The present invention relates to the preparation of enantiomerically enriched ligands based on ferrocenyl derivatives. In particular, the invention relates to the preparation of compounds of the general formula (I) , (II) or (III) .

R1R2P. -Rfe

PR1R2 PR1R2 PR1R2 R1R2P

Bisphosphonyl ligands based on ferrocene are important compounds which are used in enantioselective organic catalysis and can play a critical role in ensuring a high chiral induction in the reaction concerned.

The use of bisphosphine catalysts for enantioselective homogeneous catalytic hydrogenation for the purpose just mentioned 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, 4545-4448) describe Pd complexes with C2-symmetric ferrocenyl (bis-tertiary- phosphine) ligands for asymmetric allylation.

On the other hand, Yamamoto et al . (Bull. Chem. Soc. Jpn. 1980, 53, 1132-1137) report the use of ferrocenyl (bis- tertiary-phosphine) ligands which do not have C2 symmetry in enantioselective homogeneous catalytic hydrogenation. However, good enantiomeric excesses are obtained only very rarely when using these ligands.

The in-principle suitability of ferrocenyl ligands which do not have C2 symmetry for enantioselective hydrogenation is disclosed in EP1140956, WO 96/32400 and WO 95/21151. EP967015 demonstrates the usability of C2-symmetric ligands in the enantioselective hydrogenation of double bonds.

In principle, the ferrocenyl ligands in question can be prepared by methods reported in the abovementioned publications. In a more recent publication, Knochel et al. refer to the possibility of the stereoselective copper- catalyzed addition of alkynes onto enamines (Chem. Eur. J. 2003,9, 2797-11) .

It was an object of the present invention to develop a further process for preparing bisphosphonyl ligands based on ferrocene. In particular, the present process should allow the ligands to be prepared in an industrial process which is advantageous from economic and ecological points of view, with the yield which can be achieved and the achievable enantiomeric excesses being of particular significance.

These objects and further objects which are not mentioned in detail but are prompted by the prior art are achieved by a process having the features of claim 1. Preferred embodiments of the process of the invention are claimed in the subordinate claims 2 to 7 dependent on claim 1. Claim 8 relates to a stereoselective catalytic variant of the reaction according to the invention. Claim 9 is directed at advantageous intermediate compounds, which can be prepared by the process claimed in claim 10. Claim 11 is directed at novel catalysts of the general formula (III) .

The achievement of the abovementioned objects by preparing enantiomerically enriched bisphosphonyl ligands having the structure of the general formula (I) , (II) or (III)

R1R2P1 Rc RJ R RB FT PR1R2 PR1R2 10 PR1R2 R1R2P (II) (I) R

where n = 0 or 1, R,1, R,-,2\ -R-.I-1-' , R2' can each be, independently of one another, (C6-C18) -aryl, (C1-C8) -alkyl- (C6-Ci8) -aryl, (C3-C8) -cycloalkyl, (C1-C8) -alkyl- (C3-C8) -cycloalkyl, R3 can be (C1-C8) -alkyl, (C6-C18) -aryl- (C2-C8) -alkyl, ( (C1-C8) -alkyl) 1-3- (C6-C18) -aryl- (C2-C8) -alkyl, (C3-C8) -cycloalkyl- (C2-C8) -alkyl, ( (C1-C8)-alkyl-(C3-C8) )i_ 3-cycloalkyl- (C2-C8) -alkyl, R4 can be NR5R6, OR6, SR6, R5 and R6 are each, independently of one another, H, (C1-C8) -alkyl, (C2-C8)-alkenyl, (C2-C8) -alkoxyalkyl, (C1-C8) -acyl, (C6-C18) -aryl, (C7-C19) -aralkyl, (C3-C18) -heteroaryl, (C4-C19) -heteroaralkyl, (C1-C8) -alkyl- (C6-C18) -aryl, (C1-C8) -alkyl- (C3-C19) -heteroaryl, (C3-C8) -cycloalkyl, (C1-C8) -alkyl- (C3-C8) -cycloalkyl, (C3-C8) -cycloalkyl- (C1-C8) -alkyl, or R5 and R6 form a (C3-C7) -carbocycle which may be substituted by one or more linear or branched (C1-C8) -alkyl, (Cχ-C8) -acyl, (Ci-C8)- alkoxy, (C2-C8) -alkoxyalkyl groups and/or have further heteroatoms such as N, 0, P, S in the ring, R8 is PR11R2', R9, R10, R11, R12 are each, independently of one another, (C1-C8) -alkyl, (C6-C18) -aryl, (C7-C19) -aralkyl, (C3-C1S) -heteroaryl, (C4-C19) -heteroaralkyl, (Ci-C8) -alkyl- (C6-C18) -aryl, (C1-C8) -alkyl- (C3-C19) -heteroaryl, (C3-C8) -cycloalkyl, (C1-C8) -alkyl- (C3-C8) -cycloalkyl, (C3-C8) -cycloalkyl- (C1-C8) -alkyl, or R9 and R10 and/or R11 and R12 form a (C3-C7) -carbocycle which can be part of an aromatic or heteroaromatic system or form a (Cβ-C1o)- carbobicycle, with the carbocycles just mentioned being able to be substituted by one or more linear or branched (C1-C8) -alkyl groups and/or have heteroatoms such as N, 0, P, S, Si and/or further double bonds in the ring, in a process in which a) ferrocenylcarbaldehyde or 1, 1 '-ferrocenylbiscarbaldehyde is used as starting material and is reacted with an enantiomerically enriched amino alcohol ether and a 1-alkyne in the presence of a copper catalyst, b) the triple bond in the compound obtained is fully hydrogenated or, in the case of compounds of the general formula (III) , converted into a double bond by means of suitable measures, c) a deprotonation is carried out in the ortho position on the ferrocenyl ring and d) the anion obtained is reacted with XPR1R2, where X is a nucleofugic leaving group, and e) in the case of the compound (I) , the group R8 is introduced, is totally surprising but nevertheless very advantageous. The proposed synthetic route accordingly comprises a diastereoselective three-component coupling which extremely advantageously allows highly enantiomerically enriched starting compounds for the preparation of the ligands described to be synthesized. These starting compounds can, after further modification, be converted elegantly and in high yields into the bisphosphonyl ligands.

