Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-10
2002-06-04
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S184000, C564S149000, C562S450000, C562S512000, C568S715000, C568S814000
Reexamination Certificate
active
06399787
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to chiral phosphine ligands for asymmetric catalysis.
2. Description of Related Arts
Molecular chirality plays a very important role in science and technology. The biological activities of many pharmaceuticals, fragrances, food additives and agrochemicals are often associated with their absolute molecular configuration. While one enantiomer gives a desired biological function through interactions with natural binding sites, another enantiomer usually does not have the same function and sometime has deleterious side effects.
The sale of enantiomerically pure pharmaceuticals was about $61 billion in 1995, about 26 percent of the $240 billion total market for final formulation pharmaceuticals (Cannaesa, M. S. Symposium, Chiral '97, Matrix, 1997; Cannarsa, M. J. Chemistry & Industry, 1996, May 20, page 374). There is a growing demand in the pharmaceutical and fine chemicals industries to develop cost-effective processes for the manufacture of single-enantiomeric products.
To meet this fascinating challenge, chemists have explored many approaches for acquiring enantiomerically pure compounds ranging from optical resolution and structural modification of naturally occurring chiral substances to asymmetric catalysis using synthetic chiral catalysts and enzymes. Among these methods, asymmetric catalysis is perhaps the most efficient because a small amount of a chiral catalyst can be used to produce a large quantity of a chiral target molecule. During the last two decades, great attention has been devoted to discovering new asymmetric catalysts and many commercial industrial processes have used asymmetric catalysis as the key step in the production of enantiomerically pure compounds. See (a) Morrison, J. D., Ed. Asymmetric Synthesis Academic Press: New York, 1985, Vol. 5; (b) Bosnich, B., Ed. Asymmetric Catalysis Martinus Nijhoff Publishers: Dordrecht, The Netherlands, 1986; (c) Brunner, H. Synthesis 1988, 645; (d) Noyori, R.; Kitamura, M. In Modern Synthetic Methods; Scheffold, R., Ed.; Springer-Verlag: Berlin Hedelberg, 1989, Vol. 5, p 115: (f) Nugent, W. A., RajanBabu, T. V., Burk, M. J. Science 1993, 259, 479; (g) Ojima, I., Ed. Catalytic Asymmetric Synthesis, VCH: New York, 1993; and (h) Noyori, R. Asymmetric Catalysis In Organic Synthesis, John Wiley & Sons, Inc: New York, 1994.
In order to develop efficient synthetic methods that have a real impact in the pharmaceutical industry, it is useful to categorize the chiral building blocks according to their functionality and analyze what is needed in each area. A recent survey by Technology Catalysts International shows that amino acid derivatives, chiral amines, and chiral alcohols comprise over 40 percent of developmental enantiomerically pure pharmaceuticals. Asymmetric hydrogenation plays a dominant role in the manufacture of enantiomerically pure compounds. Major pharmaceutical and fine chemical companies have devoted significant effort in developing and commercializing asymmetric hydrogenation technology. The key element of the research is developing chiral phosphine ligands to increase reaction selectivity and activity.
In fact, asymmetric hydrogenation accounts for major part of all asymmetric synthesis on a commercial scale. Many important advances have been achieved based on the discovery of structurally different chiral phosphine motifs. Some dramatic examples of industrial applications of asymmetric synthesis include Monsanto's L-DOPA synthesis (asymmetric hydrogenation of a dehydroamino acid, 94% ee, 20,000 turnovers with a Rh-DIPAMP complex) (Knowles, W. S., Acc. Chem. Res. 1983, 16, 106), Takasago's L-menthol synthesis (asymmetric isomerization, 98% ee, 300,000 turnovers with a Rh-BINAP complex) (Noyori, R. Science 1990, 248, 1194; Noyori, R. et al., Acc. Chem. Res. 1990, 23, 345) and Ciba-Geigy's (S)-Metolachlor synthesis (asymmetric hydrogenation of an imine, 80% ee, 1,000,000 turnovers with an Ir-ferrocenyl phosphine complex) (see Proceeding of the Conference on Catalysis of Organic Reactions, Spindler, F., et al., Altanta, 1996; Chem. Ind. (Dekker), 1996, 63; Tongni, A. Angew. Chem. lnt. Ed. Engl. 1996, 356, 14575).
