Ligands and complexes for enantioselective hydrogenation

A ferroceneylphosphine ligand and complexes prepared therefrom for homogeneous catalytic enantioselective hydrogenation, the ligand having the formula (I): ##STR1## Another aspect of the invention is directed to a ferroceneylphosphine ligand of formula (II), ##STR2##

BACKGROUND OF THE INVENTION
 1. Field of the Invention
 The present invention is related to ligands and complexes for homogeneous
 catalytic enantioselective hydrogenation. More particularly, the invention
 relates to ligands of formula (I)
 ##STR3##
 Another aspect of the invention is related to complexes of formula (II),
 and to
 ##STR4##
 a method for their preparation and use.
 Enantioselective introduction of stereogenic centers into organic molecules
 by homogeneously catalyzed hydrogenation is established industrially for
 special applications. The enantioselective products are valuable starting
 substances for the production of biologically active agents.
 2. Discussion of the Background
 The use of catalysts containing bisphosphine ligands for enantioselective
 homogeneous catalytic hydrogenation for the above purposes is known (Burk
 et al., Tetrahedron, 1994, 4399).
 Knochel et al. (Chem. Eur. J. 1988, 4, 950-968), Hayashi et al. (J. Chem.
 Soc., Chem. Commun. 1989, 495-496) and Ikeda et al. (Tetrahedron Lett.
 1996, 4545-4448) describe Pd complexes with C.sub.2 symmetric ferrocenyl
 (bis-tert-phosphine) ligands. However, these complexes were used only in
 asymmetric allylations.
 In contrast, Yamamoto et al. (Bull. Chem. Soc. Jpn. 1980, 53, 1132-1137)
 reported the use of non-C.sub.2 -symmetric ferrocenyl(bis-tert-phosphine)
 ligands in enantioselective homogeneous catalytic hydrogenation reactions.
 However, only very sporadically good enantiomer excesses are obtained with
 these ligands.
 The basic suitability of non C.sub.2 symmetric ferrocenyl ligands for
 enantioselective hydrogenation is taught in WO 96/32400 and WO 95/21151.
 SUMMARY OF THE INVENTION
 Accordingly, one object of the present invention is to provide an
 enantiomer-enriched bisphosphine ligand system and catalysts derived
 therefrom which are consistently of good effectiveness for the homogeneous
 enantioselective catalytic hydrogenation of multiple bonds.
 Multiple bonds within the scope of the invention are understood to mean
 double bonds between a carbon atom and another carbon atom or oxygen atom
 or nitrogen atom.
 Briefly, this object and other objects of the present invention as
 hereinafter will become more readily apparent can be attained by an
 enantiomer-enriched ligand and salts thereof of formula (I)
 ##STR5##
 wherein
 R.sup.1 and R.sup.2, independent of one another, are R.sup.8, NR.sup.6
 R.sup.7, SR.sup.6, (C.sub.1 -C.sub.18)-alkyl, (C.sub.1 -C.sub.18,)-alkoxy,
 (C.sub.2 -C.sub.18)-alkoxyalkyl, (C.sub.1 -C.sub.18)-acyloxy, (C.sub.6
 -C.sub.18)-aryl, (C.sub.7 -C.sub.19)-aralkyl, (C.sub.3
 -C.sub.18)-heteroaryl, (C.sub.4 -C.sub.19)-heteroaralkyl, (C.sub.1
 -C.sub.8)-alkyl-(C.sub.6 -C.sub.18)-aryl, (C.sub.1
 -C.sub.19)-alkyl-(C.sub.3 -C.sub.19)-heteroalkyl, (C.sub.3
 -C.sub.8)-cycloalkyl, (C.sub.1 -C.sub.8)-alkyl-(C.sub.3
 -C.sub.8)-cycloalkyl, (C.sub.3 -C.sub.8)-cycloalkyl-(C.sub.1
 -C.sub.8)-alkyl;
