Field of the Invention

The present invention relates to a complex of the Formula 2, a compound of the Formula 1 , a phosphinous acid borane of the Formula 4, or a salt and/or co-crystal thereof, use of the compound of the Formula 1 for the synthesis of the complex of the Formula 2, a process for the synthesis of the compound of the Formula 1 , and use of the complex of the Formula 2 for the asymmetric hydrogenation of:

(i) at least one cyclic enamide; and/or

(ii) at least one imine.

Background to the Invention

Asymmetric hydrogenation is of great importance in the pharmaceutical and agrochemical sectors. Transition metal complexes capable of performing asymmetric hydrogenation are known, but for certain substrates the conversion or yield and/or enantiomeric excess of the asymmetric hydrogenation products is not always good. In particular, substrates such as cyclic enamides and imines invariably give low conversion or yield and/or enantiomeric excesses. Consequently, new transition metal catalysts suitable for asymmetric hydrogenation are sought which provide asymmetric hydrogenation products in high yield and enantiomeric excess for those difficult substrates.

Phosphino-oxazoline compounds and a method of preparation thereof are disclosed in [1], but despite mentioning that said compounds may be coordinated with metals to catalyse asymmetric hydrogenation reactions, this patent application does not disclose the provision of asymmetric hydrogenation products in high yield and enantiomeric excess. Likewise, [2] and [3] also cannot disclose the provision of asymmetric hydrogenation products in high yield and enantiomeric excess because, although ligand scaffolds for asymmetric catalysis are disclosed in these scientific articles, they do not disclose asymmetric hydrogenation. Document [4] discloses asymmetric hydrogenation of imines using phosphine-oxazoline iridium complexes built around a conformationally restricted backbone as catalysts. Document [5] discloses chemistry of the H ₃ B(CH ₃ )2P group and mentions trihydro(methyl dimethylphosphinite-P)-boron.

Thus, it is a problem solved by the present invention to provide in high yield and enantiomeric excess, novel transition metal complexes suitable as catalysts for efficient asymmetric hydrogenation of difficult substrates such as cyclic enamides and imines.

In addition it is a problem also solved by the present invention to provide new compounds which may be used as ligands in the synthesis of said novel transition metal complexes. Therefore, those new ligands are intermediates in the process of synthesis of the transition metal complexes of the invention.

Brief Description of the Invention

The present invention relates to a complex of the Formula 2

Formula 2

wherein,

M is a transition metal selected from Ir, Rh, Co, Ni, Pd, Pt, Cu, Ag, Au, Ru and Fe;

Ru and R12 are each independently selected from H, C1-C6 alkyl, C5-C10 aryl and C1-C6 alkyl substituted with a C5-C10 aryl moiety;

R21 and R22 are each independently selected from H, C1-C6 alkyl, C5-C10 aryl and C1-C6 alkyl substituted with a C5-C10 aryl moiety;

R3 and R ₄ are each independently selected from C1-C10 alkyl;

Li and L2 are each independently selected from C2-C10 alkene, or Li and L2 together represent a C4-C10 dialkene;

A ^" is a counter-anion selected from tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetrakis(phenyl)borate, tetrafluoroborate, hexafluoroantimonate, trifluoromethanesulfonate and hexafluorophosphate; and

n is a whole number represented by an oxidation state of M;

with the proviso that

(i) one and only one of Ru and R12 is H; and

(ii) R3 and R ₄ are different.

In one embodiment of the complex of the Formula 2 of the present invention

M is selected from Ir, Rh, Co, Ni, Pd and Pt;

R11 and R12 are each independently selected from H, C1-C6 alkyl and C5-C10 aryl;

R21 and R22 are each independently selected from H, C1-C6 alkyl and C1-C6 alkyl substituted with a C5-C10 aryl moiety;

R3 and R ₄ are each independently selected from C1-C10 alkyl;

Li and L2 are each independently selected from C2-C8 alkene, or Li and L2 together represent a C ₄ -Ce dialkene; A ^" is a counter-anion selected from tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetrakis(phenyl)borate and tetrafluoroborate; and

n is a whole number between 0 and 4,

with the proviso that

(i) one and only one of Ri i and Ri2 is H;

(ii) R3 and R ₄ are different; and

(iii) one and only one of R21 and R22 is H.

In addition, the present invention Formula 1 , or a co-crystal thereof

Formula 1

wherein,

R11 and R12 are each independently selected from H, C1-C6 alkyi, C5-C10 aryl and C1-C6 alkyi substituted with a C5-C10 aryl moiety;

R21 and R22 are each independently selected from H, C1-C6 alkyi, C5-C10 aryl and C1-C6 alkyi substituted with a C5-C10 aryl moiety;

R3 and R ₄ are each independently selected from C1-C10 alkyi;

with the proviso that

(i) one and only one of Rn and R12 is H; and

(ii) R3 and R ₄ are different.

In one embodiment of the compound of the Formula 1 of the present invention

R11 and R12 are each independently selected from H, C1-C6 alkyi and C5-C10 aryl;

R21 and R22 are each independently selected from H, C1-C6 alkyi and C1-C6 alkyi substituted with a C5-C10 aryl moiety; and

R3 and R ₄ are each independently selected from C1-C10 alkyi,

with the proviso that

(i) one and only one of Rn and R12 is H;

(ii) R3 and R ₄ are different; and

(iii) one and only one of R21 and R22 is H.

Moreover, the present invention relates to a phosphinous acid borane of the Formula 4, or a salt and/or co-crystal thereof,

Formula 4 wherein R3 and R ₄ are each independently selected from C1-C10 alkyl,

with the proviso that R3 and R ₄ are different.

Furthermore, the present invention relates to use of the compound of the Formula 1 , or a co- crystal thereof, for the synthesis of the complex of the Formula 2.

In one embodiment of the use of the compound of the Formula 1 , or a co-crystal thereof, for the synthesis of the complex of the Formula 2 of the present invention, said synthesis is performed by reacting a compound of the Formula 1 , or a co-crystal thereof, with an amine base and subsequently reacting the resulting product with

(i) a metal complex of the formula [ML.1L.2XJ2, followed by treatment with Q ^z+ zA ^_ ; or

(ii) a metal complex of the formula [M(l_il_2)2] ⁿ⁺ nA ^" , wherein

M is a transition metal selected from Ir, Rh and Co;

Li and L2 are each independently selected from a C2-C10 alkene, or Li and L2 together represent a C ₄ -Cio dialkene;

X is a halogen;

Q is an alkali metal or an alkaline earth metal;

z is a whole number represented by an oxidation state of Q;

A ^" is a counter-anion selected from tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetrafluoroborate, tetrakis(phenyl)borate, hexafluoroantimonate, trifluoromethanesulfonate and hexafluorophosphate; and

n is a whole number represented by an oxidation state of M.

The present invention additionally relates to a process for the synthesis of the compound of the Formula 1 , or a co-crystal thereof, wherein said compound is synthesized by:

(i) reaction of an aminooxazoline of the Formula 3

Formula 3 with a phosphinous acid borane of the Formula 4, or a salt and/or co-crystal thereof, which has been previously reacted with a sulfonic anhydride and a base

Formula 4; cyclisation of a aminophosphine alcohol of the Formula 6

Formula 6

wherein

Rii and R12 are each independently selected from H, C1-C6 alkyl, C5-C10 aryl and C1-C6 alkyl substituted with a C5-C10 aryl moiety;

R21 and R22 are each independently selected from H, C1-C6 alkyl, C5-C10 aryl and C1-C6 alkyl substituted with a C5-C10 aryl moiety;

R3 and R ₄ are each independently selected from C1-C10 alkyl;

with the proviso that

(i) one and only one of Rn and R12 is H; and

(ii) R3 and R ₄ are different.

In one embodiment of the process for the synthesis of the compound of the Formula 1 , or a co- crystal thereof, of the present invention, the aminooxazoline of the Formula 3 is synthesized by reaction of an alpha-amino acid with a 1 ,2-amino alcohol; the phosphinous acid borane of the Formula 4 is synthesized by acid hydrolysis of an amino phosphine borane of the Formula 7

Formula 7;

and

the aminophosphine alcohol of the Formula 6 is synthesised by reaction of an amino alcohol of the Formula 5

Formula 5 with a phosphinous acid borane of the Formula 4, or a salt and/or co-crystal thereof, which has been previously reacted with a sulfonic anhydride and a base.

Furthermore, the present invention relates to the use of the complex of the Formula 2 for the asymmetric hydrogenation of:

(i) at least one cyclic enamide; and/or

(ii) at least one imine,

wherein said asymmetric hydrogenation is performed under a hydrogen atmosphere.

Detailed Description of the Invention

The present invention relates to a complex of the Formula 2

Formula 2.