Chiral ligands for transition metal-catalyzed reactions play a critical role in asymmetric catalysis. Not only the enantioselectivity depends on the framework of chiral ligands; reactivities can often be altered by changing the steric and electronic structure of the ligands. Since small changes in the ligand can influence the (delta)(delta)G of the rate determining step, it is very hard to predict which ligand can be effective for any particular reaction or substrate. The majority of breakthroughs in asymmetric catalysis have come from the empirical match of the right ligands with the right transition metals. Perusal of the literature shows that over 100 chiral phosphines were investigated to discover the original L-Dopa asymmetric hydrogenation catalyst.
While ideas based on conformational analysis or steric and electronic properties are useful for ligand design and for generating working hypotheses, overemphasis on these ideas can potentially misguide and hinder the development of truly efficient ligands. Creation of a new ligand motif and fine-tuning (trouble-shooting) established chiral ligand systems are equally important in asymmetric catalysis. For example, many chiral diphosphines have similar chemical structures (e.g., chelating bis-diphenyl phosphine with chiral backbones), yet most of these ligands have different profiles in terms of enantioselectivity and activity for transition metal-catalyzed reactions. Understanding of the subtle changes which makes a particular ligand more effective for a certain reaction than another similar ligand is the intellectual frontier of current study in asymmetric catalysis. In the process of creating low molecular weight catalysts with enzymatic properties, the invention of effective chiral ligands is analogous to generating new enzyme frameworks.
The development of chiral phosphines has had a profound impact in the field of asymmetric catalysis.
FIG. 1
shows several important chiral phosphines studied during the last three decades. Knowles' DIPAMP (Knowles, W. S. et al., J. Chem. Soc., Chem. Commun. 1972, 10; Vineyard, B. D. et al., J. Am. Chem. Soc. 1977, 99, 5946) and Kagan's Diop (Kagan, H. B.; Dang, T.-P. J. Am. Chem. Soc. 1972, 94, 6429) ligands were reported for Rh (I) catalyzed asymmetric hydrogenation at about the same time. The great success in asymmetric hydrogenation of a-acylaminoacrylic acids stimulated continuing research on new chiral phosphine ligands.
Various bidentate chiral diphosphines such as Chiraphos (Fryzuk, M. D. et al., J. Am. Chem. Soc. 1977, 99, 6262), BPPM (Achiwa, K. J. Am. Chem. Soc. 1976, 98, 8265; Ojima, I., Tetrahedron Lett. 1980, 21, 1051), DegPhos (Nagel, U., et al., Chem. Ber. 1986, 119, 3326) and ferrocenyl chiral phosphines (Hayashi, T. et al., Fundamental Research in Homogeneous Catalysis, Ishii, Y. et al., (Eds.) Plenum: New York, 1978; Vol. 2, p 159; Hayashi, T., et al., Acc.. Chem. Res. 1982, 15, 395; Ito, Y., et al., Am. Chem. Soc. 1986, 108, 6405) were discovered in both academic labs and in industry. Two benchmark ligands come out of extensive ligand studies: BINAP (Miyashita, A., et al., J. Am. Chem. Soc. 1980, 102, 7932; Miyashita, A., et al., Tetrahedron 1984, 40, 1245; Takaya, H., et al., J. Org. Chem. 1986, 51, 629; Takaya, H., et al., Org. Synth. 1988, 67, 20) in the early 80's is one of the most frequently used bidentate chiral phosphines, and DuPhos (Burk, M. J., et al., Organometallics 1990, 9, 2653; Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518; Burk, M. J., et al., J. Am. Chem. Soc. 993, 115, 10125) in the early 90's has also shown impressive enantioselectivities.
The Rh, Ru and Ir complexes of these ligands have been used as catalysts for asymmetric hydrogenation of olefins, ketones and imines. These ligands are also useful for other asymmetric reactions such as isomerization,
Penn State Research Foundation
Vollano Jean F.
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