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.

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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 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 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.

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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

■ 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

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 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.

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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.

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Dinuclear Zinc Proline-Derived Catalysts Transition state hypothesis

■ Proposed transition state

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

Ar H R

O ! α-hydroxy 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 O Zn Zn O N O N

Me

Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2001, 123, 3367.

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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.

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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

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.

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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. Cl vs. OTs, etc.)

Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936. Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360.

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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

■ Proposed mechanism X O X [Co] OH 3a R [Co] [Co] O O R O R OH RDS R OH R OH OH OH X OH [Co] R L [Co] [Co] L L

Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360.

Metal Salen Complexes as Bifunctional Catalysts Enforcing cooperative catalysis through covalent linkage

■ Covalently linked dimers could effect cooperative catalysis more efficiently

! Rate greatly accelerated compared to monomeric catalyst - rate highly dependent on tether length N N Cr t-Bu O O O ! No loss in enantioselectivity N3 O t-Bu t-Bu

( )n t-Bu t-Bu O t-Bu O N3 O O Cr N N

■ Mechanistic considerations

! Kinetic studies indicate involvement of both inter- and intramolecular pathways

2 - considering two-term rate equation: kintra[cat] + kinter[cat] , and plotting rate/[cat] vs. [cat]

- y-intercept = kintra, slope = kinter

Konsler, R. G.; Karl, J.; Jacobsn, E. N. J. Am. Chem. Soc. 1998, 120, 10780.

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Metal Salen Complexes as Bifunctional Catalysts Enforcing cooperative catalysis through covalent linkage

■ Covalently linked dimers could effect cooperative catalysis more efficiently

! Rate greatly accelerated compared to monomeric catalyst - rate highly dependent on tether length N N Cr t-Bu O O O ! No loss in enantioselectivity N3 O t-Bu t-Bu

( )n t-Bu t-Bu O t-Bu O N3 O O Cr N N

■ Mechanistic considerations

! Comparing nonlinear effects in plot of catalyst ee vs. reaction ee with monomeric catalyst

- high concentrations, attenuated nonlinear effect – participation of both 1st and 2nd-order pathways - low concentrations, strictly linear effect – expected for purely intramolecular pathway

Konsler, R. G.; Karl, J.; Jacobsn, E. N. J. Am. Chem. Soc. 1998, 120, 10780.

Metal Salen Complexes as Bifunctional Catalysts Enforcing cooperative catalysis through covalent linkage

■ One step further: oligomeric catalysts

O O ! Oligomeric catalysts can provide a dramatic

O O O increase in both rate and selectivity

t-Bu t-Bu ! Polymer-supported and dendrimeric catalysts also N O O N Co OTf TfO Co provide similar significant rate enhancments N O O N t-Bu t-Bu

O O O Annis, D. A.; Jacobsen, E. NJ. Am. Chem. Soc. 1999, 121, 4147. O O n Breinbauer, R.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2000, 39, 3604. n=1–4 Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 2687.

■ Intramolecular ring-opening of oxetanes

monomer O or O R oligomer 76–98% yield

TBME or MeCN R up to 99% ee OH OH

R = H, alkyl, aryl, F, OH

Loy, R. N.; Jacobsen, E. N. J. Am. Chem. Soc. 2009, 131, 2786.

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Metal Salen Complexes as Bifunctional Catalysts Enantioselective Conjugate Addition of Cyanide

■ Asymmetric conjugate addition of cyanide to α,β-unsaturated imides

O O 10–15 mol% 4 O O TMSCN Ph N Ph N N N H i-PrOH (2.5–4 eq) H Al R PhMe, up to 45 °C NC R t-Bu O Cl O t-Bu

70–90% yield t-Bu t-Bu R= alkyl 94–98% ee 4

Sammis. G. N.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442.

■ High catalyst loadings and temperatures required

! Al(salen) complexes promote conjugate additions of other nucleophiles to unsaturated imides efficiently ! Insufficient activation of cyanide nucleophile?

