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SPECIAL FEA TURE PERSPECTIVE

Design of chiral ligands for asymmetric catalysis:


From C2-symmetric P,P- and N,N-ligands to sterically
and electronically nonsymmetrical P,N-ligands
Andreas Pfaltz* and William J. Drury III
Department of Chemistry, University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland

Edited by Barry M. Trost, Stanford University, Stanford, CA, and approved February 26, 2004 (received for review November 4, 2003)

For a long time, C2-symmetric ligands have dominated in asymmetric catalysis. More recently, nonsymmetrical modular P,N-ligands
have been introduced. These ligands have been applied successfully in various metal-catalyzed reactions and, in many cases, have
outperformed P,P- or N,N-ligands.

ost asymmetric catalysts lar advantage in mechanistic studies be-

M that have been developed


so far are metal complexes
with chiral organic ligands.
The chiral ligand modifies the reactivity
and selectivity of the metal center in
cause it facilitates analysis of the ligand–
substrate interactions that may be
responsible for enantioselection.
The design principles that led Dang
and Kagan to this ligand had a marked
such a way that one of two possible en- influence on the course of research in
antiomeric products is formed preferen- asymmetric catalysis, and many diphos-
tially. Based on this concept, many phine ligands that were introduced sub-
metal complexes have been found that sequently were patterned after DIOP.
catalyze various reactions with impres- Knowles (7), for example, prepared a
sive enantioselectivity. Despite impres- dimeric analogue of one of his previ-
sive progress in this field, the design of ously synthesized monophosphines,
suitable chiral ligands for a particular which he termed DiPAMP (Fig. 2).
application remains a formidable task. Based on this ligand, he developed an
The complexity of most catalytic processes industrial catalytic asymmeric process,
precludes a purely rational approach an Rh-catalyzed hydrogenation of a
based on mechanistic and structural cri- dehydro-amino acid derivative, used as
teria. Therefore, most new chiral cata- the key step in the production of 3,4-
lysts are still found empirically, with dihydroxy-L-phenylalanine (L-Dopa).
chance, intuition, and systematic screening Since then, the concept of C2 symmetry
all playing important roles. Nevertheless, has led to many further highly efficient
for certain reactions such as Rh-catalyzed diphosphines, such as BINAP (8) and
hydrogenation (1, 2) or Pd-catalyzed Fig. 1. Privileged ligand structures.
DuPhos (9), and it has been applied suc-
allylic substitution (3, 4), the mechanism cessfully to other ligand classes with coor-
is known, allowing at least a semira- dinating N or O atoms (Fig. 1) (5, 10–13).
tional approach to catalyst development. C2-symmetric ligand with two equivalent
P atoms was to reduce the number of We, too, were attracted by the advan-
Moreover, useful general concepts have tages and aesthetics of C2 symmetry
been developed during the last three possible isomeric metal complexes, as
well as the number of different sub- when we introduced the semicorrins
decades that greatly facilitate the devel- (Fig. 3) as a new type of ligand. To our
opment of new chiral ligands, even in strate–catalyst arrangements and reac-
tion pathways, when compared with a delight, these ligands gave excellent results
the absence of mechanistic information. in the Cu-catalyzed cyclopropanation of
nonsymmetrical ligand. This conse-
Some of these concepts are described in olefins and Co-catalyzed conjugate re-
quence of C2 symmetry can have a benefi-
the following sections, mainly from the duction of ␣,␤-unsaturated carboxylic
cial effect on enantioselectivity because
perspective of our own research. acid derivatives (10). The planar ␲-
the competing less-selective pathways
are possibly eliminated. Because fewer system and the two five-membered rings
C2-Symmetric Ligands
reaction intermediates must be taken confine the conformational flexibility,
Of the thousands of chiral ligands pre- which simplifies a prediction of the 3D
into account, C2 symmetry is of particu-
pared so far, a relatively small number structure of semicorrin metal complexes.
of structural classes stand out because The two substituents at the stereogenic
of their broad applicability. These ‘‘priv- centers are positioned in close proximity
ileged ligands,’’ as they may be called to the coordination site, and they shield
(5), allow high levels of enantiocontrol the metal center from two opposite di-
in many different metal-catalyzed reac-
tions. A survey of their structures reveals
that, at first sight, a surprisingly large This paper was submitted directly (Track II) to the PNAS
number of them possess C2 symmetry office.
(Fig. 1). Abbreviation: PHOX, phosphinooxazoline.
The C2-symmetric ligand DIOP (Fig. *To whom correspondence should be addressed. E-mail:
2) was introduced by Dang and Kagan Fig. 2. Kagan’s DIOP and Knowles’ DiPAMP andreas.pfaltz@unibas.ch.
in 1971 (6). The reason for choosing a ligands. © 2004 by The National Academy of Sciences of the USA