 or R.sup.1 and R.sup.2 are bonded via a (C.sub.3 -C.sub.7)-carbocycle,
 which is optionally substituted at least once by linear or branched
 (C.sub.1 -C.sub.8)-alkyl, (C.sub.1 -C.sub.8)-acyl, (C.sub.1
 -C.sub.8)-alkoxy, (C.sub.2 -C.sub.8)-alkoxyalkyl and/or optionally
 contains at least one heteroatom selected from the group consisting of N,
 O, P and S, in the ring;
 R.sup.3 and R.sup.4, independent of one another, are H, (C.sub.1
 -C.sub.18)-alkyl, (C.sub.1 -C.sub.18)-alkoxy, (C.sub.2
 -C.sub.18)-alkoxyalkyl, (C.sub.1 -C.sub.18)-acyloxy, (C.sub.6
 -C.sub.18)-aryl, (C.sub.7 -C.sub.19)-aralkyl, (C.sub.3
 -C.sub.18)-heteroaryl, (C.sub.4 -C.sub.19)-heteroaralkyl, (C.sub.1
 -C.sub.8)-alkyl-(C.sub.6 -C.sub.18) aryl, (C.sub.1
 -C.sub.8)-alkyl-(C.sub.3 -C.sub.19)-heteroalkyl, (C.sub.3
 -C.sub.8)-cycloalkyl, (C.sub.1 -C.sub.8)-alkyl-(C.sub.3 -C.sub.8)
 cycloalkyl and (C.sub.3 -C.sub.8)-cycloalkyl-(C.sub.1 -C.sub.8)-alkyl;
 or R.sup.3 and R.sup.4 arc bonded via a (C.sub.3 -C.sub.5)-bridge, which
 optionally contains at least one double bond and/or is optionally
 substituted at least once by linear or branched (C.sub.1 -C.sub.8)-alkyl,
 (C.sub.1 -C.sub.8)-acyl, (C.sub.1 -C.sub.8)-alkoxy, (C.sub.2
 -C.sub.8)-alkoxyalkyl or optionally contains at least one heteroatom
 selected from the group consisting of N, O, P and S in the ring;
 R.sup.5 is (C.sub.1 -C.sub.18)-alkyl, (C.sub.6 -C.sub.18)-aryl, (C.sub.3
 -C.sub.8)-heteroaryl, (C.sub.1 -C.sub.8)-alkyl-(C.sub.6 -C.sub.18)-aryl,
 (C.sub.1 -C.sub.8)-alkyl-(C.sub.3 -C.sub.19)-heteroalkyl, (C.sub.3
 -C.sub.8)-cycloalkyl, (C.sub.1 -C.sub.8)-alkyl-(C.sub.3
 -C.sub.8)-cycloalkyl, where the radical R.sup.5 on the same phosphorus
 atom and/or the two phosphorus atoms can be different;
 R.sup.6 and R.sup.7, independent of one another, are H, (C.sub.1
 -C.sub.18)-alkyl, (C.sub.1 -C.sub.18)-alkoxy, (C.sub.2
 -C.sub.18)-alkoxyalkyl, (C.sub.1 -C.sub.18)-acyl, (C.sub.6
 -C.sub.18)-aryl, (C.sub.7 -C.sub.19)-aralkyl, (C.sub.3
 -C.sub.18)-heteroaryl, (C.sub.4 -C.sub.19)-heteroaralkyl, (C.sub.1
 -C.sub.8)-alkyl-(C.sub.6 -C.sub.18)-aryl, (C.sub.1
 -C.sub.18)-alkyl-(C.sub.3 -C.sub.19)-heteroalkyl, (C.sub.3
 -C.sub.8)-cycloalkyl, (C.sub.1 -C.sub.8)-alkyl-(C.sub.3
 -C.sub.8)-cycloalkyl and (C.sub.3 -C.sub.8)-cycloalkyl-(C.sub.1
 -C.sub.8)-alkyl,
 or R.sup.6 and R.sup.7 are bonded via a (C.sub.3 -C.sub.7)-carbocycle,
 which is optionally substituted at least once by linear or branched
 (C.sub.1 -C.sub.8) alkyl, (C.sub.1 -C.sub.8) acyl, (C.sub.1 -C.sub.8)
 alkoxy, (C.sub.2 -C.sub.8)-alkoxyalkyl and/or optionally contains at least
 one heteroatom selected from the group consisting of N, O, P and S in the
 ring;
 R.sup.8 is H or a moiety B-X-Z, where B is a radical selected from the
 group consisting of CR.sup.9.sub.2, NR.sup.9, O, S and SiR.sup.9.sub.2, X
 is a spacer selected from the group consisting of 1,4'-biphenyl,
 1-,2-ethylene, 1-,3-propylene, PEG-(2-10) and Z is a radical bonded to a
 polymer via a functional group selected from the group consisting of
 --O--, --NH--, --CONH, -ethenyl-, --NHCONH--, --OCONH-- or --NHCOO--, or
 the radical R.sup.8 of the two cyclopentadienyl rings is bonded via an
 .alpha.,.omega.-(C.sub.2 -C.sub.4)-alkylene bridge to each other;
 R.sup.9 is H or (C.sub.1 -C.sub.18)-alkyl.