! Ln(pybox) complexes efficiently promote addition of TMSCN to epoxides O O N ! Displays little to no reactivity for the above conjugate addition reaction N N Ln Cl Cl R Cl R Can one utilize each catalyst’s independent activation in a cooperative manner?

Schaus, S. E.; Jacobsen, E. N. Org. Lett. 2000, 2, 1001.

Metal Salen Complexes as Bifunctional Catalysts Mixed catalytic systems

■ Conjugate addition with individual catalysts vs. dual-catalyst system

O O O O TMSCN (2 eq) N N Ph N i-PrOH (2 eq) Ph N Al H H PhMe, 23 °C t-Bu O O O t-Bu i-Pr NC i-Pr t-Bu t-Bu entry catalyst system conversion (%) ee (%) Al(salen) 5 1 (S,S)-5 <3 -

2 (S,S)-6 <3 -

3 99 96 O O (S,S)-5 + (S,S)-6 N N N Er Cl Cl i-Pr Cl i-Pr ■ Diastereomeric ligand combination 6 ! Use of (R,R)-6 led to substantially decreased selectivities and rate ! When achiral Ln(pybox) was used, intermediate levels of selectivities were produced ! Achiral Al(salen) + 6 resulted in selectivity greater than with 6 alone (16% after 17 d)

Both complexes engage in rate-determining step and function cooperatively in asymmetric induction

Sammis. G. N.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 9928.

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Metal Salen Complexes as Bifunctional Catalysts Improved reaction conditions

■ Asymmetric conjugate addition of cyanide to α,β-unsaturated imides

O O 10–15 mol% 4 O O TMSCN Ph N Ph N N N H i-PrOH (2.5–4 eq) H Al R PhMe, up to 45 °C NC R t-Bu O Cl O t-Bu

70–90% yield t-Bu t-Bu R= alkyl 94–98% ee 4

Sammis. G. N.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442.

O O 2 mol% 5 O O 3 mol% 6 N N Ph N Ph N H H Al O O TMSCN (2 eq) N t-Bu O O O t-Bu R NC R N N i-PrOH (2 eq) Er t-Bu t-Bu Cl Cl PhMe, 23 C i-Pr Cl i-Pr ° 80–94% yield Al(salen) R= alkyl 93–97% ee 5 6

Sammis. G. N.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 9928.

Dinuclear Ti(Salen) Complexes Michael North

■ Cyanation of aldehydes

t-Bu t-Bu

0.1 mol% 7 O TMSCN OTMS t-Bu t-Bu N O O N O R H CH2Cl2, rt R CN Ti Ti O N O O N R = alkyl, aryl up to 92% ee t-Bu t-Bu

Belokon’, North, et al. J. Am. Chem. Soc. 1999, 121, 3968. t-Bu t-Bu 7

O 1 mol% 7 O O O OAc 5 mol% 7 O R' KCN, Ac2O + R H R' CN CH Cl R H R CN 2 2 R CN CH2Cl2, –40 °C –40 °C R = alkyl, aryl, styrenyl 64–95% yield R = alkyl, aryl 64–99% yield up to 93% ee R' = OEt, Me up to 96% ee

Belokon’, North, et al. Helv. Chim. Acta 2002, 85, 3301. Belokon’, North, et al. Org. Lett. 2003, 5, 4505. Moberg et al. J. Am. Chem. Soc. 2005, 127, 11592.

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Dinuclear Ti(Salen) Complexes Structure of dinuclear Ti-catalysts

■ Bridged dinculear Ti(salen) catalyst

t-Bu t-Bu

N O O N O Ti Ti O N O O N

t-Bu t-Bu

• 4 CHCl3

■ Central metallocycle consists of two long Ti–O bonds, and two short Ti–O bonds

O O O N O O N diastereomers O O N ■ Two bridging oxygens must be cis to one another M M M M N O O N O O ! Forces salen ligands out of planarity N N N O anti- ■ syn-ΔΔ diastereomer believed to be active catalyst syn-!! !" (only two of 8 possible stereoisomers shown)

Belokon’, North, et al. Tetrahedron 2007, 63, 5287.