It can be particularly advantageous to prepare compounds of the general formulae (I), (II) and (III) in which n = 0, R1 or R2 is (C6-C18) -aryl, R3 is (C1-C8) -alkyl, (C6-C18)-aryl- (C2-C8)-alkyl, R4 = NR5R6, where R5.and R6 are each, independently of one another, (C1-C8) -alkyl, (C1-C8) -acyl, (C3-C8) -cycloalkyl, or R5 and R6 form a (C3-C7) -carbocycle which may be substituted by (C2-C8) -alkoxyalkyl, R8 is PR11R2', R9 and R10 form a (C3-C7) -carbocycle which can be part of an aromatic system and/or have heteroatoms such as O, S, Si and/or further double bonds in the ring.

As stated above, the present invention starts out from a three-component coupling. This is carried out using a chiral amino alcohol ether which carries the chiral information. As copper catalyst, a copper(I) salt, advantageously a copper halide such as copper chloride or copper bromide, is chosen. The diastereoselectivities of the reaction in question are generally greater than 90% de, preferably greater than 95% de and very particularly preferably greater than 98% de. As amino alcohol ethers, preference is given to using ones which can be obtained by reduction of the corresponding natural amino acid esters (Bayer-Walter, Lehrbuch der organischen Cheπiie, S. Hirzel Verlag, Stuttgart, 22nd edition, p. 822ff) . Otherwise, the methods of preparing this class of compounds are known to those skilled in the art (Tetrahedron Asymmetry 1990, 12, 877-880; Organic Synthesis 1987, 65, 173-182) . Very particular preference is given to using prolinol methyl ether.

The 1-alkyne which is likewise used for the three-component coupling can be chosen by a person skilled in the art according to his criteria. In making the choice, the person skilled in the art will be guided by the fact that the 1-alkyne should react as smoothly as possible and without formation of by-products. Use is advantageously made here of compounds selected from the group consisting of trimethylsilylethyne, phenylethyne or phenylethyne substituted in the ortho position by phosphine (PR11R2') or phosphine oxide radicals (POR1 R2 ) . In the case of the preparation of compounds of the formula (III) in which n=0, it is also possible to use phenylethynes substituted in the ortho position by OR6, SR6 or NHR6. These can easily be converted in subsequent steps into the corresponding phosphine-substituted derivatives (see below) . Very particular preference is given to using trimethylsilylethyne, phenylethyne, for this purpose.

The process steps of the present process can in principle be carried out in any solvent which a person skilled in the art considers suitable for this purpose. The solvent should be inert in respect of the reaction in question. The reaction should be able to proceed optimally and with very little formation of by-products. Solvents from the group consisting of aprotic nonpolar solvents are preferably employed in the three-component coupling. These are very particularly preferably solvents selected from the group consisting of benzene, toluene, xylene. Very particular preference is given to using toluene as solvent. For the further reaction through to the end products, a person skilled in the art can select the solvent according to his general technical knowledge (cf. EP967015; EP965574) .

The individual process steps are carried out at temperatures which a person skilled in the art considers suitable for the respective reactions. The initial three- component coupling is preferably carried out in a temperature range from -30 to +100 degrees Celsius. Greater preference is given to a range from -20 to +50 degrees Celsius. This reaction is very particularly preferably carried out in a temperature range from -10 degrees Celsius to +30 degrees C. For the further hydrogenation, deprotonation and substitution, it is possible to employ temperatures which are customary in the prior art (analogous to EP967015; EP965574) .

The deprotonation to introduce the radical PR1R2 into the ring is carried out by a method based on EP967015 or EP965574. As nucleofugic leaving group X in the compounds of the formula XPR1R2, it is possible to choose radicals selected from the group consisting of Hal. Hal is preferably chloride or bromide.

The introduction of the radical R8 for preparing the compounds of the general formula (I) can be carried out by methods known to those skilled in the art (EP 0564406; Ferrocenes, Ed. A. Togni, T. Hayashi, VCH Verlagsgesellschaft mbH, 1995, p.lO5ff) . An advantageous procedure is to react the corresponding compounds of the formula (I) in which substituents such as NR5R6 are present in place of R8, as are present after deprotonation and reaction with XPR1R2, with the appropriate phosphines (HPR11R2') in organic solvents at elevated temperature. The preferred organic solvent here is glacial acetic acid. The temperature is determined by a person skilled in the art with a view to an optimal reaction. It is advantageously in the range from +200C to +1500C, preferably from +500C to +1000C.

In a further embodiment, the present invention is concerned with the preparation of the compounds of the general formulae (I) to (III) , in which embodiment the chiral information is introduced into the products in the form of a chirally modified copper catalyst. In principle, merely a nonchiral amine in combination with a chiral enantiomerically enriched ligand is used in this process in place of the enantiomerically enriched amino alcohol ether. Chiral ligands for the abovementioned purpose are known to those skilled in the art (Catalytic Asymmetric Synthesis, Ed. : I.Ojima, Wiley-VCH, 1993, p. 67ff) . In this context, reference may be made, in particular, to the publication by Knochen et al . in which numerous ligands which can be used are disclosed. (Chem. Eur. J. 2003, 9, 2797 - 2811) .

An advantage of the catalytic variant is that it is not necessary to use stoichiometric amounts of a relatively expensive chiral auxiliary. Furthermore, the required recovery of this chiral auxiliary can be dispensed with. In addition, an additional process step which is necessary when the amino alcohol ether is used is avoided. The elimination of the auxiliary can be dispensed with. The present catalytic process is illustrated by way of example by the reaction of scheme 1.

The preferred embodiments described for the stoichiometric variants presented above apply analogously here.

