

20. Synthesis
Schneider, J. F.; Falk, F. C.; Fröhlich, R.; Paradies, J. Eur. J. Org. Chem. 2010, 2265–2269. 20 20

21. Synthesis
Schneider, J. F.; Falk, F. C.; Fröhlich, R.; Paradies, J. Eur. J. Org. Chem. 2010, 2265–2269. 21 21

22. [2.2]Paracyclophanes – Synthetic Approaches22 22

23. [2.2]Paracyclophanes – Synthetic Approaches23 23

24. Synthesis 24 24

25. Synthesis N Br N O Br
Versatile precursor synthesis 25 25

26. Synthesis
Schneider, J. F.; Fröhlich, R.; Paradies, J. Synthesis 2010, 20, 3486–3492. 26 26

27. Synthesis
Schneider, J. F.; Fröhlich, R.; Paradies, J. Synthesis 2010, 20, 3486–3492. 27 27

28. Synthesis Variation of the steric environment
Variation of the H-bond donor functionality 28 28

29. Organocatalytic applications
Asymmetric transfer hydrogenation of
nitro olefins
possible catalyst-substrate
complex
Schneider, J. F.; Falk, F. C.; Fröhlich, R.; Paradies, J. Eur. J. Org. Chem. 2010, 2265–2269. 29 29

30. Organocatalytic applications
Asymmetric transfer hydrogenation of
nitro olefins
possible catalyst-substrate
complex
42%; <5% ee
30%; 24% ee
29%; 21% ee
Schneider, J. F.; Falk, F. C.; Fröhlich, R.; Paradies, J. Eur. J. Org. Chem. 2010, 2265–2269. 30 30

31. 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 31 31

32. 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 32

33. Structural analysis - Comparison of relative energies
- „Ranking“ dependent on applied method 33

34. 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
0.0
kJ/mol
kJ/mol
kJ/mol 34 34

35. Structural analysis – NMR-titration1 2 3
Determination of the
catalyst/substrate stoichiometry
Addition (equiv)
of the substrate
Observing the complexation of substrates 35 35

36. Structural analysis – anion-complexation
co-crystal structure of a
thiourea–NMe4Cl complex
double hydrogen bonding
2.41 Å
2.49 Å
NMe4+
Cl– 36 36

37. Structural analysis – anion-complexation
Complexation of DMSO
DMSO
δ (DMSO) = ppm
δ = ppm
δ = ppm
δ = ppm
δ = ppm
Δδ = ppm 37 37

38. Structural analysis Binding mode of the thiourea catalyst:
weak H-bond-
interactions
strong H-bond-
interactions 38 38

39. 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:
Schneider, J. F.; Lauber, M. B.; Muhr, V.; Kratzer, D.; Paradies, J. Org. Biomol. Chem. 2011, asap. 39 39

40. 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 40 40

41. 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 41 41

42. Application of amino acid-based catalysts
mechanistic considerations
Schneider, J. F.; Lauber, M. B.; Muhr, V.; Kratzer, D.; Paradies, J. Org. Biomol. Chem. 2011, asap. 42 42

43. Conclusion Development of planar-chiral organocatalysts
Organocatalytic applications: transfer
hydrogenation
Conformational / substrate-binding
analysis
Synthesis and application of amino acid-
based catalysts 43 43

44. Acknowledgements Montréal, 11.04.2011
Dr. Jan Paradies
Prof. Stefan Bräse
German Chemical Industry Association
Landesgraduiertenförderung Baden-Württemberg 44