 Especially preferred are ligands in which R.sup.1, R.sup.2, independent of
 one another, are H, NR.sup.6 R.sup.7, (C.sub.1 -C.sub.8)-alkyl, (C.sub.1
 -C.sub.8)-acyloxy, (C.sub.6 -C.sub.18)-aryl and (C.sub.3
 -C.sub.8)-cycloalkyl;
 or R.sup.1 and R.sup.2 are bonded via a (C.sub.3 -C.sub.7)-carbocycle;
 R.sup.3 and R.sup.4, independent of one another, are (C.sub.1
 -C.sub.8)-alkyl, (C.sub.6 -C.sub.18)-aryl, (C.sub.3 -C.sub.8)-cycloalkyl;
 or R.sup.3 and R.sup.4 arc bonded via a (C.sub.3 -C.sub.5)-bridge, which
 optionally contains at least one double bond;
 R.sup.5 is (C.sub.6 -C.sub.18)-aryl or (C.sub.3 -C.sub.8)-cycloalkyl,
 R.sup.6 and R.sup.7, independent of one another, are (C.sub.1
 -C.sub.18)-alkyl, (C.sub.1 -C.sub.18)-acyl, (C.sub.6 -C.sub.18)-aryl and
 (C.sub.3 -C.sub.8)-cycloalkyl;
 or R.sup.6 and R.sup.7 are bonded via a (C.sub.3 -C.sub.7)-carbocycle; and
 R.sup.8 is H.
 Another aspect of the invention is an enantiomer-enriched complex of
 formula (II) and salts thereof;
 ##STR6##
 wherein R.sup.1 and R.sup.9 have the meanings given above and M is a metal
 atom or ion of subgroup 7 or 8 including Co, Ni, Rh, Ru, Ir, Pd, Re and
 Pt.
 Especially preferred are complexes of formula (II), in which R.sup.1 and
 R.sup.2, independent of one another, are H, NR.sup.6 R.sup.7 (C.sub.1
 -C.sub.8)-alkyl, (C.sub.1 -C.sub.8)-acyloxy, (C.sub.6 -C.sub.8)-aryl and
 (C.sub.3 -C.sub.8)-cycloalkyl;
 or R.sup.1 and R.sup.2 are bonded together as a (C.sub.3
 -C.sub.7)-carbocycle;
 R.sup.3 and R.sup.4, independent of one another, are (C.sub.1
 -C.sub.8)-alkyl, (C.sub.6 -C.sub.18)-aryl and (C.sub.3 -C,)-cycloalkyl;
 or R.sup.3 and R.sup.4 are bonded via a (C.sub.3 -C.sub.5)-bridge, which
 optionally contains at least one double bond;
 R.sup.5 is (C.sub.6 -C.sub.18)-aryl or (C.sub.3 -C.sub.18)-cycloalkyl;
 R.sup.6 and R.sup.7, independent of one another, are (C.sub.1
 -C.sub.18)-alkyl, (C.sub.1 -C.sub.18)-acyl, (C.sub.6 -C.sub.18)-aryl and
 (C.sub.3 -C.sub.8)-cycloalkyl;
 or R.sup.6 and R.sup.7 are bonded via a (C.sub.3 -C.sub.7)-carbocycle; and
 R.sup.8 is H;
 and M is a metal atom or ion of Group 8 such as Rh, Ru or Pd.
