Chiral aminophosphine ligands, iridium catalysts comprising these ligands and use of these catalysts in asymmetric hydrogenations

Abstract

The invention comprises chiral aminophosphine ligands of the formula I, iridium catalysts containing the chiral aminophosphine ligands of the formula I, of the formula II or III;, and the use of the iridium catalysts in the asymmetric hydrogenation of a compound, containing at least one prochiral keto group preparation and the formation of chiral alcohols.

Description

[0001] Case P39242 Chiral aminophosphine ligands, iridium catalysts comprising these ligands and use of these catalysts in asymmetric hydrogenations The invention relates to chiral aminophosphine ligands of the formula I wherein R1to R8, independent of each other are hydrogen, C1-8-alkyl, C1-8-alkoxy, hydroxyl, halogen or phenyl, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R9to R12, independent of each other, are hydrogen, C1-8-alkyl or C1-8-alkoxy; halogen C1-8- alkyl, di-C1-8-alkylamino or nitro; RAU 14.04.2025 R14or R15are independent of each other hydrogen or C1-8-alkyl; R20is C1-8-alkyl, or optionally substituted, C3-8-cycloalkyl, phenyl, naphthyl or heteroaryl, wherein the substituents are selected from one or five groups selected from C1-8-alkyl, C1-8-alkoxy, phenyl, trihalogen-C1-4-alkyl, di-C1-4-alkylamino or tri-C1-4-alkylsilyl, or enantiomers thereof, with the proviso that ligands of formula I wherein R1, R2, R7, R8and R9are hydrogen; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; R14and R15are hydrogen; and R20is phenyl or wherein R1, R2, R7and R9are hydrogen; R8is phenyl; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; R14and R15are hydrogen; and R20is phenyl are excluded. In a further embodiment the invention relates to iridium catalysts comprising chiral aminophosphine ligands of the formula I, particularly to iridium catalysts of formula II or III,

[0002] ; wherein X is either a coordinated ligand or a counter anion selected from a C1-6- alkylsulfonyloxy group which is optionally substituted with one or more halogen atoms; from halogen, C1-6-alkoxy, tetrahalogenoborate, hexahalogenophosphate, tetrakis(3,5-bis(trihalogeno-C1-6- alkyl)phenyl)borate, p-tolylsulfonate or trihalogenomethanesulfonate; R1to R8, independent of each other are hydrogen, C1-8-alkyl, C1-8-alkoxy hydroxyl, halogen or phenyl, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R9to R12, independent of each other, are hydrogen, C1-8-alkyl or C1-8-alkoxy; halogen C1-8-alkyl, di-C1- 8-alkylamino or nitro; R14or R15are independent of each other hydrogen or C1-8-alkyl; R20is optionally substituted C1-8-alkyl, C3-8-cycloalkyl, phenyl, naphthyl or heteroaryl, wherein the substituents are selected from one or five groups selected from C1-8-alkyl, C1-8-alkoxy, phenyl, trihalogen-C1-4-alkyl, di-C1-4-alkylamino or tri-C1-4-alkylsilyl; and L in formula II is a bidentate coordinated diene ligand selected from 1,5-cyclooctadiene (COD), or 2,5-norbornadiene (NBD), or a monodentate coordinated olefin ligand selected from cyclooctene (COE). For the later, two of such ligands are coordinated to the iridium metal center, whereas for bidentate coordinated only one ligand is coordinated to the iridium metal center; or enantiomers thereof. The invention, in a further embodiment, also relates to the preparation of iridium catalysts of formula II or III comprising a treatment of a chiral aminophoshine ligand of formula I with a suitable iridium catalyst precursor. In still a further embodiment the invention relates to a process for the preparation of a chiral alcohol comprising the asymmetric hydrogenation of a compound, containing at least one prochiral keto group, with hydrogen in the presence of the novel iridium catalyst as defined above. The term “presence” either means that the iridium catalyst of formula II or III is added as pre-formed catalyst to the reaction, or, that the iridium catalyst of formula II or III is in-situ formed from an iridium catalyst precursor and a ligand of formula I. Chiral alcohols are versatile building blocks for the preparation of various pharmaceutically active drug substances such as for instance for statin drugs (A. Lenhart, W.D. Chey “Adv. Nutr.2017, 8(4), 587-596). The International Patent Publication WO2022152769A1 discloses a process for the asymmetric hydrogenation of ketones and the formation of a chiral triol with iridium spiro-pyridylamidophosphine catalyst (Ir-SpiroPAP catalysts). While the process is scalable and provides the triol in high enantiomeric and diastereomeric purity and high yield, the therein reported Ir-SpiroPAP catalysts turned out to be a massive cost driver for the process as its synthesis employs costly optically pure Spinol to install the chirality in the backbone of the SpiroPAP ligands, resp. the corresponding iridium catalysts thereof. The object of the present invention was to provide easily accessible, less costly alternative ligands and iridium catalysts, the latter of which equally are able to deliver chiral alcohols in high enantiomeric and, if applicable, diastereomeric purity and yield, but at much more moderate costs. The object of the invention could be reached with the novel chiral aminophosphine ligands of the formula I, with the respective iridium catalysts and with a process for the preparation of a chiral alcohol via asymmetric hydrogenation with hydrogen, applying the iridium catalysts as defined above. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below. The term “chiral” denotes the circumstance, when a structure of a molecule is not superimposable with its mirror image. Chiral molecules are optically active, i.e., they have the ability to rotate the plane of plane-polarized light. Whenever a chiral center is present in a chemical structure, it is intended that all stereoisomers associated with that chiral center are encompassed by the present invention. The term “chiral” signifies that the molecule can exist in the form of optically pure enantiomers, mixtures of enantiomers, optically pure diastereoisomers or mixtures of diastereoisomers. In a preferred embodiment of the invention the term “chiral” denotes optically pure enantiomers or optically pure diastereoisomers. The term “stereoisomer” denotes a compound that possesses identical molecular connectivity and bond multiplicity, but which differs in the arrangement of its atoms in space. The term “diastereomer” denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers may have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. The term “enantiomers” denotes two stereoisomers of a compound which are non- superimposable mirror images of one another. In the structural formula presented herein a dashed bond (a) denotes that the substituent is below the plane of the paper a wedged bond (b) denotes that the substituent is above the plane of the paper and the spiral bond (c) denotes both options i.e. either a dashed bond (a) or a wedged bond The term “C1-8-alkyl” denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 8 carbon atoms. Examples of C1-8-alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso- butyl, sec-butyl, tert-butyl or pentyl, hexyl, heptyl or octyl with its isomers. Preferably the term denotes a C1-6-alkyl group. The term “C3-8-cycloalkyl” denotes a saturated carbocycle of 3 to 8 carbon atoms. Examples of C3-8-cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Preferably the term encompasses C4-7-cycloalkyl, more preferably cyclopentyl and cyclohexyl. The term “C1-6-alkoxy” denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms attached to an oxygen atom. Examples of C1-6-alkoxy include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, or pentoxy or hexoxy with its isomers. Preferably the term denotes a C1-4-alkoxy group, more preferably the methoxy group. The term “halogen” denotes fluoro, chloro, bromo, or iodo, preferably fluoro, bromo or chloro. In its function as counter anion the preferred halogen is chloro. The term “C1-8-halogenalkyl” denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 8 carbon atoms which is substituted by one or more halogen atoms. Preferably the term denotes C1-4-halogenalkyl, more preferably a methyl group which is substituted with one or more halogen atoms such as trifluoromethyl. The term “heteroaryl” refers to an aromatic 5 to 6 membered monocyclic ring or 9 to 10 membered bicyclic ring which can comprise 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and / or sulphur, such as pyridinyl, pyrazolyl, pyrimidinyl, benzoimidazolyl, quinolinyl, thienyl, benzothienyl, furanyl and isoquinolinyl, preferably furanyl, thienyl, or benzothienyl. The term coordinated ligand signifies a ligand which donates one of its electron lone pair to the complexing metal atom. For example, if X is chlorine in the iridium catalysts of formula II, chlorine donates one of its electron lone pair to the complexing iridium atom. The ketone of formula IVa may occur in the tautomeric structures IVa1or IVa2as outlined in Scheme 1. For the sake of clarity, the formula IVa is consistently used throughout this description. Scheme 1 As outlined above the invention relates in one embodiment to chiral aminophosphine ligands of the formula I wherein R1to R8, independent of each other are hydrogen, C1-8-alkyl, C1-8-alkoxy hydroxyl, halogen or phenyl, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R9to R12, independent of each other, are hydrogen, C1-8-alkyl or C1-8-alkoxy; halogen C1-8- alkyl, di-C1-8-alkylamino or nitro; R14or R15are independent of each other hydrogen or C1-8-alkyl; R20is optionally substituted C1-8-alkyl, C3-8-cycloalkyl, phenyl, naphthyl or heteroaryl, wherein the substituents are selected from one or five groups selected from C1-8-alkyl, C1-8-alkoxy, phenyl, trihalogen-C1-4-alkyl, di-C1-4-alkylamino or tri-C1-4-alkylsilyl, or enantiomers thereof, with the proviso that the ligand of formula I wherein R1, R2, R7, R8and R9are hydrogen; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; R14and R15are hydrogen; and R20is phenyl, or, wherein, R1, R2, R7and R9are hydrogen; R8is phenyl; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; R14and R15are hydrogen; and R20is phenyl is excluded. More preferred are chiral aminophosphine ligands of the formula I, wherein R1to R8, independent of each other are hydrogen or C1-8-alkoxy; or, R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; or R3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R9to R12, independent of each other, are hydrogen or C1-8-alkyl; R14or R15are independent of each other hydrogen or C1-4-alkyl; R20is optionally substituted C1-8-alkyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, furanyl, thienyl, or benzothienyl, wherein the substituents are selected from one or two groups selected from C1-8-alkyl, C1-8-alkoxy, phenyl, trihalogen-C1-4-alkyl, di-C1-4-alkylamino or tri-C1-4-alkylsilyl, or enantiomers thereof, with the proviso that the ligand of formula I wherein R1, R2, R7, R8and R9are hydrogen; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; and R20is phenyl, or, wherein, R1, R2, R7and R9are hydrogen; R8is phenyl; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; R14and R15are hydrogen and R20is phenyl is excluded. Even more preferred are chiral aminophosphine ligands of the formula I, wherein R1to R8, independent of each other are hydrogen or methoxy; or, R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; or R3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R9to R12, independent of each other, is hydrogen or methyl; R14or R15are independent of each other hydrogen or methyl; R20is cyclopentyl, cyclohexyl, naphthyl, furanyl, thienyl, benzothienyl or phenyl optionally substituted with one or two substituents selected from C1-8-alkyl, C1-8-alkoxy, trihalogen-C1-4-alkyl, di- C1-4-alkylamino or tri-C1-4-alkylsilyl, or enantiomers thereof, with the proviso that the ligand of formula I wherein R1, R2, R7, R8and R9are hydrogen; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; R14and R15are hydrogen and R20is phenyl, or, wherein, R1, R2, R7and R9are hydrogen; R8is phenyl; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; and R20is phenyl is excluded. Still more preferred are chiral aminophosphine ligands of the formula I, wherein R1to R3and R6to R8are hydrogen; R4and R5is methoxy; R9is methyl and R10to R12are hydrogen; R14and R15are hydrogen; R20is phenyl, 3,5-dimethylphenyl, 3,5-di-tert-butyl phenyl, 3,5-di-tert-pentyl phenyl or 3,5 di- (triethylsilyl) phenyl, or enantiomers thereof and chiral aminophosphine ligands of the formula I, wherein R1, R2, R7, R8are hydrogen; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; R9is hydrogen or methyl and R10to R12are hydrogen; R14and R15are hydrogen or methyl; R20is phenyl, 3,5-dimethylphenyl, 3,5-di-tert-butyl phenyl, 3,5-di-tert-pentyl phenyl or 3,5 di- (triethylsilyl) phenyl, or enantiomers thereof. Also for these preferred ligands, the ligand of formula I wherein R1, R2, R7, R8and R9are hydrogen; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; R14and R15are hydrogen and R20is phenyl, or, wherein, R1, R2, R7and R9are hydrogen; R8is phenyl; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; R14and R15are hydrogen and R20is phenyl is excluded. The chiral aminophosphine ligands of the formula I can be prepared in analogy to procedures reported in the literature (a: Q.-L. Zhou et al., Angew. Chem. Int. Ed.2013, 52, 7833; b: M. Kitamura et al., Angew. Chem. Int. Ed.2013, 52, 9313) either via a chiral resolution route or a stereoselective route as outlined in Scheme 2, resp. Scheme 3. Chiral Resolution Route: Ligands of type I were prepared in 8 steps starting from phenols of type A which were MOM protected first (step 1). After deprotonation with BuLi and treatment with FeCl3 the racemic biphenyl products B were obtained (step 2). In the subsequent steps 3 and 4, the MOM protecting groups were removed and the free diols converted with Tf2O / pyridine into their bis triflates E. Subsequent palladium catalyzed C-P cross coupling furnished the phosphine oxides F (step 5) which were reduced with aid of HSiCl3 to their phosphines G (step 6). After coupling with 2-(azidomethyl)-pyridines and subsequent treatment with NaOH, the racemic aminophosphine oxides J were resolved via chiral chromatography to deliver the pure (S)- and (R)-enantiomers of K (step 7). In the final step the phosphine oxides were reduced with aid of PhSiH3 to furnish the enantiopure aminophosphine ligands of type I

[0003] Scheme 2: Stereoselective Route: Ligands of type I were prepared in 5 steps starting from enantiopure biphenols of type D which were converted with Tf2O / pyridine into their bis triflates E. Subsequent palladium catalyzed C-P cross coupling furnished the phosphine oxides F (step 2) which were reduced with aid of HSiCl3 to their phosphines G (step 3). After coupling with 2-(azidomethyl)-pyridines and subsequent treatment with NaOH, the enantiopure (S)- or (R)-aminophosphine oxides K (step 4). In the final step the phosphine oxides were reduced with aid of PhSiH3 to furnish the enantiopure aminophosphine ligands of type I Scheme 3: The invention relates in a further embodiment to iridium catalysts which are comprising chiral aminophosphine ligands of the formula I as defined above, particularly to iridium catalysts of formula II or III,

[0004] ; wherein, X is either a coordinated ligand or a counter anion selected from a C1-6-alkylsulfonyloxy group, which is optionally substituted with one or more halogen atoms; from halogen, C1-6-alkoxy, tetrahalogenoborate, hexahalogenophosphate, tetrakis(3,5-bis(trihalogeno-C1-6-alkyl)phenyl)borate, p- tolylsulfonate or trihalogenomethanesulfonate; R1to R8, independent of each other are hydrogen, C1-8-alkyl, C1-8-alkoxy hydroxyl, halogen or phenyl, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R9to R12, independent of each other, are hydrogen, C1-8-alkyl or C1-8-alkoxy; halogen C1-8- alkyl, di-C1-8-alkylamino or nitro; R14or R15is independent of each other hydrogen or C1-8-alkyl; R20is optionally substituted C1-8-alkyl, C3-8-cycloalkyl, phenyl, naphthyl or heteroaryl, wherein the substituents are selected from one or five groups selected from C1-8-alkyl, C1-8-alkoxy, phenyl, trihalogen-C1-4-alkyl, di-C1-4-alkylamino or tri-C1-4-alkylsilyl; and L in formula II is a bidentate coordinated diene ligand selected from 1,5-cyclooctadiene (COD), or 2,5-norbornadiene (NBD), or a monodentate coordinated olefin ligand selected from cyclooctene (COE). For the later, two of such ligands are coordinated to the iridium metal center, whereas for bidentate coordinated only one ligand is coordinated to the iridium metal center; or enantiomers thereof. Preferred are iridium catalysts of formula II or III, wherein X is either a coordinated ligand or a counter anion from halogen, tetrahalogenoborate or tetrakis(3,5-bis(trihalogeno-C1-6-alkyl)phenyl)borate; R1to R8, independent of each other are hydrogen or C1-8-alkoxy; or, R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; or R3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R9to R12, independent of each other, are hydrogen or C1-8-alkyl; R14or R15is independent of each other hydrogen or C1-4-alkyl; R20is optionally substituted C1-8-alkyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, furanyl, thienyl, or benzothienyl, wherein the substituents are selected from one or two groups selected from C1-8-alkyl, C1-8-alkoxy, phenyl, trihalogen-C1-4-alkyl, di-C1-4-alkylamino or tri-C1-4-alkylsilyl; and L in formula II is a bidentate coordinated diene ligand selected from 1,5-cyclooctadiene (COD), or 2,5-norbornadiene (NBD); or enantiomers thereof. More preferred are iridium catalysts of formula II or III, wherein X is a coordinated ligand from halogen; R1to R8, independent of each other are hydrogen or methoxy; or, R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; or R3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R9to R12, independent of each other, is hydrogen or methyl; R14or R15are independent of each other hydrogen or methyl; R20is cyclopentyl, cyclohexyl, naphthyl, furanyl, thienyl, benzothienyl or phenyl optionally substituted with one or two substituents selected from C1-8-alkyl, C1-8-alkoxy, trihalogen-C1-4-alkyl, di- C1-4-alkylamino or tri-C1-4-alkylsilyl, or enantiomers thereof; and L in formula II is a bidentate coordinated diene ligand selected from 1,5-cyclooctadiene (COD), or 2,5-norbornadiene (NBD); or enantiomers thereof. Even more preferred are iridium catalysts of formula II or III, wherein X is a coordinated chloride; R1to R3and R6to R8are hydrogen; R4and R5is methoxy; R9is methyl and R10to R12are hydrogen; R14and R15are hydrogen; R20is phenyl, 3,5-dimethylphenyl, 3,5-di-tert-butyl phenyl, 3,5-di-tert-pentyl phenyl or 3,5 di- (triethylsilyl) phenyl; and L in formula II is 1,5-cyclooctadiene (COD); or enantiomers thereof; or iridium catalysts of formula II or III, wherein X is chloride; R1, R2, R7, R8are hydrogen; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; R9is hydrogen or methyl and R10to R12are hydrogen; R14and R15are hydrogen or methyl; R20is phenyl, 3,5-dimethylphenyl, 3,5-di-tert-butyl phenyl, 3,5-di-tert-pentyl phenyl or 3,5 di- (triethylsilyl) phenyl; and L in formula II is 1,5-cyclooctadiene (COD); or enantiomers thereof. The iridium catalyst of formula II can be prepared by treatment of a chiral aminophoshine ligand with a suitable iridium catalyst precursor of the type [Ir(L)X]2 or [Ir(L)2]X, wherein L and X are as defined above, such as [Ir(COD)X]2, [Ir(COD)2]X, [Ir(NBD)X]2, [Ir(NBD)2]X or [Ir(COE)2X]2 in an organic solvent, such as a protic or aprotic solvent, for instance ethanol, dichloromethane or tetrahydrofuran, or a mixture thereof, at room temperature according to the general Scheme 4.

[0005] Scheme 4: The iridium catalyst of formula III can be prepared by treatment of a chiral aminophoshine ligand with a suitable iridium catalyst precursor of the type [Ir(L)X]2 or [Ir(L)2]X, wherein L and X are as defined above, such as [Ir(COD)X]2 or [Ir(COD)2]X, in an organic solvent, such as a protic or aprotic solvent, for instance ethanol, dichloromethane or tetrahydrofuran, or a mixture thereof between 10°C and 100 °C, at a hydrogen pressure of 1 to 100 bar, according to the general Scheme 5. Scheme 5: As outlined above in a further embodiment the invention relates to a process for the preparation of a chiral alcohol comprising the asymmetric hydrogenation of a compound, containing at least one prochiral keto group, with hydrogen in the presence of the novel iridium catalyst of formula II or III as defined above. The process of the present invention can be illustrated with the Scheme 6. Scheme 6: wherein formula IV signifies the compound containing at least one prochiral keto group and formula V the chiral alcohol. The asymmetric hydrogenation can be performed according to method a) to c) in the presence of hydrogen and a base. a) Asymmetric hydrogenation of the ketone of formula IV in the presence of a pre-formed iridium catalyst of formula II or III. b) Asymmetric hydrogenation of the ketone of formula IV in in the presence of an iridium catalyst of formula II or III, in-situ formed from an iridium catalyst precursor [Ir(L)X]2or [Ir(L)2]X, wherein L and X are as defined above, and a ligand of formula I. c) Asymmetric hydrogenation of the ketone of formula IV according to method a) or method b) but with the additional presence of an iridium-phenylendiamine (Ir-PEN) catalyst of the formula VIa, VIb orVIc wherein, R13is C1-6-alkylsulfonyl wherein the alkyl group is optionally substituted with one or more halogen atoms; with a 7,7-dimethyl-2-oxobicyclo[2.2.1] heptane-1-yl group or phenyl sulfonyl, wherein the phenyl group is optionally substituted by one or more C1-6-alkyl groups and Y is either a coordinated ligand or a counter anion selected from a C1-6-alkylsulfonyloxy group which is optionally substituted with one or more halogen atoms; from halogen, C1-6-alkoxy, tetrahalogenoborate, hexahalogenophosphate, tetrakis(3,5-bis(trihalogeno-C1-6-alkyl)phenyl)borate, p- tolylsulfonate or trihalogenomethanesulfonate. a) Asymmetric hydrogenation of the ketone of formula IV in the presence of a pre-formed iridium catalyst of formula II or III. The asymmetric hydrogenation can be performed in the presence of suitable organic solvent and a base at a hydrogen pressure of 5 bar to 100 bar, preferably of 30 bar to 70 bar and at a reaction temperature of 10°C to 90°C, preferably of 20°C to 40°C. The organic solvent can be selected from aliphatic alcohols selected from methanol, ethanol, isopropanol, tert-amylalcohol, from halogen substituted alcohols like 1,1,1-trifluoroethanol, from haloalkanes like dichloromethane, from ethers like tetrahydrofuran or methyl tetrahydrofuran or from aromatic solvents like toluene or mixtures thereof. Also suited are mixtures of aliphatic alcohols such as methanol or ethanol with water or with methyl tetrahydrofuran. The preferred solvent is methanol or ethanol, even more preferred ethanol. Suitable bases are inorganic bases selected from alkali or earth alkali carbonates or hydrogen carbonates or phosphates or hydrogenphosphates or dihydrogenphosphates or acetates or formates or organic bases selected from amines, alkali alcoholates or amidines. Organic bases are usually preferred. Typical representatives of organic bases are potassium tert-butylate or 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo(2.2.2)octane (DABCO) and 7-methyl-1,5,7- triazabicyclo[4.4.0]dec-5-ene (MTBD), most preferred is DBU. A substrate-to-catalyst ratio can expediently be chosen in a range of 100 to 10000, preferably in a range of 1000 to 5000. The suitable separation method can depend on the structure of the chiral alcohol of formula V, but as a rule is common for the skilled practioner. Typically, the chiral alcohol of formula V is obtained by evaporation of the solvent. Subsequent purification e.g. by distillation, or chromatography or crystallization in a suitable solvent, typically in ketones like methyl iso-butyl ketone or esters like isopropyl acetate renders the chiral alcohol of formula V in good yields, high purity and, high enantiomeric and, if applicable, diastereomeric excess. b) Asymmetric hydrogenation of the ketone of formula IV in in the presence of an iridium catalyst formed in-situ from an iridium catalyst precursor and a chiral aminophosphine ligand of the formula I. In this embodiment the iridium catalyst of formula II or III are formed in situ in the course of the asymmetric hydrogenation reaction by bringing together a suitable iridium catalyst precursors of the type [Ir(L)X]2 or [Ir(L)2]X, wherein L and X are as defined above, with a chiral aminophosphine ligand of the formula I. Typically the iridium catalyst of formula II is formed upon mixing the ligand of formula I with the iridium catalyst precursor. In the presence of hydrogen gas, the iridium catalyst of formula II is transformed into the iridium catalyst of formula III. Suitable iridium catalyst precursors are commercially available e.g. from Sigma Aldrich and can be selected e.g. from [Ir(COD)2]BF4, [IrCl(COD)]2, [Ir(acac)(COD)], [Ir(OMe)(COD)]2, [Ir(COD)2]BARF, [Ir(COD)2]PF6, [IrCl(COE)2]2 wherein COD has the meaning of 1,5-cyclooctadiene, COE the meaning of cylooctene, acac the meaning of acetylacetonate, BARF the meaning of tetrakis(3,5-bis(trifluoromethyl)phenyl)borate and OMe the meaning of methoxy. Preferred iridium catalyst precursor is [IrCl(COD)]2. Usually, the iridium catalyst precursor and the chrial aminophosphine ligand are typically mixed in the presence of the organic solvent and the base mentioned under embodiment a). The substrate-to-iridium ratio as a rule is adjusted between 100 and 10000, preferably between 1000 and 5000. The iridium-to-ligand ratio as a rule is adjusted between 0.5 and 1.5, preferably between 0.9 and 1.1. The asymmetric hydrogenation conditions and the isolation of the chiral alcohol of formula V can otherwise be chosen as for the process of embodiment a). Also the preferred embodiments outlined in embodiment a) apply likewise. c) Asymmetric hydrogenation of the ketone of formula IV according to method a) or method b) but with the additional presence of an Ir-PEN catalyst of the formula VIa, VIb or VIc. In this embodiment the asymmetric hydrogenation is performed with a mixture of an iridium catalyst of formula II or III or of an iridium catalyst formed from an iridium catalyst precursor and a chiral aminophosphine ligand of the formula I and an Ir-PEN catalyst of the formula VIa, VIb or VIc. The substrate-to-iridium (2nd, formula VI type catalyst) ratio as a rule is adjusted between 100 and 10000, preferably between 500 and 2500. In a preferred embodiment the Ir-PEN catalysts of the formulas VIa, VIb or VIc, or enantiomers thereof, wherein R5is methylsulfonyl, trifluoromethylsulfonyl, 7,7-dimethyl-2-oxobicyclo[2.2.1] heptane-1-yl; tolylsulfonyl or 1,3,5-tri-isopropylphenyl sulfonyl; Y is either a coordinated ligand or a counter anion selected from a methylsulfonyloxy group which is optionally substituted with one or more fluoro atoms; from halogen, methoxy, tetrafluoroborate (BF4), tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (BARF), acetylacetonate (acac), hexafluorophosphate (PF6), p-tolylsulfonate (OTs) or trifluoromethanesulfonate (OTf;). In a further preferred embodiment, the Ir-PEN catalysts are of the formula VIa or VIc, or enantiomers thereof, wherein, R5is methylsulfonyl, trifluoromethylsulfonyl, 7,7-dimethyl-2-oxobicyclo[2.2.1] heptane-1-yl; tolylsulfonyl or 1,3,5-tri-isopropylphenyl sulfonyl; Y is a trifluoromethylsulfonyl group; In a further preferred embodiment, the Ir-PEN catalysts are of the formula IVc, or enantiomers thereof, wherein, R5is methylsulfonyl, trifluoromethylsulfonyl, 7,7-dimethyl-2-oxobicyclo[2.2.1] heptane-1-yl; tolylsulfonyl or 1,3,5-tri-isopropylphenyl sulfonyl. In a further preferred embodiment, the Ir-PEN catalysts are selected from compounds of the formula VIa-1 and VIc-1 The asymmetric hydrogenation conditions and the isolation of the chiral alcohol of formula V can be chosen as for the process of embodiment a). Also the preferred embodiments outlined in embodiment a) apply likewise. In a preferred embodiment the process of the present invention comprises the process as illustrated in Scheme 7. Scheme 7: wherein, R18is hydrogen or halogen and R19is C1-4-alkyl. Further preferred is the process as illustrated in Scheme 8. Scheme 8: wherein R19is C1-4-alkyl, preferably ethyl. According to method a) the ketone of formula IVa is reacted to the chiral alcohol of formula Va in the presence of a pre-formed iridium catalyst of formula II or III, under the asymmetric hydrogenation conditions outlined for embodiment a) above.. According to method b) the ketone of formula IVa is reacted to the chiral alcohol of formula Va in the presence of an iridium catalyst in-situ formed from an iridium catalyst precursor and a chiral aminophosphine ligands of the formula I. According to method c) the ketone of formula IVa is reacted to the chiral alcohol of formula Va in the presence of an Ir-PEN catalyst of formula VIa, VIb or VIc, whereby the Ir-PEN catalyst of formula VIa, VIb or VIc only catalyzes the conversion of the ketone of formula IVa to the intermediate ketone IVb. Accordingly, method c) offers to the possibility to c1) react the ketone of formula IVa to intermediate ketone IVb in the sole presence of the Ir- PEN catalyst of formula VIa, VIb or VIc and the subsequent asymmetric hydrogenation to the chiral alcohol of formula Va, according to method a) or method b); or c2) react the ketone of formula IVa to the chiral alcohol of formula Va in the presence of an Ir- PEN catalyst of formula VIa, VIb or VIc and the presence of a pre-formed iridium catalyst of formula II or III under the asymmetric hydrogenation conditions, according to method a); or c3) react the ketone of formula IVa to the chiral alcohol of formula Va in the presence of an Ir- PEN catalyst of formula VIa, VIb or VIc and the presence of an iridium catalyst in-situ formed from an iridium catalyst precursor and a chiral aminophosphine ligands of the formula I, according to method b).

