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Title:
CHIRAL METAL COMPLEX COMPOUNDS
Document Type and Number:
WIPO Patent Application WO/2018/189060
Kind Code:
A1
Abstract:
The invention comprises novel chiral metal complex compounds of the formula (I) wherein M, PR2, R3 and R4 are outlined in the description, its stereoisomers, in the form as a neutral complex or a complex cation with a suitable counter ion. The chiral metal complex compounds can be used in asymmetric reactions, particularly in asymmetric reductions of ketones, imines or oximes.

Inventors:
BACHMANN, Stephan (Grenzacherstrasse 124, 4070 Basel, 4070, CH)
BELLER, Matthias (Leibniz-Institut für Katalyse e.V, Albert-Einstein-Strasse 29a, Rostock, 18059, DE)
GARBE, Marcel (Leibniz-Institut für Katalyse e.V, Albert-Einstein-Strasse 29a, Rostock, 18059, DE)
JUNGE, Kathrin (Leibniz-Institut für Katalyse e.V, Albert-Einstein-Strasse 29a, Rostock, 18059, DE)
SCALONE, Michelangelo (Grenzacherstrasse 124, 4070 Basel, 4070, CH)
Application Number:
EP2018/058949
Publication Date:
October 18, 2018
Filing Date:
April 09, 2018
Export Citation:
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Assignee:
F. HOFFMANN-LA ROCHE AG (Grenzacherstrasse 124, 4070 Basel, 4070, CH)
HOFFMANN-LA ROCHE INC. (Overlook at Great Notch, 150 Clove Road,8th Floor, Suite 8 - Legal Departmen, Little Falls New Jersey, 07424, US)
International Classes:
C07C29/145; C07B53/00; C07C67/30; C07D307/44; C07D307/80; C07D309/06; C07D333/16; C07D335/02; C07F13/00; C07F15/02
Domestic Patent References:
WO2004096735A22004-11-11
Other References:
BURK M J ED - WATKIN DAVID: "New chiral phospholanes; synthesis, characterization, and use in asymmetric hydrogenation reactions", TETRAHEDRON ASYMMETRY, PERGAMON PRESS LTD, OXFORD, GB, vol. 2, no. 7, 1 January 1991 (1991-01-01), pages 569 - 592, XP002146730, ISSN: 0957-4166, DOI: 10.1016/S0957-4166(00)86109-1
P.G. ANDERSON ET AL., J. AM. CHEM. SOC., vol. 139, 2017, pages 1346
R.H. MORRIS ET AL., ACS CATAL., vol. 7, 2017, pages 316
M. J. BURK; J. E. FEASTER; R. L. HARLOW, TETRAHEDRON: ASYMMETRY, vol. 2, 1991, pages 569 - 592
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 791630-00-7
SHELDRICK, G. M., ACTA CRYST., vol. A64, 2008, pages 112
G. M. SHELDRICK, ACTA CRYST., vol. C71, 2015, pages 3
T. HAMMERER; A. DAMBKES; W. BRAUN; A. SALZER; G. FRANCIO; W. LEITNER, SYNTHESIS, vol. 44, 2012, pages 2793 - 2797
A. A. DANOPOULOS; A. R. WILLIS; P. G. EDWARDS, POLYHEDRON, vol. 13, 24 September 1990 (1990-09-24), pages 2418
M. J. BURK; J. E. FEASTER; R. L. HARLOW, TETRAHEDRON. ASYMMETRY, vol. 2, 1991, pages 569 - 592
Attorney, Agent or Firm:
RAUBER, Beat (Grenzacherstrasse 124, 4070 Basel, 4070, CH)
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Claims:
Claims:

1. Chiral metal complex compound of the formula

wherein denotes either a broken bond (a) or a wedged bond (b) a) b) ■

M is a metal selected from the manganese group or the iron group of the periodic system;

PR is

Ha

wherein R5 and R6 independent of each other are Ci-4-alkyl or aryl; or

M b ; or l ie wherein R 7 and R 8 independent of each other are Ci_4-alkyl;

RJ is CO, halogen or hydrogen and

R4 is CO, halogen or H-BH3; and its stereoisomers in the form as a neutral complex or a complex cation with a suitable counter ion.

2. Chiral metal complex compound of the formula

wherein denotes either a broken bond (a) or a wedged bond (b)

M is a metal selected from the manganese group or the iron group of the periodic system; PR2

M b ; or He wherein R 7 and R 8 independent of each other are Ci_4-alkyl;

R is CO or hydrogen and R4 is CO or H-BH3; and its stereoisomers in the form as a neutral complex or a complex cation with a suitable counter ion.