 A still another aspect of the invention is directed to a method for
 preparation of the ligands of the invention.
 Compounds of formula (III):
 ##STR7##
 where R.sup.3, R.sup.4 and R.sup.8 are as defined above and R.sup.10 =Hal,
 can be converted enantioselectively to compounds of formula (IV):
 ##STR8##
 where R.sup.1 and R.sup.2 are H or OH, where R.sup.1 and R.sup.2 must not
 be the same, R.sup.3, R.sup.4 and R.sup.8 have the meanings stated above
 and R.sup.10 is Hal.
 Then compounds of formula (IV), where R.sup.1 and R.sup.2 are H or OH,
 where R.sup.1 and R.sup.2 must not be the same, R.sup.3, R.sup.4 and
 R.sup.8 have the meanings stated above and R.sup.10 =H, are converted to
 compounds of formula (V)
 ##STR9##
 where R.sup.1 and R.sup.2 are H or N(C.sub.1 -C.sub.8)-alkyl.sub.2, where
 R.sup.1 and R.sup.2 must not be the same, R.sup.3, R.sup.4 and R.sup.8
 have the meanings stated above and R.sup.10 =Hal.
 In the next step compounds of formula (V), where R.sup.1 and R.sup.2 are H
 or N(C.sub.1 -C.sub.8)-alkyl.sub.2, where R.sup.1 and R.sup.2 must not be
 the same, R.sup.3, R.sup.4 and R.sup.8 have the meanings stated above and
 R.sup.10 =Hal, can advantageously be converted to compounds of formula
 (VI):
 ##STR10##
 where R.sup.1 and R.sup.2 are H or N(C.sub.1 -C.sub.8)-alkyl.sub.2, where
 R.sup.1 and R.sup.2 must not be the same, R.sup.3, R.sup.4 and R.sup.8 can
 take on the meaning given above, and R.sup.10 =Li.
 Finally, compounds of general formula (VI), where R.sup.1 and R.sup.2 are H
 or N(C.sub.1 -C.sub.8)-alkyl.sub.2, where R.sup.1 and R.sup.2 must not be
 the same, R.sup.3, R.sup.4 and R.sup.8 have the meanings stated above and
 R.sup.10 =Li, can be converted to compounds of formula (I):
 ##STR11##
 where R.sup.1 and R.sup.9 have the meanings described above.
 The preparation of the ligand system of the invention can thus take place
 in a modular fashion, as described in the following scheme.
 ##STR12##
 In a first preparation step commercially available ferrocene A is
 monoacylated under Friedel-Crafts conditions (J. Org. Chem. 1957, 22,
 903-906).
 For simultaneous insertion of a preferred central and planar chirality the
 acylated ferrocene B can in principle be converted by any of the methods
 that are possible to the skilled artisan for this reaction (J. Am. Chem.
 Soc. 1957, 79, 2742, J. Organometal. Chem. 1973, 52, 407-424). However,
 reduction with the so-called CBS reagent (J. Am. Chem. Soc. 1987, 109,
 5551-5553, Tetrahedron Lett. 1996, 37, 25-28) is preferred. This procedure
 ensures that the reaction products are produced in very good yields and
 with very high optical and diastereometric purity. Another conceivable
 path for preparation of the desired enantiomer-enriched ligands can take
 place, for example, by preparing the acylated ferrocenes by means of
 enantioselective reductive amination. One equally arrives at the
 enantiomer-enriched ligands with an amine substituent at the stereogenic
 center in this manner.
 Other possibilities for introduction of chirality are described in
 principle in Tetrahedron Asymmetry 1991, 2, 601-612, J. Org. Chem. 1991,
 56, 1670-1672, J. Org. Chem. 1994, 59, 7908-7909, J. Chem. Soc., Chem.
