Optimization of asymmetric catalysts using achiral ligands: metal geometry-induced ligand asymmetry.

Article abstract of DOI:10.1021/ol016003d

[reaction: see text] Traditionally, asymmetric catalysts have been optimized by modification of resolved chiral ligands. In this Letter, we optimize the asymmetric addition of diethylzinc to aldehydes by modification of achiral methylene bis(phenol) ligands. Upon coordination of the substrate, the achiral ligand becomes asymmetric, a concept termed Metal Geometry-Induced Ligand Asymmetry. The enantioselectivity of the catalyst formed from a single resolved ligand and several achiral ligands ranged from 9% (R) to 83% (S).

Full text of DOI:10.1021/ol016003d

ORGANIC
LETTERS
2001
Vol. 3, No. 14
2161-2164
Optimization of Asymmetric Catalysts
Using Achiral Ligands: Metal
Geometry-Induced Ligand Asymmetry†
Timothy J. Davis, Jaume Balsells, Patrick J. Carroll, and Patrick J. Walsh*
Department of Chemistry, UniVersity of PennsylVania, 231 South 34th Street,
Philadelphia, PennsylVania 19104-6323
pwalsh@sas.upenn.edu
Received April 19, 2001
ABSTRACT
Traditionally, asymmetric catalysts have been optimized by modification of resolved chiral ligands. In this Letter, we optimize the asymmetric
addition of diethylzinc to aldehydes by modification of achiral methylene bis(phenol) ligands. Upon coordination of the substrate, the achiral
ligand becomes asymmetric, a concept termed Metal Geometry-Induced Ligand Asymmetry. The enantioselectivity of the catalyst formed from
a single resolved ligand and several achiral ligands ranged from 9% (R) to 83% (S).
Various flexible achiral and meso ligands (L) possess chiral
conformations.1 If a metal (M) bearing one such ligand
supports a second ligand that is chiral (L*), the conforma-
tional preferences of the achiral ligand will be influenced
by its interaction with the chiral ligand. The enantiomeric
conformations of the unbound achiral ligand (L) become
diastereomeric and differ in energy in M(L*)L. If the achiral
ligand in a catalyst M(L*)L is in a chiral conformation, it
can have an integral, or even a dominant, role in the relay
of chiral information to the substrate in an asymmetric
process.
epoxidation with achiral manganese salen complexes resulted
in high enantioselectivities with resolved N-oxide ligands.4
In the first successful report of optimization of an asymmetric
catalyst by modification of large, flexible achiral ligands,
we demonstrated that variation of meso ligands in M(L*)2L
had a profound impact on the enantioselectivity of the
catalyst.7 Taken together, these results indicate that optimiza-
tion of asymmetric catalysts can be accomplished through
variation of conformationally flexible achiral ligands rather
than using more costly resolved ligands.
(3) Hashihayata, T.; Ito, Y.; Katsuki, T. Synlett 1996, 1079-1081.
(4) Miura, K.; Katsuki, T. Synlett 1999, 783-785.
(5) Chavarot, M.; Byrne, J. J.; Chavant, P. Y.; Guindet, P.; Vallee, Y.
Tetrahedron: Asymmetry 1998, 9, 3889-3894.
(6) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.;
Noyori, R. Angew. Chem., Int. Ed. 1999, 38, 495-497.
(7) Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 1802-1803.
(8) Vogl, E. M.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed. .
1999, 38, 1570-1577.
(9) Mun˜iz, K.; Bolm, C. Chem. Eur. J. 2000, 6, 2309-2316.
(10) Reetz, M. T.; Neugebauer, T. Angew. Chem., Int. Ed. 1999, 38,
179-181.
Recently published results indicate the effectiveness with
which flexible achiral ligands can be used in asymmetric
catalysis.2-10 Pioneering work by Katsuki2,3 in the asymmetric
† Dedicated to Professor D. C. Bradley, a pioneer in metal alkoxide
chemistry.
(1) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley & Sons: New York, 1994.
(2) Hashihayata, T.; Ito, Y.; Katsuki, T. Tetrahedron 1997, 53, 9541-
9552.
10.1021/ol016003d CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/09/2001