In addition, the present invention Formula 1 , or a co-crystal thereof

Formula 1.

In said complex of Formula 2 and the compound of the Formula 1 of the present invention

Rii and R12 are each independently selected from H, a C1-C6 alkyl, a C5-C10 aryl and a C1-C6 alkyl substituted with a C5-C10 aryl moiety;

R21 and R22 are each independently selected from H, a C1-C6 alkyl, a C5-C10 aryl and a C1-C6 alkyl substituted with a C5-C10 aryl moiety; R3 and R ₄ are each independently selected from C1-C10 alkyl;

with the proviso that

(i) one and only one of Rn and R12 is H; and

(ii) R3 and R ₄ are different.

In another more preferred proviso of the present invention,

(i) one and only one of Rn and R12 is H;

(ii) R3 and R ₄ are different; and

(iii) one and only one of R21 and R22 is H.

Bearing in mind said provisos, in a preferred embodiment, Rn and R12 are each independently selected from H, a C1-C6 alkyl and a C5-C10 aryl; and R21 and R22 are each independently selected from H, a C1-C6 alkyl and a C1-C6 alkyl substituted with a C5-C10 aryl moiety. More preferably, R11 and R12 and R21 and R22 are each independently selected from H and C1-C6 alkyl. Furthermore preferably, Rn and R12 and R21 and R22 are each independently selected from H, methyl, ethyl, n-propyl, /sopropyl, n-butyl, / ^' so-butyl, sec-butyl and te/t-butyl.

Additionally bearing in mind said proviso that (ii) R ₃ and R ₄ are different, in a preferred embodiment, R ₃ and R ₄ are each independently selected from C1-C10 alkyl, preferably C1-C6 alkyl, more preferably C1-C4 alkyl, wherein said alkyl group is a linear, branched or cyclic alkyl group, furthermore preferably a linear or branched alkyl group, even more preferably methyl, ethyl, n- propyl, /sopropyl, n-butyl, / ^' so-butyl, sec-butyl or tert-butyl. Most preferably, R3 is methyl and R ₄ is tert-butyl, and/or where R3 is tert-butyl and R ₄ is methyl. Said limitations also apply to the following embodiments relating to the complex of Formula 2 and the compound of the Formula 1 of the present invention, as well as to the aminooxazoline of the Formula 3, the phosphinous acid borane of the Formula 4, the aminophosphine alcohol of the Formula 6, the amino alcohol of the Formula 5 and the aminophosphine borane of the Formula 7, as described in the following. In one especially preferred embodiment of the complex of Formula 2 and/or the compound of the Formula 1 of the present invention,

R11 and R12 are each independently selected from H, C1-C6 alkyl and C5-C10 aryl;

R21 and R22 are each independently selected from H, C1-C6 alkyl and C1-C6 alkyl substituted with a C5-C10 aryl moiety; and

R3 and R ₄ are each independently selected from C1-C10 alkyl, more preferably C1-C6 alkyl, furthermore preferably C1-C4 alkyl, most preferably methyl, ethyl, /sopropyl and tert-butyl, with the proviso that,

(i) one and only one of Rn and R12 is H;

(ii) R3 and R ₄ are different; and

(iii) one and only one of R21 and R22 is H.

Specific examples of the compounds of the Formula 1 of the present invention include the following:

In another more preferred embodiment of the complex of Formula 2 and/or the compound of the Formula 1 of the present invention, and bearing in mind the aforementioned provisos, Ri i and R12 are each independently selected from H and C1-C6 alkyl;

R21 and R22 are each independently selected from H and C1-C6 alkyl; and

R3 and R ₄ are each independently selected from C1-C6 alkyl, furthermore preferably C1-C4 alkyl, most preferably methyl, ethyl, / ^' so-propyl and te/t-butyl.

In an even more preferred embodiment of the complex of Formula 2 and/or the compound of the Formula 1 of the present invention, and bearing in mind the aforementioned provisos, R11 and R12 are each independently selected from H and C3-C4 alkyl;

R21 and R22 are each independently selected from H and C3-C4 alkyl; and

R3 and R4 are each independently selected from C1-C4 alkyl, most preferably methyl, ethyl, / ^' so- propyl, and tert-butyl.

In a furthermore preferred embodiment of the complex of Formula 2 and/or the compound of the Formula 1 of the present invention,

R11 and R12 are each independently selected from H, / ^' so-propyl and tert-butyl;

R21 and R22 are each independently selected from H and / ^' so-propyl; and

R3 and R4 are each independently selected from methyl, ethyl, / ^' so-propyl, and te/t-butyl, with the proviso that,

(i) one and only one of Rn and R12 is H;

(ii) R3 and R ₄ are different; and

(iii) one and only one of R21 and R22 is H.

In the co-crystal of the compound of the Formula 1 of the present invention, said co-crystal is selected from water, methanol, ethanol, dichloromethane, ethyl acetate, HCI, h PCu and h SC co-crystals, preferably water, ethanol and dichloromethane co-crystals.

In the complex of Formula 2 of the present invention, M is a transition metal selected from Ir, Rh, Co, Ni, Pd, Pt, Cu, Ag, Au, Ru and Fe. Bearing in mind the foregoing embodiments, M is preferably selected from Ir, Rh, Co, Ni, Pd and Pt, more preferably Ir, Rh and Co, yet more preferably Ir and Rh. Most preferably, M is Ir.

In the complex of Formula 2 of the present invention, l_i and L ₂ are each independently selected from a C2-C10 alkene, or l_i and L ₂ together represent a C ₄ -Cio dialkene. Preferably, l_i and L ₂ together represent a C ₄ -Cio dialkene and said C ₄ -Cio dialkene is preferably selected from 1 ,3- butadiene, isoprene, cyclooctadiene (1 ,5-cyclooctadiene, COD) and norbornadiene, more preferably, cyclooctadiene and norbornadiene. However, when l_i and L ₂ are each independently selected from a C2-C10 alkene, said C2-C10 alkene is preferably selected from ethene, propene, butene, pentene, cyclopentene, hexene, cyclohexene, cycloheptene, cyclooctene and norbornene, more preferably, ethene, propene, butene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and norbornene, furthermore preferably ethene, propene, butene, cyclopentene and cyclohexene.

In the complex of Formula 2 of the present invention, A ^" is a counter-anion selected from tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BArF), tetrafluoroborate, tetrakis(phenyl)borate, hexafluoroantimonate, trifluoromethanesulfonate and hexafluoroophosphate, preferably tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetrafluoroborate and tetrakis(phenyl)borate, more preferably A ^" is tetrakis[3,5-bis(trifluoromethyl)phenyl]borate or tetrafluoroborate.

In the complex of Formula 2 of the present invention, n is a whole number represented by an oxidation state of M. Preferably, n is a whole number selected from 0, 1 , 2, 3, 4, 5 and 6, more preferably selected from 0, 1 , 2, 3 or 4, furthermore preferably selected from 1 or 2.

Thus, in one especially preferred embodiment of the complex of the Formula 2,

M is selected from Ir, Rh, Co, Ni, Pd and Pt;

R11 and R12 are each independently selected from H, C1-C6 alkyl and C5-C10 aryl;

R21 and R22 are each independently selected from H, C1-C6 alkyl and C1-C6 alkyl substituted with a C5-C10 aryl moiety;

R3 and R ₄ are each independently selected from C1-C10 alkyl;

Li and L2 are each independently selected from C2-C8 alkene, or Li and L2 together represent a C ₄ -Ce dialkene; A ^" is a counter-anion selected from tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetrakis(phenyl)borate and tetrafluoroborate; and

n is a whole number between 0 and 4,

with the proviso that

(i) one and only one of Rn and R12 is H;

(ii) R3 and R ₄ are different; and

(iii) one and only one of R21 and R22 is H.

Specific examples of the complex of Formula 2 of the present invention include the following:

Bearing in mind the aforementioned provisos, in another more preferred embodiment of the complex of Formula 2 of the present invention, and bearing in mind the aforementioned provisos, M is selected from Ir, Rh and Co;

R11 and R12 are each independently selected from H and C1-C6 alkyl;

R21 and R22 are each independently selected from H and C1-C6 alkyl;

R3 and R ₄ are each independently selected from C1-C6 alkyl;

Li and L2 together represent a dialkene selected from cyclooctadiene or norbornadiene; A ^" is a counter-anion selected from tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetrakis(phenyl)borate and tetrafluoroborate anions; and

n is a whole number between 0 and 2.