 Commun. 1990, 888-889.
 The enantiomer-enriched alcohols C that are obtained by the above described
 CBS reaction can now be converted to other derivatives of formula E in all
 of the ways that are known to the skilled artisan. Preferably the
 derivatives are made by replacing the OH function at the stereogenic
 center by an amino group. Especially preferred is the preparation of the
 dialkylamino derivatives, since these can be employed directly for the
 further conversion to F or via G to H.
 In this step the dialkylamino derivatives F can advantageously be
 deprotonated in the .alpha. position at the cyclopentadienyl ring and then
 reacted with a reagent to introduce a halogen atom, preferably bromine.
 The deprotonation reaction can take place with all of the agents that arc
 commonly known to the skilled aitisan for this purpose, but preferred is
 the use of the strong base n-butyllithium (n-BuLi) or t-butyllithium
 (t-BuLi) in an inert solvent. Preferably the lithium bonded to ferrocene
 is converted to the brome derivative with (CCl.sub.2 Br).sub.2. Because of
 the chirality present in the molecule, of the two a positions in the ring,
 one is preferably deprotonated and substituted.
 The subsequent introduction of the phosphine groups into the .alpha.
 position of the ferrocene ring and at aromatic compounds occurs
 advantageously by double halogen-lithium exchange followed by reaction
 with a phosphine reagent. Preferred possibilities as phosphine reagents
 are compounds that have a leaving group at the phosphorus atom and thus
 exhibit electrophilic character. Such reagents are sufficiently well known
 to the skilled artisan (J. Am. Chem. Soc. 1955, 77, 3526-29). The use of
 diphenylphosphine chloride is preferred.
 The introduction of the phosphine groups can also take place starting from
 a derivative E. By protonation and halogen-lithium exchange with two
 equivalents of base, one obtains extremely preferred double lithiated
 intermediates, which can be converted to G by the above pathway with
 phosphine groups.
 If the radical R.sup.8 is not initially present in the starting molecule A,
 one can subsequently deprotonate the second position possible for
 deprotonation, the .delta. position on the ferrocene ring, in another
 deprotonation experiment like the one just described and then reacted with
 a suitable electrophilic reagent for introduction of radical R.sup.8.
 The radical R.sup.8 can, among other things, be employed for binding the
 complexes in accordance with the invention to a polymer matrix such as a
 linear PMMA, polystyrene or PEG or a nonlinear dendrimer.
 The bonding of the radical R.sup.8 to the cyclopentadienyl ring of the
 complex in the invention is altogether quite variable with respect to the
 free positions on the ring and the rings. Consequently, the introduction
 of one radical R.sup.8 is sufficient. All of the radicals that are known
 to the skilled artisan as possibilities for this purpose can be used. An
 appropriate review of molecular enlargement of complex catalysts is
 provided in Tetrahedron Assymmetry 1998, 9, 691-696. Preferably, radical
 RW consists of the arrangement B-X-Z, where B is a radical selected from
 the group consisting of CR.sup.9.sub.2, NR.sup.9, O, S and
 SiR.sup.9.sub.2, X is a spacer such as 1,4'-biphenyl, 1- or 2- ethylene,
 1- or 3-propylene, PEG-(2-10) and Z is a radical bonded to a polymer like
 the ones mentioned above, via a functional group such as --O--, --NH--,
 --COO, --CONH, -ethenyl,-, --NHCONH--, --OCONH-- or --NHCOO--.
 Alternatively, the radicals R.sup.8 of the two cyclopentadienyl rings can
 be bonded to each other via an .alpha.-.omega.-(C.sub.2 -C.sub.4)-alkylene
 bridge.
 In principle all of the substituent groups needed for the reaction under
 consideration are present in the molecule. However, the ligand system can
 be modified by methods known to the skilled artisan in any way, examples
 of which are pathways I, J and K shown in the scheme above.