Dinuclear Ti(Salen) Complexes Mechanistic Analysis

■ Preliminary investigations

t-Bu t-Bu

! Ti already 6-coordinate t-Bu t-Bu - existing bond must break to accommodate additional ligand N O O N O Ti Ti O 17 1 N O O N ! O and H NMR suggests equilibrium of dimeric and t-Bu t-Bu monomeric species

O O (salen)Ti Ti(salen) O O t-Bu t-Bu Ti O 7 N N 7

■ Addition of electrophilic carbonyl compound results in metalla-

CF3

O O O CF3 CD2Cl2 (salen)Ti Ti(salen) + O O Ti O F3C CF3 N N 7 O

Belokon’, North, et al. Eur. J. Org. Chem. 2000, 2655.

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Dinuclear Ti(Salen) Complexes Mechanistic Analysis

■ Addition of TMSCN results in disilated catalyst

SiMe3 O CD Cl O (salen)Ti Ti(salen) 2 2 + TMSCN (salen)Ti Ti(salen) O (10–30 eq) O 7 SiMe3

! Proposed structure difficult to isolate - new signals in 1H NMR corresponding to incorporation of TMS groups - FAB mass spectrometry suggests dimeric structure

! Readily decomposes into proposed monomeric species:

CN OSiMe3 OSiMe3 O O O O O O Ti Ti Ti N N N N N N

CN OSiMe3 CN

Belokon’, North, et al. Eur. J. Org. Chem. 2000, 2655.

Dinuclear Ti(Salen) Complexes Mechanistic Analysis

■ Kinetic studies suggest active catalyst is dimeric in nature

X X ! First order in TMSCN ! Zero order in aldehyde Y Y N O O N ! O Order with respect to catalysts 7a–7c: Ti Ti O N O O N - 7a: 1.6 Y Y - 7b: 1.3 - 7c: 1.8 X X

7a: X = H, Y = H 7b: X = t-Bu, Y = t-Bu What do these orders tell us?

7c: X = NO2, Y = t-Bu

! Assume rapid equilibrium between mono- and dinuclear complexes of precatalyst 7

- initial concentration of [C]0

! Two situations can arise for presumed mononuclear catalyst (Catmono) and dinuclear catalyst (Catdi):

Assume mononuclear species Catmono is catalyst Assume dinuclear species Catdi is catalyst 2 - if Catmono is predominant species, rate = k[C]0 - if Catmono is predominant species, rate = k[C]0 1/2 1 - if Catdi is predominant species, rate = k[C]0 - if Catdi is predominant species, rate = k[C]0

For full derivation of rate laws, see: Belokon’, North, et al. Eur. J. Org. Chem. 2000, 2655.

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Dinuclear Ti(Salen) Complexes Mechanistic Analysis

■ Kinetic studies suggest active catalyst is dimeric in nature

t-Bu t-Bu t-Bu t-Bu

t-Bu t-Bu t-Bu t-Bu N O O N N O O N O O Ti Ti Ti Ti O O N O O N N O O N t-Bu t-Bu t-Bu t-Bu

t-Bu t-Bu t-Bu t-Bu

7 7d

! Catalyst 7d catalyzes reaction, but at rate much slower than 7 (by 1000 at 0 °C)

entry* catalyst system conversion (%) ee (%) ! Normally would expect 7 to 1 7 100 82 dominate catalysis, leading to 2 7d 34 0 high yield and ee

3 7 + 7d 20 34

*Runs were conducted at room temperature 7 + 7d forms new, bimetallic species in situ

Belokon’, North, et al. Tetrahedron 2007, 63, 5287.