In an even more preferred embodiment of the complex of Formula 2 of the present invention, and bearing in mind the aforementioned provisos,

M is selected from Ir and Rh;

Rii and R12 are each independently selected from H and C3-C4 alkyl;

R21 and R22 are each independently selected from H and C3-C4 alkyl;

R3 and R ₄ are each independently selected from C1-C4 alkyl, most preferably methyl, ethyl, iso- propyl, and tert-butyl;

Li and L2 together represent cyclooctadiene;

A ^" is a counter-anion selected from tetrakis[3,5-bis(trifluoromethyl)phenyl]borate and tetrafluoroborate anions; and

n is 1.

In a furthermore preferred embodiment of the complex of Formula 2 of the present invention, M is Ir;

R11 and R12 are each independently selected from H, / ^' so-propyl and tert-butyl;

R21 and R22 are each independently selected from H and / ^' so-propyl;

R3 and R4 are each independently selected from a C1-C4 alkyl;

Li and L2 together represent cyclooctadiene;

A ^" is a counter-anion selected from tetrakis[3,5-bis(trifluoromethyl)phenyl]borate and tetrafluoroborate; and

n is 1 ,

with the proviso that,

(i) one and only one of R11 and R12 is H;

(ii) R3 and R4 are different; and

(iii) one and only one of R21 and R22 is H.

The present invention also relates to a phosphinous acid borane of the Formula 4, or a salt and/or co-crystal thereof,

Formula 4

wherein R3 and R4 are each independently selected from C1-C10 alkyl,

with the proviso that R3 and R4 are different (i.e. the phosphinous acid borane is chiral). Preferably, R3 and R4 are each independently selected from C1-C6 alkyl, furthermore preferably C1-C4 alkyl, wherein said alkyl group is a linear, branched or cyclic alkyl group, furthermore preferably a linear or branched alkyl group, even more preferably methyl, ethyl, n-propyl, iso- propyl, n-butyl, / ^' so-butyl, sec-butyl or tert-butyl, yet more preferably methyl, ethyl, /sopropyl and tert-butyl. Most preferably, the phosphinous acid borane of the Formula 4 is that where R3 is methyl and R ₄ is tert-butyl, and/or where R3 is tert-butyl and R ₄ is methyl.

In the aforementioned phosphinous acid borane of the Formula 4 of the present invention, each salt referred to therein is independently selected from the lithium, sodium, potassium, magnesium and ammonium salts, and each co-crystal referred to therein is independently selected from water, methanol, ethanol, dichloromethane, ethyl acetate, HCI, H3PO4 and H2SO4 co-crystals, preferably water, ethanol and dichloromethane co-crystals.

The present invention additionally relates to use of the compound of the Formula 1 , or a co-crystal thereof, for the synthesis of the complex of the Formula 2, as per Scheme 1.

Scheme 1.

In one embodiment of the use according to the present invention, the synthesis of the complex according to Formula 2, as described herein, is performed by reacting a compound of the Formula 1 , or a co-crystal thereof, as described herein, with an amine base and subsequently reacting the resulting product with

(i) a metal complex of the formula [ML.1 L.2XJ2, followed by treatment with Q ^z+ zA ^_ ; or

(ii) a metal complex of the formula [Μ(Ι_ιΙ_2)2] ^η+ ηΑ ^_ ,

wherein

M is a transition metal selected from Ir, Rh and Co, more preferably Ir or Rh, most preferably Ir; Li and L ₂ are each independently selected from a C2-C10 alkene, or l_i and L ₂ together represent a C4-C10 dialkene;

X is a halogen;

Q is an alkali metal or an alkaline earth metal;

z is a whole number represented by an oxidation state of Q;

A ^" is a counter-anion selected from tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetrafluoroborate, tetrakis(phenyl)borate, hexafluoroantimonate, trifluoromethanesulfonate and hexafluorophosphate; and n is a whole number represented by an oxidation state of M.

In a more preferred embodiment of the use of the compound of the Formula 1 , or a co-crystal thereof, the amine base is furthermore preferably a cyclic amine base, even more preferably a cyclic amine base selected from pyrrolidine, piperadine, piperazine, morpholine and pyridine, still more preferably pyrrolidine and piperadine.

In another more preferred embodiment of the use of the compound of the Formula 1 , or a co- crystal thereof, and l_2 together represent a C4-C10 dialkene (as disclosed in the foregoing), and said C4-C10 dialkene is even more preferably selected from 1 ,3-butadiene, isoprene, cyclooctadiene (1 ,5-cyclooctadiene, COD) and norbornadiene, furthermore preferably, cyclooctadiene and norbornadiene. However, as disclosed in the foregoing, when Li and L2 are each independently selected from a C2-C10 alkene, said C2-C10 alkene is preferably selected from ethene, propene, butene, pentene, cyclopentene, hexene, cyclohexene, cycloheptene, cyclooctene and norbornene, more preferably, ethene, propene, butene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and norbornene, furthermore preferably ethene, propene, butene, cyclopentene and cyclohexene.

In addition, in another more preferred embodiment of the use of the compound of the Formula 1 , or a co-crystal thereof, X is selected from F, CI and Br, even more preferably CI.

Moreover, in another more preferred embodiment of the use of the compound of the Formula 1 , or a co-crystal thereof, Q is an alkali metal or an alkaline earth metal, even more preferably an alkali metal or an alkaline earth metal selected from lithium, sodium, potassium, magnesium and calcium, furthermore preferably selected from sodium and potassium. Since z is a whole number represented by an oxidation state of Q, when Q is an alkali metal, z is 1 , and when Q is an alkaline earth metal, z is 2.

In another more preferred embodiment of the use of the compound of the Formula 1 , or a co- crystal thereof, as stated in the foregoing, A ^" is a counter-anion selected from tetrakis[3,5- bis(trifluoromethyl)phenyl]borate (BArF), tetrafluoroborate, tetrakis(phenyl)borate, hexafluoroantimonate, trifluoromethanesulfonate and hexafluoroophosphate, yet more preferably tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, tetrafluoroborate and tetrakis(phenyl)borate, furthermore preferably A ^" is tetrakis[3,5-bis(trifluoromethyl)phenyl]borate or tetrafluoroborate. In yet another more preferred embodiment of the use of the compound of the Formula 1 , or a co- crystal thereof, as stated in the foregoing, n is a whole number represented by an oxidation state of M. Preferably, n is a whole number selected from 0, 1 , 2, 3, 4, 5 and 6, more preferably selected from 0, 1 , 2, 3 or 4, furthermore preferably selected from 1 or 2.

In an especially preferred embodiment of the use of the compound of the Formula 1 , or a co- crystal thereof, of the present invention, the amine base is a cyclic amine base, the metal complex is [M(cyclooctadiene)X]2 or [M(norbornadiene)X]2, and Q ^z+ zA ^" is sodium tetrakis[3,5- bis(trifluoromethyl)phenyl]borate potassium tetrakis[3,5-bis(trifluoromethyl)phenyl]boratem, sodium tetrafluoroborate or potassium tetrafluoroborate. Even more preferably, in the use of the compound of the Formula 1 , the amine base is a cyclic amine, the metal complex is [M(cyclooctadiene)X]2, and Q ^z+ zA ^" is sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate or sodium tetrafluoroborate.

In an even more preferred embodiment of the use of the compound of the Formula 1 , or a co- crystal thereof, of the present invention,

the amine base is a cyclic amine;

M is selected from Ir, Rh and Co;

Rii and R12 are each independently selected from H and C1-C6 alkyl;

R21 and R22 are each independently selected from H and C1-C6 alkyl;

R3 and R ₄ are each independently selected from C1-C6 alkyl;

Li and L ₂ together represent a dialkene selected from cyclooctadiene or norbornadiene;

X is selected from F, CI and Br;

Q is selected from sodium and potassium;

z is 1 ;

A ^" is a counter-anion selected from tetrakis[3,5-bis(trifluoromethyl)phenyl]borate and tetrafluoroborate anions; and

n is a whole number between 0 and 2,

with the proviso that

(i) one and only one of R11 and R12 is H; and

(ii) R3 and R ₄ are different.

In a yet more preferred embodiment of the use of the compound of the Formula 1 , or a co-crystal thereof, of the present invention,

the amine base is a cyclic amine;

M is selected from Ir and Rh;

R11 and R12 are each independently selected from H and C3-C4 alkyl;

R21 and R22 are each independently selected from H and C3-C4 alkyl;

R3 and R ₄ are each independently selected from C1-C4 alkyl, most preferably methyl, ethyl, iso- propyl, and tert-butyl;

Li and L ₂ together represent cyclooctadiene;

X is CI;

Q is selected from sodium and potassium;

z is 1 ;

A ^" is a counter-anion selected from tetrakis[3,5-bis(trifluoromethyl)phenyl]borate and tetrafluoroborate anions; and

n is 1 ,

with the proviso that (i) one and only one of Rn and R12 is H; and

(ii) R3 and R ₄ are different.

