Homogeneous asymmetric hydrogenation using phosphine ligands...

Details Homogeneous asymmetric hydrogenation using phosphine ligands... Homogeneous asymmetric hydrogenation using phosphine ligands...

1998-12-17

2001-03-27

Wilson, James O. (Department: 1621)

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

Organic compounds

Carboxylic acid esters

C560S081000, C560S085000, C560S087000, C560S115000, C560S127000, C560S193000, C562S830000, C562S401000

Reexamination Certificate

active

06207853

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to processes suitable for the large scale preparation of enantiomerically enriched 2-substituted succinic acid derivatives. In particular, it relates to asymmetric hydrogenation of isomeric mixtures of (E)- and (Z)-itaconate derivatives, as well as &bgr;,&bgr;-disubstituted itaconate derivatives, using a transition metal catalyst complex.
BACKGROUND OF THE INVENTION
Enantiomerically enriched 2-substituted succinic acids (see formulae 2a and 2b, below) have recently attracted interest as useful chiral building blocks and peptidomimetics in the design of pharmaceuticals, flavours and fragrances, and agrochemicals with improved properties. For example, the utility of 2-substituted succinic acid derivatives has been amply demonstrated through the synthesis of a range of new potent orally bioavailable drugs [J. J. Talley et al., in
Catalysis of Organic Reactions
, J. R. Kosak, T. A. Johnson (eds.), Marcel Dekker, Inc. (1994) Chapter 6; and H. Jendralla,
Synthesis
(1994) 494].
Chiral succinates can be prepared simply (e.g., via Stobbe condensation) from unsubstituted succinic esters and aldehydes or ketones, followed by asynmmetric hydrogenation of the intermediate &bgr;-substituted itaconate derivatives. The latter reaction may be represented as
The unsubstituted parent substrate, itaconic acid (1, R
1
═R
2
═R
3
═R
4
=H), or its sodium salt, can be enantioselectively hydrogenated to 2-methylsuccinic acid with rhodium catalysts bearing the chiral ligand N-acyl-3,3′-bis(diphenylphosphino)pyrrolidine (BPPM) in up to 92% enantiomeric excess (ee) [I. Ojima et al.,
Chem. Lett.,
1978, 567; I. Ojima et al.,
Chem. Lett.,
1978, 1145; K. Achiwa,
Tetrahedron Lett.,
1978, 1475]. A rhodium catalyst bearing the chiral diphosphine DIP AMP affords 2-methylsuccinate in up to 88% ee [W. C. Christofel, B. D. Vineyard,
J. Am. Chem. Soc.
1979, 101, 4406; and U.S. Pat. No. 4,939,288]. Similar results have been obtained with a ruthenium catalyst containing the chiral diphosphine ligand BINAP [H. Kawano et al.,
Tetrahedron Lett.,
1987, 28, 1905]. Rhodium catalysts bearing modified DIOP ligands provide 2-methylsuccinic acid derivatives with variable enantioselectivities, between 7 and 91% ee. In these latter reactions, the ee value is very dependant on the rhodium catalyst precursor and whether the free acid or the ester is used [T. Morimoto et al.,
Tetrahedron Lett.,
1989, 30, 735]. Better results have been reported with a neutral rhodium catalyst of the chiral diphosphine 2,2′-bis(dicyclohexylphosphino)-6,6′-dimethyl-1,1′-biphenyl (BICHEP), whereby dimethylitaconate was hydrogenated in 99% ee [T. Chiba et al.,
Tetrahedron Lett.,
1991, 32, 4745].
In contrast to the success achieved with unsubstituted itaconate derivatives, asymmetric hydrogenation of &bgr;-substituted itaconic acid derivatives of general structure 3 and 4 (R
3
≠H) has been more challenging; relatively few reports of high enantioselectivity (over 90% ee) have appeared. The curtailed effectiveness of known asymmetric catalysts for the hydrogenation of &bgr;-substituted itaconic acids derivatives 3 and/or 4 is particularly apparent when R
3
is an alkyl group, in which case no enantioselectivities above 90% ee have been reported.
It should be noted that enantiomerically pure compounds are required for many applications in, for example, the pharmaceutical industry. Consequently, providing enantiomeric purity is the ultimate objective of an asymmetric process, and achieving high enantioselectivity in a transformation of the type described herein is crucial from a process standpoint. 90% ee is often selected as a lower acceptable limit, because compounds often may be purified to enantiomeric purity through recrystallisation when the initial value is above 90% ee. Enantiomeric excesses lower than 90% ee become increasingly more difficult to purify.