 Complexes can be prepared from the ligands of the invention by methods
 known to the skilled artisan. Preferably, however, a complex is prepared
 just before it is used in a hydrogenation reaction by mixing a ligand and
 derivative or salt of a transition metal in a reaction solvent.
 A desired objective of the invention is to use the ligands of the invention
 in catalysts for homogeneous enantioselective hydrogenation as well as for
 catalytic homogeneous enantioselective hydrogenation.
 The reactions presented in Table 1 were conducted with ligands 8a-c. The
 results obtained and the reaction conditions employed are shown in Table
 1.
 TABLE 1
 8a 8b
 8c
 ##STR13##
 ##STR14##
 ##STR15##
 Ligand and
 No. Substrate Conversion, ee value (%) Conditions
 1
 ##STR16##
 quant., 95% ee (with R = Me 8a, [Rh].sup.+, MeOH/toluene 1:1, 1
 bar, RT, 0.5 h
 2
 ##STR17##
 quant, 76% ee (with R = Et, R' = H) 8b, [Rh].sup.+, MeOH, 10 bar,
 RT, 22 h
 3
 ##STR18##
 quant., 72% ee (with R = Me) 8a, [RH].sup.+, MeOH, 5 bar, RT, 22 h
 4
 ##STR19##
 quant., 91% ee 8a, [Rh].sup.+, MeOH, 1 bar, RT, 14 h
 5
 ##STR20##
 quant., 53% ee (with R = Ph) 8c, [Rh].sup.+, MeOH, 30 bar, RT, 21 h
 6
 ##STR21##
 95%, 60% ee 8c, [Rh].sup.+, MeOH, 30 bar, RT, 25 h
 7
 ##STR22##
 quant., 63% ee 8a, [Rh].sup.+, MeOH, 30 bar, RT, 10 h
 8
 ##STR23##
 33%, 42% ee (with R = Ph) 8a, [Rh].sup.+, MeOH, 50 bar, RT, 24 h
 9
 ##STR24##
 23%, 30% ee 8a, [Rh].sup.+, MeOH, 50 bar, RT, 24 h
 10
 ##STR25##
 quant., 16% ee 8a, [Rh].sup.+, MeOH, 50 bar, RT, 23 h
 As is clear from Table 1, the present ligand/catalyst system permits
 various substrates to be hydrogenated with moderate to very good excess
 amounts of enantiomer.
 On top of that, the ligand systems are insensitive to oxidation so that
 they are storable without alteration for a long time under ambient
 conditions. This is an advantage for storage in possible industrial
 applications on a large scale.
 Suitable linear or branched (C.sub.1 -C.sub.18) alkyl radicals include
 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
 tert-butyl, penyl, hexyl, heptyl and octyl up to radicals containing 18 C
 atoms together with all of their isomers. The radicals (C.sub.1
 -C.sub.18)-alkoxy include the (C.sub.1 -C.sub.18) alkyl radicals with the
 additional feature that the alkyl radical is bonded via an oxygen atom to
 the molecule. (C.sub.2 -C.sub.8)-alkoxyalkyl radicals are defined as those
 in which the alkyl chain is interrupted by at least one oxygen function,
 where two oxygen atoms cannot be bonded to each other. The number of
 carbon atoms gives the total number of the carbon atoms present in the
 residue. The same thing is valid for (C.sub.1 -C.sub.8) alkyl radicals
 with the stipulation that only a maximum of 8 C atoms can be present in
 the radical.
 The radicals described can be substituted one or more times with halogen
 and/or radicals that contain N, O, P or S. These are in particular alkyl
 residues of the above type, which have at least one of these heteroatoms
 in the chain or which are bonded via one of these heteroatoms to the
 molecule. The above is correspondingly valid for residues with up to 8 C
 atoms.
 (C.sub.3 -C.sub.8)-Cycloalkyl is understood to include cyclopropyl,
 cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl residues. The
 cycloalkyl groups can be substituted with at least one halogen atom and/or
 N-, O-, P- and S-containing residues and/or can have N-, O-, P-,
 S-containing radicals in the ring, such as 1-, 2-, 3-, 4-piperidyl, 1-,
 2-, 3-, 4-piperidyl, 1-, 2-, 3-pyrrolidinyl, 2- or 3-tetrahydrofuryl, 2-,
 3-, 4- morpholinyl.