In a furthermore preferred embodiment of the use of the compound of the Formula 1 , or a co- crystal thereof, of the present invention,

the amine base is pyrrolidine;

M is Ir;

R11 and R12 are each independently selected from H, / ^' so-propyl and tert-butyl;

R21 and R22 are each independently selected from H and / ^' so-propyl;

R3 and R ₄ are each independently selected from a Ci-C ₄ alkyl;

Li and L2 together represent cyclooctadiene;

X is CI;

Q is sodium;

z is 1 ;

A ^" is a counter-anion selected from tetrakis[3,5-bis(trifluoromethyl)phenyl]borate and tetrafluoroborate; and

n is 1 ,

with the proviso that,

(i) one and only one of Rn and R12 is H;

(ii) R3 and R ₄ are different; and

(iii) one and only one of R21 and R22 is H.

The present invention also relates to a process for the synthesis of the compound of the Formula 1 , or a co-crystal thereof, wherein said compound is synthesized by

(i) reaction of an aminooxazoline of the Formula 3,

Formula 3 with a phosphinous acid borane of the Formula 4, or a salt and/or co-crystal thereof, which has been previously reacted with a sulfonic anhydride and a base

Formula 4; cyclisation of a aminoph

Formula 6.

In a preferred embodiment of the aforementioned process for the synthesis of the compound of the Formula 1 , or a co-crystal thereof, the aminooxazoline of the Formula 3 is synthesized by reaction of an alpha-amino acid with a 1 ,2-amino alcohol; the phosphinous acid borane of the Formula 4 is synthesized by acid hydrolysis of an amino phosphine borane of the Formula 7

Formula 7;

and

the aminophosphine alcohol of the Formula 6 is synthesised by reaction of an amino alcohol of the Formula 5

with a phosphinous acid borane of the Formula 4, or a salt and/or co-crystal thereof, which has been previously reacted with a sulfonic anhydride and a base.

Thus, in one embodiment, said compound of the Formula 1 , or a co-crystal thereof, is synthesized according to Scheme 2 or Scheme 3.

Scheme 2.

Scheme 3.

Moreover, in one embodiment, said phosphinous acid borane of the Formula 4 is synthesized as per Scheme 4.

4

Scheme 4.

In said processes, Rn , R12, R21, R22, R3 and R ₄ are defined as per the foregoing, wherein R11 and R12 are each independently selected from H, a C1-C6 alkyl, a C5-C10 aryl and a C1-C6 alkyl substituted with a C5-C10 aryl moiety;

R21 and R22 are each independently selected from H, a C1-C6 alkyl, a C5-C10 aryl and a C1-C6 alkyl substituted with a C5-C10 aryl moiety;

R3 and R ₄ are each independently selected from C1-C10 alkyl;

with the proviso that

(i) one and only one of Rn and R12 is H; and

(ii) R3 and R ₄ are different.

In another more preferred proviso of the process for the synthesis of the compound of the Formula 1 , or a co-crystal thereof, of the present invention,

(i) one and only one of R11 and R12 is H;

(ii) R3 and R ₄ are different; and

(iii) one and only one of R21 and R22 is H. Bearing in mind said provisos, in a preferred embodiment of said processes, Rn and R12 are each independently selected from H, a C1-C6 alkyi and a C5-C10 aryl; and R21 and R22 are each independently selected from H, a C1-C6 alkyi and a C1-C6 alkyi substituted with a C5-C10 aryl moiety. More preferably, Rn and R12 and R21 and R22 are each independently selected from H and C1-C6 alkyi. Furthermore preferably, Rn and R12 and R21 and R22 are each independently selected from H, methyl, ethyl, n-propyl, / ^' so-propyl, n-butyl, / ^' so-butyl, sec-butyl and tert-butyl. Additionally bearing in mind said proviso that (ii) R3 and R ₄ are different, in a preferred embodiment of said processes, R3 and R ₄ are each independently selected from C1-C10 alkyi, preferably C1-C6 alkyi, more preferably Ci-C ₄ alkyi, wherein said alkyi group is a linear, branched or cyclic alkyi group, furthermore preferably a linear or branched alkyi group, even more preferably methyl, ethyl, n-propyl, / ^' so-propyl, n-butyl, / ^' so-butyl, sec-butyl or tert-butyl. Most preferably, R3 is methyl and R ₄ is fert-butyl, and/or where R3 is tert-butyl and R ₄ is methyl.

In one especially preferred embodiment of the process for the synthesis of the compound of the Formula 1 , or a co-crystal thereof, of the present invention,

R11 and R12 are each independently selected from H, C1-C6 alkyi and C5-C10 aryl;

R21 and R22 are each independently selected from H, C1-C6 alkyi and C1-C6 alkyi substituted with a C5-C10 aryl moiety; and

R3 and R ₄ are each independently selected from C1-C10 alkyi, more preferably C1-C6 alkyi, furthermore preferably Ci-C ₄ alkyi, most preferably methyl, ethyl, / ^' so-propyl and te/t-butyl, with the proviso that,

(i) one and only one of Rn and R12 is H;

(ii) R3 and R ₄ are different; and

(iii) one and only one of R21 and R22 is H.

In another more preferred embodiment of the process for the synthesis of the compound of the Formula 1 , or a co-crystal thereof, of the present invention, and bearing in mind the aforementioned provisos,

R11 and R12 are each independently selected from H and C1-C6 alkyi;

R21 and R22 are each independently selected from H and C1-C6 alkyi; and

R3 and R ₄ are each independently selected from C1-C6 alkyi, furthermore preferably Ci-C ₄ alkyi, most preferably methyl, ethyl, / ^' so-propyl and te/t-butyl.

In an even more preferred embodiment of the process for the synthesis of the compound of the Formula 1 , or a co-crystal thereof, of the present invention, and bearing in mind the aforementioned provisos,

R11 and R12 are each independently selected from H and C3-C ₄ alkyi;

R21 and R22 are each independently selected from H and C3-C ₄ alkyi; and

R3 and R ₄ are each independently selected from Ci-C ₄ alkyi, most preferably methyl, ethyl, / ^' so- propyl, and te/t-butyl. In a furthermore preferred embodiment of the process for the synthesis of the compound of the Formula 1 , or a co-crystal thereof, of the present invention,

Rii and R12 are each independently selected from H, / ^' so-propyl and tert-butyl;

R21 and R22 are each independently selected from H and / ^' so-propyl; and

R3 and R ₄ are each independently selected from methyl, ethyl, / ^' so-propyl, and te/t-butyl, with the proviso that,

(i) one and only one of Rn and R12 is H;

(ii) R3 and R ₄ are different; and

(iii) one and only one of R21 and R22 is H.

In the aforementioned process for the synthesis of the compound of the Formula 1 , or a co-crystal thereof, of the present invention, each salt referred to therein is independently selected from the lithium, sodium, potassium, magnesium and ammonium salts, and each co-crystal referred to therein is independently selected from water, methanol, ethanol, dichloromethane, ethyl acetate, HCI, H3PO4 and H ₂ S0 ₄ co-crystals, preferably water, ethanol and dichloromethane co-crystals. In the aforementioned process for the synthesis of the compound of the Formula 1 , or a co-crystal thereof, of the present invention, each sulfonic anhydride referred to therein is independently selected from (Ch SC^O (methanesulfonic anhydride), ( -Ch -Cel-USC^O (p-toluenesulfonic anhydride) or (CFsS02)20 (trifluoromethanesulfonic anhydride). Preferably said sulfonic anhydride is (CH ₃ S0 ₂ )20.

In the aforementioned process for the synthesis of the compound of the Formula 1 , or a co-crystal thereof, of the present invention, the base referred to therein is preferably an alkyl amine base, more preferably a trialkylamine base, even more preferably a trialkylamine base selected from triethylamine or tri/ ^' so-propylamine.

In the process for the synthesis of the compound of the Formula 1 , or a co-crystal thereof, of the present invention, the most preferred sulfonic anhydride and base combination is (Ch SC^O and triethylamine.

In the aforementioned processes for the synthesis of the compound of the Formula 1 , or a co- crystal thereof, of the present invention, acid hydrolysis is performed using an aqueous acid selected from sulfuric acid, phosphoric acid, nitric acid, hydrochloric acid or mixtures thereof. Furthermore, the present invention relates to use of the complex of the Formula 2 of the present invention, as described herein, for the asymmetric hydrogenation of:

(i) at least one cyclic enamide; and/or

(ii) at least one imine,

wherein said asymmetric hydrogenation is performed under a hydrogen atmosphere.

