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Title:
CATALYTIC HYDROGENATION PROCESS
Document Type and Number:
WIPO Patent Application WO/2024/100405
Kind Code:
A1
Abstract:
The present invention relates to the field of catalytic hydrogenation and, more particularly, to methods of manganese-catalysed asymmetric hydrogenation of prochiral ketimine moieties to chiral amines.

Inventors:
CLARKE MATTHEW LEE (GB)
OATES CONOR (GB)
Application Number:
PCT/GB2023/052927
Publication Date:
May 16, 2024
Filing Date:
November 09, 2023
Export Citation:
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Assignee:
UNIV COURT UNIV ST ANDREWS (GB)
International Classes:
C07C209/02; B01J31/18; C07C209/52; C07C211/42; C07C211/45; C07C213/02; C07C217/84; C07F9/36
Domestic Patent References:
WO2009136409A22009-11-12
Foreign References:
US6822118B12004-11-23
US20050209487A12005-09-22
Other References:
K. GANGULI ET AL., DALTON TRANS., vol. 48, 2019, pages 7358
Z. WANG ET AL., CHINESE CHEMICAL LETTERS, vol. 31, 2020, pages 1890 - 1894
Y. WANG ET AL., J. AM. CHEM. SOC., vol. 141, 2019, pages 17337 - 17349
M.B. WIDEGREN ET AL., ANGEW. CHEM. INT. ED, vol. 56, 2017, pages 5825 - 5828
C. LIU ET AL., ANGEW. CHEM. INT. ED, vol. 60, 2021, pages 5108 - 5113
M. P. WIESENFELDT ET AL., ANGEW. CHEM. INT. ED. ENGL, vol. 58, no. 31, 2019, pages 10460 - 10476
A. LIMURO ET AL., ANGEW. CHEM. INT. ED, vol. 52, no. 7, 2013, pages 2046 - 2050
A. D. JENKINS ET AL.: "Pure & Appl. Chem.", vol. 68, 1996, IUPAC COMPENDIUM OF CHEMICAL TERMINOLOGY (GOLD BOOK, pages: 2287 - 2311
V VASILENKO ET AL., ANGEW. CHEM. INT. ED., vol. 56, 2017, pages 8393 - 8397
X MA ET AL., ACS OMEGA,, vol. 2, 2017, pages 4688 - 25 4692
NGUYEN ET AL.: "report on such an oxidation with an amino ligand to produce reduction catalysts", ACS CATAL., vol. 7, 2017, pages 2022 - 2032
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H NIE ET AL., TETRAHEDRON: ASYMMETRY., vol. 24, 2013, pages 1567 - 1571
ORGANOMETALLICS, vol. 33, 2014, pages 2109 - 2114
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HU BLASE ET AL., TOPICS IN CATALYSIS, vol. 19, no. 1, 2002, pages 3 - 16
C-J HOUX-P HU, ORG. LETT., vol. 18, 2016, pages 2938 - 2941
"Greene's Protective Groups in Organic Synthesis", 2014, WILEY
K. JAROWICKIP. KOCIENSKI, J. CHEM. SOC., PERKIN TRANS, vol. 1, 2000, pages 2495 - 2527
M. B. WIDEGREN ET AL., CAT. SCI. TECH, vol. 9, 2019, pages 6047
"CRC Handbook of Chemistry and Physics", 2010, article "Dissociation Constants of Organic Acids and Bases, and Dissociation Constants of Inorganic Acids and Bases"
TP SILVERSTEIN ET AL., J. CHEM. EDUC., vol. 94, no. 6, 2017, pages 690 - 695
M. B. WIDEGREN ET AL., ANGEW CHEM. INT. ED, vol. 56, 2017, pages 5825
C. L. OATES ET AL., ANGEW CHEM. INT. ED, 2022, pages e202212479
D. BRENNA ET AL., ORG. BIOMOL. CHEM, vol. 15, 2017, pages 5685
Attorney, Agent or Firm:
MARKS & CLERK LLP (GB)
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Claims:
CLAIMS 1. A method comprising hydrogenating a prochiral ketimine moiety in the presence of a chiral catalyst in enantiomeric excess, the catalyst comprising a charged or neutral complex of formula (I): wherein: Mn is a manganese atom or a manganese ion in oxidation state (I) to (VII); R1 and R2 are each independently C1-20hydrocarbyl or C2-10heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of aliphatic C1-6hydrocarbyl, C1-6alkoxy, halo, haloC1-6aliphatic hydrocarbyl, phenyl, C2-8heteroaryl, hydroxy, nitro, amino, C1-6alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, carbamido and sulfonamido; Fc denotes ferrocene (bis( ^5-cyclopentadienyl)iron) covalently bonded via adjacent carbon atoms of one of the two cyclopentadienyl moieties, and is optionally further substituted, in either cyclopentadienyl ring, with one or more substituents independently selected from the group consisting of aliphatic C1-6hydrocarbyl, C1- 6alkoxy, halo, haloC1-6aliphatic hydrocarbyl, phenyl, C2-8heteroaryl, hydroxy, nitro, amino, C1-6alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, carbamido and sulfonamido; Z is an alkylene linker of formula (CH2)1-6 optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, phenyl, C1- 6alkoxy, hydroxyl, C2-8heteroaryl, nitro, amino, alkylthio and thiol, wherein the phenyl of Z is optionally substituted with one or more substituents independently selected from the group consisting of aliphatic C1-6hydrocarbyl, halo, C1-6alkoxy, haloC1-6aliphatic hydrocarbyl; Nx is a nitrogen-containing C2-10hetercyclyl optionally substituted with one or more substituents independently selected from the group consisting of amino, aliphatic C1-6hydrocarbyl, C1-6alkoxy, hydroxy, amido, halo, haloC1-6aliphatic hydrocarbyl, phenyl, 55148442-1 C2-8heteroaryl, nitro, C1-6alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, carbamido and sulfonamido; and L1-L3 constitute one, two or three ligands in which each of L1-L3 independently represents a monodentate neutral or anionic ligand; or one of L1-L3 represents a monodentate neutral or anionic ligand and the other two of L1-L3 together represent a bidentate neutral or anionic ligand; or L1-L3 together represent a tridentate neutral or anionic ligand. 2. The method of claim 1 wherein the manganese ion is in oxidation state (I). 3. The method of claim 1 or claim 2, wherein R1 and R2 are each an optionally substituted moiety independently selected from the group consisting of phenyl, C3- 10cycloalkyl, and monocyclic C4-5heteroaryl. 4. The method of claim 1 or claim 2, wherein R1 and R2 are each an optionally substituted moiety independently selected from the group consisting of phenyl, cyclohexyl and furanyl. 5. The method of any one of claims 1 to 4, wherein R1 and R2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of aliphatic C1-6hydrocarbyl, C1-6alkoxy, halo, and haloC1-6aliphatic hydrocarbyl. 6. The method of any one of claims 1 to 4, wherein R1 and R2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halo, and trihalomethyl. 7. The method of claim 1 or claim 2, wherein R1 and R2 are each 4-methoxy-3,5- dimethylphenyl, phenyl, 4-methoxy-3,5-di-tert-butylphenyl, 3,5-dimethylphenyl, 3,5- di(tertbutyl)phenyl, furanyl or cyclohexyl. 8. The method of any one of claims 1 to 7, wherein neither cyclopentadienyl ring of the ferrocene moiety ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ connectivity with the remainder of the complex of formula (I). 55148442-1

9. The method of claim 1 or claim 2, wherein the R1R2P-Fc-CH(Me)-NH- component of the complex is (S)-1-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2- [(R)-1-(HN)ethyl]ferrocene, (R)-1-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2-[(S)- 1-(HN)ethyl]ferrocene or a mixture thereof; (S)-1-[(R)-1-(HN)ethyl]-2- (diphenylphosphino)ferrocene, (R)-1-[(S)-1-(HN)ethyl]-2-(diphenylphosphino)ferrocene or a mixture thereof; (S)-1-[bis(4-methoxy-3,5-di-tert-butylphenyl)phosphino]-2-[(R)-1- (HN)ethyl]ferrocene, (R)-1-[bis(4-methoxy-3,5-di-tert-butylphenyl)phosphino]-2-[(S)-1- (HN)ethyl]ferrocene or a mixture thereof; (S)-1-(difuranylphosphino)-2-[(R)-1- (HN)ethyl]ferrocene, (R)-1-(difuranylphosphino)-2-[(S)-1-(HN)ethyl]ferrocene or a mixture thereof; (S)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]-2-[(R)-1- (HN)ethyl]ferrocene, (R)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]-2-[(S)-1- (HN)ethyl]ferrocene or a mixture thereof; or (S)-1-(dicyclohexylphosphino)-2-[(R)-1- (HN)ethyl]ferrocene, (R)-1-(dicyclohexylphosphino)-2-[(S)-1-(HN)ethyl]ferrocene or a mixture thereof. 10. The method of any one of claims 1 to 9, wherein Z is CH2. 11. The method of any one of claims 1 to 10, wherein the one or more optional substituents of Nx are independently selected from the group consisting of amino, C1- 6alkyl, C1-6alkoxy, hydroxy and amido. 12. The method of any one of claims 1 to 11, wherein Nx is any one optionally substituted nitrogen-containing C2-10hetercyclyl selected from the group consisting of pyridyl, quinolinyl, isoquinolinyl, pyrimidinyl, quinoxalinyl, pyridazinyl and triazinyl. 13. The method of any one of claims 1 to 11, wherein Nx is an optionally substituted monocyclic nitrogen-containing C2-10heteroaryl. 14. The method of any one of claims 1 to 10, wherein Nx is a pyridyl ring optionally substituted one or more times with an amino substituent. 15. The method of any one of claims 1 to 10, wherein Nx is a pyridyl, a 6- dimethylamino pyridyl or a 4-dimethylamino pyridyl, which is bonded to Z at the 2- position. 55148442-1

16. The method of any one of claims 1 to 15, wherein each of the one, two or three ligands L1-L3 is selected from the group consisting of: (i) neutral ligands selected from the group consisting of carbon monoxide, nitrogen monoxide, amines, ethers, thioethers, sulfoxides, nitriles (RCN), isocyanide (RNC), phosphorus-containing ligands based on either phosphorus (III) or phosphorus (V) and water; and (ii) anionic ligands selected from the group consisting of halides, alkoxides, anions of carboxylic, sulfonic and phosphoric acids, amido ligands, thiolates, phosphides, cyanide, thiocyanate, isothiocyanate and enolate ions. 17. The method of any one of claims 1 to 16 wherein, when the complex of formula (I) is charged, the catalyst comprises one or more additional counterions selected from the group consisting of halides, tetraarylborates, SbF6-, SbCl6-, AsF6-, BF4-, PF6-, ClO4- and CF3SO3-. 18. The method of claim 1, wherein the catalyst is selected from the group consisting of formulae (Ia) to (If): 55148442-1 (Ie) (If). The method of any one of claims 1 to 18, wherein when R1 and/or R2 are substituted, Nx is unsubstituted. 20. The method of any one of claims 1 to 19, wherein the catalyst has an enantiomeric excess of about 50 to about 100%. 21. The method of any one of claims 1 to 20, wherein the method comprises contacting a R1R2P-Fc-CH(Me)-NH-Z-Nx ligand with a manganese salt. 22. The method of any one of claims 1 to 21, wherein the ketimine moiety is acyclic or exocyclic. 23. The method of any one of claims 1 to 22, wherein the nitrogen atom of the ketimine moiety is bonded to any one of the groups consisting of optionally substituted aryl, phosphinyl oxide, optionally substituted heteroaryl, optionally substituted arylC1- 6alkyl, optionally substituted C1-6alkyl, sulfonyl, carbamyl, acyl and ester. 24. The method of any one of claims 1 to 22, wherein the ketimine is formed in situ. 25. The method of claim 24, comprising contacting a ketone with an optionally substituted primary aromatic amine, an optionally substituted primary benzylic amine, or an optionally substituted primary heteroaromatic amine. 26. The method of any one of claims 1 to 25, wherein the method is carried out in the presence of a base. 27. The method of any one of claims 1 to 26, wherein the method is carried out in the presence of hydrogen gas. 55148442-1

Description:
PROCESS TECHNICAL FIELD OF THE INVENTION The present invention relates to the field of catalytic hydrogenation and, more particularly, to methods of manganese-catalysed asymmetric hydrogenation of prochiral ketimine moieties to chiral amines. BACKGROUND OF THE INVENTION Amines are fundamental chemical building blocks, and are used in the production of pharmaceuticals, pesticides, polymers and dyes. Chiral amines may be synthesised from prochiral imines, and a number of industrial processes implement this. However, such processes make use of scarce precious metals like iridium (see US 6,822,118 B1, Syngenta Crop Protection, Inc.) and ruthenium (US 2005/0209487 A1, Kamaluddin Abdur-Rashid), which are more ecologically problematic to mine than earth-abundant metals. In addition, due to their scarcity, such precious metals are considered unsustainable resources. Also, owing to toxicity concerns, traces of iridium and ruthenium metals are tightly regulated as by-products in Active Pharmaceutical Ingredients (APIs) to just 5 ppm or less, and it can be energetically demanding and costly to remove these metals from the APIs. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ture applications of precious metals like iridium and ruthenium in hydrogenation reactions. The development of replacement earth abundant and less toxic transition metal catalysts is desirable. Manganese is the third most abundant transition metal in the ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ is cheap, relatively safe and diverse in oxidation states. Accordingly, manganese has been identified as a potential replacement of precious metals. Manganese complexes comprising bidentate and tridentate ligands containing benzimidazole and secondary amine moieties are described by K. Ganguli et al. in Dalton Trans., 2019, 48, 7358 as catalysts for the transfer hydrogenation of aldimines ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^-propanol as the hydrogen source. It was found that the benzimidazole and secondary amine N ^H protons played a vital role in the enhancement of the catalytic activity. Simple manganese complexes of formula [Mn2(CO)10] or [MnBr(CO)5] are described by Z. Wang et al. in Chinese Chemical Letters 31 (2020) 1890 ^1894 as catalysts for the hydrogenation of quinolines and imines. It was found that additional ligands were not required for efficient catalysis. In fact, the addition of phosphine 55148442-1 ligands drastically lowered the efficiency of the reaction ^ in some cases leading to no measurable reaction. NNP- and PNP-manganese pincer complexes are compared by Y. Wang et al. in J. Am. Chem. Soc. 2019, 141, 17337-17349 for their ability to catalyse the hydrogenation of quinolines and other N-heterocycles. The NNP-manganese complexes were found to be consistently more active than the PNP-manganese pincer complexes. In respect of asymmetric hydrogenation, the use of chiral pincer manganese catalysts for asymmetric hydrogenation of ketones is described by M.B. Widegren et al. in Angew. Chem. Int. Ed.56 (2017) 5825 ^5828. C. Liu et al. in Angew. Chem. Int. Ed. 2021, 60, 5108 ^5113 describe manganese-catalysed asymmetric hydrogenation of quinolines using manganese complexed to a chiral NNP-tridentate ligand comprising an imidazole and a secondary amine moiety. Similarly to the findings of K. Ganguli et al. (2019, supra), C. Liu et al. found that the benzimidazole and amine N ^H protons played a vital role in the enhancement of the catalytic activity. M. P. Wiesenfeldt et al. in Angew. Chem. Int. Ed. Engl. 2019, 58, 31, 10460- 10476 describe