www.pnas.org兾cgi兾doi兾10.1073兾pnas.0307152101 PNAS 兩 April 20, 2004 兩 vol. 101 兩 no. 16 兩 5723–5726


Fig. 3. Structure of a semicorrin metal complex.

rections (Fig. 3). Therefore, these sub- Fig. 6. Structure of PHOX ligands and x-ray data
stituents are expected to have a strong of an allyl–Pd complex.
direct effect on a reaction taking place
in the coordination sphere.
Variation of the semicorrin structure illustrated by the industrial synthesis of
led to analogous bisoxazoline (BOX) the important herbicide metolachlor
ligands; Fig. 1).† Ligands of this type (Fig. 5) (23). The key step, an Ir-
were reported independently by research Fig. 4. Achiwa’s hydrogenation studies with de- catalyzed imine hydrogenation, was
groups in 1990–1991 (14–21), and since symmetrized DIOP. improved dramatically by systematic
then they have been established as one variation of the individual substituents
of the most versatile ligand classes for at the P atoms. In contrast to applica-
asymmetric catalysis (10, 11). Bisoxazo- ordinated substrate is primarily steric in tions in the pharmaceutical sector, ex-
lines are attractive because various de- nature, whereas Ptrans exerts mainly an tremely high enantioselectivity was not
rivatives can be readily prepared from electronic effect (electronic effects of a required here. The crucial issues in this
simple amino alcohols as chiral precur- ligand are transmitted preferentially to case were the turnover number and rate.
sors, allowing the ligand to be tailored the trans-coordination site). Similar ar- Under carefully optimized conditions
to a specific catalytic process. It is unre- guments can be given for other interme- with the chiral ligand XYLIPHOS, more
alistic to expect that one particular li- diates in the catalytic cycle. Because the than a million turnovers and extremely
gand will exert perfect enantiocontrol in two phosphine groups influence the re- high rates could be achieved in very
many reactions for many different sub- activity and selectivity of the metal cata- concentrated solution, making this com-
strates. Therefore, it is crucial that the lyst in different manners, their structures mercial process highly attractive.
synthesis is flexible and simple, to allow should be optimized individually, to ob-
structural optimization of a ligand for a tain a perfect ligand. From C2-Symmetric Bisoxazolines to
particular application. Achiwa and coworkers have illustrated Nonsymmetrical P,N-Ligands
this by desymmetrizing the DIOP ligand An even more effective way to desym-
C2 Versus C1 Symmetry (Fig. 4). Indeed, replacing one of the metrize a P,P- or N,N-ligand is to switch
Although the concept of C2 symmetry diphenylphosphine units by a more elec- to mixed donor P,N-ligands, because of
has been very successful, there is no tron-rich dicyclohexylphosphino group the distinctly different characteristics of
fundamental reason why C2-symmetric resulted in a significant increase of both a ‘‘soft’’ P-ligand with ␲-acceptor prop-
ligands should necessarily be superior to catalyst activity and enantioselectivity. erties and a ‘‘hard’’ N-ligand acting pri-
their nonsymmetrical counterparts. In Although this strategy of desymmetriz- marily as an ␴-donor.‡ This line of
ing C2-symmetric ligands appears to be thought led us and, independently,
fact, efficient nonsymmetrical ligands
straightforward, it does not necessarily Helmchen (24) and Williams (42) to a
have been found that in some reactions
guarantee an improvement of the per- new, highly versatile class of ligands, the
give even higher enantioselectivities
formance of the catalyst. If catalytically phosphinooxazoline (PHOX) ligands 1
than the best C2-symmetric ligands.
active, isomeric metal complexes are (Fig. 6).
Moreover, convincing arguments can be
formed in which the coordinating atoms The reaction that we were investigat-
made for certain reactions as to why
(e.g., Pcis and Ptrans of ligand B; Fig. 4) ing at that time, an enantioselective Pd-
nonsymmetrical ligands with two elec-
have exchanged positions, all efforts to catalyzed allylic substitution, is shown in
tronically and sterically divergent coordi-
individually optimize the coordinating Fig. 7 (3, 4). Starting from a racemic
nating units should, in principle, permit
groups are futile. However, if this prob- mixture of allylic acetates 2 and ent-2,
more effective enantiocontrol than C2-
lem can be avoided (which is often diffi- containing two identical substituents at
symmetric ligands.
cult), the results may be spectacular, as the allylic termini, an allyl complex 3 is
Asymmetric hydrogenation with Rh
catalysts provides an instructive exam- formed. Because both allylic acetate 2
ple. As pointed out by Achiwa and co- and ent-2 are converted to the same inter-
workers (22), the intermediates in the mediate, the stereochemical information is
catalytic cycle are nonsymmetrical and, lost in this step. It is the subsequent
consequently, the two phosphine groups step, a nucleophilic addition to the allyl
interact with a metal-bound substrate in system, that determines which enantio-
an electronically and sterically different mer is formed. Nucleophilic attack at C
manner. In a substrate complex (Fig. 4), (1) leads to product 4, attack at C (3) to
the interaction between Pcis and the co- the enantiomer ent-4. Consequently, the
problem of inducing enantioselectivity is