3. Chiral metal complex compound of claim 1 or 2, wherein the metal M is selected from the manganese group or the iron group of the periodic system. 4. Chiral metal complex compound of anyone of claims 1 to 3, wherein the metal M is selected from manganese or iron.

5. Chiral metal complex compound of anyone of claims 1 to 4, wherein PR is the ligand of formula Hal

I l a1 wherein , R and R are as above, but R and R preferably are Ci_4-alkyl.

6. Chiral metal complex compound of anyone of claims 1 to 5, wherein PR is the of formula IIa2' or IIa2' '

N a2' N a2"

wherein R5 and R6 are as above, but preferably is C1-4-alkyl.

7. Chiral metal complex compound of anyone of claims 1 to 6, having the formula la

la

wherein M, PR 2 , R 3 and R 4 are as above in the form as a neutral complex or as a complex cation with a suitable counter ion.

8. Chiral metal complex compound of anyone of claims 1 to 7, having the formula lb

lb wherein PR 2 , R 3 and R 4 are as above in the form as a neutral complex or as a complex cation with a suitable counter ion.

9. Chiral metal complex com ound of anyone of claims 1 to 7, having the formula Ic

Ic wherein PR 2 , R 3 and R 4 are as above.

10. Chiral metal complex compound of anyone of claims 1 to 8, of the formula;

Id wherein PR is as above and X is a halogen or a pseudohalogen.

11. Chiral metal complex compound of anyone of claims 1 to 7 and 9, of the formula;

le wherein PR is as above

12. Chiral metal complex compound of anyone of claims 1 to 8 and 10, of the formula;

13. Chiral metal complex compound of anyone of claims 1 to 7, 9 and 11, of the formula

14. Process for the preparation of a Chiral Metal Complex compounds of formula I, comprising the reaction of a Bis(phospholanoethyl)amine derivative of the formula III

wherein PR is as above with a metal salt.

15. Process for the pre aration of the chiral metal complex compound of formula Id

Id wherein PR is as above, comprising the reaction of a Bis(phospholanoethyl) derivative of the formula III

H

wherein PR is as above with Mn(CO)5 X", wherein X" is a halogen or a pseudohalogen, preferably a halogen. 16. Process for the preparation of the chiral metal complex compound of formula Ie

le wherein PR is as above comprising the reaction of a bis(phospholanoethyl)amine derivative of the formula III

wherein PR is as above with FeX2, wherein X is a halogen and with carbon monoxide to an iron complex intermediate of the formula IV

X IV wherein PR is as above and X is a halogen; and subsequent transformation into the chiral metal complex compound of formula Ie with a suitable hydride forming agent.

17. Chiral iron complex intermediate of formula IV

X IV

wherein PR is as above and X is a halogen.

18. Use of the chiral metal complex compounds of claims 1 to 13 in the catalysis of asymmetric reactions.

19. Use of claim 18, wherein the asymmetric reaction is an asymmetric reduction, particularly an asymmetric reductions of C=X double bonds, namely of ketones, ketoesters, imines or oximes.

Description:
Chiral Metal Complex Compounds

The invention relates to novel chiral metal complex compounds of the formula

wherein M, PR 2 , R 3 and R 4 are as defined below and its stereoisomers in the form as a neutral complex or a complex cation with a suitable counter ion.

The invention also relates to processes for the preparation of the chiral metal complexes and to their use in asymmetric reactions, particularly in asymmetric reductions of C=X double bonds, namely of ketones (C=0), a- or β-ketoesters (a: -(C=0)-(C=0)-OR) or β: -(C=0)-CR 2 - (C=0)-OR), imines (-C=N-R) or oximes (-C=N-OH).

Research in the field of catalysts for asymmetric reaction such as in asymmetric hydrogenations tend to move away from the platinum group metal catalysts to environmentally friendly non platinum group metal catalysts. ( P.G. Anderson et al., J. Am. Chem. Soc. 2017, 139, 1346; R.H. Morris et al, ACS Catal. 2017, 7, 316).

Object of the present invention is to provide chiral metal complex catalysts which are both environmentally friendly and which show high enantio selectivity and conversion rates.

