Mechanistic Studies of Proline-Catalyzed Reactions

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1 chanistic Studies of Proline-Catalyzed Reactions N C 2 Jack Liu July 25, 2006

2 ow It Got Started (L)-proline (47 mol %), 1 N Cl 4, CN, reflux, 22 h 87%, e.r. = 84/16 Eder, U.; Sauer, G.; Wiechert, R. German patent DE , Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. 1971, 10, 496. (L)-proline (3 mol %), DMF, rt, 22 h 100%, e.r. = 93.4/6.6 Ts, benzene, reflux, 15 min. 92%, e.r. = 87.7/12.3 ajos, Z. G.; Parrish, D. R. German patent DE , ajos, Z. G.; Parrish, D. R. J. rg. Chem. 1974, 39, 1615.

3 of Proline Catalysis + N 2 (L)-proline (30 mol %), DMS, rt, 4 h N 2 68%, 76% ee List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc. 2000, 122, 2395.

4 Proline-Catalyzed Aldol with Aldehyde Donors + (L)-proline (10 mol %), DMF, 4 C, 11 h 88%, anti/syn = 3/1, 97% ee Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, TIPS + TIPS (L)-proline (10 mol %), DMS, rt TIPS TIPS 92%, anti/syn = 4/1, 95% ee TIPS TIPS TIPS Ac protected glucose Northrup, A. B.; Mangion, I. K.; ettche, F.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1753.

5 More Recent Developments Mannich reaction PMP (L)-proline (5 mol %), N PMP N + n-c 5 11 dioxane, rt C 2 Et C 2 Et n-c %, syn/anti > 19/1, >99% ee Córdova, A.; Watanabe, S.-I.; Tanaka, F.; Notz, W.; Barbas, C. F. III J. Am. Chem. Soc. 2002, 124, Ketone donor: Barbas, C. F. III et al. J. Am. Chem. Soc. 2002, 124, α-amination Cbz Cbz N 1. (L)-proline (10 mol %), + N Cbz N N Cbz CN, 0 C to rt, 3 h 2. NaB 4, Et 97%, >95% ee List, B. J. Am. Chem. Soc. 2002, 124, Ketone donor: Jørgensen, K. A. et al. J. Am. Chem. Soc. 2002, 124, α-aminoxylation (L)-proline (10 mol %), + Ph N N Ph CCl 3, 4 C, 4 h 88%, 97% ee Brown, S. P.; Bochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, Ketone donor: Córdova, A. et al. Angew. Chem. Int. Ed. 2004, 43, ayashi, Y. et al. Angew. Chem. Int. Ed. 2004, 43, 1112.

6 chanistic Studies of Proline-Catalyzed Reactions Proline-catalyzed aldol reaction chanistic investigations Computational studies ther related reactions Asymmetric amplification

7 chanistic Questions (L)-proline What is the intermediate? ow does proline catalyze the C-C bond formation? What is the origin of enantioselectivity?

8 The First chanistic Proposal (L)-proline N C - 2! N carbinolamine intermediate Supporting evidence: the Lack of 18 incorporation Control experiment: (L)-proline (3 mol %), 2 18 (2.2 mol %), CN, rt, 7 d (L)-proline (3 mol %), 2 18 (2.2 mol %), CN, rt, 7 d ajos, Z. G.; Parrish, D. R. J. rg. Chem. 1974, 12, Mass spectral analysis for 18 -labeled C 2 of the sample indicated 7.2% 18 enrichment Mass spectral analysis for 18 -labeled C 2 of the sample indicated 33.1% 18 enrichment What do you think?