NBn

1. HNBn. + 2. CuBr/L*

Scheme 1

In a further embodiment, the present invention is concerned with compounds of the general formula (III) or (IV) where

-R'

(III) where R4 can be as defined above or can be a chiral amino alcohol ether, R7 is selected from the group consisting of trimethylsilyl, (C6-C18) -aryl, ( (C1-C8) -alkyl)i_3- (C6-C18) -aryl, (C3-C8) -cycloalkyl, ( (C1-C8) -alkyl) 1-3- (C3-C8) -cycloalkyl, (C1-C8) -alkyl, where the (Cβ-C1s)-aryl radical can be substituted by OR6, SR6, NR5R6, PR11R2' or POR11R2' in the ortho position relative to the alkyne radical, and R5, R6, R1' and R2' can be as defined above. The compounds presented here serve as preferred intermediates on the way to the preparation of the bisphosphonyl ligands.

The preparation of the compounds of the general formula (III) or (IV) can, as indicated above, be effected by means of three-component coupling starting from ferrocenyl- carbaldehyde or 1, 1 v-ferrocenylbiscarbaldehyde, an enantiomerically enriched amino alcohol ether or a nonchiral amine and a chiral enantiomerically enriched ligand and compounds of the general formula (VI)

H ^ R7 (Vl) where R7 can be as defined above, in the presence of a copper catalyst.

The above-described preferred embodiments for the three- component coupling apply analogously here.

In a further embodiment, the present invention is concerned with bisphosphinyl ligands of the general formula (III)

R1R2P. -Ra

PR1R2 where n = 1, and the radicals R1 to R12 are as defined above.

The synthesis of the bisphosphonyl ligands described can, by way of example, be depicted as follows :Example - Josiphos analogues (corresponding to formula (I))

PR 2 PR 2

Figure 1.

The first step is based on a copper-catalyzed preparation of chiral propargylamines (Scheme 2) .

.OMe

.OMe CuBr (0.05 eαuiv)

1 equiv. 1 equiv R = 3: TMS 74 %, 96 % de 4: Ph 79 %, > 98 % dβ

Scheme 2

The preparation of the propargylamines can be carried out by a method based on the publication of Knochel et al . (see above) by combining the appropriate components in appropriate organic solvents . The ratio of the individual components should advantageously be about 1:1:1. It has been found that the exclusion of traces of water has an advantageous effect on the reaction. The use of dried organic solvents, for example toluene, and the addition of molecular sieves, MS 4A, has been found to be advantageous for this purpose. The order of addition of the reactants is immaterial .

To synthesize a first, e.g. ethyl-substituted, Josiphos ligand, it is possible firstly to remove the TMS group from the propargylamine 3 and subsequently to reduce the triple bond. This is achieved by hydrogenation under customary conditions (e.g. Pd/C in alcohol) (Scheme 3) .

,OMe .OMe '"//// N 1)KOH(I M), MeOH -TMS 5: 99%

2) Pd/C, H2(1 bar) EtOH, NaOH 6: 91 %

Scheme 3

Starting from 6, the preparation of the diphosphine ligand 11 occurs in 5 steps (Scheme 4) . .OMe "" '"""H//I/

I) Ac2O, 600C 7: 75 % ^- 2) HNMe2, CH3CN 6O0C 8: 87% 1) f-BuLi 2)CIPPh2 9: 70%

I)HPCy21AcOH PCy2 2)BH3SMe2 NMe2 10:88%

r^N^^NH2 H2N.^N^ 11:98% 11

Scheme 4

With regard to compounds of the general formula (II), a person skilled in the art will start from 1,1Λ- ferrocenylbiscarbaldehyde. The three-component coupling is carried out as described above with the exception that in this case the ratio of the components is modified in an appropriate way (about 1:2:2) . The further reactions are carried out by methods based on the above scheme, with the final replacement of the dimethylamino group (see above scheme) by the phosphine group being able to be omitted. Reference may be made to EP967015 in this regard.

In the case of compounds of the general formula (III) , ferrocenylcarbaldehyde can advantageously be reacted with phenylethynes which are appropriately substituted in the ortho position in accordance with the above-described three-component coupling. Substituents are preferably phosphines or phosphine oxides of the species mentioned or radicals which can be converted into phosphines in a simple manner. After the three-component coupling has been carried out, the triple bond present in the molecule is converted into a double bond by methods known to those skilled in the art. The radicals formerly present on the triple bond should be present in the cis position. Suitable methods of converting the triple bond into a double bond include, inter alia, the reaction sequences shown in the following scheme.

3Me OMe

Y= O, S, NR ph2P Y= 0, S, NR E = SnBu3, TMS, Br, I, PPh2 XY= OR SR NRR' Z= CIPPh2, CISnBu3, TMSCI Br2, I2 ■Me o. OMe

Scheme 5

1. References relating to the upper half of reaction scheme 5

B. L. Flynn, P. Verdier-Pinard, E. Hamel Org. Lett. 2001, 3, 651-654.

D. Yue, R. C. Larock J. Org. Chem. 2002, 67, 1905-1909.

K. R. Roesch, R. C. Larock J. Org. Chem. 2002, 67, 86-94.

2. Reference relating to the lower half of reaction scheme 5

P. Savignac, B. Iorga Modern Phosphonate Chemistry, CRC Press, (2003) p.12. As indicated above, the process of the invention is extremely attractive for preparing the compounds in question. The high-priced bisphosphonyl ligands are obtained in high enantiomeric and diastereomeric enrichments . From a commercial point of view, the variant described here for preparing the compounds in question offers an advantageous alternative to the synthetic methods known from the prior art.

For the purposes of the present invention, (C1-Ce)-alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl including all structural isomers. The alkyl radical can be monosubstituted or polysubstituted by halogen.

For the purposes of the present invention, (C2-Cs)-alkenyl is a (C1-Cs) -alkyl radical as mentioned above with the exception of methyl which has at least one double bond.

For the purposes of the present invention, (C2-C8)-alkynyl is a (C1-C8)-alkyl radical as mentioned above with the exception of methyl which has at least one triple bond.

For the purposes of the present invention, (C1-C8)-acyl is a (C1-C8) -alkyl radical bound to the molecule via a C=O function.

For the purposes of the present invention, the term (C3-C8) -cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radicals, etc.

