11/20/10 Polymetallic Asymmetric Catalysts A review of the prominent catalytic systems MacMillan Group Meeting, November 17, 2010 Brian Ngo Laforteza Multimetallic Bifunctional Catalysis Defining the concept ■ What do we consider “bifunctional catalysis”? Catalyst 1 Substrate 1 ! Simultaneous activation of multiple reaction partners by different catalytically active centers ! Activation sites can either be in separate complexes or linked together Catalyst 2 Substrate 2 Tyr113' ■ Familiar examples 92 His 2- O OPO3 H O t-Bu S His94 O Brønsted base H 2+ N Zn Me N N R H H H Lewis acid O H N O O i-Pr i-Pr 155 His H O– Brønsted base R R' NC H O Glu73 ! Organocatalysis ! Enzymes: Class II Aldolase Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 15872. 1 11/20/10 Multimetallic Bifunctional Catalysis Defining the concept ■ What do we consider “bifunctional catalysis”? Catalyst 1 Substrate 1 ! Simultaneous activation of multiple reaction partners by different catalytically active centers ! Activation sites can either be in separate complexes or linked together Catalyst 2 Substrate 2 ■ Substrates must be activated by different catalytic centers, unlike the following examples: Me R E O O O Me ! Only one Rh center acts as OR E O O RO O O ! One Ti center activates/ a carbene binding site Ti Ti Rh Rh R R O O O coordinates both peroxide O O ! Other Rh site acts as an O and allylic alcohol Me O O extra “ligand” for stability O t-Bu EtO Me Rhodium carbene chemistry Sharpless asymmetric epoxidation Dinuclear Zinc Proline-Derived Catalysts Barry M. Trost ■ Trost pioneered the use of dinuclear zinc complexes as bifunctional catalysts Ph OH HO Ph Ar Et Ph Ph O O Ar Ar Zn Zn N OH N Ar ! C2-symmetric Bis-ProPhenol ligand ZnEt N O N 2 ! One zinc center believed to act as Lewis acid ! Remaining zinc-alkoxide acts as Brønsted base Me Me 1 ■ Very few structural and mechanistic studies have been done ! Addition of 2 equiv. of ZnEt2 liberates 3 equiv. of ethane ! Addition of H2O liberates fourth equiv. of ethane from catalyst Me Ph O O ! Addition of acetic acid results in proposed structure O O Ph Zn Ph Zn Ph ! Electrospray mass spectrometry provides mass peaks N O N consistent with molecular formula Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. Me Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367. 2 11/20/10 Dinuclear Zinc Proline-Derived Catalysts Barry M. Trost ■ Trost pioneered the use of dinuclear zinc complexes as bifunctional catalysts ! C2-symmetric Bis-ProPhenol ligand ! One zinc center believed to act as Lewis acid ! Remaining zinc-alkoxide acts as Brønsted base ■ Kuiling Ding – first crystal structure of related complex NO2 THF Ph O O O Ph Zn Ph Zn Ph N O N THF Me Xiao, Y.; Wang, Z.; Ding, K. Chem. Eur. J. 2005, 11, 3668. Dinuclear Zinc Proline-Derived Catalysts Enantioselective aldol reactions ■ Direct catalytic enantioselective aldol Ph OH HO Ph Ar Et Ph Ph O O10 moAl%r ZnEt2 Ar Zn Zn N OH N O O 5 mol%A rligand 1 OH O + N O N ZnEt2 R H Me Ar 15 mol% Ph3P=S R Ar molecular sieves 24–79% yield THF, 5 °C up to 99% ee Me Me 1 Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. ■ Syn-selective aldol using α-hydroxy ketones as donors 10 mol% ZnEt2 O O 5 mol% ligand 1 OH O + HO up to 35:1 dr R H Ar molecular sieves R Ar up to 98% ee THF, –35 °C OH 62–97% yield Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367. 3 11/20/10 Dinuclear Zinc Proline-Derived Catalysts Proposed catalytic cycle ■ Proposed mechanism Ar R Ar O O H O O O Ar Zn Zn Ar Ar R H N O N Ar R O H Ar Et O O Ar O Ar O Me Ar O Ar Ar Zn Zn O O Ar O O Ar Ar Zn Zn Zn Ar Zn Ar Ar N O N Me Ar Ar N O N N O N Me Me Me Ar R O H Me O O Ar O Ar O O Ar OH O Zn Zn Me Ar Ar Ar R Ar N O N Me Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. Dinuclear Zinc Proline-Derived Catalysts Enantioselective aldol reactions ■ Direct catalytic enantioselective aldol 10 mol% ZnEt2 O O 5 mol% ligand 1 OH O + R H Me Ar 15 mol% Ph3P=S R Ar molecular sieves 24–79% yield THF, 5 °C up to 99% ee Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. ■ Syn-selective aldol using α-hydroxy ketones as donors 10 mol% ZnEt2 O O 5 mol% ligand 1 OH O + HO up to 35:1 dr R H Ar molecular sieves R Ar up to 98% ee THF, –35 °C OH 62–97% yield Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367. 