The object could be reached with the novel chiral metal complex compounds of the formula

wherein denotes either a broken bond (a) or a wedged bond (b)

M is a metal selected from the manganese group or the iron group of the periodic system; 2 is

5 and R 6 independent of each other are Ci_ 4 -alkyl or aryl; or

Mb ; or He wherein R 7 and R 8 independent of each other are Ci_ 4 -alkyl;

R 3 is CO, halogen or hydrogen R 4 is CO, halogen or H-BH 3; and its stereoisomers in the form as a neutral complex or a complex cation with a suitable counter ion.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below.

The term "chiral" denotes the ability of non-superimposability with the mirror image, while the term "achiral" refers to embodiments which are superimposable with their mirror image. Chiral molecules are optically active, i.e., they have the ability to rotate the plane of plane-polarized light. Whenever a chiral center is present in a chemical structure, it is intended that all stereoisomers associated with that chiral center are encompassed by the present invention.

The term "chiral" signifies that the molecule can exist in the form of optically pure enantiomers, mixtures of enantiomers, optically pure diastereoisomers or mixtures of

diastereoisomers .

In a preferred embodiment of the invention the term "chiral" denotes optically pure enantiomers or optically pure diastereoisomers.

The term "stereoisomer" denotes a compound that possesses identical molecular connectivity and bond multiplicity, but which differs in the arrangement of its atoms in space.

The term "diastereomer" denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities.

The term "enantiomers" denotes two stereoisomers of a compound which are non- superimposable mirror images of one another.

In the structural formula presented herein a broken bond (a) denotes that the substituent is below the plane of the paper and a wedged bond (b) denotes that the substituent is above the plane of the paper. a) b) ■ The spiral bond (c) denotes both options i.e. either a broken bond (a) or a wedged bond

(b). c)

The term "C- 1-4 - alkyl" denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 4 carbon atoms. Examples of Ci- 4 -alkyl include methyl, ethyl, propyl, isopropyl, n- butyl, iso-butyl, sec-butyl, or tert-butyl.

The term "halogen" denotes fluoro, chloro, bromo, or iodo.

The term "pseudohalogen" denotes analogues of halogens whose chemistry resembles that of halogens. Examples of pseudohalogens are cyano, isocyanide, cyanate or isocyanate. The term "aryl" denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms which optionally may be substituted. Examples of aryl moieties include phenyl and naphthyl. Phenyl is the preferred aryl group.

The term "optionally substituted" in connection with the term "aryl" denotes that the aryl group may be unsubstituted or substituted by one or more substituents, independently selected from Ci_ 4 -alkyl, Ci_ 4 -alkoxy or halogen.

M stands for a metal of the manganese group or the iron group of the periodic system.

Suitable metals of the manganese group are manganese or rhenium, preferably manganese.

Suitable metals of the iron group are iron, ruthenium or osmium, preferably iron. In a preferred embodiment of the present invention the metal M is selected from the manganese group or the iron group of the periodic system more preferably the metal M is selected from manganese or iron.

PR stands for the ligands

Ha wherein R 5 and R 6 independent of each other are Ci_ 4 -alkyl or aryl, preferably Ci_ 4 -alkyl or phenyl, more preferably Ci_ 4 -alkyl and even more preferably methyl; or

l lb ; or l ie

wherein R 7 and R 8 independent of each other are Ci_ 4 -alkyl, more preferably methyl. PR particularly is the ligand of formula Hal

I la1 wherein , R 5 and R 6 are as above, but wherein R 5 and R 6 preferably are Ci_ 4 -alkyl, more preferably methyl.

More particularly PR is the ligand of formula IIa2' or IIa2' '

Na2' Ma2' wherein R 5 and R 6 are as above, but preferably is Ci_ 4 -alkyl, more preferably methyl.

In a preferred embodiment of the present invention the chiral metal complex compounds have the formula la

la

wherein M, PR 2 , R 3 and R 4 are as above in the form as a neutral complex or a complex cation with a suitable counter ion.

Applying manganese as preferred metal M the chiral manganese complex compounds have the formula lb

lb wherein PR 2 , R 3 and R 4 are as above in the form as a neutral complex or a complex cation with a suitable counter ion, more preferably the chiral manganese complex compounds have the formula Id

Id wherein PR is as above and X is a halogen or a pseudohalogen. X preferably stands for a halogen, more preferably for bromine or chlorine, even more preferably for bromine.

Likewise with iron as preferred metal M the chiral iron complex compounds have the formula Ic

Ic wherein PR 2 , R 3 and R 4 are as above, more preferably the chiral iron complex compounds have the formula Ie

wherein PR is as above.