[0006] Examples Abbreviations: TES Triethylsilyl DTP 3,5-Di-tert.-pentyl-phenyl DM 3,5-Dimethyl-phenyl DTB 3,5-Di-tert.-butyl-phenyl EtOH Ethanol EtOAc Ethylacetate iPr2O Diisopropylether MeOH Methanol DCM Dichloromethane DMSO Dimethylsulfoxide iPrOH 2-Propanol TMEDA N,N,N`,N`-Tetramethylethylendiamine DIPEA Diisopropylethylamine dppb 1,4-Bis(diphenylphosphino)butane iPrOAc Isopropyl acetate BARF Tetrakis(3,5-bis(trifluoromethyl)phenyl)borate THF Tetrahydrofuran Hexane n-Hexane Pentane n-Pentane Heptane n-Heptane DBU Diazabicycloundecene MOMBr Methoxymethyl bromide DABCO 1,4-Diazabicyclo(2.2.2)octane tBu tert.-Butyl COD Cyclooctadiene rt Room temperature T Temperature p Pressure eq Equivalent rct Reaction time Conv Conversion exp Experiment S / C Substrate-to-catalyst ratio V: V Volume: volume S / L Substrate-to-ligand ratio S / B Substrate-to-base ratio S / Ir Substrate-to-iridium ratio Cat Catalyst (prepared by reacting a pre-catalyst with a ligand) Pre-Cat Pre-catalyst, catalyst precursor 2nd-Cat 2ndcatalyst of type Ir-28, Ir-29, Ir-30 or Ir-31 Exp Experiment number Use-test Substrates 1, 7, 9, 11 1 4-(4-Chlorophenyl)-2-hydroxy-4-keto-butyric-2-en-acid ethyl ester (R)-3 (2R)-4-(4-Chlorophenyl)-2-hydroxy-4-keto-butyric acid ethyl ester (R,R)-4 (2R,4R)-4-(4-Chlorophenyl)-2,4-dihydroxy-butyric acid ethyl ester trans-4 mixture of (R,R)-4 and (S,S)-4 cis-4 mixture of (R,S)-4 and (S,R)-4 (R,R)-5 (3R,5R)-5-(4-Chlorophenyl)-3-hydroxy-butyrolactone cis-5 mixture of (R,R)-5 and (S,S)-5 trans-5 mixture of (R,S)-5 and (S,R)-5 (R,R)-6 (2R,4R)-4-(4-Chlorophenyl)-butane-1,2,4-triol trans-6 mixture of (R,R)-6 and (S,S)-6 cis-6 mixture of (R,S)-6 and (S,R)-6 7 Acetophenone (R)-8 (R)-1-Phenylethanol 9 Methyl 4,4-dimethyl-3-oxopentanoate (R,R)-10 (R)-Methyl 3-hydroxy-4,4-dimethylpentanoate 11 3,3-Dimethyl-2-butanon (R)-12(R)-3,3-Dimethyl-2-butanolCatalysts, Pre-catalysts, Ligands and 2nd-Catalysts: Ir-1, Ir-2, Ir-4, Ir-80, Lig-685 and Lig-766 are commercially available e.g. from Strem, Sigma Aldrich or Raybow Pharmaceuticals. Ir-28, Ir-29, Ir-30 and Ir-31 (= 2nd-catalysts) were prepared according to T. Ohjuma et al. Organic Letters, 2007, 9, 2565. Lig-1305 was prepared according to M. Kitamura et al., Angew. Chem. Int. Ed.2013, 52, 9313. Pre-Catalysts, Catalysts, Ligands Number Name Structure Ir-80[IrCl(H)2((S)-DTB-SpiroPAP-3-Me)] Ir-198 [IrCl(H)2((S)-DTB-BINAN-3-Me-Py)] Ir-196[Ir(S)-DTB-BINAN-3-Me-Py)(COD)]Cl Ir-195 [Ir((S)-DTB-MeOBIPHAN-3-Me- Py)(COD)]ClIr-199[Ir((S)-DTB-BINAN-3-Me-Py)(COD)]BF4Ir-200 [Ir((R)-MeOBIPHAN-3-Me- Py)(COD)]BARF Ir-1[Ir(COD)2]BF4Ir-2[Ir(COD)Cl]2Ir-4[Ir(COD)2]BARFIr-30[Ir(Cp*)((R,R)-Ms-DPEN-{2H})]Ir-31[Ir(Cp*)((R,R)-Ms-DPEN-{H})](OTf)Ir-28[Ir(Cp*)((S,S)-Ms-DPEN-{2H})]Ir-29[Ir(Cp*)((S,S)-Ms-DPEN-{H}](OTf)Lig-685(S)-DTB-SpiroPAP-3-MeLig-766(R)-DTB-SpiroPAP-3-MeLig-1306 (S)-DTB-BINAN-3-Me-Py Lig-1305 (S)-BINAN-Py Lig-1249 (S)-MeOBIPHAN-3-Me-Py Lig-1250 (R)-MeOBIPHAN-3-Me-Py Lig-1251 (R)-DM-MeOBIPHAN-3-Me-Py Lig-1252 (S)-DM-MeOBIPHAN-3-Me-Py Lig-1264 (R)-DTB-MeOBIPHAN-3-Me-Py Lig-1265 (S)-DTB-MeOBIPHAN-3-Me-Py Lig-1319 (R)-DTB-BINAN-3-Me-Py Lig-1336 (R)-DTP-BINAN-3-Me-Py Lig-1337 (R)-TES-BINAN-3-Me-Py Lig-1359 (R)-DTB-BINAN-Py Lig-1361 (R)-DTB-BINAN-Me2Py Lig-1379 (S)-DTB-SEGPHAN-Py Lig-1380 (S)-DTB-SYNPHAN-Py Lig-1381 (S)-DTB-GARPHAN-Py Lig-1368 (R)-DTB-BINAN-4-MeO-Py Lig-1371 (R)-DTB-BINAN-4-NO2-Py

