The Use of Ferrocenyl Ligands in Asymmetric Catalytic Hydrogenation

1
The Use of Ferrocenyl Ligands in Asymmetric
Catalytic Hydrogenation

• Beth Moscato-Goodpaster
• April 12, 2007

2
Utility of Ferrocenyl Ligands
Weiss, M et al. Angew. Chem. Int. Ed. 2006, 45,
5694. Genov, M. et al. Tetrahedron Asymmetry
2006, 17, 2593
3
Utility of Ferrocenyl Ligands
Lopez, F. et al. JACS 2004, 126, 12784-12785.
Cho, Y.-h. et al. JACS 2006, 128, 6837.
Harutyunyan, S. R. et al. JACS 2006, 128, 9103.
4
Asymmetric Hydrogenation
hydrogenation is arguably the most important
catalytic method in synthetic organic
chemistry. Of the lt20 full-scale
chemo-catalyzed asymmetric reactions known to
be running in industry currently, more than
half are used for reducing various
functionalities.
Blaser, H. et al. Adv. Synth. Catal. 2003, 345,
103-151. Federsel, H. Nat. Rev. Drug Discovery
2005, 4, 685-697.
5
General Scope of Hydrogenation
Olefins
Ketones and Imines
Blaser, H. et al. Adv. Synth. Catal. 2003, 345,
103-151.
6
Outline

• Features of Ferrocenyl Ligands
• why ferrocenes?
• reactivity and synthesis
• modularity
• Applications of Ferrocenyl Ligands to Specific
  Substrates in Asymmetric Hydrogenation
• Conclusions

7
Why Ferrocenes?
Xiao, D. Zhang, X. Angew. Chem. Int. Ed. 2001,
40, 3425-3428. Xiao, D Zhang, Z. Zhang, X. Org.
Lett. 1999, 1, 1679-1681.
8
Why Ferrocenes?

• low rotation barrier of ferrocenyl backbone
  offers flexibility, facilitating binding of
  sterically demanding imines.
• electron donating ability and large P-M-P bite
  angle increases electron back-donating ability
  from Ir to an imine substrate.

Xiao, D. Zhang, X. Angew. Chem. Int. Ed. 2001,
40, 3425-3428. Vargas, S. et al. Tetrahedron
Let. 2005, 46, 2049.
9
Why Ferrocenes?
(R,R)-f-binaphane has unprecedented
enantioselectivity!
Xiao, D. Zhang, X. Angew. Chem. Int. Ed. 2001,
40, 3425-3428. Vargas, S. et al. Tetrahedron
Let. 2005, 46, 2049.
10
Synthesis of Chiral Ferrocenes Lithiation
Marquarding, D. et al. JACS 1970, 92, 5389-5393.
11
SN1 Retention of Stereochemistry
Hayashi, T. et al. Tetrahedron Let. 1974, 15,
4405.
12
Synthesis of BPPFA Derivatives
Hayashi, T. Kawamura, N. Ito, Y. JACS 1987 109,
7876. Hayashi, T Kawamura, N Ito, Y.
Tetrahedron Let. 1988, 29, 5969-5972 Hayashi,
T. et al. Tetrahedron Let. 1976, 17, 1133-1134
13
Modular Synthesis Josiphos
Togni, A. et al. JACS 1994, 116, 4062-4066.
14
Modular Electronic Effects
Best results are obtained with s-donating,
electron-rich pyrazole nitrogen and strongly
p-accepting phosphorous. The resulting
electronic asymmetry at the metal
center enhances enantioselectivity.
Schnyder, A. Hintermann, L. Togni, A. Angew.
Chem. Int. Ed. 1995, 34, 931-933
15
Outline

• Features of Ferrocenyl Ligands
• Applications of Ferrocenyl Ligands to Specific
  Substrates in Asymmetric Hydrogenation
• hydrogenation of unprotected enamines
• hydrogenation of 2- and 3-substituted indoles
• hydrogenation of vinyl boronates
• hydrogenation of (S)-Metolachlor
• Conclusions