Most preferred chiral metal complexes have the formula If

If or the formula Ig

ig

The invention also comprises a process for the preparation of the chiral metal complex compound of formula I which comprises the reaction of a Bis(phospholanoethyl)amine derivative of the formula III

H

wherein PR is as above with a metal salt. The metal salt suitable for the reaction largely depends on the metal M applied.

The bis(phospholanoethyl)amine derivative of the formula III can be synthesized starting from the respective phosphines HPR following methods known in the art.

Accordingly for the phosphine wherein PR stands for the ligand

Ha the synthesis of the Bis(phospholanoethyl)amine derivative of the formula III with R and R 6 being methyl can be accomplished according to M. J. Burk, J. E. Feaster, R. L. Harlow, Tetrahedron: Asymmetry 1991, 2, 569-592 via the reaction of dimethylphospholane with bis(2- chloroethyl) trimethylsilylamine.

The Bis(phospholanoethyl)amine derivative of the formula III with the phosphine ligand

PR of the formula

is commercially available (CAS No. 791630-00-7) for instance from Sigma-Aldrich. For the phosphine with the ligand PR

l ie with R 7 and R 8 as described above can be accomplished in analogy of the ligand PR 2 of formula Ila according to M. J. Burk, J. E. Feaster, R. L. Harlow, Tetrahedron: Asymmetry 1991, 2, 569-592 via the reaction of the phosphine with the ligand of formula lie with bis(2-chloroethyl) trimethylsilylamine.

The synthesis of the bis(phospholanoethyl)amine derivative of the formula III can be accomplished according to M. J. Burk, J. E. Feaster, R. L. Harlow, Tetrahedron: Asymmetry

1991, 2, 569-592.

The preparation of the chiral metal complex compounds of formula Id

Id wherein PR is as above comprises the reaction of a bis(phospholanoethyl) derivative of the formula III

H

Ill wherein PR is as above with Mn(CO)sX, wherein X " is a halogen or a pseudohalogen, preferably a halogen, more preferably chlorine or bromine and even more preferably bromine.

The reaction is expediently performed in a suitable organic solvent under inert gas atmosphere at reaction temperatures from 20°C to 150°C, preferably from 80°C to 110°C.

Suitable solvents are non-polar solvents such as aromatic hydrocarbons like toluene or benzene.

The complexes can be isolated by standard techniques and further be purified via crystallization.

The preparation of the chiral metal complex compound of formula Ie

le comprises the reaction of a Bis(phospholanoethyl)amine derivative of the formula III

Ill wherein PR is as above with FeX 2 , wherein X is a halogen and with carbon monoxide to form an iron complex intermediate of formula IV

X

IV and the subsequent transformation into the chiral metal complex compound of formula Ie with a suitable hydride forming agent.

FeX 2 preferably is iron chloride or iron bromide, more preferably iron bromide.

The reaction of a Bis(phospholanoethyl)amine derivative of the formula III with FeX 2 usually takes place in a suitable organic solvent such as in polar aprotic solvents like

tetrahydrofuran at reaction temperatures from 0°C to 50°C, preferably from 20°C to 30°C during 2h to 8h.

The subsequent reaction with carbon monoxide to form the intermediate of formula IV can take place at reaction temperatures from 0°C to 50°C, preferably from 20°C to 30°C during 0.5h to 6h.

Isolation of the intermediate can easily be accomplished by removing the solvent and washing of the crude intermediate compound with a suitable solvent e.g. with ethanol.

The chiral iron complex intermediate of formula IV

X

IV wherein PR is as above and X is a halogen are compounds which are not known in the state of the art and therefore are also an embodiment of the present invention.

In a more preferred embodiment X is chlorine or bromine, more preferably bromine.

PR particularly is the ligand of formula Hal

I l a1 wherein " , R 5 and R 6 are as above, but wherein R 5 and R 6 preferably are Ci- 4 -alkyl, more preferably methyl.

More particularly PR .2 i ·s the ligand of formula IIa2' or IIa2' '

Ma2' Na2" wherein R 5 and R 6 are as above, but preferably is C 1-4 -alkyl, more preferably methyl.

Most preferred chiral iron complex intermediate has the formula IV wherein X is bromine and PR 2 has the formula IIa2' with R 5 and R 6 methyl.

Suitable hydride forming agent for the transformation of the chiral iron complex intermediate of formula IV into the chiral metal complex compound of formula Ie can be selected from complex metal hydrides like lithium aluminum hydride, diisobutyl aluminum hydride or sodium borohydride, preferably sodium borohydride.

The reaction usually takes place in a suitable organic solvent such as in non-polar solvents like toluene at reaction temperatures of 0°C to 50°C.