[0007] Preparation of Ligands & Catalysts Preparation of Lig-1249 (RBRC-060) Step 1: To a solution of RBRC-060-10 (105.4 g, 0.85 mol)) in THF (800 mL) was added 60 wt% NaH (60 g, 1.5 mol) at 0oC, and the reaction mixture was warmed up to rt and stirred for additional 2 h. Then, MOMBr (113 mL, 1.39 mol) was added dropwise to the reaction mixture. After complete consumption of compound RBRC-060-10, the reaction mixture was quenched by the addition of H2O (200 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (100:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-060-20 as colorless oil in 42% yield (60.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.22 (t, J = 8.0 Hz, 1H), 6.73 – 6.64 (m, 2H), 6.63-6.60 (m, 1H), 5.20 (s, 2H), 3.82 (s, 3H), 3.52 (s, 3H). Step 2: To a mixture of RBRC-060-20 (7.1 g, 42.2 mmol) and TMEDA (6.9 mL, 46 mmol) in THF (106 mL) was slowly added a solution of n-BuLi (2.5 M in hexane, 19 mL, 47.5 mmol) at -78oC. Then, the reaction mixture was warmed up to rt and stirred for additional 2 h at the same temperature. Then the reaction mixture was cooled to 0oC and FeCl3(8.2 g, 50.6 mmol) was added to the reaction mixture in one portion at 0oC. The reaction mixture was warmed to rt and stirred for 12 h. After complete consumption of compound RBRC-060-20, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-060-30 as white solid in 25% yield (2.5 g). Step 3: To a mixture of RBRC-060-30 (20.0 g, 59.8 mmol) was added CHCl3 (200 mL), MeOH (200 mL), aqueous HCl solution (1 N, 50 mL), and the reaction mixture was stirred at 70oC for 1 h. After complete consumption of compound RBRC-060-30, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (5:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product Lig-1249 (RBRC-060-40) as white solid in 90% yield (14.2 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.37 – 7.27 ppm (m, 2H), 6.74 (dd, J = 8.4, 1.2 Hz, 2H), 6.64 (dd, J = 8.4, 1.2 Hz, 2H), 5.09 (s, 2H), 3.79 (s, 6H). Step 4: To a solution of RBRC-060-40 (16.0 g, 65 mmol) in DCM (250 mL), was added pyridine (14 mL, 174 mmol) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (24 mL, 142.7 mmol). The reaction mixture was warmed up to 20oC and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL), and extracted with DCM (250 mL). The combined organic layer was dried over with Na2SO4 and filtered. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-060- 50 as white solid in 90% yield (30.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.50 (t, J = 8.4 Hz, 2H), 7.05-7.02 (m, 4H), 3.82 (s, 6H). Step 5: To a mixture of RBRC-060-50 (12.0 g, 23.5 mmol), the corresponding phosphine oxide (5.3g, 26 mmol), palladium acetate (300 mg, 1.34 mmol) and dppb (760 mg, 1.78 mmol) was added DMSO (80 mL) and DIPEA (17 mL, 97.6 mmol). The resulting mixture was heated with stirring at 100oC for 6 h. After cooling to 20oC, the reaction mixture was diluted with EtOAc (300 mL), washed with 5% aqueous HCl (100 mL) and saturated NaHCO3 (100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (2:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-060-60 as white solid in 60% yield (8.0 g). Step 6: To a mixture of RBRC-060-60 (8.5 g, 15.1 mmol) and DIPEA (108 mL, 0.62 mol) in toluene (150 mL) was added Cl3SiH (24.5 mL, 242.7 mmol) at 0oC. The reaction mixture was stirred at 110oC for 12 h. After cooling to 20oC, the mixture was quenched with aqueous NaOH (12 N, 10 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (300 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-060-70 as white solid in 90% yield (8.0 g). Step 7: A dry 1000 mL flask was charged with RBRC-060-70 (18 g, 33 mmol), toluene (70 mL), and 2-(azidomethyl)-3-methylpyridine (5.86 g, 39.5 mmol) was added. The solution was stirred at 115 °C for 48 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with DCM / MeOH (50:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-060-80 as white solid in 70% yield (14.7 g). Step 8: RBRC-060-80 (12.7 g, 19 mmol) was dissolved in EtOH (300 mL) and 0.1 M NaOH aq (300 mL) and stirred at 65 °C for 12 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. Filtration followed by concentration gave a nearly pure RBRC-060-90 as a white solid (10.0 g, 98% yield).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.25 (dd, J = 4.8, 1.6 Hz, 1H), 7.66 – 7.29 (m, 9H), 7.27 – 6.91 (m, 8H), 6.06-6.00 (m, 2H), 4.26-4.13 (m, 2H), 3.70 (s, 3H), 3.36 (s, 3H), 2.28 (s, 3H) ppm.31P-NMR (162 MHz, CDCl3): δ 28.06. Full separation of the enantiomers was accomplished by preparative chiral LC (method description see below). Hereby, 10.0 g of RBRC-060-90 were resolved to deliver (S)-RBRC-060-90 (4.00 g, 40%, 98.2% ee) and (R)-RBRC-060-90 (4.00 g, 40%, 97.5% ee) Preparative chiral LC method for separation of (S)-RBRC-060-90 and (R)-RBRC-060-90: Stationary phase: AunoTech DAC50 (diameter = 50 mm) Eluent: Hexane / isopropanol (100:8) Run time: 100 min Flow: 50 mL / min Column oven temperature: 30 °C Injection volume: 400 mL Detection: 210 nm Retention Times: (S)-RBRC-060-90, 28.0-36.5 min; (R)-RBRC-060-90, 39.0-48.5 min Chiral LC method to determine the enantiomeric purity of (S)-RBRC-060-90 and (R)-RBRC-060-90: Stationary phase: Chiralpak AD-H 4.6 mm x 250 mm x 5 μm Eluent: 0.05% triethylamine in hexane / isopropanol (8:2) Run time: 25 min Flow: 1 mL / min Column oven temperature: 30 °C Injection volume: 5 μL Detection: DAD 250 nm Retention Times: (S)-RBRC-060-90, 10.9 min; (R)-RBRC-060-90, 18.4 min Step 9: (S)-RBRC-060-90 (4.0 g, 7.5 mml) and phenylsilane (15 mL, 121.5 mmol) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 37 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (5:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product Lig-1349 as white solid in 67% yield (2.7 g). [^]20D -117° (conc. = 1.0 g / mL, CHCl3).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.23 (dd, J = 4.8, 1.6 Hz, 1H), 7.43-7.41 (m, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.30 – 7.27 (m, 3H), 7.24-7.20 (m, 3H), 7.15 – 6.98 (m, 7H), 6.80-6.77 (m, 1H), 6.47 (dd, J = 8.0, 0.8 Hz, 1H), 6.27 (dd, J = 8.4, 0.8 Hz, 1H), 5.27 (s, 1H), 4.33 (d, J = 15.6 Hz, 1H), 4.05 (d, J = 15.6 Hz, 1H), 3.74 (s, 3H), 3.28 (s, 3H), 2.27 (s, 3H).31P- NMR (162 MHz, CDCl3): δ -12.94. Preparation of Lig-1250 (RBRC-070) Step 1: To a solution of RBRC-070-10 (105.5 g, 0.85 mol) in THF (800 mL) was added 60 wt% NaH (60 g, 1.5 mol) at 0oC, and the reaction mixture was warmed up to rt and stirred for additional 2 h. Then, MOMBr (113 mL, 1.39 mol) was added dropwise to the reaction mixture. After complete consumption of compound RBRC-060-10, the reaction mixture was quenched by the addition of H2O (200 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (100:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-070-20 as colorless oil in 42% yield (60.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.22 (t, J = 8.0 Hz, 1H), 6.73 - 6.64 (m, 2H), 6.63 - 6.60 (m, 1H), 5.20 (s, 2H), 3.82 (s, 3H), 3.52 (s, 3H). Step 2: To a mixture of RBRC-070-20 (7.1 g, 42.2 mmol) and TMEDA (6.9 mL, 46 mmol) in THF(106 mL) was slowly added a solution of n-BuLi (2.5 M in hexane, 19 mL, 47.5 mmol) at -78oC. Then, the reaction mixture was warmed up to rt and stirred for additional 2 h at the same temperature. Then the reaction mixture was cooled to 0oC and FeCl3 (8.2 g, 50.6 mmol) was added to the reaction mixture in one portion at 0oC. The reaction mixture was warmed to rt and stirred for 12 h. After complete consumption of compound RBRC-060-20, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-070-30 as white solid in 25% yield (2.5 g). Step 3: To a mixture of RBRC-070-30 (20.0 g, 59.8 mmol) was added CHCl3 (200 mL), MeOH (200 mL), aqueous HCl solution (1 N, 50 mL), and the reaction mixture was stirred at 70oC for 1 h. After complete consumption of compound RBRC-060-30, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (5:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-070-40 as white solid in 90% yield (14.2 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.37 - 7.27 (m, 2H), 6.74 (dd, J = 8.4, 1.2 Hz, 2H), 6.64 (dd, J = 8.4, 1.2 Hz, 2H), 5.09 (s, 2H), 3.79 (s, 6H). Step 4: To a solution of RBRC-070-40 (16.0 g, 65 mmol) in DCM (250 mL), was added pyridine (14 mL, 174 mmol) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (24 mL, 142.7 mmol). The reaction mixture was warmed up to 20oC, and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL) and extracted with DCM (250 mL). The combined organic layer was dried over with Na2SO4 and filtered. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-070- 50 as white solid in 90% yield (30.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.50 (t, J = 8.4 Hz, 2H), 7.05-7.02 (m, 4H), 3.82 (s, 6H). Step 5: To a mixture of RBRC-070-50 (12.0 g, 23.5 mmol), the corresponding phosphine oxide (5.3g, 26 mmol), palladium acetate (300 mg, 1.34 mmol) and dppb (760 mg, 1.78 mmol) was added DMSO (80 mL) and DIPEA (17 mL, 97.6 mmol). The resulting mixture was heated with stirring at 100oC for 6 h. After cooling to 20oC, the reaction mixture was diluted with EtOAc (300 mL), washed with 5% aqueous HCl (100 mL) and saturated NaHCO3 (100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (2:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-070-60 as white solid in 60% yield (8.0 g). Step 6: To a mixture of RBRC-070-60 (8.5 g, 15.1 mmol) and DIPEA (108 mL, 0.62 mol) in toluene (150 mL) was added Cl3SiH (24.5 mL, 242.7 mmol) at 0oC. The reaction mixture was stirred at 110oC for 12 h. After cooling to 20oC, the mixture was quenched with aqueous NaOH (12 N, 10 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (300 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-070-70 as white solid in 90% yield (8.0 g). Step 7: A dry 1000 mL flask was charged with RBRC-070-70 (18.0 g, 33 mmol), toluene (70 mL), and 2-(azidomethyl)-3-methylpyridine (5.86 g, 39.5 mmol) was added. The solution was stirred at 115 °C for 48 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with DCM / MeOH H (50:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-070-80 as white solid in 70% yield (14.7 g). Step 8: RBRC-070-80 (12.7 g, 19 mmol) was dissolved in EtOH (300 mL) and 0.1 M NaOH aq (300 mL) and stirred at 65 °C for 12 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1800 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. Filtration followed by concentration gave a nearly pure RBRC-070-90 as a white solid (10.0 g, 98% yield).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.25 (dd, J = 4.8, 1.6 Hz, 1H), 7.66 – 7.29 (m, 9H), 7.27 – 6.91 (m, 8H), 6.06-6.00 (m, 2H), 4.26-4.13 (m, 2H), 3.70 (s, 3H), 3.36 (s, 3H), 2.28 (s, 3H).31P-NMR (162 MHz, CDCl3): δ 28.06. Full separation of the enantiomers was accomplished by preparative chiral LC (method description see below). Hereby, 10.0 g of RBRC-070-90 were resolved to deliver (S)-RBRC-070-90 (4.00 g, 40%, 98.2% ee) and (R)-RBRC-070-90 (4.00 g, 40%, 97.5% ee) Preparative chiral LC method for separation of (S)-RBRC-070-90 and (R)-RBRC-070-90: Stationary phase: AunoTech DAC50 (diameter = 50 mm) Eluent: Hexane / isopropanol (100:8) Run time: 100 min Flow: 50 mL / min Column oven temperature: 30 °C Injection volume: 400 mL Detection: 210 nm Retention Times: (S)-RBRC-070-90, 28.0-36.5 min; (R)-RBRC-070-90, 39.0-48.5 min Chiral LC method to determine the enantiomeric purity of (S)-RBRC-070-90 and (R)-RBRC-070-90: Stationary phase: Chiralpak AD-H 4.6 mm x 250 mm x 5 μm Eluent: 0.05% Triethylamine in hexane / isopropanol (8:2) Run time: 25 min Flow: 1 mL / min Column oven temperature: 30 °C Injection volume:5 ^LDetection: DAD 250 nm Retention Times: (S)-RBRC-070-90, 10.9 min; (R)-RBRC-070-90, 18.4 min Step 9: (R)-RBRC-070-90 (4.0 g, 7.5 mmol) and phenylsilane (15 mL,121.5 mmol) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 37 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (5:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product Lig-1250 as white solid in 67% yield (2.6 g). [^]20D111° (conc. = 1.0 g / mL, CHCl3).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.23 (dd, J = 4.8, 1.6 Hz, 1H), 7.43-7.41 (m, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.30 – 7.27 (m, 3H), 7.24-7.20 (m, 3H), 7.15 – 6.98 (m, 7H), 6.80-6.77 (m, 1H), 6.47 (dd, J = 8.0, 0.8 Hz, 1H), 6.27 (dd, J = 8.4, 0.8 Hz, 1H), 5.27 (s, 1H), 4.33 (d, J = 15.6 Hz, 1H), 4.05 (d, J = 15.6 Hz, 1H), 3.74 (s, 3H), 3.28 (s, 3H), 2.27 (s, 3H).31P- NMR (162 MHz, CDCl3): δ -12.94. Preparation of Lig-1251 (RBRC-061) Step 1: To a solution of RBRC-061-10 (105.5 g, 0.85 mol) in THF (800 mL) was added 60 wt% NaH (60 g, 1.5 mol) at 0oC, and the reaction mixture was warmed up to rt and stirred for additional 2 h. Then, MOMBr (113 mL, 1.39 mol) was added dropwise to the reaction mixture. After complete consumption of compound RBRC-061-10, the reaction mixture was quenched by the addition of H2O (200 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (100:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-061-20 as colorless oil in 42% yield (60.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.22 (t, J = 8.0 Hz, 1H), 6.73 - 6.64 (m, 2H), 6.63-6.60 (m, 1H), 5.20 (s, 2H), 3.82 (s, 3H), 3.52 (s, 3H). Step 2: To a mixture of RBRC-061-20 (7.1 g, 42.2 mmol) and TMEDA (6.9 mL, 46 mmol) in THF (106 mL) was slowly added a solution of n-BuLi (2.5 M in hexane, 19 mL, 47.5 mmol) at -78oC. Then, the reaction mixture was warmed up to rt and stirred for additional 2 h at the same temperature. Then the reaction mixture was cooled to 0oC and FeCl3 (8.2 g, 50.6 mmol) was added to the reaction mixture in one portion at 0oC. The reaction mixture was warmed to rt and stirred for 12 h. After complete consumption of compound RBRC-061-20, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-061-30 as white solid in 25% yield (2.5 g). Step 3: To a mixture of RBRC-061-30 (20.0 g, 59.8 mmol) was added CHCl3 (200 mL), MeOH (200 mL), aqueous HCl solution (1 N, 50 mL), and the reaction mixture was stirred at 70oC for 1 h. After complete consumption of compound RBRC-061-30, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (5:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-061-40 as white solid in 90% yield (14.2 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.37 - 7.27 (m, 2H), 6.74 (dd, J = 8.4, 1.2 Hz, 2H), 6.64 (dd, J = 8.4, 1.2 Hz, 2H), 5.09 (s, 2H), 3.79 (s, 6H). Step 4: To a solution of RBRC-061-40 (16.0 g, 65 mmol) in DCM (250 mL), was added pyridine (14 mL, 174 mmol) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (24 mL, 142.7 mmol). The reaction mixture was warmed up to 20oC, and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL), and extracted with DCM (250 mL). The combined organic layer was dried over with Na2SO4 and filtered. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-061- 50 as white solid in 90% yield (30.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.50 (t, J = 8.4 Hz, 2H), 7.05 - 7.02 (m, 4H), 3.82 (s, 6H). Step 5: To a mixture of RBRC-061-50 (13.4 g, 26.3 mmol), the corresponding phosphine oxide (7.4g, 28.6 mmol), palladium acetate (300 mg, 1.33 mmol) and dppb (760 mg, 1.78 mmol) was added DMSO (80 mL) and DIPEA (17 mL, 97.6 mol). The resulting mixture was heated with stirring at 100oC for 6 h. After cooling to 20oC, the reaction mixture was diluted with EtOAc (300 mL), washed with 5% aqueous HCl (100 mL) and saturated NaHCO3 (100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (2:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-061-60 as white solid in 61% yield (8.2 g). Step 6: To a mixture of RBRC-061-60 (9.7 g, 15.7 mmol) and DIPEA (108 mL, 0.62 mol) in toluene (150 mL) was added Cl3SiH (24.5 mL, 242.7 mmol) at 0oC. The reaction mixture was stirred at 110oC for 12 h. After cooling to 20oC, the mixture was quenched with aqueous NaOH (12 N, 10 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (300 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-061-70 as white solid in 86% yield (8.7 g). Step 7: A dry 1000 mL flask was charged with RBRC-061-70 (21.0 g, 35 mmol), toluene (70 mL), and 2-(azidomethyl)-3-methylpyridine (5.9 g, 40 mmol) was added. The solution was stirred at 115 °C for 48 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with DCM / MeOH (50:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-061-80 as white solid in 72% yield (18.7 g). Step 8: RBRC-061-80 (18.7 g, 25.9 mmol) was dissolved in C2H5OH (300 mL) and 0.1 M NaOH aq (300 mL) and stirred at 65 °C for 12 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. Filtration followed by concentration gave a nearly pure RBRC-061-90 as a white solid (16.0 g, 98% yield). Full separation of the enantiomers was accomplished by preparative chiral LC (method description see below). Hereby, 16.0 g of RBRC-061-90 were resolved to deliver (S)-RBRC-061-90 (4.00 g, 25%, 99.2% ee) and (R)-RBRC-061-90 (4.00 g, 25%, 99.2% ee) Preparative chiral LC method for separation of (S)-RBRC-061-90 and (R)-RBRC-061-90: Stationary phase: AunoTech DAC50 (diameter = 50 mm) Eluent: 0.1 % Et3N in hexane / isopropanol (90:10) Run time: 100 min Flow: 50 mL / min Column oven temperature: 30 °C Injection volume: 5 mL Detection: 210 nm Retention Times: (R)-RBRC-061-90, 10.7-25.9 min; (S)-RBRC-061-90, 43.8-54.5 min Chiral LC method to determine the enantiomeric purity of (S)-RBRC-061-90 and (R)-RBRC-061-90: Stationary phase: Chiralpak IB N-34.6 mm x 250 mm x 3 μm Eluent: 0.05% Triethylamine in hexane / isopropanol (95:5) Run time: 40 min Flow: 0.8 mL / min Column oven temperature: 30 °C Injection volume: 5 μL Detection: DAD 232 nm Retention Times: (R)-RBRC-061-90, 21.8 min; (S)-RBRC-061-90, 26.4 min Step 9: (R)-RBRC-061-90 (4.0 g, 6.8 mmol) and phenylsilane (15 mL, 121.5 mmol) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 37 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (5:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product 1251 as white solid in 67% yield (2.7 g). [^]20D126° (conc. = 1.0 g / mL, CHCl3).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.22 (dd, J = 4.8, 1.6 Hz, 1H), 7.41 - 7.39 (m, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.26 (t, J = 8.4 Hz, 1H), 7.10 - 6.98 (m, 2H), 6.89 (s, 1H), 6.87 - 6.79 (m, 3H), 6.77 (s, 1H), 6.72 - 6.64 (m, 2H), 6.47 (dd, J = 8.4, 0.8 Hz, 1H), 6.27 (dd, J = 8.4, 0.8 Hz, 1H), 5.20 (s, 1H), 4.32 (d, J = 15.6 Hz, 1H), 4.09 (d, J = 15.6 Hz, 1H), 3.73 (s, 3H), 3.32 (s, 3H), 2.28 (s, 3H), 2.24 (s, 6H), 2.03 (s, 6H).31P-NMR (162 MHz, CDCl3): δ -12.40. Preparation of Lig-1252 (RBRC-071) Step 1: To a solution of RBRC-071-10 (105.5 g, 0.85 mol) in THF (800 mL) was added 60wt% NaH (60 g, 1.5 mol) at 0oC, and the reaction mixture was warmed up to rt and stirred for additional 2 h. Then, MOMBr (113 mL, 1.39 mol) was added dropwise to the reaction mixture. After complete consumption of compound RBRC-071-10, the reaction mixture was quenched by the addition of H2O (200 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4, and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (100:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-071-20 as colorless oil in 42% yield (60.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.22 (t, J = 8.0 Hz, 1H), 6.73 - 6.64 (m, 2H), 6.63-6.60 (m, 1H), 5.20 (s, 2H), 3.82 (s, 3H), 3.52 (s, 3H). Step 2: To a mixture of RBRC-071-20 (7.1 g, 42.2 mmol) and TMEDA (6.9 mL, 46 mmol) in THF (106 mL) was slowly added a solution of n-BuLi (2.5 M in hexane, 19 mL, 47.5 mmol) at -78oC. Then, the reaction mixture was warmed up to rt and stirred for additional 2 h at the same temperature. Then the reaction mixture was cooled to 0oC and FeCl3 (8.2 g, 50.6 mmol) was added to the reaction mixture in one portion at 0oC. The reaction mixture was warmed to rt and stirred for 12 h. After complete consumption of compound RBRC-071-20, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-071-30 as white solid in 25% yield (2.5 g). Step 3: To a mixture of RBRC-071-30 (20.0 g, 59.8 mmol) was added CHCl3 (200 mL), MeOH (200 mL), aqueous HCl solution (1 N, 50 mL), and the reaction mixture was stirred at 70oC for 1 h. After complete consumption of compound RBRC-071-30, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (5:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-071-40 as white solid in 90% yield (14.2 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.37 - 7.27 (m, 2H), 6.74 (dd, J = 8.4, 1.2 Hz, 2H), 6.64 (dd, J = 8.4, 1.2 Hz, 2H), 5.09 (s, 2H), 3.79 (s, 6H). Step 4: To a solution of RBRC-071-40 (16.0 g, 65 mmol) in DCM (250 mL), was added pyridine (14 mL, 174 mmol) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (24 mL, 142.7 mmol). The reaction mixture was warmed up to 20oC and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL) and extracted with DCM (250 mL). The combined organic layer was dried over with Na2SO4 and filtered. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-071- 50 as white solid in 90% yield (30.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.50 (t, J = 8.4 Hz, 2H), 7.05-7.02 (m, 4H), 3.82 (s, 6H). Step 5: To a mixture of RBRC-071-50 (13.4 g, 26.3 mmol), the corresponding phosphine oxide (7.4 g, 28.6 mmol), palladium acetate (300 mg, 1.33 mmol) and dppb (760 mg, 1.78 mmol) was added DMSO (80 mL) and DIPEA (17 mL, 97.6 mmol). The resulting mixture was heated with stirring at 100oC for 6 h. After cooling to 20oC, the reaction mixture was diluted with EtOAc (300 mL), washed with 5% aqueous HCl (100 mL) and saturated NaHCO3 (100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (2:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-071-60 as white solid in 61% yield (8.2 g). Step 6: To a mixture of RBRC-071-60 (9.7 g, 15.7 mmol) and DIPEA (108 mL, 0.62 mol) in toluene (150 mL) was added Cl3SiH (24.5 mL, 242.7 mmol) at 0oC. The reaction mixture was stirred at 110oC for 12 h. After cooling to 20oC, the mixture was quenched with aqueous NaOH (12 N, 10 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (300 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-071-70 as white solid in 86% yield (8.7 g). Step 7: A dry 1000 mL flask was charged with RBRC-071-70 (21.0 g, 35 mmol), toluene (70 mL), and 2-(azidomethyl)-3-methylpyridine (5.9 g, 40 mmol) was added. The solution was stirred at 115 °C for 48 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with DCM / MeOH (50:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-071-80 as white solid in 72% yield (18.7 g). Step 8: RBRC-071-80 (18.7 g, 25.9 mmol) was dissolved in C2H5OH (300 mL) and 0.1 M NaOH aq (300 mL) and stirred at 65 °C for 12 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. Filtration followed by concentration gave a nearly pure RBRC-071-90 as a white solid (16.0 g, 98% yield). Full separation of the enantiomers was accomplished by preparative chiral LC (method description see below). Hereby, 16.0 g of RBRC-071-90 were resolved to deliver (S)-RBRC-071-90 (4.00 g, 25%, 99.2% ee) and (R)-RBRC-071-90 (4.00 g, 25%, 99.2% ee) Preparative chiral LC method for separation of (S)-RBRC-071-90 and (R)-RBRC-071-90: Stationary phase: AunoTech DAC50 (diameter = 50 mm) Eluent: 0.1 % Et3N in hexane / isopropanol (90:10) Run time: 100 min Flow: 50 mL / min Column oven temperature: 30 °C Injection volume: 5 mL Detection: 210 nm Retention Times: (R)-RBRC-071-90, 10.7-25.9 min; (S)-RBRC-071-90, 43.8-54.5 min Chiral LC method to determine the enantiomeric purity of (S)-RBRC-071-90 and (R)-RBRC-071-90: Stationary phase: Chiralpak IB N-34.6 mm x 250 mm x 3 cm Eluent: 0.05% Triethylamine in hexane / isopropanol (95:5) Run time: 40 min Flow: 0.8 mL / min Column oven temperature: 30 °C Injection volume: 2.5 μL Detection: DAD 232 nm Retention Times: (R)-RBRC-071-90, 21.8 min; (S)-RBRC-071-90, 26.4 min Step 9: The (S)-RBRC-071-90 (4.0 g, 6.8 mmol) and phenylsilane (15 mL, 121.5 mmol) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 37 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (5:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product Lig-1252 as white solid in 67% yield (2.7 g). [^]20D-112° (conc. = 1.0 g / mL, CHCl3).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.22 (dd, J = 4.8, 1.6 Hz, 1H), 7.44 - 7.30 (m, 2H), 7.25 (d, J = 8.0 Hz, 1H), 7.08 - 7.01 (m, 2H), 6.92 - 6.75 (m, 5H), 6.68 (dd, J = 7.6, 1.6 Hz, 2H), 6.47 (dd, J = 8.4, 0.8 Hz, 1H), 6.27 (dd, J = 8.4, 0.8 Hz, 1H), 5.17 (s, 1H), 4.33 (d, J = 15.6 Hz, 1H), 4.09 (d, J = 15.6 Hz, 1H), 3.73 (s, 3H), 3.33 (s, 3H), 2.28 (s, 3H), 2.24 (s, 6H), 2.03 (s, 6H).31P-NMR (162 MHz, CDCl3): δ -12.40. Preparation of Lig-1264 (RBRC-062) Step 1: To a solution of RBRC-062-10 (105.4 g, 0.85 mol) in THF (800 mL) was added 60 wt% NaH (60 g, 1.5 mol)) at 0oC, and the reaction mixture was warmed up to rt and stirred for additional 2 h. Then, MOMBr (113 mL, 1.39 mol) was added dropwise to the reaction mixture. After complete consumption of compound RBRC-060-10, the reaction mixture was quenched by the addition of H2O (200 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4, and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (100:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-062-20 as colorless oil in 42% yield (60.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.22 (t, J = 8.0 Hz, 1H), 6.73 - 6.64 (m, 2H), 6.63 - 6.60 (m, 1H), 5.20 (s, 2H), 3.82 (s, 3H), 3.52 (s, 3H). Step 2: To a mixture of RBRC-062-20 (7.1 g, 42.2 mmol) and TMEDA (6.9 mL, 46 mmol) in THF (106 mL) was slowly added a solution of n-BuLi (2.5 M in hexane, 19 mL, 47.5 mmol) at -78oC. Then, the reaction mixture was warmed up to rt and stirred for additional 2 h at the same temperature. Then the reaction mixture was cooled to 0oC and FeCl3 (8.2 g, 50.6 mmol) was added to the reaction mixture in one portion at 0oC. The reaction mixture was warmed to rt and stirred for 12 h. After complete consumption of compound RBRC-060-20, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-062-30 as white solid in 25% yield (2.5 g). Step 3: To a mixture of RBRC-062-30 (20.0 g, 59.8 mmol) was added CHCl3 (200 mL), MeOH (200 mL), aqueous HCl solution (1 N, 50 mL), and the reaction mixture was stirred at 70oC for 1 h. After complete consumption of compound RBRC-060-30, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (5:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-062-40 as white solid in 90% yield (14.2 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.37 - 7.27 (m, 2H), 6.74 (dd, J = 8.4, 1.2 Hz, 2H), 6.64 (dd, J = 8.4, 1.2 Hz, 2H), 5.09 (s, 2H), 3.79 (s, 6H). Step 4: To a solution of RBRC-062-40 (16.0 g, 65 mmol) in DCM (250 mL), was added pyridine (14 mL, 174 mmol) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (24 mL, 142.7 mmol). The reaction mixture was warmed up to 20oC, and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL), and extracted with DCM (250 mL). The combined organic layer was dried over with Na2SO4 and filtered. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-062- 50 as white solid in 90% yield (30.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.50 (t, J = 8.4 Hz, 2H), 7.05 - 7.02 (m, 4H), 3.82 (s, 6H). Step 5: To a mixture of RBRC-062-50 (13.0 g, 25.5 mmol), the corresponding phosphine oxide (12g, 28 mmol), palladium acetate (300 mg, 1.34 mmol) and dppb (760 mg, 1.78 mmol) was added DMSO (80 mL) and DIPEA (17 mL, 97.6 mmol). The resulting mixture was heated with stirring at 100oC for 6 h. After cooling to 20oC, the reaction mixture was diluted with EtOAc (300 mL), washed with 5% aqueous HCl (100 mL) and saturated NaHCO3 (100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (2:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-062-60 as white solid in 64% yield (8.6 g). Step 6: To a mixture of RBRC-062-60 (9.5 g, 12 mmol) and DIPEA (108 mL, 0.62 mol) in toluene (150 mL) was added Cl3SiH (24.5 mL, 242.7 mmol) at 0oC. The reaction mixture was stirred at 110oC for 12 h. After cooling to 20oC, the mixture was quenched with aqueous NaOH (12 N, 10 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (300 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-062-70 as white solid in 88% yield (8.8 g). Step 7: A dry 1000 mL flask was charged with RBRC-062-70 (21.0 g, 27.2 mmol), toluene (70 mL), and 2-(azidomethyl)-3-methylpyridine (5.9 g, 40 mmol) was added. The solution was stirred at 115 °C for 48 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with DCM / MeOH (50:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-062-80 as white solid in 62% yield (13.7 g). Step 8: RBRC-062-80 (18.7 g, 21 mmol) was dissolved in C2H5OH (300 mL) and 0.1 M NaOH aq (300 mL) and stirred at 65 °C for 12 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. Filtration followed by concentration gave a nearly pure RBRC-062-90 as a white solid (16.0 g, 98% yield). Full separation of the enantiomers was accomplished by preparative chiral LC (method description see below). Hereby, 16.0 g of RBRC-062-90 were resolved to deliver (S)-RBRC-062-90 (4.00 g, 25%, 98.2% ee) and (R)-RBRC-062-90 (4.00 g, 25%, 99.2% ee). Preparative chiral LC method for separation of (S)-RBRC-062-90 and (R)-RBRC-062-90: Stationary phase: AunoTech DAC50 (diameter = 50 mm) Eluent: Hexane / isopropanol (98:2) Run time: 100 min Flow: 50 mL / min Column oven temperature: 30 °C Injection volume: 100 mL Detection: 210 nm Retention Times: (R)-RBRC-062-90, 47.8-53.0 min; (S)-RBRC-062-90, 71.8-82.8 min Chiral LC method to determine the enantiomeric purity of (S)-RBRC-062-90 and (R)-RBRC-062-90: Stationary phase: Chiralpak IB N-34.6 mm x 250 mm x 3 μm Eluent: 0.05% Triethylamine in hexane / isopropanol (98:2) Run time: 30 min Flow: 1 mL / min Column oven temperature: 30 °C Injection volume: 5 uL Detection: DAD 250 nm Retention Times: (R)-RBRC-062-90, 6.1 min; (S)-RBRC-062-90, 7.1 min Step 9: (R)-RBRC-062-90 (4.0 g, 5 mmol) and phenylsilane (15 mL, 121.5 mmol) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 37 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (5:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product Lig-1264 as white solid in 69% yield (2.7 g). [^]20D 76° (conc. = 1.0 g / mL, CHCl3).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.21 (dd, J = 4.8, 1.6 Hz, 1H), 7.41 - 7.30 (m, 3H), 7.25 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 2.0 Hz, 1H), 7.11 - 6.98 (m, 4H), 6.94 - 6.84 (m, 3H), 6.51 (d, J = 8.0 Hz, 1H), 6.23 (dd, J = 8.4, 0.8 Hz, 1H), 5.15 (s, 1H), 4.32 (d, J = 15.6 Hz, 1H), 4.16 (d, J = 15.6 Hz, 1H), 3.72 (s, 3H), 3.15 (s, 3H), 2.27 (s, 3H), 1.24 (s, 18H), 1.09 (s, 18H).31P-NMR (162 MHz, CDCl3): δ -10.61. Preparation of Lig-1265 (RBRC-072) Step 1: To a solution of RBRC-072-10 (105.4 g, 0.85 mol)) in THF (800 mL) was added 60 wt%NaH (60 g, 1.5 mol)) at 0oC, and the reaction mixture was warmed up to rt and stirred for additional 2 h. Then, MOMBr (113 mL, 1.39 mol) was added dropwise to the reaction mixture. After complete consumption of compound RBRC-060-10, the reaction mixture was quenched by the addition of H2O (200 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (100:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-072-20 as colorless oil in 42% yield (60.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.22 (t, J = 8.0 Hz, 1H), 6.73 - 6.64 (m, 2H), 6.63 - 6.60 (m, 1H), 5.20 (s, 2H), 3.82 (s, 3H), 3.52 (s, 3H). Step 2: To a mixture of RBRC-072-20 (7.1 g, 42.2 mmol) and TMEDA (6.9 mL, 46 mmol) in THF (106 mL) was slowly added a solution of n-BuLi (2.5 M in hexane, 19 mL, 47.5 mmol) at -78oC. Then, the reaction mixture was warmed up to rt and stirred for additional 2 h at the same temperature. Then the reaction mixture was cooled to 0oC and FeCl3 (8.2 g, 50.6 mmol) was added to the reaction mixture in one portion at 0oC. The reaction mixture was warmed to rt and stirred for 12 h. After complete consumption of compound RBRC-060-20, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4 and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-072-30 as white solid in 25% yield (2.5 g). Step 3: To a mixture of (20.0 g, 59.8 mmol) was added CHCl3 (200 mL), MeOH (200 mL), aqueous HCl solution (1 N, 50 mL), and the reaction mixture was stirred at 70oC for 1 h. After complete consumption of compound RBRC-060-30, the reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (800 mL). The organic layer was combined, dried over Na2SO4, and concentrated. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (5:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-072-40 as white solid in 90% yield (14.2 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.37 - 7.27 (m, 2H), 6.74 (dd, J = 8.4, 1.2 Hz, 2H), 6.64 (dd, J = 8.4, 1.2 Hz, 2H), 5.09 (s, 2H), 3.79 (s, 6H). Step 4: To a solution of RBRC-072-40 (16.0 g, 65 mmol) in DCM (250 mL), was added pyridine (14 mL, 174 mmol) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (24 mL, 142.7 mmol). The reaction mixture was warmed up to 20oC, and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL), and extracted with DCM (250 mL). The combined organic layer was dried over with Na2SO4 and filtered. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-072- 50 as white solid in 90% yield (30.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.50 (t, J = 8.4 Hz, 2H), 7.05-7.02 (m, 4H), 3.82 (s, 6H). Step 5: To a mixture of RBRC-072-50 (13.0 g, 25.5 mmol), the corresponding phosphine oxide (12g, 28 mmol), palladium acetate (300 mg, 1.34 mmol) and dppb (760 mg, 1.78 mmol) was added DMSO (80 mL) and DIPEA (17 mL, 97.6 mmol). The resulting mixture was heated with stirring at 100oC for 6 h. After cooling to 20oC, the reaction mixture was diluted with EtOAc (300 mL), washed with 5% aqueous HCl (100 mL) and saturated NaHCO3 (100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (2:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-072-60 as white solid in 64% yield (8.6 g). Step 6: To a mixture of RBRC-072-60 (9.5 g, 12 mmol) and DIPEA (108 mL, 0.62 mol) in toluene (150 mL) was added Cl3SiH (24.5 mL, 242.7 mmol) at 0oC. The reaction mixture was stirred at 110oC for 12 h. After cooling to 20oC, the mixture was quenched with aqueous NaOH (12 N, 10 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (300 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (10:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-072-70 as white solid in 88% yield (8.8 g). Step7: A dry 1000 mL flask was charged with RBRC-072-70 (21 g, 27.2 mmol), toluene (70 mL), and 2-(azidomethyl)-3-methylpyridine (5.9 g, 40 mmol) was added. The solution was stirred at 115 °C for 48 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with DCM / MeOH (50:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product RBRC-072-80 as white solid in 62% yield (13.7 g). Step 8: RBRC-072-80 (18.7 g, 21 mmol) was dissolved in C2H5OH (300 mL) and 0.1 M NaOH aq (300 mL) and stirred at 65 °C for 12 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1200 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. Filtration followed by concentration gave a nearly pure RBRC-072-90 as a white solid (16.0 g, 98% yield). Full separation of the enantiomers was accomplished by preparative chiral LC (method description see below). Hereby, 16.0 g of RBRC-072-90 were resolved to deliver (S)-RBRC-072-90 (4.00 g, 25%, 98.2% ee) and (R)-RBRC-072-90 (4.00 g, 25%, 99.2% ee). Preparative chiral LC method for separation of (S)-RBRC-072-90 and (R)-RBRC-072-90: Stationary phase: AunoTech DAC50 (diameter = 50 mm) Eluent: Hexane / isopropanol (98:2) Run time: 100 min Flow: 50 mL / min Column oven temperature: 30 °C Injection volume: 100 mL Detection: 210 nm Retention Times: (R)-RBRC-072-90, 47.8-53.0 min; (S)-RBRC-072-90, 71.8-82.8 min Chiral LC method to determine the enantiomeric purity of (S)-RBRC-072-90 and (R)-RBRC-072-90: Stationary phase: Chiralpak IB N-34.6 mm x 250 mm x 3 μm Eluent: 0.05% Triethylamine in hexane / isopropanol (98:2) Run time: 30 min Flow: 1 mL / min Column oven temperature: 30 °C Injection volume: 5 μL Detection: DAD 250 nm Retention Times: (R)-RBRC-072-90, 6.1 min; (S)-RBRC-072-90, 7.1 min Step 9: (S)-RBRC-072-90 (4.0 g, 5 mmol) and phenylsilane (15 mL, 121.5 mmol) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 37 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil. The crude mixture was purified by short flash column chromatography on silica (250 g, elute with pentane / EtOAc (5:1), Rf = 0.2, 2 kg elution solvent) to provide the desired product Lig-1265 as white solid in 67% yield (2.7 g). [^]20D -75° (conc. = 1.0 g / mL, CHCl3).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.26 - 8.17 (m, 1H), 7.42 - 7.30 (m, 3H), 7.25 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 1.6 Hz, 1H), 7.08 - 70.1 (m, 4H), 6.90 - 6.87 (m, 3H), 6.52 (d, J = 8.0 Hz, 1H), 6.24 (d, J = 8.0 Hz, 1H), 4.32 (d, J = 15.6 Hz, 1H), 4.17 (d, J = 15.6 Hz, 1H), 3.72 (s, 3H), 3.14 (s, 3H), 2.27 (s, 3H), 1.24 (s, 18H), 1.09 (s, 18H).31P-NMR (162 MHz, CDCl3): δ -12.94.31P-NMR (CDCl3, 162 MHz) δ -10.62. Preparation of Lig-1305 (RBRC-083) Step 1: To a solution of RBRC-083-10 (10.0 g, 35.0 mmol) in DCM (1500 mL), was added pyridine (8.6 mL) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (14.7 mL). The reaction mixture was warmed up to 20oC, and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (100 mL), and extracted with DCM (450 mL). The combined organic layer was dried over with Na2SO4 and filtered. The mixture was concentrated to provide the desired product RBRC-083-20 as yellow oil in 97% yield (28.1 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.14 (dt, J = 8.8, 3.2 Hz, 2H), 8.00 (dt, J = 7.6, 2.8 Hz, 2H), 7.66 – 7.53 (m, 4H), 7.40 (d, J = 6.8 Hz, 2H), 7.25 (t, J = 6.4 Hz, 2H). Step 2: To a mixture of RBRC-083-20 (10.0 g, 18.2 mmol), palladium acetate (250 mg, 1.10 mmol), dppb (780 mg, 1.80 mmol) and diphenylphosphine oxide (7.4 g, 36.40 mmol) was added DMSO (150 mL) and DIPEA (13 mL). The resulting mixture was heated with stirring at 100oC for 12 h under N2. After cooling to 20oC, the reaction mixture was quenched with water (300 mL) and extracted with EtOAc (900 mL). The organic layer was concentrated to get crude product. The crude mixture was purified by short flash column chromatography on silica (pentane / EtOAc, 3:1) to provide the desired product RBRC-083-30 as yellow oil in 80% yield (9.2 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.02-7.82 (m, 4H), 7.71 - 7.54 (m, 2H), 7.49 - 7.27 (m, 9H), 7.29 - 7.23 (m, 4H), 7.16 (m, 2H),7.01 - 6.99 (m, 1H). Step 3: To a mixture of RBRC-083-30 (7.0 g, 11.62 mmol) and DIPEA (81.2 mL) in toluene (150 mL) was added HSiCl3 (18.9 mL) at 0oC. The reaction mixture was stirred at 115oC for 12 h under N2. After cooling to 20oC, the mixture was quenched with aqueous NaOH (12 N, 10 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (300 mL). The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product RBRC-083-40 as yellow oil in 81% yield (6.3 g). MS (ESI, m / z): 586.7 [M+H]+. Step 4: A dry 250 mL flask was charged with RBRC-083-40 (6.1 g, 10.3 mmol), toluene (50 mL) and 2-(azidomethyl) pyridine (2.1 g, 15.48 mmol) was added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in EtOH (50 mL) and 0.1 M NaOH aq (50 mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (450 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4 to get crude product. The crude product was purified by short flash column chromatography on silica (DCM / MeOH, 40:1) to provide the desired product RBRC-083-50 as yellow solid in 55% yield (3.3 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.48 - 8.47 (m, 1H), 8.04 - 8.01 (m, 1H), 7.99 - 7.83 (m, 2H), 7.63 - 7.50 (m, 4H), 7.47 - 7.41 (m, 2H), 7.40 - 7.35 (m, 1H), 7.32 - 7.22 (m, 9H), 7.14 - 6.99 (m, 3H), 6.98 - 6.85 (m, 3H), 6.70 (dd, J = 8.8, 1.6 Hz, 1H), 6.61 - 6.58 (m, 1H), 5.30 (s, 1H), 4.44 - 4.38 (m, 2H). Step 5: The RBRC-083-50 (3.1 g, 5.5 mmol) and phenylsilane (13 mL) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 37 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil. The crude mixture was purified by short flash column chromatography on silica (pentane / EtOAc, 5:1) to provide the desired product Lig-1305 as yellow solid in 47% yield (1.4 g). [^]20D -18° (conc. = 1.0 g / mL, CHCl3).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.45 - 8.41 (m, 1H), 7.92 (dd, J = 8.4, 0.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.72 (dt, J = 8.0, 0.8 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.44 - 7.26 (m, 5H), 7.25 (s, 2H), 7.23 - 7.02 (m, 9H), 7.00 - 6.91 (m, 2H), 6.67 (dd, J = 8.4, 1.2 Hz, 1H), 4.26 (dd, J = 17.2, 6.0 Hz, 1H), 4.17 - 3.97 (m, 2H).31P-NMR (162 MHz, CDCl3): δ -14.36. Preparation of Lig-1306 (RBRC-085) Step 1: To a solution of RBRC-085-10 (10.0 g, 35.0 mmol) in DCM (1500 mL), was added pyridine (8.6 mL) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (14.7 mL). The reaction mixture was warmed up to 20oC and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (100 mL) and extracted with DCM (450 mL). The combined organic layer was dried over with Na2SO4and filtered. The mixture was concentrated to provide the desired product RBRC-085-20 as yellow oil in 97% yield (28.1 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.14 (dt, J = 8.8, 3.2 Hz, 2H), 8.00 (dt, J = 7.6, 2.8 Hz, 2H), 7.66 - 7.53 (m, 4H), 7.40 (d, J = 6.8 Hz, 2H), 7.25 (t, J = 6.4 Hz, 2H). Step 2: To a mixture of RBRC-085-20 (7.6g, 13.8 mmol), palladium acetate (190 mg, 0.83 mmol), dppb (593 mg, 1.38 mmol) and bis(3,5-di-tert-butylphenyl) phosphine oxide (7 g, 16.60 mmol) was added DMSO (150 mL) and DIPEA (10 mL). The resulting mixture was heated with stirring at 100oC for 12 h under N2. After cooling to 20oC, the reaction mixture was quenched with water (300 mL) and extracted with EtOAc (900 mL). The organic layer was concentrated to get crude product. The crude mixture was purified by short flash column chromatography on silica (pentane / EtOAc, 2:1) to provide the desired product RBRC-085-30 as yellow oil in 86.6% yield (9.7 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.00 - 7.94 (m, 2H), 7.93 - 7.91 (m, 1H), 7.84 (dd, J = 8.4, 1.2 Hz, 1H), 7.57 - 7.45 (m, 6H), 7.37 - 7.26 (m, 3H), 7.19 - 7.12 (m, 3H), 6.95 - 6.91 (m, 1H), 6.75 (dd, J = 8.4, 1.2 Hz, 1H), 1.25 (s, 18H), 1.14 (s, 18H). Step 3: To a mixture of RBRC-085-30 (9.7 g, 12.0 mmol) and DIPEA (86.5 mL) in toluene (150 mL) was added HSiCl3 (20.1 mL) at 0oC. The reaction mixture was stirred at 115oC for 12 h under N2. After cooling to 20oC, the mixture was quenched with aqueous NaOH (12 N, 10 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (300 mL). The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product RBRC-085-40 as yellow oil (8.9 g, crude) which was use further reaction without any purification.1H-NMR (400 MHz, CDCl3): δ [ppm] 7.98 (d, J = 9.2 Hz, 1H), 7.89 - 7.77 (m, 3H), 7.52 (d, J = 8.8 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.21 - 7.15 (m, 3H), 7.12 - 7.01 (m, 6H), 6.73 (dd, J = 8.8, 1.9 Hz, 2H), 1.15 (s, 18H), 1.02 (s, 18H). Step 4: A dry 250 mL flask was charged with RBRC-085-40 (8.9 g, 11.19 mmol), toluene (100 mL) and 2-(azidomethyl) pyridine (2.5 g, 16.79 mmol) were added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in EtOH (100 mL) and 0.1 M NaOH aq. (100mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (450 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4 to get crude product. The crude product was purified by short flash column chromatography on silica (pentane / EtOAc (1:1)) to provide the desired product RBRC-085-50 as yellow solid in 65% yield (5.8 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.06 (s, 1H), 7.99 - 7.89 (m, 3H), 7.72 (dd, J = 12.0, 2.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.47 - 7.40 (m, 3H), 7.18 - 7.05 (m, 6H), 6.99 - 6.91 (m, 2H), 6.69 - 6.64 (m, 1H), 6.29 (d, J = 8.4 Hz, 1H), 5.36-5.29 (m, 1H), 4.54 (s, 2H), 2.18 (s, 3H), 1.21 (s, 11H), 1.10 (s, 25H). Step 5: The RBRC-085-50 (5.8 g, 7.3 mmol) and phenylsilane (26 mL) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 37 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil. The crude mixture was purified by short flash column chromatography on silica (pentane / EtOAc, 10:1) to provide the desired product Lig-1306 as yellow solid in 35% yield (2.0 g). [^]20D 120° (conc. = 1.0 g / mL, CHCl3).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.01 (d, J = 4.8 Hz, 1H), 7.96 - 7.84 (m, 3H), 7.64 (d, J = 8.0 Hz, 1H), 7.53 - 7.50 (m, 1H), 7.47 - 7.35 (m, 2H), 7.29 - 7.22 (m, 3H), 7.20 - 7.11 (m, 2H), 7.04 - 6.88 (m, 4H), 6.84 (d, J = 8.4 Hz, 2H), 6.67 (t, J = 7.6 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 5.14 (t, J = 4.8 Hz, 1H), 4.45 - 4.27 (m, 2H), 2.10 (s, 3H), 1.11 (t, J = 2.2 Hz, 36H).31P-NMR (162 MHz, CDCl3): δ -10.63. Preparation of Lig-1319 (RBRC-087) Step 1: To a solution of RBRC-087-10 (15.0 g, 52.4 mmol) in DCM (200 mL), was added pyridine (12.4 g) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (36.9 g). The reaction mixture was warmed up to 20oC, and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL), and extracted with DCM (600 mL). The combined organic layer was dried over with Na2SO4and filtered. The mixture was concentrated to provide the desired product RBRC-087-20 as yellow oil in 97% yield (28.1 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.17 (dd, J = 9.2, 0.8 Hz, 2H), 8.04 (dt, J = 8.4, 0.8 Hz, 2H), 7.69 - 7.58 (m, 4H), 7.46 - 7.42 (m, 2H), 7.32 - 7.26 (m, 2H). Step 2: To a mixture of RBRC-087-20 (20.0 g, 36.3 mmol), palladium acetate (490 mg, 2.18 mmol), dppb (1.55 g, 3.63 mmol) and bis(3,5-di-tert-butylphenyl) phosphine oxide (15.5 g, 36.33 mmol) was added DMSO (250 mL) and DIPEA (20 mL). The resulting mixture was heated with stirring at 100oC for 12 h under N2. After cooling to 20oC, the reaction mixture was quenched with water (300 mL) and extracted with EtOAc (900 mL). The organic layer was concentrated to get crude product. The crude mixture was purified by short flash column chromatography on silica (pentane / EtOAc, 2:1) to provide the desired product RBRC-087-30 as yellow solid in 64 % yield (19.2 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.04 - 7.91 (m, 3H), 7.87 (d, J = 8.0 Hz, 1H), 7.61 - 7.46 (m, 6H), 7.39 - 7.29 (m, 3H), 7.22 - 7.13 (m, 3H), 6.90 - 6.94 (m, 1H), 6.81 - 6.72 (m, 1H), 1.28 (d, J = 2.8 Hz, 20H), 1.16 (s, 16H) Step 3: To a mixture of RBRC-087-30 (19.2 g, 23.2 mmol) and DIPEA (161.7 mL) in toluene (150 mL) was added HSiCl3 (37.5 mL) at 0oC. The reaction mixture was stirred at 115oC for 12 h under N2. After cooling to 20oC, the mixture was quenched with aqueous NaOH (12 N, 30 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through celite and the solid was washed with EtOAc (300 mL). The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product RBRC-087-40 as yellow oil (18.5 g, crude) which was use further reaction without any purification. Step 4: A dry 250 mL flask was charged with RBRC-087-40 (18.5 g, 22.8 mmol), toluene (200 mL) and 2-(azidomethyl) pyridine (5.1 g, 34.2 mmol) were added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in EtOH (200 mL) and 0.1 M NaOH aq. (200mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (600 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4 to get crude product. The crude product was purified by short flash column chromatography on silica (pentane / EtOAc (1:1)) to provide the desired product RBRC-087-50 as yellow solid in 71 % yield (13.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.07 (d, J = 4.8 Hz, 1H), 8.02 - 7.92 (m, 2H), 7.71 - 7.65 (m, 2H), 7.53 - 7.45 (m, 5H), 7.31 (s, 1H), 7.27 (d, J = 1.2 Hz, 1H), 7.19 - 7.09 (m, 5H), 6.98 - 6.88 (m, 2H), 6.72 - 6.68 (m, 1H), 6.33 (d, J = 8.4 Hz, 1H), 5.42 - 5.32 (m, 1H), 4.55 (s, 2H), 2.16 (s, 3H), 1.23 (s, 18H), 1.12 (s, 18H). Step 5: The RBRC-087-50 (13.0 g, 16.3 mmol) and phenylsilane (57 mL) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 37 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil. The crude mixture was purified by short flash column chromatography on silica (pentane / EtOAc (10:1)) to provide the desired product Lig-1319 as yellow solid in 86% yield (11.0 g). [^]20D -112° (conc. = 1.0 g / mL, CHCl3).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.01 (dd, J = 4.8, 1.6 Hz, 1H), 7.95 - 7.84 (m, 3H), 7.64 (d, J = 8.0 Hz, 1H), 7.52 (dt, J = 8.4, 2.0 Hz, 1H), 7.46 - 7.36 (m, 2H), 7.27 - 7.22 (m, 3H), 7.19 - 7.12 (m, 2H), 7.03 - 6.89 (m, 4H), 6.84 (dt, J = 8.4, 1.6 Hz, 2H), 6.69 - 6.65 (m,1H), 6.37 (d, J = 8.4 Hz, 1H), 5.15 (t, J = 4.8 Hz, 1H), 4.48 - 4.25 (m, 2H), 2.10 (s, 3H), 1.14 - 1.08 (m, 36H).31P-NMR (162 MHz, CDCl3): δ -10.64. Preparation of Lig-1359 (RBRC-114) Step 1: To a solution of RBRC-087-10 (30.0 g, 104.6 mmol) in DCM (400 mL), pyridine (24.8 g) was added at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (73.8 g). The reaction mixture was warmed up to 20oC and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (400 mL) and extracted with DCM (1.2 L). The combined organic layer was dried over with Na2SO4and filtered. The mixture was concentrated to provide the desired product RBRC-087-20 as yellow oil in 97% yield (57.5 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.17 (dd, J = 9.2, 0.8 Hz, 2H), 8.04 (dt, J = 8.4, 0.8 Hz, 2H), 7.69 - 7.58 (m, 4H), 7.46 - 7.42 (m, 2H), 7.32 - 7.26 (m, 2H). Step 2: To a mixture of RBRC-087-20 (54.0 g, 98.1 mmol), palladium acetate (1.32 g, 5.88 mmol), dppb (5.50 g, 9.82 mmol) and bis(3,5-di-tert-butylphenyl) phosphine oxide (46.0 g, 107.92 mmol), DMSO (500 mL) and DIPEA (68 mL) were added. The resulting mixture was heated with stirring at 100oC for 12 h under N2. After cooling to 20oC, the reaction mixture was quenched with water (1000 mL) and extracted with EtOAc (900 mL). The organic layer was concentrated to get crude product. The crude mixture was purified by silica gel flash column chromatography (pentane / EtOAc, 2:1) to provide the desired product RBRC-087-30 as yellow solid in 61 % yield (42.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.04 - 7.91 (m, 3H), 7.87 (d, J = 8.0 Hz, 1H), 7.61 - 7.46 (m, 6H), 7.39 - 7.29 (m, 3H), 7.22 - 7.13 (m, 3H), 6.90 - 6.94 (m, 1H), 6.81 - 6.72 (m, 1H), 1.28 (d, J = 2.8 Hz, 20H), 1.16 (s, 16H) Step 3: To a mixture of RBRC-087-30 (42.0 g, 50.8 mmol) and DIPEA (177.0 mL) in toluene (250 mL), HSiCl3 (41.0 mL) was added at 0oC. The reaction mixture was stirred at 115oC for 12 h under N2. After cooling to 20oC, the mixture was quenched with aqueous NaOH (12 N, 40 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through celite and the solid was washed with EtOAc (900 mL). The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product RBRC-087-40 as yellow oil (36.5 g, crude) which was used in step 4 without any purification. Step 4: A dry 1 L flask was charged with RBRC-087-40 (10.7 g, 13.2 mmol), toluene (100 mL) and 2- (azidomethyl) pyridine (2.7 g, 19.8 mmol) were added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in EtOH (100 mL) and 0.1 M NaOH aq. (100 mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, this was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (600 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4 to get crude product. The crude product was purified by short silica gel column chromatography (pentane / EtOAc (1:1)) to provide the desired product RBRC-114-10 as yellow solid in 89% yield (8.9 g). Step 5: The RBRC-114-10 (8.9 g, 11.3 mmol) and phenylsilane (20 mL) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 48 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil. The crude mixture was purified by silica gel flash column chromatography (pentane / EtOAc (10:1)) to provide the desired product Lig-1359 as yellow solid in 69% yield (6.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.47 – 8.45 (m, 1H), 7.96 (dd, J = 8.4, 1.6 Hz, 2H), 7.82 (d, J = 8.8 Hz, 1H), 7.74 – 7.69 (m, 1H), 7.56 – 7.52 (m, 2H), 7.38 – 7.29 (m, 4H), 7.24 (t, J = 2.0 Hz, 1H), 7.19 – 7.00 (m, 6H), 6.95 (dd, J = 8.4, 2.0 Hz, 2H), 6.90 (ddd, J = 8.0, 64, 1.2 Hz, 1H), 6.62 (dd, J = 8.4, 0.8 Hz, 1H), 4.41 (t, J = 6.0 Hz, 2H), 1.19 (d, J = 5.2 Hz, 36H).31P-NMR (162 MHz, CDCl3): δ [ppm] -12.21.

