Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2000-03-10
2001-02-13
Ramsuer, Robert W. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
active
06187918
ABSTRACT:
FIELD OF INVENTION
The invention generally relates to novel chiral aminoalcohol catalysts. The first is prepared by selectively hydrogenating one of two benzene rings in a precursor. The second is by selective dialkylation of a 3-exo-aminoisoborneol with a 2-haloethyl ether. In both cases, the aminoalcohol promotes the asymmetric addition of organozinc reagents to aldehydes to yield optically active alcohols or their esters.
BACKGROUND OF THE INVENTION
Modern organic chemists have as one goal the development of new synthetic routes for the controlled, efficient production of asymmetric compounds. Saturated carbon atoms, constituting the backbones of most organic compounds, are attached to adjacent atoms through a tetrahedral arrangement of chemical bonds. If the four bonds are to different atoms or groups, the central carbon provides a chiral, or asymmetric, center and the compound therefore may have the ability to exist in two mirror image, or enantiomeric, forms. It is crucial when synthetic organic chemists attempt to prepare these asymmetric compounds to have a means to produce the desired enantiomer because compounds of the wrong enantiomeric form often lack desirable biological, physical or chemical properties.
A particularly attractive approach to the synthesis of optically active compounds is the catalytic asymmetric generation of carbon-carbon bonds. This approach is highly efficient because the optical activity is installed during the assembly of the carbon skeleton rather than as a separate, subsequent operation. Among such reactions the enantioselective addition of organometallic reagents to aldehydes has received much attention in the literature. This transformation represents the enantioselective version of the venerable Grignard addition and affords broadly useful, optically active secondary alcohols as products. Organozinc reagents are usually employed as the organometallic reactant since they do not react with aldehydes in the absence of a catalyst.
General reviews cite the use of optically active &bgr;-aminoalcohols to catalyze the asymmetric addition of organozinc reagents to aldehydes (Noyori, R., Kitamura, M., Angew. Chem., Int. Ed. Engl. 1991, 30,49; Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833). Among such catalysts, the best known and most widely used appears to be 3-exo-(dimethylamino)isoborneol, more commonly known as DAIB (Kitamura, M. et al.,
J. Am. Chem. Soc.
1986, 108, 6071). DAIB allows highly selective addition of organozinc reagents to certain aldehydes, especially aryl derivatives. However, DAIB requires an expensive and complex 6-step synthesis and is not suitable for addition of organozinc reagents to sterically encumbered aldehydes such as pivalaldehyde. Other aminoalcohols such as N,N-dibutylnorephedrine or DBNE (Soai, K. et al.,
J. Org. Chem.
1991, 56, 4264) are easier to prepare but are less selective catalysts than DAIB.
Clearly, a need exists for an improved catalyst for the asymmetric addition of organozinc reagents to aldehydes which is both readily synthesized and provides high selectivity with a wide range of aldehyde substrates. The present invention provides an improved process for the synthesis of compounds in a desired enantiomeric form. Other objects and advantages of the invention will become apparent to those skilled in the art upon reference to the detailed description, which hereinafter follows.
SUMMARY OF THE INVENTION
The present invention provides for an erythro-&bgr;-aminoalcohol compound of Formula 1. The compound is preferably optically active.
The invention also provides for a process to prepare an erythro-&bgr;- aminoalcohol compound of Formula 1 comprising selectively hydrogenating an erythro-&bgr;-aminoalcohol of Formula 2 to form the erythro-&bgr;-aminoalcohol of Formula 1.
The hydrogenation is preferably performed in the presence of a catalyst comprising rhodium supported on an inorganic support. More preferably, the catalyst is 5% rhodium on alumina. A preferred form of the process is where the erythro-&bgr;-aminoalcohol compound of Formula 1 is optically active. Also preferred is where &bgr;-aminoalcohol of Formula 2 is prepared by reacting stilbene oxide with morpholine.
Another aspect of the invention provides for a process to prepare a compound of the Formula 6:
comprising: a) contacting an aldehyde of formula RC(O)H with a zinc compound of formula R′ZnR″ in the presence of a catalytic amount of an erythro-&bgr;-aminoalcohol of Formula 1; b) further contacting the reactants with Y
2
O to form the corresponding ester or alcohol of Formula 6 wherein R, R′, and R″ are hydrocarbyl or substituted hydrocarbyl; Y is a hydrogen or alkanoyl group; and Y
2
O is a carboxylic acid anhydride or water.
A preferred process is where the erythro-&bgr;-aminoalcohol and the compound of Formula 6 are optically active. More preferred is where the compound of Formula 6 has an enantiomeric excess of greater than about 80%, and most preferred is where the compound of Formula 6 has a high level of enantiomeric purity.
Another preferred process is where Y is hydrogen or acetyl. More preferred is where R is selected from the group consisting of phenyl, n-hexyl, 3-thienyl, cyclohexyl, 1,1-dimethyl-3-butenyl, isopropyl, 1-butenyl and isobutyl; and R′ is selected from the group consisting of ethyl, methyl and 5-chloropentenyl.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention consists of a morpholine-substituted erythro-&bgr;-aminoalcohol compound comprising one of the compounds of Formula 1
and a process for their preparation.
The following definitions are used herein:
The term “alkanoyl” means a monovalent radical of the formula —C(O)R″, where R″ is hydrogen, hydrocarbyl or substituted hydrocarbyl group.
The term “carboxylic acid anhydride” means a compound containing the grouping —C(O)O(O)C—, wherein the free valencies are to other carbon atoms.
The term “chiral” means “existing as a pair of enantiomers”. These stereoisomers, designated the R and S enantiomers, are mirror images of one another. A chiral material may either contain an equal amount of the R and S isomers (in which case it is called “racemic”) or it may contain inequivalent amounts of R and S isomer (in which case it is called “optically active”). The extent of this inequivalence is measured as the “enantiomeric excess”.
When two chiral centers exist in one molecule, there can be up to four different stereoisomers. In such a molecule, if the two centers have one substituent in common, they can be further characterized as “erythro” or “threo”. When the two identical substituents are on the same side when drawn in the standard Fischer convention, the molecule is labeled erythro. (For a further discussion, see
Advanced Organic Chemistry,
2
nd
edition, J. March, Ed., 1977, pp 104-106.) The term “enantiomeric excess” means the difference between the percent of R enantiomer and the percent of S enantiomer of an optically active compound. For example, a compound that contains 75% S isomer and 25% R isomer will have an enantiomeric excess of 50%.
The term “high level of enantiomeric purity” means having an enantiomeric excess of greater than or equal to about 90%, preferably greater than or equal to about 95%.
The term “enantioselective” means having the ability to produce a product in an optically active form.
By the term “hydrocarbyl” Applicant includes all alkyl, aryl, aralkyl or alkylaryl carbon substituents, either straight chain, branched or cyclic. “Substituted hydrocarbyl” means a hydrocarbyl group containing a substituent such as, but not limited to, halide or oxygen functionalities such as, but not limited to, ether, ester, and acetal.
A preferred form of the invention is a morpholine-substituted &bgr;-amino-alcohol compound that is optically active.
Applicant has further discovered that the aminoalcohol of Formula 1 is an enantioselective catalyst for the addition of organozinc reagents to many aldehydes, including sterically hindered aldehydes, to produce optically active secondary alcohols
Dolan Peter L.
DuPont Pharmaceuticals Company
Ferguson Blair Q.
Ramsuer Robert W.
Rubin Kenneth B.
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