Metallocene Based Chiral Phosphine Or Arsine Ligands

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Metallocene Based Chiral Phosphine Or Arsine Ligands

Abstract: The present invention relates to metallocene-based phosphine ligands having chirality at phosphorus and at least one other element of chirality (planar chirality and/or chirality at carbon); and to the use of such ligands in asymmetric transformation reactions to generate high enantiomeric excesses of formed compounds. A method for the preparation of ligands according to the invention involving the conversion of the ortho-lithiated substituted metallocene to a phosphine chiral at phosphorus is also disclosed.

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Patent Information

Application #

Filing Date

14 July 2006

Publication Number

15/2007

Publication Type

INA

Invention Field

CHEMICAL

Status

Parent Application

Patent Number

Legal Status

Grant Date

2010-07-16

Renewal Date

Applicants

PHOENIX CHEMICALS LIMITED

34 Thursby Road,Croft Business Park,Bromborough, Wirral,CH62 3PW,

Inventors

1. CHEN,Wei-Ping

Stylacats Limited The Health Business & Technical Park, Runcorn,Cheshire,WA7 4QX,

2. WHITTALL,John

Stylacats Limited The Health Business & Technical Park, Runcorn,Cheshire,WA7 4QX,

Specification

FORM 2 THE PATENT ACT 1970 (39 of 1970)&The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rulel3) 1. TITLE OF THE INVENTION: "METALLOCENE-BASED CHIRAL PHOSPHINE OR ARSINE LIGANDS" 2. APPLICANT (a) NAME: PHOENIX CHEMICALS LIMITED (b) NATIONALITY: GB company incorporated under GB Act (c) ADDRESS: 34 Thursby Road, Croft Business Park, Bromborough, Wirral, CH62 3PW, Great Britain 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it has to be performed. WO 2005/068477 PCT/GB2005/000112 METALLOCENE-BASED CHIRAL PHOSPHINE OR ARSINE LIGANDS This invention relates to novel metallocene-based phosphine ligands 5 incorporating up to four elements of chirality, planar chirality, chirality at phosphorus, and optionally chirality at carbon and axial chirality, and methods for their preparation. In addition, this invention relates to the metal-ligand complexes that can be used as catalysts or precatalysts for asymmetric transformation reactions to generate products of high enantiomeric excess. 10 Similarly structured arsines are also within the scope of this invention. Ferrocene as a backbone for diphosphine ligands was introduced by Kumada and Hayashi based on the pioneering work of Ugi related to the synthesis of enantiopure substituted metallocenes1. A number of these ligands are shown 15 below: 4 Me Me w Me w ^^y^NMe2 ^^^5^A*NMe2 ^>^R Fe ^r^ ^r*pph> ^> ^^ Ugi's Amine PPFA R = Me2N,BPPFA R = OH,BPPFOH Ppfa as well as bppfa and bppfoh proved to be effective ligands for the catalysis of a variety of asymmetric transformations. From this starting point, many chiral WO 2005/068477 PCT/GB2005/000112 ferrocene-based bisphosphine ligands with a range of structural variation have been developed in the last few years. Certain types of known ligands exhibit both planar and carbon chirality: Me ^PP^*'2 FT^PR'2 BoPhoz R. J* f Ph2 Josiphos: R « Cy, R' = Ph PPF-tBu2: R ■ t-Bu, R' = Ph Xyliphos: R = 3,5-Me2Ph, R' = Ph cy2PF-Pcy2: R » R' = Cy B1 Fe PPh2 lp^Me^PRa ^ R^O R1 PPh2 TRAP 1a: R = H, R" = NMe2 Mandyphos (FERRIPHOS) 1b: R - OMe, R' * H Togni and Spindler2 have reported a class of non-C2-symmetrical ferrocene-based bisphosphines: the Josiphos-type ligands. Josiphos ligands are in widespread commercial use, having been found effective for Rh-catalyzed 10 hydrogenation of a-acetamidocinnamate, dimethyl itaconate, and β-ketoesters. Because the two phosphine