Process for the enantioselective epoxidation of C═C...

Details Process for the enantioselective epoxidation of C═C... Process for the enantioselective epoxidation of C═C...

1999-11-30

2001-05-01

Dentz, Bernard (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S524000, C549S529000, C549S531000

Reexamination Certificate

active

06225482

ABSTRACT:

CROSS-REFERENCE TO RELATED APPLICATION
This application claims priority from German Application No. 198 55 858.9, filed on Dec. 3, 1998, the subject matter of which is hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention provides a process for the enantioselective epoxidation of C═C double bonds. In particular, the invention relates to the epoxidation of compounds of the general formula I
in which
R
1
and R
2
, independently, represent (C
1
-C
18
)-alkyl,
(C
2
-C
128
)-alkenyl, (C
2
-C
18
)-alkynyl, (C
6
-C
18
)-aryl,
(C
7
-C
19
)-aralkyl, (C
3
-C
18
)-heteroaryl, (C
4
-C
19
)-heteroaralkyl,
(C
1
-C
8
)-alkyl-(C
6
-C
18
)-aryl,
(C
1
-C
8
)-alkyl-(C
3
-C
19
)-heteroaryl, (C
3
-C
8
)-cycloalkyl,
(C
1
-C
8
)-alkyl-(C
3
-C
8
)-cycloalkyl,
(C
3
-C
8
)-cycloalkyl-(C
1
-C
8
)-alkyl,
wherein the groups mentioned above may be substituted once or several times with heteroatoms such as a halogen, NR
3
R
4
, PO
0-3
R
3
R
4
, OR
3
, SR
3
, SOR
3
, SO
2
R
3
, SO
3
R
3
or groups such as CO
2
R
3
, CONHR
3
and one or more CH
2
groups may be substituted by heteroatoms such as NR
3
, PR
3
, O or S,
R
3
and R
4
, independently, represent H, (C
1
-C
18
)-alkyl,
(C
2
-C
8
)-alkenyl, (C
6
-C
18
)-aryl, (C
3
-C
18
)-heteroaryl,
(C
1
-C
8
)-alkyl-(C
6
-C
18
)-aryl,
(C
1
-C
8
)-alkyl-(C
3
-C
19
)-heteroaryl, (C
3
-C
8
)-cycloalkyl, or
(C
1
-C
8
)-alkyl-(C
3
-C
8
)-cycloalkyl,
wherein the groups mentioned above may be substituted once or several times with a halogen, by means of a diastereomer and enantiomer enriched homopolyamino acid and an oxidizing agent.
2. Background Information
Enantioselective epoxidation reactions are important reactions for building up chiral intermediates for organic syntheses. In particular, the asymmetric epoxidation of allyl alcohols according to Sharpless et al. and manganese salt promoted enantioselective epoxidation according to Jacobsen et al. are well established in organic syntheses for the building up of chiral molecules (Sharpless et al., J. Am. Chem. Soc. 1980, 102, 5974; J. Am. Chem. Soc. 1987, 109, 5765; J. Org. Chem. 1986, 51, 1922; Jacobsen et al., J. Am. Chem. Soc. 1990, 112, 2801; J. Am. Chem. Soc. 1991, 113, 7063).
Another possibility for the asymmetric epoxidation of C═C double bonds has been disclosed in the reaction of chalcones with hydrogen peroxide in the presence of enantiomer enriched polyamino acids (Colonna et al., Org. Synth.; Mod. Trends, Proc. IUPAC Symp. 6th, 1986, 275; Julia et al., Angew. Chem., Int. Ed. Engel, 1980, 19, 929).
The methods of synthesis just mentioned all have the disadvantage that they can be applied to a relatively narrow range of substrates. For this reason, and because of the continuing research taking place in this area, there is a need to provide improved epoxidation procedures.
Two different variants of the Julia-Colonna epoxidation reaction, the two phase and the three phase variants, have been disclosed in the prior art to date (S. M. Roberts et al. Chem. Commun. 1998, 1159; WO 96/33183). The two phase variant makes use of an organic solvent and operates with oxidizing agents which are soluble in these solvents, in the presence of insoluble homopolyamino acids. The three phase variant uses water as the third phase, in addition to the water-insoluble organic solvent. Thus, water-soluble oxidizing agents can advantageously be used for the reaction; optionally in the presence of phase transfer catalysts.
From documents relating to the last-mentioned epoxidation reaction, however, it is clear that there are critical defects in this method of epoxidation with regard to its use in an industrial process, these being the occasionally low space/time yield (reaction times of the order of days) and the poor ee-values which are sometimes obtained for many substrates.
SUMMARY OF THE INVENTION
