Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2003-03-14
2003-12-09
O'Sullivan, Peter (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C568S810000, C568S812000, C568S813000, C568S814000
Reexamination Certificate
active
06660884
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
The present invention relates to compounds useful as catalysts in asymmetric synthesis of chiral compounds, methods for the synthesis of said catalysts, and methods for synthesizing chiral compounds with high enantioselectivity.
2. Background
The addition of alkyl groups to ketones is a reaction that is so fundamental that it is studied in nearly all first year organic chemistry courses in this country. The lack of direct methods to perform this simple transformation enantioselectively represent a marked deficiency in prior organic methodology. We have developed a catalyst to promote the synthesis of tertiary alcohols with high enantioselectivity, which will be highly useful to chemists working in academics and industry.
The enantioselective formation of C—C bonds is an area of intense research effort. Traditionally, optimization of asymmetric catalysts has been performed by modification of chiral ligands. Some groups have used achiral additives to modify catalyst enantioselectivities and a few have used achiral ligands with chiral conformations to transfer asymmetry. We have developed asymmetric catalysts by variation of large, flexible achiral and meso ligands with chiral conformations.
Importance of Chiral Substances of High Optical Purity. Medications sold as single enantiomers comprise 50 of the 100 top selling drugs, and represent a $133 billion industry. The precursors of these medications are chiral substances of high optical purity, which constitute an important class of starting materials for organic and medicinal chemists. Using the stereochemistry of these materials to control generation of subsequent stereogenic centers allows the preparation of biologically and medicinally important target molecules as single enantiomers. Organic compounds of very high optical purity are essential for testing and evaluation of biological activity, because each enantiomer can interact with a distinct site in an organism and elicit very different responses.
Chemists and medical scientists have understood the significance of producing drugs as single enantiomers for many years. As chemists have honed their ability to generate chiral molecules and efficiently analyze their enantiopurity, the Food and Drug Administration (“FDA”) has encouraged the pharmaceutical industry to introduce medications as single enantiomers. As a result of the FDA's actions, medications are increasingly being synthesized, tested, and sold as single enantiomers.
Historically, the production of medications as single enantiomers has been accomplished primarily by four different techniques: 1) use of natural sources as starting materials, 2) resolution of racemates, 3) chiral auxiliary chemistry, and 4) asymmetric catalysis. Increasingly, the use of chiral catalysts is displacing the application of chiral reagents and chiral auxiliaries in the asymmetric synthesis of natural and unnatural products. An active asymmetric catalyst enables the chemist to prepare large quantities of material with high enantiopurity from small amounts of enantiopure material, without the need to cleave and recover the chiral auxiliary. Despite recent advances in the art of asymmetric synthesis, many formidable challenges have remained. Significant among these has been the construction of chiral quarternary stereocenters, which are carbon centers with four different non-hydrogen substituents.
Asymmetric Synthesis of Tertiary Alcohols. Numerous attempts to accomplish asymmetric additions of alkyl groups to ketones have been reported, but few have been successful due to low enantioselectivities, high chiral ligand loadings, or extreme reaction conditions. Despite the fact that chemists have been studying the addition of organometallic reagents to ketones for almost 50 years, the catalytic asymmetric synthesis of complex molecules with tertiary alcohols has been one of the most challenging problems in chemical synthesis.
The chemistry of the prior art has not been practical because it was stoichiometric; it did not work with aryl, vinyl or alkynyl Grignard reagents; an excess of the reagent was needed to maximize enantioselectivity; and the reaction required very low temperature, below −100° C. The prior art reagents did not react, or reacted inefficiently, with ketones; new approaches are needed to address this important class of addition reactions.