selective heteroarene hydrogenation. Heteroarenes differ from ketimines in that (unlike in ketimine moieties) the C=N moieties within heteroarenes are part of an aromatic ring, stabilised by delocalisation across a ring of p orbitals. Consequently, the properties and reactivities of heteroarenes are expected to differ from ketimines. Indeed, M. P. Wiesenfeldt et al. describe the hydrogenation of heteroarenes to be hindered with respect to that of imines by the added kinetic barrier resulting from the aromatic stabilisation energy. A. Limuro et al. in Angew. Chem. Int. Ed.2013, 52, 7, 2046-2050 describe the asymmetric hydrogenation of isoquinolinium salts catalysed by chiral iridium catalysts. However, there is no mention of the same catalytic system being used to hydrogenate ketimines and the same catalytic system is shown to be unsuccessful in hydrogenating ketones. Owing to the difference in properties and reactivities, the hydrogenation of heteroaromatic compounds containing one or more aromatic C=N bonds is considered separately in the art from the hydrogenation of ketimines, and it is difficult to make predictions as to which catalysts may be suitable as imine hydrogenation catalysts. There is a need in the art for alternative catalysts for the asymmetric hydrogenation of prochiral ketimine moieties to chiral amines, in particular alternative 55148442-1 catalysts that make use of earth abundant and less toxic transition metal catalysts such as manganese. SUMMARY OF THE INVENTION The present invention is based on the unexpected finding that the chiral manganese-based catalysts described herein are able to hydrogenate prochiral ketimine moieties to chiral amines, which may be produced in high yield and with a high enantiomeric excess (ee). The inventors have demonstrated successful asymmetric hydrogenation of a variety of ketimines at low temperature. The inventors have also found that, in certain cases, the ketimines comprising prochiral ketimine moieties can be made in situ by contacting a ketone with an optionally substituted primary aromatic amine or an optionally substituted primary alkyl amine, without needing to be isolated and purified. The chiral manganese-based catalysts described herein may also be made in situ by contacting a ligand of formula R 1 R 2 P-F c -CH(Me)- NH-Z-N x (defined infra) with a manganese salt. Viewed from a first aspect, the invention provides a method comprising hydrogenating a prochiral ketimine moiety in the presence of a chiral catalyst in enantiomeric excess, the catalyst comprising a charged or neutral complex of formula (I): wherein: Mn is a manganese atom or a manganese ion in oxidation state (I) to (VII); R 1 and R 2 are each independently C 1-20 hydrocarbyl or C 2-10 heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of aliphatic C 1-6 hydrocarbyl, C 1-6 alkoxy, halo, haloC 1-6 aliphatic hydrocarbyl, phenyl, C 2-8 heteroaryl, hydroxy, nitro, amino, C 1-6 alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, carbamido and sulfonamido; Fc denotes ferrocene (bis ^ ^ 5 -cyclopentadienyl)iron) covalently bonded via adjacent carbon atoms of one of the two cyclopentadienyl moieties, and is optionally 55148442-1 further substituted, in either cyclopentadienyl ring, with one or more substituents independently selected from the group consisting of aliphatic C1-6hydrocarbyl, C1- 6alkoxy, halo, haloC1-6aliphatic hydrocarbyl, phenyl, C2-8heteroaryl, hydroxy, nitro, amino, C1-6alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, carbamido and sulfonamido; Z is an alkylene linker of formula (CH 2 ) 1-6 optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, phenyl, C 1- 6 alkoxy, hydroxyl, C 2-8 heteroaryl, nitro, amino, alkylthio and thiol, wherein the phenyl of Z is optionally substituted with one or more substituents independently selected from the group consisting of aliphatic C 1-6 hydrocarbyl, halo, C 1-6 alkoxy, haloC 1-6 aliphatic hydrocarbyl; N x is a nitrogen-containing C 2-10 hetercyclyl optionally substituted with one or more substituents independently selected from the group consisting of amino, aliphatic C 1-6 hydrocarbyl, C 1-6 alkoxy, hydroxy, amido, halo, haloC 1-6 aliphatic hydrocarbyl, phenyl, C 2-8 heteroaryl, nitro, C 1-6 alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, carbamido and sulfonamido; and L 1 -L 3 constitute one, two or three ligands in which each of L 1 -L 3 independently represents a monodentate neutral or anionic ligand; or one of L 1 -L 3 represents a monodentate neutral or anionic ligand and the other two of L 1 -L 3 together represent a bidentate neutral or anionic ligand; or L 1 -L 3 together represent a tridentate neutral or anionic ligand. Further aspects and embodiments of the present invention will become apparent from the detailed discussion of the invention that follows below. DETAILED DESCRIPTION OF THE INVENTION As described above, the inventors have found that the chiral manganese-based catalysts described herein are unexpectedly able to hydrogenate prochiral ketimine moieties to chiral amines, which may be produced in high yield and with a high ee. In the discussion that follows, reference is made to a number of terms, which are to be understood to have the meanings provided below, unless a context indicates to the contrary. The nomenclature used herein for defining compounds, in particular the compounds described herein, is intended to be in accordance with the rules of the International Union of Pure and Applied Chemistry (IUPAC) for chemical compounds, ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ Jenkins et al., Pure & Appl. Chem., 68, 2287-2311 (1996)). For the avoidance of doubt, 55148442-1 if an IUPAC rule is contrary to a definition provided herein, the definition herein is to prevail. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ inclusion of a stated element, integer or step, or group of elements, integers or steps, and the exclusion of any other element, integer or step or group of elements, integers or steps. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ values that lie, where possible, within ± 5% of the value specified. For example, if the chiral catalyst of the invention is defined as having an enantiomeric excess of about 50% to about 100%, enantiomeric excesses of 47.5% to 100% are included. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ spatial arrangement of points or atoms within the molecule are not superpos ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ mirror image. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ spatial arrangement of points ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ mirror image. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ to the points or atoms within a ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ centre comprises a point or an atom in a spatial arrangement that is not superposable on its mirror image. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^in in respect of ketimine moieties and is used to refer to a ketimine moiety that contains an achiral trigonal system, which can be made into a centre of chirality by the addition to the system of a new atom or achiral group (such as a hydrogen atom). For example, addition of hydrogen to one of the enantiotopic faces of the prochiral ketimine CH3CH2C(=N(C6H5))CH3 gives one of the enantiomers of the chiral amine CH3CH2CH(NH(C6H5))CH3. For the avoidance of doubt, the ketimine molecule that is hydrogenated in accordance with the present invention may be chiral (the ketimine moiety of the chiral ketimine being prochiral). Addition of hydrogen to prochiral ketimine moieties of chiral ketimines may produce diastereomeric amines. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ imine of structure R a R b C=NR c , where R a and R b ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ the portion of the ketimine within the wavy bonds indicated below: 55148442-1 . Where a ketimine moiety is prochiral, R a and R b are different, i.e. have different chemical structures. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ of a ring. For the avoidance of doubt, acyclic ketimine moieties may be part of ketimines that comprise one or more cyclic moieties, provided that the ketimine moiety of the acyclic ketimine does not form part of the one or more rings. Examples of such ketimines include P,P-diphenyl-N-[(1Z)-1-phenylethylidene]phosphinic amide and N-(1- phenylethylidene)aniline. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ring, wherein the =N of the ketimine moiety lies outside the ring structure. Examples of ketimines comprising exocyclic ketimine moieties include 1-phenylimino-indane, (1E)- N-Benzyl-1-indanimine, (1E)-N-(4-Methoxyphenyl)-1-indanimine and N-[(1E)-2,3- dihydro-1H-inden-1-ylidene]-P,P-diphenylphosphinic amide. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ hydrocarbon by the removal of a hydrogen atom from the hydrocarbon. A hydrocarbon is any molecule comprising only the elements carbon and hydrogen. Hydrocarbons may be aliphatic, aromatic, unsaturated or saturated. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ heterocycle. A heterocycle is a cyclic compound (a compound comprising one or more rings of connected atoms) having as ring members atoms of at least two different elements (such as carbon and nitrogen). ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^cyclic or cyclic, saturated or unsaturated compounds, excluding aromatic compounds, where ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ conjugated molecular entity with a stability (due to delocalisation) significantly greater than that of a hypothetical localised structure. The Hückel rule is often used in the art to assess aromatic character; monocyclic planar (or almost planar) systems of trigonally ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^-electrons (where n is a non-negative integer) will exhibit aromatic character. The rule is generally limited to n = 0 to 5. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ monovalent groups derived from alcohols or thiols respectively by removal of the 55148442-1 hydrogen atom bonded to the hydroxy or thio group. The te ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ define groups derived from alkanes, in which one hydrogen atom has been replaced with a hydroxy or thio group. Methoxy is an example of a C1alkoxy group and methylthio is an example of a C1alkylthio group. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ hydrogen atom has been replaced with a halo atom, such as fluoro, chloro or bromo, often fluoro. Trifluoromethyl is an example of a halohydrocarbyl. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ed on removing a hydrogen ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ aromatic hydrocarbons. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ hydrogen atom from a heteroarene ring atom such as carbon or nitrogen. The term ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ or more methine ( ^C=) and/or vinylene ( ^CH=CH ^) groups by trivalent or divalent heteroatoms, respectively, in such a way as to maintain the cont ^ ^ ^ ^ ^ ^ ^-electron system characteristic of aromatic systems. Typically, the heteroaryl groups herein comprise any one or a combination of heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms. Examples of heteroaryl groups include pyridyl, quinolinyl, isoquinolinyl, pyrimidinyl, quinoxalinyl, pyridazinyl, triazinyl, oxazolyl, isooxazolyl, pyrazolyl, triazolyl and oxadiazolyl. For example, a heteroaryl may be a pyridyl, quinolinyl, isoquinolinyl, pyrimidinyl, quinoxalinyl, pyridazinyl or a triazinyl. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^N(R) 2 , wherein each R is independently selected from the group consisting of hydrogen, C1-6hydrocarbyl and C2-8heteroaryl, or both R moieties together form an alkylene diradical, derived formally from an alkane from which two hydrogen atoms have been abstracted, typically from terminal carbon atoms, whereby to form a ring together with the nitrogen atom of the amino. Sometimes, the alkylene (and the alkane from which the alkylene may be regarded as formally derived) is interrupted with one or more heteroatoms, typically O, N or S, more typically O or N, most typically one of O or N. Where interrupted by N, the alkylene comprises a moiety - ^ ^ ^-, in which R is H or C1-6hydrocarbyl. The C1-6hydrocarbyl and C2-8heteroaryl of R and C1-6 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ substituted with one or more substituents independently selected from the group consisting of halo, C1-4hydrocarbyl, haloC1-4hydrocarbyl, hydroxy, C1-6alkoxy, phenyl, and C2-8heteroaryl. Often, the optional substituents are selected from the group consisting of halo, C1-4hydrocarbyl and haloC1-4hydrocarbyl. Typically, where both R 55148442-1 moieties together form an alkylene diradical to form a ring together with the nitrogen atom of the amino, the amino is piperidinyl or morpholino. Typically, amino herein denotes -N(R) 2, wherein each R independently denotes hydrogen or C1-6hydrocarbyl. Often, amino denotes -NH2, or simple monoalkyl or dialkylamino moieties (for example the dialkylamino moiety dimethylamino ( ^N(CH3)2)). References to amino herein are also to be understood as embracing within their ambit quaternised or protonated derivatives of the amines resultant from compounds comprising such amino groups. Examples of the latter may be understood to be salts such as hydrochloride salts. Where an amine or amino group is referred to as a primary amine or amino, the nitrogen atom of the amine or amino group is bonded to one non-hydrogen moiety. Where an amine or amino group is referred to as a secondary amine or amino group, the nitrogen atom of the amine or amino is bonded to two non-hydrogen moieties. Where an amine or amino group is referred to as a tertiary amine or amino group, the nitrogen atom of the amine or amino is not bonded to three non-hydrogen moieties. By carboxylate, sulfonate and phosphate are meant herein the functional groups -CO 2 -, -SO 3 - and -PO 4 2- respectively, which may be in their protonated forms. By formyl is meant a group of formula ^C(H)O. By ester is meant a functional group comprising the moiety -OC(=O)-. In some cases, ester refers to a ^C(O)OR moiety, wherein R is a hydrocarbyl (such as a C 1-6 alkyl (such as tert-butyl) an aryl (such as phenyl), a C 3-6 cycloalkyl group or an arylC 1-6 alkyl (such as benzyl or 9-fluorenylmethyl)) optionally substituted with one or more substituents selected from the group consisting of halo, C1-4alkyl, phenyl and C2-5heteroaryl. In some cases, R is C1-6alkyl (such as methyl) or C1-6haloalkyl (such as trifluoromethyl). By acyl is meant the functional group of formula ^C(O)R, wherein R is as hereinbefore defined for ester. Analogously, thioacyl denotes a functional group of the formula -C(O)R, wherein R is as hereinbefore defined for ester. By carbamido is meant herein a functional group, either of formula -NHCOR or of formula -CONHR, wherein R is as hereinbefore defined for ester. Analogously, sulfonamido denotes a functional group, either of formula ^NHSO2R, or of formula -SO2NHR, wherein R is as hereinbefore defined for ester. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ from alkanes by removal of a hydrogen atom from any carbon atom, wherein the term ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^rocarbons having the 55148442-1 general formula CnH2n+2 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ cycloalkanes ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ defines saturated monocyclic unbranched hydrocarbons, having the general formula C n H 2n ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 3-6 cycloalkyl refers to any one selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ has been replaced with a halo atom, such as fluoro, chloro or bromo, often fluoro. Trifluoromethyl is an example of a trihaloalkyl. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ defines bivalent groups derived from alkanes by removal of two hydrogen atoms from any carbon atoms (including the removal of two hydrogen atoms from the same carbon atom). In some cases, the alkylene is a C 2-4 alkylene, which refers to any one selected from the group consisting of ethylene, n-propylene, iso-propylene, n-butylene, sec- butylene, iso-butylene and tert-butylene. Where a ligand is stated to be monodentate, it is capable of coordinating (i.e. to the manganese centre) through one donor site. Where a ligand is bidentate, it is capable of coordinating through two discrete donor sites, and where a ligand is tridentate, it is capable of coordinating through three discrete donor sites. The oxidation state of an atom (such as a manganese atom) is the charge of the atom after ionic approximation of its heteronuclear bonds. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^P(O)R2, where R is as hereinbefore defined for ester. Examples of phosphinyl oxides include ^P(O)(C6H5)2 and -P(O)(CH3)2. Often, R is an optionally substituted phenyl, such as ^P(O)(C6H5)2. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^SO2R, where R is as hereinbefore defined for ester. For example, R may be an optionally substituted phenyl. Examples of sulfonyls include ^SO2(p-tolyl) and ^SO2Ph. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^C(O)NH2. ^ ^ ^in situ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ture. Where a species is described ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^in situ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ isolated from the mixture before it is modified (e.g. by further reaction). It is generally advantageous to form a species in situ (if possible), since this avoids the costs associated with isolating and purifying the species. 55148442-1 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ identical molecular formulae and sequence of bonded atoms, but which differ in the arrangement of their atoms in space. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ images of each other and non-superimposable, i.e. cannot be brought into coincidence by translation and rigid rotation transformations. Enantiomers are chiral molecules, i.e. are distinguishable from their mirror image. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ enantiomeric purity of a sample. It is the absolute difference between the mole fractions of each enantiomer, converted into a percentage by multiplying by 100. For example, where a sample is racemic, it has an enantiomeric excess of 0%. Where a sample contains only one enantiomer, it has an enantiomer excess of 100%. Where a sample contains 80% of one enantiomer and 20% of the other enantiomer, it has an enantiomeric excess of 60% (80%-20%). ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ racemate defines a substantially equimolar mixture (about 50% of one enantiomer and about 50% of the other enantiomer) of a pair of enantiomers. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ stereoisomers that are not related as mirror images. The catalyst used in accordance with the invention is characterised by comprising a complex of formula (I), as described herein. The nature of the complex is discussed in detail below. Although (without wishing to be bound by theory) the catalytic species that constitutes the starting point of the catalytic hydrogenation reaction may be one comprising a manganese ion in a specific oxidation state (such as oxidation state (I)), it is well known in the field of transition metal catalysis that initial pre-catalysts may be presented with a transition metal centre in a variety of oxidation states and bound to a variety of different ligands. These may be converted, with appropriate oxidation or reduction of the transition metal (here a manganese) atom or ion to a catalytically active species during the course of the reaction being catalysed, i.e. with any necessary oxidation or reduction of the manganese centre. Appropriate oxidation or reduction of the manganese atom or ion may be achieved, for example, with a suitable reducing or oxidising agent, or reactive ligand. Two examples of the uses of manganese (II) pre-catalysts in which the manganese is present in oxidation state (II), different to that of the active catalytic 55148442-1 species, are described by V Vasilenko et al. (Angew. Chem. Int. Ed., 56, 8393-8397 (2017)) in connection with the hydroboration of ketones and X Ma et al. (ACS Omega, 2, 4688-254692 (2017)) in connection with the hydrosilylation of aryl ketones. Moreover, it is well known that manganese (0) species such as Mn2(CO)10 undergo oxidation to the desired Mn species. Indeed, Nguyen et al. report on such an oxidation with an amino ligand to produce reduction catalysts (ACS Catal., 7, 2022- 2032 (2017)). Z. Wang et al. (2020, supra) also report the use of Mn 2 (CO) 10 pre- catalysts, which react with hydrogen to produce active MnH(CO) 5 catalysts (in which manganese has an oxidation state of (I)) for the reduction of quinolines and imines. While there is no necessity to employ a higher oxidation state Mn precursor, reduction of high oxidation state manganese (e.g. in the context of oxidation reagents) to Mn(II) is well known. Even simple alkoxide salts can reduce higher valent metal salts to the desired low valent species, see JH Docherty et al. (Nature Chemistry, 9, 595-600 (2017)). Accordingly, with the appropriate reducing agents, manganese-containing compounds in oxidation states > (II) may be expected to be of use in conjunction with the present invention. In other words and/or for these reasons, the complex of formula (I) need not itself be an active catalytic species. It may instead act as a pre-catalyst and form one or more active catalytic species in situ, e.g by undergoing ligand exchange and/or by oxidising or reducing the manganese. Accordingly, the complex of formula (I) may comprise a manganese ion in oxidation state (I) to (VII), often a manganese ion in oxidation state (I) or (II), and very often a manganese ion in oxidation state (I). In addition, the complex of formula (I) need not be isolated before its use in the method of the invention. It may rather form in situ, for example by contacting a R 1 R 2 P- Fc-CH(Me)-NH-Z-N x ligand with a manganese salt, such as the commercially available manganese (I) salt bromopentacarbonylmanganese (I) (Mn(CO)5Br). Whilst this salt is particularly convenient, it will be understood that other commercially available (for example manganese (0) carbonyl (Mn2(CO)10)) or readily accessible manganese compounds may also be used to prepare complexes for use in the method of the invention. As is evident from the structure of the complex of formula (I), R 1 and R 2 are substituents of the phosphine moiety within the tridentate ligand of formula R 1 R 2 P-Fc- CH(Me)-NH-Z-N x within the complex of formula (I). As will be understood by those skilled in the art, there is generally the possibility to significantly vary within such ligands, inter alia, the substituents R 1 and R 2 of such phosphino moieties. Routine 55148442-1 variation of these, for example through variation in steric bulk around and/or electronic influences upon the phosphorus atoms of such phosphino moieties, allows the skilled person to optimise such ligands in catalysts and complexes comprising these for any given reaction. For example, the R 1 and R 2 ligands may be aliphatic or aromatic (or heteroaromatic) with significant substitution possible, without disrupting the function of catalysts comprising such moieties in their role as hydrogenation catalysts. Moreover, there exists a large variety of commercially available or otherwise easily accessible phosphorus-containing reagents from which R 1 - and R 2 -containing ligands may be prepared. Still further, it has been demonstrated in the art both that a variety of relevant ligands can be made and that complexes comprising these (including ferrocene-based PNN tridentate ligands of the formula R 1 R 2 P-Fc-CH(Me)-NH-Z-N x defined in formula (I) herein) may be used in the context of catalytic hydrogenation reactions. For example, H Nie et al. (Tetrahedron: Asymmetry., 24, 1567-1571 (2013) and Organometallics, 33, 2109-2114 (2014)) describe variation in the substitution of phenyl groups within the terminal diphenylphosphino moieties of such ligands, e.g. with a variety of alkyl substitution. When constructing diphenylphosphino-substituted ferrocenes, Nie et al. describe introduction of the diphenylphosphino moiety via selective lithiation ortho to a substituent corresponding to the -C(CH 3 )N-fragment within the tridentate ligand of formula R 1 R 2 P-Fc-CH(Me)-NH-Z-N x , within the complex of formula (I) defined herein, followed by treatment with a variety of chlorodiaryphosphines. In view of the huge variety of analogous electrophilic chlorophosphines that are available to the skilled person, it is well within his routine ability to prepare related ligands having other substituents on the phosphorus atom, for example optionally substituted aliphatic, heteroaryl and other aryl R 1 and R 2 moieties, for example to allow access to dialkylphosphino-containing ligands such as diethylphosphino-and ditert- butylphosphino-. As detailed in the experimental section, the inventors have synthesised a ligand of formula R 1 R 2 P-Fc-CH(Me)-NH-Z-N x in which ZN x is 2-pyridylmethyl by reaction between a N,N-dimethyl-1-ethylamino-substituted ferrocene in the presence of acetic anhydride and 2-picolylamine (2-aminomethylpyridine). The inventors have also synthesised such a ligand where ZN x is 4-dimethylaminopyridin-2-ylmethyl or 2- dimethylaminopyridin-6-ylmethyl by reaction between a 1-ethylamino-substituted 55148442-1 ferrocene with 4-dimethylamino-2-formylpyridine or 2-dimethylamino-6-formylpyridine in the presence of sodium borohydride. Furthermore, as an example to illustrate the accessibility of complexes of formula (I), we note that the commercial availability of alternatively substituted ferrocenes, sold under the trade name PFA from Solvias AG, Switzerland, makes straightforward the synthesis of alternative R 1 - and R 2 -substituted ligands of formula R 1 R 2 P-Fc-CH(Me)-NH-Z-N x by substitution of a different commercially available ferrocene to (S)-1-[Bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2-[(R)-1- (DMA)ethyl]ferrocene or ((R)-1-[(S)-1-(dimethylamino)ethyl]-2-(diphenylphosphino) ferrocene), the use of which is described herein. In particular, the following ferrocenes are commercially available from Solvias, in which DMA denotes dimethylamino (see https://www.solvias.com/docs/download/en/000_Brochures_amp_F lyers/Ligands_and_ Catalysts_Catalogue.pdf): ^ (S)-1-[(R)-1-(DMA)ethyl]-2-(diphenylphosphino)ferrocene; ^ (R)-1-[(S)-1-(DMA)ethyl]-2-(diphenylphosphino)ferrocene; ^ (S)-1-[Bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2-[(R)-1- (DMA)ethyl]ferrocene ^ (R)-1-[Bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2-[(S)-1- (DMA)ethyl]ferrocene; ^ (S)-1-(Difuranylphosphino)-2-[(R)-1-(DMA)ethyl]ferrocene; ^ (R)-1-(Difuranylphosphino)-2-[(S)-1-(DMA)ethyl]ferrocene; ^ (S)-1-[Bis[3,5-bis(trifluoromethyl)phenyl]phosphino]-2-[(R)- 1- (DMA)ethyl]ferrocene; ^ (R)-1-[Bis[3,5-bis(trifluoromethyl)phenyl]phosphino]-2-[(S)- 1- (DMA)ethyl]ferrocene; ^ (S)-1-(Dicyclohexylphosphino)-2-[(R)-1-(DMA)ethyl]ferrocene; and ^ (R)-1-(Dicyclohexylphosphino)-2-[(S)-1-(DMA)ethyl]ferrocene. These may be used to provide a complex for use in accordance with the present invention in which the R 1 R 2 P-Fc-CH(Me)-NH- moiety of the complex of formula (I) is: ^ (S)-1-[(R)-1-(HN)ethyl]-2-(diphenylphosphino)ferrocene; ^ (R)-1-[(S)-1-(HN)ethyl]-2-(diphenylphosphino)ferrocene; ^ (S)-1-[Bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2-[(R)-1- (HN)ethyl]ferrocene; 55148442-1 ^ (R)-1-[Bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2-[(S)-1- (HN)ethyl]ferrocene; ^ (S)-1-(Difuranylphosphino)-2-[(R)-1-(HN)ethyl]ferrocene; ^ (R)-1-(Difuranylphosphino)-2-[(S)-1-(HN)ethyl]ferrocene; ^ (S)-1-[Bis[3,5-bis(trifluoromethyl)phenyl]phosphino]-2-[(R)- 1- (HN)ethyl]ferrocene; ^ (R)-1-[Bis[3,5-bis(trifluoromethyl)phenyl]phosphino]-2-[(S)- 1- (HN)ethyl]ferrocene; ^ (S)-1-(Dicyclohexylphosphino)-2-[(R)-1-(HN)ethyl]ferrocene; or ^ (R)-1-(Dicyclohexylphosphino)-2-[(S)-1-(HN)ethyl]ferrocene, i.e. in which the dimethylamino (DMA) moiety is replaced with the NH moiety within the tridentate ligands of formula R 1 R 2 P-Fc-CH(Me)-NH-Z-N x described herein. A wide range of R 1 and R 2 moieties are both accessible synthetically, and useful in accordance with the hydrogenation of the present invention. Thus, R 1 and R 2 are each independently C 1-20 hydrocarbyl or C 2-10 heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of aliphatic C 1-6 hydrocarbyl, C 1-6 alkoxy, halo, haloC 1-6 aliphatic hydrocarbyl, phenyl, C 2-8 heteroaryl, hydroxy, nitro, amino, C1-6alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, carbamido and sulfonamido. Often, the optionally substituted C 1-20 hydrocarbyl is a C 1-18 hydrocarbyl, a C 1- 16 hydrocarbyl, a C 1-14 hydrocarbyl, a C 1-12 hydrocarbyl or a C 1-10 hydrocarbyl. For example, the optionally substituted C 1-20 hydrocarbyl may be a C 1-10 hydrocarbyl. The optionally substituted C 1-20 hydrocarbyl may be aliphatic or aromatic. In some cases, the optionally substituted C 1-20 hydrocarbyl is cyclic, such as an optionally substituted phenyl or an optionally substituted C 3-10 cycloalkyl. Sometimes, the C 1- 20 hydrocarbyl is any one optionally substituted moiety selected from the group consisting of phenyl, cyclohexyl and cyclopentyl, such as optionally substituted phenyl or optionally substituted cyclohexyl. Sometimes, the optionally substituted C 2-10 heterocyclyl is an optionally substituted monocyclic C2-10heterocyclyl, typically an optionally substituted monocyclic C2-10heteroaryl. Often, the optionally substituted C2-10heterocyclyl comprises one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. For example, the optionally substituted C2-10heterocyclyl may be an optionally substituted monocyclic C2-10heteroaryl comprising one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur (such as oxygen). 