groups are introduced into the ligand in consecutive steps with high yields, a variety of ligands are available with widely differing steric and electronic properties. The ligands have already been applied in three production processes3, several pilot processes and many other syntheses. For WO 2005/068477 PCT/GB2005/000112 -3- example, PPF-tBu2, a Josiphos type ligand with a di-(tert-butyl)phosphino group, has been applied as the ligand in asymmetric hydrogenation for commercial synthesis of (+)-biotin.4 Another notable example is the application of XyliPhos in the Ir-catalyzed hydrogenation of imines for the synthesis of the 5 herbicide (S)-metolachlor5. Bophoz6 is a combination of a phosphine and an aminophosphine and is prepared in 3 steps from ppfa with high overall yields. The ligand is air stable and effective for the hydrogenation of enamides, itaconates and α-keto acid 10 derivatives. As observed for several ligands forming seven-membered chelates, high activities can be reached and TONs up to 10,000 have been claimed. The full scope of this modular ligand class has not yet been explored. A class of non-C2-symmetrical, ferrocene-based 1,5-diphosphine ligands, 15 Taniaphos, has been developed by Knochel7,8. Compared to the Josiphos ligands, Taniaphos has an additional phenyl ring inserted at the side chain of the Ugi amine. Taniaphos gave excellent results in Rh- and Ru-catalyzed asymmetric hydrogenation. The configuration of α-position of Taniaphos plays an important role in the enantioselectivities and activities. The Taniaphos 1b 20 with αS configuration leads to higher enantioselectivities and activities than with αR configuration in a wide range of asymmetric transformations. WO 2005/068477 PCT/GB2005/000112 -4- Weissensteiner and Spindler9 have reported a series of structurally different ferrocene-based 1,5-diphosphine ligands, Walphos. Like Josiphos, Walphos is modular and is also made from the Ugi amine. It shows promise for the enantioselective hydrogenation of olefins and ketones. 5 Mandyphos is a bidentate version of ppfa with C2 symmetry, where in addition to the PPh2 moieties, R and R' can be used for fine tuning the functionality of the ligand10. The scope of this ligand family has not yet been fully explored, but preliminary results indicate high enantioselectivities for the Rh-catalyzed 10 hydrogenation of enamides, itaconates and enol acetates. The TRAP ligands developed by Ito11 form 9-membered metallocycles. However, it is not clear whether the cis-isomer, present in small amounts, or the major trans-isomer is responsible for the catalytic activity. Up to now only a few 15 different PR2 fragments have been tested, but it is clear that the choice of R strongly affects the catalytic performance. The Rh complexes work best at very low pressures of 0.5 ± 1 bar and effectively reduces indole-derivatives, enamides and itaconic acid derivatives. 20 Another class of known ligands exhibit only planar chirality: WO 2005/068477 PCT/GB2005/000112 „CHR, -5- PR2 Fe "PPI12 PW" Fe Fe PP»2 2 PPh2 PPh2 O ferroPHOS JAFAPhos Fe pPh2 Kang12 reported the C2.symmetry FerroPHOS with only planar chirality. FerroPHOS ligands are air-stable and are very efficient for the asymmetric 5 hydrogenation of various dehydroamino acid derivatives (up to 99% ee). Another (C2-symmetry planar chiral diphosphine, JAFAPhos, has been developed by Jendralla13. JAFAPhos gave excellent results in asymmetric hydrogenation, allylic alkylation, Grignard cross coupling and aldol reactions. 