Ligands for chiral catalysis

Details Ligands for chiral catalysis Ligands for chiral catalysis

2000-03-07

2002-10-29

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S237000

Reexamination Certificate

active

06472533

ABSTRACT:

The present invention relates to novel optically active phosphine oxazoline ligands, a process for the preparation thereof, metal complexes containing such novel ligands and the use of such complexes, or combinations of ligand with metal salts or complexes, as catalysts for asymmetric syntheses.
The development of novel catalytic systems exhibiting unique reactivity and high enantioselectivity is of great importance in science and technology. The activity of many pharmaceuticals, agrochemicals, fragrances and food additives are associated with a specific enantiomer. Thus, the ability to produce enantiomerically pure compounds is essential. Many approaches have been explored to acquire such enantiomerically pure compounds, ranging from optical resolution and structural modification of naturally occurring chiral substances to asymmetric catalysis using synthetic chiral catalysts and enzymes. Asymmetric catalysis has been found to be one of the most efficient, if not the most efficient method of producing enantiomerically pure compounds since a small amount of a chiral catalyst can be used to produce a large quantity of a chiral compound.
One class of ligands which have played a significant role in the development of chiral catalysts are asymmetric phosphine ligands. Although over 1000 chiral diphosphine ligands have been prepared since the application of the DIPAMP ligand in the production of L-Dopa, only a few of these have the efficiency and selectivity of commercial applications. Some of the most well known phosphine ligands used include BINAP, BPPM, DEGPHOS, DIOP, Chiraphos, Skewphos, Duphos and BPE. However, these ligands have their disadvantages and are not ideal for all applications.
There is still, therefore, the need to develop novel chiral catalysts which are highly enantiomerically selective and carry out the required reaction giving a high yield.
Accordingly, the present invention provides a phosphine oxazoline ligand of formula (I)
wherein
m is 1, 2, 3 or 4;
n, p, q, r are independently zero or 1 provided that at least one of n, p, q and r is 1;
X is O, S, Se, CH
2
, NH;
Y is N, P, As, S;
R is H; a straight, branched or cyclo alkyl optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine, ether; aryl optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine, ether; ferrocenyl; a thioalkyl group; a thioaryl group; or R is part of a polymeric structure, for example polyacrylic acid;
R
1
to R
13
are independently selected from H; a straight, branched or cyclo alkyl optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine, ether; aryl optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine, ether.
By the term “alkyl” we mean a straight, branched or cyclo alkyl group having any number of carbon atoms, for example from 1 to 14 carbon atoms, such as from 1 to 10 carbon atoms. The cyclo alkyl groups may have only one or more than one ring structure e.g. adamantyl.
By the term “aryl” we mean an aromatic monovalent hydrocarbon radical, for example phenyl, benzyl, naphthyl, etc.
Suitably, m is 1 or 2; preferably 1.
Suitably, at least two of n, p, q and r are 1, the remaining two being zero or 1; preferably, two of n, p, q and r are 1, the remaining two being zero.
Suitably, X is O, S, CH
2
or NH; preferably O.
Suitably, Y is P, N or S; preferably P.
A first embodiment of the invention provides a compound of formula (IA)
wherein m, X, Y, R, and R
1
to R
5
and R
12
and R
13
are as hereinbefore defined.
A second embodiment of the invention provides a compound of formula (IB)
wherein m, X, Y, R and R
1
to R
7
and R
12
and R
13
are as hereinbefore defined.
A third embodiment of the invention provides a compound of formula (IC)
wherein m, X, Y, R and R to R
1
and R
12
and R
13
are as hereinbefore defined.
A fourth embodiment of the invention provides a compound of formula (ID)
wherein m, X, Y, R and R
1
to R
13
are as hereinbefore defined.
A particularly preferred embodiment of the invention provides a compound of the following structure:
wherein R is C
1-4
alkyl optionally substituted by one or more groups selected from phenyl or halo; phenyl optionally substituted by one to five substituents selected from the group consisting of halo, C
1-4
alkyl, C
1-4
alkoxy or nitro; ferrocenyl or adamantyl; and R
12
and R
13
are Ph or cyclohexyl.
Particularly preferred compounds include those of the following formulae:
Compounds of formula (I) are novel and. accordingly a further aspect. of the resent invention provides a process for the preparation of a compound of formula (I). compounds of formula (I) may be prepared by the reaction of a compound of formula (II)
wherein m, n, p, q, r, X, Y and R
1
to R
13
are as hereinbefore defined; R
14
and R
15
are alkyl groups which may be the same of different and Pro is a nitrogen protecting group, for example BOC, with a compound of formula (III)
wherein R is as hereinbefore defined, R
16
is an alkyl group, for example ethyl, and Hal is a halogen atom, for example chloro. The reaction is carried out by the addition of for example gaseous HCl, in the presence of an alcohol, such as methanol to the compound of formula (II), followed by the addition of a compound of formula (III) in the presence of a base, for example triethylamine, in a suitable solvent such as dichloromethane.
Compounds of formula (III) are known in the literature (Meyers, A. I.; Schmidt, W; McKennon, M. J., Synthesis, 1993, 250-262).
Compounds of formula (II) may be prepared by the reaction of a compound of formula (IV)
wherein m, n, p, q, r, X, R
1
to R
15
and Pro are as hereinbefore defined, and L is a suitable leaving group, such as tosylate, iodide, triflate, bromide, with a compound of formula LiYR
12
R
13
, wherein Y, R
12
and R
13
are as hereinbefore defined. The reaction is carried out in the presence of an organic solvent, such as THF, and with the addition of BH
3
.
Compounds of formula (IV) may be prepared from the corresponding alcohol of formula (V)
wherein m, n, q, r, X, R
1
to R
15
and Pro are as herinbefore defined. The reaction is carried out with a suitable compound to give the desired leaving group, L. For example is the leaving group is tosyl, the reaction is carried out with for example tosyl chloride, in the presence of a base, for example triethylamine, and a suitable solvent, for example dichloromethane. A catalytic amount of 4-dimethylaminopyridine (DMdAP) may also be added.
Compounds of formula (V) are known in the literature (Ksander, G. M.; de Jesus, R.; Yuan, A.; Ghai, R. D.; Trapani, A.; McMarrin, C.; Bohacek, R., J. Med. Chem. 1997, 40, 495-505)
Compounds of formulae (II) and (IV) are also novel and accordingly form a further aspect of the invention.
A yet further aspect of the present invention provides a metal complex containing a ligand of formula (I), a metal and optionally other known ligands as may be required to stabilise the complex, e.g. chloride, acetate etc. Suitably, the metal is a transition metal; for example, the metal may be selected from the group consisting of Ni, Pd, Rh, Ir, Cu, Ag, Au and Zn.
A metal complex of the present invention may be of use in any chemical reaction requiring an asymmetric catalyst. Examples of such reactions include but are not limited to Heck type reactions, Suzuki type reactions, allylation reactions, cross-coupling reactions, hydrogenations, hydroformylations and isomerisation reactions. Therefore, a still further aspect of the invention provides a metal complex of the invention for use in asymmetric catalytic reactions. Alternatively, the invention provides the use of a metal complex of the invention in asymmetric catalytic reactions. Alternatively, there is provided a method for performing an asymmetric catalytic reaction, said method comprising the use of a metal complex of the invention.
The metal complex of the invention may

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