9 Evidence Favouring An Enamine Intermediate ajos, Z. G.; Parrish, D. R. J. rg. Chem. 1974, 12, N benzene, reflux, 16 h N Ph C 2 Ph K! 0.12 DMS N Ph % List, B.; oang, L.; Martin,. J. Proc. Nat. Acad. Sci. USA 2004, 101, N Ph N Ph + 2 F F 1. pyrrolidine (1 mol %), benzene, reflux 2. Cl, 2 F N N 25% characterized by 1, 19 F NMR Moline,.; Wakselman, C. Tetrahedron 1976, 32, non-fluorinated by-products

10 18 -Incorporation Reexamined >90% of 18 incorporation for both 5 and 6 GC-MS trace of 4 day List, B.; oang, L.; Martin,. J. Proc. Nat. Acad. Sci. USA 2004, 101, 5839.

11 The Dual Proline Model (L)-proline N C 2-2 C N N C 2 Supporting evidence: 1. Dilution effect 2. Non-linear effect of enantioselectivity Agami, C.; Levisalle, J.; Puchot, C. J. Chem. Soc., Chem. Comm. 1985, 441. Agami, C.; Puchot, C. J. Mol. Catal. 1986, 38, 341. Puchot, C.; Samuel,.; Duñach, E.; Zhao, S.; Agami, C.; Kagan,. B. J. Am. Chem. Soc. 1986, 108, Agami, C.; Platzer, N.; Sevestre,. Bull. Soc. Chim. Fr. 1988, 499.

12 Dilution Effect (L)-proline (5 mol %), DMS, rt ee values were determined from the specific totation of the enantiomerically pure ketol. Agami, C.; Levisalle, J.; Puchot, C. J. Chem. Soc., Chem. Comm. 1985, 441.

13 Non-Linear Effect proline (3 mol %), DMF, 50 C, 6.5 h 80% 1.0 M in DMF The kinetic process of this catalytic reaction is complicated to such extent that it would not be wise to draw any definite conclusion as regards to homo or heterochiral nature of the favored diastereomeric transition state. Puchot, C.; Samuel,.; Duñach, E.; Zhao, S.; Agami, C.; Kagan,. B. J. Am. Chem. Soc. 1986, 108, 2353.

14 The Absence of Non-Linear Effect + N 2 proline (20 mol %), DMS N M 1 y = 0.69x R 2 = ee determined by chiral PLC Sakthivel, K.; Notz, W.; Bui, Tommy, Barbas, C. F. III J. Am. Chem. Soc. 2001, 123, 5260.

15 The Absence of Non-Linear Effect proline (20 mol %), 1M 2 S 4, DMS, 24 h DMF, 95 C n n a n=1 b n= n 0.1 M in DMS ee determined by chiral PLC oang, L.; Bahnmanyar, S.; ouk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16.

16 The Absence of Non-Linear Effect 1.0 M in DMF proline (3 mol %), 1M 2 S 4, DMF, 50 C, 6.5 h DMF, 95 C Agami s experiments repeated 3a ee determined by chiral PLC oang, L.; Bahnmanyar, S.; ouk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16. SI.

17 The Absence of Dilution Effect (L)-proline (6.7 mol %), 1M 2 S 4, DMS, 1-3 d DMF, 95 C n n a n=1 b n= n ee determined by chiral PLC oang, L.; Bahnmanyar, S.; ouk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16.

18 Kinetic rder of Proline in Retro-Aldol The rate of retro-aldol was found to be first order in proline oang, L.; Bahnmanyar, S.; ouk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16.

19 Currently Accepted chanistic Picture List, B.; oang, L.; Martin,. J. Proc. Nat. Acad. Sci. USA 2004, 101, 5839.

20 Time for a Quick Break

21 What is the Nature of the Aldolization Transition State? (L)-proline Clemente, F. R.; ouk, K. N. Angew. Chem. Int. Ed. 2004, 43, 5766.