In preferred embodiment, the complex of the Formula 2 used in the asymmetric hydrogenation is selected from complexes 2b, 2c, 2e, 2f, 2g, 2h and 2i. More preferably, when said asymmetric hydrogenation involves asymmetric hydrogenation of (i) at least one cyclic enamide, said complex is selected from complexes 2b, 2c, 2f, 2g, 2h and 2i, furthermore preferably complexes 2b, 2c, 2f, 2g and 2h, even more preferably complexes 2c, 2f, 2g, 2h and 2i; and/or

(ii) at least one imine, said complex is selected from complexes 2b, 2c, 2e, 2g and 2h, furthermore preferably complexes 2b, 2c, 2e and 2h.

Preferably, said asymmetric hydrogenation is performed using the complex of the Formula 2 as a catalyst in between 0.01 and 10 mol%, more preferably 0.1 and 5 mol% under a hydrogen atmosphere of between 1 and 1000 bar (0.1 and 100 MPa), more preferably 10 and 100 bar (1 and 10 MPa). Said asymmetric hydrogenation is ideally performed at between 0 and 100 °C, more preferably at between 10 and 50 °C, furthermore preferably at between 20 and 25 °C, with or without solvent. Nevertheless, a solvent selected from dichloromethane, chloroform, toluene, benzene, ethyl acetate or diethyl ether may be used as solvent, preferably a solvent selected from dichloromethane and toluene. Most preferably, said solvent is dichloromethane.

Preferably, the use of the complex of the Formula 2 of the present invention involves asymmetric hydrogenation of at least one cyclic enamide is a cyclic enamide which is conjugated with an aromatic ring and/or at least one imine is an imine which is conjugated with an aromatic ring. The following examples are merely intended to illustrate the present invention without limiting the scope of said invention in any way. Examples

(I) General methods:

(a) General synthesis of metal complexes of Formula 2

Metal complexes of Formula 2 are prepared according to Scheme 1 . Reaction of phosphino- oxazolines of Formula 1 with an amine base in the suitable solvent followed by reaction with a metal complex of formula [ML.1 L.2Xj2 and subsequent treatment with a salt of formula Q ^z+ zA ^" in a suitable solvent provides complexes of Formula 2.

In the following, phosphino-oxazoline compound of Formula 1 (1 eq.) was dissolved in freshly distilled pyrrolidine and the solution was stirred 16 h at 90 °C. After this period of time, pyrrolidine was removed in vacuo. When all the pyrrolidine was removed, the crude was left under vacuum at 50 °C for 30 minutes, keeping always the crude under N ₂ . A solution of [lr(COD)(CI)] ₂ (0.5 eq.) in CH2CI2 was added to the free P,N ligand via cannula or syringe. The resulting mixture was left to stir for 40 minutes at room temperature. NaBAr _F (1 eq.) was then added and the solution was stirred for 1 h at room temperature. The formation of an apolar product was observed by TLC; Rf = 0.9 (100% CH2CI2). The crude was then filtered through a small plug of silica gel (washed first with Et.20) under N2 eluting with hexaneiChbC (50-100%) mixtures. The orange fraction was collected and concentrated in vacuo to yield the desired Ir complexes of Formula 2 as orange solids. (b) General synthesis of compounds of Formula 1

Phosphino-oxazoline borane compounds of Formula 1 can be prepared by two synthetic routes as depicted in Scheme 2 and Scheme 3.

(i) The reaction of amino oxazoline of Formula 3 with the phosphinous acid borane of Formula 4 using mesylanhydride as activation agent and a base like triethylamine provides the phosphino-oxazoline borane ligands of Formula 1 , as illustrated in Scheme 2. Amino oxazolines of Formula 3 are known compounds that can be prepared by any person skilled in the art following the procedures described in [6].

Specifically, a phosphinous acid borane of Formula 4 (1 eq.) and methansulfonic anhydride (1 .2 eq.) were dissolved in CH2CI2 and the mixture was cooled down to -20 °C. Triethylamine (2.5 eq.) was slowly added and the mixture was stirred 1 h at -20 °C. Amino oxazoline of Formula 3 (1.9 eq.) was then added and the solution was stirred overnight at -20 °C. Water was added and the mixture was allowed to warm up to room temperature. The organic layer was separated and the aqueous phase was extracted twice with CH2CI2. The combined organic layers were washed twice with NaOH _aq (1 M). The organic layer was dried over MgS04 and concentrated on a rotary evaporator under reduced pressure. Purification by column chromatography on silica gel (eluting with hexane/ethyl acetate mixtures) yielded the corresponding compounds of Formula 1.

(ii) Compounds of Formula 1 can also be synthesized according the synthetic route depicted in Scheme 3. Using mesylanhydride as activation agent in the presence of a base like triethyamine, amino alcohol of Formula 5 is coupled with the phosphinous acid borane of Formula 4 and provides the aminophosphine alcohol of Formula 6. Amino alcohol of Formula 5 are known compounds that can be prepared by any person skilled in the art following the procedure described in [6]. Cyclization of aminophosphine alcohol of Formula 6 with the proper activation agent like thionylchloride and a suitable solvent provides the phosphino-oxazoline borane ligands of Formula 1 .

Specifically, a solution of phosphinous acid borane of Formula 4 (1 eq) and methansulfonic anhydride (1.5 eq.) in Ch C was cooled to -20 °C. To this solution, anhydrous triethylamine (2.5 eq.) was slowly added, and the mixture was stirred 1 h at -20 °C. An amino alcohol of Formula 5 (3 eq.) was then added and the solution was stirred overnight at -20 °C. Water was added and the mixture was allowed to warm to room temperature. The organic layer was separated and the aqueous phase was extracted twice with CH2CI2. The combined extracts were washed with brine and concentrated on a rotary evaporator under reduced pressure. Purification by column chromatography on silica gel (eluting with hexane/ethyl acetate mixtures) yielded the corresponding aminophosphine alcohol of Formula 6.

Subsequently, the aminophosphine alcohol of Formula 6 (1 eq.) was dissolved in CH2CI2 and SOC (2.4 eq.) was added dropwise at 0 °C. The solution was stirred 4 h at room temperature. The solution was cooled down to 0 °C again and saturated aqueous solution of NaHCOs was added until pH 8 - 9 was reached. The mixture was stirred 15 min at room temperature. The two phases were separated and the aqueous phase was extracted twice with ChbC ^ x 10 ml_). The combined organic layers were washed twice with brine (2 x 5 ml_). The organic layer was dried over MgS04 and concentrated on a rotary evaporator under reduced pressure. Purification by column chromatography on silica gel (hexane:EtOAc; 20%) yielded the desired phosphino- oxazoline borane ligands of Formula 1 as white solids.

(c) General synthesis of phosphinous acid boranes of Formula 4

Optically-enriched phosphinous acid boranes of Formula 4 are prepared from the selective acidic hydrolysis of the aminophosphine boranes of Formula 7, as per Scheme 4. Optically pure aminophosphines of Formula 7 were previously described in [7], [8] and [9].

(d) General asymmetric hydrogenation of cyclic enamides and imines

Cyclic enamide (1 eq.) and metal complexes of Formula 2 (as catalyst) (0.01 eq.) were weighed and placed in a stainless steel high pressure autoclave. The reactor was introduced into the glove box, and anhydrous deoxygenated solvent was added to the reaction mixture. The reactor was removed from the glove box and connected to a hydrogen manifold. With stirring, the reactor was then purged with the aid of vacuum and hydrogen, and finally charged with the desired pressure of hydrogen gas. The reactor was then removed from the hydrogen manifold, and the mixture was left under stirring to react overnight at room temperature. The reactor was then depressurized and the reaction mixture was filtered through a short pad of S1O2 and subsequently eluted with EtOAc. The resulting solution was concentrated under vacuum to afford the desired compounds. Conversion was determined by ¹ H NMR analysis. Enantiomeric excess (ee) of the resulting products is determined by chiral HPLC analysis.

(II) Working examples

Example 1: Synthesis of (+)-(S)-tert-butyl(methyl)phosphinous acid borane, 4a

The aforementioned general procedure (c) was performed wherein R3 is methyl and R ₄ is tert- butyl. (-)-(f?)-te/?-butyl(methyl)aminophosphine borane, 7a (1 .00 g, 7.5 mmol), was dissolved in a mixture of methanol (60 ml.) and water (3 ml.) and sulfuric acid (96% wt. %) (2.5 ml_, 45.4 mmol) was slowly added. The solution was stirred 2 h at 50 °C. Most of the methanol was removed in vacuo and CH2CI2 and H ₂ 0 were added. The phases were separated and the aqueous phase was extracted with CH2CI2. The combined organic phases were washed with brine and dried over MgS0 ₄ . Solvent removal under vacuum yielded 1.46 g of 4a as a semisolid (97%) which did not require further purification. [a] _D : + 4.8 (c 1 .50, CHCI ₃ ). IR (KBr) u _max : 3361 , 2971 , 2376, 1476, 921 cm ^"1 . ³¹ P-NMR (121 MHz, CDCI3) δ; 121.1 (q, J _P = 68 Hz, P-BH ₃ ) ppm. HRMS (ESI): calculated for [C ₅ Hi ₆ BOP - BH ₃ + H] ⁺ : 121 .0777, found 121 .0777.

