Asymmetric synthesis catalyzed by transition metal complexes...

Details Asymmetric synthesis catalyzed by transition metal complexes... Asymmetric synthesis catalyzed by transition metal complexes...

2001-06-12

2002-04-30

Vollano, Jean F. (Department: 1621)

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

Organic compounds

Phosphorus esters

C562S443000, C562S553000

Reexamination Certificate

active

06380416

ABSTRACT:

BACKGROUND OF THE INVENTION
Molecular chirality plays an 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 sometimes has deleterious side effects.
A growing demand in pharmaceutical industries is to market a chiral drug in enantiomerically pure form. 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 several decades, great attention has been devoted to discovering new asymmetric catalysts and more than a half-dozen commercial industrial processes have used asymmetric catalysis as the key step in the production of enantiomerically pure compounds. The worldwide sales of chiral drugs in 1997 was nearly $90 billion.
Many chiral phosphines (as shown in
FIG. 1
) have been made to facilitate asymmetric reactions. Among these ligands, BINAP is one of the most frequently used bidentate chiral phosphines. The axially dissymmetric, fully aromatic BINAP ligand has been demonstrated to be effective for many asymmetric reactions. DUPHOS and related ligands have also shown impressive enantioselectivities in numerous reactions. However, there are many disadvantages associated with these ligands which hinder their applications.
These phosphines are difficult to make and some of them are air sensitive. For DIPAMP, the phosphine chiral center is difficult to make. This ligand is only useful for limited application in assymmetric hydrogenation. For BPPM, DIOP, and Skewphos, the methylene group in the ligands causes conformational flexibility and enantioselectivities are moderate for many catalytic asymmetric reactions. DEGPHOS and CHIRAPHOS coordinate transition metals in five-membered rings. The chiral environment created by the phenyl groups is not close to the substrates and enantioselectivities are moderate for many reactions.
BINAP, DuPhos, and BPE ligands are good for many asymmetric reactions. However, the rotation of the aryl—aryl bond makes BINAP very flexible. The flexibility is an inherent limitation in the use of a phosphine ligand. Furthermore, because the phosphine of BINAP contains three adjacent aryl groups, it is less electron donating than a phosphine that has less aryl groups. This is an important factor which influences reaction rates. For hydrogenation reactions, electron donating phosphines are more active. For the more electron donating DUPHOS and PBE ligands, the five-membered ring adjacent to the phosphines is flexible.
In co-pending application Ser. No. 08/876,120, the inventors herein disclosed, inter alia, the (2,2′)-bis(diorganophosphino)-(1,1′)-bis(cyclic) family of chiral ligands, the (2,2′)-bis(diorganophosphinoxy)-(1,1′)-bis(cyclic) family of chiral ligands, and the family of chiral ligands comprising a rigid, fused phosphabicyclo[2.2.1]heptane structure named PennPhos, after Penn State University where the ligand was created. The common feature of these ligands is that they contain rigid ring structures which restrict conformational flexibility and promote efficient chiral transfer from the rigid ligand to desired products.
SUMMARY OF THE INVENTION
An object of the invention is to provide new chiral ligands.
A further object of the invention is to provide a detailed synthetic plan for making chiral ligands.
A further object of the invention is to provide methods of carrying out asymmetric synthesis using the chiral phosphine ligands of the present invention.
A further object of the invention is to provide methods for the efficient asymmetric synthesis of alcohols by enantioselective hydrogenation of ketones catalyzed by the chiral ligands of the invention.
A further object of the invention is to provide methods of using selected additives to improve the yield and enantioselectivity of selected asymmetric reactions.
Additional objects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
To achieve the objects and in accordance with the purpose of the invention, as embodied and broadly described herein, the invention comprises a chiral bisphosphinite ligand having restricted conformational flexibility, wherein said ligand comprises an enantiomer of a substituted or unsubstituted (2,2′)-bis(diarylphosphinoxy)-(1,1′)-dicyclo compound having saturated carbons at the 2,2′, 1, and 1′ positions.
Exemplary embodiments of said ligand include (2S, 2′S)-bis (diphenylphosphinoxy)-(1R, 1R′)-dicyclopentane and (2R, 2′R)-bis (diphenylphosphinoxy)-(1R, 1R′)-dicyclopentane. These ligands are sometimes referred to herein as (S, S′) BICPO, and (R, R′) BICPO, respectively, or simply as BICPO.
The invention also comprises a chiral bisphosphine ligand for performing asymmetric synthesis, wherein said ligand is an enantiomer of a (2, 2′)-bis (diarylphosphino)-(1, 1′)-dicyclo compound having saturated carbons at the 2, 2′, 1, and 1′ positions. In certain preferred embodiments, the ligand comprises an enantiomer of a (2, 2′)-bis(diarylphosphino)-(1, 1′)-dicyclo compound having saturated carbons at the 2, 2′, 1, and 1′ positions, and each aryl is 3, 5-alkyl substituted or 4-alkyl substituted. These ligands are sometimes referred to herein as modified BICP.
The invention comprises various methods for performing chiral synthesis using catalysts comprising the ligands disclosed in this application, and in the parent Application Ser. No. 08/876,120, including methods for synthesis of a chiral product in an enantiomeric excess from an organic substrate, comprising metal catalyzed asymmetric hydrogenation, wherein said asymmetric hydrogenation comprises the step of reacting an organic substrate in the presence of a catalyst, wherein the catalyst comprises a transition metal and a chiral ligand, and said chiral ligand comprises a phosphabicyclo[2.2.1] heptyl compound.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.


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J Org Chem by Zhu 63 pages 3133-3136, Feb. 1998.*
Sutton, B.M., “An Alternate Synthesis, X-Ray Crystal Structure and P388 Activity of 1,2-Bis(dibenzophospholyl-1)ethane [1]. A

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