55148442-1 In some cases, the optionally substituted C2-10heterocyclyl is an optionally substituted monocyclic C4-5heteroaryl comprising one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur (such as oxygen). Examples of such groups include furanyl, thiophenyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl. Sometimes, the optionally substituted C 2-10 heterocyclyl is any one optionally substituted moiety selected from the group consisting of a furanyl, thiophenyl and pyrrolyl, such as a furanyl. In some embodiments, R 1 and R 2 are each an optionally substituted moiety independently selected from the group consisting of C 1-10 hydrocarbyl and monocyclic C 2-10 heterocyclyl. In more specific embodiments, R 1 and R 2 are each an optionally substituted moiety independently selected from the group consisting of phenyl, C 3-10 cycloalkyl, and monocyclic C 4-5 heteroaryl. In even more specific embodiments, R 1 and R 2 are each an optionally substituted moiety independently selected from the group consisting of phenyl, cyclohexyl and furanyl, such as an optionally substituted phenyl. In some cases, R 1 and R 2 are each optionally substituted aromatic moieties, such as optionally substituted phenyl or optionally substituted furanyl. As described above, R 1 and R 2 may each be optionally substituted with one or more substituents independently selected from the group consisting of aliphatic C 1- 6 hydrocarbyl, C 1-6 alkoxy, halo, haloC 1-6 aliphatic hydrocarbyl, phenyl, C 2-8 heteroaryl, hydroxy, nitro, amino, C 1-6 alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, carbamido and sulfonamido. In some embodiments, R 1 and R 2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of aliphatic C1-6hydrocarbyl, C1-6alkoxy, halo, and haloC1-6aliphatic hydrocarbyl. The aliphatic C1-6hydrocarbyl may be a C1-6alkyl, C2-6alkenyl or a C2-6alkynyl, wherein the alkenyl and alkynyl may have any number of double or triple bonds, but typically comprise one double or one triple bond. Typically, the aliphatic C1- 6hydrocarbyl is a C1-6alkyl, such as a C1-4alkyl (e.g. methyl). The C1-6alkoxy may be a C1-4alkoxy such as methoxy. The halo may be any one or a combination selected from fluoro, chloro, bromo or iodo. Typically the halo is fluoro. 55148442-1 The haloC1-6aliphatic hydrocarbyl may be a haloC1-6alkyl, haloC2-6alkenyl or a haloC2-6alkynyl, wherein the haloalkenyl and haloalkynyl may have any number of double or triple bonds, but typically comprise one double or one triple bond. Typically, the haloC1-6aliphatic hydrocarbyl is a haloC1-6alkyl, such as a haloC1-4alkyl (e.g. halomethyl). The haloC1-6aliphatic hydrocarbyl may comprise one or more halo moieties selected from fluoro, chloro, bromo or iodo. Typically, the haloC 1-6 aliphatic hydrocarbyl is a fluoroC 1-6 aliphatic hydrocarbyl such as trifluoromethyl. In some embodiments, R 1 and R 2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halo, and trihalomethyl. In particular embodiments, R 1 and R 2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl and C 1-6 alkoxy. In yet more particular embodiments, R 1 and R 2 are each 4-methoxy-3,5- dimethylphenyl, phenyl, 4-methoxy-3,5-di-tert-butylphenyl, 3,5-dimethylphenyl, 3,5- di(tertbutyl)phenyl, furanyl or cyclohexyl, such as 4-methoxy-3,5-dimethylphenyl, phenyl, 4-methoxy-3,5-di-tert-butylphenyl and 3,5-dimethylphenyl. In some cases, are each 4-methoxy-3,5-dimethylphenyl or phenyl. According to these and other R 1 and R 2 moieties, both R 1 and R 2 will generally, but not necessarily, be the same moiety. Analogously to the flexibility of access, synthetically, to a variety of R 1 and R 2 moieties, the skilled person has access to complexes of formula (I) comprising a large variety of Fc moieties, with relevant reagents both available commercially (see supra with respect to the reagents commercially available from Solvias), but also which may be incorporated within complexes of formula (I) using methodology of which the skilled person is well aware. In this regard, TD Appleton et al. (J. Organomet. Chem., 279(1- 2), 5-21 (1985)) describe ready functionalisation of the cyclopentadiene rings of ferrocene. As described above, the Fc moiety of formula (I) is optionally further substituted, in either cyclopentadienyl ring, with one or more substituents independently selected from the group consisting of aliphatic C1-6hydrocarbyl, C1-6alkoxy, halo, haloC1-6aliphatic hydrocarbyl, phenyl, C2-8heteroaryl, hydroxy, nitro, amino, C1-6alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, carbamido and sulfonamido. The aliphatic C1-6hydrocarbyl, C1-6alkoxy, halo, haloC1-6aliphatic hydrocarbyl may be as described above in respect of the same optional substituents of R 1 and R 2 . 55148442-1 According to particular embodiments of the invention, one or more carbon atoms of either cyclopentadienyl ring of the ferrocene moiety Fc may be substituted with one or more halo and/or C1-6alkyl substituents, in addition that is to the inherent substitution of the Fc moiety at those carbon atoms of one of its cyclopentadienyl rings, which connect Fc with the remainder of the complex of formula (I). According to still more particular embodiments of the invention, however, neither cyclopentadienyl ring of the Fc moiety within formula (I) is substituted (other than the inherent substitution ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ formula (I) that is). Access to the CH(Me) moiety within the complex of formula (I) that is adjacent to the Fc moiety is readily available to the skilled person owing to the commercial ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^N,N-dimethyl-1- ferrocenylethylamine), available as either enantiomer. N,N-dimethyl-1- ferrocenylethylamine may be reacted, using methodology described for example by H Nie et al. (supra), to access the corresponding 2-phosphino derivatives (which may incorporate the R 1 and R 2 moieties described herein), by selection of an appropriate chlorophosphine as described above. The N,N-dimethylamino moieties of the resultant 2-phosphino derivatives may then be transformed to the corresponding unsubstituted amino moieties before effecting reductive amination with an appropriate Nx -containing aldehyde (wherein N x is as defined herein), as also described by H Nie et al. (supra) and described herein to allow access to ligands of formula R 1 R 2 P-Fc-CH(Me)-NH-Z-N x described herein. Alternatively, as described herein, the unsubstituted amino moieties may be reacted with an amine of formula N x -Z-NH2, wherein N x and Z are as defined herein, in order to access the ligands of formula R 1 R 2 P-Fc-CH(Me)-NH-Z-N x . It will be understood that variation of either the aldehyde or amine of formula N x -Z-NH2 will allow access to variations of the -Z-N x terminus of the ligands of R 1 R 2 P-Fc-CH(Me)-NH-Z-N x . More generally, a wide variety of compounds of formula R 1 R 2 P-Fc-CH(Me)-LG, wherein LG is a leaving group such as acetate or NMe2, are accessible to the skilled person. These may then be converted to the ligands of formula R 1 R 2 P-Fc-CH(Me)-NH-Z-N x through the methodologies described herein. Accordingly, it is readily within the normal ability of the skilled person to access ligands of formula R 1 R 2 P-Fc-CH(Me)-NH-Z-N x . Still further, additional ways and strategies for incorporating into the ferrocene a structurally diverse array of substituents may be appreciated with reference to HU Blaser et al. (Topics in Catalysis, 19(1), 3-16 (2002)), which provides further teaching 55148442-1 of assistance to the skilled person, in particular with respect to variation of the CH(Me)- NH-Z-N x portion of the ligands of formula R 1 R 2 P-Fc-CH(Me)-NH-Z-N x . In the complexes of formula (I), -Z- is an alkylene linker of formula (CH2)1-6 optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, phenyl, C1-6alkoxy, hydroxyl, C2-8heteroaryl, nitro, amino, alkylthio and thiol, wherein the phenyl of Z is optionally substituted with one or more substituents independently selected from the group consisting of aliphatic C 1- 6 hydrocarbyl, halo, C 1-6 alkoxy, haloC 1-6 aliphatic hydrocarbyl. The aliphatic C 1- 6 hydrocarbyl, C 1-6 alkoxy, halo, and haloC 1-6 aliphatic hydrocarbyl may be as described above in respect of the same optional substituents of R 1 and R 2 . Access to variations in such linkers may be achieved, for example by reacting compounds of formula R 1 R 2 P-Fc-CH(Me)-LG, as described above, for example in which LG = NMe 2 , with different primary amines having Z groups other than methylene (-CH 2 -) as is present in 2-picolylamine, for example. (Analogously, it will be appreciated that access to different N x groups may additionally (to varying the Z group that is) or alternatively be achieved by reacting compounds of formula R 1 R 2 P-Fc-CH(Me)-LG with different primary amines having N x groups other than the 2-pyridyl present in 2- picolylamine, for example). An alternative strategy to vary the -Z-groups in the complexes of formula (I) may be appreciated by consultation of C-J Hou and X-P Hu (Org. Lett., 18, 5592-5595 (2016)) in which the authors describe ligands of formula R 1 R 2 P-Fc-CH(Me)-NH-Z-N x , wherein the -Z-moiety may be a substituted methylene linker (for example by reaction of 1-(2-pyridinyl)ethylmethanesulfonate with a compound of formula R 1 R 2 P-Fc-CH(Me)- NH2 (whereby to provide a methyl-substituted methylene linker -Z-)); or by condensing various 2-acylpyridines with the same compound of formula R 1 R 2 P-Fc-CH(Me)-NH2 followed by hydrogenation of the resultant Schiff bases (whereby to provide a series of substituted methylene linkers -Z-in which the substituent corresponds to the R group in the 2-acylpyridines of formula 2-PyC(=O)R). (Analogously, it will be appreciated that access to N x groups different to 2-pyridyl may additionally (to varying the Z group that is) or alternatively be achieved by reacting compounds of formula R 1 R 2 P-Fc-CH(Me)- NH2 with derivatives of the 1-(2-pyridinyl)ethylmethanesulfonate and the 2- acylpyridines having N x groups other than 2- pyridyl). Z of formula (I) may be an optionally substituted alkylene linker of formula (CH2)1-4, such as optionally substituted (CH2)1-2. In some embodiments, Z is CH2, CHR 3 or (CH2)2, wherein R 3 is C1-6alkyl, phenyl, C1-6alkoxy, hydroxy, C2-8heteroaryl, 55148442-1 nitro, amino, alkylthio and thiol, and wherein the phenyl of Z is optionally substituted with one or more substituents independently selected from the group consisting of C1- 6alkyl, halo, C1-6alkoxy and C1-6haloalkyl. In particular embodiments, Z is CH2, CHR 3 or (CH2)2, wherein R 3 is C1-6alkyl or phenyl optionally substituted with one or more substituents independently selected from C 1-6 alkyl or halo. In more particular embodiments, Z is CH 2 , CHR 3 or (CH 2 ) 2 , wherein R 3 is methyl or phenyl optionally substituted with one or more substituents independently selected from C 1-6 alkyl or halo. Often (but not necessarily in view of the discussion herein of the availability of substituted alkylene linkers of formula Z), Z is unsubstituted. In yet more particular embodiments, Z is CH 2 , CH(CH 3 ) or (CH 2 ) 2 , such as CH 2 . Various ways in which the N x moiety within the ligands of formula R 1 R 2 P-Fc- CH(Me)-NH-Z-N x may be varied have been described above. In addition, however, it may be noted that W Wu et al. (Org. Lett., 18, 2938-2941 (2016)) illustrate a further strategy for constructing such ligands, wherein -Z-is methylene and N x is a substituted oxazolyl by reacting a primary amine of formula R 1 R 2 P-Fc-CH(Me)-NH 2 with a variety of substituted chloromethyloxazoles. It will be readily understood that both the Z and N x moieties may be varied according to such a synthetic strategy. From the discussion herein, it will be appreciated that there is no particular limitation on the architecture of the nitrogen atom-containing moiety N x in the complex of formula (I). This notwithstanding, the nitrogen atom of N x is within a C 2-10 hetercyclyl optionally substituted with one or more substituents independently selected from the group consisting of amino, aliphatic C1-6hydrocarbyl, C1-6alkoxy, hydroxy, amido, halo, haloC1- 6aliphatic hydrocarbyl, phenyl, C2-8heteroaryl, nitro, C1-6alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, carbamido and sulfonamido. The aliphatic C1-6hydrocarbyl, C1-6alkoxy, halo, and haloC1-6aliphatic hydrocarbyl may be as described above in respect of the same optional substituents of R 1 and R 2 . In some embodiments, the one or more optional substituents of N x are independently selected from the group consisting of amino, C1-6alkyl, C1-6alkoxy, hydroxy, amido, halo, haloC1-6alkyl, phenyl and C2-8heteroaryl. In particular embodiments, the one or more optional substituents of N x are independently selected from the group consisting of amino, C1-6alkyl, C1-6alkoxy, hydroxy and amido. 