10 Kagan14 reported plane chiral ferrocene-based bisphosphorus ligands 2 and 3, and up to 95% ee's have been obtained in asymmetric hydrogenation of dimethyl itaconate using these ligands as catalyst. WO 2005/068477 PCT/GB2005/000112 -6- Another class of known diphosphine ligands exhibit chirality only at the phosphorus atoms: R _ ^ i R Fe R FerroTane rr <^Fe 4a: R = o-anisyl 4b: R = 1-naphthyl Fe >CCM^ f-binaphane The synthesis of chiral 1,1'-bis(phosphetano) ferrocenes (FerroTANE) has been independently reported by Marinetti15 and Burk16. FerroTANE has been successfully applied in Rh-catalyzed hydrogenation of itaconates and (E)-β-(acylamino) acrylates17. Mezzetti18 and van Leeuwen19 have independently reported P-chiral ferrocenyl bisphosphines 4a and 4b. These two ligands have shown excellent enantioselectivities (up to 99% ee) for asymmetric hydrogenation of α- dehydroamino acid derivatives. WO 2005/068477 PCT/GB2005/000112 -7- Zhang has reported a 1,1'-bis(Phospholanyl) ferrocene ligand 5 with ketal substitutes at the 3 and 4 positions. 20 The ligand has shown excellent enantioselectivities in hydrogenation of (β-dehydroamino acid derivatives. The ketal groups of the ligand are important for achieving the high enantioselectivity, 5 since the corresponding ligand without ketal groups only provides moderate ee's. Zhang has also developed a 1,1'-bis(dinaphthophosphepinyl) ferrocene ligand, f-binaphane, which has been successfully applied in the Ir-catalyzed hydrogenation of acyclic aryl imines. 21 10 Reetz has developed a binaphthol-derived ferrocene-based bisphosphonite ligand 622, which has shown excellent reactivities and enantioselectivities in Rh-catalyzed hydrogenation of itaconates and α-dehydroamino acid derivatives. Another class of known ligands exhibits both planar and phosphorus chirality: Fe ^ 7a:R = 1-naphthyl 15 7b: R= 2-biphenylyl Van Leeuwen has reported ferrocene-based bisphosphines combining planar and phosphorus chirality 4a and 4b23. These two ligands have shown excellent enantioselectivities (up to 99% ee) for asymmetric allylic alkylations. WO 2005/068477 PCT/GB2005/000112 8- Thus, most of the known ferrocene-based diphosphines contain planar and carbon chirality, only planar chirality or only phosphorus chirality. More recently, Togni reported the first tridentate ferrocene-based phosphine ligand 12 combining planar, phosphorus and carbon chirality.24 Me Me Ph Fe >Pha Fe "Wto (R)c-(S)Fe-(S)p-12 (R)c-(S)Fe-(R)P-12 It would be advantageous to design bisphosphine ligands incorporating up to three elements of chirality, planar chirality, chirality at phosphorus, and chirality 10 at carbon for use in enantioseiective catalysis. It would also be advantageous to design ligands that exhibit three different types of chirality; carbon, planar and phosphorus. According to the present invention there is provided a metallocene-based 15 phosphine having up to three or four elements of chirality; planar chirality, chirality at phosphorus, and optionally chirality at carbon and axial chirality. The invention also provides a metallocene-based arsine having up to three elements of chirality; planar chirality, chirality at arsenic, and optionally chirality 20 at carbon. In the following description reference will be made for convenience WO 2005/068477 PCT/GB2005/000112 -9- to phosphine ligands. It should be understood that although phosphines are the preferred ligands in accordance with the invention, the corresponding arsines are also within the scope of the invention. 