Dinuclear Ti(Salen) Complexes Proposed Mechanism

■ Proposed mechanism

SiMe3 CN O Ti(salen) (salen)Ti Ti(salen) O CN (salen)Ti Ti(salen) O CN O R CN SiMe3 O H R

O (salen)Ti O Ti(salen) O

R H O (salen)Ti Ti(salen) O (salen)Ti Ti(salen) CN O

CN CN NC R H

TMSCN

OTMS

R CN

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Dinuclear Ti(Salen) Complexes Proposed Mechanism

■ Proposed mechanism

SiMe3 CN O Ti(salen) (salen)Ti Ti(salen) O CN (salen)Ti Ti(salen) O CN O R CN SiMe3 O H R

O (salen)Ti O Ti(salen) O

R H O (salen)Ti Ti(salen) O (salen)Ti Ti(salen) CN O CN CN N NC R H N O R Ti R O N R C TMSCN R O O R H R R OTMS Ti O O R R CN N N

Dinuclear Ti(Salen) Complexes Enforcing cooperative catalysis

■ Ding – tethering the (salen) ligand

0.05 mol% 7a 0.05 mol% 7a O OTMS O OAc TMSCN NaCN, Ac2O R H R H CH2Cl2, 25 °C R CN CH2Cl2, 25 °C R CN R = aryl, styrenyl R = aryl, styrenyl 86–99% yield 90–99% yield 82–97% ee 90–96% ee

O O O O ! Significant improvement over parent catalyst

t-But-Bu ! Activity/selectivity highly dependent on tether choice N O O N O Ti Ti ! Catalyst enantiopurity vs. reaction enantioselectivity O N O O N t-But-Bu - strict linear relationship: intramolecular pathway

t-Bu t-Bu

Zhang, Z.; Wang, Z.; Zhang, R.; Ding, K. Angew. Chem. Int. Ed. 2010, 49, 6746.

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BINOL-Derived Bimetallic Catalysts Masakatsu Shibasaki

■ Akali metal heterobimetallic asymmetric catalysis

O O O O 10 mol% 8 O O + Al RO OR O O ( ) THF, rt CO2R n M CO R n = 1, 2 R = Me, Et, Bn 2 43–100% yield M = Li, Na, K, Ba 84–99% ee 8

Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.; Shibasaki, M. Angew. Chem. Int. Ed. 1996, 35, 104.

BINOL-Derived Bimetallic Catalysts Masakatsu Shibasaki

■ Akali metal heterobimetallic asymmetric catalysis

O O Al O O Li

• 3 THF

Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.; Shibasaki, M. Angew. Chem. Int. Ed. 1996, 35, 104.

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BINOL-Derived Bimetallic Catalysts Mechanism

■ Proposed mechanism

O O O

O O RO OR RO2C * Al * O O O O O CO2R Al Li O O Li H ALB O O H * Al * "ALB" O O O O Al Li O * * O O

Li O O O

RO OR RO2C CH2O2R

■ Aluminum center acts as Lewis acid

■ -alkoxide behaves as Brønsted base

Rare Earth––BINOL (REMB) Catalysts Masakatsu Shibasaki

■ REMB catalysts are among the most prominent multifunctional catalysts in organic synthesis

M

* O O * M O O RE O O O M RE M O O M O O O * M ! Center of asymmetry at central rare earth metal - configuration at central metal defined by BINOL ligand

■ Lewis acidic lanthanide rare earth metal center ■ Lewis and Brønsted basic BINOLate oxygens

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Rare Earth–Alkali Metal–BINOL (REMB) Catalysts The asymmetric nitroaldol reaction

■ Seminal work – asymmetric Henry reaction

Li 10 mol% 9 * O O * O CH3NO2 OH 79–91% yield O La O NO LiCl, H2O 2 73–90% ee R H R Li O O Li THF, –40 °C

R = (CH2)2Ph, i-Pr, Cy 9 "LLB"

Li OH * O O * NO2 R O La O CH3NO2

Li O O Li

* Li Li R O O O O O * H * * O Li O La O O O H O La O H Li La Li O O Li O O N O O N O O O Li O Li O Li * * R Li O O * O O H H R O La O H CH2 Li O O O N

Li O * Shibasaki et al.. J. Am. Chem. Soc. 1992, 114, 4418.