Example 2: Synthesis of phosphino-oxazoline, 2a

The aforementioned general procedure (b)(i) was performed wherein Rn is phenyl, R21 is iso- propyl, R12 and R22 are hydrogen, R ₃ is methyl and R ₄ is tert-butyl, using (S)-tert- butyl(methyl)phosphinous acid borane, 4a (250 mg, 1.86 mmol), methansulfonic anhydride (390 mg, 2.24 mmol), CH2CI2 (8 ml_), triethylamine (0.65 ml_, 4.65 mmol) and (fl)-2-methyl-1-[(S)-4- phenyl-4,5-dihydrooxazol-2-yl]propan-1 -amine 3a (756 mg, 3.47 mmol). Purification by column chromatography on silica gel (hexane:EtOAc; 10-15%) yielded 269 mg (43%) of 1 a as a white solid.

Mp: [66-67] °C. [a] _D : + 14.8 (c 1 .00, CHCI3). I (KBr) u _max : 2964, 2380, 1660, 1466, 1 137, 916 crrr ¹ . ³¹ P-NMR (162 MHz, CDCI ₃ ) δ; 71.8-73.0 (m, P-BH ₃ ) ppm. HRMS (ESI): calculated for [Ci ₈ H ₃ 2BN ₂ OP+H] ⁺ : 335.2416, found 335.2416.

Example 3: Synthesis of phosphino-oxazoline, 1b

The aforementioned general procedure (b)(ii) was performed wherein Rn is tert-butyl, R21 is iso- propyl, R12 and R22 are hydrogen, R ₃ is methyl and R ₄ is iert-butyl. Firstly, (S)-tert- butyl(methyl)phosphinous acid borane, 4a (140 mg, 1 .08 mmol, 1 eq.), methansulfonic anhydride (230 mg, 1.29 mmol, 1 .5 eq.), CH2CI2 (7 ml_), anhydrous triethylamine (0.38 ml_, 2.70 mmol, 2.5 eq.) and amino alcohol 5b (700 mg, 3.24 mmol, 3 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 30-40%) yielded 230 mg (69%) of aminophosphine alcohol 6b as a white solid.

Mp: [140-141 ] °C. [a] _D : - 9.2 (c 0.98, CHCI3). IR (KBr) i 3256, 2961 , 2354, 1644, 1564, 1367, 1075, 945cm- ¹ . ³¹ P-NMR (202 MHz, CDCI ₃ ) δ; 70.3 - 71.8 (m, P-BH ₃ ) ppm. HRMS (ESI): calc for [Ci6H ₃₈ BN ₂ 02P +H] ⁺ : 333.2837, found 333.2836.

Subsequently, aminophosphine alcohol 6b (150 mg, 0.45 mmol, 1 eq.), CH2C (6 ml.) and SOCI2 (0.078 ml_, 1 .08 mmol, 2.4 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 20%) yielded 120 mg (85%) of 1 b as a white solid.

Mp: [55-56] °C. [a] _D : - 3.0 (c 1.00, CHCI3). IR (KBr) i 3334, 2961 , 2379, 1667, 1365, 1 138, 921 cm- ¹ . ³¹ P-NMR (202 MHz, CDCI ₃ ) δ; 69.5-73.4 (m, P-BH ₃ ) ppm. HRMS (ESI): calc for [Ci6H ₃₆ BN ₂ OP+H] ⁺ : 315.2731 , found 315.2733. E.A: calc for Ci6H ₃₆ BN ₂ OP: C, 61.15; H, 1 1 .55; N, 8.91 ; found C, 61 .33; H, 12.04; N, 8.41.

Example 4: Synthesis of phosphino-oxazoline, 1c

The aforementioned general procedure (b)(ii) was performed wherein Rn is tert-butyl, R21 is iso- propyl, R12 and R22 are hydrogen, R ₃ is tert-butyl and R ₄ is methyl. Firstly, (R)-tert- butyl(methyl)phosphinous acid borane, 4b (200 mg, 1 .49 mmol, 1 eq.), methansulfonic anhydride (31 1 mg, 1.79 mmol, 1 .5 eq.), CH2CI2 (6 ml_), anhydrous triethylamine (0.52 ml_, 3.73 mmol, 2.5 eq.) and amino alcohol 5c (600 mg, 2.77 mmol, 3 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 30-40%) yielded 336 mg (63%) of aminophosphine alcohol 6c as a white solid.

Mp: [122-123] °C. [a] _D : + 7.3 (c 1.00, CHCI ₃ ). IR (KBr) u _max : 3348, 2962, 2381 , 1658, 1526, 1366, 1066, 893 cm ^"1 . ³¹ P-NMR (162 MHz, CDCI ₃ ) δ; 72.1 -74.5 (m, P-BH ₃ ) ppm. HRMS (ESI): calc for [C16H38BN2O2P +H] ⁺ : 333.2837, found 333.2844.

Subsequently, aminophosphine alcohol 6c (280 mg, 0.84 mmol, 1 eq.), ChbC ^ ml.) and SOCI2 (0.15 ml_, 2.02 mmol, 2.4 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 20%) yielded 182 mg (69%) of 1c as a white solid.

Mp: [84-85] °C. [a] _D : + 1 1 .3 (c 1 .00, CHCI ₃ ). IR (KBr) u _max : 3349, 2960, 2384, 1669, 1365, 1 143, 1067, 918, 780 crrr ¹ . ³¹ P-NMR (202 MHz, CDCI ₃ ) δ; 71 .3-75.0 (m, P-BH ₃ ) ppm. HRMS (ESI): calc for [Ci ₆ H36BN ₂ OP+H] ⁺ : 315.2731 , found 315.2730. E.A: calc for Ci ₆ H ₃₆ BN ₂ OP: C, 61 .15; H, 1 1 .55; N, 8.91 ; found C, 61 .02; H, 1 1.93; N, 8.64.

Example 5: Synthesis of phosphino-oxazoline, 1d

The aforementioned general procedure (b)(ii) was performed wherein Rn is /sopropyl, R22 is benzyl, R12 and R21 are hydrogen, R3 is methyl and R ₄ is te/t-butyl. Firstly, (S)-tert- butyl(methyl)phosphinous acid borane, 4a (180 mg, 1 .33 mmol, 1 eq.), methansulfonic anhydride (279 mg, 1.60 mmol, 1 .5 eq.), CH2CI2 (13 ml_), anhydrous triethylamine (0.47 ml_, 3.33 mmol, 2.5 eq.) and amino alcohol 5d (1.00 g, 4 mmol, 3 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 30-50%) yielded 300 mg (62%) of aminophosphine alcohol 6d as a white solid.

³¹ P-NMR (202 MHz, CDCI3) δ; 73.8 - 71 .7 (m, P-BH ₃ ) ppm.

Subsequently, aminophosphine alcohol 6d (187 mg, 0.51 mmol, 1 eq.), CH2C (7 ml.) and SOCI2 (89 μΙ_, 1.23 mmol, 2.4 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 20%) yielded 152 mg (87%) of 1d as a white solid.

3 ¹ P-NMR (202 MHz, CDCI3) δ; 73.2 - 70.9 (m, P-BH ₃ ) ppm.

Example 6: Synthesis of phosphino-oxazoline, 1e

The aforementioned general procedure (b)(ii) was performed wherein Rn and R21 are each / ^' sopropyl, R12 and R22 are hydrogen, R ₃ is methyl and R ₄ is tert-butyl. Firstly, (S)-tert- butyl(methyl)phosphinous acid borane, 4a (134 mg, 1 .00 mmol, 1 eq.), methansulfonic anhydride (209 mg, 1.20 mmol, 1 .2 eq.), CH ₂ CI ₂ (5 ml_), anhydrous triethylamine (0.35 ml_, 2.50 mmol, 2.5 eq.), and amino alcohol 5e (607 mg, 3.00 mmol, 3 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 30-50%) yielded 81 mg (25%) of aminophosphine alcohol 6e as a white solid. Subsequently, aminophosphine alcohol 6e (80 mg, 0.25 mmol, 1 eq.), CH2Cl2 (3.5 mL) and SOC (44 μΙ_, 0.60 mmol, 2.4 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 20%) yielded 66 mg (87%) of 1e as an oily solid.