5 Similarly, whilst ferrocene based ligands are preferred, other suitable metals may be used in the ligands of the invention, and hence reference is made herein to metallocenes generally. The invention further provides a metallocene-based diphosphine having planar, 10 phosphorus and carbon chirality. Ligands according to the invention have particular advantages over prior art ligands because the provision of up to three or four chiralities allows the designer of a ligand greater scope than has hitherto been the case to design 15 ligands for a particular purpose. Preferred ligands in accordance with the invention are selected from ligands having Formula (1), (II) or (III): " H-cki-P" w R m^§E^ * # (I) R1 'R2 (") WO 2005/068477 PCT/GB2005/000112 -10- wherein W is phosphorus or arsenic; M is a metal; R1 and R2 are different from each other, and are independently selected from 5 from substituted and unsubstituted, branched- and straight-chain alkyl, alkoxy, alkylamino, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkoxy, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocyclic aryloxy, substituted and unsubstituted heteroaryl, substituted and 10 unsubstituted heteroaryloxy, substituted and unsubstituted carbocyclic arylamino and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; R3 and R4 are the same or different, and are independently selected from substituted and unsubstituted, branched- and straight-chain alkyl, substituted 15 and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; n is 0 to 3; m is 0 to 5; 20 Q is selected from: R8 y^-WR6R7 WO 2005/068477 PCT/GB2005/000112 -11- wherein W is phosphorus or arsenic; R6 and R7 are the same or different, and are independently selected from substituted and unsubstituted, branched- and straight-chain alkyl, alkoxy, alkylamino, substituted and unsubstituted cycloalkyl, substituted and 5 unsubstituted cycloalkoxy, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocyclic aryloxy, substituted and unsubstituted heteroaryl, substituted and unsubstituted heteroaryloxy, substituted and unsubstituted carbocyclic arylamino and substituted and unsubstituted heteroarylamino, wherein the or 10 each heteroatom is independently selected from sulphur, nitrogen, and oxygen; and R8 is selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, 15 nitrogen, and oxygen; or Q is selected from: R8 WR6R7 wherein W is phosphorus or arsenic; R6, R7 and R8 are, independently, as previously defined; and R9 is selected from 20 hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted WO 2005/068477 PCT/GB2005/000112 -12- carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; or Q is selected from: R9 ^10 o' wherein R6, R7, R8 and R9 are, independently, as previously defined; and R10 is selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl 10 wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; or Q is selected from: WR6R7 wherein W is phosphorus or arsenic; 15 R6, R7 are, as previously defined; R11 is selected from OR13, SR13, NHR13, NR13R14, wherein R13 and R14 are the same or different and are independently selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl WO 2005/068477 PCT/GB2005/000112 -13- wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; R12 is selected from hydrogen, halogen, OR13, R13, NR13R14, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyi, substituted and unsubstituted 5 carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; wherein R13, R14 are, as previously defined and n' is 0 to 4; or Q is selected from: R8 10 wherein R8 and R9 are as previously defined; R5 is selected from: R1*R16 wherein R15, R16 and R17 are the same or different and are independently selected from hydrogen, OR13, SR13, NR13R14, substituted and unsubstituted, 15 branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; wherein R13, R14 are, as previously defined; or 20 R5 is selected from: WO 2005/068477 PCT/GB2005/000112 -14-R18 R18 V^NR^R14 wherein R13, R14 are as previously defined; the two