In this Letter we employ a conceptually new approach to
the use of achiral ligands in asymmetric catalysis. This
concept involves ligands that are symmetric in certain metal
coordination geometries but can become asymmetric on
binding an additional ligand. We propose that this feature is
responsible for the significant changes in the enantioselec-
tivity of the catalyst (from 9% R to 83% S) in the asymmetric
addition of alkyl groups to aldehydes (eq 1). Furthermore,
the concept outlined herein is general and potentially
applicable to many asymmetric catalysts.
Several groups have used substituted 2,2′-methylene-bis-
(phenol) ligands (MBP-H2 1, Figure 1) to prepare polym-
Figure 2. When X ) Cl, S ) THF, coordination of THF leads to
two enantiomeric five-coordinate titanium centers (3). When X )
OR* and S ) aldehyde substrate, the five-coordinate titanium
complexes (5) are diastereomers.
Figure 1.
Our test reaction for this idea was the asymmetric transfer
of alkyl groups to aldehydes from diethylzinc.18,19 This
reaction is particularly suitable because it has a highly
ordered transition state, making it very sensitive to catalyst
modification.19-24
In the presence of the resolved alkoxide complex (S)-Ti-
(OR*)4 [OR* ) (S)-OCHEt(p-Tol)] without any other ligands
added, the asymmetric addition resulted in formation of the
(S)-alcohol with 39% ee (eq 1 and Table 1, entry 13).
A series of achiral derivatives of MBP-H2 (20 mol %)
were combined with Ti(OR*)4 in the asymmetric addition
to aldehydes (eq 1). The reactions were run for 40 h (45 to
erization catalysts of the type (MBP)MX2 with group(IV)
metals (Figure 1).11-16 As illustrated in Figure 1, the MBP
ligand in 2 adopts a boat-type conformation in which the
methylene hydrogens are inequivalent by NMR spectrometry
at room temperature.
The four-coordinate (MBP)TiCl2 (2, X ) Cl) contains a
plane of symmetry and is achiral. Okuda and co-workers
have shown that (MBP)TiCl2 coordinated THF, forming
(MBP)TiCl2(THF) in which the MBP oxygens occupied
apical and equatorial positions (Figure 2).14
Because of the inequivalence of the MBP oxygens in
(MBP)TiCl2(THF), the (MBP)Ti metallocycle is asymmetric
and (MBP)TiCl2(THF) exists as enantiomers. Similar ge-
ometries were reported by Floriani for (MBP)Zr(BH4)2THF12
and by Hessen for (MBP)Ti(OTf)(η2-2-C6H4-CH2NMe2).17
We imagined that if it were possible to substitute a substrate
for the THF in one of the enantiomers of (MBP)TiCl2(THF),
the (MBP)Ti metallocycle would provide an asymmetric
environment for the substrate, differentiating its prochiral
faces. Intrigued by this prospect, we explored the possibility
of using the metal geometry-induced ligand asymmetry of
the (MBP)Ti metallocycle to influence the relay of chiral
information in an asymmetric reaction.
99% conversion, see the Supporting Information for details);
however, ee values are reported at low conversion (5-8%)
to avoid complications arising from autoinduction (eq 1,
Table 1). Examination of the results indicates that addition
of achiral MBP ligands can have a striking effect on the ee
of the product [9% (R) to 83% (S)]. MBP-H2 ligands with
small substituents R gave lower enantioselectivities (entries
1-5). However, it is noteworthy that when R ) H the
resulting catalysts exhibited considerable differences in
(11) van der Linden, A.; Schaverien, C. J.; Meijboom, N. J. Am. Chem.
Soc. 1995, 117, 3008-3021.
(12) Corazza, F.; Floriani, C.; Chiesi-Villa, A. Inorg. Chem. 1991, 30,
145-148.
(13) Floriani, C.; Corazza, F.; Lesueur, W.; Chiesi-Villa, A.; Guastini,
C. Angew. Chem., Int. Ed. Engl. 1989, 28, 66-67.
(14) Okuda, J.; Fokken, S.; Kang, H.-C.; Massa, W. Chem. Ber. 1995,
128, 221-227.
(18) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833-856.
(19) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824.
(20) Goldfuss, B.; Houk, K. N. J. Org. Chem. 1998, 63, 8998-9006.
(21) Goldfuss, B.; Steigelmann, M.; Khan, S. I.; Houk, K. N. J. Org.
Chem. 2000, 65, 77-82.
(15) Sernetz, F. G.; Mu¨lhaupt, R.; Fokken, S.; Okuda, J. Macromolecules
1997, 30, 1562-1569.
(22) Vidal-Ferran, A.; Moyano, A.; Pericas, M. A.; Riera, A. Tetrahedron
Lett. 1997, 38, 8773-8776.
(16) Takeuchi, D.; Nakamura, T.; Aida, T. Macromolecules 2000, 33,
725-729.
(17) Gielens, E. E. C. G.; Dijkstra, T. W.; Berno, P.; Meetsma, A.;
Hessen, B.; Teuben, J. H. J. Organomet. Chem. 1999, 591, 88-95.
(23) Yamakawa, M.; Noyori, R. Organometallics 1999, 18, 128-133.
(24) Rasmussen, T.; Norrby, P.-O. J. Am. Chem. Soc. 2001, 123, 2464-
2465.
2162
Org. Lett., Vol. 3, No. 14, 2001

