1. Quantitative aspects of asymmetric catalysis David Avnir Institute of Chemistry The Hebrew University of Jerusalem Schulich Symposium on Asymmetric Catalysis Technion, Haifa, March 2, 2008

2. 1. Background: Quantifying chirality

3. By how much is one molecule more chiral than the other?

5. Gradual changing chirality and C 2 -ness in aggregates Is it possible to quantify these changes?

6. In fact, asymmetry and chirality are very common: Given a sufficiently high resolution in space or time it is quite difficult to find a fully symmetric, achiral molecule. Time resolution: Consider watching methane on a vibrational time-scale: Only one in zillion frames will show achirality

7. Or consider two perfect achiral tetrahedra - a catalyst and a substrate - approaching each other for reaction: The approaching geometry and encounter complex are more likely to be chiral than not

8. Spatial resolutions: Often, symmetry is lost and chirality emerges at the condensed phase: # An adsorbed molecule # A matrix-entrapped molecule # A molecule packed in the crystal # A molecule in the glassy state # A molecule within a cluster

9. A methodology is needed in order to quantify the degree of chirality: # Comparing different molecules # Following changes within a single molecule

10. The proposed methodology for a symmetry-measure design: Find the minimal distance between the original structure, and the one obtained after the G point- group symmetry is operated on it. Dr. H. Zabrodzky Hel-Or

11. The continuous symmetry measure * The scale is 0 - 1 (0 - 100): The larger S(G) is, the higher is the deviation from G-symmetry : The original structure : The symmetry-operated structure N : Number of vertices d : Size normalization factor H. Zabrodsky

12. G: The achiral symmetry point group which minimizes S(G) Achiral molecule: S(G) = 0 The more chiral the molecule is, the higher is S(G) S(G) as a continuous chirality measure

14. The most chiral monodentate metal complex S. Alvarez P. Algemany

15. Dr. Mark Pinsky, S. Alvarez

16. M. Pinsky et al, Statistical analysis of the estimation of distance measures J. Comput. Chem., 24, 786–796 (2003) How small can the measure be and still indicate chirality? The error bar # Typical limit: In quartz, S(Chir) of SiO 4 = 0.0007 # For S values near zero, the error bar is not symmetric: The + and - are different. # If the lower bound of S touches 0.00000, then the molecule is achiral.

17. 2. Some applications

18. Chirality as a process coordinate: Stone-Wales Enantiomerizations in Chiral Fullerenes Y. Pinto, P. Fowler (Exeter)

19. Hückel energy changes along the enantiomerization

20. Low Quartz SiO 2, P3 2 21 Temperature and pressure effects on the chirality and symmetry: Quartz * Support for metals in asymmetric catalysis * Possible contributor to bio-homochirality

21. The building blocks of quartz: All are chiral! SiO 4 Si(OSi) 4 SiSi 4 -O(SiO 3 ) 4 -

22. Combining temperature and pressure effects through degree of helicity analysis b S(C 2 ) of a four tetrahedra unit: A measure of helicity A correlation between global and specific geometric parameters

23. Recognition/chirality relations The pioneering work of Gil-Av on chiral separations of helicenes E. Gil-Av, F. Mikes, G. Boshart, J. Chromatogr, 1976, 122, 205 A pair of enantiomers of a [6]-helicene Silica derivatized with a chiral silylating agent

24. Enantioselectivity of a chiral chormatographic column towards helicenes Is there a relation between this behavior and the degree of chirality of helicenes?

25. The chiral separation of helicenes on Gil-Avs column is dictated by their degree of chirality O. Katzenelson Tetrahedron-Asymmetry, 11, 2695 (2000) Gil-Av Quantitative chirality

26. 3. Asymmetric catalysis

27. Catalytic Chiral Diels-Alder Reaction Data: Davies, 1996. Analysis: Lipkowitz, Katzenelson

28. The nearest symmetry plane of the catalyst n = 1

29. The enantiomeric excess of the product as a function of the degree of chirality of the catalyst Lipkowitz, JACS 123 6710 (2001)

30. Which smallest fragment carries the essential chirality? S. Alvarez

31. The smallest fragment which carries the essential chirality for catalysis

32. Prediction 1: Replace the exocyclic ring with C=O or C=CH 2 to get good homologue catalysts

33. Prediction 2: Increase the twist angle

34. Continuous Chirality Measure in reaction pathways of Ruthenium catalyzed transfer hydrogenation of ketones Joost N. H. Reek (Amsterdam), Francesco Zerbetto (Bologna) Adv. Synth. Catal. 2005, 347, 792 Ruthenium catalyzed reduction of acetophenone and of 2-hexanone. Two catalysts, a more enantio- selective one, 1, and a poorer one, 2. (1: 52% ee; 2 6% ee (Petra, D. G. I. et al, Chem. Eur. J. 2000, 6, 2818.)

35. * Ten reaction pathways were examined with two approaches. (a)Intermediate complex of catalyst and substrate in step (b)The transition state with the concerted transfer of the proton (c)The complex of dehydrogenated catalyst and chiral product

36. In the transition states, acetophenone is forced by the catalyst 1 in a conformation with a higher chirality that facilitates enantio-induction. The lack of performance of catalyst 1 for the reduction of 2- hexanone is ascribed to its inability to generate a chirality difference/gradient in the substrate between paths that give mirror image enantiomers.