For the purposes of the present invention, a (Cβ-C1β) -aryl radical is an aromatic radical having from 6 to 18 carbon atoms. Examples are, in particular, compounds such as phenyl, naphthyl, anthryl, phenanthryl, biphenyl radicals. The aryl radical can be monosubstituted or polysubstituted by (C1-C8) -alkoxy, (C1-C8) -haloalkyl, halogen. A (C7-Ci9)-aralkyl radical is a (Cβ-C1s) -aryl radical bound to the molecule via a (C1-C8) -alky1 radical.

(C1-C8) -Alkoxy is a (C1-C8) -alkyl radical bound to the molecule in question via an oxygen atom.

(C2-Cs) -Alkoxyalkyl is a (C1-C8) -alkyl radical having an oxygen atom in the carbon chain.

(C1-C8) -Haloalkyl is a (C1-C8) -alkyl radical substituted by one or more halogen atoms .

A (C3-C18) -heteroaryl radical is, for the purposes of the invention, a five-, six- or seven-membered aromatic ring system which has from 3 to 18 carbon atoms and has heteroatoms such as nitrogen, oxygen or sulfur in the ring. Heteroaromatics of this type 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, acridinyl, quinolinyl, phenanthridinyl, 2-, 4-, 5-, 6-pyrimidinyl. The heteroaromatic can be monosubstituted or polysubstituted by (C1-C8)-alkoxy, (C1-C8) -haloalkyl, halogen.

For the purposes of the present invention, a (C4-C19) -heteroaralkyl radical is a heteroaromatic system corresponding to the (C7-C19) -aralkyl radical.

A (C3-C7) -carbocycle is a corresponding alkylene chain which is linked via the outer two carbon atoms to the molecule in question.

A (C6-C10) -carbobicycle is an alkylene chain which is bound via two different carbon atoms to the molecule and has a -CH2-, -CH2CH2 unit as further bridge on two carbon atoms of this alkylene chain. If the carbobicycle contains heteroatoms, these instead preferably form a bridge (e.g. - O-, -S-, -NR6-, -SiR62) . Possible halogens (Hal, halogen atom) are fluorine, chlorine, bromine and iodine. Preference is given to chlorine and bromine. This applies correspondingly to the halide ions.

The chemical structures shown encompass all possible stereoisomers which can be obtained by altering the configuration of the individual chiral centers, axes or planes, i.e. all possible diastereomers and also all optical isomers (enantiomers - R,R; R,S;, S,S; S,R compounds) and mixtures thereof.

For the purposes of the invention, the term enantiomerically enriched refers to the proportion of one enantiomer in a mixture with the other enantiomer being in the range from >50% to <100%.

For the purposes of the invention, the term diastereomeric enrichment refers to the proportion of one diastereomer in a mixture with other corresponding diastereomers being in the range from >50% to <100%.

Examples:

Preparation of (S)- [α- (N-2- (R) -methoxymethylpyrrolidino) -γ- trimethylsilylpropynyl]ferrocene (3)

'/(///^^-OMe

TMS

CuBr (72 mg, 0.5 mmol, 0.05 mol%) is placed under nitrogen in a 50 ml Schlenk flask, dried in a high vacuum, suspended in dry toluene (20 ml) under nitrogen and MS 4A (5 g) are added. Trimethylsilylacetylene (0.98 g, 10.0 mmol, 1 equiv.), ferrocenecarbaldehyde (2.14 g, 10.0 mmol, 1 equiv.) and (2R) -2- (methoxymethyl)pyrrolidine (1.15 g, 10.0 mmol, 1 equiv.) are added in succession and the reaction mixture is stirred at RT for 5 days. The MS are subsequently filtered off, washed with Et2O and the solvent is distilled off on a rotary evaporator. The crude product is purified by column chromatography (silica gel, n- pentane/Et2O 4:1) and gives the product 3 (3.03 g, 7.4 mmol, 74%) as a red oil.

[α]D20 = -248.0 (c = 0.29, CHC13) .

IR (KBr) : 3096 (m) , 2960 (s), 2874 (s) , 2825 (m) , 2161 (m) , 1449 (m) , 1249 (s) , 1106 (s) , 999 (s), 843 (vs) .

IH-NMR (CDC13, 300 MHz) : δ/ppm = 4.71 (s, IH), 4.35-4.33 (m, IH), 4.22-4.20 (m, IH), 4.16 (s, 5H), 4.09-4.08 (m, 2H), 3.39 (dd, J = 9.2, 5.8 Hz, IH), 3.38 (s, 3H), 3.28 (dd, J = 9.2, 6.6 Hz, IH), 3.12-3.03 (m, IH), 2.66-2.59 (m, 2H), 1.86-1.80 (m, IH), 1.67-1.62 (m, 3H), 0.24 (s, 9H) .

13C-NMR (CDC13, 75 MHz) : δ/ppm = 103.5, 89.2, 86.7, 76.8, 69.1, 68.7, 68.3, 68.1, 67.5, 59.9, 59.1, 54.2, 48.5, 28.7, 23.0, 0.3.

MS (EI) : 365 (M+-2H, 1) , 311 (23) , 310 (100), 91 (64) .

C22H3IFeNOSi (409.43) : calc. :C 64.54, H 7.63, N 3.42. found:C 64.46, H 7.49, N 3.82.

Preparation of (S) - [α- (N-2- (R) - methoxymethylpyrrolidino)propynyl] ferrocene (5)

'""nil. -OMe N In a 100 ml round-bottomed flask, 3 (2.86 g, 7.0 mmol, 1 equiv.) is dissolved in methanol (25 ml) . At RT, KOH solution (10.5 ml, 10.5 mmol, 1 M in H2O, 1.5 equiv.) is added dropwise and the mixture is stirred for one hour. The reaction mixture is diluted with H2O (10 ml) and extracted with Et2O (3 X 10 ml) . After removal of the solvent, the crude product is purified by column chromatography (silica gel, n-pentane, Et2O 2:1) and gives (S) - [α- (N-2- (R) - methoxymethylpyrrolidino)propynyl] ferrocene (5) (2.34 g, 6.9 mmol, 99%) as a red oil.