coordinate 4 (Figure 2) exists as a single enantiomer.
Coordination of the substrate (S) can give six trigonal
bipyramidal isomers (Figure 3).
Table 1. 2,2-Methylene Bis(phenol) Derivatives 1a-l
(MBP-H2) Used in the Asymmetric Addition of Alkyl Groups
to Aldehydes
Figure 3. Possible geometries of substrate adducts. Diastereomers
which are generated by inversion of the MBP ligand are not shown.
In isomers A-C the MBP ligand is bound through apical
and equatorial positions as in the structures of (MBP)TiCl2-
(THF), (MBP)Zr(BH4)2THF, and (MBP)Ti(OTf)(η2-2-C6H4-
CH2NMe2) whereas in D-F it binds only in the equatorial
plane. Investigation into the dynamics of geometrical changes
along a reaction pathway in species of this type has long
plagued studies in catalysis due to difficulties associated with
direct observation of reactive species. This system is no
exception, especially given the paucity of information
concerning the zinc in these Ti/Zn-based systems.19
Nonetheless, examination of possible titanium-aldehyde
interactions is informative. In D-F the MBP ligand is
approximately symmetric with respect to the substrate and
the chirality would be transferred from just one (D, F) or
two (E) proximal chiral alkoxide ligands. In contrast, in
geometries A-C the MBP ligand is asymmetric with respect
to the bound substrate. Because of the large impact of the
MBP ligand on the ee of the product [from 9% ee (R) to
83% ee (S)], it is likely that the MBP ligand is directly
involved in the transfer of asymmetry to the substrate. We
favor coordination geometry A based on Okuda’s structural
determination (Figure 1) and our structure of (MBP)Ti-
(OR*)2(NMe2H), 6g, [OR* ) (S)-OCHEt(4-C6H4-Cl)]
shown in Figure 4. In this complex the HNMe2 is a substrate
analogue and is trans to the axial MBP phenoxide oxygen
in the distorted trigonal bipyramidal geometry.
enantioselectivity from that of the background reaction [9%
ee (R) in entry 2 vs 39% ee (S)]. As the size of the R group
was increased to t-Bu, the enantioselectivities rose markedly
(entries 6-8). When R ) adamantyl (entry 9), the product
ee reached 83%. Substitution in the methylene position
(entries 11 and 12) led to a decrease in ee values. (MBP)-
Ti(OR*)2 (5g) was prepared from 1g, Ti(OiPr)4, and 2R*OH
by removal of the volatile materials and found to be in
equilibrium with (MBP)2Ti and Ti(OR*)4.14 When this
mixture was combined with an additional 5 equiv of
Ti(OR*)4, as under the reaction conditions, greater than 95%
of the MBP ligand was determined to be in (MBP)Ti(OR*)2
(1H NMR). Using an equilibrium mixture of (MBP)Ti(OR*)2,
(MBP)2Ti, and Ti(OR*)4 gave slightly higher ee values (83%
vs 79% ee in entry 7). The enantioselectivity with 1i and
Ti(OR*)4 (83% at 20 mol % and 87% stoichiometrically) is
25,26
approaching that of BINOL and Ti(OiPr)4
(89% ee in
our hands).
Our working hypothesis on the mechanism of the chirality
relay involving (MBP)Ti complexes is as follows. Four-
(25) Zhang, F.-Y.; Yip, C.-W.; Cao, R.; Chan, A. S. C. Tetrahedron:
Asymmetry 1997, 8, 585-589.
(26) Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38, 6233-6236.
Org. Lett., Vol. 3, No. 14, 2001
2163

tetrahedral to trigonal bipyramidal on coordination of a
substrate can induce asymmetry in the (MBP)Ti metallocycle.
Once in an asymmetric geometry the (MBP)Ti moiety can
participate in, or even control, the relay of asymmetry to
the aldehyde substrate. Furthermore, we propose that catalysts
with achiral ligands that become asymmetric when the
catalyst binds the substrate will be more effective in the
development and optimization of asymmetric catalysts.
Acknowledgment. This work was supported by the
National Science Foundation (CHE-9733274) and the Na-
tional Institute of Health (GM58101). P.J.W. is a Camille
Dreyfus Teacher Scholar.
Supporting Information Available: Characterization of
ligands, procedures for the asymmetric additions reactions,
and details of the structure of 6g. This material is available
free of charge via the Internet at http://pubs.acs.org.
Figure 4. Structure of 6g. The 4-chlorophenyl groups are omitted
for clarity. Bond distances and angles are unexceptional and are
located in the Supporting Information.
OL016003D
In summary, substrate coordination can temporarily in-
crease the number of stereocenters in a catalyst.27,28 In this
system, it is proposed that a change in metal geometry from
(27) Brunner, H. Angew. Chem., Int. Ed. 1999, 38, 1194-1208.
(28) von Zelewsky, A. Stereochemistry of Coordination Compounds; John
Wiley & Sons Ltd.: West Sussex, 1996.
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Org. Lett., Vol. 3, No. 14, 2001