55148442-1 N x may be any optionally substituted nitrogen-containing C2-10heterocyclyl selected from the group consisting of pyridyl, quinolinyl, isoquinolinyl, pyrimidinyl, quinoxalinyl, pyridazinyl, triazinyl, oxazolyl, isooxazolyl, pyrazolyl, triazolyl and oxadiazolyl. For example, N x may be any optionally substituted nitrogen-containing C2- 10hetercyclyl selected from the group consisting of pyridyl, quinolinyl, isoquinolinyl, pyrimidinyl, quinoxalinyl, pyridazinyl and triazinyl. In some embodiments, N x is an optionally substituted monocyclic nitrogen- containing C 2-10 heteroaryl, such as pyridyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, isooxazolyl, pyrazolyl, triazolyl and oxadiazolyl. In some cases, N x is any optionally substituted nitrogen-containing C 2-10 hetercyclyl selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl and triazinyl. Sometimes, N x is an optionally substituted monocyclic nitrogen-containing 6- membered C 2-10 heteroaryl. In some embodiments, N x is a pyridyl ring optionally substituted one or more times with an amino substituent. The amino substituent of N x may be a tertiary amino, substituted with two C 1-6 alkyl substituents such as with two C 1-4 alkyl substituents. Sometimes, the two substituents on the tertiary amino are the same. In some embodiments, the substituents on the tertiary amino are the same and are C 1-4 alkyl substituents. In some embodiments, N x is a pyridyl, a 6-dimethylamino pyridyl or a 4- dimethylamino pyridyl, which is bonded to Z at the 2-position. In particular embodiments, N x is pyridin-2-yl, 2-dimethylaminopyridin-2-yl or 4- dimethylaminopyridin-2-yl. As well as the tridentate ligand of formula R 1 R 2 P-Fc-CH(Me)-NH-Z-N x , the complex of the invention additionally comprises ligands L 1 -L 3 . These may constitute one, two or three ligands depending on whether one of them is a bidentate or a tridentate ligand: each of L 1 -L 3 may independently represent a monodentate neutral or anionic ligand; one of L 1 -L 3 may represent a monodentate neutral or anionic ligand and the other two of L 1 -L 3 together represent a bidentate neutral or anionic ligand; or L 1 -L 3 together may represent a tridentate neutral or anionic ligand. The nature of the L 1 -L 3 ligands is not of particular significance to the present invention: any convenient neutral or anionic ligand may be used, which may be monodentate, bidentate or tridentate, typically monodentate or bidentate. The ligands L 1 -L 3 may be, for example, selected from the group consisting of (i) neutral ligands selected from the group consisting of carbon monoxide, nitrogen monoxide, amines, 55148442-1 ethers, thioethers, sulfoxides, nitriles, for example acetonitrile, isocyanides, for example methyl isocyanide, phosphorus-containing ligands based on either phosphorus (III) or phosphorus (V) and water; and (ii) anionic ligands selected from the group consisting of halides, alkoxides, anions of carboxylic, sulfonic and phosphoric acids, amido ligands, thiolates, phosphides, cyanide, thiocyanate, isothiocyanate, and enolate ions, for example acetylacetonate. Where L 1 -L 3 together represent a tridentate ligand, this is often, but not necessarily neutral. An example of a neutral tridentate ligand is diglyme. According to particular embodiments of this invention L 1 -L 3 constitute three ligands selected from neutral monodentate ligands. According to these and other embodiments, L 1 -L 3 may be the same. For example, L 1 -L 3 may constitute three carbon monoxide ligands. Where the complex of formula (I) is charged, the catalyst comprises one or more additional counterions to balance the charge of the complex, i.e. the charge resultant from the complex formed by the manganese centre Mn, and the ligand or ligands L 1 -L 3 and R 1 R 2 P-Fc-CH(Me)-NH-Z-N x . As with the ligand or ligands L 1 -L 3 , the nature of any such additional counterions is not of particular importance to the working of the present invention. Where these are present, they may be, for example, selected from the group consisting of halides, tetraarylborates, SbF 6 -, SbCl 6 -, AsF 6 -, BF 4 -, PF 6 -, ClO 4 - and CF 3 SO 3 -, optionally wherein the tetraarylborate ligands are selected from the group consisting of [B{3,5-(CF 3 ) 2 C 6 H 3 } 4 ^ ^ ^ ^ ^ ^ ^ ^ ^-(CH 3 ) 2 C 6 H 3 } 4 ^ ^ ^ ^ ^ ^ ^ 6 F 5 ) 4 ^ ^ ^ ^ ^ [B(C 6 H 5 ) 4 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^-(CF 3 ) 2 C 6 H 3 } 4 ^ ^ ^ which is known as tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (BARF)). According to particular embodiments of the invention, the complex has a single positive charge (for example resultant from the manganese centre being a manganese ion in oxidation state (I) and the ligand or ligands L 1 -L 3 being three neutral monodentate ligands, for example three carbon monoxide ligands) and the catalyst further comprises one halide (e.g. a bromide) or tetrarylborate counteranion. According to still more particular embodiments of such catalysts, the counteranion is bromide or BARF. In specific embodiments, the catalyst is any one selected from the group consisting of formulae (Ia) to (If) (in either enantiomeric form or a non-racemic mixture of enantiomeric forms): 55148442-1 (Ia) (Ib) (Ic) (Id) (Ie) (If). In more particular embodiments, the catalyst is of formula (Ia) or (Ib), such as (Ia). In some cases, when R 1 and/or R 2 are substituted, N x is unsubstituted. In such cases, the catalyst may be, for example, any one selected from the group consisting of formulae (Ia), (Ic) and (Id). 55148442-1 In specific cases, R 1 and/or R 2 are substituted. In such cases, the catalyst may be, for example, any one selected from the group consisting of formulae (Ia), (Ib) and (Ie). Sometimes, R 1 and/or R 2 are substituted and N x is unsubstituted. For example, the catalyst may be of formulae (Ia). As will be recognised, the complexes of formula (I) exhibit chirality, both on account of the stereogenic centre adjacent to the Fc moiety (which bears the methyl group depicted within the compounds of formula (I)), and also on account of the planar chirality resultant from the 1,2-connectivity to the remainder of the complex of formula (I), from one of the two cyclopentadienyl rings of the Fc moiety. As described above, the present invention is based on the unexpected finding that the chiral manganese-based catalysts described herein are able to hydrogenate prochiral ketimine moieties to chiral amines, which may be produced in high yield and with a high enantiomeric excess (ee). In order to favour the formation of one amine enantiomer over the other, the chiral manganese-based catalysts described herein are in enantiomeric excess, i.e. the enantiomeric excess (ee) is >0%. In other words, the catalysts are non-racemic enantiomeric mixtures of complexes of formula (I). In some embodiments, the catalyst has an enantiomeric excess of about 50 to about 100%. It is advantagous, in the method of the invention, to use catalysts with a high enantiomeric excess, such as an enantiomeric excess of about 80 to about 100%, e.g. an enantiomeric excess of about 90 to about 100%. As exemplified below, the inventors have synthesised complexes of formula (I) in high enantiomeric excess from commercially available chiral starting materials of high enantiomeric purity. Where enantiomerically pure chiral starting materials are not commercially available, and complexes of formula (I) are produced with low enantiomeric excess, each enantiomer may be separated from the other using chiral resolution techniques that are well known in the art. For example, the enantiomers can be converted to diastereoisomers by reaction with suitable chiral resolving agents, such as chiral acids. The diastereoisomers can be separated owing to their different physical properties, e.g. the diastereoisomers may have different solubilities in a specific solvent, which solvent may be used to precipitate one diastereoisomer in preference to the other. Once separated, the chiral resolving agent may be removed from the diastereoisomers to re-form the enantiomers. Alternatively, enantiomers may be separated using chiral column chromatography, in which the stationary phase 55148442-1 comprises chiral resolving agents which preferentially interact with one enantiomer over the other. As described above, the complex of formula (I) need not be isolated before its use in the method of the invention. It may rather form in situ, for example by contacting a R 1 R 2 P-Fc-CH(Me)-NH-Z-N x ligand with a manganese salt, such as the commercially available manganese (I) salt bromopentacarbonylmanganese (I) (Mn(CO) 5 Br). The manganese salt often comprises the ligand or ligands L 1 -L 3 , but this need not be the case. L 1 -L 3 could instead be sourced separately. It will be readily appreciated by those skilled in the art that, if desired, recognised methods of immobilisation of catalysts of formula (I) herein can be used to generate heterogeneous catalysts, for example by absorption onto a suitable solid support or reacted with such a support to form a covalently bound ligand or catalyst. The catalyst of formula (I) may be isotopically-labelled. Isotopically-labelled compounds are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. Examples of isotopes that can be incorporated into catalysts of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, and 36 Cl, respectively. In some embodiments, the ketimine moiety of the invention is acyclic or exocyclic. In some cases, the ketimine comprises a cyclic moiety, such as an optionally substituted phenyl or indanyl. The ketimine moiety of the invention may be a primary or a secondary ketimine. In some cases, the ketimine moiety of the invention is a secondary ketimine moiety (i.e. a ketimine moiety in which the nitrogen atom is not bonded to a hydrogen atom). Such ketimines may be referred to as Schiff bases. It may be advantageous for the group bonded to the nitrogen atom of the ketimine moiety to be controllably removable. In this way, the chiral secondary amine resultant from hydrogenation of the ketimine moiety can be converted to the corresponding chiral primary amine by removal of the group. Accordingly, in some embodiments, the nitrogen atom of the ketimine moiety is bonded to a group which is an amino protecting group. The skilled person is familiar with and can determine without undue burden appropriate amino protecting groups compatible with the method of the invention, for example with reference to the detailed guidance provided in Greene’s Protective Groups in Organic Synthesis (5 th Edition P. G. M Wuts, Wiley, 55148442-1 2014) and the review of protecting groups provided by K. Jarowicki and P. Kocienski in J. Chem. Soc., Perkin Trans. 1, 2000, 2495-2527. Accordingly, the skilled person is quite capable of determining suitable protecting groups for use in the methods of the invention. Such protecting groups include those described in https://www.organic- chemistry.org/protectivegroups/amino.shtm, such as benzyl, triphenylmethyl, para- toluene sulfonyl, carbamyl, -C(O)CH 3 , -C(O)CF 3 , 9-fluorenylmethoxycarbonyl, tert- butoxycarbonyl and benzyloxycarbonyl. In some embodiments, the group bonded to the nitrogen atom of the ketimine moiety is any one of the groups consisting of optionally substituted aryl, phosphinyl oxide, optionally substituted heteroaryl, optionally substituted arylC 1-6 alkyl, optionally substituted alkyl, sulfonyl, carbamyl, acyl, and ester. The optionally substituted aryl may be a phenyl, optionally substituted with one or more substituents independently selected from the group consisting of aliphatic C 1- 6 hydrocarbyl, C 1-6 alkoxy, halo and haloC 1-6 aliphatic hydrocarbyl, which may be as described above in respect of the same optional substituents of R 1 and R 2 . The phosphinyl oxide may comprise two phenyl moieties each optionally substituted with one or more substituents independently selected from the group consisting of aliphatic C 1-6 hydrocarbyl, C 1-6 alkoxy, halo and haloC 1-6 aliphatic hydrocarbyl, which may be as described above in respect of the same optional substituents of R 1 and R 2 . The two optionally substituted phenyl moieties may be and typically are the same, for example the phosphinyl oxide may be diphenylphosphinyl oxide. The optionally substituted heteroaryl may be an optionally substituted C4-10heteroaryl comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (e.g. as nitrogen and oxygen). Sometimes, the optionally substituted heteroaryl is an optionally substituted monocyclic C4-5heteroaryl. Examples of such groups include furanyl, thiophenyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl. The optionally substituted heteroaryl may be substituted with one or more substituents independently selected from the group consisting of aliphatic C1-6hydrocarbyl, C1-6alkoxy, halo and haloC1-6aliphatic hydrocarbyl, which may be as described above in respect of the same optional substituents of R 1 and R 2 . The optionally substituted arylC1-6alkyl may be an optionally substituted arylC1-4alkyl, such as an optionally substituted arylmethyl. The aryl of the optionally substituted arylC1-6alkyl may be a phenyl, optionally substituted with one or more 55148442-1 substituents independently selected from the group consisting of aliphatic C1-6hydrocarbyl, C1-6alkoxy, halo and haloC1-6aliphatic hydrocarbyl, which may be as described above in respect of the same optional substituents of R 1 and R 2 . In some cases, the alkyl moiety of the optionally substituted arylC1-6alkyl is substituted, for example with one or more substituents selected from the group consisting of aryl, aliphatic C 1-6 hydrocarbyl, C 1-6 alkoxy, halo and haloC 1-6 aliphatic hydrocarbyl, wherein the aliphatic C 1-6 hydrocarbyl, C 1-6 alkoxy, halo and haloC 1-6 aliphatic hydrocarbyl may be as described above in respect of the same optional substituents of R 1 and R 2 . For example, the optionally substituted arylC 1-6 alkyl may be triphenylmethyl. Sometimes, each of the alkyl moiety and the aryl moiety of the arylC 1-6 alkyl is substituted. Alternatively, both the alkyl moiety and the aryl moiety of the arylC1-6alkyl may be unsubstituted. For example, the optionally substituted arylC 1-6 alkyl may be benzyl. The optionally substituted alkyl may be an optionally substituted C 1-12 alkyl such as C 1-6 alkyl. It may be substituted, for example with one or more substituents selected from the group consisting of aryl, aliphatic C 1-6 hydrocarbyl, C 1-6 alkoxy, halo and haloC 1- 6 aliphatic hydrocarbyl, wherein the aliphatic C 1-6 hydrocarbyl, C 1-6 alkoxy, halo and haloC 1-6 aliphatic hydrocarbyl may