37. Acetophenone (solid line) and 2-hexanone (dotted line) CCM along the reaction pathway for 1a. Black: the path that gives the S enantiomer; red: the path that gives the R enantiomer.

38. Ligand Distortion Modes Leading to Increased Chirality Content of Katsuki-Jacobsen Catalysts Kenny B. Lipkowitz et al, Chirality, 14, 677 (2002) Evaluation of the degree of chirality content of several Katuski-Jacobsen catalysts, a set of salen ligands coordinated to metals (Mn mostly) that epoxidize olefins. An assessment of Mn(salen) molecules shows … variation in CCM, and, the chirality content for several triplet state complexes of these catalysts purported in the literature to be the active species show even larger CCM values.

39. Puckered and step-like triplet geometries of Mn(salen) Top: cis triplet; bottom trans triplet Significantly, we now find that both the step and puckered structures have enhanced chirality content compared to the singlet state.

40. We believe these [ligand] distortion modes are the genesis of this catalysts ability to give high ees. Several deformation modes were analyzed to examine how chirality content changes as catalyst distortion is induced. The most influential distortion modes that can be used for ligand design are twisting and step induction.

41. Chirality content of Mn(salen) as a function of C1-C2 contraction and elongation. Chirality content as a function of Mn(salen) pucker angle.

42. Enantioselectivity of immobilized Mn-salen complexes Kourosh Malek et al, (Eindhoven), J. Catalysis 246 (2007) 127 The origin of enhanced enantioselectivity of an anchored Mn-salen catalytic complex in MCM-41 in epoxidation of -methyl styrene, compared to homogeneous conditions. Si O O OEt OMn(salen)

43. We show that the immobilized linker influences the enantioselectivity of the catalyst due to the increasing chirality content of the Mn-salen complex. cis- and trans-substrates [β-methyl styrene] have different level of asymmetric induction to the Mn-salen catalyst: A trans-substrate induces higher chirality to the immobilized Mn-salen complex than cis-olefin. ACM Anchored Complex in MCM-41(ACM)

44. Chirality profile: High asymmetric induction by trans-olefin! OACM (cis) OACM (tr) FCL ACM FCM FCV FCV: free complex in vacuo FCM: free complex inside a MCM-41 channel ACM: anchored complex inside MCM-41 channel OAMC: complex anchored along with docked olefin

45. Reaction pathway I IV II III VII VIII VI V (I) Isolated oxo-Mn-salen; (II) the anchored complex; (III) docked olefin and encounter-complex of catalyst and substrate; (IV) radical intermediate complex of catalyst and substrate; (V) intermediate state; (VI) complex of reacted catalyst and product; (VII) de-oxygenated anchored catalyst; (VIII) isolated de-oxygenated catalyst.

46. I II III IV V VI VII VIII - A transition from cup-like to step-like - At V: the trans-olefin strongly interacts with oxo-center, at a high chiral configuration CCM of Mn-salen along the reaction pathway for cis- and trans-methyl styrene substrates

47. 4. Asymmetric biocatalysis

48. Trypsin inhibitors S. Keinan JACS 98

49. Attempt to find a correlation between the inhibition constant and the chirality of the whole inhibitor No correlation; but…

50. The correlation follows the degree of chirality but not the length of the alkyl chain Correlation between inhibition and the chirality of the pharmacophor

51. Inhibition of acetylcholine esterase by chiral organophosphates

52. 5. Web-sites

53. Our web-site (beta) http://chirality.ch.huji.ac.il/ or http://www.csm.huji.ac.il/

56. 6. In the pipeline: Chiral aluminosilicate zeolites A holy-grail

57. GOO – Goosecreekite |Ca 2+ 2 (H 2 O) 10 | [Si 12 Al 4 O 32 ] Rouse, R.C. et al : Am. Mineral., 71, 1494-1501 (1986) Space group : C222 1 (no. 20) AlO4 SiO4

58. Al(I)O 4 Al(I)Si 4 Al(I)(OSi) 4 S C = 0.0068 S C = 2.05 S C = 1.86 S C = 0.0018 S C = 1.57 S C = 1.46 S C = 0.0021 S C = 1.56 S C = 1.66 Al(II)O 4 Al(II)Si 4 Al(II)(OSi) 4 Si(I)O 4 Si(I)T 4 Si(I)(OT) 4 The chirality of the building blocks of GOO

59. The J. Am. Chem. Soc. Series: 114, 7843 (1992) 115, 8278 (1993) 117, 462 (1995) 120, 6152 (1998) 122, 4378 (2000) 123, 6710 (2001) 125, 4368 (2003) 126, 1755 (2004) Literature Some recent: D. Yogev-Einot et al, "The temperature-dependent optical activity of quartz: from Le Chaˆtelier to chirality measures, Tetrahedron: Asymmetry 17, 2723 – 2725 (2006) D. Yogev-Einot et al, "Left/right handedness assignment to chiral tetrahedral AB 4 structures, Tetrahedron: Asymmetry 18, 2295–2299 (2007) M. Pinsky et al, "Symmetry operation measures, J. Comput. Chem., 29, 190 -197 (2008)