[0008] Preparation of Lig-1361 (RBRC-115) Step 1: To a solution of RBRC-087-10 (30.0 g, 104.6 mmol) in DCM (400 mL), pyridine (24.8 g) was added at 0oC. The mixture was allowed to stir for 5 min followed by dropwise addition of Tf2O (73.8 g). The reaction mixture was warmed up to 20oC and allowed to stir until full consumption of the starting materials. The resulting mixture was quenched with water (400 mL) and extracted with DCM (1.2 L). The combined organic layer was dried over with Na2SO4and filtered. The mixture was concentrated to provide the desired product RBRC-087-20 as yellow oil in 97% yield (57.5 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.17 (dd, J = 9.2, 0.8 Hz, 2H), 8.04 (dt, J = 8.4, 0.8 Hz, 2H), 7.69 - 7.58 (m, 4H), 7.46 - 7.42 (m, 2H), 7.32 - 7.26 (m, 2H). Step 2: To a mixture of RBRC-087-20 (54.0 g, 98.1 mmol), palladium acetate (1.32 g, 5.88 mmol), dppb (5.50 g, 9.82 mmol) and bis(3,5-di-tert-butylphenyl) phosphine oxide (46.0 g, 107.92 mmol), DMSO (500 mL) and DIPEA (68 mL) were added. The resulting mixture was heated with stirring at 100oC for 12 h under N2. After cooling to 20oC, the reaction mixture was quenched with water (1000 mL) and extracted with EtOAc (900 mL). The organic layer was concentrated to get crude product which was then purified by silica gel flash column chromatography (pentane / EtOAc, 2:1) to provide the desired product RBRC-087-30 as yellow solid in 61 % yield (42.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.04 - 7.91 (m, 3H), 7.87 (d, J = 8.0 Hz, 1H), 7.61 - 7.46 (m, 6H), 7.39 - 7.29 (m, 3H), 7.22 - 7.13 (m, 3H), 6.90 - 6.94 (m, 1H), 6.81 - 6.72 (m, 1H), 1.28 (d, J = 2.8 Hz, 20H), 1.16 (s, 16H) Step 3: To a mixture of RBRC-087-30 (42.0 g, 50.8 mmol) and DIPEA (177.0 mL) in toluene (250 mL), HSiCl3 (41.0 mL) was added at 0oC. The reaction mixture was stirred at 115oC for 12 h under N2. After cooling to 20oC, the mixture was quenched with aqueous NaOH (12 N, 40 mL) and diluted with EtOAc (300 mL). The resulting suspension was filtered through celite and the solid was washed with EtOAc (900 mL). The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product RBRC-087-40 as yellow oil (36.5 g, crude) which was used in step 4 without any purification. Step 4: A dry 1 L flask was charged with RBRC-087-40 (15.0 g, 18.5 mmol), toluene (200 mL) and BnN3 (3.7 g, 27.2 mmol) was added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in EtOH (100 mL) and 0.1 M NaOH aq. (100 mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, the reaction mixture was poured into H2O (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (600 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4 to get crude product. The crude product was purified by silica gel flash column chromatography (pentane / EtOAc (5:1)) to provide the desired product RBRC-115-10 as yellow solid in 68 % yield (9.9 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.96 – 7.89 (m, 2H), 7.69 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.64 – 7.50 (m, 4H), 7.42 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.25 – 7.11 (m, 6H), 7.10 (s, 2H), 7.04 (d, J = 8.8 Hz, 1H), 6.88 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.73 (ddd, J = 8.4, 6.8, 1.6 Hz, 1H), 6.29 (dd, J = 8.4, 1.0 Hz, 1H), 4.50 (d, J = 4.8 Hz, 2H), 4.39 (d, J = 5.6 Hz, 1H), 1.30 (s, 18H), 1.10 (s, 17H).31P-NMR (162 MHz, CDCl3): δ [ppm] 28.16. Step 5: To a solution of RBRC-115-10 (9.9 g, 12.1 mmol) in MeOH (100 mL), Pd / C (1.0 g, 10 wt%) was added. The mixture was stirred at rt for 12 h under H2 (1 bar atmosphere), filtered and concentrated to get crude product. The crude product was purified by silica gel flash column chromatography (pentane / EtOAc, 2:1) to provide the desired product RBRC-115-20 as yellow solid in 87 % yield (7.5 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.95 – 7.88 (m, 2H), 7.71 (dd, J = 12.0, 1.6 Hz, 2H), 7.60 (dd, J = 11.6, 8.4 Hz, 1H), 7.57 – 7.48 (m, 3H), 7.46 – 7.42 (m, 1H), 7.22 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.16 (dd, J = 12.8, 1.6 Hz, 2H), 7.09 – 7.04 (m, 2H), 6.99 – 6.90 (m, 2H), 6.79 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 6.37 (d, J = 8.6 Hz, 1H), 1.31 (s, 18H), 1.10 (s, 18H).31PNMR (162 MHz, CDCl3): δ [ppm] 27.18. Step 6: The RBRC-115-20 (6.5 g, 9.4 mmol) and phenylsilane (15 mL) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 48 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil. The crude mixture was purified by silica gel flash column chromatography (pentane / EtOAc, 10:1) to provide the desired product RBRC-115-30 as yellow solid in 87% yield (5.5 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.89 (dd, J = 8.4, 2.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.51 – 7.45 (m, 2H), 7.33 (t, J = 2.0 Hz, 1H), 7.27 (d, J = 5.6 Hz, 2H), 7.21 (t, J = 2.0 Hz, 1H), 7.16 (dd, J = 8.0, 2.0 Hz, 2H), 7.13 – 7.08 (m, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.94 (ddd, J = 8.4, 4.4, 1.6 Hz, 3H), 6.69 – 6.66 (m, 1H), 3.30 (s, 2H), 1.23 (s, 18H), 1.16 (s, 18H).31P-NMR (162 MHz, CDCl3): δ [ppm] -11.18. Step 7: To a solution of RBRC-115-30 (2.5 g, 3.5 mmol) in toluene (20 mL), 1-(pyridin-2-yl)ethan-1- one (2.1 g, 17.5 mmol), TsOH (67 mg, 0.4 mmol) and 4Ǻ molecular sieve (1.0 g) were added. The mixture was stirred at 140 °C for 6 h. After cooling to 20 °C, the mixture was removed toluene under vacuum. To the resulting mixture toluene (10 mL) was added and the mixture was degassed with N2 (three times). Then AlMe3 (14.0 mL, 28.0 mmol, 2 M) was added and the reaction mixture was stirred at 120 °C for 4 h. After cooling to 20 °C, the mixture was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4 to get crude product which was then purified by silica gel flash column chromatography (pentane / EtOAc, 20:1) to provide the desired product Lig-1361 as yellow solid in 76 % yield (2.2 g).1H NMR (400 MHz, CDCl3): δ [ppm] 7.97 – 7.82 (m, 4H), 7.69 (d, J = 8.0 Hz, 1H), 7.53 – 7.41 (m, 3H), 7.35 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.24 – 7.14 (m, 3H), 7.06 – 6.96 (m, 3H), 6.87 (dd, J = 7.6, 4.8 Hz, 1H), 6.82 (dd, J = 8.4, 2.0 Hz, 2H), 6.73 (dd, J = 8.4, 6.8 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 4.67 (q, J = 6.0 Hz, 1H), 4.25 (d, J = 6.4 Hz, 1H), 2.60 (dt, J = 16.8, 6.4 Hz, 1H), 2.45 (dt, J = 16.8, 6.8 Hz, 1H), 2.16 (ddt, J = 12.8, 8.2, 4.4 Hz, 1H), 1.72 – 1.64 (m, 1H), 1.50 (dddd, J = 20.8, 16.8, 8.8, 3.6 Hz, 2H), 1.11 (d, J = 2.0 Hz, 36H). Preparation of Lig-1337 (RBRC-089) Step 1: To a solution of RBRC-089-01 (10.0 g, 31.8 mmol) in ether (100 mL) was added nBuLi (13.9 mL, 33.4 mmol) at -78oC under N2. The mixture was stirred at -78oC for 15 min. The resulting mixture was added TESCl (5.27 g, 34.9 mmol) and stirred at rt for 1 h. And then the mixture was added nBuLi (13.9 mL, 33.4 mmol) at -78oC and stirred at -78oC for 15 min. The mixture was added TESCl (6.20 g, 41.3 mmol) and stirred at rt for 12 h. The mixture was quenched with NH4Cl solution (50 mL) and extracted with EtOAc (150 mL). The organic layer was concentrated to get crude product. The crude mixture was purified by flash column chromatography on silica (pentane) to provide the desired product RBRC-089-02 as yellow oil in 80 % yield (9.8 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.58 (d, J = 18.0 Hz, 2H), 7.48 (s, 1H), 0.97 (q, J = 7.6 Hz, 18H), 0.78 (q, J = 8. Hz, 12H). Step 2: A vigorously stirred solution of RBRC-089-02 (9.8 g, 25.2 mmol) in 100 mL THF was placed in a -78oC acetone bath. After 30 min, nBuLi (10.9 mL, 26.1 mmol) was added dropwise. The bath was maintained at -78oC for 2 h, then (Et2N)PCl2 (1.89 g, 10.9 mmol) was added. The reaction was stirred at rt for 16 h and cooled to 0oC. Concentrated HCl (6 mL) was added and stirred at rt for 5 h. The solution was poured into 1M HCl (100 mL), extracted with EtOAc (300 mL). The organic layer was concentrated to get crude product. The crude mixture was purified by flash column chromatography on silica (pentane / EtOAc =20:1) to provide the desired product RBRC-089-03 as yellow oil in 39 % yield (2.7 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.78 (s, 2H), 7.75 (s, 2H), 7.71 (s, 2H), 0.91 (t, J = 8.0 Hz, 36H), 0.77 (q, J = 8.0 Hz, 24H). Step 3: To a solution of RBRC-089-10 (15.0 g, 52.39 mmol) in DCM (200 mL), was added pyridine (12.6 mL) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (36.9 g, 130.78 mmol). The reaction mixture was warmed up to 20oC and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL) and extracted with DCM (600 mL). The combined organic layer was dried over with Na2SO4 and filtered. The mixture was concentrated to provide the desired product RBRC-089-20 as yellow oil in 97% yield (28.1 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.17 (dd, J = 9.2, 0.8 Hz, 2H), 8.04 (dt, J = 8.4, 0.8 Hz, 2H), 7.69-7.58 (m, 4H), 7.46 - 7.42 (m, 2H), 7.32-7.26 (m, 2H). Step 4: To a mixture of RBRC-089-20 (1.0 g, 1.81 mmol), palladium acetate (25 mg, 0.11 mmol), dppb (77 mg, 0.18 mmol) and RBRC-089-03 (1.44 g, 2.2 mmol) was added DMSO (25 mL) and diisopropylethylamine (1 mL). The resulting mixture was heated with stirring at 100oC for 12 h under N2. After cooling to 20oC, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The organic layer was concentrated to get crude product. The crude mixture was purified by short flash column chromatography on silica (pentane / EtOAc = 20:1) to provide the desired product RBRC-089-30 as yellow oil in 78 % yield (1.5 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.98 (dt, J = 20.4, 6.8 Hz, 3H), 7.83 (d, J = 8.4 Hz, 1H), 7.7 – 7.64 (m, 3H), 7.64–7.38 (m, 5H), 7.32 (dd, J = 16.4, 9.6 Hz, 3H), 7.21 (d, J = 8.8 Hz, 1H), 6.79 (t, J = 8.0 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 0.93–0.76 (m, 36H), 0.75 – 0.56 (m, 24H). Step 5: To a mixture of RBRC-089-30 (1.5 g, 1.4 mmol) and diisopropylethylamine (9.7 mL) in toluene (15 mL) was added HSiCl3 (2.3 mL) at 0oC. The reaction mixture was stirred at 115oC for 12 h under N2. After cooling to 20oC, the mixture was quenched with 12 N aqueous NaOH (10 mL) and diluted with EtOAc (60 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (20 mL). The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product RBRC-089-40 as yellow oil (1.3 g, crude) which was use further reaction without any purification. Step 6: A dry 100 mL flask was charged with RBRC-089-40 (1.3 g, 1.3 mmol), toluene (20 mL) and 2-(azidomethyl) pyridine (230 mg, 1.9 mmol) was added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in EtOH (10 mL) and 0.1 M NaOH aq. (10 mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, this was poured into H2O (10 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (60 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4 to get crude product. The crude product was purified by short flash column chromatography on silica (pentane / EtOAc = 3:1) to provide the desired product RBRC-089-50 as yellow oil in 39 % yield (0.5 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.07–7.89 (m, 3H), 7.74–7.57 (m, 3H), 7.55–7.45 (m, 4H), 7.40 (q, J = 1.4 Hz, 1H), 7.34–7.27 (m, 3H), 7.26–7.23 (m, 1H), 7.18 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 6.97– 6.89 (m, 1H), 6.83 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.56 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 6.26–6.14 (m, 1H), 5.39 (dd, J = 6.4, 3.6 Hz, 1H), 4.52 (t, J = 4.4 Hz, 2H), 2.19 (s, 3H), 0.82 (td, J = 7.6, 1.1 Hz, 36H), 0.68–0.53 (m, 24H). Step 7: The RBRC-089-50 (0.5 g, 0.5 mmol) and phenylsilane (3 mL) were placed in a dry 50 mL flask, and the reaction mixture was stirred at 115 °C for 37 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil. The crude mixture was purified by short flash column chromatography on silica (pentane / EtOAc = 10:1) to provide the desired product Lig-1337 as yellow oil in 32% yield (0.15 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.95–7.79 (m, 3H), 7.56 (dd, J = 8.0, 1.2 Hz, 1H), 7.45–7.33 (m, 3H), 7.31–7.20 (m, 4H), 7.1 –6.99 (m, 6H), 6.89–6.80 (m, 2H), 6.53 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 6.27 (dd, J = 8.4, 1.0 Hz, 1H), 5.01 (t, J = 4.8 Hz, 1H), 4.46–4.01 (m, 2H), 2.00 (s, 3H), 0.83–0.65 (m, 36H), 0.64–0.43 (m, 24H).31P-NMR (162 MHz, CDCl3): δ [ppm] -13.41.