4 11/20/10 Dinuclear Zinc Proline-Derived Catalysts Transition state hypothesis ■ Proposed transition state Ar H R O ! α-hydroxy ketone bridges both zinc metal centers O O O O ! Aldehyde coordinates to most sterically accessible Zn Zn face of catalyst N O N Me Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367. Dinuclear Zinc Proline-Derived Catalysts Other nucleophiles and electrophiles ■ Vinylogous nucleophility of butenolide O O 10 mol% Bis-ProPhenol O up to >20:1 dr + NO2 O R molecular sieves up to 95% ee NO2 THF, rt R R = aryl, styrenyl, alkyl 47–78% yield R O N O O ! Binds as bidentate bridging aromatic enolate O 10 mol% ZnEt2 O O O 5 mol% ligand 1 OH O Zn Zn O + HO up to 35:1 dr R H N O ANr molecular sieves R Ar up to 98% ee THF, –35 °C OH 62–97% yield Me Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2001, 123, 3367. 5 11/20/10 Dinuclear Zinc Proline-Derived Catalysts Other nucleophiles and electrophiles ■ Desymmetrization of 1,3-diols 10 mol% ZnEt2 OH OBz OH OH O 5 mol% ligand + O Ph PhMe R R H R = alkyl, aryl 78–99% yield 70–93% ee R O Ph O ! Diol coordinates both zinc centers O O O ZnH Zn O N O N Me Trost, B. M.; Malhotra, S.; Mino, T.; Rajapaksa, N. S. Chem. Eur. J. 2008, 123, 3367. Dinuclear Zinc Proline-Derived Catalysts Other nucleophiles and electrophiles ■ Desymmetrization of 1,3-diols 10 mol% ZnEt2 OH OBz OH OH O 5 mol% ligand + OBz PhMe R R H R = alkyl, aryl 78–99% yield 70–93% ee R O Ph O ! Diol coordinates both zinc centers O O O ZnH Zn O ! Proton transfer proposed to account for N O N sense of induced stereochemistry Me Trost, B. M.; Malhotra, S.; Mino, T.; Rajapaksa, N. S. Chem. Eur. J. 2008, 123, 3367. 6 11/20/10 Dinuclear Zinc Proline-Derived Catalysts Other nucleophiles and electrophiles ■ Select examples O OH NO2 R1 R1 + NO2 H + H TMS R R' R N N H TMS H R' R2 R3 R2 R3 Asymmetric alkynylation Asymmetric Friedel–Crafts alkylation J. Am. Chem. Soc. 2006, 128, 8-9. J. Am. Chem. Soc. 2008, 130, 2438. O O O PPh2 O OH PPh O HN + 2 + CH3NO2 N NO2 Ar R H R Ar R OH R H OH Asymmetric Henry reaction Asymmetric Mannich reaction Angew. Chem. Int. Ed. 2006, 41, 861. J. Am. Chem. Soc. 2006, 128, 2778. Metal Salen Complexes as Bifunctional Catalysts Eric N. Jacobsen ■ Ring-opening of meso epoxides with TMSN3 O 2a or 2b TMSO N3 N N TMSN3 Cr t-Bu O Y O t-Bu X Et2O or TBME X t-Bu t-Bu 2a: Y=Cl X= CH2, CHR, CH2CH2, CH=CH, N-R, O, C=O 2b: Y=N3 ■ Preliminary investigations support activation of TMS-N3 by Cr(salen) complex ! Catalyst 2a is precatalyst, while 2b is active catalyst in reaction mixture - IR studies: observance of Cr-N3 stretch - use of catalyst 2b directly affords product Can Cr(salen) complex also act as a Lewis acid? Hansen, K. B.; Leighton, J. L.; Jacobsn, E. N. J. Am. Chem. Soc. 1996, 118, 10924. 7 11/20/10 Metal Salen Complexes as Bifunctional Catalysts Support for cooperative catalysis ■ Crystal structure of 2b∙THF N3 N N Cr t-Bu O O t-Bu O t-Bu t-Bu 2b•THF Supports possibility of Lewis acid activation of epoxides ■ Kinetic studies ! Second-order rate dependence on catalyst Pdt (%ee) ■ Investigation of enantiomeric purity of 2b vs. enantioselectivtiy of reaction ! Significant non-linear effects* observed (supports interaction between two chiral entities) 2b (%ee) Hansen, K. B.; Leighton, J. L.; Jacobsn, E. N. J. Am. Chem. Soc. 1996, 118, 10924. *Nonlinear effects: Guillaneux, D.; Zhao, S. H.; Samuel, O.; Rainford, D.; Kagan, H. B. J. Am. Chem. Soc. 1994, 116, 9430. Metal Salen Complexes as Bifunctional Catalysts Hydrolytic Kinetic Resolution of Terminal Epoxides ■ Hydrolytic kinetic resolution (HKR) of terminal epoxides, and 1,2-diol synthesis <1 mol% 3a N N OH O H2O (0.5–0.7 eq) O Co (±) + R OH t-Bu O O t-Bu R solvent-free R X t-Bu t-Bu 84–99% ee 86–98% ee 3a: X = OAc 3b: X = OH ■ Mechanistic investigations ! Both enantiomers bind to catalyst with similar affinity - selectivity arises from only one of the epoxide complexes ! Ratio of 3a to 3b throughout reaction plays crucial role in reaction rate - Rate = kcat’f[Co–OH]tot[Co–X]tot - 1:1 ratio optimal - ratio is affected by reactivity of counterion (X = OAc vs.