Rare Earth–Alkali Metal–BINOL (REMB) Catalysts Structural analysis of catalysts

■ Role of rare earth metal center in REMB

! Early solid-state and solution phase analysis indicated solvation of only alkali metals by lewis M O basic ligands (THF, Et2O, etc.) O O M Ln O O ! Only occasionally do Ln centers bind a O M single H2O molecule

Do lanthanide centers bind substrate, or are they only a structural element?

Aspinall, H. C. Chem. Rev. 2002, 102, 1807. Bari, L. D.; Lelli, M.; Pintacuda, G.; Pescitelli, G.; Marchetti, F.; Salvadori, P. J. Am. Chem. Soc. 2003, 125, 5549.

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Rare Earth–Alkali Metal–BINOL (REMB) Catalysts Structural analysis of catalysts

■ Patrick Walsh – first successful crystal structures organic base-coordinated REMB catalysts

•THF O Li O O THF• Li Pr•THF O O O Li •THF

! 7-coordinate Li3(THF)4(BINOL)3Pr(THF)

Wooten, A. J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130, 7407.

Rare Earth–Alkali Metal–BINOL (REMB) Catalysts Structural analysis of catalysts

■ Patrick Walsh – first successful crystal structures organic base-coordinated REMB catalysts

•2 py O Li O O 2 py• Li La•2 py O O O Li •py

! 8-coordinate Li3(py)5(BINOL)3Pr(py)2

Wooten, A. J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130, 7407.

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Rare Earth–Alkali Metal–BINOL (REMB) Catalysts Structural analysis of catalysts

■ Patrick Walsh – solution-phase structural analysis

! DMEDA shown not to be displaced by Lewis basic ligands ! If substrate binds, it must be to lanthanide center

N N MeN NMe Li Li Li O * O O Me * * O O * N O O O La O Li Eu O Eu O N O O Li O N N Me O Li Li O O Li O Me N Li N N * * MeN ! 1H NMR of cyclohexenone-bound complexes both display similar lanthanide-induced shifts (LIS) - can only be attributed to carbonyl binding to lanthanide center

! 6-coordinate Li3(DMEDA)3(BINOL)3Eu

First definitive evidence for solution binding of Lewis bases to REMB complexs

Wooten, A. J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130, 7407.

Rare Earth–Alkali Metal–BINOL (REMB) Catalysts Structural analysis of catalysts

■ Patrick Walsh – effect of alkali metal size

! Small Yb center compared to other lanthanide complexes

- for M = Na, K, lanthanide center does not bind even H2O

•n THF ! Solution-phase NMR studies reveal that both O M cyclohexenone and DMF experience significant LIS O O when M = Li n THF• M Yb O O O M n THF • Overriding factor in controlling binding ability is radius of main group metal, not lanthanide center

! M3(THF)n(BINOL)3Yb

Takaoka, E.; Yoshikawa, N.; Yamada, Y. M. A.; Sasai, H.; Shibasaki, M. Heterocylces 1997, 46, 157. Bari, L. D.; Lelli, M.; Pintacuda, G.; Pescitelli, G.; Marchetti, F.; Salvadori, P. J. Am. Chem. Soc. 2003, 125, 5549. Wooten, A. J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130, 7407.

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Rare Earth–Alkali Metal–BINOL (REMB) Catalysts Structural analysis of catalysts

■ Select REMB-catalyzed reactions

Shibasaki, M.; Kanai, M.; Matsunaga, S.; Kumagai, N. Acc. Chem. Res. 2009, 42, 1117.