[0009] Preparation of Lig-1336 (RBRC-088) Step 1: To a solution of RBRC-088-01 (20.0 g, 94.4 mmol) in THF (300 mL) was added CH3MgBr (94.3 mL, 283.1 mmol) at rt under N2. The mixture was stirred at rt for 12 h. The mixture was quenched with NH4Cl solution (200 mL) and extracted with EtOAc (600 mL). The organic layer was concentrated to get crude product. The crude mixture was purified by flash column chromatography on silica (pentane / EtOAc =1:1) to provide the desired product RBRC-088-02 as yellow oil in 63.0 % yield (14.5 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.39 (t, J = 1.6 Hz, 2H), 7.26 (d, J = 2.0 Hz, 1H), 4.82 (q, J = 6.4 Hz, 2H), 2.39 (s, 2H), 1.45 (d, J = 6.4 Hz, 6H). Step 2: To a solution of RBRC-088-02 (14.5 g, 59.2 mmol) in DCM (250 mL) was added Dess-Martin reagent (75.4 g, 177.45 mmol). The mixture was stirred at rt for 12 h. The reaction was quenched by water (300 mL) and extracted with DCM (900 mL). The organic layer was concentrated to get crude product. The crude mixture was purified by flash column chromatography on silica (pentane / EtOAc =5:1) to provide the desired product RBRC-088-03 as white solid in 67.2 % yield (10.0 g).1H NMR (400 MHz, CDCl3): δ [ppm] 8.34 (t, J = 1.6 Hz, 1H), 8.18 (t, J = 1.2 Hz, 2H), 2.58 (d, J = 1.2 Hz, 6H). Step 3: To a solution of RBRC-088-03 (10.0 g, 41.5 mmol) in THF (200 mL) was added CH3CH2MgBr (41.5 mL,124.5 mmol) at rt under N2. The mixture was stirred at rt for 12 h. The mixture was quenched with NH4Cl solution (200 mL) and extracted with EtOAc (600 mL). The organic layer was concentrated to get crude product. The crude mixture was purified by flash column chromatography on silica (pentane / EtOAc =3:1) to provide the desired product RBRC-088-04 as yellow oil in 71.4 % yield (8.9 g). Step 4: To a solution of RBRC-088-04 (8.9 g, 29.56 mmol) in DCM (100 mL) was added 150 mL conc. HCl. The mixture was stirred at rt for 12 h. The resulting mixture was added water (100 mL) and extracted with DCM (300 mL). The combined organic layer was dried over Na2SO4 and concentrated. The product in DCM (100 mL) was added AlMe3 (52 mL, 118.24 mL) at -78oC. The reaction was stirred at rt for 12 h. The reaction was quenched with 1M HCl (100 mL) and extracted with DCM (300 mL). The organic layer was concentrated to get crude product. The crude mixture was purified by flash column chromatography on silica (pentane) to provide the desired product RBRC-088-05 as yellow oil in 56.8 % yield (5.0 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.18 (t, J = 1.6 Hz, 2H), 7.11 (t, J = 1.6 Hz, 1H), 1.54 (q, J = 7.6 Hz, 4H), 1.18 (s, 12H), 0.59 (t, J = 7.6 Hz, 6H). Step 5: A vigorously stirred solution of RBRC-088-05 (5.0 g, 16.8 mmol) in 50 mL THF was placed in a -78oC acetone bath. After 30 min, nBuLi (7.3 mL, 17.6 mmol) was added dropwise. The bath was maintained at -78oC for 2h, then (Et2N)PCl2 (1.3 g, 7.6 mmol) was added. The reaction was stirred at rt for 16 h and cooled to 0oC. Concentrated HCl (6 mL) was added and stirred at rt for 5 h. The solution was poured into 1M HCl (100 mL), extracted with EtOAc (300 mL). The organic layer was concentrated to get crude product. The crude mixture was purified by flash column chromatography on silica (pentane / EtOAc =1:1) to provide the desired product RBRC-088-06 as yellow oil in 33.3 % yield (1.2 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 7.78 (s, 2H), 7.75 (s, 2H), 7.71 (s, 2H), 0.91 (t, J = 8.0 Hz, 36H), 0.77 (q, J = 8.0 Hz, 24H). Step 6: To a solution of RBRC-088-10 (15.0 g, 52.4 mmol) in DCM (200 mL), was added pyridine (12.6 mL) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (36.9 g, 130.8 mmol). The reaction mixture was warmed up to 20oC, and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (200 mL) and extracted with DCM (600 mL). The combined organic layer was dried over with Na2SO4 and filtered. The mixture was concentrated to provide the desired product RBRC-088-20 as yellow oil in 97% yield (28.1 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.17 (dd, J = 9.2, 0.8 Hz, 2H), 8.04 (dt, J = 8.4, 0.8 Hz, 2H), 7.69-7.58 (m, 4H), 7.46-7.42 (m, 2H), 7.32 - 7.26 (m, 2H). Step 7: To a mixture of RBRC-088-20 (1.0 g, 1.8 mmol), palladium acetate (25 mg, 0.1 mmol), dppb (77 mg, 0.2 mmol) and RBRC-088-06 (1.1 g, 2.2 mmol) was added DMSO (25 mL) and diisopropylethylamine (1 mL). The resulting mixture was heated with stirring at 100oC for 12 h under N2. After cooling to 20oC, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (90 m). The organic layer was concentrated to get crude product. The crude mixture was purified by short flash column chromatography on silica (pentane / EtOAc = 1:1) to provide the desired product RBRC-088-30 as yellow oil in 52.9 % yield (1.1 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.10–8.02 (m, 3H), 7.98–7.89 (m, 5H), 7.59–7.53 (m, 2H), 7.50 (d, J = 9.0 Hz, 1H), 7.43–7.41 (m, 1H), 7.31 (ddd, J = 8.4, 6.8, 1.2 Hz, 2H), 7.17 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 6.91 (dd, J = 8.4, 1.0 Hz, 1H), 1.55–1.47 (m, 8H), 1.20–1.09 (m, 24H), 0.57 (q, J = 7.4 Hz, 12H). Step 8: To a mixture of RBRC-088-30 (1.1 g, 1.3 mmol) and diisopropylethylamine (11 mL) in toluene (15 mL) was added HSiCl3 (30 mL) at 0oC. The reaction mixture was stirred at 115oC for 12 h under N2. After cooling to 20oC, the mixture was quenched with 12 N aqueous NaOH (10 mL) and diluted with EtOAc (60 mL). The resulting suspension was filtered through Celite and the solid was washed with EtOAc (20 mL). The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product RBRC-088-40 as yellow oil (1.0 g, crude) which was use further reaction without any purification. Step 9: A dry 100 mL flask was charged with RBRC-088-40 (1.0 g, 1.2 mmol, 1.0 eq), toluene (20 mL) and 2-(azidomethyl) pyridine (214 mg, 1.7 mmol) was added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in EtOH (10 mL) and 0.1 M NaOH aq. (10 mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, this was poured into H2O (10 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (60 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4 to get crude product. The crude product was purified by short flash column chromatography on silica (DCM: MeOH = 100:1) to provide the desired product RBRC-088-50 as yellow solid in 51.7 % yield (0.51 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.39–8.30 (m, 1H), 8.08–8.02 (m, 1H), 7.98–7.92 (m, 2H), 7.91–7.84 (m, 2H), 7.77–7.71 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.51–7.48 (m, 1H), 7.38 (d, J = 9.6 Hz, 1H), 7.16 (d, J = 5.2 Hz, 4H), 7.03 (d, J = 2.0 Hz, 2H), 7.00 (t, J = 2.0 Hz, 2H), 6.88 (dd, J = 7.6, 4.8 Hz, 1H), 6.79–6.75 (m, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.10 (d, J = 5.6 Hz, 1H), 4.50–4.36 (m, 2H), 2.14 (s, 3H), 1.45 (dd, J = 16.0, 7.6 Hz, 8H), 1.21–1.00 (m, 24H), 0.58-0.49 (m, 12H). Step 10: The RBRC-088-50 (0.51 g, 0.6 mmol) and phenylsilane (3 mL) were placed in a dry 50 mL flask, and the reaction mixture was stirred at 115 °C for 37 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil. The crude mixture was purified by short flash column chromatography on silica (pentane / EtOAc = 10:1) to provide the desired product Lig-1336 as yellow solid in 58% yield (0.29 g).1H-NMR (400 MHz, CDCl3): δ [ppm] 8.01 (dd, J = 5.2, 2.0 Hz, 1H), 7.97–7.87 (m, 4H), 7.73–7.67 (m, 2H), 7.47–7.37 (m, 3H), 7.33–7.26 (m, 2H), 7.25–7.23 (m, 1H), 7.20-7.16 (m, 1H), 7.06 – 7.01 (m, 2H), 6.94 (dd, J = 7.6, 4.8 Hz, 1H), 6.90-6.85 (m, 3H), 6.61 (d, J = 8.8 Hz, 1H), 5.23 (t, J = 4.4 Hz, 1H), 4.50 (dd, J = 15.6, 5.2 Hz, 1H), 4.42 (dd, J = 15.6, 3.6 Hz, 1H), 2.20 (s, 3H), 1.47 (q, J = 7.2 Hz, 5H), 1.34–1.23 (m, 8H), 1.12 (d, J = 5.6 Hz, 19H), 0.57 (dt, J = 20.8, 7.2 Hz, 12H).31P-NMR (162 MHz, CDCl3): δ [ppm] -11.27.

[0010] Preparation of Lig-1379 (RBRC-122) Step 1: To a mixture of RBRC-122-01 (15.0 g, 137 mmol, 1.00 eq) in toluene (150 mL) was added DBU (23.0 g, 151 mmol, 1.10 eq) and DPPA (37.8 g, 137 mmol, 1.00 eq) at 0oC under N2. And then, the mixture stirred at room temperature overnight. The resulting mixture was quenched with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layer was dried over with Na2SO4 and was purified by flash column chromatography on silica (450 g, elute with hexan / EtOAc (5:1), Rf = 0.4) to provide the desired product RBRC-122-02 (18.0 g, 97% yield) as yellow oil. Step 2: To a mixture of RBRC-122-10 (50.0 g, 362 mmol, 1.00 eq) in DMF (500 mL) was added NaH (60%, 17.4 g, 434 mmol, 1.20 eq) at 0oC. The reaction mixture was stirred at 25oC for 2 hours. And then, the reaction mixture was added MOMBr (54.3 g, 434 mmol, 1.20 eq) at 0oC. The resulting mixture was quenched with water (500 mL) after stir at 25oC for 12 h. And extracted with EtOAc (500 mL x 3). The combined organic layer was dried over with Na2SO4 and filtered. The crude product was purified by flash column chromatography on silica (750 g, elute with hexane / EtOAc (10:1), Rf = 0.4) to provide the desired product RBRC-122-20 (65.9 g, 99% yield) as yellow oil.1H-NMR (400 MHz, CDCl3) δ [ppm] 6.70 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 6.49 (dd, J = 8.4, 2.4 Hz, 1H), 5.92 (s, 2H), 5.08 (s, 2H), 3.48 (s, 3H). Step 3: To a mixture of RBRC-122-20 (45.0 g, 247 mmol, 1.00 eq) in Et2O (500 mL) was addednBuLi (2.5 M, 109 mL, 272 mmol, 1.10 eq) at 0oC. The reaction mixture was stirred at 25oC for 2 hours under N2. And then, the mixture was added FeCl3 (44.2 g, 272 mmol, 1.10 eq) at 0oC. The supernatant Et2O was removed after stirred at 25oC for 4 hours. The crude mixture was purified by short flash column chromatography on silica (850 g, elute with hexane / EtOAc (5:1), Rf = 0.3) to provide the desired product RBRC-122-30 (26.5 g, 59% yield) as yellow solid.1H-NMR (400 MHz, CDCl3) δ [ppm] 6.75 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 5.93 (d, J = 1.6 Hz, 2H), 5.91 (d, J = 1.6 Hz, 2H), 4.99 (d, J = 0.8 Hz, 4H), 3.34 (s, 6H). Step 4: To a mixture of RBRC-122-30 (26.5 g, 73.2 mmol, 1.00 eq) in MeOH (250 mL) was added concentrated hydrochloric acid (11.7 mL, 146 mmol, 2.00 eq) at 0oC. The solution was stirred at 70 °C for 2 h. After cooling to 20 °C, the supernatant MeOH was removed and the residue was purified by flash column chromatography on silica (800 g, elute with hexane / EtOAc (3:1), Rf = 0.4) to provide the desired product RBRC-122-40 (17.1 g, 85% yield) as white solid.1H-NMR (400 MHz, DMSO-d6) δ [ppm] 8.93 (s, 2H), 6.68 (d, J = 8.4 Hz, 2H), 6.28 (d, J = 8.4 Hz, 2H), 5.85 (s, 4H). Step 5: To a solution of RBRC-122-40 (8.60 g, 31.4 mmol, 1.00 eq) in DCM (100 mL) was added Et3N (12.7 g, 125 mmol, 4.00 eq) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (26.5 g, 94.1 mmol, 3.00 eq). The reaction mixture was warmed up to 20oC, and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layer was dried over with Na2SO4 and filtered. The mixture was purified by flash column chromatography on silica (260 g, elute with hexane / EtOAc (10:1), Rf = 0.5) to provide RBRC-122-50 (12.0 g, 71% yield) as yellow oil.1H-NMR (400 MHz, CDCl3) δ [ppm] 6.90 (s, 4H), 6.11 (d, J = 1.6 Hz, 2H), 6.07 (d, J = 1.6 Hz, 2H).19F-NMR (376 Hz, CDCl3) δ -73.98. Step 6: To a mixture of RBRC-122-50 (12.0 g, 22.3 mmol, 1.00 eq), palladium acetate (300 mg, 1.34 mmol, 0.0600 eq), dppb (950 mg, 2.23 mmol, 0.100 eq) and bis(3,5-di-tert-butylphenyl)phosphine oxide (11.1 g, 24.5 mmol, 1.10 eq) was added DMSO (150 mL) and diisopropylethylamine (12.0 g, 89.2 mmol, 4.00 eq). The resulting mixture was heated with stirring at 100oC for 12 hours under N2. After cooling to 20oC, the reaction mixture was quenched with water (300 mL) and extracted with EtOAc (300 mL x 3). The organic layer was concentrated to get crude product. The crude mixture was purified by short flash column chromatography on silica (400 g, elute with hexane / EtOAc (3:1), Rf = 0.3) to provide the desired product RBRC-122-60 (8.60 g, 48% yield) as yellow solid.1H-NMR (400 MHz, CDCl3) δ [ppm] 7.53 - 7.48 (m, 4H), 7.41 (dd, J = 12.4, 2.0 Hz, 2H), 6.89 - 6.81 (m, 2H), 6.68 - 6.63 (m, 2H), 6.07 (d, J = 1.2 Hz, 1H), 5.96 (d, J = 1.2 Hz, 1H), 5.82 (d, J = 1.6 Hz, 1H), 5.39 (s, 1H), 1.27 (s, 18H), 1.26 (s, 18H).31P-NMR (162 MHz, CDCl3) δ 27.16.19F-NMR (376 MHz, CDCl3) δ -74.20. Step 7: To a mixture of RBRC-122-60 (8.60 g, 10.6 mmol, 1.00 eq) and diisopropylethylamine (57.1 g, 422 mmol, 40.0 eq) in toluene (100 mL) was added HSiCl3 (21.8 g, 169 mmol, 16.0 eq) at 0oC. The reaction mixture was stirred at 115oC for 12 hours under N2. After cooling to 20oC, the mixture was quenched with 12 N aqueous NaOH (200 mL) and diluted with EtOAc (200 mL). The resulting suspension was extracted with EtOAc (200.0 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product RBRC-122-70 (7.90 g, crude) yellow oil which was used further reaction without any purification. Step 8: A dry 250 mL flask was charged with RBRC-122-70 (7.90 g, 9.90 mmol, 1.00 eq), toluene (100 mL) and 2-(azidomethyl) pyridine (1.90 g, 14.9 mmol, 1.50 eq) was added. The solution was stirred at 115 °C for 12 h. After cooling to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in C2H5OH (50.0 mL) and 1.0 M NaOH aq. (50.0 mL) and stirred at 65 °C for 2 h. After cooling to 20 °C, the reaction was poured into H2O (100 mL). The mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. The crude product was purified by flash column chromatography on silica (240 g, elute with hexane / EtOAc (1:1), Rf = 0.2) to provide the desired product RBRC-122-80 (4.60 g, 62% yield) as yellow solid.1H-NMR (400 MHz, CDCl3) δ [ppm] 8.53 - 8.51 (m, 1H), 7.68 - 7.64 (m, 4H), 7.57 (q, J = 1.6 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.13 (s, 1H), 6.95 (dd, J = 13.6, 8.0 Hz, 1H), 6.81 (dd, J = 8.0, 2.0 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 6.02 (d, J = 1.2 Hz, 1H), 5.99 (d, J = 1.2 Hz, 1H), 5.91 (d, J = 8.4 Hz, 1H), 5.49 (d, J = 1.6 Hz, 1H), 4.87 (s, 1H), 4.52 (s, 2H), 1.30 (s, 18H), 1.24 (s, 18H).31P-NMR (162 MHz, CDCl3) δ 28.13. Step 9: Full separation of diastereosisomers was accomplished by preparative chiral LC with a CHIRALPAK IK column (5.0 cm I.D. × 25 cm L, 10 μm). The preparative chiral LC method for separation of (S)-RBRC-122-90 (2.09 g) and (R)-RBRC-122-90 (2.09 g) Stationary phase: CHIRALPAK IK (5.0 cm I.D. × 25 cm L, 10 μm) Eluent: EtOH / DIPEA = 100 / 0.1(V / V) Flow: 50 ml / min Column oven temperature: 38oC Detection: UV 254 nm Chiral LC method to determine the enantiomeric purity of (S)-RBRC-122-90: Stationary phase: CHIRALPAK IB N-34.6 mm x 250 mm x 3 μm Eluent: Hexane / iPrOAc = 75 / 25 (V / V) Run time: 15 min Flow: 1.0 mL / min Column oven temperature: 30oC Injection volume 5 μL Detection 208 nm Retention Times: (S)-RBRC-122-90, 13.07 min; (R)-RBRC-122-90, 4.91 min(S)-RBRC-122-90 ([ ]20D -97° (conc. = 1.0 g / mL, CHCl3Step 10: To a solution of (S)-RBRC-122-90 (2.09 g, 2.70 mmol, 1.00 eq) in PhSiH3(2.92 g, 27.0 mmol, 10.0 eq). The mixture was stirred at 115 °C for 48 h under N2atmosphere. The mixture was filtered and concentrated to get crude product. The crude product was purified by flash column chromatography on silica (60.0 g, elute with hexane / EtOAc (5:1), Rf = 0.3) to provide the desired product Lig-1379 (1.65 g, 79% yield) as yellow solid. [^]20D= -50° (conc. = 1.0 g / mL, CHCl3).1H-NMR (400 MHz, CDCl3) δ [ppm] 8.51 - 8.49 (m, 1H), 7.52 (td, J = 7.6, 1.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.32 (q, J = 2.0 Hz, 2H), 7.11 - 7.08 (m, 1H), 7.07 (d, J = 1.6 Hz, 2H), 7.04 (d, J = 2.0 Hz, 2H), 6.82 (d, J = 8.0 Hz, 1H), 6.65 (dd, J = 8.0, 3.2 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 6.02 (d, J = 1.2 Hz, 1H), 5.98 (d, J = 1.6 Hz, 1H), 5.94 (d, J = 8.4 Hz, 1H), 5.61 (d, J = 1.6 Hz, 1H), 4.92 (d, J = 1.6 Hz, 1H), 4.42 - 4.32 (m, 2H), 4.18 (s, 1H), 1.22 (s, 18H), 1.19 (s, 18H).31P-NMR (162 MHz, CDCl3) δ -9.73.

[0011] Preparation of 1380 (RBRC-123) Step 1: To a solution of RBRC-123-10 (49.3 g, 365 mmol, 1.00 eq) in DCM (500 mL) was added m- CPBA (126 g, 730 mmol, 2.00 eq) at 0oC. The mixture was allowed to stir at 0oC for 4 h followed by dropwise addition of 4.0 M NaOH aq. (183 mL, 730 mmol, 2.00 eq). The reaction mixture was warmed up to 20oC and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (400 mL) and extracted with DCM (400 mL x 3). The combined organic layer was dried over with Na2SO4 and filtered. The mixture was concentrated to provide the desired product RBRC-123-20 (41.1 g, 92% yield) as yellow oil.1H-NMR (400 MHz, CDCl3) δ [ppm] 6.72 (d, J = 8.8 Hz, 1H), 6.40 (d, J = 2.8 Hz, 1H), 6.33 (dd, J = 8.8, 2.8 Hz, 1H), 5.15 (s, 1H), 4.26 - 4.21 (m, 2H), 4.21 - 4.18 (m, 2H). Step 2: To a mixture of RBRC-123-20 (41.1 g, 270 mmol, 1.00 eq) in DMF (400 mL) was added NaH (60%, 7.80 g, 324 mmol, 1.20 eq) at 0oC. The reacction mixture was stirred at 25oC for 2 hours. And then, the reacction mixture was added MOMBr (42.5 g, 324 mmol, 1.20 eq) at 0oC. The resulting mixture was quenched with water (500 mL) after stir at 25oC for 12 h. And extracted with EtOAc (500 mL x 3). The combined organic layer was dried over with Na2SO4 and filtered. The crude product was purified by flash column chromatography on silica (800 g, elute with hexane / EtOAc = (10:1), Rf = 0.3) to provide the desired product RBRC-123-30 (47.6 g, 90% yield) as yellow oil.1H-NMR (400 MHz, CDCl3) δ [ppm] 6.77 (d, J = 8.8 Hz, 1H), 6.61 (d, J = 2.8 Hz, 1H), 6.54 (dd, J = 8.8, 2.8 Hz, 1H), 5.08 (s, 2H), 4.29 - 4.17 (m, 4H), 3.47 (s, 3H). Step 3: To a mixture of RBRC-123-30 (46.1 g, 235 mmol, 1.00 eq) in Et2O (400 mL) was addednBuLi(2.5 M, 103 mL, 258 mmol, 1.10 eq) at 0oC. The reaction mixture was stirred at 25oC for 2 hours under N2. And then, the mixture was added FeCl3 (41.9 g, 258 mmol, 1.10 eq) at 0oC. The supernatant Et2O was removed after stirred at 25oC for 4 hours. The crude mixture was purified by short flash column chromatography on silica (800 g, elute with hexane / EtOAc = (2:1), Rf = 0.3) to provide the desired product RBRC-123-40 (12.2 g, 32% yield) as yellow oil.1H-NMR (400 MHz, CDCl3) δ [ppm] 6.84 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 4.99 - 4.92 (m, 4H), 4.23 - 4.17 (m, 8H), 3.32 (s, 6H). Step 4: To a mixture of RBRC-123-40 (12.2 g, 31.3 mmol, 1.00 eq) in MeOH (150 mL) was added concentrated hydrochloric acid (5.20 mL, 62.5 mmol, 2.00 eq) at 0oC. The solution was stirred at 70 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant MeOH was removed. The crude product was purified by flash column chromatography on silica (200 g, elute with hexane / EtOAc = (1:1), Rf = 0.3) to provide the desired product RBRC-123-50 (8.40 g, 89% yield) as yellow solid.1H-NMR (400 MHz, CDCl3) δ [ppm] 6.88 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 8.8 Hz, 2H), 4.25 - 4.20 (m, 8H). Step 5: To a solution of RBRC-123-50 (8.40 g, 27.8 mmol, 1.00 eq) in DCM (100 mL), was added pyridine (6.70 g, 83.7 mmol, 3.00 eq) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (19.7 g, 69.8 mmol, 2.50 eq). The reaction mixture was warmed up to 20oC and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layer was dried over with Na2SO4 and filtered. The crude product was purified by flash column chromatography on silica (180 g, elute with hexane / EtOAc = (10:1), Rf = 0.3) to provide the desired product RBRC-123-60 (13.4 g, 85% yield) as yellow solid.1H-NMR (400 MHz, CDCl3) δ [ppm] 7.01 (d, J = 9.2 Hz, 2H), 6.89 (d, J = 9.2 Hz, 2H), 4.33 - 4.21 (m, 8H).19F-NMR (376 MHz, CDCl3) δ -74.36. Step 6: To a mixture of RBRC-123-60 (13.4 g, 23.7 mmol, 1.00 eq), palladium acetate (314 mg, 1.42 mmol, 0.0600 eq), dppb (1.10 g, 2.37 mmol, 0.100 eq) and bis(3,5-di-tert-butylphenyl)phosphine oxide (11.1 g, 26.0 mmol, 1.10 eq) was added DMSO (150 mL) and diisopropylethylamine (12.3 g, 94.6 mmol, 4.00 eq). The resulting mixture was heated with stirring at 100oC for 12 hours under N2. After cooling to 20oC, the reaction mixture was quenched with water (300 mL) and extracted with EtOAc (300 mL x 3). The organic layer was concentrated to get crude product. The crude mixture was purified by short flash column chromatography on silica (150 g, elute with hexane / EtOAc = (1:1), Rf = 0.5) to provide the desired product RBRC-123-70 (10.8 g, 57% yield) as yellow solid.1H-NMR (400 MHz, CDCl3) δ [ppm] 7.53 - 7.45 (m, 4H), 7.36 (d, J = 1.6 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 6.90 (dd, J = 8.4, 2.8 Hz, 1H), 6.80 (dt, J = 8.4, 6.0 Hz, 2H), 6.58 (d, J = 9.2 Hz, 1H), 4.26 (dt, J = 22.0, 4.0 Hz, 4H), 4.17 - 4.00 (m, 4H), 1.27 (s, 18H), 1.24 (s, 18H)..31P-NMR (162 MHz, CDCl3) δ 29.77.19F-NMR (376 MHz, CDCl3) δ -74.71. Step 7: To a mixture of RBRC-123-70 (10.8 g, 13.1 mmol, 1.00 eq) and diisopropylethylamine (67.6 g, 523 mmol, 40.0 eq) in toluene (100 mL) was added HSiCl3 (28.2 g, 209 mmol, 16.0 eq) at 0oC. The reaction mixture was stirred at 115oC for 12 hours under N2. After cooling to 20oC, the mixture was quenched with 12 N aqueous NaOH (200 mL) and diluted with EtOAc (200 mL). The resulting suspension was extracted with EtOAc (200 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product RBRC-123-80 (10.2 g, 96% yield) as yellow oil which was used further reaction without any purification. Step 8: A dry 250 mL flask was charged with RBRC-123-80 (10.2 g, 12.6 mmol, 1.00 eq), toluene (100 mL) and 2-(azidomethyl) pyridine (2.50 g, 18.9 mmol, 1.50 eq) was added. The solution was stirred at 115 °C for 12 h. After cooling to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in C2H5OH (50.0 mL) and 1.0 M NaOH aq. (50.0 mL) and stirred at 65 °C for 2 h. After cooling to 20 °C, the mixture was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (EtOAc) (100 mL x 3). The combined organic layers were washed with brine (100 mL), and dried over anhydrous Na2SO4 to get crude product. The crude product was purified by flash column chromatography on silica (200 g, elute with hexane / EtOAc = (1:1), Rf = 0.1) to provide the desired product RBRC-123-90 (7.60 g, 76% yield) as yellow solid.1H-NMR (400 MHz, CDCl3) δ [ppm] 8.49 (d, J = 4.8 Hz, 1H), 7.66 - 7.36 (m, 9H), 7.11 (s, 1H), 6.97 - 6.82 (m, 2H), 6.53 (d, J = 8.8 Hz, 1H), 6.02 (d, J = 8.8 Hz, 1H), 4.43 (s, 2H), 4.29 (s, 2H), 4.17 (s, 2H), 3.82 (d, J = 46.0 Hz, 2H), 3.51 (s, 2H), 1.28 (s, 18H), 1.24 (s, 18H).31P-NMR (162MHz, CDCl3) δ 27.13. Step 9: Full separation of diastereosisomers was accomplished by preparative chiral LC with a CHIRALPAK IK column (5.0 cm I.D. × 25 cm L, 10 μm). The preparative chiral LC method for separation of (S)-RBRC-123-100 (3.10 gand (R)-RBRC-123-100 (3.10 g): Preparative chiral LC method for separation of (S)-RBRC-123-100 and (R)-RBRC-123-100: Stationary phase: CHIRALPAK IK (5.0 cm I.D. × 25 cm L, 10 μm) Eluent: Hexane / EtOH / DIPEA=70 / 30 / 0.1(V / V / V) Flow: 60 ml / min Column oven temperature: 38oC Detection: UV 254 nm Chiral LC method to determine the enantiomeric purity of (S)-RBRC-123-100 Stationary phase: CHIRALPAK IN-34.6 mm x 250 mm x 3 μm Eluent: Hexane / iPrOAc =75:25 (V / V) Run time: 25 min Flow: 1.0 mL / min Column oven temperature: 30oC Injection volume: 5 μL Detection: 208 nm Retention Times: (S)-RBRC-123-100, 6.94 min; (R)-RBRC-123- 100, 5.23 min (S)-RBRC-123-100 ([^]20D-74° (conc. = 1.0 g / mL, CHCl3) Step 10: The (S)-RBRC-123-100 (3.10 g, 3.83 mmol, 1.00 eq) and phenylsilane (4.72 mL, 38.3 mmol, 10.0 eq) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 48 h. The mixture was concentrated to get crude product. The crude product was purified by flash column chromatography on silica (100 g, elute with hexane / EtOAc (2:1), Rf = 0.5) to provide the desired product Lig-1380 (1.90 g, 64% yield) as white solid. [^]20D-10° (conc. = 1.0 g / mL, CHCl3).1H-NMR (400 MHz, CDCl3) δ [ppm] 8.50 – 8.48 (m, 1H), 7.49 (td, J = 7.6, 2.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 2.0 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.08 - 7.05 (m, 3H), 6.96 (dd, J = 8.0, 2.0 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.79 - 6.65 (m, 2H), 6.05 (d, J = 8.8 Hz, 1H), 4.38 - 4.19 (m, 6H), 4.02 – 3.97 (m, 1H), 3.89 (s, 1H), 3.83 – 3.77 (m, 2H), 3.41 – 3.31 (m, 1H), 1.23 (s, 18H), 1.16 (s, 18H).31P-NMR (162 MHz, CDCl3) δ -12.07.