22 A Closer Look at the Aldolization Transition State Both transition states chair-like C=C, C= bonds are synclinal Anti-enamine more stable Carboxylic acid of proline very important - distance very short for (R,R)-4 Enamine of (R,R)-4 less planar on C5 of proline may also stabilize the developing negative charge of carbonyl Bahnmanyar, S.; ouk, K. N. J. Am. Chem. Soc. 2001, 123, Cheong, P..-Y.; ouk, K. N.; Warrier, J. S.; anessian, S. Adv. Syn. Catal. 2004, 346, Cheong, P..-Y.; ouk, K. N. Synthesis 2005, Clemente, F. R.; ouk, K. N. J. Am. Chem. Soc. 2005, 127,

23 Energy Profile of Proline-Catalyzed Cyclization Clemente, F. R.; ouk, K. N. Angew. Chem. Int. Ed. 2004, 43, Similar calculation of proline-catalyzed intermolecular aldol: Boyd, R. J. et al. J. Phys. Chem. A 2002, 106, 5155.

24 Energy Profile of Proline-Catalyzed Cyclization Rate determining steps: Iminium-enamine tautomerization aldolization Stereochemistry determining step: aldolization The energy profiles of intra- and intermolecular reaction similar Clemente, F. R.; ouk, K. N. Angew. Chem. Int. Ed. 2004, 43, 5766.

25 rigin of Enantioselectivity for the Intermolecular Reactions + t-bu (L)-proline t-bu Re-face attack on aldehyde most favourable R = t-bu Bahnmanyar, S.; ouk, K. N.; Martin,. J.; List, B. J. Am. Chem. Soc. 2003, 123, 2475.

26 ow accurate/inaccurate are the Calculations? Intermolecular aldol reactions ajos-parrish-eder-sauer-wiechert cyclization Cheong, P..-Y.; ouk, K. N.; Warrier, J. S.; anessian, S. Adv. Syn. Catal. 2004, 346, Bahnmanyar, S.; ouk, K. N.; Martin,. J.; List, B. J. Am. Chem. Soc. 2003, 123, 2475.

27 A Brief Look at Proline-Catalyzed Mannich Reaction PMP + N C 2 Et (L)-proline N PMP C 2 Et Transition state giving rise to the major product Cheong, P..-Y.; Zhang,.; Thayumanavan, R.; Tanaka, F.; ouk, K. N.; Barbas, C. F. III rg. Lett. 2006, 8, 811.

28 A Brief Look at Proline-Catalyzed α-aminoxylation (L)-proline + N Ph Ph N Transition state giving rise to the major product ayashi model Zhong model MacMillan model Enamine reacts with monomeric Ph-N Regioselectivity depends on the basicity of the heteroatom Transition states correspond to 4b and 4c cannot be located Cheong, P..-Y.; ouk, K. N. J. Am. Chem. Soc. 2004, 126,

29 An Interesting Twist Non-Linear Effect Revisited + Cl proline (5 mol % or saturated), DMS, 25 C Cl 0.5 M : [proline] = M : total [proline] = 0.1 M When the solvent is saturated with proline, a non-linear effect is observed. Klussmann, M.; Iwamura,.; Mathew, S. P.; Wells, D.. Jr.; Pandya, U.; Armstrong, A.; Blackmond, D. G. Nature 2006, 441, 621.

30 Asymmetric Amplification by Dissolution All experiment carried out in DMS with 0.8 wt% 2 at 25 ºC. Concentration of dissolved proline and enantiomeric composition determined by chiral PLC. Total proline concentration: 0.1 M. Klussmann, M.; Iwamura,.; Mathew, S. P.; Wells, D.. Jr.; Pandya, U.; Armstrong, A.; Blackmond, D. G. Nature 2006, 441, 621.

31 Ternary Phase Diagram of (L)-, (D)-Proline, and DMS Klussmann, M.; Iwamura,.; Mathew, S. P.; Wells, D.. Jr.; Pandya, U.; Armstrong, A.; Blackmond, D. G. Nature 2006, 441, 621.