†Other oxazoline-based ligands have been reported by


Brunner and Obermann [Brunner, H. & Obermann U. ‡Applicationof chiral P,N-ligands was reported by Hayashi
(1989) Chem. Ber. 122, 499 –507] and Nishiyama et al. et al. [Hayashi, T., Tajika, M., Tamao, K. & Kumada, M.
[Nishiyama, H., Sakaguchi, H., Nakamura, T., Horihata, M. Fig. 5. Industrial process for the production of (1976) J. Am. Chem. Soc. 98, 3718 –3719]. However, these
Kondo, M. & Itoh, K. (1989) Organometallics 8, 846 – 848]. (S)-metolachlor. ligands were chosen for different reasons.

5724 兩 www.pnas.org兾cgi兾doi兾10.1073兾pnas.0307152101 Pfaltz and Drury


Fig. 8. Modular construction of PHOX ligands 1.

isopropyl-allyl acetates, only moderate


enantioselectivities were recorded for
Fig. 7. Mechanism of enantioselective Pd- the ‘‘smaller’’ dimethyl- and diethyl-
catalyzed allylic substitution. substituted analogues. In this respect,
the PHOX ligands display opposite reac-
tivity when compared with the diphos-
equivalent to controlling the regioselect- phine ligands, developed by Trost, that
ivity of nucleophilic attack. give excellent results with ‘‘small’’ sub-
Initially, we tested bisoxazolines and strates but unsatisfactory enantiomeric
related C2-symmetric ligands in this re- excess and yield with 1,3-diphenylallyl
action. Although good results were ob- acetate (3, 4). However, because of the
tained in certain cases, the scope of this modular nature of the PHOX ligands
ligand class proved to be limited. There- (Fig. 8), many different derivatives Fig. 9. Ligand optimization for regioselective
and enantioselective allylic substitution.
fore, we turned our attention to other could be readily synthesized, which
ligands such as the PHOX ligands 1 made it possible to optimize the ligand
(Fig. 6) (24). From this ligand class, we structure for certain substrates that ini-
hoped to gain an additional means of tially had given unsatisfactory results. In (Fig. 9) (24, 27). The analogous methyl-
controlling the regioselectivity, based on this way, Helmchen (24) achieved high allyl ester gave unsatisfactory results.
electronic effects. In contrast to allyl enantioselectivities with small substrates However, a further modification of
complexes with C2-symmetric N,N- or such as 1,3-dimethylallyl or cylopentenyl P,N-ligands was reported recently,
P,P-ligands, complexation by P,N- and cylohexenyl acetate. which resulted in high regioselectivity
ligands should result in effective elec- We wondered whether the ligand and enantioselectivity for this substrate
tronic discrimination of the allylic termini structure could also be adapted to the as well (28).
because of the different trans-influence of problems of regiocontrol and enantio- Although the PHOX ligands were de-
the two electronically dissimilar hetero control for monsubstituted allyl esters veloped originally for Pd-catalyzed al-
atoms. (For other effective approaches (Fig. 9). In general, Pd catalysts induce lylic substitution, they could be applied
to enantiocontrol in Pd-catalyzed allylic the formation of the linear, achiral
substitution, see refs. 3 and 4.) Elec- product 8 with high preference over the
tronic differentiation of this type had branched, chiral regioisomer 7. [Other
been demonstrated by Faller et al. (25) metal catalysts (e.g., Mo, W, and Ir)
(stoichiometric reaction of allyl–Mo show opposite regioselectivity in favor
complexes with CO and (NO)⫹ as trans of the branched product. Examples of
ligands) and by Åkermark et al. (26) chiral catalysts of this type are
(NMR studies of allyl–Pd complexes). W–PHOX and Ir–PHOX complexes, as
Crystal structure and NMR data con- well as Mo complexes with N,N-ligands
firmed that complexation with a PHOX (3, 4).] By rendering the transition state
ligand results in a strong electronic dif- more cationic in character, nucleophilic
ferentiation of the allylic termini, as re- attack at the substituted allyl terminus
flected by the different Pd–C distances should become more favorable. Conse-
(Fig. 6) (3, 24). As we had hoped, Pd– quently, we introduced electronegative
PHOX complexes were found to be substituents on the P atom to increase
highly reactive and selective catalysts, the electrophilicity at the Pd center.
providing up to 99% enantiomeric ex- Also, by introduction of sterically de-
cess with a range of C-terminal and N- manding P-substituents, we wanted to
terminal nucleophiles (Fig. 7). The se- shift the equilibrium between the inter-
lectivities could be rationalized by a mediate allyl complexes toward isomer
combination of steric and electronic 6. Because of the trans influence of the
effects, the preference of nucleophilic P atom, the predominance of this iso-
attack at the allylic C atom trans the mer should promote nucleophilic attack
phosphino group being a key factor (24). at the substituted terminus. These con-
siderations led us to ligands 9 and 10,
The Importance of a Modular Ligand which in contrast to the original PHOX
Structure ligands 1 induced formation of the
Although PHOX ligands gave excellent branched products with high regioselec- Fig. 10. Ir-catalyzed asymmetric hydrogenation
results in reactions of diphenyl- and di- tivity and excellent enantioselectivity of olefins.