[α]D20 = - 119.3 (c = 0.91, CHC13) .

IR (KBr) : 3296 (s), 3095 (m) , 2963 (s) , 2923 (s), 2874 (s), 2826 (s), 1106 (vs), 820 (s) , 505 (s) .

IH-NMR (CDC13, 300 MHz) : δ/ppm = 4.28 (d, J = 2.2 Hz, IH) , 4.36 (q, J = 1.7 Hz, IH), 4.24 (q, J = 2.2 Hz, IH), 4.16 (s, 5H), 4.09 (dd, J = 1.7, 1.9 Hz, 2H), 3.40 (dd, J = 9.2, 5.8 Hz, IH), 3.39 (s, 3H), 3.32 (dd, J = 9.2, 5.8 Hz, IH) , 3.10-3.15 (m, IH) , 2.64-2.59 (m, 2H), 2.41 (d, J = 2.2 Hz, IH), 1.88-1.79 (m, IH), 1.67-1.48 (m, 3H) .

13C-NMR ( CDC13 , 75 MHz ) : δ/ppm = 86 . 6 , 80 . 9 , 76 . 9 , 72 . 8 , 69 . 1 , 68 . 6 , 68 . 3 , 68 . 2 , 67 . 4 , 59 . 8 , 59 . 1 , 53 . 4 , 48 . 3 , 28 . 5 , 22 . 7 .

MS ( EI ) : 337 (M+ , 12 ) , 224 ( 47 ) , 223 ( 100 ) , 120 ( 40 ) , 7 0 ( 17 ) , 56 ( 34 ) , 45 ( 34 ) , 42 ( 20 ) .

Ci9H23FeNO ( 337 . 24 ) : calc . : C 67 . 67 , H 6 . 87 , N 4 . 15 . found : C 67 . 60 , H 6 . 96 , N 4 . 13 .

Preparation of ( S ) - [ α- ( N-2 - ( R ) - methoxymethylpyrrol idino ) propyl ] f errocene ( 6 ) '"nil. -OMe N

5 (508 mg, 1.51 mmol) is dissolved in ethanol (15 ml) and admixed with 2N sodium hydroxide solution (0.1 ml) and palladium on activated carbon (cat.) . The gas atmosphere is replaced by hydrogen and the reaction mixture is stirred at room temperature for 24 hours. The reaction solution is filtered and the solvent is distilled off on a rotary evaporator. The crude product obtained is purified by column chromatography (silica gel, n-pentane/Et2θ 2:1 + 0.5% of NEt3) and gives 6 (396 mg, 1.38 mmol, 91%) as an orange-brown oil which is stored under argon in a refrigerator.

[α]D20 = - 80.7 (c = 0.96, CHC13) .

IR (KBr) : 3927 (w) , 3094 (m) , 2959 (s) , 2872 (s) , 2822 (s) , 1640 (br, w) , 1461 (m) , 1412 (m) , 1370 (m) , 1323 (m) , 1262 (m) , 1225 (m) , 1195 (m) , 1146 (m) , 1107 (vs), 1058 (m) , 1025 (m) , 1001 (m) .

IH-NMR (CDC13, 300 MHz) : δ/ppm = 4.10-4.09 (m, IH), 4.05- 4.00 (m, 8H), 3.41 (dd, J = 9.6, 3.9 Hz, IH), 3.25 (s, 3H), 3.14 (dd, J = 8.9, 4.1 Hz, IH) , 2.97 (t, J = 8.7 Hz, IH) , 2.90-2.75 (m, 2H), 2.70-2.61 (m, IH), 2.01-1.88 (m, IH), 1.73-1.29 (m, 5H), 1.05 (t, J = 7.4 Hz, 3H) .

13C-NMR (CDC13, 75 MHz) : δ/ppm = 90.6, 68.9, 68.8, 67.6, 67.5, 67.3, 61.8, 59.3, 57.6, 51.4, 29.4, 26.1, 24.2, 12.9.

MS (EI) : 341 (M+, 4), 312 (27), 228 (11), 227 (41), 226 (97) , 225 (14), 199 (13) , 186 (10), 160 (12), 158 (10) , 134 (25) , 121 (43), 70 (100), 56 (42) , 45 (13), 44 (15) , 42 (13) . FeNO ( 341 . 27 ) : HRMS : calc . : 341 . 1442 . f ound : 341 . 1430 .

Preparation of (S)- (α-acetoxypropyl) ferrocene (7)

OAc

(5) -[α-N-2- (R)-Methoxymethylpyrrolidino)propyl] ferrocene (6) (95 mg, 0.28 mmol) is dissolved in acetic anhydride (3 ml) and stirred at 600C for 18 hours. The reaction solution is subsequently cooled to 00C and taken up in Et2O (10 ml) and 2N sodium hydroxide solution (10 ml) . The phases are separated, the organic phase is washed with 2N sodium hydroxide solution (7 ml) and saturated NaCl solution (7 ml) , dried over MgSO4 and the solvent is distilled off on a rotary evaporator. Purification of the crude product by column chromatography (silica gel, n-pentane/Et2O 2:1 + 1% of NEt3) gives (S) -(α- acetoxypropyl) ferrocene (7) (59 mg, 0.21 mmol, 75%) as an orange solid (m.p.: 50.50C).

[α]D20 = + 83.0 (c = 0.07, CHC13).

IR (KBr): 3431 (br, m) , 3083 (w) , 2966 (m) , 1733 (s), 1638 (br, w), 1454 (w) , 1415 (w) , 1373 (m) , 1244 (vs), 1106 (m) , 1082 (m) , 1036 (m) , 1021 (m) , 1001 (m) .

IH-NMR (CDC13, 300 MHz): 6/ppm = 5.65-5.60 (m, IH), 4.19- 4.18 (m, IH), 4.10-4.06 (m, 8H), 2.03 (s, 3H), 1.91-1.69 (m, 2H), 0.87 (t, J = 4.4 Hz, 3H).