Isolation of the desired iron complex can happen via removal of the solvent and washing of the crude complex compound with a suitable solvent e.g. with n-heptane. In a further embodiment of the present invention the chiral metal complex compounds described above can be used in the catalysis of asymmetric reactions, particularly asymmetric reduction, more particularly asymmetric reductions of C=X double bonds, namely of ketones (C=0), a- or β-ketoesters (a: -(C=0)-(C=0)-OR) or β: -(C=0)-CR 2 -(C=0)-OR), imines (-C=N- R) or oximes (-C=N-OH).

In a more preferred embodiment of the present invention the chiral metal complex compounds described above can be used in the catalysis of asymmetric hydrogenations of C=X double bonds, namely of ketones, ketoesters, imines or oximes, particularly of ketones.

The chiral metal complexes are active on a broad substrate spectrum of compounds with C=X functionality.

Thus for the ketones dialkylketones, arylalkylketones, cycloalkylalkyl ketones, a- and β- ketoesters, cycloalkanones, heterocyclylalkylketones or even ketogroup containing heterocyclic compounds are suitable substrates.

The reaction conditions for the asymmetric hydrogenation largely depends on the selected chiral metal complex and the substrate, but in principle the reaction conditions are known to the skilled in the art.

In a typical procedure for the asymmetric hydrogenation of ketones with the preferred manganese complex of formula Id the complex is dissolved under inert gas atmosphere in a suitable organic solvent in the presence of a base. Thereafter the ketone substrate is added and the hydrogenation is performed in an autoclave as a rule at elevated temperature and a hydrogen pressure of 5 bar to 100 bar, preferably between 10 bar and 60 bar.

In a typical procedure for the asymmetric hydrogenation of ketones with the preferred iron complex of formula Ie the complex is dissolved under inert gas atmosphere in a suitable organic solvent. Thereafter the ketone substrate is added and the hydrogenation is performed in an autoclave as a rule at elevated temperature and a hydrogen pressure of 5 bar to 100 bar, preferably between 10 bar and 60 bar. The following examples shall further illustrate the invention. Examples:

Abbreviations:

X-ray crystal structure analysis of X: Data were collected on a Bruker Kappa APEX II Duo diffractometer. The structures were solved by direct methods (SHELXS-97: Sheldrick, G. M. Acta Cryst. 2008, A64, 112.) and refined by full-matrix least-squares procedures on F2

(SHELXL-2014: G. M. Sheldrick, Acta Cryst. 2015, C71, 3.). XP (Bruker AXS) was used for graphical representations. l.Ligand Synthesis:

1.1 Synthesis of (2R,5R)-2,5-dimethylphospholane

The title compound was synthesized according to the reported procedure (T. Hammerer, A. Dambkes, W. Braun, A. Salzer, G. Francio, W. Leitner, Synthesis 2012, 44, 2793-2797).

To a cooled solution of (R,R)-2,5-dimethyl-l-(trimethylsilyl) phospholane (9.42 g, 50.0 mol) with an isopropanol cooling bath (-79 °C) MeOH (1.63 g, 51.0 mol) was added dropwise. The resulting solution was allowed to warm up to room temperature and stirred overnight. The side products were condensed into another Schlenk flask by heating the solution up to 60 °C. The product was isolated as a colorless liquid with a yield of 95 % (5.52 g, 47.5 mmol). 1.2 Syntheses of Bis(2-chloroethyl)trimethylsilylamine

TMS

The title compound was synthesized following the reported procedure (A. A. Danopoulos, A. R. Willis, P. G. Edwards, Polyhedron 1990, 9, 2413-2418).

To a stirred and cooled (0°C) suspension of Bis(2-chloroethyl)amine hydrochloride (10 g, 56.0 mmol) in 100 mL Et 2 0, 0.25 mL DMSO and Triethylamine (17.0 g, 168.0 mmol)

Trimethylchlorosilane (21.3 g, 196 mmol) was added dropwise over half an hour at 0 °. The solution was stirred for one hour at 0 °C, warmed up to room temperature and stirred for further 3-5 days. The solution was filtered and the volatiles of the liquid portion were removed in vacuo and the product was achieved as yellow viscose liquid (9.96 g, 46.5 mmol, 83 % yield).

1.3 Synthesis of Bis(2-((2R,5R)-2,5-dimethylphospholanoethyl))amine

The title compound was synthesized referring to the reported procedure (M. J. Burk, J. E. Feaster, R. L. Harlow, Tetrahedron. Asymmetry 1991, 2, 569-592).