Pfaltz and Drury PNAS 兩 April 20, 2004 兩 vol. 101 兩 no. 16 兩 5725
successfully to various other metal- Again, the modular nature of the ciency and good to excellent enantio-
catalyzed processes, including Heck re- PHOX ligands made it possible to ex- selectivity.
actions, Cu-catalyzed 1,4-additions, and tend the application range of these cata-
Ru-catalyzed transfer hydrogenation of lysts. Among the many PHOX analogues Conclusion
ketones (24). Another reaction class that that we tested, readily available phos- The concept of steric and electronic de-
gave very promising results was Ir- phinites of type 12 and 13 proved to be symmetrization has led to a new class of
catalyzed asymmetric hydrogenation of the most versatile ligands. Subsequently, chiral ligands, the PHOX ligands 1 and
CAC and CAN bonds (29, 30). We we added phosphinoimidazolines, such related P,N-ligands. Because of the
modular construction, these ligands
thought that Ir–PHOX complexes might as type 14, to our collection of ligands
could be adapted to many metal-
behave like chiral analogues of the (32, 33), as well as pyridine- and catalyzed reactions and in many cases,
Crabtree catalyst, an achiral (tricyclo- quinoline-derived P,N-ligands of type 15 they outperformed P,P- or N,N-ligands.
hexylphosphine)(pyridine)Ir(I) complex and 16 (34), all of which gave very Chiral ligands based on other combina-
that displays unusually high reactivity promising results. Recently, other re- tions of coordinating atoms, such as the
toward trisubstituted and tetrasubsti- search groups have become interested in P,S; P,O; or N,S varieties, have also
tuted olefins (31). Pleasingly, after opti- this class of catalysts and have reported been reported and, considering the
mization of the catalyst structure and additional variants of Ir complexes with enormous diversity of possible ligand
the reaction parameters, good to excel- P,N-ligands (35–40) and, as a further structures of this type, further work in
lent enantiomeric-excess values and high modification, oxazoline ligands with a this area seems worthwhile. Although
turnover numbers could be obtained in heterocyclic carbene unit instead of a the concept of C2 symmetry will remain
the hydrogenation of imines and unfunc- phosphino group (41). Clearly, Ir com- an attractive design principle for new
tionalized aryl-substituted olefins (Fig. plexes derived from P,N-ligands ligands, sterically and electronically non-
10). Until now, olefins of this kind could represent a new class of catalysts that symmetrical heterobidentate ligands are
not be hydrogenated with high enantio- significantly expands the application likely to play an increasing role in the
selectivity at such low catalyst loadings. range of asymmetric hydrogenation. Sev- development of asymmetric catalysis.
In this respect, Ir-PHOX complexes eral types of functionalized and nonfunc-
This work was supported by the Swiss Na-
clearly distinguish themselves from Ru tionalized olefins, for which no suitable tional Science Foundation, the Federal Com-
and Rh catalysts that require a polar catalysts were known previously, can mission of Technology and Innovation (KTI),
coordinating group near the CAC bond. now be hydrogenated with high effi- and Solvias.