13C-NMR (CDC13, 75 MHz): δ/ppm = 171.1, 88.4, 73.9, 69.1, 68.4, 68.0, 67.9, 66.9, 28.6, 21.6, 10.7. MS ( EI ) : 286 (M+ , 17 ) , 227 ( 18 ) , 22 6 ( 100 ) , 225 ( 14 ) .

Ci 5Hi8FeO2 ( 286 . 15 ) : calc . : C 62 . 96 , H 6 . 34 . found : C 62 . 99 , H 6 . 37 .

Preparation of (S) - [α- (N,N-dimethylamino)propyl] ferrocene (8)

(S)- (α-Acetoxypropyl) ferrocene (7) (129 mg, 0.45 iranol) is dissolved in acetonitrile (2 ml) in a bomb tube and admixed with dimethylamine (2 ml, 40% strength solution in water). The reaction solution is stirred at 600C for 19 hours and subsequently evaporated in an oil pump vacuum. Acid-base work-up gives (S) -[α- (N,N- dimethylamino)propyl] ferrocene (8) (106 mg, 0.39 mmol, 87%) as an orange-yellow solid (m.p. : 66-67°C) .

[α]D20 = + 54.8 (c = 1.39, CHC13).

IR (KBr): 3088 (m) , 2961 (s), 2932 (vs), 2884 (m) , 2852 (m) , 2818 (m) , 2777 (m) , 1632 (br, w) , 1472 (m) , 1446 (m) , 1264 (m) , 1208 (w) , 1176 (m) , 1156 (w) , 1105 (s), 1046 (m) , 1024 (m) , 1002 (m) .

IH-NMR (CDC13, 300 MHz): δ/ppm = 4.06-3.99 (m, 8H), 3.94- 3.93 (m, IH), 3.18 (dd, J = 11.0, 3.5 Hz, IH), 2.03-1.93 (m, 7H), 1.73-1.57 (m, IH), 1.03 (t, J = 1.4 Hz, 3H).

13C-NMR (CDC13, 75 MHz): δ/ppm = 86.1, 69.7, 68.9, 67.8, 67.5, 67.2, 65.3, 40.9, 24.8, 12.7.

MS (EI): 271 (M+, 17), 243 (13), 242 (100), 227 (15), 226 (15) . Ci5H2IFeN (271.18) : calc. :C 66.44, H 7.81, N 5.17. found:C 66.23, H 7.70, N 5.09.

Preparation of (Rp) -l-diphenylphosphino-2- [α-(S)-(N,N- dimethy1amino)propyl] ferrocene (9)

NMe2

(S) - [α- (N,N-Dimethylamino)propyl] ferrocene (8) (227 mg, 0.84 mmol) is dissolved in dry Et2O (7 ml) , cooled to 00C and admixed with t-BuLi (0.61 ml, 0.92 mmol, 1.5 M solution in pentane, 1.1 equiv.) . After stirring at 00C for 1 hour, chlorodiphenylphosphine (0.18 ml, 1.00 mmol, 1.2 equiv.) is added dropwise and the reaction solution is warmed to RT overnight while stirring. After hydrolysis with H2O (10 ml), the aqueous phase is extracted with Et2O (2 X 10 ml), the combined organic phases are washed with saturated NaCl solution (15 ml) , dried over MgSO4 and the solvent is distilled off on a rotary evaporator. The crude product obtained is purified by column chromatography (silica gel, n-pentane/Et2O 1:1 + 1% of Net3) and gives 9 (267 mg, 0.59 mmol, 70%) as an orange solid (m.p. : 138- 139°C) .

[α]D20 = + 521.1 (c = 0.57, CHC13) .

IR (KBr) : 3436 (br, s), 3065 (w) , 2959 (m) , 2922 (m) , 2822 (m) , 1638 (br, w) , 1476 (m) , 1434 (m) , 1166 (m) , 1105 (m) , 745 (s) , 698 (vs) .

IH-NMR (CDC13, 300 MHz) : δ/ppm = 7.55-7.50 (m, 2H) , 7.29- 7.26 (m, 3H), 7.19-7.08 (m, 5H) , 4.25-4.24 (m, IH) , 4.21- 4.19 (m, IH) , 3.85-3.81 (m, 6H), 3.80-3.77 (m, IH), 1.81- 1.71 (m, 8H), 1.11 (t, J = 7.5 Hz, 3H) . 13C-NMR ( CDC13 , 75 MHz ) : δ/ppm = 141 . 1 ( d , J = 7 . 2 Hz ) , 139 . 6 ( d , J = 9 . 4 Hz ) , 13 5 . 6 ( d , J = 21 . 4 Hz ) , 132 . 7 ( d , J = 19 . 1 Hz ) , 129 . 0 , 128 . 2 ( d , J = 7 . 6 Hz ) , 127 . 7 ( d , J = 6 . 9 Hz ) , 127 . 5 , 97 . 1 ( d, J = 23 . 7 Hz ) , 7 6 . 5 ( d , J = 8 . 2 Hz ) , 71 . 8 ( d, J = 5 . 1 Hz ) , 70 . 1 - 69 . 9 (m) , 68 . 6 , 63 . 7 ( d , J = 6 . 1 Hz ) , 40 . 0 , 22 . 5 , 13 . 9 .

31P-NMR ( CDC13 , 81 MHz ) : δ/ppm = -22 . 4 .

MS ( EI ) : 456 (M+ +1 , 17 ) , 455 (M+ , 52 ) , 440 ( 19 ) , 427 ( 28 ) , 426 ( 94 ) , 412 ( 27 ) , 411 ( 35 ) , 410 ( 100 ) , 409 ( 18 ) , 395 ( 21 ) , 345 ( 11 ) , 255 ( 11 ) , 226 ( 32 ) , 225 ( 16 ) , 183 ( 23 ) , 121 ( 29 ) , 86 ( 16 ) , 56 ( 11 ) .

C27H30FeNP ( 455 . 35 ) : calc . : C 71 . 22 , H 6 . 64 , N 3 . 08 . found : C 70 . 90 , H 6 . 72 , N 3 . 06 .