(2R,5R)-2,5-dimethylphospholane (6.9 g, 0.059 mmol) was dissolved in 80 mL w-hexane and cooled to -79 °C. w-Butyllithium (2.5 M in w-hexane, 25 mL, 62.5 mmol) was added dropwise to the solution. The solution was stirred for half an hour at this temperature, warmed up to room temperature and the resulting slightly yellow solution was stirred for further five hours. 10 mL of THF was added and the solution was again cooled down to -79 °C. 6.32 g (29.5 mmol) Bis(2- chloroethyl)trimethylsilylamine diluted in 10 mL of THF was dropwise added while a white solid precipitated. The slightly yellow suspension was stirred for 16 h at room temperature.

Afterwards 30 mL of water and 60 mL of TBAF (1M solution in THF, 60 mmol) was added and the resulting two-phase system was stirred for further 3-5 days. Most of the organic solvents were removed in vacuo and the product was extracted three times with Et 2 0 from the aqueous phase. The organic layer was dried over MgS0 4 , filtered, the volatiles of the liquid portion were removed and the yellow product was dried in vacuo (6.76 g, 22.4 mmol, 71 % yield). The pincer ligand was used without further purification. 1H NMR (400.13 MHz; CD 3 C1): δ = 1.08-1.12 (dd, 6H, CH 3 , / = 7.2 Hz); 1.16-1.23 (dd, 6H, CH 3 , / = 7.2 Hz; m, 2H, CH 2 ); 1.34-1.47 (m, 4H, CH 2 ); 1.61-1.68 (m, 2H, CH 2 ); 1.84-1.92 (m, 2H, CH); 1.93-2.02 (m, 2H, CH 2 ); 2.03-2.15 (m, 4H, CH 2 , CH); 2.62-2.78 (m, 4H, CH 2 ), 3.8 (br, 1H, NH).

31 P NMR (121.5 MHz; CD 3 C1): δ = -5.2 ppm.

2. Complex Synthesis

2.1 Synthesis of manganese complexes

If

To the suspension of [MnBr(CO) 5 ] (275 mg, 1 mmol) in toluene (20 mL) Bis(2-((2R,5R)-2,5 dimethylphospholanoethyl)) amine (331.5 mg, 1.1 mmol, dissolved in 2 mL toluene) was added. The [MnBr(CO) 5 ]was dissolved, the solution was heated up to 100 °C and further stirred for 20 h under argon flow. The reaction mixture was cooled to room temperature and concentrated in vacuo resulting in a yellow solid with red inclusions. The crude solid was washed three times with 5 mL of pentane resulting in a clean yellow/orange solid (359.5 mg, 72.4 mmol, 72 % yield).

31 P{1H} NMR (122 MHz, C 6 D 6 ): δ = 97.14.

IR-ATR (solid) ϋ [cm "1 ]: 2009 (s, ϋ CO), 1908 (s, ϋ CO), 1821 (s, ϋ CO). EA % ber. (gef) Ci 7 H 38 BrMnN0 3 P 2 , M = 520.27 g/mol: C 43.86 (44.97); H 6.39 (6.61) N 2.69 (2.74). 2.2 Synthesis of iron complexes a) Synthesis of the precursor

= PR 2

2.07 g of Bis(2-((2R,5R)-2,5-dimethylphospholanoethyl))amine (6.8 mmol) was dissolved in 30 mL THF. Afterwards a solution of FeBr 2 THF (2.84 g, 6.8 mmol) in 20 mL THF was added. The resulting brown/yellow solution was stirred overnight at room temperature. By reacting with CO over three hours a blue solid was formed. The solvent was removed in vacuo and the resulted crude solid was washed with 5 mL EtOH getting a pure compound with a yield of 63 % (2.35 g, 4.3 mmol). 1H NMR (400.13 MHz; CD 3 C1): δ = 1.11-1.16 (m, 6H, CH 3 ); 1.22-1.38 (m, 3Η, P-CH 2 ); 1.42- 1.52 (m, 2Η, P-CH 2 ); 1.59-1.78 (m, 9Η, 2x CH 3 ; P-CH 2 ); 1.80-1.90 (m, 1Η, P-CH 2 ); 1.99-2.16 (m, 3Η, P-CH); 2.29-2.36 (m, 1Η, P-CH); 2.37-2.45 (m, 1Η, P-CH); 2.54-2.78 (dd, 2Η, N-CH 2 ), 2.82-2.92 (m, 1Η, N-CH 2 ); 2.94-3.04 (m, 2Η, P-CH); 3.14-3.26 (m, 1Η, N-CH 2 ); 4.32-4.44 (br, 1Η, NH). 31 P{1H} NMR (122 MHz, C 6 D 6 ): δ = 95.91 (d, J PP = 174.19 Hz), 98.54 (d, J PP = 174.19). IR-ATR (solid) ϋ [cm -1 ]: 1935 (s, ϋ CO), b) Synthesis of iron complex Ie