3 ¹ P-NMR (202 MHz, CDCI3) δ; 72.5 - 70.8 (m, P-BH ₃ ) ppm.

Example 7: Synthesis of phosphino-oxazoline, 1f

The aforementioned general procedure (b)(ii) was performed wherein Rn is / ^' so-propyl, R22 is iso- propyl, R12 and R22 are hydrogen, R3 is methyl and R ₄ is tert-butyl. Firstly, (S)-tert- butyl(methyl)phosphinous acid borane, 4a (134 mg, 1.00 mmol, 1 eq.), methanesulfonic anhydride (209 mg, 1.20 mmol, 1 .2 eq.), CH2CI2 (6 mL), anhydrous triethylamine (0.35 mL, 2.50 mmol, 2.5 eq.), and amino alcohol 5f (303 mg, 1.50 mmol, 1.5 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 30-50%) yielded 104 mg (33%) of aminophosphine alcohol 6f as a white solid.

3 ¹ P-NMR (202 MHz, CDCI ₃ ) δ; 74.0- 71.7 (m, P-BH ₃ ) ppm.

Subsequently, aminophosphine alcohol 6f (90 mg, 0.28 mmol, 1 eq.), CH ₂ Cl2 (7 mL) and SOCI2 (0.49 μί, 0.68 mmol, 2.4 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 20%) yielded 71 mg (84%) of 1f as a white solid.

3 ¹ P-NMR (202 MHz, CDCI3) δ; 73.7 - 71 .5 (m, P-BH ₃ ) ppm.

Example 8: Synthesis of phosphino-oxazoline, 1g

The aforementioned general procedure (b)(ii) was performed wherein R12 is / ^' so-propyl, R21 is iso- propyl, Rn and R22 are hydrogen, R3 is methyl and R ₄ is tert-butyl. Firstly, (S)-tert- butyl(methyl)phosphinous acid borane, 4a (134 mg, 1 .00 mmol, 1 eq.), methansulfonic anhydride (209 mg, 1.20 mmol, 1 .2 eq.), CH2CI2 (6 mL), anhydrous triethylamine (0.35 mL, 2.50 mmol, 2.5 eq.) and amino alcohol 5g (303 mg, 1 .50 mmol, 1 .5 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 30-50%) yielded 261 mg (82%) of aminophosphine alcohol 6g as a white solid.

³¹ P NMR (202 MHz, CDCI3) δ; 72.5 - 69.9 (m, P-BH ₃ ) ppm.

Subsequently, aminophosphine alcohol 6g (150 mg, 0.47 mmol, 1 eq.), CH2C (6 mL) and SOCI2 (0.82 L, 1.13 mmol, 2.4 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 20%) yielded 1 18 mg (84%) of 1g as an oily solid.

3 ¹ P-NMR (202 MHz, CDCI ₃ ) δ; 73.0 - 71 .3 (m, P-BH ₃ ) ppm.

Example 9: Synthesis of phosphino-oxazoline, 1h

The aforementioned general procedure (b)(ii) was performed wherein R12 is / ^' so-propyl, R22 is / ^' so- propyl, R11 and R21 are hydrogen, R ₃ is methyl and R ₄ is tert-butyl. Firstly, (S)-tert- butyl(methyl)phosphinous acid borane, 4a (402 mg, 3.00 mmol, 1 eq.), methansulfonic anhydride (627 mg, 3.60 mmol, 1 .2 eq.), CH2CI2 (18 mL), anhydrous triethylamine (1 .04 mL, 7.50 mmol, 2.5 eq.) and amino alcohol 5h (909 mg, 4.50 mmol, 1 .5 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 30-50%) yielded 644 mg (67%) of aminophosphine alcohol 6h as a white solid.

³¹ P-NMR (202 MHz, CDCI ₃ ) δ; 74.1 - 72.1 (m, P-BH ₃ ) ppm.

Subsequently, aminophosphine alcohol 6h (644 mg, 2.02 mmol, 1 eq.), CH2CI2 (25 ml.) and SOC (0.35 ml_, 4.86 mmol, 2.4 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 20%) yielded 564 mg (93%) of 1 h as a white solid.

3 ¹ P-NMR (202 MHz, CDCI3) δ; 74.6 - 71 .4 (m, P-BH ₃ ) ppm.

Example 10: Synthesis of phosphino-oxazoline, 1i

The aforementioned general procedure (b)(ii) was performed wherein R12 is phenyl, R22 is iso- propyl, Rn and R21 are hydrogen, R3 is methyl and R ₄ is tert-butyl. Firstly, (S)-tert- butyl(methyl)phosphinous acid borane, 4a (281 mg, 2.1 mmol, 1 eq.), methansulfonic anhydride (438 mg, 2.52 mmol, 1 .2 eq.), CH ₂ CI ₂ (12 ml_), anhydrous triethylamine (0.73 ml_, 7.22 mmol, 2.5 eq.), and amino alcohol 5i (739 mg, 3.14 mmol, 1.5 eq.) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 30-50%) yielded 280 mg (38%) of aminophosphine alcohol 6i as a white solid.

³¹ P-NMR (202 MHz, CDCI ₃ ) δ; 73.9 - 71 .8 (m, P-BH ₃ ) ppm.

Subsequently, aminophosphine alcohol 6i (263 mg, 7.47 mmol, 1 eq.), CH2Cl2 (12 ml.) and SOCI2 (0.13 ml_, 1.79 mmol) were used. Purification by column chromatography on silica gel (hexane:EtOAc; 20%) yielded 244 mg (98%) of 1 i as a white solid.

3 ¹ P-NMR (202 MHz, CDCI3) δ; δ 73.9 - 72.4 (m, P-BH ₃ ) ppm.

Example 1 1: Synthesis of complex [lr(1a)(COD)]BAr _F , 2a

The aforementioned general procedure (a) was performed using phosphino-oxazoline 1 a (200 mg, 0.60 mmol) and pyrrolidine (10 ml_). After the deprotection of the ligand, [lr(COD)(CI)] ₂ (200 mg, 0.30 mmol) in CH2CI2 (8 ml.) was added. After 40 min, NaBAr _F (531 mg, 0.60 mmol) was added. Purification by filtration through Si0 ₂ (CH2CI2, 100%) yielded 800 mg (89%) of [lr(COD)(1a)]BAr _F , 2a as orange solid.

Mp: [190-191 ] °C. [a] _D : + 57.9 (c 0.50, CHCI3). I (KBr) i 2925, 1612, 1354, 1276, 1 134, 886, 701 cm ^"1 . ³¹ P-NMR (162 MHz, CDCI3) δ; 57.4 ppm. ¹⁹ F NMR (376 MHz, CDCI3) δ -62.38 ppm. HRMS (ESI): calc for [0 ₂₆ Η ₄ Ι Ι ΓΝ ₂ ΟΡ] ⁺ : 621.2580, found 621.2573. Calc for [C ₃ 2Hi2BF ₂₄ ]-: 863.0654, found 863.0627.

Example 12: Synthesis of complex [lr(1b)(COD)]BAr _F , 2b

The aforementioned general procedure (a) was performed using phosphino-oxazoline 1 b (50 mg, 0.16 mmol) and pyrrolidine (3 ml_). After the deprotection of the ligand, [lr(COD)(CI)]2 (53 mg, 0.08 mmol) in CH2CI2 (2 mL) was added. After 40 min, NaBAr _F (142 mg, 0.16 mmol) was added. Purification by filtration through S1O2 (CH ₂ CI ₂ : hexane 50% to CH ₂ CI ₂ : 100%) yielded 136 mg (58%) of [lr(1 b)(COD)]BAr _F , 2b as orange solid. Mp: [216-217] °C. [a] _D : + 79.0 (c 1.00, CHCI3). IR (KBr) u _max : 3404, 2970, 1608, 1353, 1276, 1 168, 1 134, 887 cm- ¹ . ³¹ P-NMR (202 MHz, CDCI ₃ ) δ; 57.2 ppm. ¹⁹ F NMR (376 MHz, CDCI ₃ ) δ -62.42 ppm. HRMS (ESI): calc for [C24H ₄ 5lrN ₂ OP] ⁺ : 601.2893, found 601 .2890. Calc for [C32H12BF24]-: 863.0654, found 863.0643.

Example 13: Synthesis of complex [lr(1c)(COD)]BAr _F , 2c

The aforementioned general procedure (a) was performed using phosphino-oxazoline 1 c (100 mg, 0.32 mmol) and pyrrolidine (6 mL). After the deprotection of the ligand, [lr(COD)(CI)] ₂ (107 mg, 0.16 mmol) in CH2CI2 (4 mL) was added. After 40 min, NaBAr _F (312 mg, 0.35 mmol) was added. Purification by filtration through Si02 (CH ₂ CI ₂ : hexane 50% to CH ₂ CI ₂ : 100%) yielded 350 mg (75%) of [lr(1c)(COD)]BAr _F , 2c as orange solid.

