Bifunctional Asymmetric Catalysts: Design and Applications. Junqi Li CHEM Sep 2010

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1 Bifunctional Asymmetric Catalysts: Design and Applications Junqi Li CHEM Sep 2010

2 Enzyme Catalysis vs Small-Molecule Catalysis Bronsted acid Lewis acid Lewis acid Bronsted base Activation of both substrates intramolecular reaction Activation of electrophile intermolecular reaction

3 Dual activation of reacting partners 2nd order kinetic dependence on catalyst Proposed mechanism: 3 Cr 3 Cr Dual activation by coordination of azide and epoxide to Cr catalyst Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. J. Am. Chem. Soc. 1995, 117, Hansen, K. B.; Leighton, J. L.; Jacobsen, E.. J. Am. Chem. Soc. 1996, 118,

4 Bridging two reactive sites by covalent tethering Intermolecular reaction k obs /[cat]= min -1 94% ee Intramolecular reaction k obs /[cat]= 0.97 min -1 93% ee Rate enhancement through covalent linkage without loss in enantioselectivity Konsler, R. G.; Karl, J.; Jacobsen, E. J. Am. Chem. Soc. 1998, 120,

5 Reaction types catalyzed by bifunctional catalysts Ph Ph P Al Cl P Ph Ph H H H

6 Bifunctional catalysis 1. Lewis acid-lewis base catalysts 2. Lewis acid-bronsted base catalysts 3. Lewis acid-lewis acid catalysts 4. Hydrogen-bonding catalysts

7 Al-BIL-phosphine oxide: a Lewis acid-lewis base catalyst Substrates Additive Yields (%) ee R = alkyl Bu 3 P= R = alkenyl Bu 3 P= R = aromatic CH 3 P()Ph phosphine oxide reduces Lewis acidity of catalyst Slow addition of TMSC Takamura, M.; Kunabashi, Kanai, M.; Shibasaki; M. J. Am. Chem. Soc. 1999, 121, 2641.

8 Al-BIL-phosphine oxide: cyanosilylation of aldehydes by bifunctional catalysis Proposed mechanism: R Ph Ph - P + H Cl Al - P + R R R Ph Ph P + - Lewis acid-activation of aldehyde Lewis base-activation of TMSC Takamura, M.; Kunabashi, Kanai, M.; Shibasaki; M. J. Am. Chem. Soc. 1999, 121, 2641.

9 Al-BIL-phosphine oxide: cyanosilylation of aldehydes by bifunctional catalysis Catalysts: Yield: 97% ee: 97% Ph Ph P Al Cl P Ph Ph o reaction at -40 o C Yield: 56% ee: 10% Ph Ph H Al Cl H Ph Ph Ph Ph P Al Cl P Ph Ph Low yield Internal quenching Takamura, M.; Kunabashi, Kanai, M.; Shibasaki; M. J. Am. Chem. Soc. 1999, 121, 2641.

10 Expanding Al-BIL-phosphine oxidecatalyzed reactions: the Reissert-type reaction Challenges in the asymmetric catalytic reaction: Rotatable bond R Highly reactive cationic intermediate Weakly Lewis basic Two limiting geometries two different enantiomers

11 Al-BIL-phosphine oxide-catalyzed Reisserttype reaction Ar= Me Me P R = Me R' C First catalytic asymmetric Reissert-type reaction 83-96% ee, 72-99% yield for electron-rich quinolines Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki; M.. J. Am. Chem. Soc. 2001, 123, 6801.

12 Cooperative Lewis base-lewis acid catalysis for β-lactam synthesis Me BQ= H Product In(Tf) 3 Yield (%) ee d.r. R = Ph /1 10 mol% /1 R = Ph /1 10 mol% /1 Without Lewis acid: yields: 45-65%, dr 50/7 99/1, ee 95-99% With Lewis acid: yields: 92-98%, dr 9/1 60/1, ee 96-99% Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc. 2002, 124, France, S.; Wack, H; Hafez, A. M.; Taggi, A. E.; Witsil, D. R.; Lectka, T. rg. Lett. 2002, 4, 1603.

13 Tandem activation of nucleophile and electrophile Me BQ= H Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc. 2002, 124, France, S.; Wack, H; Hafez, A. M.; Taggi, A. E.; Witsil, D. R.; Lectka, T. rg. Lett. 2002, 4, 1603.

14 A possible working model Et H Me - H Me - Ts In 2+ Most stable conformation from molecular mechanics calculations Et 2 C - BQ* H or Et 2 C BQ* Ts - Ph H Ts Ph H H Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc. 2002, 124, Paull, D. H.; Abraham, C. J.; Scerba, M. T.; Alden-Danforth, E.; Lectka, T. Acc. Chem. Res. 2008, 41, 655.

15 Bifunctional catalysis 1. Lewis acid-lewis base catalysts Combining well-studied modes of catalysis to generate new catalytic systems 2. Lewis acid-bronsted base catalysts 3. Lewis acid-lewis acid catalysts 4. Hydrogen-bonding catalysts

16 Lewis acid-bronsted base catalysts from selfassembled metal complexes REMB catalyst RE = rare earth metals (Ln, Pr, Eu, Yb) M = alkali metals (Li, a, K) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem. Int. Ed. Engl. 1997, 36, 1236

17 Lewis acid-bronsted base catalysts from selfassembled metal complexes RE = rare earth metals (Ln, Pr, Eu, Yb) M = alkali metals (Li, a, K) Simplified general mechanism: H-u E = electrophiles with Lewis basic site H-u = aryl ketones, malonates, thiols, nitroalkanes Shibasaki, M.; Yoshikawa,.; Chem. Rev. 2002, 102, 2187.

