Chiral ligands for asymmetric catalysis

Details Chiral ligands for asymmetric catalysis Chiral ligands for asymmetric catalysis

2001-06-04

2003-01-21

Nazario-Gonzalez, Porfirio (Department: 1621)

Harvesters

C556S023000, C564S398000, C568S017000, C568S799000, C568S814000, C585S275000, C585S277000

Reexamination Certificate

active

06508753

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to improved phosphine ligands and catalysts derived therefrom that are useful for asymmetric hydrogenation processes.
BACKGROUND OF THE INVENTION
Asymmetric hydrogenation is an important reaction for providing chiral intermediates for pharmaceutical agents, and other products useful in the life sciences, required in the necessary single stereoisomer form. In particular the reaction provides economically viable manufacturing processes because the raw materials can be inexpensive, the reaction conditions are simple, and the catalyst may be used at a very low loading.
The diversity of substrates amenable to transformation into enantiomerically enriched chiral products by asymmetric hydrogenation means that a complementary range of catalysts is required in order to find the best match of substrate and catalyst for a given application. One class of catalysts that has received considerable attention is transition metal complexes of so-called biaryl diphosphine ligands represented by general formulae 1 and 2 Such ligands typically, although not always, possess a plane of symmetry and exist as stable atropisomers by virtue of hindered rotation about the C—C bond between the two aromatic rings bearing the phosphine groups. As a consequence these ligands have great utility for asymmetric catalysis when used in enantiomerically pure form. In particular, ruthenium complexes of the ligands are well suited to the asymmetric hydrogenation of C═X bonds, wherein X is a heteroatom, typically oxygen or nitrogen. Substrates possessing such functionality include, but are not limited to, &bgr;-keto esters, &bgr;-diketones, aromatic ketones, imines and oximes.
In the subclass of biaryl phosphines represented by formula 2, the presence of small substituents at 6- and 6′-positons, e.g. R
1
is methyl or methoxy, is sufficient to confer atropisomerism. Prototype ligands of this subclass are BIPHEMP (3) (U.S. Pat. No. 3,798,241 and Schmid et al,
Helv. Chim. Acta,
1988, 71, 897) ad BIPHEP (4) (Schmid et al.,
Pure
&
Appl. Chem.,
1996, 68, 131). Numerous variants have been reported in which extra substitution occurs on the phenyl rings bearing the phosphine groups (i e at least one of R
2
-R
4
is not hydrogen) and/or the diphenylphosphino groups are replaced with other diarylphosphino groups. Variants of this nature can profoundly effect the electronic and stearic properties of the ligand, which may in turn alter the efficiency and selectivity of derived catalysts Representative examples are described in U.S. Pat. Nos. 5,847,222 and 5,801,261
For application in industrial asymmetric catalysis, an asymmetric hydrogenation catalyst comprising a transition metal complex of a chiral ligand needs to exhibit high activity and enantioselectivity in the desired transformation of a particular substrate. It is equally important that the chiral ligand precursor can be prepared efficiently by a synthetic route that is amendable to scale-up. Although a very large number of chiral phosphine ligands have been prepared and investigated in small quantities for research, a much lesser number have been developed commercially and in such context synthetic accessibility can often be the limiting factor Of the biaryl diphosphines reported in the literature, only the BINAP (1) and BIPHEP (4) systems have been developed sufficiently for large-scale industrial use. In contrast, the reported synthetic route to BIPHEMP (3) (Schmid et al., 1988) appears unsuitable for scale-up. A particular problem with this route is the tendency for optically pure intermediates to racemise during the latter stages of the route.
SUMMARY OF THE INVENTION
The present invention is based on the unexpected discovery that novel [4,4′,5,5′,6,6′-hexamethyl(1,1′-diphenyl)-2,2′-diyl]bis(diarylphosphine)ligands of formula 5, and the opposite enantiomers thereof, have utility as components of catalysts for asymmetric synthesis
In particular, transition metal complexes of the ligand (5) can give superior performance in the asymmetric hydrogenation of certain prochiral substrates, in terms of improved enantioselectivity and/or catalytic activity, when compared with equivalent complexes of alternative biaryl diphosphine ligands. The ligand (5) is prepared efficiently via phenolic coupling.
DESCRIPTION OF THE INVENTION
Ar
1
and Ar
2
in formula (5) represent aromatic groups of up to 20 C atoms, which may be either the same or different groups. Preferred compounds of the present invention are those where Ar
1
and Ar
2
are the same and both are phenyl, optionally substituted with one, two or more alkyl or alkoxy groups (e.g. para-tolyl,3,5-dimethylphenyl, 4-methoxy-3,5-dimethylphenyl) and ruthenium complexes thereof. Typically, the complexes will be of the form Ru(5)X
2
, wherein X is selected from halide (e.g. chloride), carboxylate (e.g. trifluoroacetate) or an allylic radical (e.g. methallyl) Such ruthenium complexes can also incorporate chiral diamine ligands and have particular utility in the asymmetric hydrogenation, in the presence of base, of certain ketones and imines Cationic rhodium complexes of (5), e.g [Rh(5)COD]BF
4
, can also be prepared.
Without wishing to be bound by theory, the unique properties of the ligand 5 might be attributable to the buttressing effects of three methyl groups at adjacent positions of each phenyl ring in the biaryl moiety. The proximity of these groups means that at least one of the groups may be forced out of plane with the phenyl ring, in order to relieve non-bonded interactions. In turn, this stearic crowding may serve to influence the P-Ru-P bite angle in complexes thereof. The same methyl groups may also exert an electronic effect, by making the phenyl rings in the biaryl moiety and in turn the complexed ruthenium atom more electron-rich. Such an effect may be manifested through enhanced enantioselectivity in the hydrogenation of electron-deficient substrates such as the olefin (&agr;) or &bgr;-ketoester (b).
More generally, a substrate to be hydrogenated may have at least one C═O, C═N or C═C bond. For example, the substrate is a ketone and the product is a chiral alcohol. The substrate may be prochiral, and the product generated in enantiomerically enriched form, e.g. in an enantiomeric excess (ee) of at least 70%, 80% or 90%.
Another advantage of the present invention is that the ligands of type 5 may be assembled rapidly by a concise synthetic route, as represented in Scheme 1. The route commences with the oxidative phenolic coupling of commercially available 3,4,5-trimethylphenol (7). The symmetry and substitution pattern of this phenol ensures that only a single regioisomer is formed in this reaction, which may be effected conventionally with stoichiometric reagents such as FeCl
3
, according to the method of Takaya et al. (U.S. Pat. No. 5,530,150), although catalytic reagents such as V(O)acac
2
(Hwang et al.,
Chem. Commun.,
1999, 1207) provide a viable alternative. The resulting diol (8) is converted to an activated derivative suitable for use in a coupling reaction to form carbon-phosphorus bonds. For convenience, the activated derivative may be the bis-triflate (9). Completion of the synthesis then entails coupling with either a diarylphosphine, a diarylphosphine oxide or synthetic equivalents thereof. For expediency the coupling is carried out with a diaryiphosphine under conditions in which both carbon-phosphorus bonds are formed. Alternatively, formation of each carbon-phosphorus bond in a separate step, via 10 or 11, allows the introduction of different diarylphosphino groups. The use of diarylphosphine oxide reagents necessitates one or two extra steps (reduction) to provide the ligand (5), although the adducts (11), (12) and (13) are amenable to resolution into constituent enantiomers by formation of an inclusion complex with a chiral resolving agent. It will be recognized by a skilled practitioner that other methods are applicable in order to obtain the ligand (5) in enant

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