be as described above in respect of the same optional substituents of R 1 and R 2 . Alternatively, the alkyl may be unsubstituted. The sulfonyl may comprise a phenyl moiety optionally substituted with one or more substituents independently selected from the group consisting of aliphatic C 1- 6 hydrocarbyl, C 1-6 alkoxy, halo and haloC 1-6 aliphatic hydrocarbyl, which may be as described above in respect of the same optional substituents of R 1 and R 2 . The sulfonyl may comprise a phenyl moiety optionally substituted with one or more C1-4alkyl substituents. For example, the sulfonyl may be ^SO2(p-tolyl). The acyl may comprise a C1-6alkyl (such as methyl) or C1-6haloalkyl (such as trifluoromethyl). The ester may be of formula ^C(O)OR a , wherein R a is a C1-6alkyl (such as tert- butyl) or an arylC1-6alkyl (such as benzyl or 9-fluorenylmethyl). The group bonded to the nitrogen atom of the ketimine moiety may be any one of the group consisting of phenyl, diphenylphosphinyl oxide, benzyl, triphenylmethyl, para-toluene sulfonyl, carbamyl, -C(O)CH3, -C(O)CF3, 9-fluorenylmethoxycarbonyl, tert- butoxycarbonyl and benzyloxycarbonyl. In some embodiments, the nitrogen atom of the ketimine moiety is bonded to an optionally substituted aryl, optionally substituted benzyl or phosphinyl oxide, which may 55148442-1 be as defined above. In more specific embodiments, the nitrogen atom of the ketimine moiety is bonded to an optionally substituted aryl or phosphinyl oxide. The ketimine need not be isolated before its use in the method of the invention. The ketimine may form in situ, for example by contacting a ketone with an optionally substituted primary aromatic amine, an optionally substituted primary benzylic amine or an optionally substituted primary heteroaromatic amine. The optionally substituted primary aromatic amine may be of formula H 2 N-R, wherein R is a phenyl, optionally substituted with one or more substituents independently selected from the group consisting of aliphatic C 1-6 hydrocarbyl, C 1- 6 alkoxy, halo and haloC 1-6 aliphatic hydrocarbyl, which may be as described above in respect of the same optional substituents of R 1 and R 2 . The optionally substituted primary benzylic amine may be of formula H 2 N-CH 2 - R, wherein R is a phenyl, optionally substituted with one or more substituents independently selected from the group consisting of aliphatic C 1-6 hydrocarbyl, C 1- 6 alkoxy, halo and haloC 1-6 aliphatic hydrocarbyl, which may be as described above in respect of the same optional substituents of R 1 and R 2 . Alternatively, the optionally substituted primary heteroaromatic amine may be of formula H 2 N-R, wherein R is an optionally substituted C 4-10 heteroaryl comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (such as nitrogen and oxygen). Sometimes, the optionally substituted heteroaryl is an optionally substituted monocyclic C 4-5 heteroaryl. Examples of such groups include furanyl, thiophenyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl. The optionally substituted heteroaryl may be substituted with one or more substituents independently selected from the group consisting of aliphatic C1-6hydrocarbyl, C1-6alkoxy, halo and haloC1-6aliphatic hydrocarbyl, which may be as described above in respect of the same optional substituents of R 1 and R 2 . In some embodiments, the method of the invention is carried out in the presence of a base. In cases where bases, such as amines, are present in the reaction mixture (e.g. owing to their having been added to the reaction mixture to form a ketimine), additional bases need not necessarily be added for hydrogenation of ketimines to occur. See, for example, M. B. Widegren et al., Cat. Sci. Tech. 2019, 9, 6047. Furthermore, the chiral amine product of the reaction of the invention may itself act as a base for the hydrogenation of ketimines. 55148442-1 In some embodiments, the base is selected from the group consisting of metal alkoxides, metal carbonates, metal hydride, metal phosphate, metal hydroxide and metal bicarbonate. The metal may be any one or a combination selected from the group consisting of lithium, beryllium, sodium, magnesium, potassium, calcium and cesium. Alternatively, the base may already be present in the reaction mixture, e.g. as an amine. In some embodiments, the base is selected from the group consisting of sodium methoxide, potassium carbonate, sodium hydride, potassium hydride, potassium phosphate, potassium hydroxide, sodium carbonate, cesium carbonate, sodium hydroxide, lithium carbonate, lithium hydroxide, calcium hydroxide, potassium bicarbonate, sodium bicarbonate and lithium bicarbonate. According to particular embodiments of the invention, the conjugate acid of the base has a pKa of about 6.3 to about 14. For the avoidance of doubt, these pKa values relate to determinations conducted in water, at 25°C, for the reaction BH + H + + B, wherein BH + denotes the conjugate acid of the base concerned, as described in the CRC Handbook of Chemistry and Physics, 91 st edition, 2010, Dissociation Constants of Organic Acids and Bases, and Dissociation Constants of Inorganic Acids and Bases, and the references cited therein. Accordingly, where the base used is potassium bicarbonate (KHCO 3 ), for example, the conjugate acid is carbonic acid (H 2 CO 3 ); where the base used is potassium carbonate (K 2 CO 3 ), for example, the conjugate acid is bicarbonate (HCO 3 -). For further avoidance of doubt, the pKa of water at 25°C is defined herein, as is generally recognised in the art, as being 14.0. Accordingly, for example, the pKa of the conjugate acid of both sodium hydroxide and potassium hydroxide (i.e. water) is 14.0. In some texts, the pKa of water is indicated as being 15.74 (higher than that of methanol (15.50) which is incorrect for reasons explained in detail by TP Silverstein et al. (J. Chem. Educ., 94(6), 690 ^695 (2017)). According to still more particular embodiments of the invention, the base is selected from the group consisting of potassium carbonate, potassium phosphate, potassium hydroxide, sodium carbonate, cesium carbonate, sodium hydroxide, lithium carbonate, lithium hydroxide, and calcium hydroxide, for example the group consisting of potassium carbonate, potassium phosphate, potassium hydroxide, sodium carbonate and cesium carbonate. According to other embodiments of the invention, the base used in accordance with these methods of hydrogenation may be a tertiary amine, typically of the formula 55148442-1 N(C1-6alkyl)3, in which each alkyl group need not necessarily be the same. Examples of tertiary amines that may be used include triethylamine, N,N-dimethylamine and N,N- diisopropylethylamine (also known as Hünig's base). According to particular embodiments of the invention, the conjugate acid of the base has a pKa from 10.3 to 14. Such pKas exclude, for example, bicarbonates. Suitable amounts of base that may be used can be determined by the skilled person. Examples of suitable amounts of base to use may vary from about 0.1 mol% to about 1000 mol%, with respect to the ketimine, for example from about 1 mol% to about 100 mol%, e.g. from about 5 to about 50 mol%. It may on occasion be convenient or advantageous to use greater quantities of base, however, for example up to 2000 mol% or more. Combinations of more than one base may also be used. A particular advantage of avoiding strong bases in hydrogenation reactions in accordance with the present invention is the ability to hydrogenate optically active substrates, for example those susceptible to racemisation via deprotonation of relatively acidic C-H bonds, e.g. alpha to carbonyl moieties, with at least less disruption to optical purity than corresponding reactions in which strong bases are used. The methods of the invention are typically conducted in the presence of hydrogen gas, under pressure. Generally the pressure at which the reactions are typically conducted is in the range of about 1 bar (100 kPa) to about 100 bar (10,000 kPa), for example from about 20 bar (2,000 kPa) to about 80 bar (8,000 kPa), although higher or lower pressures may on occasion be convenient. The reactions may be carried out in any convenient solvent as may be suitable for the substrate for the reaction (i.e. the ketimine). Any of the commonly encountered solvents in organic chemistry can potentially be utilised. However, solvents comprising ketone or ester functionalities, such as acetone or ethyl acetate respectively, are preferably avoided. In certain embodiments, it may be convenient to conduct the hydrogenation reaction in the absence of solvent. Typical solvents for use in the present invention include simple alcohols, such as C1-10hydrocarbyl alcohols, often saturated aliphatic C2-8alcohols, for example, ethanol, isopropanol and tert-butanol; polyhydroxy alcohols such as ethylene glycol, propylene glycol, 1,2-propanediol and glycerol; ethers, for example tetrahydrofuran (THF) 1,4-dioxane, methyl tert-butyl ether, cyclopentyl methyl ether; aliphatic and aromatic hydrocarbon solvents, for example C5-12alkanes, benzene, toluene and xylene and halogenated (typically chlorinated) hydrocarbon solvents, for example dichloromethane and chlorobenzene, or mixtures thereof, in particular, mixtures of 55148442-1 alcohols, for example ethanol or isopropanol, and hydrocarbon solvents such as hexanes, xylenes (e.g. isomeric mixtures) or toluene. Hydrogenation reactions of the present invention can typically be conducted in C1-10hydrocarbyl alcohols alone (i.e. in which the only solvent is the alcohol, or there is minimal (e.g. less than 10 vol%, more typically less than 5 vol%) contamination with other liquid, for example water), in particular in ethanol or isopropanol. According to some embodiments of the invention, therefore the solvent for the reaction is isopropanol. According to other embodiments, the solvent is ethanol. It will be understood that the precise conditions for any given hydrogenation reaction may be varied within the routine ability of those of normal skill in the art. Thus, the concentration of catalyst and hydrogen pressure may typically be varied within the ranges already discussed. Operating temperatures that may be used typically vary from about -20 °C to about 200 °C, often from about 0 °C to about 120 °C, for example from about 20 °C to about 80 °C; and durations of reaction may vary from about 5 minutes to about 36 hours, for example from about 1 hour to about 24 hours or from about 2 hours to about 18 hours. Sometimes, the method of the invention is carried out at temperatures of 35 to 50 °C. The inventors have found that the method of the invention is surprisingly effective even when such mild temperatures are used. Each and every patent and non-patent reference referred to herein is hereby incorporated by reference in its entirety, as if the entire contents of each reference were set forth herein in its entirety. Aspects and embodiments of the invention are further described in the following clauses: 1. A method comprising hydrogenating a prochiral ketimine moiety in the presence of a chiral catalyst in enantiomeric excess, the catalyst comprising a charged or neutral complex of formula (I): wherein: 55148442-1 Mn is a manganese atom or a manganese ion in oxidation state (I) to (VII); R 1 and R 2 are each independently C1-20hydrocarbyl or C2-10heterocyclyl, optionally substituted with one or more substituents independently selected from the group consisting of aliphatic C1-6hydrocarbyl, C1-6alkoxy, halo, haloC1-6aliphatic hydrocarbyl, phenyl, C2-8heteroaryl, hydroxy, nitro, amino, C1-6alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, carbamido and sulfonamido; Fc denotes ferrocene (bis ^ ^ 5 -cyclopentadienyl)iron) covalently bonded via adjacent carbon atoms of one of the two cyclopentadienyl moieties, and is optionally further substituted, in either cyclopentadienyl ring, with one or more substituents independently selected from the group consisting of aliphatic C1-6hydrocarbyl, C1- 6 alkoxy, halo, haloC 1-6 aliphatic hydrocarbyl, phenyl, C 2-8 heteroaryl, hydroxy, nitro, amino, C 1-6 alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, carbamido and sulfonamido; Z is an alkylene linker of formula (CH 2 ) 1-6 optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, phenyl, C 1- 6 alkoxy, hydroxyl, C 2-8 heteroaryl, nitro, amino, alkylthio and thiol, wherein the phenyl of Z is optionally substituted with one or more substituents independently selected from the group consisting of aliphatic C 1-6 hydrocarbyl, halo, C 1-6 alkoxy, haloC 1-6 aliphatic hydrocarbyl; N x is a nitrogen-containing C 2-10 hetercyclyl optionally substituted with one or more substituents independently selected from the group consisting of amino, aliphatic C1-6hydrocarbyl, C1-6alkoxy, hydroxy, amido, halo, haloC1-6aliphatic hydrocarbyl, phenyl, C2-8heteroaryl, nitro, C1-6alkylthio, carboxylate, sulfonate, phosphate, cyano, thio, formyl, ester, acyl, thioacyl, carbamido and sulfonamido; and L 1 -L 3 constitute one, two or three ligands in which each of L 1 -L 3 independently represents a monodentate neutral or anionic ligand; or one of L 1 -L 3 represents a monodentate neutral or anionic ligand and the other two of L 1 -L 3 together represent a bidentate neutral or anionic ligand; or L 1 -L 3 together represent a tridentate neutral or anionic ligand. 2. The method of clause 1 wherein Mn is a manganese ion in oxidation state (I) or (II). 3. The method of clause 1 wherein the manganese ion is in oxidation state (I). 55148442-1 4. The method of any one of clauses 1 to 3, wherein R 1 and R 2 are each an optionally substituted moiety independently selected from the group consisting of C1- 10hydrocarbyl and monocyclic C2-10heterocyclyl. 5. The method of any one of clauses 1 to 3, wherein R 1 and R 2 are each an optionally substituted moiety independently selected from the group consisting of phenyl, C 3-10 cycloalkyl, and monocyclic C 4-5 heteroaryl. 6. The method of any one of clauses 1 to 3, wherein R 1 and R 2 are each an optionally substituted moiety independently selected from the group consisting of phenyl, cyclohexyl and furanyl. 7. The method of any one of clauses 1 to 6, wherein R 1 and R 2 are each optionally substituted aromatic moieties. 8. The method of any one of clauses 1 to 7, wherein R 1 and R 2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of aliphatic C 1-6 hydrocarbyl, C 1-6 alkoxy, halo, and haloC 1-6 aliphatic hydrocarbyl. 