690 mg of IV (1.27 mmol) was dissolved in 20 mL of benzene or toluene. A freshly prepared solution of NaBH 4 (383 mg, 10.12 mmol, in 20 mL EtOH) was added dropwise to the solution whereas a gas evolution was directly noticeable. After stirring the solution for 3-5 h the solvents were removed and the remaining solid was dried in vacuo. The product was extracted with benzene or toluene (in total 40 mL) and the solvent was afterwards removed in vacuo. The crude solid was washed three times with 10 mL of w-heptane and the expected product was achieved with a yield of 80 % (403 mg). 1H-NMR (300 K, C 6 D 6 , 400.13 MHz): δ = -19.20 (t, IH, Fe-H, 2 J HP = 51.85 Hz, (minor isomer)), -18.80 (t, IH, Fe-H, 2 J HP = 51.75 Hz, (major isomer)), -2.77 (bs, 4H, HBH 3 ), 0.95 (m, 3Η, CH 3 ), 1, 15 (m, 3Η, CH-CH 2 ), 1.25 (m, 5Η, CH 3 and P-CH 2 and CH-CH 2 ), 1.32 (m, 1Η, CH- CH 2 ), 1.41 (m, 3Η, CH 3 ), 1.51 (m, 2Η, N-CH 2 ), 1.58 (m, 1Η, CH), 1.66 (m, 1Η, P-CH 2 ), 1.73 (m, 6Η, CH3, P-CH2 and CH-CH 2 ), 1.91 (m, 4Η, CH-CH 2 and CH), 2.08 (m, 1Η, P-CH 2 ), 2.27 (m, 1Η, CH), 2.62 (m, 3Η, CH and N-CH 2 ), 3.76 (m, 1Η, N-H).

31 P-NMR - major isomer (300 K, C 6 D 6 , 100.616 MHz): δ = 109.18 (d, IP, 2 J PP = 122.93 Hz), 107.02 (d, IP, 2 Jpp = 120.75 Hz).

31 P-NMR - minor isomer (300 K, C 6 D 6 , 100.616 MHz): δ = 114.41 (d, IP, 2 J PP = 116.87 Hz), 104.98 (d, IP, 2 Jpp = 116.64 Hz).

IR-ATR (solid) ϋ [cm -1 ]: 1894 (s, ϋ CO). 3. Asymmetric Hydrogenation Results

3.1 Hydrogenation of ketones or ketoesters with Manganese Complex of example 2.1

General Procedure:

All catalytic hydrogenation experiments using molecular hydrogen were carried out in a Parr Instruments autoclave (300 mL) advanced with an internal alloy plate include up to 8 uniform reaction vials (4 mL) equipped with a cap and needle penetrating the septum. Representative experiment:

Under an argon atmosphere, a vial was charged with Manganese Complex of example 2.1 and base which were dissolved in 2 mL of dried solvent. The resulting red solution was stirred briefly before the ketone or ketoester (0.5 or 1 mmol) was added. The vial was placed in the alloy plate which was then placed into the autoclave. Once sealed, the autoclave was purged 5 times with hydrogen, then pressurized to 30 bar and heated to desired temperature. Afterwards, the autoclave was cooled to RT, depressurized, and the reaction mixture was analyzed by GC-FID or HPLC as well as GC-MS. Product isolation was performed via column chromatography using silica gel as stationary phase and w-pentane / ethylacetate or w-pentane / acetone mixture as eluent. Individual reaction conditions:

[a] 2 mol cat., 5 mol NaOiBu, 0.5 mmol substrate, 30 bar, 3h, 50 °C, EtOH (1,5 mL)

[b] 2 mol cat., 5 mol NaOiBu, 0.5 mmol substrate, 30 bar, 3h, 70 °C, EtOH (1,5 mL) [c] 2 mol% cat., 5 mol% NaOiBu, 0.5 mmol substrate, 30 bar, 3h, 50 °C, toluene (1,5 mL)

[d] 2 mol% cat., 5 mol% NaOiBu, 0.5 mmol substrate, 30 bar, 3h, 50 °C, z ' PrOH (1,5 mL)

