Synthesis of non-C2-symmetric bisphosphine ligands as...

Details Synthesis of non-C2-symmetric bisphosphine ligands as... Synthesis of non-C2-symmetric bisphosphine ligands as...

2002-02-27

2004-02-10

Vollano, Jean F. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Phosphorus containing

C568S017000

Reexamination Certificate

active

06689915

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to non-C
2
-symmetric bisphosphine (BisP) ligands and a method for their preparation. In addition, this invention relates to forming metal/bisphosphine complexes that catalyze asymmetric transformation reactions to generate high enantiomeric excesses of formed compounds. The invention also relates to a method for preparing BisP.
BACKGROUND OF THE INVENTION
A growing trend in the pharmaceutical industry is to market chiral drugs in enantiomerically pure form 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 for the synthesis of enantiomerically enriched compounds 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
, New York: Academic Press, 1985:5; Bosnich B., ed.
Asymmetric Catalysis
, Dordrecht, Netherlands: Martinus Nijhoff Publishers, 1986; Brunner H.
Synthesis
, 1988:645; Noyori R., Kitamura M. In Scheffold R., ed.
Modern Synthetic Methods
, Berlin Hedelberg: Springer-Verlag, 1989;5: 115; Nugent W. A., RajanBabu T. V., Burk M. J.
Science
, 1993;259:479; Ojima I., ed.
Catalytic Asymmetric Synthesis
, New York: VCH, 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 1970s 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):5946-52; Knowles W. S., Sabacky M. J., Vineyard B. D., Weinkauff D. J.
J. Am. Chem. Soc
. 1975;97(9):2567-8).
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
, New York: VCH Publishers, Inc, 1993; Ager D. J., ed.
Handbook of Clinical 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
1998; 1(1 1):787-802 (CODEN: CHEMFW ISSN:1431-9268. CAN 130:38423; AN 1998:698087 CAPLUS); 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., Gregory P., Kalberg C. S.
J. An. 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, DC 1883-) 1993;259(5094):479-483; Burk M. J., Feaster J. E., Harlow R. L.
Tetrahedron: Asymmetry
1991;2(7):569-592; Burk M J.
J. Am. Chem. Soc
. 1991;113(22):8518-8519; Imamoto T., Watanabe J., Wada Y., Masuda H., Yamada H., Tsuruta H. et al.
J. Am. Chem. Soc
. 1998; 120(7):1635-1636; Zhu G, Cao P, Jiang Q, Zhang X.
J. Am. Chem. Soc
. 1997; 119(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 C
2
-symmetric structure. If the spatial area of a metal/phosphine ligand structure, such as BisP, is divided into four quadrants, as shown in
FIG. 1
, alternating hindered and unhindered quadrants are formed.
This structural feature creates areas of hindrance in the BisP/metal complexes and produces desired stereochemical results in asymmetric hydrogenation reactions. However, there are a variety of reactions in which only modest enantioselectivity has been achieved with these ligands. While high selectivity has been observed in many reactions using these chiral diphosphine ligands, there are many reactions where these ligands are not very efficient in terms of activity and selectivity. Further, there are many disadvantages associated with these ligands, which limits their application.
For example, multiple chiral centers in these ligands increases the difficulty in synthesis of these compounds. Further, the multiple chiral centers could increase the cost associated with forming the ligands.
High enantioselectivities have been observed in asymmetric hydrogenation for a narrow range of substrates, such as enamides, enol esters, and succinates. Many of these successful results have been obtained using optically pure C
2
-symmetric rhodium-phosphine complexes as hydrogenation catalysts. Therefore, C
2
-symmetry has become a popular characteristic in the design of chiral ligands that are used to make these complexes. Unique to the substrates for which asymmetric hydrogenation has been successful is an olefin and a carbonyl group which are separated by one atom. During asymmetric hydrogenation, the olefin and the carbonyl bind to the metal center in a well-defined conformation. This is thought to be of consequence in an asymmetric hydrogenation.
C
2
-symmetric bisphosphines, such as BisP, have been synthesized and used in asymmetric catalysis, as shown in
FIG. 2
(Imamoto, T., Watanabe J., Wada Y., Masuda H., Yamada H., Tsuruta I-I., Matsukawa S., Yamaguchi K. J
Am. Chem. Soc
. 1998;120(7):1635-1636). A proton from one of the methyl groups of t-butyldimethyl phosphine is selectively deprotonated with a chiral base, such as s-BuLi and (−)-sparteine, and then the resulting anion couples with itself in the presence of copper(II) chloride to provide the bisphosphine borane protected ligand, in about 40% yield and >99% enantiomeric excess after recrystallization. The rhod

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