9. The method of any one of clauses 1 to 7, wherein R 1 and R 2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halo, and trihalomethyl. 10. The method of any one of clauses 1 to 7, wherein R 1 and R 2 are independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-6alkyl and C1-6alkoxy. 11. The method of any one of clauses 1 to 10, wherein R 1 and R 2 are the same. 12. The method of any one of clauses 1 to 3, wherein R 1 and R 2 are each 4- methoxy-3,5-dimethylphenyl, phenyl, 4-methoxy-3,5-di-tert-butylphenyl, 3,5- dimethylphenyl, 3,5-di(tertbutyl)phenyl, furanyl or cyclohexyl. 55148442-1 13. The method of any one of clauses 1 to 3, wherein R 1 and R 2 are each 4- methoxy-3,5-dimethylphenyl, phenyl, 4-methoxy-3,5-di-tert-butylphenyl, 3,5- dimethylphenyl or 3,5-di(tertbutyl)phenyl. 14. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ points of connectivity to the remainder of the complex of formula (I), one or more carbon atoms of either cyclopentadienyl ring of the ferrocene moiety are independently optionally substituted with halo or C 1-6 alkyl substituents. 15. The method of any one of clauses 1 to 13, wherein neither cyclopentadienyl ring of the ferrocene moiety ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ connectivity with the remainder of the complex of formula (I). 16. The method of any one of clauses 1 to 3 wherein the R 1 R 2 P-Fc-CH(Me)-NH- component of the complex is 1-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2-[1- (HN)ethyl]ferrocene; 1-[1-(HN)ethyl]-2-(diphenylphosphino)ferrocene; 1-[bis(4-methoxy- 3,5-di-tert-butylphenyl)phosphino]-2-[1-(HN)ethyl]ferrocene; 1-(difuranylphosphino)-2- [1-(HN)ethyl]ferrocene; 1-[bis[3,5-bis(trifluoromethyl)phenyl] phosphino]-2-[1- (HN)ethyl]ferrocene or 1-(dicyclohexylphosphino)-2-[1-(HN)ethyl]ferrocene. 17. The method of any one of clauses 1 to 3, wherein the R 1 R 2 P-Fc-CH(Me)-NH- component of the complex is (S)-1-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2- [(R)-1-(HN)ethyl]ferrocene, (R)-1-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2-[(S)- 1-(HN)ethyl]ferrocene or a mixture thereof; (S)-1-[(R)-1-(HN)ethyl]-2- (diphenylphosphino)ferrocene, (R)-1-[(S)-1-(HN)ethyl]-2-(diphenylphosphino)ferrocene or a mixture thereof; (S)-1-[bis(4-methoxy-3,5-di-tert-butylphenyl)phosphino]-2-[( R)-1- (HN)ethyl]ferrocene, (R)-1-[bis(4-methoxy-3,5-di-tert-butylphenyl)phosphino]-2-[( S)-1- (HN)ethyl]ferrocene or a mixture thereof; (S)-1-(difuranylphosphino)-2-[(R)-1- (HN)ethyl]ferrocene, (R)-1-(difuranylphosphino)-2-[(S)-1-(HN)ethyl]ferrocene or a mixture thereof; (S)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]-2-[(R)- 1- (HN)ethyl]ferrocene, (R)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]-2-[(S)- 1- (HN)ethyl]ferrocene or a mixture thereof; or (S)-1-(dicyclohexylphosphino)-2-[(R)-1- (HN)ethyl]ferrocene, (R)-1-(dicyclohexylphosphino)-2-[(S)-1-(HN)ethyl]ferrocene or a mixture thereof. 55148442-1 18. The method of any one of clauses 1 to 17, wherein Z is CH2, CHR 3 or (CH2)2, wherein R 3 is C1-6alkyl, phenyl, C1-6alkoxy, hydroxy, C2-8heteroaryl, nitro, amino, alkylthio and thiol, and wherein the phenyl of Z is optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, halo, C1-6alkoxy and C1-6haloalkyl. 19. The method of any one of clauses 1 to 17, wherein Z is CH 2 , CHR 3 or (CH 2 ) 2 , wherein R 3 is C 1-6 alkyl or phenyl optionally substituted with one or more substituents independently selected from C 1-6 alkyl or halo. 20. The method of any one of clauses 1 to 17, wherein Z is CH2, CHR 3 or (CH2)2, wherein R 3 is methyl or phenyl optionally substituted with one or more substituents independently selected from C 1-6 alkyl or halo. 21. The method of any one of clauses 1 to 17, wherein Z is CH 2 , CH(CH 3 ) or (CH 2 ) 2 . 22. The method of any one of clauses 1 to 17, wherein Z is CH 2 . 23. The method of any one of clauses 1 to 22 wherein the one or more optional substituents of N x are independently selected from the group consisting of amino, C 1- 6 alkyl, C 1-6 alkoxy, hydroxy, amido, halo, haloC 1-6 alkyl, phenyl and C 2-8 heteroaryl. 24. The method of any one of clauses 1 to 22, wherein the one or more optional substituents of N x are independently selected from the group consisting of amino, C1- 6alkyl, C1-6alkoxy, hydroxy and amido. 25. The method of any one of clauses 1 to 24, wherein N x is any one optionally substituted nitrogen-containing C2-10heterocyclyl selected from the group consisting of pyridyl, quinolinyl, isoquinolinyl, pyrimidinyl, quinoxalinyl, pyridazinyl, triazinyl, oxazolyl, isooxazolyl, pyrazolyl, triazolyl and oxadiazolyl. 26. The method of any one of clauses 1 to 24, wherein N x is any one optionally substituted nitrogen-containing C2-10hetercyclyl selected from the group consisting of pyridyl, quinolinyl, isoquinolinyl, pyrimidinyl, quinoxalinyl, pyridazinyl and triazinyl. 55148442-1 27. The method of any one of clauses 1 to 26, wherein N x is an optionally substituted monocyclic nitrogen-containing C2-10heteroaryl. 28. The method of any one of clauses 1 to 22, wherein N x is a pyridyl ring optionally substituted one or more times with an amino substituent. 29. The method of clause 28, wherein the amino substituent of N x is a tertiary amino, substituted with two C 1-6 alkyl substituents. 30. The method of clause 29, wherein the two C 1-6 alkyl substituents are the same and are C1-4alkyl substituents. 31. The method of any one of clauses 1 to 22, wherein N x is a pyridyl, a 2- dimethylamino pyridyl or a 4-dimethylamino pyridyl, which is bonded to Z at the 2- or 6- position. 32. The method of any one of clauses 1 to 22, wherein N x is pyridin-2-yl, 2- dimethylaminopyridin-6-yl or 4-dimethylaminopyridin-2-yl. 33. The method of any one of clauses 1 to 32, wherein each of the one, two or three ligands L 1 -L 3 is selected from the group consisting of: (i) neutral ligands selected from the group consisting of carbon monoxide, nitrogen monoxide, amines, ethers, thioethers, sulfoxides, nitriles (RCN), isocyanide (RNC), phosphorus-containing ligands based on either phosphorus (III) or phosphorus (V) and water; and (ii) anionic ligands selected from the group consisting of halides, alkoxides, anions of carboxylic, sulfonic and phosphoric acids, amido ligands, thiolates, phosphides, cyanide, thiocyanate, isothiocyanate and enolate ions. 34. The method of clause 33, wherein L 1 -L 3 constitute three ligands. 35. The method of clause 33 or clause 34 wherein each of L 1 -L 3 is selected from neutral monodentate ligands. 36. The method of clause 34 or clause 35, wherein each of L 1 -L 3 is the same. 55148442-1 37. The method of clause 34, wherein each of L 1 -L 3 is carbon monoxide. 38. The method of any one of clauses 1 to 37 wherein, when the complex of formula (I) is charged, the catalyst comprises one or more additional counterions selected from the group consisting of halides, tetraarylborates, SbF 6 -, SbCl 6 -, AsF 6 -, BF 4 -, PF 6 -, ClO 4 - and CF 3 SO 3 -. 39. The method of any one of clauses 1 to 37 wherein, when the complex of formula (I) is charged, the catalyst comprises one or more additional counterions selected from the group consisting of halides, SbF6-, SbCl6-, AsF6-, BF4-, PF6-, ClO4-, CF 3 SO 3 -, [B{3,5-(CF 3 ) 2 C 6 H 3 } 4 ] ^ , [B{3,5-(CH 3 ) 2 C 6 H 3 } 4 ] ^ , [B(C 6 F 5 ) 4 ] ^ and [B(C 6 H 5 ) 4 ] ^ . 40. The method of any one of clauses 1 to 39, wherein the complex of formula (I) has a single positive charge and the catalyst further comprises one halide or tetrarylborate counteranion. 41. The method of clause 40, wherein the counteranion is bromide or [B{3,5- (CF 3 ) 2 C 6 H 3 } 4 ] ^ . 42. The method of clause 1, wherein the catalyst is selected from the group consisting of formulae (Ia) to (If): 55148442-1 (Ic) (Id) (Ie) (If). 43. The method of clause 42, wherein the catalyst is of formula (Ia) or (Ib). 44. The method of any one of clauses 1 to 43, wherein when R 1 and/or R 2 are substituted, N x is unsubstituted. 45. The method of clause 44, wherein R 1 and/or R 2 are substituted. 46. The method of any one of clauses 1 to 45, wherein the catalyst has an enantiomeric excess of about 50 to about 100%. 47. The method of any one of clauses 1 to 46, wherein the method comprises contacting a R 1 R 2 P-Fc-CH(Me)-NH-Z-N x ligand with a manganese salt. 48. The method of any one of clauses 1 to 47, wherein the ketimine moiety is acyclic or exocyclic. 55148442-1 49. The method of any one of clauses 1 to 48, wherein the nitrogen atom of the ketimine moiety is bonded to any one of the groups consisting of optionally substituted aryl, phosphinyl oxide, optionally substituted heteroaryl, optionally substituted arylC1- 6alkyl, optionally substituted alkyl, sulfonyl, carbamyl, acyl, and ester. 50. The method of any one of clauses 1 to 49, wherein the nitrogen atom of the ketimine moiety is bonded to an optionally substituted aryl, phosphinyl oxide or optionally substituted benzyl. 51. The method of any one of clauses 1 to 50, wherein the nitrogen atom of the ketimine moiety is bonded to an optionally substituted aryl or a phosphinyl oxide. 52. The method of any one of clauses 1 to 51, wherein the ketimine is formed in situ. 53. The method of any one of clauses 1 to 48, wherein the ketimine is formed in situ and the method comprises contacting a ketone with an optionally substituted primary aromatic amine, an optionally substituted primary benzylic amine, or an optionally substituted primary heteroaromatic amine. 54. The method of any one of clauses 1 to 53, wherein the method is carried out in the presence of a base. 55. The method of clause 54, wherein the base is selected from the group consisting of metal alkoxide, metal carbonate, amine, metal hydride, metal phosphate, metal hydroxide and metal bicarbonate. 56. The method of any one of clauses 1 to 55, wherein the method is carried out in the presence of hydrogen gas. The non-limiting examples below more fully illustrate the embodiments of this invention. 55148442-1 EXAMPLES General experimental procedures The preparation of solutions for the use in catalytic reactions were carried out under either argon or nitrogen atmospheres. All glassware was used oven dried or flame dried and cooled under vacuum before use. Solvents were degassed either by bubbling argon or nitrogen through the solvent for at least 1 hour prior to use or freeze- pumped-thawed before use. Unless otherwise noted all precursor chemicals were purchased from Sigma-Aldrich, Acros, Alfa Aesar, Strem or TCI and used as received (excepts when further degassed as stated above). Room temperature (rt) or ambient temperature refers to the temperature range 15-25°C. Heating the reaction mixtures were effected by either an oil bath or a Drysyn heating block. Reported temperature is the oil bath or heating block temperature and not internal temperature unless stated and was measured using a contact thermometer (PT-1000). In vacuo refers to either the use of a Heidolph Laborota 4001 rotary evaporator or the use of a high-vacuum line. Analytical thin layer chromatography (TLC) was carried out on pre-coated plastic plates (Kieselgel 60 F254 silica). TLC visualisation was carried out using a UV lamp (254nm) or using a 1% potassium permanganate aqueous solution. Flash silica chromatography was performed using Kieselgel 60 silica. 1H, 13 C, 31 P, 19 F NMR was carried out using either a Bruker Avance 300 (300 MHz for 1 H, 75 MHz for 13 C, 121 MHz for 31 P and 282 MHz for 19 F), a Bruker Avance II 400 (400 MHz 1 H, 100 MHz 13 C, 161 MHz 31 P and 376 MHz for 19 F) or a Bruker Ultrashield 500 (500 MHz 1 H, 125 MHz 13 C, 201 MHz 31 P and 470 MHz for 19 F). NMR analyses were carried out at room temperature in the deuterated. The chemical shifts are quoted as parts per million (ppm). Coupling constants, J, are quoted in Hz. Multiplicities are indicated by: s (singlet), d (doublet), t (triplet), q (quartet) and m ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ Infrared spectra were recorded on a Shimadzu IRAffinity-1 using Pike attenuated total reflectance (ATR) accessory. Peaks are reported as weak (w), medium ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ denote a sharp peak shape. All units are reported in cm -1 . Mass spectrometric (m/z) data were acquired by electrospray ionisation (ESI) or electron impact (EI) either at the University of St Andrews Mass Spectrometry facility (using Micromass LCT spectrometer or Micromass GCT spectrometer) or at the EPRSC National Mass Spectrometry Service Centre, Swansea (using Orbitrap nano- 55148442-1 ESI, Finnigan MAT 900 XLT or Finnigan MAT 95 XP). Values are reported as a ratio of mass to charge in Daltons. Optical rotations were measured on a Perkin Elmer 341 polarimeter using a 1 ml cell with a 1 dm path length at room temperature using the sodium D-line, and a suitable solvent that is reported along with the concentration (c = g/100ml). HPLC analysis has been determined using a Varian Prostar operated by Galaxie workstation PC software. For the synthesis of ligands and catalysts, see the following publications: M. B. Widegren et al., Angew Chem. Int. Ed.2017, 56, 5825; M. B. Widegren et al., Cat. Sci. Tech.2019, 9, 6047, and C. L. Oates et al. Angew Chem. Int. Ed.2022, e202212479. Experimental procedures General Procedure for preparation of N-diphenylphosphinoyl imines (step i: oxime formation): To a 50 mL round bottom flask fitted with condenser and charged with a magnetic stirrer was added: ketone (10 mmol, 1 eq.), hydroxylamine HCl (15 mmol, 1.5 eq.) and sodium acetate (25 mmol, 2.5 eq.). The reagents were dissolved in a H 2 O (6.25 mL)/ EtOH (3.75 mL) mixture ( 1 M solution) and stirred at reflux (73 °C) for 24 h. Upon which time the solution was cooled to rt and then to 0 °C resulting in the precipitation of oxime product. This precipitate was collected by filtration, allowed to air dry overnight and used in next step without further purification. (Step ii Preparation of N-diphenylphosphinoyl imines.) A flame dried 50 mL 2-neck flask fitted with rubber septa was cycled between vacuum and Ar atmosphere 3 times. A rubber septum was removed and the flask fitted quickly with a thermometer. A rubber septum was briefly removed to allow oxime (7 mmol, 1 eq.) to be added. NEt3 (7 mmol, 1 eq.) was then added via syringe. The reagents were dissolved in a CH2Cl2 (5 mL)/ Hexane (5 mL) mixture (0.7 M solution) and the solution cooled to -40 °C with stirring. Diphenylphosphine chloride (7 mmol, 1 eq. as 1 M solution in CH2Cl2) was then added to the flask over 30 minutes whilst maintaining a temperature of -40 °C. The reaction was then warmed to rt and allowed to stir for another 2.5 h. The reaction was then filtered and concentrated in vacuuo. The crude material was then dissolved in Acetone (20 mL) and filtered again to remove insoluble material. The products were then purified by column chromatography. 