32 Some Important Definitions Racemic Compound IUPAC: A crystalline racemate in which the two enantiomers are present in equal amounts in a well defined arrangement within the lattice of a homogeneous crystalline addition compound. Eliel: A racemate in which the two enantiomers form a crystalline compound. The unit cell contains equal numbers of enantiomeric molecules. Conglomerate IUPAC: An equimolar mechanical mixture of crystals each one of which contains only one of the two enantiomers present in a racemate. Eliel: An equimolar mechanical mixture of crystals that form a eutectic of two enantiomers. Solid Solution IUPAC: A crystal containing a second constituent which fits into and is distributed in the lattice of the host crystal. Eliel: Two enantiomers are miscible in the solid state.

33 Binary phase diagrams More on Phase Diagrams conglomerate Ternary phase diagrams racemic compounds solid solution conglomerate Temperature dependence of the solubility of histidine Cl in water Eliel, E. L.; Wilen, S.. Stereochemistry of rganic Compounds. New York: Wiley

34 Ternary Phase Diagram of (L)-, (D)-Proline, and DMS What would happen if an unsaturated solution of (L)-proline/(D)-proline = 4/1 is concentrated isothermally? Klussmann, M.; Iwamura,.; Mathew, S. P.; Wells, D.. Jr.; Pandya, U.; Armstrong, A.; Blackmond, D. G. Nature 2006, 441, 621.

35 What About ther Amino Acids? + Cl amino acid, DMF, 25 C Cl 0.5 M Klussmann, M.; Iwamura,.; Mathew, S. P.; Wells, D.. Jr.; Pandya, U.; Armstrong, A.; Blackmond, D. G. Nature 2006, 441, 621.

36 Asymmetric Amplification by Catalyst Improvement proline (10 mol %), + Ph N N Ph CCl 3, 25 C The non-linear effect observed. The progress of reaction catalyzed by (L)-proline with 40% ee. Mathew, S. P.; Iwamura,.; Blackmond, D. G. Angew. Chem. Int. Ed. 2004, 43, 3317.

37 Proposed chanistic Scheme N C 2 + N C 2 4 major 4 minor + Ph N N Ph CCl 3, 25 C is more kinetically competent than proline as a catalyst Mathew, S. P.; Iwamura,.; Blackmond, D. G. Angew. Chem. Int. Ed. 2004, 43, 3317.

38 Kinetic Resolution of Proline N C 2 + N C 2 4 major 4 minor + Ph N N Ph CCl 3, 25 C Mathew, S. P.; Iwamura,.; Blackmond, D. G. Angew. Chem. Int. Ed. 2004, 43, 3317.

39 Summary Proline-catalyzed aldol reaction proceeds via enamine intermediate nly one proline is involved at the C-C bond formation Evidence for above conclusions: 18 incorporation Absence of dilution effect Absence of non-linear effect Kinetics of retro-aldol DFT computation Rate determining steps: Iminium-enamine tautomerization C-C bond formation The carboxylic acid functionality of proline very important in asymmetric induction of: Aldol reaction Mannich reaction α-aminoxylation Modes of asymmetric amplification in proline-catalyzed reations Dissolution Catalyst improvement

40 Kinetic Assumptions of Dilution Effect Assuming: 1. Bi-molecular enantioselective process only produces S product. 2. The rate of non-enantioselective process is first order in proline. i.e., rate E = k E [proline] 2 [s.m.] rate NE = k NE [proline][s.m.] Thus, rate E /rate NE = k[proline] Also, rate E /rate NE = ([S]-[R])/2[R] = ([S]-[R])/{([R]+[S])-([S]-[R])} = ([S]-[R])/{1-([S]-[R])} = ee/(1-ee) Therefore, rate E /rate NE = k[proline] = ee/(1-ee) back

41 Energy Profile of Proline-Catalyzed Intermolecular Aldol Reaction Rankin, N. R.; Cauld, J. W.; Boyd, R. J. J. Phys. Chem. A 2002, 106, 5155.

42 Calculated Structures of Different Transition States Clemente, F. R.; ouk, K. N. J. Am. Chem. Soc. 2005, 127,

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