18 A Lewis acid-bronsted base catalyst for different reactions catalyst ee = 30-93%, yields = 50-91% a a Sm ee = 84-93%, yields = 86-98% a Li Li La Shibasaki, M.; Yoshikawa,.; Chem. Rev. 2002, 102, ee = 36-95%, yields = 63-93% Li

19 Proposed working model for the aldol reaction Yoshikawa,.; Shibasaki, M. Chem. Rev. 2002, 102, 2187.

20 Expanding the reaction scope of REMB catalysts Lewis acid-bronsted base catalysis: H-u H-u = only nucleophiles with sufficiently low pk a Lewis acid-lewis acid catalysis? M M R 1 RE R 2 H 2 R M Lewis acid Lewis acid

21 REMB-catalyzed aza-michael addition R 1 R 2 Yields (%) ee aromatic aromatic R catalyst Yields (%) ee alkyl YLB aromatic DyLB Yamagiwa,.; Qin, H.; Matsunaga, S.; Shibasaki, M. J. J. Am. Chem. Soc. 2005, 127, 7407.

22 A Lewis acid catalyst or a bifunctional catalyst? actual catalyst structure during catalysis? the role of the Ln center: structural element or Lewis acid? Woolten, A. J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130, 7407.

23 The 7- and 8-coordinate LLB complex 7-coordinate LLB complex 8-coordinate LLB complex The metal can expand its coordination number beyond 6 Woolten, A. J.; Carroll, P. J.; Walsh, P. J. Angew. Chem. Int. Ed. 2006, 45, 2549.

24 Substrate binding at Ln center EuLB complex, DMEDA adduct Cyclohexanone binds to both EuLB and EuLB-DMEDA adduct Woolten, A. J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130, 7408.

25 Bifunctional catalysis 1. Lewis acid-lewis base catalysts 2. Lewis acid-bronsted base catalysts 3. Lewis acid-lewis acid catalysts A general class of catalysts with 2 possible modes of activation Heterobimetallic catalysis and twocenter catalysis Mechanistic data that supports working model may be difficult to obtain 4. Hydrogen-bonding catalysts

26 rganocatalytic cyanosilylation of ketones R 1 R 2 Yields (%) ee Aryl or vinyl Me Alkyl Me n.d Fuerst, D. E.; Jacobsen, E.. J. Am. Chem. Soc. 2005, 127, 8964 Zuend, S. J.; Jacobsen, E.. J. Am. Chem. Soc. 2007, 129, 15872

27 rganocatalytic cyanosilylation of ketones: mechanistic studies Reaction rate shows first-order dependence of rate on [catalyst], [ketone] and [HC] Pyridine is a potent inhibitor of the reaction Plot of rate against [pyridine] Plot of chemical shift against [pyridine] Zuend, S. J.; Jacobsen, E.. J. Am. Chem. Soc. 2007, 129, 15872

28 rganocatalytic cyanosilylation of ketones: mechanistic studies Added trialkylamines decrease rate and enantioselectvitiy Me 2 Et Et 3 ipr 2 Et Plot of rate against [amine] Plot of ee against [amine] Bronsted basicity of amine affects reaction Zuend, S. J.; Jacobsen, E.. J. Am. Chem. Soc. 2007, 129, 15872

29 rganocatalytic cyanosilylation of ketones: 2 possible mechanisms

30 rganocatalytic cyanosilylation of ketones: DFT calculations co-planarity of C= and C=C bonds preferred in transition state

31 rganocatalytic cyanosilylation of ketones: enantioselectivity explained

32 Bifunctional organocatalysts based on cinchona alkaloids 6' Me H 9 8 H ee: 16% Conversion: 78% Me R H ee: 6-13% Conversion: 10-46% H H R H ee: 75% Conversion: 90% ee: 79-82% Conversion: 84 - >98% Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906

33 Bifunctional organocatalysts based on cinchona alkaloids R Yields (%) ee Aryl Alkyl Quinidine itself gives low selectivity Phenol does not catalyze reaction Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906

34 Bifunctional organocatalysts based on cinchona alkaloids Michael donors: Yields = 73-94%, d.r. = 86:14 - >98:2, ee = 92 - >99% Various Michael donors and nitroalkenes are competent Implies that catalyst is tolerant of substitution pattern changes Li, H.; Wang, Y.; Tang, L Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem. Int. Ed. 2005, 44, 105

35 Probing the active conformation of organocatalysts in Michael addition Reaction was carried out with 2 catalysts: ee values were comparable Longer reaction time for rigid catalyst? Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem. Int. Ed. 2005, 44, 105

36 Bifunctional catalysis 1. Lewis acid-lewis base catalysts 2. Lewis acid-bronsted base catalysts 3. Lewis acid-lewis acid catalysts 4. Hydrogen-bonding catalysts ne of the most well-characterized organocatalysts Hydrogen-bonding catalysis is a fundamentally new mode of catalysis

37 There are many types of catalysis: Concluding remarks Lewis acid catalysis Lewis base catalysis Transition-metal catalysis Bronsted acid catalysis Bronsted base catalysis Iminium catalysis Enamine catalysis SM catalysis Hydrogen-bonding catalysis Counterion catalysis Phase-transfer catalysis Bifunctional catalysis is a combination of 2 or more of these types

38 Conclusions and outlook Combining known catalysts can lead to better reactivities and enantioselectivies Structural complexity of bifunctional catalysts can make mechanistic studies difficult Mix-and-match or combinatorial catalytic systems are likely to become more popular Merging transition-metal catalysis with other forms of catalysis may lead to discovery of new reactions

39 Acknowledgements Prof Hartwig CHEM 535 class Prof Burke Burke group