55148442-1 Preparation of (E)-N-phenyl-2,3-dihydro-1H-inden-1-imine Standard grade toluene (100 mL) was added under Ar atmosphere to a Schlenk flask containing activated 3Å molecular sieves (20 g, 20 % w/v). The flask was sealed and the toluene allowed to dry for 72 h. A 50 mL Schlenk flask fitted with rubber septum and charged with magnetic stirrer was flame dried under vacuum. The flask was cycled between vacuum and Ar atmosphere 3 times and the rubber septum briefly removed to allow addition of indanone (25 mmol, 1 eq.) and activated 4Å molecular sieves (10 g, 0.5 w/v). Aniline (30 mmol, 1.2 eq.) was then added via syringe followed by the dried toluene (20 mL) via syringe. The reaction was then allowed to stir at rt under Ar atmosphere for 16 h. The reaction was then concentrated in vacuuo and the resulting oil was triturated from hexane at 0 °C. The solid resulting from this was then washed extensively with hexane. General Procedure for hydrogenation of N-diphenylphosphinoyl imines: A microwave vial charged with magnetic stirrer bar and fitted with rubber septum was flame dried under vacuum. The vial was cooled to rt and then cycled between vacuum and Ar atmosphere three times. Working quickly, the rubber septum was removed then: N-diphenylphosphinoyl imine (1 eq.), Cat. (0.01 eq.) and K 2 CO 3 (0.1 eq.) were added and the vial fitted with a crimp camp and septum. The vial was placed back under vacuum for a further 10 minutes. After cycling vacuum and argon atmosphere three more times, EtOH (0.67 M) was added via syringe, the septum pierced by two 21G needles and the vial placed directly into an autoclave which had been cycled between vacuum and Ar atmosphere 3 times. The autoclave was sealed and pressurised to 15 Bar of H2 which was subsequently vented, this was repeated two more times to displace any air in the solvent. Finally the autoclave was pressurised to 50 Bar H2 and the autoclave was then placed in an oil bath preheated to 35 °C and stirred at 700 rpm for the desired reaction time e.g.18 h. After the desired time, the autoclave was cooled to rt, carefully vented in a fume cupboard and 1,4- dimethoxybenzene (0.25 eq. [relative to N-diphenylphosphinoyl imine]) was added to the sample as internal standard. The reaction was diluted in CDCl3 (1 mL) and a small aliquot taken for 1 H NMR analysis to determine conversion. The NMR sample was retrieved and all solvent was removed in vacuo prior to chromatographic purification. Enantioselectivity was measured using chiral HPLC. 55148442-1 General Procedure for hydrogenation of (E)-N-phenyl-2,3-dihydro-1H-inden-1- imine: A microwave vial charged with magnetic stirrer bar and fitted with rubber septum was flame dried under vacuum. The vial was cooled to rt and then cycled between vacuum and Ar atmosphere three times. Working quickly, the rubber septum was removed then: (E)-N-phenyl-2,3-dihydro-1H-inden-1-imine (1 eq.), Cat. (0.01 eq.) and K 2 CO 3 (0.1 eq.) were added and the vial fitted with a crimp camp and septum. The vial was placed back under vacuum for a further 10 minutes. After cycling vacuum and argon atmosphere three more times, EtOH (0.67 M) was added via syringe, the septum pierced by two 21G needles and the vial placed directly into an autoclave which had been cycled between vacuum and Ar atmosphere 3 times. The autoclave was sealed and pressurised to 15 Bar of H 2 which was subsequently vented, this was repeated two more times to degas the solvent. Finally the autoclave was pressurised to 50 Bar H 2 and the autoclave was then placed in an oil bath preheated to 50 °C and stirred at 700 rpm for 18 h. Upon which time, the autoclave was cooled to rt, carefully vented in a fume cupboard and 1,4-dimethoxybenzene (0.25 eq. [relative to (E)-N-phenyl-2,3- dihydro-1H-inden-1-imine]) was added to the sample as internal standard. The reaction was diluted in CDCl 3 (1 mL) and a small aliquot taken for 1 H NMR analysis to determine conversion. The NMR sample was retrieved and all solvent was removed in vacuo prior to chromatographic purification. Enantioselectivity was measured using chiral HPLC. General Procedure for hydrogenation of in situ generated ketimines: A microwave vial charged with magnetic stirrer bar and fitted with rubber septum was flame dried under vacuum. The vial was cooled to rt and then cycled between vacuum and Ar atmosphere three times. The septum was briefly removed to allow addition of: activated 4Å molecular sieves (100% w/v with respect to reaction solvent), ketone (1 eq.) (if ketone was solid at rt) and amine (1 eq.) (if amine was solid at rt). If either ketone or amine were liquid at rt 1 eq. was added by microsyringe after fitting the septum. A sufficient volume of toluene to create 1M solution of ketone was then added by micro-syringe (toluene dried by standing over activated 3 Å mol. sieves for 72 h).. The reaction was placed in a preheated oil bath at 70 °C and stirred for 4 h under Ar atmosphere. 55148442-1 A separate microwave vial charged with magnetic stirrer bar and fitted with rubber septum was flame dried under vacuum. The vial was cooled to rt and then cycled between vacuum and Ar atmosphere three times. Working quickly, the rubber septum was removed then: Cat. (0.01 eq.) and K2CO3 (0.1 eq.) were added and the vial fitted with a crimp camp and septum. The vial was placed back under vacuum for a further 10 minutes. After cycling vacuum and argon atmosphere three more times and allowing the imine formation reaction to cool to rt, the solution was decanted into the vial containing the catalyst and base via syringe. EtOH (0.67 M with respect to ketone) was added via syringe to the vial in which the imine formation had taken place in two portions and subsequently decanted into the other vial each time. The septum of the vial was then pierced by two 21G needles and the vial placed directly into an autoclave which had been cycled between vacuum and Ar atmosphere 3 times. The autoclave was sealed and pressurised to 15 Bar of H 2 which was subsequently vented, this was repeated two more times to degas the solvent. Finally the autoclave was pressurised to 50 Bar H 2 and the autoclave was then placed in an oil bath preheated to 50 °C and stirred at 700 rpm for 18 h. Upon which time, the autoclave was cooled to rt, carefully vented in a fume cupboard and 1,4-dimethoxybenzene (0.25 eq. [relative to ketone]) was added to the sample as internal standard. The reaction was diluted in CDCl 3 (1 mL) and a small aliquot taken for 1 H NMR analysis to determine conversion. The NMR sample was retrieved and all solvent was removed in vacuo prior to chromatographic purification. Enantioselectivity was measured using chiral HPLC. Specific Procedure for N-benzyl substrate: N-benzyl-2,3-dihydro-1H-inden-1-amine A microwave vial charged with magnetic stirrer bar and fitted with rubber septum was flame dried under vacuum. The vial was cooled to rt and then cycled between vacuum and Ar atmosphere three times. The septum was briefly removed to allow addition of: activated 4Å molecular sieves (100% w/v with respect to reaction solvent), indanone (33.0 mg, 0.25 mmol, 1eq.). Benzylamine (27 µL, 0.25 mmol, 1 eq.) was added via micro-syringe and then toluene (dried by standing over activated 3 Å mol. Sieves for 72 h) (0.25 mL) was added. The reaction was placed in a preheated oil bath at 70 °C and stirred for 4 h under Ar atmosphere. A separate microwave vial charged with magnetic stirrer bar and fitted with rubber septum was flame dried under vacuum. The vial was cooled to rt and then cycled between vacuum and Ar atmosphere three times. Working quickly, the rubber septum 55148442-1 was removed then: Cat. (2.1 mg, 0.0025 mmol, 0.01 eq.) and K2CO3 (3.5 mg, 0.025 mmol, 0.1 eq.) were added and the vial fitted with a crimp camp and septum. The vial was placed back under vacuum for a further 10 minutes. After cycling vacuum and argon atmosphere three more times and allowing the imine formation reaction to cool to rt, the solution was decanted into the vial containing the catalyst and base via syringe. EtOH (0.67 M with respect to ketone) was added via syringe to the vial in which the imine formation had taken place in two portions and subsequently decanted into the other vial each time. The septum of the vial was then pierced by two 21G needles and the vial placed directly into an autoclave which had been cycled between vacuum and Ar atmosphere 3 times. The autoclave was sealed and pressurised to 15 Bar of H2 which was subsequently vented, this was repeated two more times to degas the solvent. Finally the autoclave was pressurised to 50 Bar H 2 and the autoclave was then placed in an oil bath preheated to 50 °C and stirred at 700 rpm for 18 h. Upon which time, the autoclave was cooled to rt, carefully vented in a fume cupboard and 1,4-dimethoxybenzene (8.6 mg, 0.0625 mmol, 0.25 eq. [relative to indanone]) was added to the sample as internal standard. The reaction was diluted in CDCl 3 (1 mL) and a small aliquot taken for 1 H NMR analysis to determine conversion. The NMR sample was retrieved and all solvent was removed in vacuo. The reaction was then dissolved in CH 2 Cl 2 (5 mL) and then Boc 2 O (43.7 mg, 0.20 mmol, 0.8 eq.) and NEt 3 (70 µL, 0.5 mmol, 2 eq.) were added. The reaction was then stirred at rt for 72 h. The reaction was diluted with water (15 mL) and extracted with CH2Cl2 (3 x 5 mL) and the combined organic layers dried over Na2SO4. The solution was filtered and solvent removed before removing remaining imine by flash column chromatography on silica gel using hexane/ EtOAc (14:1) as eluent. The resultant Boc- amine product was not analytically pure but was now amenable to HPLC analysis. N-phenyl-2,3-dihydro-1H-inden-1-amine HPLC analysis conducted with Daicel Chiralcel OD-H column, hexane/iPrOH (95:5) as mobile phase with a 0.5 mL/min flowrate. t R (R)= 14.61 min (3%) t R (S)= 15.70 min (97%.) ee = 94%. 55148442-1 N-(4-methoxyphenyl)-2,3-dihydro-1H-inden-1-amine HPLC analysis conducted with Daicel Chiralcel OD-H column, hexane/iPrOH (95:5) as mobile phase with a 0.5 mL/min flowrate. t R (R)= 16.06 min (5%) t R (S)= 16.95 min (95%.) ee = 90%. N-benzyl-2,3-dihydro-1H-inden-1-amine After conversion to its N-Boc derivative (see experimental procedure): HPLC analysis conducted with Daicel Chiralcel OD-H column, hexane/iPrOH (99:1) as mobile phase with a 0.5 mL/min flowrate. t R (R)= 9.59 min (2%) t R (S)= 11.63 min (98%.) ee= 96% N-(1-phenylethyl)aniline HPLC analysis conducted with Daicel Chiralcel OD-H column, hexane/iPrOH (99:1) as mobile phase with a 0.5 mL/min flowrate. tR(R)= 17.97 min (18%) tR(S)= 21.56 min (82%.) ee= 64%. N-(2,3-dihydro-1H-inden-1-yl)-P,P-diphenylphosphinic amide HPLC analysis conducted with Daicel Chiralcel OD-H column, hexane/iPrOH (90:10) as mobile phase with a 0.5 mL/min flowrate. t R (S)= 17.46 min (6%) t R (S)= 21.57 min (94%.) ee= 88%. 55148442-1 Results Asymmetric Hydrogenation of ketimines When catalysts are formed in situ, the ligands are denoted L1a-L1e and pre-catalysts, Mn/L1a etc. Table 1 shows that a diphenylphosphinyl-imine can be hydrogenated in the presence of the Mn catalysts, including those formed in situ. Variation of pyridine structure leads to unpredictable changes in enantioselectivity. Table 2 shows that an N-aryl imine can be hydrogenated. The amino-indane products are potential precursors to various compounds of value, including, for example, the drug Rasagiline (see: D. Brenna et al., Org. Biomol. Chem.2017, 15, 5685). Tables 4-6 show that ketimines can be prepared in situ from two different aromatic primary amines or an alkyl amine. Table 1: Enantioselective hydrogenation of an N-diphenylphosphinyl-imine. a: Yield refers to % of the converted starting material to form reduced product. Yields of amines obtained after chromatographic purification are in brackets. b Enantioselective determined by HPLC: see experimental for further details. Table 2: Enantioselective hydrogenation of an N-aryl-imine. aYield refers to % of the converted starting material to form reduced product relative to internal standard; conversion corresponds to % imine remaining. Yields of amines obtained after chromatographic purification are in brackets. b Enantioselectivity determined by HPLC: see experimental for further details. 55148442-1 Table 3: Enantioselective hydrogenation of an in-situ synthesised N-aryl-imine. aYield refers to % of the converted starting material to form reduced product relative to internal standard; conversion corresponds to % imine remaining. Yields of amines obtained after chromatographic purification are in brackets. b Enantioselectivity determined by HPLC: see experimental for further details. Table 4: Enantioselective hydrogenation of an in-situ synthesised N-aryl-imine with Para- Methoxy-Phenyl (PMP) group. aYield refers to % of the converted starting material to form reduced product relative to internal standard; conversion corresponds to % imine remaining. Yields of amines obtained after chromatographic purification are in brackets. b Enantioselectivity determined by HPLC: see experimental for further details. Table 5: Enantioselective hydrogenation of an in-situ synthesised N-alkyl-imine with benzyl group. aYield refers to % of the converted starting material to form reduced product relative to internal standard; conversion corresponds to % imine remaining. b Enantioselectivity determined by HPLC after conversion to N-Boc derivative: see experimental for further details. 55148442-1 Table 6: Enantioselective hydrogenation of an in-situ synthesised acyclic N-aryl-imine. aYield refers to % of the converted starting material to form reduced product relative to internal standard; conversion corresponds to % imine remaining. Yields of amines obtained after c hromatographic purification are in brackets. b Enantioselectivity determined by HPLC: see experimental for further details. 55148442-1



 
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