1. Brown, J. M. (1999) in Comprehensive Asymmetric 15. Müller, D., Umbricht, G., Weber, B. & Pfaltz, A. 30. Schnider, P., Koch, G., Prétôt, R., Wang, G.,
Catalysis, eds. Jacobsen, E. N., Pfaltz, A. & (1991) Helv. Chim. Acta 74, 232–240. Bohnen, F. M., Krüger, C. & Pfaltz, A. (1997)
Yamamoto, H. (Springer, Berlin), Vol. 1, pp. 16. Evans, D. A., Woerpel, K. A., Hinman, M. M. & Chem. Eur. J. 3, 887–892.
121–182. Faul, M. M. (1991) J. Am. Chem. Soc. 113, 726–728. 31. Crabtree, R. H. (1979) Acc. Chem. Res. 12, 331–337.
2. Ohkuma, T., Kitamura, M. & Noyori, R. (2000) in 17. Corey, E. J., Imai, N. & Zhang, H.-Y. (1991) J. Am. 32. Menges, F. Neuburger, M. & Pfaltz, A. (2002) Org.
Catalytic Asymmetric Synthesis, ed. Ojima, I. Chem. Soc. 113, 728–729. Lett. 4, 4713–4716.
(Wiley–VCH, New York), 2nd Ed., pp. 1–110. 18. Helmchen, G., Krotz, A., Ganz K. T. & Hansen, D. 33. Busacca, C. A., Grossbach, D., So, R. C., O’Brien,
3. Pfaltz, A. & Lautens, M. (1999) in Comprehensive (1991) Synlett, 257–259. E. M. & Spinelli, E. M. (2003) Org. Lett. 5,
Asymmetric Catalysis, eds. Jacobsen, E. N., Pfaltz, 19. Hall, J., Lehn, J.-M., DeCian, A. & Fischer, J. 595–598.
A. & Yamamoto, H. (Springer, Berlin), Vol. 2, pp. (1991) Helv. Chim. Acta 74, 1–6. 34. Drury, W. J., III, Zimmermann, N., Keenan, M.,
833–884. 20. Onishi, M. & Isagawa, K. (1991) Inorg. Chim. Acta Hayashi, M., Kaiser, S., Goddard, R. & Pfaltz, A.
4. Trost, B. M. & Lee, C. (2000) in Catalytic Asym- 179, 155–156. (2004) Angew. Chem. Int. Ed. 43, 70–74.
metric Synthesis, ed. Ojima, I. (Wiley–VCH, New 21. Yang, R.-Y., Chen, Y.-H. & Dai, L.-X. (1991) Acta 35. Hou, D.-R., Reibenspies, T. J., Colacot, T. J.
York), 2nd Ed., pp. 593–649.
Chim. Sin. 49, 1038–1040. & Burgess, K. (2001) Chem. Eur. J. 7,
5. Yoon, P. Y. & Jacobsen, E. N. (2003) Science 299,
22. Inoguchi, K., Sakuraba, S. & Achiwa, K. (1992) 5391–5400.
1691–1693.
Synlett, 169–178. 36. Cahill, J. P., Lightfoot, A. P., Goddard, R., Rust,