[e] 2 mol% cat., 5 mol% NaOiBu, 0.5 mmol substrate, 30 bar, 3h, 50 °C, /PrOH (1,5 mL)

[f] 1 mol% cat., 5 mol% KOiBu, 0.5 mmol substrate, 30 bar, 4-5h, 40 °C, tert-amyl alcohol (1,5 mL)

[g] 1 mol% cat., 5 mol% KOiBu, 0.5 mmol substrate, 30 bar, 16h, 50 °C, toluene (1,5 mL)

[h] 2 mol% cat., 5 mol% KOiBu, 0.5 mmol substrate, 30 bar, 8h, 100 °C, dioxan (1,5 mL)

[i] 1 mol% cat., 5 mol% KOiBu, 1 mmol substrate, 30 bar, 4h, 30 °C, 1,4-dioxane (2 mL)

[j] 1 mol% cat., 5 mol% KOiBu, 1 mmol substrate, 30 bar, 4h, 40 °C, tert-amyl alcohol (2 mL) [k] 1 mol% cat., 5 mol% KOiBu, 1 mmol substrate, 30 bar, 4h, 80 °C, tert-amyl alcohol (2 mL) [1] 2 mol% cat., 5 mol% KOiBu, 1 mmol substrate, 30 bar, 4h, 50 °C, toluene (2 mL)

[m] 2 mol% cat., 5 mol% KOiBu, 1 mmol substrate, 30 bar, 4h, 80 °C, tert-amyl alcohol(2 mL) [n] 2 mol% cat., 5 mol% NaOiBu, 0.5 mmol substrate, 30 bar, 3h, 70 °C, PrOH (1,5 mL) [o] 2 mol% cat., 5 mol% NaOiBu, 0.5 mmol substrate, 30 bar, lh, 50 °C, /PrOH (1 mL)

SP = side product (Hydrogenation of double bond) Table 1:

Example Substrate Reaction Conversion e.e.

Conditions (%)

3.1. l.a d 90 (36 SP) 67

3.1. l.b o 90 (36 SP) 67 (20 %

for the SP)

3.2 Hydrogenation of ketones or ketoesters with Iron Complex of example 2.2

General procedure: All catalytic hydrogenation experiments using molecular hydrogen were carried out in a Parr Instruments autoclave (300 mL) advanced with an internal alloy plate include up to 8 uniform reaction vials (4 mL) equipped with a cap and needle penetrating the septum.

Representative experiment: Under an argon atmosphere, a vial was charged with Iron Complex of example 2.2 which were dissolved in 2 mL of dried solvent. The resulting yellow solution was stirred briefly before the ketone or ketoester (0,5 or 1 mmol). The vial was placed in the alloy plate which was then placed into the autoclave. Once sealed, the autoclave was purged 5 times with hydrogen, then pressurized to 30 bar and heated to desired temperature. Afterwards, the autoclave was cooled to RT, depressurized, and the reaction mixture was analyzed by GC-FID or HPLC as well as GC- MS. Product isolation was performed via column chromatography using silica gel as stationary phase and w-pentane / ethylacetate or w-pentane / acetone mixture as eluent.

Individual reaction conditions:

[a] 1 mol% cat., 0.5 mmol substrate, 30 bar, 3h, 30 °C, CH 2 C1 (1,5 mL)

[b] 3 mol cat., 0.5 mmol substrate, 30 bar, 3h, 70 °C, z ' PrOH (1,5 mL)

[c] 2 mol cat., 0.5 mmol substrate, 30 bar, 2h, 50 °C, EtOH (1,5 mL)

[d] 1 mol cat., 0.5 mmol substrate, 30 bar, 3h, 70 °C, z ' PrOH (1,5 mL)

[f] lmol cat., 1 mmol substrate, 30 bar, 22h, 40°C, n-heptane (1,5 mL)

[g] 1 mol cat., 1 mmol substrate, 30 bar, 3h, 30 °C, EtOH (2 mL)

[h] 1 mol cat., 1 mmol substrate, 30 bar, 6h, 30 °C, EtOH (2 mL)

[i] 1 mol cat., 1 mmol substrate, 30 bar, 6h, 60 °C, EtOH (2 mL)

j] 1 mol cat., 1 mmol substrate, 30 bar, 6h, 30°C, EtOH (2 mL)

[k] 3 mol cat., 1 mmol substrate, 30 bar, 3h, 70°C, THF (2 mL)

SP = side product (Hydrogenation of double bond) T le 2: