Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-24
2004-03-02
Lambkin, Deborah (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S531000, C549S535000
Reexamination Certificate
active
06700004
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to a novel process for the enantioselective epoxidation of &agr;,&bgr;-unsaturated enones and &agr;,&bgr;-unsaturated sulfones using specific polyamino acids as catalysts and phase-transfer catalysts as cocatalysts.
Chiral, nonracemic epoxides are known as valuable synthons for preparing optically active drugs and materials (for example, (a)
Bioorg. Med. Chem
., 1999, 7, 2145-2156; and (b)
Tetrahedron Left
., 1999, 40, 5421-5424). These epoxides can be prepared by enantioselective epoxidation of double bonds. In this case, two stereocenters are produced in one synthetic step. It is therefore not surprising that a large number of methods have been developed for the enantioselective epoxidation of double bonds. However, there is still a great need for novel, improved methods for enantioselective epoxidation.
The epoxidation methods limited to the specific substrates in each case include methods for the enantioselective epoxidation of &agr;,&bgr;-unsaturated enones.
Thus, for example, the use of chiral, nonracemic alkaloid-based phase-transfer catalysts for the epoxidation of enones is described in
Tetrahedron Left
., 1998, 39, 7563-7566
, Tetrahedron Lett.,
1998, 39, 1599-1602, and
Tetrahedron Lett.,
1976, 21, 1831-1834.
Tetrahedron Left.,
1998, 39, 7353-7356,
Tetrahedron Left.,
1998, 39, 7321-7322, and
Angew. Chem., Int. Ed. Engl.,
1997, 36, 410-412, furthermore, describe possibilities for the metal-catalyzed asymmetric epoxidation of enones using organic hydroperoxides.
WO-A 99/52886 describes the possibility of enantioselective epoxidation of enones in the presence of catalysts based on sugars. Another method for epoxidation using Zn organyls and oxygen in the presence of an ephedrine derivative has been published in
Liebigs Ann./Recueil,
1997, 1101-1113.
Angew. Chem., Int. Ed. Engl.,
1980, 19, 929-930,
Tetrahedron
, 1984, 40, 5207-5211, and
J. Chem. Soc., Perkin Trans.
1, 1982, 1317-24 describe the Juliá epoxidation method in which enantiomer- and diastereomer-enriched polyamino acids are able, in the presence of aqueous hydrogen peroxide and NaOH solution and of an aromatic or halogenated hydrocarbon as solvent, to catalyze the enantioselective epoxidation of &agr;,&bgr;-unsaturated enones. Further developments of these so-called three-phase conditions are to be found in
Org. Synth; Mod. Trends, Proc. IUPAC Symp.
6
th
., 1986, 275. The method is now generally referred to as the Juliá-Colonna epoxidation.
According to EP-A 403, 252, it is possible also to employ aliphatic hydrocarbons advantageously in this Juliá-Colonna epoxidation in place of the original solvents.
Furthermore, epoxidation under three-phase conditions has distinct disadvantages. The reaction times under the original conditions are in the region of days even for reactive substrates. For example, 1 to 6 days are required for a trans-chalcone, depending on the polyamino acid used (
Tetrahedron,
1984, 40, 5207-5211). A preactivation of the polyamino acid carried out in the reaction vessel, by stirring in the solvent with the addition of NaOH solution for 12 to 48 h, shortens the reaction time for many substrates to 1 to 3 days. In this case, no intermediate workup of the catalyst is necessary (EP-A 403, 252). The preactivation can be reduced to a minimum of 6 in the presence of the NaOH/hydrogen peroxide system (
J. Chem. Soc., Perkin Trans.
1, 1995, 1467-1468).
Despite this improvement, the three-phase method cannot be applied to substrates which are sensitive to hydroxide ions (
J. Chem. Soc., Perkin Trans.
1, 1997, 3501-3507). A further disadvantage of these classical conditions is that the polyamino acid forms a gel during the reaction (or even during the preactivation). This restricts the required mixing during the reaction and impedes the working up of the reaction mixture.
WO-A 96/33183 describes as a specific embodiment the possibility of carrying out the enantioselective epoxidation of enones also in the presence of the phase-transfer catalyst Aliquat®336 ([(CH
3
)(C
8
H
17
)
3
N
+
]Cl
−
) if at the same time a polyamino acid, an organic solvent (such as, for example, dichloromethane), sodium perborate (which is of low solubility in water) as oxidant, and alkali (for example, NaOH) are present. In this context, no more detail is given about the polyamino acid.
Tetrahedron Lett.,
2001, 42, 3741-43 merely describes very generally that Aliquat 336 can likewise be added as phase-transfer catalyst (PTC) in the epoxidation of phenyl E-styryl sulfone under conventional three-phase conditions. However, only a slow reaction rate (reaction time 4 days) and a poor enantiomeric excess (21% ee) is achieved. No further information is given about the way this reaction was carried out.
In addition to the original Juliá-Colonna epoxidation under three-phase conditions and the variants mentioned above, other reaction procedures have also been developed. According to
Chem. Commun.,
1997, 739-740, (pseudo)-anhydrous reaction conditions can be implemented by using THF, 1,2 dimethoxyethane, tert-butyl methyl ether, or ethyl acetate as solvent, a non-nucleophilic base (for example, DBU), and a urea/hydrogen peroxide complex as oxidant. The epoxidation takes place distinctly more quickly under these so-called two-phase reaction conditions. According to
J. Chem. Soc., Perkin Trans.
1, 1997, 3501-3507, therefore, the enantioselective epoxidation of hydroxide-sensitive enones under the Juliá-Colonna conditions is also possible for the first time in this way.
However, the observation that, on use of the two-phase conditions, the polyamino acid must be preactivated in a separate process in order to achieve rapid reaction times and high enantiomeric excesses proves to be a distinct disadvantage. Several days are needed for this preactivation, which takes place by stirring the polyamino acid in a toluene/NaOH solution. According to
Tetrahedron Lett.,
1998, 39, 9297-9300, the required preactivated catalyst is then obtained after a washing and drying procedure. This activated polyamino acid forms a paste under the two-phase conditions, which impedes mixing during the reaction and the subsequent workup. According to EP-A 1,006,127, this problem can be solved by adsorbing the activated polyamino acid onto a solid support. Polyamino acids on a silica gel support are referred to as SCATs (silica adsorbed catalysts).
A further disadvantage of the previous two-phase conditions is that the use of relatively costly, non-nucleophilic bases (for example, DBU) is necessary in order to make the reaction possible.
According to EP-A 1,006,111, a further variant of the Juliá-Colonna epoxidation is catalysis of the enantioselective epoxidation by the activated polyamino acid in the presence of water, a water-miscible solvent (for example, 1,2-dimethoxyethane), and sodium percarbonate. The use of water-miscible solvents complicates the workup (extraction) in this process.
In the Juliá-Colonna epoxidation, the reaction rate and the enantiomeric excess (ee) that can be achieved depend greatly on the polyamino acid used and the mode of preparation thereof (
Chirality
, 1997, 9, 198-202). In order to obtain approximately comparable results, a standard system with poly-L-leucine (pII) as catalyst and trans-chalcone as precursor is used throughout for the development and description of novel methods in the literature. However, besides D- or L-polyleucine, other polyamino acids (such as, for example, D- or L-neopentylglycine) are also used successfully (EP-A 1,006,127).
The object of the present invention was to provide a process that makes the polyamino acid-catalyzed enantioselective epoxidation of (&agr;,&bgr;-unsaturated enones and &agr;,&bgr;-unsaturated sulfones possible but is not subject to the disadvantages of the above-described variants of the Juliá-Colonna epoxidation. It was intended in particular to find a rapid and broadly applicable method that avoids the use of costly bases and oxidants and potentially problematic types of reaction procedure
Geller Thomas
Krüger Christa Maria
Militzer Hans-Christian
Akorli Godfried R.
Bayer Aktiengesellschaft
Eyl Diderico van
Lambkin Deborah
LandOfFree
Polyamino acid-catalyzed process for the enantioselective... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Polyamino acid-catalyzed process for the enantioselective..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Polyamino acid-catalyzed process for the enantioselective... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3189917