Organic compounds -- part of the class 532-570 series – Organic compounds – Silicon containing
Reexamination Certificate
2000-01-14
2001-03-27
Shaver, Paul F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Silicon containing
Reexamination Certificate
active
06207847
ABSTRACT:
FIELD OF INVENTION
The invention generally relates to the preparation of optically active &bgr;-halohydrins protected as their trimethylsilyl ethers using enantioselective Lewis acid catalyst complexes of zirconium or hafnium. The complexes comprise an alkoxide of Hf(IV) or Zr(IV) and an optically active triisopropanolamine.
BACKGROUND OF THE INVENTION
One of the principal goals of modern organic chemistry is the development of new synthetic routes toward the controlled, efficient production of asymmetric compounds. Saturated carbon atoms, which constitute the backbone 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. When synthetic organic chemists attempt preparation of these asymmetric compounds it is crucial to have a means to produce the desired enantiomer because compounds of the wrong enantiomeric form often lack the desired biological, physical or chemical properties. The present invention provides a new process for the synthesis of compounds in a desired enantiomeric form.
An attractive route to such optically active compounds is the enantioselective opening of meso-epoxides with nucleophiles. This procedure is highly efficient because it simultaneously establishes the absolute stereochemistry on two adjacent carbon atoms and results in a useful bifunctional product. An especially attractive version of these reactions involves the use of an enantioselective catalyst to control the position of attack by the nucleophile. In such cases a small amount of a chiral catalyst can be used to produce a large amount of enantiopure product. Prior to the Applicant's discovery, only three catalysts seem to have been reported which promote such reactions in highly enantioselective (>90% enantiomeric excess) fashion. In two cases, the nucleophile is azide (Nugent, William, J. Am. Chem. Soc., 1992, 114, 2768; Martinez, Luis et al., J. Am. Chem. Soc., 1995, 117, 5897). In the remaining case, the nucleophile is t-butyl thiol (Iida, Takehiko et al., J. Am. Chem. Soc., 1997, 119, 4783). To the Applicant's knowledge, there have, however, been no reports of catalysts which promote the enantioselective addition of halides (e.g., Cl, Br, I) to meso-epoxides.
A general review of enantioselective ring opening of meso-epoxides is provided in Hodgson, D. M. Gibbs, A. R.: Lee G. P., Tetrahedron 1996, 52, 46, 14361. One report discloses the use of halodiisopinocamphenylboranes to prepare enantiopure halohydrins [Srebnik M.; Joshi. N. N.; Brown, H. C.; Israel J. of Chem. 1989, 29, 229]. This reaction however, is not catalytic but, rather. stoichiometric. Chiral trivalent aluminum compounds and aluminum chelates were also used to convert meso-epoxides to the chlorohydrin, but low enantiomeric excess was achieved in the stoichiometric process [Naruse, et al; Tetrahedron. 1988, 44, 15, 4747].
Clearly, there is a need to provide a catalytic process for the manufacture of optically active halohydrins as their trimethylsilyl esters. 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 a process for the manufacture of optically active compounds comprising:
reacting a meso-epoxide with azidotrimethylsilane and a compound of the formula R′X, where R′ is an optionally substituted hydrocarbyl and X is selected from the group consisting of Cl, Br, and I;
to produce a compound of the formula (1)
wherein:
R is an optionally substituted hydrocarbyl, or both together can form a ring;
in the presence of a catalytic amount of a catalyst formed from the sequential treatment of hafnium t-butoxide or zirconium t-butoxide with one equivalent of homochiral optically active triisopropanolamine, water and a source of trifluoroacetate ion.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following definitions are used herein:
The term “hydrocarbyl” means all alkyl, aryl, aralkyl or alkylaryl carbon substituents, either straight-chain, branched or cyclic.
The term “chiral”, means “existing as a pair of enantiomers”. These stereoisomers, designated the R and S isomers, 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 term “optically active”, means a compound which contains inequivalent amounts of the R and S enantiomers. The extent of this inequivalence is measured as the “enantiomeric excess”.
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 which contains 75% S isomer and 25% R isomer will have an enantiomeric excess of 50%.
The term “enantioselective” means the ability to produce a product in an optically active form.
The term “Me”, as used in the equations or formulas, means a methyl group.
The term “meso-epoxide” means an epoxide which contains a mirror plane bisecting the epoxide oxygen atom such that one half of the molecule represents the mirror image of the other half.
The Applicant has discovered a method of using a previously known chiral Lewis acid catalyst to prepare optically active &bgr;-halohydrins protected as their trimethylsilyl ethers from the corresponding epoxides. Optically active &bgr;-halohydrins are important intermediates in many biologically active compounds (e.g., enantiopure cis-vicinal aminoalcohols including carbocyclic nucleoside antiviral agents). After base induced elimination, the halohydrins can also afford enantiopure cyclopentanones which are intermediates to pharaceutically important prostaglandins.
The general reaction can be described as follows:
where
R is an optionally substituted hydrocarbyl, or both together can form a ring;
R′ is an optionally substituted hydrocarbyl; and
X is Cl, Br, or I.
Compound I can be any cyclic or acyclic meso-epoxide which may additionally contain other substiuents, for example halide or oxygen functionalities such as, but not limited to, ether, ester, and acetal. The epoxide can be part of a larger ring system. Examples of suitable meso-epoxides include, but are not limited to, 1,5-cyclooctadiene monoepoxide, cycloheptene oxide, 1,4-cyclohexadiene monoepoxide, 3,4-epoxy-2,5-dihydrofuran, cyclopentene oxide, cis-2-butene oxide, and trans-1,2-epoxy-4-(methoxymethyl)cyclopentane. Most preferred are cyclopentene oxide and 4-substituted cyclopentene oxide.
Compound II can be any reactive organic halide where X is selected from the group consisting of Cl, Br, and I. R′ is any optionally substituted hydrocarbyl. Examples of suitable R′X compounds include, but are not limited to, allyl bromide, allyl iodide, and 2,3-dichloro-1-propene, 3-bromo-2-methylpropene, and benzyl bromide. Preferably, R′X should be selected so that the coproduct R′N
3
boils at less than about 150° C. thus facilitating product isolation. Most preferred are allyl bromide and allyl iodide.
The procedure involves treatment of a meso-epoxide in an aprotic organic solvent with from about 1 to 2 molar equivalents of azidotrimethylsilane (preferably about 1.1 molar equivalent) and from about 1.1 to 100 molar equivalents of a reactive organic halide (preferably about 2 to 20 molar equivalents) in the presence of about 0.01 to 0.20 molar equivalents (preferably about 0.08 molar equivalents) of the zirconium or hafnium catalyst.
The reaction may be carried out between about −25° C. and 50° C., preferably at between about 0° C. and 25° C. It is, however, most convenient to carry out the reaction at ambient temperature and pressure.
Suitable solvents
E. I. Du Pont de Nemours and Company
Shaver Paul F.
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