16
Synthesis of Unprotected ß-Amino Acids Catalyst
Screening
1
Hsiao, Y. et al. JACS 2004, 126, 9918-9919.
17
Synthesis of Unprotected ß-Amino Acids
Hsiao, Y. et al. JACS 2004, 126, 9918-9919.
18
Product Inhibition
Results are consistent with either a first-order
dependence on substrate OR product inhibition.
Results are consistent with product inhibition!
Hansen, K. B. et al. Org. Lett. 2005, 7, 4935.
19
Product Inhibition
Addition of Boc2O selectively protects the free
amine, preventing product inhibition and
accelerating the overall reaction.
Hansen, K. B. et al. Org. Lett. 2005, 7, 4935.
20
Synthesis of ß-Amino Acid Pharmacophore
Kubryk, M. Hansen, K. Tetrahedron Asymmetry
2006, 17, 205-209.
21
Hydrogenation of Indoles
Kuwano, R. et al. Tetrahedron Asymmetry. 2006,
17, 521-535.
22
Hydrogenation of 2-Substituted Indoles
Kuwano, R. et al. JACS 2000, 122, 7614-7615.
23
Hydrogenation of 3-Substituted Indoles
71-94 yield 95-98 ee
Kuwano, R. et al. Org. Lett. 2004, 6, 2213..
24
Hydrogenation of N-Boc Protected Indoles
Kuwano, R. Kashiwabara, M. Org. Lett. 2006, 8,
2653-2655.
25
Hydrogenation of Vinyl Bis(boronates)
Morgan, J. B. Morken, J. P. JACS 2004, 126,
15338-15339.
26
Hydrogenation of Vinyl Bis(boronates)
Single Pot Diboronation / Hydrogenation /
Oxidation of Phenylacetylene
Single Pot Hydrogenation / Homologation /
Oxidation of Vinyl Bis(boronate)
Morgan, J. B. Morken, J. P. JACS 2004, 126,
15338-15339.
27
Hydrogenation of Vinyl Bis(boronates)
Morgan, J. B. Morken, J. P. JACS 2004, 126,
15338-15339.
28
Hydrogenation of Vinyl Boronates
1 BCl3, then BnN3 22 C 2 (i) ClCH2Li, THF, -78
C (ii) NaOH, H2O2
Moran, W. J. Morken, J. P. Org. Lett. 2006, 8,
2413-2415.
29
Hydrogenation of Vinyl Boronates
Moran, W. J. Morken, J. P. Org. Lett. 2006, 8,
2413-2415.
30
Hydrogenation of Vinyl Boronates
70 conv
84 conv
lt10 conv
32 conv
Boronate is activating sterics alone are not
responsible for high reactivity.
Moran, W. J. Morken, J. P. Org. Lett. 2006, 8,
2413-2415.
31
Hydrogenation of Vinyl Boronates
70 conv
84 conv
lt10 conv
32 conv
Reactivity not due solely to the p-acceptor
properties of boronate methyl methacrylate
exhibits much less reactivity.
Moran, W. J. Morken, J. P. Org. Lett. 2006, 8,
2413-2415.
32
Hydrogenation of Vinyl Boronates
70 conv
84 conv
lt10 conv
32 conv
Enhanced reactivity not due to inductive donation
from boron to carbon inductively withdrawing
phenyl ring provides similar levels of
reactivity, but no enantioselectivity.
Moran, W. J. Morken, J. P. Org. Lett. 2006, 8,
2413-2415.
33
(S)-Metolachlor Dual Magnum

• Important grass herbicide used in corn and other
  crops.
• Over 10,000 tons / year produced by Syngenta AG
  (trademark Dual Magnum)
• Hydrogenation is largest enantioselective
  catalytic process used in industry one of
  fastest homogeneous systems known.