Preparation of (Rp) -l-diphenylphosphino-2- [α- (S) - (dicyclohexylphosphino)propyl] ferrocene-diborane complex (10)

(Rp) -l-Diphenylphosphino-2- [α- (S) - (N,N- dimethylamino)propyl] ferrocene (9) (108 mg, 0.24 mmol) is dissolved in degassed, concentrated acetic acid (5 ml) under argon and admixed with dicyclohexylphosphine (0.05 ml, 0.25 mmol, 1.13 equiv.) . The reaction solution is stirred at 7O0C for 4% hours. All volatile constituents are subsequently removed in an oil pump vacuum, the crude product is taken up in dry THF (4 ml) and reacted with borane-dimethyl sulfide complex (0.23 ml, 2.4 mmol, 10 equiv.) . After stirring at RT for 1 hour, the reaction solution is taken up in Et2O (10 ml) and carefully hydrolyzed by addition of water (10 ml) . The phases are separated and the aqueous phase is extracted with CH2Cl2 (2 x 7 ml) . The combined organic phases are washed with saturated NaCl solution (10 ml) , dried over MgSO4 and the solvents are distilled off on a rotary evaporator. The crude product is purified by column chromatography (silica gel, CH2Cl2/Et2O 1:1) and gives the diborane complex (10) (131 mg, 0.21 mmol, 88%) as an orange foam (m.p. : 113- 114°C) .

[α]D20 = + 333.3 (c = 0.20, CHC13) .

IR (KBr) : 3436 (br, vs) , 2930 (m) , 2853 (m) , 2391 (m) , 1629 (br, m) , 1437 (m) , 1158 (w) , 1103 (w) , 1062 (w) , 1003 (w) .

IH-NMR (CDC13, 300 MHz) : 6/ppm = 7.82-7.70 (m, 4H), 7.43- 7.31 (m, 6H), 4.85 (s, IH), 4.48 (t, J = 2.7 Hz, IH), 4.17- 4.15 (m, IH), 3.89-3.88 (m, 5H) , 3.33-3.25 (m, IH) , 2.34- 2.03 (m, IH), 1.95-1.91 (m, IH), 1.74-1.50 (m, 5H), 1.39- 1.10 (m, 12H), 1.00-0.74 (m, 5H) , 0.54-0.44 (m, IH) .

13C-NMR (CDC13, 75 MHz) : δ/ppm = 133.6 (d, J = 9.4 Hz), 133.3 (d, J = 9.1Hz), 132.7, 131.9, 131.5-131.4 (m) , 130.8, 129.1 (d, J = 9.7 Hz) , 128.6 (d, J = 10.4 Hz), 99.3 (dd, J = 17.4, 2.8 Hz), 74.1 (dd, J = 7.9, 3.2 Hz), 72.4 (d, J = 2.8 Hz), 71.2, 70.8 (d, J = 6.1 Hz), 68.8 (d, J = 2.6 Hz), 68.0 (d, J = 2.9 Hz), 66.2, 34.1 (d, J = 28.0 Hz), 32.0 (d, J = 34.9 Hz), 31.9 (d, J = 2.0 Hz) , 29.4 (d, J = 24.6Hz), 28.6 (d, J = 1.7 Hz) , 28.1 (d, J = 1.7Hz), 28.0 (d, J = 10.0 Hz) , 27.8 (d, J = 10.0 Hz), 27.7, 27.4 (d, J = 2.7Hz), 26.8-26.6 (m) , 25.9, 15.7, 15.3 (d, J = 7.0 Hz) .

31P-NMR (CDC13, 81 MHz) : δ/ppm = 34.5 (br) , 33.8 (br) .

MS (EI) : 637 (M+ +1, 13) , 636 (M+, 41), 635 (31), 634 (19), 633 (12), 632 (24) , 631 (57), 630 (31), 629 (19), 623 (23), 622 (54), 621 (48), 620 (25), 619 (10) , 526 (38), 525 (100), 436 (15), 411 (16) , 345 (11) .

C37H52B2FeP2 ( 63 6 . 22 ! calc. :C 69.85, H 8.24 found:C 70.22, H 8.57

Preparation of (Rp) -l-diphenylphosphino-2- [α-(S) (dicyclohexylphosphino)propyl] ferrocene (11)

PCy2

The diborane complex 10 (272 mg, 0.43 mmol) is dissolved in dry toluene (3 ml) under argon, admixed with l,4-bis(3- aminopropyDpiperazine (0.8 ml, 3.89 rnmol, 9 equiv.) and heated at 1000C for 16 hours. After cooling to RT, the reaction solution is taken up in dry Et2O (1 ml) and filtered through silica gel under argon. Removal of the solvents in an oil pump vacuum gives the diphosphine 11 (255 mg, 0.42 mmol, 98%) as an orange oil which is used in the catalysis without further purification.

C37H45FeP2 (607.55)

31P-NMR (CDC13, 81 MHz): δ/ppm = 21.8 (d, J =11.9 Hz), - 25.2 (d, J = 12.1 Hz) .

Preparation of (+) - [α-N,N-diallylamino) -γ- phenylpropynyl] ferrocene: Method A: racemic

CuBr (7.2 mg, 0.05 πunol, 0.05 mol%) is placed under nitrogen in a baked 10 ml Schlenk flask with septum, dried in a high vacuum and suspended in dry toluene (2 ml) under nitrogen. MS 4A (0.75 g) are added. Phenylacetylene (0.102 g, 1.0 mmol, 1 equiv. ) , ferrocenecarbaldehyde (0.214 g, 1.0 mmol, 1 equiv.) and diallylamine (97 mg, 1.0 mmol, 1 equiv.) are added in succession and the reaction mixture is stirred at RT for 40 hours. The MS are subsequently filtered off, washed with Et2O and the filtrate is freed of the solvent. The crude product is purified by column chromatography (silica gel, n- pentane/Et2O 9:1) . The product is obtained as a red oil (336 mg, 0.85 mmol, 85%) .