geminal substituents R18 together are a doubly bonded oxygen atom (i.e. (R18)2 is =O), or each substituent R18 on its own is hydrogen; and 5 G is selected from the group consisting of: -CONH-R*-NHCO-, -CO-OR*0-CO-, -CO-R*CO-, -CH=N-R*-N=CH-, -CH2NH-R*-NHCH2-, -CH2NHCO-R*-CONHCH2-, -CH(R8)NH-R*-NH(CH(R8)-, -CH(R8)NHCO-R*-CONHCH(R8)-, -CONH-R-NHCO-, -CO-ORO-CO-, -CO-RCO-, -CH=N-R-N=CH-, -CH2NH-R-NHCH2-, -CH2NHCO-R-CONHCH2-, -CH(R8)NH- 10 R-NH(CH(R8)-, -CH(R8)NHCO-R-CONHCH(R8)-; wherein R8 is, independently, as previously defined; -R*- and -R- are selected from the group consisting of: R12n\/^ ^ R19 FY Y wherein R12 is as previously defined; R19 is selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alky!, substituted and 15 unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; or (R19)2 is -(CH2)m-, n' is 0 to 4; and m' is 1 to 8; 20 WO 2005/068477 PCT/GB2005/000112 -15- The invention also relates to the enantiomers of the ligands described above, the enantiomers having the Formulae (IV), (V) and (VI): R\ J*1 4 R3n W m R3 W K n W° p3 M M R4m-^ R° (V) R2 (IV) Rn R4 (VI) wherein each of W, M, wherein each of W, M, R1-19, Q, G, n, m, n' and m' have the same meanings as assigned above, with chirality changes in the substituent groups where required. Also provided in accordance with the invention are diastereomers of the ligands 10 described above, the diastereomers having the Formulae (VII), (VIII) and (IX): (VIII) wherein each of W, M, R1-19, Q, G, n, m, n' and m' have the same meanings as assigned above, with chirality changes in the substituent groups where required. R\ kR2 RV...R2 w Mr° "^ M R3n\, M (VII) ■W"iFr R* R n Rn R n D4 w, 2 vy WO 2005/068477 PCT/GB2005/000112 -16- The introduction of phosphorus chirality may enhance the chiral discrimination produced by the catalyst when a matching among the planar chirality, carbon chirality, axial chirality and the chirality of phosphorus can be achieved. 5 (Examples 59 to 67 below demonstrate that a matching catalyst may give high ee and a mismatching one may give low ee.) Also provided in accordance with the invention is a transition metal complex containing transition metal coordinated to the ligand of the invention. The metal 10 is preferably a Group VIb or a Group VIII metal, especially rhodium, ruthenium, iridium, palladium, platinum and nickel. Synthesis of ferrocene-based phosphorus chiral phosphines may be effected with the use of a suitable chiral ortho-directing group, for example in 15 accordance with the following schemes: WO 2005/068477 PCT/GB2005/000112 17- CI ^> t-BuLi 1)n-BuLlor -^-—^—x* sec-BuLi or Fe 2)R1PCI2 >^=^v R1 R2Z 1)n-BuLlor ^^-r^j—x* sec-BuU or \z=^/ t-l Fe 2) R1PCI2 ^-x- X* CI £2 Fe T CKP"R1 R^R1 Examples of suitable chiral directing groups: X* = v*** ^ ^\ ^ ^O (ref. 28) OMe (ref. 29) (ref. 25) (ref. 26) (ref. 27) ,Me V^OR* V^N Me ^-i MeCT^Ph OMe (ref. 30) (ref. 31) (ref. 32) (ref. 33) (Similar schemes may be used to synthesise the corresponding arsines, and other metallocenes.) Accordingly, the invention provides a method for preparing a phosphine ligand chiral at phosphorus comprising providing a metallocene-based substrate having a chiral or achiral directing substituent on one or both rings, and subjecting the substituted metallocene to an ortho-lithiation step before WO 2005/068477 PCT/GB2005/000112 -18- subsequently converting the ortho-lithiated substrate to a phosphine chiral at phosphorus. Methods for the preparation of ligands having Formula (I) and (III) will now be 5 more particularly described. For example, one such method comprises providing a compound of the Formula (X) (optionally substituted on one or both cyclopentadiene rings with