6. Dang, T. P. & Kagan, H. B. (1971) J. Chem. Soc.
23. Blaser, H.-U. (2002) Adv. Synth. Catal. 344, 17–31. J. & Guiry, P. J. (1998) Tetrahedron: Asymmetry 9,
Chem. Commun., 481.
24. Helmchen, G. & Pfaltz, A. (2000) Acc. Chem. Res. 4307–4312.
7. Knowles, W. S. (2003) Adv. Synth. Catal. 345, 3–13.
33, 336–345. 37. Cozzi, P. G., Menges, F. & Kaiser, S. (2003)
8. Noyori, R. (2003) Adv. Synth. Catal. 345, 15–32.
9. Burk, M. J., Gross, M. F., Harper, G. P., Kalberg, 25. Faller, J. W., Chao, K. H. & Murray, H. H. (1984) Synlett, 833–836.
C. S., Lee, J. R. & Martinez, J. P. (1996) Pure Appl. Organometallics 3, 1231–1240. 38. Xu, G. & Gilbertson, S. R. (2003) Tetrahedron
Chem. 68, 37–44. 26. Åkermark, B., Krakenberger, B. & Hansson, S. Lett. 44, 953–955.
10. Pfaltz, A. (1993) Acc. Chem. Res. 26, 339–345. (1987) Organometallics 6, 620–628. 39. Tang, W., Wang, W. & Zhang, X. (2003) Angew.
11. Ghosh, A. K., Mathivanan, P. & Cappiello, J. 27. Prétôt, R. & Pfaltz, A. (1998) Angew. Chem. Int. Chem. Int. Ed. 42, 943–946.
(1998) Tetrahedron: Asymmetry 9, 1–45. Ed. 37, 323–325. 40. Bunlaksananusorn, T., Polborn, K. & Knochel,
12. Chen, Y., Yekta, S. & Yudin, A. K. (2003) Chem. 28. You, S.-L., Zhu, X.-Z., Luo, Y.-M., Hou, X.-L. & P. (2003) Angew. Chem. Int . Ed . 42,
Rev. (Washington, D.C.) 103, 3155–3212. Dai, L.-X. (2001) J. Am. Chem. Soc. 123, 7471–7472. 3941–3943.
13. Seebach, D., Beck, A. K. & Heckel, A. (2001) 29. Pfaltz, A., Blankenstein, J., Hilgraf, R., Hörmann, 41. Powell, M. T., Hou, D.-R., Perry, M. C., Cui, X. &
Angew. Chem. Int. Ed. Engl. 40, 92–138. E. McIntyre, S., Menges, F., Schönleber, M., Burgess, K. (2001) J. Am. Chem. Soc. 123, 8878–
14. Lowenthal, R. E., Abiko, A. & Masamune, S. Smidt, S. P., Wüstenberg, B. & Zimmermann, N. 8879.
(1990) Tetrahedron Lett. 31, 6005–6008. (2003) Adv. Synth. Catal. 345, 33–43. 42. Williams, J. M. J (1996) Synlett, 705–710.

5726 兩 www.pnas.org兾cgi兾doi兾10.1073兾pnas.0307152101 Pfaltz and Drury