Method B: enantioselective

CuBr (3.6 mg, 0.025 mmol, 0.05 mol%) and (R) -Quinap (12.1 mg, 0.0275 mmol, 5.5 mol%) were placed under nitrogen in a baked 10 ml Schlenk flask with septum, dried in a high vacuum, suspended in dry toluene (2 ml) and stirred at RT for 30 minutes. MS 4A (0.75 g) are subsequently added. Phenylacetylene (51 mg, 0.5 mmol, 1 equiv.) , ferrocenecarbaldehyde (107 mg, 0.5 mmol, 1 equiv.) and diallylamine (49 mg, 0.5 mmol, 1 equiv.) are added in succession and the reaction mixture is stirred at RT for 5 days. The MS are subsequently filtered off, washed with Et2O and the filtrate is freed of the solvent. The crude product is purified by column chromatography (silica gel, n-pentane/Et2O 9:1) . The product is obtained as a red oil (151 mg, 0.38 mrnol, 76%, 70% ee) .

[α]D20 = + 240 (c = 1.00, CHC13) .

HPLC (OD-H, 99 % n-Heptan/1 % i-Propanol, 0.2 ml/min) : tr(min) = 20.6 (-) , 23.8 (+) .

IH-NMR (300 MHz, CDC13) : δ = 7.58-7.56 (m, 2H), 7.39-7.38 (m, 3H), 5.94-5.80 (m, 2H), 5.27 (d, J= 17.1 Hz, 2H) , 5.17 (d, J= 9.9 Hz) , 4.91 (s, IH) , 4.51 (s, IH) , 4.33 (s, 1 H), 4.23 (s, 5H), 4.19-4.18 (m, 2H), 3.26 (dd, J=14.2, 5.3 Hz, 2H), 3.11 (dd, J=14.2, 7.0 Hz, 2H) .

13C-NMR (75 MHz, CDC13) : δ = 136.7, 132.5, 131.7, 128.3, 128.0, 117.2, 87.0, 85.8, 85.2, 69.2, 69.0, 68.9, 68.2, 67.4, 53.4, 53.3.

MS (70 eV, EI) : m/z(%) : 395 (M+, 24), 353 (11), 300 (32), 299 (100), 178 (52), 177 (18), 176 (25) , 152 (17), 151 (10) , 121 (23) , 70 (10) , 68 (11) .

HRMS (EI) : calcd. for C25H25FeN [M+] : 395.1336, found: 395.1370.

IR (film) : 3080 (m) , 2960 (m) , 2929 (m) , 2815 (m) , 1728 (s) , 1489 (s) , 1444 (m) , 1288 (s) , 1106 (s) , 999 (m) , 920 (m) , 756 (vs) , 691 (s) .

Anal calcd for C25H25FeN: C: 75.96, H: 6.37, N: 3.54, found: C: 75.55, H: 6.70, N: 3.02.

Preparation of (+) - [α-N,N-dibenzylamino) -γ- phenylpropynyl] ferrocene: Ph' SN' ^Ph

Ph Fe

Method A: racemic

CuBr (7.2 mg, 0.05 πunol, 0.05 mol%) is placed in a baked 10 ml Schlenk flask with septum, dried in a high vacuum and suspended in dry toluene (2 ml) under nitrogen. MS 4A (0.75 g) are added. Phenylacetylene (102 mg, 1.0 mmol, 1 equiv. ) , ferrocenecarbaldehyde (0.214 g, 1.0 mmol, 1 equiv. ) and dibenzylamine (197 mg, 1.0 mmol, 1 equiv.) are added in succession and the reaction mixture is stirred at RT for 44 hours. The MS are subsequently filtered off, washed with Et2O and the filtrate is freed of the solvent. The crude product is purified by column chromatography (silica gel, n-pentane/Et2θ 9:1) . The product is obtained as a red oil (415 mg, 0.84 mmol, 84%) .

Method B: enantioselective

CuBr (3.6 mg, 0.025 mmol, 0.05 mol%) and (R) -Quinap (12.1 mg, 0.0275 mmol, 5.5 mol%) were placed under nitrogen in a baked 10 ml Schlenk flask with septum, dried in a high vacuum, suspended in dry toluene (2 ml) and stirred at RT for 30 minutes. MS 4A (0.75 g) are subsequently added. Phenylacetylene (51 mg, 0.5 mmol, 1 equiv.) , ferrocenecarbaldehyde (107 mg, 0.5 mmol, 1 equiv.) and dibenzylamine (99 mg, 0.5 mmol, 1 equiv.) are added in succession and the reaction mixture is stirred at RT for 6 days. The MS are subsequently filtered off, washed with Et2O and the filtrate is freed of the solvent. The crude product is purified by column chromatography (silica gel, n-pentane/Et2O 9:1) . The product is obtained as a red oil (200 mg, 0.40 mmol, 81%, 76% ee) .

[α]D20 = +43 (c = 1.09, CHC13) . IH-NMR (300 MHz, CDC13) : δ = 7.65-7.61 (m, 2H), 7.44-7,24 (m, 13H), 4.80 (s, IH), 4.56-4.55 (m, IH), 4.35-4.34 (m, IH) ,4.18-4.16 (m, 2H), 4.11 (s, 5H), 3.83 (d, J=13.7, 2H), 3.59 (d, J= 13.7 Hz, 2H) .

13C-NMR (75 MHz, CDC13) : δ = 139.9, 131.8, 128.7, 128.4, 128.2, 128.0, 126.8, 123.6, 86.6, 86.3, 85.4, 69.0, 68.9, 68.8, 68.3, 67.3, 54.3, 52.9.

MS (70 eV, EI) : m/z(%) : 496 (10) , 495 (M+, 28), 300 (25), 299 (100), 121 (13), 91 (29) . HRMS (EI) : calcd. for C33H29FeN [M+]: 495.1649, found: 495.1629.

IR (film) : 3084 (m) , 3062 (m) , 3028 (m) , 2924 (m) , 2833 (m) , 2806 (m) , 1490 (s), 1443 (vs), 1071 (s), 1027 (m) , 755 (m) , 698 (vs) .