Method for homogeneous enantioselective hydrogenation using...

Details Method for homogeneous enantioselective hydrogenation using... Method for homogeneous enantioselective hydrogenation using...

1999-06-18

2002-02-19

Geist, Gary (Department: 1623)

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

Organic compounds

Carboxylic acid esters

C556S144000

Reexamination Certificate

active

06348620

ABSTRACT:

CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority from German Applications No. 198 27 311.8, filed on Jun. 19, 1998, 198 58 866.6 filed on Dec. 19, 1998 and 199 21 924.9 filed on May 12, 1999, the subject matter of each of which is hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is relates to a method for the homogeneous, catalytic, enantioselective hydrogenation of compounds of the general formula (I)
in which
n is a whole number from 0 to 3,
R═H, (C
1
-C
18
)-alkyl, (C
6
-C
18
)-aryl, (C
7
-C
19
)-aralkyl, (C
3
-C
18
)-heteroaryl, (C
4
-C
18
)-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, or signifies a carboxy protective group,
R′═H, (C
1
-C
18
)-alkyl, (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, which groups just cited can be substituted with (C
1
-C
8
)-acyl or (C
1
-C
8
)-alkyloxycarbonyl,
X═O, CHR″, NR″, NNHR″,
R″ can be ═H, OH, R′, (C
1
-C
8
)-alkoxy, (C
2
-C
18
)-alkoxyalkyl,
(C
1
-C
18
)-acyl, (C
1
-C
18
)-acyloxy and R″ can assume different shapes for different positions in the molecule,
or R and R′ or R′ and R″ or R″ and R are connected to one another via a (C
1
-C
4
) bridge which can be singly or multiply substituted with linear or branched (C
1
-C
8
)-alkyl, (C
1
-C
8
)-acyl, (C
1
-C
8
)-alkoxy, (C
2
-C
8
)-alkoxyalkyl groups and/or can contain heteroatoms such as N, O, P, S in the ring,
with the aid of C
2
-symmetric ferrocenyl catalysts.
Furthermore, the invention relates to the use of the derivatives produced by the enantioselective hydrogenation of the invention as chiral intermediates in organic synthesis.
2. Background Information
The enantioselective introduction of stereogenic centers into organic molecules by homogeneously catalyzed hydrogenation is established for special applications on an industrial scale. The enantioselective products are valuable initial substances for the production of bioactive active substances.
The use of bisphosphine catalysts for the enantioselective, homogeneous, catalytic hydrogenation for the purpose just cited is well known (Burk et al., Tetrahedron 1994, 4399).
Knochel et al. (Chem. Eur. J. 1998, 4, 950-968), Hayashi et al. (J. Chem. Soc., Chem Commun. 1989, 495-496), and Ikeda et al. (Tetrahedron Lett. 1996, 4545-4548) describe Pd complexes with C
2
-symmetric ferrocenyl-(bis-tertiary phosphine) ligands. However, these complexes were used solely in asymmetric allylations. Their use as catalysts in enantioselective hydrogenation was not known up to the present.
Yamamoto at al. (Bull. Chem. Soc. Jpn. 1980, 53, 1132-1137) reported on the use of non C
2
-symmetric ferrocenyl-(bis-tertiary phosphine) ligands in enantioselective, homogeneous, catalytic hydrogenation. However, good excesses of enantiomers are obtained only very sporadically with these ligands.
DE 19 82 7311.8 and Kang et al. (Tetrahedron Lett. 1998, 39, 5523-5526) disclose C
2
-symmetric ferrocenyl complexes as suitable catalysts for the enantioselective hydrogenation of acetamido cinnamicacid derivatives.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a method for the homogeneous, catalytic, enantioselective hydrogenation of further, unsaturated systems with the aid of C
2
-symmetric ferrocenyl catalysts.
The term “multiple bonds” denotes in the framework of the invention double bonds between a carbon atom and another carbon atom or oxygen atom or nitrogen atom.
This objective is achieved by a method using C
2
-symmetric ferrocenyl catalysts as described hereinbelow.
As a result of the fact that for the homogeneous, catalytic, enantioselective hydrogenation of compounds of the general formula (I)
in which
n is a whole number from 0 to 3,
R═H, (C
1
-C
18
)-alkyl, (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,
or signifies a carboxy protective group,
R′═H, (C
1
-C
18
)-alkyl, (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, which groups just cited can be substituted with (C
1
-C
8
)-acyl or (C
1
-C
8
)-alkyloxycarbonyl,
X═O, CHR″, NR″, NNHR″,
R″ can be H, OH, R′, (C
1
-C
18
)-alkoxy, (C
2
-C
18
)-alkoxyalkyl, (C
1
-C
18
)-acyl, (C
1
-C
18
)-acyloxy and R″ can assume different shapes for different positions in the molecule,
or R and R′ or R′ and R″ or R″ and R are connected to one another via a (C
1
-C
4
) bridge which can be singly or multiply substituted with linear or branched (C
1
-C
8
)-alkyl, (C
1
-C
8
)-acyl, (C
1
-C
8
)-alkoxy, (C
2
-C
8
)-alkoxyalkyl groups and/or can contain heteroatoms such as N, O, P, S in the ring,
catalysts of the general formula (II)
are used
in which
R
1
, R
2
signify, independently of one another, H, NR
6
R
7
, SR
6
,
(C
1
-C
18
)-alkyl, (C
1
-C
18
)-alkoxy, (C
2
-C
18
)-alkoxyalkyl,
(C
1
-C
18
)-acyloxy, (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,
or R
1
and R
2
are connected via a (C
3
-C
7
)-carbocycle which can be singly or multiply substituted with linear or branched (C
1
-C
8
)-alkyl, (C
1
-C
8
)-acyl, (C
1
-C
8
)-alkoxy, (C
2
-C
8
)-alkoxyalkyl and/or can contain heteroatoms such as N, O, P, S in the ring,
R
3
signifies (C
2
-C
18
)-alkyl, (C
1
-C
18
)-alkoxy,
(C
2
-C
18
)-alkoxyalkyl, (C
1
-C
18
)-acyloxy, (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,
R
4
signifies (C
1
-C
18
)-alkyl, (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,
R
5
signifies H or a group B-X-Z in which B is a residue selected from the groups CR
8
2
, NR
8
, O, S, and SiR
8
2
, X is a spacer such as, e.g., 1,4′-biphenyl, 1-, 2-ethylene, 1-, 3-propylene, PEG-(2-10) and Z signifies a group bound to a polymer via a functional group such as, e.g., the O—, NH—, COO—, CONH—, ethenyl—, NHCONH—, OCONH— or NHCOO—, or the groups R
5
of the two cyclopentadienyl rings are connected to each other via an a, &agr;, &ohgr;-(C
2
-C
4
)-alkylene bridge,
R
6
, R
7
signify, independently of one another, H, (C
1
-C
18
)-alkyl,
(C
1
-C
18
)-alkoxy, (C
2
-C
18
)-alkoxyalkyl, (C
1
-C
18
)-acyl,
(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,
or R
6
and R
7
are connected via a (C
3
-C
7
)-carbocycle which can be substituted simply or multiply with linear or branched (C
1
-C
8
)-alkyl, (C
1
-C
8
)-acyl, (C
1
-C
8
)-alkoxy, (C
2
-C
8
)-alkoxyalkyl and or can contain heteroatoms such as N, O, P,

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