There is a growing trend in the pharmaceutical industry to market chiral drugs in enantiomerically pure form in order to provide desired positive effects in humans. Production of enantiomerically pure compounds is important for several reasons. First, one enantiomer often provides a desired biological function through interactions with natural binding sites, but another enantiomer typically does not have the same function or effect. Further, it is possible that one enantiomer has harmful side effects, while another enantiomer provides a desired positive biological activity. To meet this demand for chiral drugs, many approaches for obtaining enantiomerically pure compounds have been explored such as diastereomeric resolution, structural modification of naturally occurring chiral compounds, asymmetric catalysis using synthetic chiral catalysts and enzymes, and the separation of enantiomers using simulated moving bed (SMB) technology.
Asymmetric catalysis is often the most efficient method because a small amount of a chiral catalyst can be used to produce a large quantity of a chiral target molecule. Over the last two decades, more than a half-dozen commercial industrial processes have been developed that use asymmetric catalysis as the key step in the production of enantiomerically pure compounds with a tremendous effort focused on developing new asymmetric catalysts for these reactions (Morrison J. D., ed. Asymmetric Synthesis, Academic Press: New York, 1985:(5); Bosnich B., ed. Asymmetric Catalysis, Martinus Nijhoff Publishers: Dordrecht, Netherlands, 1986; Brunner H., Synthesis, 1988:645; Scheffold R., ed. Modern Synthetic Methods, Springer-Verlag: Berlin Hedelberg, 1989;115(5); Nugent W. A., RajanBabu T. V., Burk M. J., Science, 1993;259:479; Ojima I., ed. Catalytic Asymmetric Synthesis, VCH: New York, 1993; Noyori R., Asymmetric Catalysis In Organic Synthesis, New York: John Wiley & Sons, Inc., 1994).
Chiral phosphine ligands have played a significant role in the development of novel transition metal catalyzed asymmetric reactions to produce enantiomeric excess of compounds with desired activities. The first successful attempts at asymmetric hydrogenation of enamide substrates were accomplished in the late 1970's using chiral bisphosphines as transition metal ligands (Vineyard B. D., Knowles W. S., Sabacky M. J., Bachman G. L., Weinkauff D. J., J. Am. Chem. Soc., 1977;99(18):5946–5952; Knowles W. S., Sabacky M. J., Vineyard B. D., Weinkauff D. J., J. Am. Chem. Soc., 1975;97(9):2567–2568).
Since these first published reports, there has been an explosion of research geared toward the synthesis of new chiral bisphosphine ligands for asymmetric hydrogenations and other chiral catalytic transformations (Ojima I., ed. Catalytic Asymmetric Synthesis, VCH Publishers, Inc., 1993; Ager D. J., ed. Handbook of Chiral Chemicals, Marcel Dekker, Inc., 1999). Highly selective rigid chiral phospholane ligands have been used to facilitate these asymmetric reactions. For example, phospholane ligands are used in the asymmetric hydrogenation of enamide substrates and other chiral catalytic transformations.
BPE, Duphos, and BisP ligands are some of the most efficient and broadly useful ligands developed for asymmetric hydrogenation to date. Burk M. J., Chemtracts 11(11), 787–802 (CODEN: CHEMFW ISSN:1431-9268. CAN 130:38423; AN 1998:698087 CAPLUS) 1998; Burk M. J., Bienewald F., Harris M., Zanotti-Gerosa A., Angew. Chem., Int. ed., 1998;37(13/14):1931–1933; Burk M. J., Casy G. Johnson N. B., J. Org. Chem., 1998;63(18):6084–6085; Burk M. J., Kalberg C. S., Pizzano A., J. Am. Chem. Soc., 1998;120(18):4345–4353; Burk M. J., Harper T. G. P., Kalberg C. S., J. Am. Chem. Soc., 1995;117(15):4423–4424; Burk M. J., Feaster J. E., Nugent W. A., Harlow R. L., J. Am. Chem. Soc., 1993;115(22):10125–10138; Nugent W. A., RajanBabu T. V., Burk M. J., Science (Washington, D.C., 1883-) 1993;259(5094):479–483; Burk M. J., Feaster J. E., Harlow R. L., Tetrahedron: Asymmetry, 1991;2(7):569–92; Burk M. J., J. Am. Chem. Soc., 1991;113(22):8518–8519; Imamoto T., Watanabe J., Wada Y., Masuda H., Yamada H., Tsuruta H., Matsukawa S., Yamaguchi K., J. Am. Chem. Soc., 1998;120(7):1635–1636; Zhu G., Cao P., Jiang Q., Zhang X., J. Am. Chem. Soc., 1997; 19(7):1799–1800. For example, a Rhodium/Duphos complex can be used to selectively form (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, known as pregabalin, which is used as an anti-seizure drug. The S-enantiomer, which is produced in an enantiomeric excess, is preferred because it shows better anticonvulsant activity than the R-enantiomer. Yuen et al., Bioorganic & Medicinal Chemistry Letters, 1994;4:823.
The success of BPE, DuPhos, and BisP transition metal complexes in asymmetric hydrogenations is derived from many factors. For example, substrate to catalyst ratios of up to 50,000/1 have been demonstrated. Also, high rates of substrate conversion to product using low hydrogen pressures have been observed with catalysts made from these ligands.
BPE, Duphos, and BisP have shown high enantioselectivities in numerous asymmetric reactions. Improved reaction of BPE, Duphos, and BisP is attributed to, among other factors, rigidity in their C2-symmetric structure. If the spatial area of a metal/phosphine ligand structure, such as BPE, is divided into four quadrants, as shown in Scheme 1, alternating hindered and unhindered quadrants are formed.

This structural feature creates areas of hindrance in the metal complexes and produces desired stereochemical results in asymmetric hydrogenation reactions. However, there are a variety of reactions, such as catalysis of simple olefins, in which these ligands are not very efficient in terms of activity and selectivity.
Further, there are many characteristics associated with these ligands, which may limit their application. For example, the chiral center of these ligands is not directly bonded to the metal center. This may reduce the effectiveness of enantioselectivity in asymmetric reactions because the chirality of the ligands helps direct the stereochemistry during the reaction of a target molecule with the metal/chiral ligand complex. Therefore, bonding a chiral atom closer to the metal center may increase the formation of enantiomeric excesses. Also, bulky substituents in the unhindered regions may limit the availability and reactivity of the metal center to the target molecule.
Improved chiral phosphine ligands are needed that can further improve the production of enantiomerically active forms of compounds through asymmetric catalysis. Thus, there is a need to develop methods for the production of and to synthesize compounds that bond a chiral phosphine atom directly to a metal center and remove prohibitive substituents from the ligand to improve enantioselectivity in asymmetric reactions.
USPTO Backgrounds
USPTO Backgrounds