Bifunctional Asymmetric Catalysts: Design and Applications Junqi Li CHEM 535 27 Sep 2010
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
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, 5897. Hansen, K. B.; Leighton, J. L.; Jacobsen, E.. J. Am. Chem. Soc. 1996, 118, 10924.
Bridging two reactive sites by covalent tethering Intermolecular reaction k obs /[cat]= 0.022 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, 10780.
Reaction types catalyzed by bifunctional catalysts Ph Ph P Al Cl P Ph Ph H H H
Bifunctional catalysis 1. Lewis acid-lewis base catalysts 2. Lewis acid-bronsted base catalysts 3. Lewis acid-lewis acid catalysts 4. Hydrogen-bonding catalysts
Al-BIL-phosphine oxide: a Lewis acid-lewis base catalyst Substrates Additive Yields (%) ee R = alkyl Bu 3 P= 96-100 83-98 R = alkenyl Bu 3 P= 91-99 97-98 R = aromatic CH 3 P()Ph 2 86-98 90-96 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.
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.
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.
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
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.
Cooperative Lewis base-lewis acid catalysis for β-lactam synthesis Me BQ= H Product In(Tf) 3 Yield (%) ee d.r. R = Ph - 65 99 99/1 10 mol% 95 98 60/1 R = Ph - 45 99 99/1 10 mol% 93 97 22/1 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, 6626. France, S.; Wack, H; Hafez, A. M.; Taggi, A. E.; Witsil, D. R.; Lectka, T. rg. Lett. 2002, 4, 1603.
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, 6626. France, S.; Wack, H; Hafez, A. M.; Taggi, A. E.; Witsil, D. R.; Lectka, T. rg. Lett. 2002, 4, 1603.
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, 6626. Paull, D. H.; Abraham, C. J.; Scerba, M. T.; Alden-Danforth, E.; Lectka, T. Acc. Chem. Res. 2008, 41, 655.
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
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
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.
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, 2187. ee = 36-95%, yields = 63-93% Li
Proposed working model for the aldol reaction Yoshikawa,.; Shibasaki, M. Chem. Rev. 2002, 102, 2187.
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
REMB-catalyzed aza-michael addition R 1 R 2 Yields (%) ee aromatic aromatic 80-97 81-96 R catalyst Yields (%) ee alkyl YLB 84-96 83-94 aromatic DyLB 49-53 80-82 Yamagiwa,.; Qin, H.; Matsunaga, S.; Shibasaki, M. J. J. Am. Chem. Soc. 2005, 127, 7407.
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.
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.
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.
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
rganocatalytic cyanosilylation of ketones R 1 R 2 Yields (%) ee Aryl or vinyl Me 81-98 89-98 Alkyl Me n.d. 8-79 Fuerst, D. E.; Jacobsen, E.. J. Am. Chem. Soc. 2005, 127, 8964 Zuend, S. J.; Jacobsen, E.. J. Am. Chem. Soc. 2007, 129, 15872
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
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
rganocatalytic cyanosilylation of ketones: 2 possible mechanisms
rganocatalytic cyanosilylation of ketones: DFT calculations co-planarity of C= and C=C bonds preferred in transition state
rganocatalytic cyanosilylation of ketones: enantioselectivity explained
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
Bifunctional organocatalysts based on cinchona alkaloids R Yields (%) ee Aryl 90-99 96-98 Alkyl 71-81 94 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
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
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
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
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
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
Acknowledgements Prof Hartwig CHEM 535 class Prof Burke Burke group