[0012] Preparation of Lig-1381 (RBRC-124) Step 1: To a mixture of RBRC-124-10 (50.0 g, 325 mmol, 1.00 eq) in DMF (500 mL) was added NaH (60 %, 15.6 g, 390 mmol, 1.20 eq) at 0oC. The reaction mixture was stirred at 25oC for 2 hours. And then, the reaction mixture was added MOMBr (4.90 g, 390 mmol, 1.20 eq) at 0oC. The resulting mixture was quenched with water (500 mL) after stir at 25oC for 12 h. And extracted with EtOAc (500 mL x 3). The combined organic layer was dried over with Na2SO4 and filtered. The crude product was purified by flash column chromatography on silica (1500 g, elute with hexane / EtOAc (10:1), Rf = 0.3) to provide the desired product RBRC-124-20 (70.1 g, 99% yield) as yellow oil.1H-NMR (400 MHz, CDCl3) δ [ppm] 6.24 (d, J = 2.0 Hz, 2H), 6.14 (t, J = 2.0 Hz, 1H), 5.14 (s, 2H), 3.77 (s, 6H), 3.48 (s, 3H). Step 2: To a mixture of RBRC-124-20 (70.1 g, 354 mmol, 1.00 eq) in Et2O (500 mL) was addednBuLi (2.5 M, 155.6 mL, 389 mmol, 1.10 eq) at 0oC. The reaction mixture was stirred at 25oC for 2 hours under N2. And then, the mixture was added FeCl3 (63.0 g, 389 mmol, 1.10 eq) at 0oC. The supernatant Et2O was removed after stirred at 25oC for 4 hours. The crude mixture was purified by flash column chromatography on silica (2100 g, elute with hexane / EtOAc (3:1), Rf = 0.5) to provide the desired product RBRC-124-30 (19.1 g, 21% yield) as yellow oil.1H-NMR (400 MHz, CDCl3) δ [ppm] 6.46 (d, J = 2.4 Hz, 2H), 6.28 (d, J = 2.4 Hz, 2H), 5.08 - 4.94 (m, 4H), 3.83 (s, 6H), 3.70 (s, 6H), 3.34 (s, 6H). Step 3: To a mixture of RBRC-124-30 (19.1 g, 48.4 mmol, 1.00 eq) in MeOH (250 mL) and THF (50.0 mL) was added acetyl chloride (20.6 mL, 290 mmol, 6.00 eq) at 0oC. The solution was stirred at rt for 12 h. The mixture was concentrated and purified by flash column chromatography on silica (600 g, elute with hexane / EtOAc (3:1), Rf = 0.2) to provide the desired product RBRC-124-40 (10.2 g, 69% yield) as yellow solid. Step 4: To a solution of RBRC-124-40 (10.2 g, 33.3 mmol, 1.00 eq) in DCM (100 mL), was added Et3N (13.9 mL, 100 mmol, 3.00 eq) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (28.2 g, 83.3 mmol, 2.50 eq). The reaction mixture was warmed up to 20oC and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layer was dried over with Na2SO4 and filtered. The mixture was concentrated and purified by flash column chromatography on silica (300 g, elute with hexane / EtOAc (3:1), Rf = 0.8) to provide the desired product RBRC-124-50 (13.4 g, 70% yield) as yellow solid.1H-NMR (400 MHz, CDCl3) δ [ppm] δ 6.28 (d, J = 2.4 Hz, 2H), 6.19 (d, J = 2.4 Hz, 2H), 3.82 (s, 6H), 3.73 (s, 6H). Step 5: To a mixture of RBRC-124-50 (13.4 g, 23.5 mmol, 1.00 eq), palladium acetate (316 mg, 1.41 mmol, 0.0600 eq), dppb (1.00 g, 2.35 mmol, 0.100 eq) and bis(3,5-di-tert-butylphenyl)phosphine oxide (11.0 g, 25.9 mmol, 1.10 eq) was added DMSO (150 mL) and diisopropylethylamine (12.1 g, 94.0 mmol, 4.00 eq). The resulting mixture was heated with stirring at 100oC for 12 hours under N2. After cooling to 20oC, the reaction mixture was quenched with water (300 mL) and extracted with EtOAc (300 mL x 3). The organic layer was concentrated to get crude product. The crude mixture was purified by flash column chromatography on silica (350 g, elute with hexane / EtOAc (3:1), Rf = 0.5) to provide the desired product RBRC-124-60 (16.5 g, 84% yield) as yellow solid.1H-NMR (400 MHz, CDCl3) δ [ppm] 7.49 - 7.47 (m, 3H), 7.45 (dd, J = 4.8, 2.0 Hz, 2H), 7.41 (d, J = 2.0 Hz, 1H), 6.64 (d, J = 2.4 Hz, 1H), 6.50 (dd, J = 14.0, 2.4 Hz, 1H), 6.27 (s, 2H), 3.77 (s, 3H), 3.68 (d, J = 15.6 Hz, 6H), 3.35 (s, 3H), 1.27 (s, 18H), 1.25 (s, 18H).31P-NMR (162 MHz, CDCl3) δ 28.05. Step 6: To a mixture of RBRC-124-60 (16.5 g, 20.5 mmol, 1.00 eq) and diisopropylethylamine (106 g, 820 mmol, 40.0 eq) in toluene (100 mL) was added HSiCl3 (44.3 g, 328 mmol, 16.0 eq) at 0oC. The reaction mixture was stirred at 115oC for 12 hours under N2. After cooling to 20oC, the mixture was quenched with 12 N aqueous NaOH (200 mL) and diluted with EtOAc (200 mL). The resulting suspension was extracted with EtOAc (200 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated to provide the desired product RBRC-124-70 (15.0 g, crude) as yellow oil which was used further reaction without any purification. Step 7: A dry 250 mL flask was charged with RBRC-124-70 (15.0 g, 19.0 mmol, 1.00 eq), toluene (100 mL) and 2-(azidomethyl) pyridine (3.70 g, 28.6 mmol, 1.50 eq) was added. The solution was stirred at 115 °C for 12 h. After cooling to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in C2H5OH (50.0 mL) and 1.0 M NaOH aq. (50.0 mL) and stirred at 65 °C for 2 h. After cooling to 20 °C, the mixture was poured into H2O (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4 to get crude product. The crude product was purified by flash column chromatography on silica (450 g, elute with hexane / EtOAc (1:2), Rf = 0.5) to provide the desired product RBRC-124-80 (7.60 g, 52%) as yellow solid.1H-NMR (400 MHz, CDCl3) δ [ppm] 8.50 - 8.48 (m, 1H), 7.67 - 7.38 (m, 8H), 7.09 (s, 1H), 6.75 - 6.58 (m, 2H), 5.59 (d, J = 2.0 Hz, 1H), 5.44 (d, J = 2.4 Hz, 1H), 4.64 (s, 1H), 4.43 (s, 2H), 3.69 (s, 3H), 3.66 (s, 3H), 3.54 (s, 3H), 3.23 (s, 3H), 1.29 (s, 18H), 1.24 (s, 18H).31P-NMR (162 MHz, CDCl3) δ 28.25. Step 8: Full separation of diastereosisomers was accomplished by preparative chiral LC with a CHIRALPAK IM column (5.0 cm I.D. × 25 cm L, 10 μm) The preparative chiral LC method for separation of (S)-RBRC-124-90 (3.40 g) and (R)-RBRC-124-90 (3.70 g): Preparative chiral LC method for separation of (S)-RBRC-124-90 and (R)-RBRC-124-90: Stationary phase: CHIRALPAK IM (5.0 cm I.D. × 25 cm L, 10 μm) Eluent: Hexane / iPrOAc / DIPEA = 60 / 40 / 0.1(V / V / V) Flow: 60 ml / min Column oven temperature: 38oC Detection: UV 254 nm Chiral LC method to determine the enantiomeric purity of (S)-RBRC-124-90: Stationary phase: CHIRALPAK IG-34.6 mm x 150 mm x 3 μm Eluent: Hexane / iPrOAc = 75 / 25 (V / V) Run time: 25 min Flow: 1.0 mL / min Column oven temperature: 30oC Injection volume: 5 μL Detection: 208 nm Retention Times: (S)-RBRC-124-90, 3.39 min; (R)-RBRC-124-90, 2.68 min (S)-RBRC-124-90 ([^]20D -94° (conc. = 1.0 g / mL, CHCl3) Step 9: To a solution of (S)-RBRC-124-90 (3.40 g, 4.25 mmol, 1.00 eq) in PhSiH3 (4.57 g, 42.5 mmol, 10.0 eq). The mixture was stirred at 115 °C for 48 h under N2 atmosphere. The mixture was concentrated to get crude product. The crude product was purified by flash column chromatography on silica (100 g, elute with hexane / EtOAc (1:2), Rf = 0.5) to provide the desired product Lig-1381 (2.80 g, 84% yield) as white solid. [^]20D -29° (conc. = 1.0 g / mL, CHCl3).1H-NMR (400 MHz, CDCl3) δ [ppm] δ 8.48 - 8.46 (m, 1H), 7.47 (td, J = 7.6, 2.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 2.0 Hz, 1H), 7.27 (t, J = 2.0 Hz, 1H), 7.13 - 6.99 (m, 5H), 6.57 (d, J = 2.4 Hz, 1H), 6.36 (t, J = 2.8 Hz, 1H), 5.86 (d, J = 2.4 Hz, 1H), 5.70 (d, J = 2.4 Hz, 1H), 4.28 (q, J = 17.6 Hz, 2H), 4.02 (s, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.59 (s, 3H), 3.26 (s, 3H), 1.23 (s, 18H), 1.17 (s, 18H).31P-NMR (162 MHz, CDCl3) δ -11.28. Preparation of Lig-1368 (RBRC-118) Step 1: To a solution of RBRC-118-10 (30.0 g, 104.77 mmol, 1.0 eq) in DCM (400.0 mL), was added pyridine (25.3 mL,314.31 mmol, 3.0 eq) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (44.1 mL, 261.92 mmol, 2.5 eq). The reaction mixture was warmed up to 20oC and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (400.0 mL) and extracted with DCM (400.0 mL x 3). The combined organic layer was dried over with Na2SO4and filtered. The mixture was concentrated to provide the desired product RBRC-118-20 as yellow oil in 99% yield (57.5 g). Step 2: To a mixture of RBRC-118-20 (54.0 g, 98.10 mmol, 1.0 eq), palladium acetate (1.32 g, 5.88 mmol, 0.06 eq), dppb (5.5 g, 9.81 mmol, 0.1 eq) and bis(3,5-di-tert-butylphenyl)phosphine oxide (46.0 g, 107.92 mmol, 1.1 eq) was added DMSO (500.0 mL) and diisopropylethylamine (68.0 mL, 392.40 mmol, 4.0 eq). The resulting mixture was heated with stirring at 100oC for 12 hours under N2. After cooling to 20oC, the reaction mixture was quenched with water (1.0 L) and extracted with EA (300.0 mL x 3) three times. The organic layer was concentrated to get crude product. The crude mixture was purified by short flash column chromatography on silica (pentane / EtOAc = 2:1) to provide the desired product RBRC-118-30 as yellow solid in 52 % yield (42.0 g). Step 3: To a mixture of RBRC-118-30 (42.0 g, 50.79 mmol, 1.0 eq) and diisopropylethylamine (177.0 mL, 1.02 mol, 20.0 eq) in toluene (250 mL) was added HSiCl3(41.0 mL, 406.32 mmol, 8.0 eq) at 0oC. The reaction mixture was stirred at 115oC for 12 hours under N2. After cooling to 20oC, the mixture was quenched with 12 N aqueous NaOH (400.0 mL) and diluted with EtOAc (300.0 mL). The resulting suspension was extracted with EtOAc (300.0 mL x 3). The combined organic layer was dried over Na2SO4and concentrated to provide the desired product RBRC-118-40 as yellow oil (36.5 g, crude) which was use further reaction without any purification. Step 4: To a solution of RBRC-118-01 (5.0 g, 35.93 mmol, 1.0 eq) in Toluene (50.0 mL) was added DBU (6.6 g, 43.12 mmol, 1.2 eq). The mixture was degassed with N2three times and cooled to 0oC. The reaction was added DPPA (9.9 g, 35.93 mmol, 1.0 eq) at 0oC and stirred at rt for 12 h. The mixture was concentrated and purified by flash column chromatography on silica (pentane / EtOAc = 5:1) to provide the desired product RBRC-118-02 as yellow oil in 98 % yield (5.8 g).1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J = 7.6, 5.2 Hz, 1H), 6.91 – 6.65 (m, 2H), 4.40 (d, J = 7.6 Hz, 2H), 3.81 (d, J = 8.8 Hz, 3H). Step 5: A dry 1L flask was charged with RBRC-118-40 (8.0 g, 9.86 mmol, 1.0 eq), toluene (80.0 mL) and RBRC-118-02 (2.4 g,14.79 mmol, 1.5 eq) was added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in C2H5OH (30.0 mL) and 0.1 M NaOH aq. (30.0 mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, this was poured into H2O (50.0 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (EtOAc) (50.0 mL x 3). The combined organic layers were washed with brine (50.0 mL) and dried over anhydrous Na2SO4 to get crude product. The crude product was purified by flash column chromatography on silica (pentane / EtOAc = 5:1) to provide the desired product RBRC-118-50 as yellow solid in 81 % yield (6.5 g).1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 5.6 Hz, 1H), 7.99–7.91 (m, 2H), 7.76–7.66 (m, 3H), 7.59– 7.50 (m, 3H), 7.43–7.38 (m, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.23–7.13 (m, 3H), 7.07–7.00 (m, 2H), 6.96 (d, J = 9.2 Hz, 1H), 6.95-6.88 (m, 1H), 6.80-6.76 (m, 1H), 6.61 (dd, J = 5.6, 2.4 Hz, 1H), 6.37 (dd, J = 8.4, 1.2 Hz, 1H), 4.95 (t, J = 6.0 Hz, 1H), 4.62-4.49 (m, 2H), 3.68 (s, 3H), 1.31 (s, 18H), 1.07 (s, 18H).31P NMR (162 MHz, CDCl3) δ 27.45. Step 6: The RBRC-118-50 (6.5 g, 7.97 mmol, 1.0 eq) and phenylsilane (9.8 mL, 79.70 mmol, 10.0 eq) were placed in a dry 50 mL flask, and the reaction mixture was stirred at 115 °C for 48 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave a yellow oil. The crude mixture was purified by flash column chromatography on silica (pentane / EtOAc = 10:1) to provide the desired product Lig-1368 as yellow solid in 63 % yield (4.0 g).1H NMR (400 MHz, CDCl3) δ 8.30-7.28 (m, 1H), 7.93 (dd, J = 8.8, 2.4 Hz, 2H), 7.80 (dd, J = 9.2, 2.8 Hz, 1H), 7.69 (dd, J = 8.4, 2.0 Hz, 1H), 7.59-7.49 (m, 2H), 7.32-7.27 (m, 3H), 7.25-7.21 (m, 1H), 7.13- 7.11 (m, 2H), 7.07-7.02 (m, 1H), 6.99-6.91 (m, 4H), 6.86-6.81 (m, 1H), 6.62–6.52 (m, 2H), 4.48–4.38 (m, 1H), 4.34–4.23 (m, 1H), 4.16-4.11 (m, 1H), 3.49 (d, J = 2.0 Hz, 3H), 1.22–1.13 (m, 36H).31P NMR (162 MHz, CDCl3) δ -11.38.