Therefore, the object of the present invention was to provide the possibility of oxidizing C═C double bonds using a method which is not inferior to the methods in the prior art with regard to the chiral induction effect, but which offers advantages with regard to the space/time yield, simplicity of application and economy when using the method on an industrial scale.
These and other objects which are not mentioned in detail, but which are produced readily and in an obvious manner from the prior art, are achieved by a process wherein the epoxidation reaction is performed in the presence of water and one or more organic solvents which are miscible with water.
As a result of the enantioselective epoxidation of compounds of the general formula I
in which
R
1
and R
2
, independently, represent (C
1
-C
18
)-alkyl,
(C
2
-C
18
)-alkenyl, (C
2
-C
18
)-alkynyl, (C
6
-C
18
)-aryl,
(C
7
-C
19
)-aralkyl, (C
3
-C
18
)-heteroaryl, (C
4
-C
19
)-heteroaralkyl,
(C
1
-C
8
)-alkyl-(C
6
-C
18
)-aryl,
(C
1
-C
8
)-alkyl-(C
3
-C
8
)-heteroaryl, (C
3
-C
8
)-cycloalkyl,
(C
1
-C
8
)-alkyl-(C
3
-C
8
)-cycloalkyl,
(C
3
-C
8
)-cycloalkyl-(C
1
-C
8
)-alkyl,
wherein the groups mentioned above may be substituted once or several times by heteroatoms such as a halogen, NR
3
R
4
, PO
0-3
R
3
R
4
, OR
3
, SR
3
, SOR
3
, SO
2
R
3
, SO
3
R
3
or groups such as CO
2
R
3
, CONHR
3
or one or more CH
2
groups may be substituted by heteroatoms such as NR
3
, PR
3
, O or S,
R
3
and R
4
, independently, represent H, (C
1
-C
18
)-alkyl,
(C
2
-C
18
)-alkenyl, (C
6
-C
18
)-aryl, (C
3
-C
18
)-heteroaryl,
(C
1
-C
8
)-alkyl-(C
6
-C
18
)-aryl,
(C
1
-C
8
)-alkyl-(C
3
-C
19
)-heteroaryl, (C
3
-C
8
)-cycloalkyl,
(C
1
-C
8
)-alkyl-(C
3
-C
8
)-cycloalkyl,
wherein the groups mentioned above may be substituted once or several times with a halogen,
by means of a diastereomer and enantiomer enriched homopolyamino acid and an oxidizing agent in such a way that epoxidation takes place in the presence of water and one or more solvents which are miscible with water, the desired highly enantiomer enriched epoxidised derivatives are obtained in a manner which was not readily predictable and in a relatively simple process with short reaction times and high yields. At the same time the method according to the invention enables the use of compounds in which the basic structure is not restricted exclusively to the chalcones used in the prior art.
In this reaction, DMF, acrylonitrile, DMSO, water-soluble alcohols or water-soluble ethers are preferably used as water-miscible organic solvents. The use of 1,2-dimethoxyethane (DME) is particularly preferred. The solvents may be used separately or as a mixture.
The monophase solvent mixture used as solvent in this method is responsible for the advantageous properties of this reaction variant. Therefore, this solvent system is not comparable to the classical 2/3-phase processes, since an organic solvent is used, as in the 3-phase process, but only a two-phase system is obtained during the reaction.
The choice of the ratio of water to organic solvent in order to produce these advantageous properties is relatively non-critical. A ratio of 10:1 to 1:10 may preferably be used. In particular, a ratio of 5:1 to 1:8 is used, quite specifically 1:1 to 1:5.
Compounds which may preferably be used as substrates of the general formula I, are those in which
R
1
represents (C
1
-C
18
)-alkyl, (C
2
-C
18
)-alkenyl,
(C
6
-C
18
)-aryl, (C
3
-C
18
)-heteroaryl,
(C
1
-C
8
)-alkyl-(C
6
-C
18
)-aryl,
(C
1
-C
8
)-alkyl-(C
3
-C
19
)-heteroaryl, (C
3
-C
8
)-cycloalkyl,
(C
1
-C
8
)-alkyl-(C
3
-C
8
)-cycloalkyl,
wherein the groups mentioned above may be substituted once or several times with a halogen or NR
3
R
4
and
R
2
represents (C
1
-C
18
)-alkyl, (C
2
-C
18
)-alkenyl,
(C
6
-C
18
)-aryl, (C
3
-C
18
)-heteroaryl,
(C
1
-C
8
)-alkyl-(C
6
-C
18
)-aryl,
(C
1
-C
8
)-alkyl-(C
3
-C
19
)-heteroaryl, (C
3
-C
8
)-cycloalkyl,
(C
1
-C
8
)-alkyl-(C
3
-C
8
)-cycloalkyl,
wherein the groups mentioned above may be substituted once or several times with a halogen or NR
3
R
4
and also
R
3
and R
4
are defined in the same way as above.
A variety of diastereomer and enantiomer enriched homopolyamino acids may be used

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