Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-10
2003-06-10
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S005000, C549S006000, C549S007000, C549S013000
Reexamination Certificate
active
06576772
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel chiral phosphines for applications in asymmetric catalysis. More particularly, the present invention relates to transition metal complexes of these chiral phosphine ligands. The transition metal complexes according to the present invention are useful as catalysts in asymmetric reactions.
2. Description of the Prior Art
Several families of conformationally rigid chiral bisphosphines suitable for use in transition metalatalyzed enantioselective transformations are known. The present invention discloses asymmetric catalysts based on chiral bidentate phosphines with multi-stereogenic centers in the backbone. Conformational analysis leads to the result that one of the stereochemical arrangements of the many diastereomers is the most enantioselective ligand for transition metal-catalyzed asymmetric reactions. A common feature of these ligands is that appropriate stereogenic centers in these ligands can restrict conformational flexibility of the ligands and thus the efficiency of chiral transfer can be enhanced through the ligand rigidity.
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. During the last few decades, asymmetric catalysis has been developed as effective method for the production of enantiomerically pure compounds.
Development of chiral phosphine ligands has played a significant role in various types of transition metal-catalyzed asymmetric synthesis (H. Brunner, W. Zettlmeier,
Handbook of Enantioselective Catalysis with Transition Metal Compounds,
Vol. 2, Ligands-References, VCH Verlagsgesellschaft, weinheim, 1993, p359). Especially, chiral diphosphines of C
2
-symmetry are of special interest due to their high enantioselectivities in asymmetric reactions. Chiral 1,4-bisphosphines, such as, DIOP (H. B. Kagan, T.-P. Dang,
J. Am. Chem. Soc.
1972, 94, 6429), BPPM (K. Achiwa,
J. Am. Chem. Soc.
1976, 98, 8265; and I. Ojima, N. Yoda,
Tetrahedron Lett.
1980, 21, 1051.), BICP (G. Zhu, P. Cao, Q. Jiang, X. Zhang,
J. Am. Chem. Soc.,
1997, 119, 1799) have been developed for transition metal-catalyzed asymmetric catalysis.
Although these ligands are effective for some asymmetric transformations, there are some areas in where these ligands are not efficient in their activity and selectivity. Thus, the design and synthesis of new chiral phosphine ligands that are effective in the more difficult asymmetric transformations remain important and challenging endeavors. The present invention discloses design and synthesis of novel chiral bisphosphines based on the conformational analysis.
The relationship between catalyst conformation and product configuration has been studied before. In general, the observed high asymmetric induction is attributed to the well define formed chiral conformation of the chelate. Based on a number of experiments, enantioselectivity with DIOP is not high in many asymmetric reactions. A possible explanation for this observation might be that the chiral centers are too far and the seven-membered chelate ring of DIOP (1) bound to transition metal (e.g., rhodium) is too conformationally flexible (the transfer of backbone chirality to the phenyl groups on the phosphine goes through a methylene group).
To overcome this drawback, Kagan synthesized ligand 2 in which there are two more chiral centers closer to the phosphorus atom (H. B. Kagan, J. C. Fiaud, C. Hoornaert, D. Meyer, J. C. Poulin,
Bull. Soc. Chim. Belg.
1979, 88, 923). Unfortunately, in this case the enantioselectivity for asymmetric hydrogenation of dehydroaminoacid was substantially lower than in the case of DIOP. We reasoned that the poor selectivity may be caused by the two newly introduced methyl groups which may have an axial position in the seven-membered chelate ring influencing enantioselectivity (R. Selke, M. Ohff, a. Riepe,
Tetrahedron
1996, 52, 15079). This explanation suggests that the revised configuration of the two chiral centers in ligand 3 (R,S,S,R)-DIOP* (star) will force every substituent to have an equatorial position and form a well defined conformation chelated with Rh so that a high enantioselectivity can be achieved. We have found that bisphosphine 3 is a much more effective ligand than DIOP (1) and 2 for asymmetric hydrogenation reactions. This led to the conclusion that appropriate conformation of chiral ligands is the key to the high enantioselectivity, thereby providing a foundation on which the new chiral phosphines of the present invention are based.
Thus, while the hydrogenation of dehydroaminoacids (an electron-withdrawing alkene) with the Rh-based catalyst gave poor enanatioselectivity {(a) Berens, U.; Leckel, D.; Oepen, S. C.
J. Org. Chem.
1995, 60, 8204. (b) Berens, U.; Selke, R.
Tetrahedron: Asymmetry
1996, 7, 2055}., we have achieved outstanding results for hydrogenation and simple enamides (an electron rich alkene) with 3 (R,S,S,R)-DIOP*.
SUMMARY OF INVENTION
The present invention includes a ligand selected from the group consisting of compounds represented by I through XI:
wherein X′ is selected from the group consisting of: alkyl, aryl, substituted alkyl, substituted aryl, hydroxy, alkoxy, aryloxy, siloxy, thioalkoxy, arylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, amido, ester, reverse ester, keto, halo silyl and SH;
wherein R′ is selected from the group consisting of: alkyl, aryl, substituted alkyl, substituted aryl, hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino and amido;
wherein each X, Z and Z′ is independently selected from the group consisting of: O, NH, NR, CH
2
, CHR, CR
2
, C═O, S, SO
2
, and SO;
wherein each Z″ is independently selected from the group consisting of: N, P, CH, and CR;
wherein each R
1
, R
2
, R
3
and R
4
is independently selected from the group consisting of: H, alkyl, aryl, substituted alkyl, substituted aryl and OR;
wherein each Y and Y′ is independently selected from the group consisting of: a diol protecting group residue, O, CO, C(OR)
2
, CH(OR), CH
2
, CHR, CR
2
, CR
2
, NR, SO
2
, —(CH
2
)
n
— wherein n is 0 or an integer from 1 to 8, —(CH
2
)
n
Q(CH
2
)
m
— wherein each n and m is independently an integer from 1 to 8, divalent phenyl, substituted divalent phenyl, 2,2′-divalent-1,1′-biphenyl, substituted 2,2′-divalent-1,1′-biphenyl, 2,2′-divalent-1,1′-binaphthyl, substituted 2,2′-divalent-1,1′-binaphthyl, 1,1′-ferrocene, substituted 1,1′-ferrocene, wherein the substituent in each of said substituted divalent phenyl, biphenyl, binaphthyl and ferrocene is one or more moiety each independently selected from the group consisting of: alkyl, aryl, aralkyl, alkaryl, alkenyl, akkynyl, F, Cl, Br, I, OH, OR, SH, SR, COOH, COOR, SO
3
H, SO
3
R, PO
3
H
2
, PO
3
HR, PO
3
R
2
, NH
2
, NHR, NR
2
, PR
2
, AsR
2
, SbR
2
and nitro; and
wherein each R is independently selected from the group consisting of: alkyl, aryl, substituted alkyl, substituted aryl, fluoroalkyl, perfluoroalkyl and —CR′
2
(CR′
2
)
q
Q(CR′
2
)
p
R′ wherein each q and p is independently an integer from 1 to 8, Q is selected from the group consisting of: O, S, NR, PR, AsR, SbR, divalent aryl, divalent fused aryl, divalent 5-membered ring heterocycle and divalent fused heterocycle.
The present invention also includes a process for preparing a ligand enantiomer in high enantiomeric purity. The process comprises the steps of:
contacting an enantiomer of tartaric acid diester and a diol protecting group in the presence of an acid catalyst to produce a bis-protected tartr
Ohlandt Greeley Ruggiero & Perle L.L.P.
The Penn State Research Foundation
Vollano Jean F.
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