 A (C.sub.3 -C.sub.8)-cycloalkyl-(C.sub.1 -C.sub.8)-alkyl radical is one in
 which the alkyl group and the cycloalkyl group are as defined above, which
 is bonded to the molecule via one of the alkyl radicals.
 (C.sub.1 -C.sub.18)-Acyloxy is defined as an alkyl residue with a maximum
 of 18 C atoms which is bonded to the molecule via a COO function. For
 (C.sub.1 -C.sub.8)-acyloxy the corresponding rule is valid for an alkyl
 radical containing 8 C atoms.
 (C.sub.1 -C.sub.18)-Acyl is defined as an alkyl radical as defined above
 with a maximum of 18 C atoms, which is bonded to the molecule via a CO
 function functional group. For (C.sub.1 -C.sub.8)-acyl the corresponding
 rule is valid for an alkyl radical containing up to and including 8 C
 atoms.
 A (C.sub.6 -C.sub.18)-aryl radical is understood to be an aromatic radical
 with 6 to 18 carbon atoms. Preferred radicals include phenyl, naphthyl,
 anthryl, phenanthryl and biphenyl, which optionally are substituted with
 (C.sub.1 -C.sub.8)-alkoxy, NR.sup.6 R.sup.7, (C.sub.1 -C.sub.8)-acyl or
 (C.sub.1 -C.sub.8)-acyloxy.
 A (C.sub.7 -C.sub.19)-aralkyl radical is a (C.sub.6 -C.sub.18) aryl radical
 bonded to the molecule via a (C.sub.1 -C.sub.8) alkyl residue.
 A (C.sub.3 -C.sub.18) heteroaryl radical is a five-, six- or seven-member
 aromatic ring system of 3 to 18 carbon atoms, which contains heteroatoms
 such as nitrogen, oxygen or sulfur in the ring. Such heteroatoms are in
 particular radicals such as 1-, 2-, 3-furyl, 1-, 2-, 3-pyrrolyl, 1-, 2-,
 3-thienyl, 2-, 3-, 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7-indolyl, 3-, 4-,
 5-pyrazolyl, 2-, 4-, 5-imidazolyl, acrindinyl, quinolinyl,
 phenanthridinyl, 2-, 4-, 5-, 6-pyrimidinyl.
 A (C.sub.4 -C.sub.19) heteroaralkyl radical is understood to mean a
 heteroaromatic system corresponding to the (C.sub.7 -C.sub.19) arallkyl
 residue.
 Suitable halogen atoms (Hal) include fluorine, chlorine, bromine and
 iodine.
 Salts are understood to mean ionic addition compounds of strong acids such
 as HCl, HBr, H.sub.2 SO.sub.4, H.sub.3 PO.sub.4, CF.sub.3 COOH,
 p-toluenesulfonic acid, methanesulfonic acid and the molecule in question.
 PEG means polyethylene glycol.
 The term enantiomer enriched is understood, within the scope of the
 invention, to mean the amount of an enantiomer in a mixture with its
 optical antipodes in a range of &gt;50% and &lt;100%.
 Salts are understood to mean ionic addition compounds of strong acids like
 HCl, HBr, H.sub.2 SO.sub.4, H.sub.3 PO.sub.4, CF.sub.3 COOH,
 p-toluenesulfonic acid and methanesulfonic acid and the molecule in
 question.
 The term diastereomer-enriched is understood to mean an excess amount of
 one diastereomer with respect to one or more other diastereomers.
 The complexes and ligands of the invention implies, within the scope of the
 invention, all possible diastereomers, where the two optical antipodes of
 a relevant diastereomer are included.
 Having now generally described this invention, a further understanding can
 be obtained by reference to certain specific examples which are provided
 herein for purposes of illustration only and are not intended to be
 limiting unless otherwise specified.