R3n (top ring) and/or R4m (bottom ring)): M 10 (X) wherein X* is chiral directing group, and is preferably selected from the group consisting of: wherein WO 2005/068477 PCT/GB2005/000112 -19- R, Ra and Rb are same or different, and are independently selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or 5 each heteroatom is independently selected from sulphur, nitrogen, and oxygen; ortho-lithiating the substrate; reacting the ortholithiated substrate with an R1 substituted phosphine or arsine, and then with an R2-bearing Grignard reagent or organolithium compound, and converting X* to Q or G as appropriate. 10 One particularly preferred X* group is R The ortho-lithiation step is preferably a mono-ortho-lithiation step using n-butyllithium, sec-butyllithium or tert- butyllithium. The resulting monolithium compound is preferably reacted in situ with a dichlorophosphine of the formula 15 R1PCl2 followed by reacting with an organometallic reagent of the formula R2Z, wherein R1 and R2 are as defined above; Z is Li or MgY wherein Y is a halide. These steps are performed to obtain phosphorus chiral compound having formula XI (optionally substituted on one or both cyclopentadiene rings with R3n (top ring) and/or R4m (bottom ring)): R2 Fe *4 20 (XI) WO 2005/068477 PCT/GB2005/000112 -20- The synthesis preferably proceeds by converting compound (XI) to compound XII, XIII, or XIV: R8 .CHO ^«^C02H R2 <^R ^R ^R (XII) (XIII) (XIV) wherein R19 is an acyl group, and R1, R2 are as previously defined; 5 and then: reacting compound XII with a secondary phosphine of the formula R6R7PH wherein R6, R7 are, as previously defined, to obtain the diphosphine combining planar, phosphorus and carbon chirality having formula XV: R8 (XV) 10 10 or; reacting compound XII with an amine of the formula R9NH2 wherein R9 is, as previously defined, to obtain compound XVI: R8 "R a- (XXXIII) .^R2 (HO (XXXV) *8 R2 R «?>2 V-N-v /-N-\ I\R1 RVI, \-N- J 2 •%—d—\ y—N—v i ^.ni R DS \_/ U9V P , to\ p"R R R9 v /niFe R Fe R R* A/^h*Y,P ^ R2 pi (XXXVI) " " (XXXVII) Synthesis of metallocene-based phosphines chiral at phosphorus may be also effected with the use of enantioselective ortho-lithiation: WO 2005/068477 PCT/GB2005/000112 - 25 - 1)n-BuLlor sec-BuLi or S—?/ ~, R2I •CI Fe ■ ► Fe T4 ^ 2)R1PC2 ^rf 1)n-BuLlor sec-BuLi or —X t-BuLi, chiral x^^y* . Ni=i/ diamine >£—>/ C| R1M Fe ► Fe X CKKR1 R2"prR1 <^-x 2)RPC'2 x^^ R1 Examples of suitable achiral directing groups: 0 X- V^NR2 |-S02R \ANR2 hP(0)R2 (ref.34) (ref.34) (ref.35) (ref.36) «rr Chiral diamine: ^T4Me2 V™^ p, NMe2 H (ref. 34) (ref ^ (ref ge) Accordingly, the invention provides a method for preparing a chiral diphosphine ligand comprising a metallocene-based substrate having an achiral directing substituent on one or both rings, and subjecting the substituted metallocene to an enantioselective ortho-lithiation step before subsequently converting the ortho-lithiated substrate to phosphorus chiral phosphines. Thus, one method according to the present invention for preparing the ligand of Formula (I) or (III) comprises providing a compound of the formula XXXVII: ForooFormula (I) or (III) comprises providing a compound of the formula XXXVII: WO 2005/068477 PCT/GB2005/000112 -26- (XXXVII) wherein X is an achiral directing group, and is preferably selected from: o ^^NR2 —SOzR ,ANR2 —P(0)R2 and subjecting the compound to enantioselective mono-ortho-lithiation using n- 5 butyllithium or sec-butyllithium or tert- butyllithium in the presence of a homochiral tertiary amine, and reacting the resulting chiral monolithium compound in situ with a dichiorophosphine of the formula R1PCI2 followed by reacting with an organometallic reagent of the formula R2M, wherein R1 and R2 are as defined hereinabove; M is Li or MgX wherein X is a halide, to obtain 10 phosphorus chiral compound having formula XXXVIII: .R2 Fe ^ (XXXVIII) and converting compound XXXVIII to compound (I) or(lll). One method according to the invention for preparing the ligand of Formula (II) 15 comprises providing a compound of the Formula XXXIX: WO 2005/068477 PCT/GB2005/000112 (R)-1 f?