Higher-Order Polymetallic Asymmetric Catalysts Masakatsu Shibasaki

■ Select REMB-catalyzed reactions

Ph Ph O P O Gd(Oi-Pr)3 (5–15 mol%) O TMSO CN HO ligand 10 (10–30 mol%) O X R Me R Me THF HO X R = alkyl, alkenyl, aryl 85–97% yield up to 97% ee X = H, F 10

■ Self assembly of active catalyst

O ! ESI-MS studies suggest 2:3 Gd : ligand ratio

Ph O ! Also observed a 4:5+oxo complex Ph P O O O O O Gd ! Changing preparation method results in formation of only one complex Gd NC O - with Gd(HMDS) , only 2:3 complex observed O CN O 3 O O R Me Shibasaki, Curran, et al. J. Am. Chem. Soc. 2001, 123, 9908. Kanai, Shibasaki, et al. J. Am. Chem. Soc. 2006, 128, 6768.

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Higher-Order Polymetallic Asymmetric Catalysts Identity of active catalysts

■ Attempts to obtain crystal structure of 2:3 complex resulted in isolation of only 4:5+oxo framework

11

! Assembly state change during crystallization process ! Use of 11 as catalyst resulted in reaction rate 5–50 times slower than with 2:3 in situ complex ! Use of 11 as catalyst switch in enantioselectivity compared to 2:3 in situ complex

Higher-order structure, not structure of individual module, is the determining factor of catalyst function

Kanai, Shibasaki, et al. J. Am. Chem. Soc. 2006, 128, 6768.

Higher-Order Polymetallic Asymmetric Catalysts Design of new higher-order catalytic structures

■ De novo design of higher-order structures nearly impossible

! Designing more stable module might help unify higher-order structure

Ph Ph O Ph Ph Ph P Ph O P P 7 X O O 6 X HO O 5 O O M X 5 O O X 5 X M M 5 O M O HO Y

X = H, F, CN Y = H, F 12 ! Presumably more stable 6,5,5 ring system in individual module

■ Higher-order structure observations

! 5:6+oxo+OH complex sole species observed by ESI-QFT-MS studies ! Attempts at crystallization resulted in 3:2+2OH complex

Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 16438.

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Higher-Order Polymetallic Asymmetric Catalysts Identity of active catalysts

■ Comparison of ligands 11 and 12

O TMSCN H R Gd(Oi-Pr) (cat.) R N Ar N 3 81–99% yield up to 99% ee ligand 10 or 12 (cat.) O NO R CN R 2

Ph Ph Ph Ph O P P O O HO HO O X O X

HO X HO Y

10 12

10 mol% Gd required 2 mol% Gd required up to 95 h reaction time complete within 24 h

Mita, T.; Fujimori, I.; Wada, R.; Wen, J.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 11252. Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 16438.

Chiral Schiff Base Catalysts Structural studies

■ Nitro-Mannich reaction

CuOAc (10 mol%) Sm(Oi-Pr)3 (10 mol%) Boc NHBoc N N N ligand 13 (10 mol%) up to >20:1 dr + R' R'CH2NO2 R up to 98% ee R H 4-t-Bu-phenol (10 mol%) OH HO NO2 THF, –40 °C R = alkyl, aryl OH HO 49–97% yield 13

■ Plot of enantiopurity of 13 vs. reaction enantioselectivity revealed weak nonlinear effect

■ In presence of phenol additive, ESI-MS revealed presence of µ-oxo trimeric species ! Also see monomeric fragment N N M ■ In absence of phenol, ESI-MS revealed presence of additional oligomeric species O O ! RE Enantioselectivity decreases in absence of phenol additive O O

■ Use of “well-ordered” Sm5O(Oi-Pr)13 leads to improved results ! Most likely prevents formation of detrimental oligomeric species

Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 4925.

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Chiral Schiff Base Catalysts Mechanism

■ Nitro-Mannich reaction

CuOAc (10 mol%) Sm(Oi-Pr)3 (10 mol%) Boc NHBoc N N N ligand 13 (10 mol%) up to >20:1 dr + R' R'CH2NO2 R up to 98% ee R H 4-t-Bu-phenol (10 mol%) OH HO NO2 THF, –40 °C R = alkyl, aryl OH HO 49–97% yield 13

■ Proposed transition state

Ot-Bu Ot-Bu

N O N O H NO2 Cu vs. R NO2 Cu

R H Sm R H Sm R' H favored disfavored

Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 4925.

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