Asymmetric Additions to Carbonyl Groups. In the catalytic asymmetric transfer of alkyl and aryl groups to carbonyls, aldehydes have served as suitable substrates. Literally hundreds of catalysts will now promote additions of zinc alkyl groups to aldehydes with excellent enantioselectivities. In sharp contrast, an effective use of ketones as alkyl group acceptors in the presence of asymmetric catalysts has not been described previously, reflecting the fact that ketones are significantly less susceptible to reaction with alkylzinc reagents than aldehydes. The best enantioselectivities achieved were in the range of 16% to 86%, which are not in the synthetically useful range. Further, a serious drawback to this methodology is the long reaction times of 4-14 days. Thus, while catalytic asymmetric addition of alkyl groups to ketones has been achieved, the prior art has had significant limitations and leaves much room for improvement.
The present invention relates to novel methods for the construction of C—C bonds with high asymmetric induction. One embodiment of this work is the generation of quarternary stereocenters with high enantioselectivity. Such centers are generally much more difficult to produce enantioselectively than secondary stereocenters, as evidenced by the limited examples of C—C bond formation with enantio- and diastereoselective nucleophilic addition to ketones. We employ chiral ligands as catalysts in asymmetric syntheses. Accordingly, Applicants have developed catalysts, methods for making said catalysts, and methods for using said catalysts in enantioselective alkylation of ketones.
SUMMARY OF THE INVENTION
The present invention relates to a compound selected from the group consisting of: Bicyclo[2.2.1]heptane-1-methanesulfonamide,N,N′-(1S,2S)-1,2-cyclohexanediylbis[2-hydroxy-7,7-dimethyl]-(1R,1′R,2S,2′S,4S,4′S)-(9CI) and Bicyclo[2.2.1]heptane-1-methanesulfonamide,N,N′-(1R,2R)-1,2-cyclohexanediylbis[2-hydroxy-7,7-dimethyl]-(1S,1′S,2R,2′R,4R,4′R)-(9CI).
The present invention further relates to a method for making a compound selected from the group consisting of: Bicyclo[2.2.1]heptane-1-methanesulfonamide,N,N′-(1S,2S)-1,2-cyclohexanediylbis[2-hydroxy-7,7-dimethyl]-(1R,1′R,2S,2′S,4S,4′S)-(9CI) and Bicyclo[2.2.1]heptane-1-methanesulfonamide,N,N′-(1R,2R)-1,2-cyclohexanediylbis[2-hydroxy-7,7-dimethyl]-(1S,1′S,2R,2′R,4R,4′R)-(9CI), comprising the steps of:
(a) reducing an enantiomer of 1,2-bis(camphorsulfonamido)-cyclohexane; and
(b) separating said compound from the reaction mixture and its diastereoisomer.
In addition, the present invention relates to a method for making a chiral tertiary alcohol with high enantioselectivity, comprising reacting a metal-alkyl donor compound with a starting ketone compound in the presence of titanium(IV) isopropoxide and a compound selected from the group consisting of: Bicyclo[2.2.1]heptane-1-methanesulfonamide,N,N′-(1S,2S)-1,2-cyclohexanediylbis[2-hydroxy-7,7-dimethyl]-(1R,1′R,2S,2′S,4S,4′S)-(9CI) and Bicyclo[2.2.1]heptane-1-methanesulfonamide,N,N′-(1R,2R)-1,2-cyclohexanediylbis[2-hydroxy-7,7-dimethyl]-(1S,1′S,2R,2′R,4R,4′R)-(9CI).
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The term “Bicyclo[2.2.1]heptane-1-methanesulfonamide, N,N′-(1S,2S)-1,2-cyclohexanediylbis[2-hydroxy-7,7-dimethyl]-(1R,1′R,2S,2′S,4S,4′S)-(9CI)”, CAS Registry Number: 470665-33-9, refers to compound B, also re
Heiman Lee C.
Nath Gary M.
Nath & Associates PLLC
O'Sullivan Peter
The Trustees of the University of Pennsylvania
LandOfFree
Catalysts, methods for making said catalysts, and methods... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Catalysts, methods for making said catalysts, and methods..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Catalysts, methods for making said catalysts, and methods... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3109130