Arrayas, R. Andreo, J. Carretaro, J. Angew.
Chem. Int. Ed. 2006, 45, 7674-7715. Blaser, H.
et al. Top. Catal. 2002, 19, 3-16. Dorta, R. et
al. Chem. Eur. J. 2004, 10, 4546-4555. Syngenta
website www.syngenta.com
34
(S)-Metolachlor Dual Magnum
ACTIVE!
INACTIVE!
1970 Metolachlor discovered 1978
rac-Metolachlor production started, gt10,000
tons/yr produced
1982 Metolachlor stereoisomers synthesized
(S)-isomer found to be active.
Blaser, H. et al. Chimia 1999, 53, 275-280.
35
(S)-Metolachlor Requirements for Industrially
Feasible Process

• Enantioselectivity
• Catalyst productivity
• Catalyst activity
• Catalyst stability
• Availability and quality of starting material

• ee gt 80
• S/C gt 50,000
• TOF gt 10,000 h-1

Spindler, F. et al. In Catalysis of Organic
Reactions Maltz, R., Jr., Ed. pp153-166.
36
(S)-Metolachlor Enantioselective Synthesis
Only possible approach!
Blaser, H. et al. Chimia 1999, 53, 275-280.
37
(S)-Metolachlor Imine Hydrogenation
(4S,5S)-diop
(2R,4R)-bdpp

• Conclusions from Initial Screening
• Addition of halogen anions increases rate, esp.
  with both Cl- and I- in soln.
• Catalyst deactivation major problem rates
  dependant on ligand structure, solvent and
  temperature.

Spindler, F. et al. In Catalysis of Organic
Reactions Maltz, R., Jr., Ed. pp153-166.
38
(S)-Metolachlor Imine Hydrogenation

• Conclusions so far
• Only ferrocenyl diphosphine ligands gave medium
  to good ees and catalyst stability.
• Matched chirality necessary.
• Aryl groups at two phosphines necessary for good
  performance.

Blaser, H. et al. J Organomet Chem 2001, 621,
34-38.
39
(S)-Metolachlor Imine Hydrogenation
In the presence of AcOH and I-, the rate of
reaction is accelerated by a factor of 5, and the
time for 100 conversion is twenty times shorter
than without additives!
Blaser, H. et al. Chimia 1999, 53,
275-280. Blaser, H. et al. J Organomet Chem
2001, 621, 34-38. Spindler, F. et al. In
Catalysis of Organic Reactions Maltz, R., Jr.,
Ed. pp153-166.
40
(S)-Metolachlor Imine Hydrogenation
While other ligands have slightly higher ees,
Xyliphos high activity makes it ideal for
industrial use.
Blaser, H. Spindler, F. Chimia 1997, 51,
297-299. Blaser, H. et al. J. Organomet Chem
2001, 621, 34-38.
41
(S)-Metolachlor Imine Hydrogenation

• Original Requirements
• ee gt 80
• S/C gt 50,000
• TOF gt 10,000 h-1

• Final Results
• ee 79
• S/C gt 1,000,000
• TOF gt 1,800,000 h-1

Blaser, H. Spindler, F. Chimia 1997, 51,
297-299. Blaser, H. et al. J. Organomet Chem
2001, 621, 34-38.
42
(S)-Metolachlor Production Scale
80 atm H2
S/C 2,000,000 50 C, 4 hrs
extraction, flash distillation, distillation
Ir is recycled
Blaser, H. Spindler, F. Chimia 1997, 51,
297-299. Blaser, H. et al. Chimia 1999, 53,
275-280.
43
Conclusions

• Ferrocenes possess unusual properties
• planar chirality
• stereoretentive SN1 substitution
• Ferrocenyl ligands have been used to hydrogenate
  a number of uncommon substrates
• N-aryl imines
• indoles
• unprotected enamines
• vinyl boronates

44
Acknowledgements

• Clark Landis and Landis Group Members
• Practice Talk Attendees
• Brian Hashiguchi
• Avery Watkins
• Katherine Traynor
• Hairong Guan
• Ram Neupane
• Family
• Dow Chemical, for funding