Mp: [210-21 1 ] °C. [a] _D : + 39.7 (c 1 .00, CHCI3). IR (KBr) i 2971 , 1597, 1354, 1277, 1 135, 887, 839, 720 cm- ¹ . ³¹ P-NMR (162 MHz, CDCI ₃ ) δ; 62.9 ppm. ¹⁹ F NMR (376 MHz, CDCI ₃ ) δ -62.40 ppm. HRMS (ESI): calc for [C ₂ 4H ₄₅ lrN ₂ OP] ⁺ : 601.2893, found 601 .2886. Calc for [C32H12BF24]-: 863.0654, found 863.0651.

Example 14: Synthesis of complex [lr(1d) (COD)]BAr _F , 2d

The aforementioned general procedure (a) was performed using phosphino-oxazoline 1d (50 mg, 0.14 mmol) and pyrrolidine (3 mL). After the deprotection of the ligand, [lr(COD)(CI)]2 (48 mg, 0.07 mmol) in CH2CI2 (3 mL) was added. After 40 min, NaBAr _F (127 mg, 0.14 mmol) was added. Purification by filtration through Si0 ₂ (CH ₂ Cl2 100%) yielded 171 mg (80%) of [lr(1d)(COD)]BAr _F , 2d as orange solid.

³¹ P-NMR (202 MHz, CDCI3) δ; 58.6 (s) ppm.

Example 15: Synthesis of complex [lr(1e)(COD)]BAr _F , 2e

The aforementioned general procedure (a) was performed using phosphino-oxazoline 1e (50 mg,

0.17 mmol) and pyrrolidine (3 mL). After the deprotection of the ligand, [lr(COD)(CI)]2 (56 mg, 0.08 mmol) in CH2CI2 (3 mL) was added. After 40 min, NaBAr _F (148 mg, 0.17 mmol) was added.

Purification by filtration through S1O2 (CH ₂ CI ₂ : hexane 50%) yielded 201 mg (84%) of

[lr(1e)(COD)]BAr _F , 2e as orange solid.

³¹ P-NMR (202 MHz, CDCI ₃ ) δ; 57.9 (s) ppm.

Example 16: Synthesis of complex [lr(1f)(COD)]BAr _F , 2f

The aforementioned general procedure (a) was performed using phosphino-oxazoline 1f (50 mg,

0.17 mmol) and pyrrolidine (3 mL). After the deprotection of the ligand, [lr(COD)(CI)]2 (56 mg,

0.08 mmol) in CH ₂ CI ₂ (3 mL) was added. After 40 min, NaBAr _F (148 mg, 0.17 mmol) was added.

Purification by filtration through S1O2 (CH ₂ CI ₂ : hexane 50%) yielded 217 mg (90%) of

[lr(1f)(COD)]BAr _F , 2f as orange solid.

3 ¹ P-NMR (202 MHz, CDCI3) δ; 59.7 (s) ppm.

Example 17: Synthesis of complex [lr(1g)(COD)]BAr _F , 2g The aforementioned general procedure (a) was performed using phosphino-oxazoline 1g (50 mg, 0.17 mmol) and pyrrolidine (3 ml_). After the deprotection of the ligand, [lr(COD)(CI)]2 (56 mg, 0.08 mmol) in CH2CI2 (3 mL) was added. After 40 min, NaBAr _F (148 mg, 0.17 mmol) was added. Purification by filtration through S1O2 (CH ₂ CI ₂ : hexane 60%) yielded 182 mg (81 %) of [lr(1 g)(COD)]BAr _F , 2g as orange solid.

³¹ P-NMR (202 MHz, CDCI3) δ; 57.7 (s) ppm.

Example 18: Synthesis of complex [lr(1 h)(COD)]BAr _F , 2h

The aforementioned general procedure (a) was performed using phosphino-oxazoline 1 h (54 mg,

0.18 mmol) and pyrrolidine (3 mL). After the deprotection of the ligand, [lr(COD)(CI)] ₂ (60 mg, 0.09 mmol) in CH ₂ CI ₂ (3 mL) was added. After 40 min, NaBAr _F (159 mg, 0.18 mmol) was added.

Purification by filtration through Si0 ₂ (CH ₂ CI ₂ : hexane 60%) yielded 177 mg (68%) of

[lr(1 h)(COD)]BAr _F , 2h as orange solid.

³¹ P-NMR (202 MHz, CDCI ₃ ) δ; 62.1 (s) ppm.

Example 19: Synthesis of complex [lr(1 i)(COD)]BAr _F , 2i

The aforementioned general procedure (a) was performed using phosphino-oxazoline 1 i (48 mg,

0.14 mmol) and pyrrolidine (3 mL). After the deprotection of the ligand, [lr(COD)(CI)] ₂ (48 mg,

0.07 mmol) in CH ₂ CI ₂ (3 mL) was added. After 40 min, NaBAr _F (127 mg, 0.14 mmol) was added.

Purification by filtration through Si0 ₂ (CH ₂ CI ₂ : hexane 55%) yielded 108 mg (52%) of

[lr(1 i)(COD)]BAr _F , 2i as orange solid.

3 ¹ P-NMR (202 MHz, CDCI3) δ; 63.1 (s) ppm.

Example 20: Asymmetric hydrogenation of a cyclic enamide

The aforementioned general asymmetric hydrogenation procedure (d) was performed on cyclic enamide S1 (1 eq.) as substrate using metal complexes 2a - 2i (0.01 eq.) as catalyst for asymmetric hydrogenation under a 50 bar (5 MPa) atmosphere of hydrogen, as per Scheme 5. The results of said procedure are presented in Table 1 .

S1

Scheme 5. Table 1. Asymmetric hydrogenation of cyclic enamide S1

Entry Formula 2< ^a > Conversion (%) ee< ^b > (%)

1 2a 100 57.7 (S)

2 2b 100 74.5 (S)

3 2c 100 >99 (S)

4 2d 100 41 .2 (R)

5 2e 100 2.7 (f?)

6 2f 100 99.9 (f?)

7 2g 100 95.8 (S)

8 2h 100 96.7 (S)

9 2i 100 94.0 (S)

(a) Formula 2 = catalyst (cat.)

(b) HPLC: CHIRALCEL OJ. Heptane/ethanol 70:30- 0.2% NEt ₃ , 0.5 mL/min, λ = 254 nm. t _R (-)= 8.1 min, t _R (+)= 9.4 min

Example 21: Asymmetric hydrogenation of a cyclic enamide

The aforementioned general asymmetric hydrogenation procedure (d) was performed on cyclic enamide S2 (1 eq.) as substrate using metal complexes 2a - 2i (0.01 eq.) as catalyst for asymmetric hydrogenation under a 50 bar (5 MPa) atmosphere of hydrogen, as per Scheme 6. The results of said procedure are presented in Table 2.

S2

Scheme 6.

Table 2. Asymmetric hydrogenation of cyclic enamide S2

Entry Formula 2< ^a > Conversion (%) ee ^(b) (%)

1 2a 92 49.0 (S)

2 2c 100 >99 (fl)

3 2d 97 41.6 (S)

_4 2h 80 99.0 (S)

(a) Formula 2 = catalyst (cat.)

(b) HPLC: CHIRALPAK ADH. Heptane/ / ^' so-propanol 90:10, 1 mL/min, λ = 210 nm. t _R (-)= 8.8 min, t _R (+)= 1 1.0 min.

Example 22: Asymmetric hydrogenation of an imine

The aforementioned general asymmetric hydrogenation procedure (d) was performed on imine S3 (1 eq.) as substrate using metal complexes 2a - 2i (0.01 eq.) as catalyst for asymmetric hydrogenation under a 50 bar (5 MPa) atmosphere of hydrogen, as per Scheme 7. The results of said procedure are presented in Table 3.

S3

Scheme 7.

Asymmetric hydrogenation of imine S3

Entry Formula 2< ^a > Conversion (%) ee< ^b > (%)

1 2a 100 60.4 (R)

2 2b 100 79.0 (f?)

3 2c 100 77.3 (f?)

4 2d 100 1 .2 (f?)

5 2e 100 89.2 (f?)

6 2f 100 36.8 (S)

7 2g 100 65.4 (S)

8 2h 100 84.5 (S)

9 2i 100 1 1.2 (S)

(a) Formula 2 = catalyst (cat.)

(b) HPLC: CHIRALCEL OD-H. Heptane// ^' so-propanol 90:10, 1 mL/min, λ = 220 nm. t _R (-)= 6.1 min, t _R (+)= 7.1 min.

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