[0013] Preparation of Lig-1371 (RBRC-121) Step 1: To a solution of RBRC-121-10 (30.0 g, 104.77 mmol, 1.0 eq) in DCM (400.0 mL), was added pyridine (25.3 mL,314.31 mmol, 3.0 eq) at 0oC. The mixture was allowed to stir at 0oC for 5 min followed by dropwise addition of Tf2O (44.1 mL, 261.92 mmol, 2.5 eq). The reaction mixture was warmed up to 20oC and allowed to stir until full consumption of starting materials. The resulting mixture was quenched with water (400.0 mL) and extracted with DCM (400.0 mL x 3). The combined organic layer was dried over with Na2SO4and filtered. The mixture was concentrated to provide the desired product RBRC-121-20 as yellow oil in 99% yield (57.5 g). Step 2: To a mixture of RBRC-121-20 (54.0 g, 98.10 mmol, 1.0 eq), palladium acetate (1.32 g, 5.88 mmol, 0.06 eq), dppb (5.5 g, 9.81 mmol, 0.1 eq) and bis(3,5-di-tert-butylphenyl)phosphine oxide (46.0 g, 107.92 mmol, 1.1 eq) was added DMSO (500.0 mL) and diisopropylethylamine (68.0 mL, 392.40 mmol, 4.0 eq). The resulting mixture was heated with stirring at 100oC for 12 hours under N2. After cooling to 20oC, the reaction mixture was quenched with water (1.0 L) and extracted with EA (300.0 mL x 3) three times. The organic layer was concentrated to get crude product. The crude mixture was purified by short flash column chromatography on silica (pentane / EtOAc = 1:1) to provide the desired product RBRC-121-30 as yellow solid in 52 % yield (42.0 g). Step 3: To a mixture of RBRC-121-30 (42.0 g, 50.79 mmol, 1.0 eq) and diisopropylethylamine (177.0 mL, 1.02 mol, 20.0 eq) in toluene (250 mL) was added HSiCl3(41.0 mL, 406.32 mmol, 8.0 eq) at 0oC. The reaction mixture was stirred at 115oC for 12 hours under N2. After cooling to 20oC, the mixture was quenched with 12 N aqueous NaOH (400.0 mL) and diluted with EtOAc (300.0 mL). The resulting suspension was extracted with EtOAc (300.0 mL x 3). The combined organic layer was dried over Na2SO4and concentrated to provide the desired product RBRC-121-40 as yellow oil (36.5 g, crude) which was use further reaction without any purification. Step 4: A dry 1L flask was charged with RBRC-121-40 (25.0 g, 30.83 mmol, 1.0 eq), toluene (300.0 mL) and BnN3 (6.2 g, 46.25 mmol, 1.5 eq) was added. The solution was stirred at 115 °C for 12 h. After cooling the reaction mixture to 20 °C, the supernatant toluene was removed. The crude mixture was dissolved in C2H5OH (100.0 mL) and 0.1 M NaOH aq. (100.0 mL) and stirred at 65 °C for 2 h. After cooling the mixture to 20 °C, this was poured into H2O (150.0 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (EtOAc) (150.0 mL x 3). The combined organic layers were washed with brine (300.0 mL) and dried over anhydrous Na2SO4to get crude product. The crude product was purified by flash column chromatography on silica (pentane / EtOAc = 5:1) to provide the desired product RBRC-121-50 as yellow solid in 99 % yield (24.0 g). Step 5: To a solution of RBRC-121-50 (24.0 g, 30.61 mmol, 1.0 eq) in MeOH (200.0 mL) was added Pd / C (2.4 g, 10% wt). The mixture was stirred at rt for 12 h under H2 atmosphere. The mixture was filtered and concentrated to get crude product. The crude product was purified by short flash column chromatography on silica (pentane / EtOAc = 2:1) to provide the desired product RBRC-121-60 as yellow solid in 63 % yield (14.7 g). Step 6: The RBRC-121-60 (14.7 g, 21.18 mmol, 1.0 eq) and phenylsilane (26.1 mL, 211.80 mmol, 10.0 eq) were placed in a dry 100 mL flask, and the reaction mixture was stirred at 115 °C for 48 h. Cooling the mixture to 20 °C followed by evaporation of the remained phenylsilane under a reduced pressure gave the crude product RBRC-121-70 as a yellow oil (14.5 g, crude) which was used further reaction without any purification. Step 7: To a solution of RBRC-121-01 (40.0 g, 260.8 mmol, 1.0 eq) in DCM (200.0 mL) was degassed with N2and cooled to 0oC. The resulting mixture was added (CF3CO)2O (108.3 mL, 782.4 mmol, 3.0 eq) and stirred at 0oC for 1 h. And then the reaction stirred at rt for 3d. The reaction was quenched with 2 N aqueous NaOH (400.0 mL) and extracted by DCM (400.0 mL x 3). The combined organic layers were washed with brine (400.0 mL), and dried over anhydrous Na2SO4 to get crude product. The crude product was purified by flash column chromatography on silica (pentane / EtOAc = 5:1) to provide the desired product RBRC-121-02 as yellow oil in 62 % yield (24.9 g).1H NMR (400 MHz, CDCl3) δ 8.86 (d, J = 5.4 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.96-7.94 (m, 1H), 4.94 (s, 2H), 3.39 (s, 1H). Step 8: To a solution of RBRC-121-02 (24.9 g, 97.98 mmol, 1.0 eq) in DCM (400.0 mL) was added Dess-Martin Oxidant (54.0 g, 127.38 mmol, 1.3 eq) and stirred at rt for 16 h. Then the reaction was quenched with saturated sodium bicarbonate (400.0 mL) and extracted by DCM (400.0 mL x 3). The combined organic layers were washed with brine (400.0 mL) and dried over anhydrous Na2SO4to get crude product. The crude product was purified by flash column chromatography on silica (pentane / EtOAc = 5:1) to provide the desired product RBRC-121-03 as yellow solid in 75 % yield (11.2 g).1H NMR (400 MHz, CDCl3) δ 10.2 (s, 1H), 9.12 (d, J = 4.6 Hz, 1H), 8.64 (d, J = 2.3 Hz, 1H), 8.27 (dd, J = 5.2, 2.2 Hz, 1H). Step 9: To a solution of RBRC-121-70 (15.0 g, 22.13 mmol, 1.0 eq) in DCM (150.0 mL) was added RBRC-121-03 (4.2 g, 27.61 mmol, 1.2 eq) and stirred at rt for 1 h. The reaction was added NaBH(OAc)3(9.4 g, 44.26 mmol, 2.0 eq) and stirred at rt for 12 h. The mixture was poured into H2O (200.0 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (DCM) (200.0 mL x 3). The combined organic layers were washed with brine (200.0 mL) and dried over anhydrous Na2SO4to get crude product. The crude product was purified by short flash column chromatography on silica (pentante : EtOAc (5:1)) to provide the desired product Lig-1371 as orange solid in 36 % yield (6.5 g).1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 5.6 Hz, 1H), 7.97-7.95 (m, 3H), 7.82-7.80 (m, 2H), 7.71 (d, J = 7.2 Hz, 1H), 7.56-7.53 (m, 2H), 7.42-7.32 (m, 3H), 7.23 (t, J = 2.0 Hz, 1H), 7.16-7.08 (m, 3H), 6.95- 6.88 (m, 4H).31P NMR (162 MHz, CDCl3) δ -11.83. Preparation of Ir-195 Under argon atmosphere, [Ir(COD)Cl]2(Ir-2, 226 mg, 0.34 mmol), Lig-1265 (500 mg, 0.67 mmol) and anhydrous EtOH (30 mL) were added into a dry 100-mL Schlenk tube. The reaction mixture was stirred at rt for 3 h to reach full conversion. Then the mixture was dried in vacuum. To the orange solid was taken up in heptane (10 mL) and the product solution was concentrated to a volume of 2-3 mL whereby product precipitation occurred. The suspension was stirred at 0° C for 30 min, filtered and dried to furnish pure Ir-195 (676 mg) as orange solid in 93% yield.1H-NMR (600 MHz, CD3OD): δ [ppm] 8.84 (d, J=5.5 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.46 (q, J=1.7 Hz, 1H), 7.26 (dd, J=5.5, 7.7 Hz, 1H), 7.20 (br d, J=10.5 Hz, 2H), 7.06 (dd, J=1.8, 11.5 Hz, 2H), 6.99 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 6.88 (dt, J=2.3, 8.0 Hz, 1H), 6.87 (dd, J=1.0, 8.1 Hz, 1H), 6.51 (dt, J=1.0, 8.0 Hz, 1H), 6.12 (dd, J=1.0, 8.4 Hz, 1H), 4.61 (d, J=18.3 Hz, 1H), 4.47 (d, J=18.4 Hz, 1H), 3.78 (s, 3H), 3.42 - 3.36 (m, 5H), 2.52 - 2.43 (m, 2H), 2.43 - 2.34 (m, 2H), 2.02 (s, 3H), 1.90 - 1.82 (m, 2H), 1.76 - 1.66 (m, 2H), 1.28 (s, 18H), 1.24 (s, 18H).31P-NMR (162 MHz, CD3OD): δ -11.05. Preparation of Ir-196 Under argon atmosphere, [Ir(COD)Cl]2 (Ir-2, 172 mg, 0.26 mmol), Lig-1306 (400 mg, 0.51 mmol) and anhydrous EtOH (25 mL) were added into a dry 50-mL Schlenk tube. The reaction mixture was stirred at rt for 2 h to reach full conversion. Then the mixture was dried in vacuum. To the orange solid was taken up in heptane (10 mL) and the product solution was concentrated to a volume of 2-3 mL whereby product precipitation occurred. The suspension was stirred at 0° C for 30 min, filtered and dried to furnish pure Ir-196 (500 mg) as orange solid in 87% yield.1H-NMR (600 MHz, CD3OD): δ [ppm] 8.90 (dd, J=1.8, 5.3 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.61 - 7.57 (m, 2H), 7.56 - 7.55 (m, 1H), 7.55 - 7.53 (m, 1H), 7.39 - 7.29 (m, 4H), 7.20 (br d, J=10.3 Hz, 2H), 7.15 - 7.12 (m, 2H), 7.02 (q, J=1.7 Hz, 1H), 6.95 (dd, J=1.8, 11.7 Hz, 2H), 6.91 (ddd, J=1.3, 6.9, 8.5 Hz, 1H), 6.20 (dd, J=1.1, 8.6 Hz, 1H), 4.56 (d, J=19.0 Hz, 1H), 4.42 (d, J=19.0 Hz, 1H), 3.40 (dt, J=3.1, 7.9 Hz, 2H), 3.34 - 3.27 (m, 5H), 2.55 - 2.44 (m, 2H), 2.43 - 2.34 (m, 2H), 1.97 - 1.87 (m, 2H), 1.75 - 1.59 (m, 2H), 1.30 (s, 18H), 1.09 (s, 18H).31P- NMR (162 MHz, CD3OD): δ 14.53. Preparation of Ir-199 Under argon atmosphere, [Ir(COD)2]BF4(Ir-1, 221 mg, 0.45 mmol), Lig-1306 (350 mg, 0.45 mmol) and anhydrous EtOH (10 mL) were added into a dry 25-mL Schlenk tube. The reaction mixture was stirred at rt for 2 h to reach 80% conversion. After the mixture was dried in vacuum, the orange residue was taken up in heptane (10 mL) and the product solution was concentrated to a volume of 2-3 mL whereby product precipitation occurred. The suspension was stirred at rt for 1 h, filtered and dried to yield the crude Ir-199. After recrystallization from ethanol / heptane (1:1) pure Ir-199 (330 mg) was isolated as orange solid in 63% yield.1H-NMR (600 MHz, CD3OD): δ [ppm] 8.91 (dd, J=1.8, 5.3 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.62 - 7.57 (m, 3H), 7.57 - 7.53 (m, 2H), 7.40 - 7.31 (m, 4H), 7.20 (br d, J=10.4 Hz, 2H), 7.16 - 7.12 (m, 2H), 7.02 (q, J=1.7 Hz, 1H), 6.95 (dd, J=1.8, 11.7 Hz, 2H), 6.91 (ddd, J=1.3, 6.9, 8.5 Hz, 1H), 6.21 (dd, J=0.8, 8.5 Hz, 1H), 4.50 (d, J=18.4 Hz, 1H), 4.43 (d, J=18.4 Hz, 1H), 3.39 (dt, J=3.1, 7.9 Hz, 2H), 3.33 - 3.28 (m, 5H), 2.49 (br d, J=7.2 Hz, 2H), 2.39 (br d, J=7.4 Hz, 2H), 1.96 - 1.88 (m, 2H), 1.72 - 1.64 (m, 2H), 1.31 - 1.29 (m, 18H), 1.10 (s, 18H).31P-NMR (162 MHz, CD3OD): δ 14.46. Preparation of Ir-200 Under argon atmosphere, [Ir(COD)2]BARF (Ir-4, 857 mg, 0.67 mmol), Lig-1250 (350 mg, 0.67 mmol) and anhydrous EtOH (15 mL) were added into a dry 25-mL Schlenk tube. The reaction mixture was stirred at rt for 2 h to reach 90% conversion. After the reaction mixture was dried in vacuum, the orange residue was taken up in heptane (10 mL) and the product solution was concentrated to a volume of 2-3 mL whereby product precipitation occurred. The suspension was stirred at rt for 1 h, filtered and dried to yield the crude Ir-200. After crystallization from DCM / heptane (1:1), pure Ir- 200 (550 mg) was isolated as orange solid in 48% yield.1H-NMR (600 MHz, CD3OD): δ [ppm] 8.67 (d, J=5.7 Hz, 1H), 8.12 (br t, J=9.0 Hz, 2H), 7.62 - 7.57 (m, 14H), 7.57 - 7.52 (m, 2H), 7.35 (d, J=7.7 Hz, 1H), 7.27 (dt, J=1.6, 7.4 Hz, 1H), 7.09 (dt, J=2.2, 7.8 Hz, 2H), 7.05 - 6.99 (m, 2H), 6.95 (t, J=8.3 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 6.83 (dd, J=1.0, 8.1 Hz, 1H), 6.74 (dt, J=2.4, 8.0 Hz, 1H), 6.05 (ddd, J=1.0, 7.8, 8.8 Hz, 1H), 5.98 (dd, J=1.0, 8.4 Hz, 1H), 4.63 (d, J=18.8 Hz, 1H), 4.41 (d, J=18.7 Hz, 1H), 3.76 (s, 3H), 3.66 - 3.61 (m, 4H), 3.36 (s, 3H), 2.82 - 2.68 (m, 2H), 2.42 - 2.30 (m, 2H), 2.07 - 1.97 (m, 2H), 1.95 (s, 3H), 1.69 - 1.57 (m, 2H).31P-NMR (243 MHz, CD3OD): δ 5.26. Preparation of Ir-198 Under argon atmosphere, [Ir(COD)Cl]2 (Ir-2, 135 mg, 0.2 mmol), Lig-1306 (165 mg,0.42 mmol) and anhydrous EtOH (10 mL) were added into a dry 25-mL Schlenk tube. Then the mixture was purged and replaced with H2 three times by Schlenk line. The reaction mixture was stirred at 75oC for 16 h to reach full conversion. Then the reaction was evaporated to dryness to provide pure Ir-198 (208 mg) as yellow solid in 45% yield.1H-NMR (400 MHz, CD3OD): δ [ppm] 8.97 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 9.2 Hz, 3H), 7.51 (dd, J = 8.0, 5.2 Hz, 3H), 7.44 (s, 1H), 7.20 (dt, J = 17.6, 8.8 Hz, 4H), 7.05 – 6.94 (m, 4H), 6.91 (d, J = 6.8 Hz, 1H), 6.83 (t, J = 7.6 Hz, 2H), 6.19 (d, J = 8.4 Hz, 1H), 4.93 (s, 1H), 3.22 (d, J = 7.6 Hz, 1H), 2.46 (s, 3H), 1.27 (s, 18H), 1.06 (s, 18H), -19.69 (s, 1H), -23.12 (s, 1H).31P-NMR (162 MHz, CD3OD): δ 11.66. Example 1.1 Asymmetric Hydrogenation of 4-(4-Chlorophenyl)-2-hydroxy-4-keto-butyric-2-en-acid ethyl ester (1) In a glove box under argon atmosphere, a 185 mL autoclave was charged with pre-catalyst Ir-2 (13.2 mg, 19.6 x 10-6mol, S / C 500), ligand Lig-1306 (30.8 mg, 39.3 x 10-6mol) and EtOH (10 mL). The mixture was stirred for 5 min at rt. Ketone 1 (5.0 g, 19.6 mmol), DBU (298.9 mg, 1.96 mmol, S / B 10), THF (50 mL) and EtOH (40 mL) were added. The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 °C. Under stirring, the hydrogenation was run at a constant hydrogen pressure of 70 bar. After a total reaction time of 20 h (>99.9% conversion), the autoclave was vented and allowed to cool to rt. The reaction mixture was transferred with aid of EtOH (20 mL) from the autoclave into a 250 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40 °C / 10 mbar to constant weight to yield crude 6 (5.0 g) with 98.4 area-% purity (DBU not integrated) in a trans / cis ratio of 6.6. (S,S)-6 was obtained with 99.7% ee. Next, crude (S,S)-6 (5.0 g) was suspended in iPrOAc (35 mL) and the slurry stirred for 2 h at 50 °C. The suspension was cooled to 0 °C and stirred at this temperature for 1 h, filtered and the filter cake washed with ice-cold iPrOAc (20 ml) in 3 portions to afford after drying (25 °C, 10 mbar) pure 6 (2.9 g, 68% yield) with 99.7 area-% purity and a trans / cis ratio of 70. (S,S)-6 was obtained with >99.9% ee. Subsequently, (S,S)-6 (2.9 g) from above was dissolved in iPrOAc (28 ml) at 90 °C. The colorless solution was cooled to 25 °C within 2 h whereby the product started to crystallize. The formed suspension was kept at 25 °C for 2 h and cooled to 0 °C within 30 min. The crystals were filtered and washed with ice-cold iPrOAc (10 ml) in 2 portions to afford after drying (25 °C, 10 mbar) off-white, crystalline 6 (2.6 g, 62% yield) with 99.8 area-% purity and a trans / cis ratio of 1100. (S,S)-6 was obtained with >99.9% ee. Analytical data for 3 LC-MS ESI (m / z): 256.0 [M+].1H-NMR (600 MHz, CDCl3): ^ [ppm] 7.89 (d, J=8.8 Hz, 2H), 7.41 - 7.50 (m, 3H), 4.65 (td, J=5.8, 3.8 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 3.46 – 3.53 (m, 1H), 3.38 – 3.45 (m, 1H), 3.27 (d, J=5.6 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H). Analytical data for trans-4 GC-MS ESI (m / z): 258.0 [M+].1H-NMR (600 MHz, DMSO-D6): ^ [ppm] 7.35 - 7.38 (m, 2 H), 7.32 - 7.35 (m, 2 H), 5.44 (br s, 2 H), 4.73 (br d, J=9.6 Hz, 1 H), 4.25 (br d, J=8.6 Hz, 1 H), 4.06 (q, J=7.1 Hz, 2 H), 1.53 - 1.78 (m, 1 H), 1.45 - 1.99 (m, 1 H), 1.17 (t, J=7.1 Hz, 3 H). Analytical data for cis-5 GC-MS ESI (m / z): 212.0 [M+].1H-NMR (600 MHz, DMSO-D6): ^ [ppm] 7.47 - 7.51 (m, 2H), 7.42 (d, J=8.3 Hz, 2H), 6.02 (br s, 1H), 5.40 (dd, J=10.8, 5.4 Hz, 1H), 4.62 (dd, J=10.7, 8.6 Hz, 1H), 2.89 (ddd, J= 12.2, 8.2, 5.4 Hz, 1H), 1.93 (dt, J=12.1, 11.0 Hz, 1H). Analytical data for trans-5 GC-MS ESI (m / z): 212.0 [M+].1H-NMR (600 MHz, DMSO-D6): ^ [ppm] 7.47 (d, J=8.7 Hz, 2 H), 7.40 - 7.42 (m, 2 H), 6.18 (br d, J=5.2 Hz, 1 H), 5.68 (t, J=6.7 Hz, 1H), 4.38 (dt, J=7.0, 4.9 Hz, 1 H), 2.44 - 2.48 (m, 1 H), 2.36 - 2.42 (m, 1 H). Analytical data for trans-6 GC-MS ESI (m / z): 216.0 [M+].1H-NMR (400 MHz, DMSO-D6): ^ [ppm] 7.40 – 7.31 (m, 4H), 5.23 (d, J = 4.9 Hz, 1H), 4.75 (dd, J = 9.9, 4.8 Hz, 1H), 4.50 (dd, J = 6.5, 5.5 Hz, 2H), 3.68 – 3.67 (m, 1H), 3.30 – 3.24 (m, 2H), 1.67 – 1.61 (m, 1H), 1.44 – 1.39 (m, 1H).13C NMR (101 MHz, DMSO-D6): δ 146.6, 131.3, 128.4, 127.9, 68.7, 68.6, 66.8, 44.3. Analytical data for cis-6 GC-MS ESI (m / z): 216.0 [M+].1H-NMR (600 MHz, CDCl3): ^ [ppm] 7.31-7.34 (m, 2H), 7.32 (s, 2H), 4.98 (dd, J=9.9, 2.5 Hz, 1H), 4.04 (br d, J= 2.4 Hz, 1H), 3.45-3.70 (m, 2H), 2.76 (s, 1H), 1.65- 1.95 (m, 2H), 1.08 (s, 2H).13C-NMR (151 MHz, CDCl3): δ 142.7, 133.3, 128.7, 127.1, 73.82, 72.3, 66.7, 41.6. Analytical Methods a) Achiral LC Method to determine the conversion and purities of 1, 3 and the cis- and trans-isomers of 4-6 Stationary phase Kinetex (2.6 µm PFP 100 Å, LC Column 50 x 4.6 mm) Eluent: A) Acetonitrile, B) H2O + 5% acetonitrile, D) TBAHS buffer (1 g TBAHS in 800 mL acetonitrile und 200 mL H2O). Pump program (gradient): 10 A: 80 B : 10 D → 80 A : 10 B : 10 D Run time: 16 min Flow: 1 mL / min Column oven temperature 40 °C Injection volume:5 ^LDetection: DAD 210 nm Retention Times: 1, 13.23 min; 3, 6.91 min; trans-4, 6.04 min; cis-4, 5.73 min; trans-5, 5.49 min; cis-5, 5.19 min; trans-6, 2.40 min; cis-6, 2.18 min b) Chiral LC Method to determine the enantiomeric purity of 3 Stationary phase: Daicel Chiralpak IC-3, L = 150 mm, ID = 4.6 mm, 3.0 µm Eluent: A) H2O + 5% acetonitrile, B) acetonitrile C), 6.25-6.35 g ammonium formate in 950 mL H2O adjusted to pH 9.0 with ammonium hydroxide solution (25%) + 50.0 mL acetonitrile pump program (isocratic): 60 A : 30 B : 10 C Run time: 20 min Flow: 1 mL / min Column oven temperature: 30 °C Injection volume:2.5 ^LDetection: DAD 254 nm Retention Times: (S)-3, 10.60 min; (R)-3, 12.20 min c) Chiral LC method to determine the enantiomeric purities of 3, 4, 5 and 6 Stationary phase: Daicel Chiralpak IB-N; L = 150mm, ID = 4.6mm, 3.0µm Eluent: A) CO2, B) isopropanol, pump program (isocratic): 90 A: 10 B Run time: 9 min Flow: 3 mL / min Column oven temperature: 20 °C Injection volume:5 ^LDetection: DAD 220 nm Retention Times: 1, 1.19 min; (R)-3, 1.85 min; (S)-3, 1.95 min; (R,R)-4, 2.24 min; (S,S)-4, 2.58 min; (R,S)-4, 3.09 min; (S,R)-4, 3.93 min; (R,R)-5, 3.08 min; (S,S)-5, 3.92 min; (R,S)-5, 2.33 min; (S,R)-5, 2.33 min; (R,R)-6, 5.11 min; (S,S)-6, 5.78 min; (R,S)-6, 6.37 min; (S,R)-6, 6.95 min Examples 1.2-1.8 In analogy to Example 1.1, keto enol ester 1 was hydrogenated for 20 h in EtOH (5 mL) at 30 °C and an initial hydrogen pressure of 70 bar in the presence DBU (S / B 10) and the pre-catalysts / ligands (S / C 1000 for Exp.1.2-5 and Exp.1.7-8 and Exp.8b, resp. S / C 500 for Exp.1.6), solvents and scales as listed in Table 1.1. Table 1.1: Exp Pre-Cat / Ligand Solvent Conv 3 / 4 / 5 6 trans-6 (Scale) [area-%] [area-%] [area-%] [%ee] (trans / cis) 1.2 Ir-2 / Lig-1265 EtOH (1 g) 98.9 89 / 2.6 / 1.3 - - 1.3 Ir-2 / Lig-1252 EtOH >99. 66.5 >99.9 (1 g) 9 0 / 11 / 21 (4.3) (R,R) 1.4 Ir-2 / Lig-1250 EtOH (1 g) 64 56 - - 1.5 Ir-2 / Lig-1305 EtOH 95.4 93.8 (0.1 g) 99.1 0 / 0.1 / 0.9 (1.4) (S,S) 1.6 Ir-2 / Lig-1306 EtOH 95.3 >99.9 (0.25 g) 99.8 0 / 0 / 0.6 (4.5) (S,S) 1.7 Ir-2 / Lig-1319 EtOH (0.25 g) 87 71 / 1 / 0.5 - - 1.8 Ir-2 / Lig-1319 EtOH / THF 95.6 >99.9 (1:1), (0.25 g) >99.9 0 / 0 / 0 (10.4) (R,R) 1.8b Ir-2 / Lig-1359 EtOH / THF 9 88.0 >99.9 (1:1), (0.40 g) 9.5 0 / 0 / 0.2 (6.0) (R,R) Examples 1.9-1.11 In analogy to Example 1.1, keto enol ester 1 (0.25 g, xx mmol) was hydrogenated for 20 h in EtOH / THF (1:1) at 30 °C and an initial hydrogen pressure of 70 bar in the presence DBU (S / B 10) and the pre-catalysts / ligands, resp. catalysts (S / C 1000) as listed in Table 1.2. Table 1.2: Exp Pre-Cat / Ligand resp. Conv 3 / 4 / 5 6 trans-6 Cat [area-%] [area-%] [area-%] [%ee] (trans / cis) 1.9 Ir-2 / Lig-1306 99.4 0 / 0 / 0.7 94.2 >99.9 (9.0) (S,S) 1.10 Ir-196 >99.9 0 / 11 / 35 49.0 >99.9 (95.0) (S,S) 1.11 Ir-198 >99.9 0 / 4 / 3 84.1 >99.9 (22.0) (S,S) Example 2.1 In a glove box under argon atmosphere, a 185 mL autoclave was charged with pre-catalyst Ir-2 (6.6 mg, 9.8 x 10-6mol, S / C 1000), ligand Lig-1306 (15.4 mg, 19.6 x 10-6mol) and EtOH (10 mL). The mixture was stirred for 5 min at rt. Ketone 1 (5.0 g, 19.6 mmol), 2nd-catalyst Ir-29 (30.1 mg, 39.3 x 10-6mol, S / C 500), DBU (298.9 mg, 1.96 mmol, S / B 10), THF (50 mL) and EtOH (40 mL) were added. The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 °C. Under stirring, the hydrogenation was run at a constant hydrogen pressure of 70 bar. After a total reaction time of 20 h (>99.9% conversion), the autoclave was vented and allowed to cool to rt. The reaction mixture was transferred with aid of EtOH (20 mL) from the autoclave into a 250 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40 °C / 10 mbar to constant weight to yield crude 6 (4.7 g) with 99.4 area-% purity (DBU not integrated) in a trans / cis ratio of 16.5. (S,S)-6 was obtained with >99.9% ee. Next, crude (S,S)-6 (5.0 g) was suspended in iPrOAc (35 mL) and the slurry stirred for 2 h at 50 °C. The suspension was cooled to 0 °C and stirred at this temperature for 1 h, filtered and the filter cake washed with ice-cold iPrOAc (20 ml) in 3 portions to afford after drying (25 °C, 10 mbar) pure 6 (3.2 g, 75% yield) with 99.2 area-% purity and a trans / cis ratio of 63. (S,S)-6 was obtained with >99.9% ee. Subsequently, (S,S)-6 (3.2 g) from above was dissolved in iPrOAc (28 ml) at 90 °C. The colorless solution was cooled to 25 °C within 2 h whereby the product started to crystallize. The formed suspension was kept at 25 °C for 2 h and cooled to 0 °C within 30 min. The crystals were filtered and washed with ice-cold iPrOAc (10 ml) in 2 portions to afford after drying (25 °C, 10 mbar) off-white, crystalline 6 (2.9 g, 68% yield) with 99.7 area-% purity and a trans / cis ratio of 622. (S,S)-6 was obtained with >99.9% ee. Examples 2.2-2.5 In analogy to Example 2.1, keto enol ester 1 was hydrogenated for 20 h in EtOH at 30 °C and an initial hydrogen pressure of 70 bar in the presence DBU (S / B 10) and the pre-catalysts / ligands (S / C 1000), 2nd-catalysts (S / C 1000), solvents and scales as listed in Table 2.1. Table 2.1: Exp Pre-Cat / Ligand Solvent Conv 3 / 4 / 5 6 trans-6 2nd-Cat (Scale) [area-%] [area-%] [area-%] [%ee] (trans / cis) 2.2 Ir-2 / Lig-685 EtOH >99.9 0 / 0.1 98.1 >99.9 Ir-31 (1 g) / 0.1 (14.0) (R,R) 2.3 Ir-2 / Lig-1265 EtOH 98.3 >99.9 Ir-31 (1 g) >99.9 0 / 1.1 / 0 (20.3) (R,R) 2.4 Ir-2 / Lig-1252 EtOH >99.9 0 / 0 / 0.9 97.8 >99.9 Ir-31 (1 g) (5.9) (R,R) 2.5 Ir-2 / Lig-1306 EtOH 99. 94.0 >99,9 Ir-29 (0.1 g) 1 0 / 0 / 1.8 (20.0) (S,S) Examples 2.6-2.9 In analogy to Example 2.1, keto enol ester 1 was hydrogenated for 20 h in EtOH at 30 °C and an initial hydrogen pressure of 70 bar in the presence DBU (S / B 10) and the pre-catalysts / ligands (S / C 1000 for Exp.2.6-7, resp. S / C 2500 for Exp.2.8), 2nd-catalysst (S / C 1000), solvents and scales as listed in Table 2.2. Table 2.2: Exp Pre-Cat / Ligand Solvent Conv 3 / 4 / 5 6 trans-6 2nd-Cat (Scale) [area-%] [area-%] [area-%] [%ee] (trans / cis) 2.6 Ir-2 / Lig-1319 EtOH 94.2 > -31 (0.25 g) >99 99.9 Ir .9 0 / 0 / 0.2 (14.0) (R,R) 2.7 Ir-2 / Lig-1319 EtOH / THF >99.9 0 / 0 / 97.9 >99.9 Ir-31 (1:1), (0.25 g) 0.1 (15.0) (R,R) 2.8 Ir-2 / Lig-1319 EtOH / THF 91.9 >99.9 Ir-31 (1:1), (0.25 g) >99.9 0 / 0 / 0.4 (35.0) (R,R) Example 3.1 Asymmetric Hydrogenation of Acetophenone (7) In a glove box under argon atmosphere, a 50 mL autoclave was charged with ligand Lig-1265 (3.71 mg, 4.99 x 10-6mol), pre-catalyst Ir-2 (1.68 mg, 2.50 x 10-6mol, S / C 5000) and EtOH (10 mL). The mixture was stirred for 5 min at rt. Ketone 7 (3.00 g, 24.7 mmol), EtOH (20 mL) and KOtBu (280.17 mg, 2.5 mmol, S / B 10) were added, the autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 °C. Under stirring, the hydrogenation was run at a constant hydrogen pressure of 70 bar. After a total reaction time of 20 h (>99.9% conversion), the autoclave was vented and allowed to cool to rt. The reaction mixture was filtered over a silica gel pad (6 g) and evaporated at 40 °C / 10 mbar to constant weight affording (R)-8 (3.0 g, 99%) with 99.9 area-% purity and 95.5% ee. Analytical data for 8 GC-MS ESI (m / z): 122 [M+]1H-NMR (600 MHz, DMSO-D6): ^ [ppm] 7.32-7.35 (m, 2H), 7.28-7.32 (m, 2H), 7.19-7.22 (m, 1H), 4.96-5.29 (m, 1H), 4.69-4.72 (m, 1H), 1.31 (d, J=6.5 Hz, 3H). Chiral LC method to determine the chemical and enantiomeric purity of 8 Stationary phase: Daicel Chiralpak IB-N-3; L = 150 mm, ID = 4.6 mm, 3.0 µm Eluent: A) Water / acetonitrile (95:5), B) acetonitrile, pump program (isocratic): 80 A : 20 B Run time: 17 min Flow: 1 mL / min Column oven temperature: 20 °C Injection volume:2 ^LDetection: DAD 200 nm Retention Times: 7, 12.22 min; (S)-8, 6.80 min; (R)-8, 6.31 min Examples 3.2-3.7 In analogy to Example 3.1, ketone 7 (0.5 g, 4.16 mmol) was hydrogenated for 20 h in EtOH at 30 °C and an initial hydrogen pressure of 70 bar in the presence of KOtBu (S / B 10) and the pre-catalysts / ligands (S / C 5000) as listed in Table 3.1. Table 3.1: Exp Pre-Cat / Ligand Conv 8 8 [area-%] [area-%] [%ee] 3.2 Ir-2 / Lig-685 >99.9 >99.9 96.4 (R) 3.3 Ir-2 / Lig-1265 99.3 99.3 95.1 (R) 3.4 Ir-2 / Lig-1252 >99.9 >99.9 86.9 (R) 3.5 Ir-2 / Lig-1250 >99.9 >99.9 66.7 (S) 3.6 Ir-2 / Lig-1305 >99.9 >99.9 54.3 (S) 3.7 Ir-2 / Lig-1306 >99.9 >99.9 91.0 (S) Examples 3.8-3.13 In analogy to Example 3.1, ketone 7 (4.7 mg, 39.2 ^mol) was hydrogenated for 20 h in EtOH at 30 °C and an initial hydrogen pressure of 70 bar in the presence KOtBu (S / B 10) and the pre-catalysts / ligands (S / C 100) as listed in Table 3.2. Table 3.2: Exp Pre-Cat / Ligand Conv 8 8 [area-%] [area-%] [%ee] 3.8 Ir-2 / Lig-766 97.8 96.4 95.0 (S) 3.9 Ir-2 / Lig-1305 >99.9 >99.9 54.4 (S) 3.10 Ir-2 / Lig-1306 >99.9 >99.9 91.4 (S) 3.11 Ir-2 / Lig-1250 >99.9 >99.9 69.8 (S) 3.12 Ir-2 / Lig-1251 >99.9 >99.9 85.7 (S) 3.13 Ir-2 / Lig-1264 >99.9 >99.9 95.6 (S) Example 4.1 Asymmetric Hydrogenation of Methyl 4,4-dimethyl-3-oxopentanoate (9) In a glove box under argon atmosphere, a 50 mL autoclave was charged with ligand Lig-1265 (140.9 mg, 0.189 mmol), pre-catalyst Ir-2 (63.7 mg, 0.095 mmol, S / C 100) and MeOH (10 mL). The mixture was stirred for 5 min at rt. Ketone 9 (3.00 g, 19.0 mmol), MeOH (20 mL) and KOtBu (212.8 mg, 1.9 mmol, S / B 10) were added, the autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 °C. Under stirring, the hydrogenation was run at a constant hydrogen pressure of 70 bar. After a total reaction time of 20 h (>99% conversion), the autoclave was vented and allowed to cool to rt. The reaction mixture was filtered over a silica gel pad (6 g) and evaporated at 40 °C / 10 mbar to constant weight affording (R)- 10 (2.99 g, 98%) with 82.9 area-% purity and 91.8% ee. Analytical data for 101H-NMR (600 MHz, DMSO-D6): ^ [ppm] 4.73 (d, J=6.1 Hz, 1H), 3.58 (s, 3H), 3.54 (ddd, J=10.3, 6.1, 2.6 Hz, 1H); 2.46 (dd, J=14.8, 2.6 Hz, 1H), 2.16 (dd, J=14.8, 10.3 Hz, 1H), 0.81 (s, 9H). Chiral GC method to determine the chemical and enantiomeric purity of 10 Stationary phase: BGB-178; L = 30 m, ID = 0.25 mm, df = 0.25 µm Carrier gas: Hydrogen Temperature program: Heating rate; temperature; hold time: n.a.; 90 °C; 0 min 3 °C / min; 112 °C; 0 min 30 °C / min; 200 °C; 5.7 min 50 °C / min; 90 °C; 0.83 min Run time: 19 min Pressure 9 psi (constant) Flow: 40 mL / min Injection volume:1 ^LDetection: 200 °C Retention Times: 9, 8.01 min; (S)-10, 7.12; (R)-10, 7.25 min Examples 4.2-3.5 In analogy to Example 4.1, ketone 9 (0.3 g, 1.9 mmol) was hydrogenated for 20 h in EtOH at 30 °C and an initial hydrogen pressure of 70 bar in the presence of DBU (S / B 10) and the catalysts, resp. pre-catalysts / ligands (S / C 100) as listed in Table 4.1. Table 4.1: Exp (Pre-)Cat / Ligand Conv 10 10 [area-%] [area-%] [%ee] 4.2 Ir-80 >99.9 81.5 % 98.7 (R) 4.3 Ir-2 / Lig-1264 66.0 62.6 % 92.5 (S) 4.4 Ir-2 / Lig-1251 99.2 94.0 % 90.5 (S) 4.5 Ir-2 / Lig-1249 99.6 94.9 % 90.3 (R) Examples 4.6-4.11 In analogy to Example 4.1, ketone 9 (6.2 mg, 38.8 ^mol) was hydrogenated for 20 h in EtOH at 30 °C and an initial hydrogen pressure of 70 bar in the presence of DBU (S / B 10) and the pre-catalysts / ligands (S / C 100) as listed in Table 4.2. Table 4.2: Exp Pre-Cat / Ligand Conv 10 10 [area-%] [area-%] [%ee] 4.6 Ir-2 / Lig-766 97.4 80.2 93.6 (S) 4.7 Ir-2 / Lig-1305 97.1 85.1 82.5 (S) 4.8 Ir-2 / Lig-1306 96.5 79.7 91.8 (S) 4.9 Ir-2 / Lig-1250 97.1 81.7 85.5 (S) 4.10 Ir-2 / Lig-1251 97.3 81.5 86.3 (S) 4.11 Ir-2 / Lig-1264 96.7 83.0 87.6 (S) Example 5.1: Asymmetric Hydrogenation of 3,3-Dimethyl-2-butanon (11) In a glove box under argon atmosphere, a 50 mL autoclave was charged with ligand Lig-1265 (222.5 mg, 0.30 mmol), pre-catalyst Ir-2 (100.6 mg, 0.149 mmol, S / C 100) and EtOH (10 mL). The mixture was stirred for 5 min at rt. Ketone 11 (3.00 g, 30.0 mmol), EtOH (20 mL) and KOtBu (336.1 mg, 3.0 mmol, S / B 10) were added, the autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 °C. Under stirring, the hydrogenation was run at a constant hydrogen pressure of 70 bar. After a total reaction time of 20 h (>99.9% conversion), the autoclave was vented and allowed to cool rt. The reaction mixture was filtered over a silica gel pad (6 g) and evaporated at 40 °C / 50 mbar to constant weight affording (R)- 12 (2.23 g, 74%) with 99.9 area-% purity and 73.4% ee. Analytical data for 12 GC-MS ESI (m / z): 102 [M+]1H-NMR (600 mHz, DMSO-D6): ^ [ppm] 4.24 (d, J=5.0 Hz, 1H), 3.25 (qd, J=6.4, 5.0 Hz, 1H), 0.97 (d, J=6.4 Hz, 3H), 0.8 (s, 9H). Chiral GC method to determine the chemical and enantiomeric purity of 12 Stationary phase: BGB-178; L = 30 m, ID = 0.25 mm, df = 0.25 µm Carrier gas: Hydrogen Temperature program: Heating rate; temperature; hold time: n.a. ; 45 °C; 0 min 2 °C / min; 61 °C; 0 min 40 °C / min; 200 °C; 1.52 min Run time: 13 min Pressure 10 psi (constant) Flow: 40 mL / min Injection volume:1 ^LDetection: 220 °C Retention Times: 11, 7.49 min; (S)-12, 6.55 min; (R)-12, 7.21 min Examples 5.2-5.7: In analogy to Example 5.1, ketone 11 (3.9 mg, 38.2 ^mol) was hydrogenated for 20 h in EtOH at 30 °C and an initial hydrogen pressure of 70 bar in the presence of DBU (S / B 10) and the pre-catalysts / ligands (S / C 100) as listed in Table 4.2. Table 5.1: Exp Pre-Cat / Ligand Conv 12 12 [area-%] [area-%] [%ee] 5.2 Ir-2 / Lig-766 >99.9 98.4 44.8 (S) 5.3 Ir-2 / Lig-1305 >99.9 98.2 72.5 (S) 5.4 Ir-2 / Lig-1306 >99.9 98.1 69.9 (S) 5.5 Ir-2 / Lig-1250 >99.9 98.2 76.0 (S) 5.6 Ir-2 / Lig-1251 >99.9 98.2 75.7 (S) 5.7 Ir-2 / Lig-1264 >99.9 98.0 71.9 (S) Example 6.1 Asymmetric Hydrogenation of 4-(4-Chlorophenyl)-2-hydroxy-4-keto-butyric-2-en-acid ethyl ester (1) In a glove box under argon atmosphere, a 385 mL autoclave was charged with ketone 1 (15.0 g, 58.9 mmol), THF (70 mL) and EtOH (75 mL). In a 10 mL Erlenmeyer flask, the pre-catalyst Ir-2 (9.9 mg, 14.7 x 10-6mol, S / C 2000) and ligand Lig-1319 (23.5 mg, 29.5 x 10-6mol) were dissolved in THF (5 mL) and the mixture was stirred for 15 min at rt. Ir-31(45.1 mg, 58.9 x 10-6mol, S / C 1000) as 2nd- catalyst was added to the 10 mL Erlenmeyer flask and the combined catalysts solution together with DBU (448.4 mg, 2.94 mmol, S / B 20) were added to the autoclave which was then sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 °C. Under stirring, the hydrogenation was run at a constant hydrogen pressure of 70 bar. After a total reaction time of 24 h (>99.9% conversion), the autoclave was vented and allowed to cool to rt. The reaction mixture was transferred with aid of EtOH (50 mL) from the autoclave into a 500 mL round-bottomed flask and the orange reaction solution rotatory evaporated at 40 °C / 10 mbar to constant weight to yield crude 6 (14.3 g) with 98.1 area-% purity (DBU not integrated) in a trans / cis ratio of 20. (R,R)-6 was obtained with >99.9% ee. Next, crude (R,R)-6 (14.3 g) was suspended in DCM (100 mL) and the slurry stirred for 2 h at 50 °C. The suspension was cooled to 0 °C and stirred at this temperature for 1 h, filtered and the filter cake washed with ice-cold DCM (60 ml) in 3 portions to afford after drying (25 °C, 10 mbar) pure 6 (11.2 g, 87% yield) with 99.6 area-% purity and a trans / cis ratio of 53. (R,R)-6 was obtained with >99.9% ee. Subsequently, (R,R)-6 (11.2 g) from above was dissolved in iPrOAc (82 ml) at 90 °C. The colorless solution was cooled to 25 °C within 2 h whereby the product started to crystallize. The formed suspension was kept at 25 °C for 2 h and cooled to 0 °C within 30 min. The crystals were filtered and washed with ice-cold iPrOAc (30 ml) in 2 portions to afford after drying (25 °C, 10 mbar) white, crystalline 6 (10.4 g, 81% yield) with 99.1 area-% purity and a trans / cis ratio of 309. (R,R)-6 was obtained with >99.9% ee. Example 6.2 Asymmetric Hydrogenation of 4-(4-Chlorophenyl)-2-hydroxy-4-keto-butyric-2-en-acid ethyl ester (1) In a glove box under argon atmosphere, a 385 mL autoclave was charged with ketone 1 (15.0 g, 58.9 mmol), THF (70 mL) and EtOH (75 mL). In a 10 mL Erlenmeyer flask, the pre-catalyst Ir-2 (9.9 mg, 14.7 x 10-6mol, S / C 2000) and ligand Lig-1319 (23.5 mg, 29.5 x 10-6mol) were dissolved in THF (5 mL) and the mixture was stirred for 15 min at rt. Ir-31(45.1 mg, 58.9 x 10-6mol, S / C 1000) as 2nd- catalyst was added to the 10 mL Erlenmeyer flask and the combined catalysts solution together with DBU (448.4 mg, 2.94 mmol, S / B 20) were added to the autoclave which was then sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30 °C. Under stirring, the hydrogenation was run at a constant hydrogen pressure of 70 bar. After a total reaction time of 24 h (>99.9% conversion), the autoclave was vented and allowed to cool to rt. The reaction mixture was transferred with aid of EtOH (50 mL) from the autoclave into a 500 mL round-bottomed flask and the orange reaction solution rotatory evaporated at 40 °C / 10 mbar to constant weight to yield crude 6 (14.3 g) with 98.1 area-% purity (DBU not integrated) in a trans / cis ratio of 20. (R,R)-6 was obtained with >99.9% ee. Next, crude (R,R)-6 (14.3 g) was suspended in DCM (100 mL) and the slurry stirred for 2 h at 50 °C. The suspension was cooled to 0 °C and stirred at this temperature for 1 h, filtered and the filter cake washed with ice-cold DCM (60 ml) in 3 portions to afford after drying (25 °C, 10 mbar) pure 6 (11.2 g, 87% yield) with 99.6 area-% purity and a trans / cis ratio of 53. (R,R)-6 was obtained with >99.9% ee. Subsequently, (R,R)-6 (11.2 g) from above was dissolved in iPrOAc (82 ml) at 90 °C. The colorless solution was cooled to 25 °C within 2 h whereby the product started to crystallize. The formed suspension was kept at 25 °C for 2 h and cooled to 0 °C within 30 min. The crystals were filtered and washed with ice-cold iPrOAc (30 ml) in 2 portions to afford after drying (25 °C, 10 mbar) white, crystalline 6 (10.4 g, 81% yield) with 99.1 area-% purity and a trans / cis ratio of 309. (R,R)-6 was obtained with >99.9% ee.