A major complication encountered with &bgr;-substituted itaconic acid derivatives is that they frequently are synthesised as a mixture of E and Z geometric isomers, i.e. formulae 3 and 4 respectively. This presents serious difficulties in subsequent hydrogenation reactions, since the different geometric isomers typically are reduced with vastly different rates and enantioselectivities. Accordingly, it has been necessary to separate the E- and Z-isomers (3 and 4) prior to the hydrogenation reaction. From a process standpoint, this is a wasteful, time-consuming, and yield-limiting feature.
Several reports have disclosed the ability to hydrogenate pure &bgr;-substituted (E)-itaconate derivatives (3). Even when the substrates are E-pure, however, high enantioselectivities have been limited to hydrogenation of &bgr;-arylitaconate derivatives (3, R
3
=aromatic ring such as phenyl or naphthyl). Isomerically pure (E)-&bgr;-phenylitaconate derivatives have been hydrogenated with a DIPAMP-Rh catalyst in up to 97% ee [U.S. Pat. No. 4,939,288]. The same substrates were hydrogenated with a Ru-BINAP catalyst in up to 90% ee [H. Kawano et al.,
Tetrahedron Lett.,
1987, 28, 1905]. A rhodium complex bearing a modified DIOP ligand allowed hydrogenation of several (E)-&bgr;-arylitaconate derivatives with enantioselectivities up to 96% ee [T. Morimoto et al.,
Tetrahedron Lett,
1989, 30, 735].
Despite these impressive results, relatively poor enantioselectivities have been reported in the hydrogenation of (E)-pure &bgr;-alkylitaconate derivatives (3, R
3
=alkyl). The DIPAMP-Rh catalyst noted above provided 2-isobutylsuccinate in only 76% ee through hydrogenation of (E)-substrate 3 (R
3
=CH(CH
3
)
2
) [U.S. Pat. No. 4,939,288]. Importantly, it is indicated that the (Z)-isomer of this substrate (i.e., 4, R
3
=CH(CH
3
)
2
) is not a suitable substrate for this reaction and must be separated from (E)-substrate prior to hydrogenation. The low enantioselectivity achieved with this particular substrate using known catalysts is regrettable since the product succinate 2 (R
3
=CH(CH
3
)
2
) serves as a critical component of numerous new drug candidates.
Itaconate derivatives that possess two substituents in the &bgr;-position (&bgr;,&bgr;-disubstituted itaconates of formula 1 where R
3
,R
4
≠H) have thus far proven impossible to hydrogenate with high enantioselectivities and high rates. The only reported example of this type revealed that dimethyl &bgr;,&bgr;-dimethylitaconate may be hydrogenated with a Rh-TRAP catalyst system with the highest enantioselectivities being 78% ee [R. Kuwano et al.,
Tetrahedron: Asymmetry,
1995, 6, 2521].
SUMMARY OF THE INVENTION
One aspect of the present invention is based on the discovery that a broad variety of different itaconate derivatives can be readily hydrogenated using certain chiral mono and diphosphine-transitional metal catalysts, to afford highly enantiomerically enriched 2-substituted succinates. Another aspect of the present invention lies in the realisation that, when R
3
and/or R
4
has an &agr;-H atom, an isomerised product is formed; this undesired product can be removed, once its presence is appreciated.
A further aspect of the present invention is based on the discovery that an efficient and high yielding preparation of an enantiomerically enriched 2-substituted succinic acid derivative (2), by asymmetric hydrogenation is the presence of a transition metal complex of a chiral phosphine, is facilitated by use of particular salt forms of the hydrogenation substrate.
Important characteristics of the present invention include: (i) the ability to hydrogenate &bgr;-alkyl-substituted itaconate derivatives with very high enantioselectivities, (ii) the ability to hydrogenate an isomeric mixture of (E)- and (Z)-itaconate derivatives with very high enantioselectivities, (iii) the ability to hydrogenate &bgr;,&bgr;-disubstituted itaconate derivatives with high enantioselectivities, (iv) the ability to hydrogenate specifically ita

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