Claims

Claims:

1. Chiral aminophosphine ligands of the formula Iwherein R1to R8, independent of each other are hydrogen, C1-8-alkyl, C1-8-alkoxy hydroxyl, halogen or phenyl, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R9to R12, independent of each other, are hydrogen, C1-8-alkyl or C1-8-alkoxy; halogen C1-8- alkyl, di-C1-8-alkylamino or nitro; R14or R15is independent of each other hydrogen or C1-8-alkyl; R20is optionally substituted C1-8-alkyl, C3-8-cycloalkyl, phenyl, naphthyl or heteroaryl, wherein the substituents are selected from one or five groups selected from C1-8-alkyl, C1-8-alkoxy, phenyl, trihalogen-C1-4 -alkyl, di-C1-4-alkylamino or tri-C1-4-alkylsilyl, or enantiomers thereof, with the proviso that the ligand of formula I whereinR1, R2, R7, R8and R9are hydrogen; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; and R20is phenyl or, wherein R1, R2, R7and R9are hydrogen; R8is phenyl; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; and R20is phenyl are excluded.

2. Chiral aminophosphine ligands of claim 1, wherein R1to R8, independent of each other are hydrogen or C1-8-alkoxy; or, R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; or R3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R9to R12, independent of each other, are hydrogen or C1-8-alkyl; R20is optionally substituted C1-8-alkyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, furanyl, thienyl, or benzothienyl, wherein the substituents are selected from one or two groups selected from C1-8-alkyl, C1-8-alkoxy, phenyl, trihalogen-C1-4-alkyl, di-C1-4-alkylamino or tri-C1-4- alkylsilyl, or enantiomers thereof.

3. Chrial aminophosphine ligands of claim 1 or 2, wherein R1to R8, independent of each other are hydrogen or methoxy; or, R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; or R3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-;R9to R12, independent of each other, is hydrogen or methyl; R20is cyclopentyl, cyclohexyl, naphthyl, furanyl, thienyl, benzothienyl or phenyl optionally substituted with one or two substituents selected from C1-8-alkyl, C1-8-alkoxy, trihalogen-C1-4- alkyl, di-C1-4-alkylamino or tri-C1-4-alkylsilyl, or enantiomers thereof.

4. Chiral aminophosphine ligands of any one of claims 1 to 3, wherein R1to R3and R6to R8are hydrogen; R4and R5is methoxy; R9is methyl and R10to R12are hydrogen; R20is phenyl, 3,5-dimethylphenyl, 3,5-di-tert-butyl phenyl, 3,5-di-tert-pentyl phenyl or 3,5 di- (triethylsilyl) phenyl, or enantiomers thereof.

5. Chiral aminophosphine ligands of any one of claims 1 to 3, wherein R1, R2, R7, R8are hydrogen; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; R9is hydrogen or methyl and R10to R12are hydrogen; R20is phenyl, 3,5-dimethylphenyl, 3,5-di-tert-butyl phenyl, 3,5-di-tert-pentyl phenyl or 3,5 di- (triethylsilyl) phenyl, or enantiomers thereof.

6. Iridium catalyst comprising chiral aminophosphine ligands of the formula I, according to any one of claims 1 to 5.

7. Iridium catalyst of claim 6, of formula II or III,;wherein X is either a coordinated ligand or a counter anion selected from a C1-6-alkylsulfonyloxy group which is optionally substituted with one or more halogen, atoms; from halogen, C1-6- alkoxy, tetrahalogenoborate, hexahalogenophosphate, tetrakis(3,5-bis(trihalogeno-C1-6- alkyl)phenyl)borate, p-tolylsulfonate or trihalogenomethanesulfonate; R1to R8, independent of each other are hydrogen, C1-8-alkyl, C1-8-alkoxy hydroxyl, halogen or phenyl, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring, optionally substituted with C1-8-alkyl or C1-8-alkoxy; orR3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R9to R12, independent of each other, are hydrogen, C1-8-alkyl or C1-8-alkoxy; halogen C1-8- alkyl, di-C1-8-alkylamino or nitro; R14or R15are independent of each other hydrogen or C1-8-alkyl; R20is optionally substituted C1-8-alkyl, C3-8-cycloalkyl, phenyl, naphthyl or heteroaryl, wherein the substituents are selected from one or five groups selected from C1-8-alkyl, C1-8- alkoxy, phenyl, trihalogen-C1-4-alkyl, di-C1-4-alkylamino or tri-C1-4-alkylsilyl; and L in formula II is a bidentate coordinated diene ligand selected from 1,5-cyclooctadiene (COD), or 2,5-norbornadiene (NBD), or a monodentate coordinated olefin ligand selected from cyclooctene (COE). For the later, two of such ligands are coordinated to the iridium metal center, whereas for bidentate coordinated only one ligand is coordinated to the iridium metal center; or enantiomers thereof.

8. Iridium catalyst of claim 7, wherein X is either a coordinated ligand or a counter anion from halogen, tetrahalogenoborate or tetrakis(3,5-bis(trihalogeno-C1-6-alkyl)phenyl)borate; R1to R8, independent of each other are hydrogen or C1-8-alkoxy; or, R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; or R3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R9to R12, independent of each other, are hydrogen or C1-8-alkyl; R14or R15are independent of each other hydrogen or C1-4-alkyl; R20is optionally substituted C1-8-alkyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, furanyl, thienyl, or benzothienyl, wherein the substituents are selected from one or two groups selected from C1-8-alkyl, C1-8-alkoxy, phenyl, trihalogen-C1-4-alkyl, di-C1-4-alkylamino or tri-C1-4- alkylsilyl; andL in formula II is a bidentate coordinated diene ligand selected from 1,5-cyclooctadiene (COD) or 2,5-norbornadiene (NBD); or enantiomers thereof.

9. Iridium catalyst of claim 7, wherein X is a coordinated ligand from halogen; R1to R8, independent of each other are hydrogen or methoxy; or, R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; or R3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R9to R12, independent of each other, is hydrogen or methyl; R14and R15are independent of each other hydrogen or C1-8-alkyl; R20is cyclopentyl, cyclohexyl, naphthyl, furanyl, thienyl, benzothienyl or phenyl optionally substituted with one or two substituents selected from C1-8-alkyl, C1-8-alkoxy, trihalogen-C1-4-alkyl, di-C1-4-alkylamino or tri-C1-4-alkylsilyl; and L in formula II is a bidentate coordinated diene ligand selected from 1,5-cyclooctadiene (COD); or enantiomers thereof.

10. Iridium catalyst of claim 7, wherein X is a coordinated chloride; R1to R3and R6to R8are hydrogen; R4and R5is methoxy; R9is methyl and R10to R12are hydrogen; R14and R15are hydrogen or methyl;R20is phenyl, 3,5-dimethyl phenyl, 3,5-di-tert-butyl phenyl, 3,5-di-tert-pentyl phenyl or 3,5 di-(triethylsilyl) phenyl; and L in formula II is 1,5-cyclooctadiene (COD); or enantiomers thereof.

11. Iridium catalyst of claim 7, wherein X is chloride; R1, R2, R7, R8are hydrogen; R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring; R9is hydrogen or methyl and R10to R12are hydrogen; R14and R15are hydrogen; R20is phenyl, 3,5-dimethylphenyl, 3,5-di-tert-butyl phenyl, 3,5-di-tert-pentyl phenyl or 3,5 di- (triethylsilyl) phenyl; and L in formula II is 1,5-cyclooctadiene (COD); or enantiomers thereof.

12. Process for the preparation of iridium catalyst of claims 7 to 11, of formula II, comprising the reaction of a chiral aminophoshine ligand of formula I with an iridium catalyst precursor in the presence of an organic solvent.

13. Process for the preparation of iridium catalyst of claims 7 to 11, of formula III, comprising the reaction of a chiral aminophoshine ligand of formula I with an iridium catalyst precursor in in the presence of hydrogen and an organic solvent.

14. Process of claims 12 or 13, wherein the iridium catalyst precursor is selected from [Ir(L)X]2 or [Ir(L)2]X, wherein L and X are as defined in claim 7 to 11.

15. Process for the preparation of a chiral alcohol comprising the asymmetric hydrogenation of a compound, containing at least one prochiral keto group, with hydrogen in the presence of an iridium catalyst of formula II or III;wherein X is either a coordinated ligand or a counter anion selected from a C1-6-alkylsulfonyloxy group which is optionally substituted with one or more halogen atoms; from halogen, C1-6- alkoxy, tetrahalogenoborate, hexahalogenophosphate, tetrakis(3,5-bis(trihalogeno-C1-6- alkyl)phenyl)borate, p-tolylsulfonate or trihalogenomethanesulfonate; R1to R8, independent of each other are hydrogen, C1-8-alkyl, C1-8-alkoxy hydroxyl, halogen or phenyl, optionally substituted with C1-8-alkyl or C1-8-alkoxy; or R3and R4, and R5and R6, taken together, form an aromatic 6-membered ring, optionally substituted with C1-8-alkyl or C1-8-alkoxy; orR3and R4, and R5and R6form a bridge together with -OCH2CH2O-, with -OCH2O-, with -N(Me)CH2CH2O-, with -OC(Me)2O-, or with -OC(F)2O-; R9to R12, independent of each other, are hydrogen, C1-8-alkyl or C1-8-alkoxy; R14and R15are independent of each other hydrogen or C1-8-alkyl; R20is optionally substituted C1-8-alkyl, C3-8-cycloalkyl, phenyl, naphthyl or heteroaryl, wherein the substituents are selected from one or five groups selected from C1-8-alkyl, C1-8- alkoxy, phenyl, trihalogen-C1-4-alkyl, di-C1-4-alkylamino or tri-C1-4-alkylsilyl; and L in formula II is a bidentate coordinated diene ligand selected from 1,5-cyclooctadiene (COD), or 2,5-norbornadiene (NBD), or a monodentate coordinated olefin ligand selected from cyclooctene (COE). For the later, two of such ligands are coordinated to the iridium metal center, whereas for bidentate coordinated only one ligand is coordinated to the iridium metal center; or enantiomers thereof.

16. Process of claim 15, wherein the asymmetric hydrogenation comprises the reaction of a ketone of formula IV to the chiral alcohol of formula V, according to the schemeaccording to the methods; a) in the presence of a pre-formed iridium catalyst of formula II or III. b) in the presence of an iridium catalyst of formula II or III, in-situ formed from an iridium catalyst precursor [Ir(L)X]2or [Ir(L)2]X, wherein L and X are as defined above, and a ligand of formula I. c) in the additional presence of an iridium-phenylendiamine (Ir-PEN) catalyst of the formula VIa, VIb or VIcwherein, R13is C1-6-alkylsulfonyl wherein the alkyl group is optionally substituted with one or more halogen atoms; with a 7,7-dimethyl-2-oxobicyclo[2.2.1] heptane-1-yl group or phenyl sulfonyl, wherein the phenyl group is optionally substituted by one or more C1-6-alkyl groups and Y is either a coordinated ligand or a counter anion selected from a C1-6-alkylsulfonyloxy group which is optionally substituted with one or more halogen atoms; from halogen, C1-6-alkoxy, tetrahalogenoborate, hexahalogenophosphate, tetrakis(3,5-bis(trihalogeno-C1-6- alkyl)phenyl)borate, p-tolylsulfonate or trihalogenomethanesulfonate.

17. Process of claim 15 or 16, wherein the asymmetric hydrogenation is performed in the presence of an organic solvent and a base at a hydrogen pressure of 5 bar to 100 bar and at a reaction temperature of 10°C to 90°C.

18. Process of anyone of claims 15 to 17, wherein the organic solvent is an aliphatic alcohol, a halogen substituted alcohol, an ether or an aromatic solvent or a mixture thereof.

19. Process of anyone of claims 15 to 18, wherein the base is an inorganic base selected from alkali or earth alkali carbonates or hydrogen carbonates or phosphates or hydrogenphosphates or dihydrogenphosphates or acetates or formates or organic bases selected from amines, alkali alcoholates or amidines.

20. Process of anyone of claims 15 to 19, wherein the substrate-to-catalyst ratio is selected in a range of 100 to 10’000.

21. Process of claim 16, wherein the ketone of formula IV has the formula IVawherein R18is hydrogen or halogen and R19is C1-4-alkyl and the chiral alcohol has the formula IVb.

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