—^T sNMe2 1)t-BuUEt20,-78°C~rt <^-^ SS—■V 2 2)PhPCI2,-78°C~rt \C_J} Fe ► 3) o-AnLi, -78 °C~rt -28- Me To a solution of (R)-N,N-dimethyl-1-ferrocenylethylamine [(R)-Ugi's amine, (R)-1] (3.86 g, 15 mmol) in Et2O (50 mL) was added 1.7 M t-BuLi solution in 5 pentane (9.7 mL, 16.5 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again, and dichlorophenylphosphine (2.24 mL, 16.5 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to 10 room temperature, and stirred for 1.5 h at room temperature. The mixture was then cooled to -78 °C again, and a solution of (2-methoxy)phenyllithium [prepared from 2-bromoanisole (3.32 g, 17.7 mmol) and 1.7 M t-BuLi solution in pentane (20.8 mL, 35.4 mmol) in Et2O (90 mL) at -78 °C] was added slowly via a cannula. The mixture was warmed to room temperature overnight, and filtered 15 through a pad of Celite. The filtrate was concentrated, and the residue was purified by chromatography (SiO2, hexane-EtOAc-Et3N = 85:10:5) to afford the title compound (6.50 g, 92%) as orange crystals. 1H NMR (CDCl3, 400.13 MHz): 5 1.29 (d, 3H, J = 6.5 Hz); 1.80 (s, 6H); 3.91 (s, 3H); 3.97 (s, 6H, overlap); 4.11 (m, 1H), 4.25 (t, 1H, J = 2.2 Hz); 4.37 (br. s, 1H); 6.87 (m, 1H); 6.94 (dd, 1H, J = 20 8.3 and 6.7 Hz); 7.12 - 7.23 (m, 6H); 7.31 (m, 1H); 31P NMR (CDCI3, 162 MHz): WO 2005/068477 PCT/GB2005/000112 -29- δ -38.82. The absolute configuration of (Re, SFe, SP)-2 was determined by single-crystal X-ray diffraction analysis. 5 Example 2 (Rc, SFe, SP)-2-[(1-N,N-Dimethylamino)ethyl]-1-[(1-naphthyl)phenylphosphino]ferrocene [(Rc, SFe, Sp)-3]: Me Me ^^T^^NMe, 1) t-BuLi, EtzO, -78 °C~rt £=£/ Ph Fe ► Fe \-„. />^-^\ 3) 1-naphthyllithium, -78°C~rt /<-:=~~S\1-Np* (R)-1 (Rc-SFe-SP)-3 10 To a solution of (R)-N,N-dimethyl-1-ferrocenylethylamine [(R)-Ugi's amine, (R)-1] (5.15 g, 20 mmol) in Et2O (60 mL) was added 1.7 M t-BuLi solution in pentane (12.94 mL, 22 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C 15 again, and dichlorophenylphosphine (2.99 mL, 22 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to room temperature, and stirred for 1.5 h at room temperature. The mixture was then cooled to -78 °C again, and a solution of 1-naphthyllithium [prepared from 1-bromonaphthalene (5.38 g, 26 mmol) and 1.7 M t-BuLi solution in pentane 20 (30.6 mL, 52 mmol) in Et20 (120 mL) at -78 °C] was added slowly via a WO 2005/068477 PCT/GB2005/000112 -30- cannula. The mixture was warmed to room temperature overnight, and filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified by chromatography (SiO2, hexane-EtOAc-Et3N 90:6:4) to afford the title compound (8.75 g, 89%) as orange crystals. 1H NMR (CDCI3,400.13 MHz): 5 δ 1.33 (d, 3H, J = 6.8 Hz); 1.91 (s, 6H); 3.59 (s, 5H); 4.00 (m, 1H); 4.17 (m, 1H); 4.26 (t, 1H, J = 2.2 Hz); 4.38 (m, 1H); 7.13 ~ 7.2 (m, 5H); 7.39 (t, 1H, J = 6.7 Hz); 7.43 -7.54 (m, 2H); 7.60 -7.63 (m, 1H); 7.87 (dd, 2H, J = 9.7 and 9.2 Hz), 9.33 (dd, 1H, J = 7.6 and 7.0 Hz). 31P NMR (CDCI3,162 MHz): 5 -38.73. 10 Example 3 (Re, SFe, SP)-2-[(1-N,N-Dimethylamino)ethyl]-1-[(1- naphthyl)phenylphosphino]ferrocene [(R^ SFe, SP)-3] and (Re, SFe, Rp)-2- [(1-N,N-Dimethylamino)ethyl]-1-[(1-naphthyl)phenylphosphino]ferrocene 15 [(Rc, SFe, RP)-4]: Me f^^y^HMez 1) t-BuLi, Et20, -78 °C~rt <^^Z NMe2 Si=2< 2)PhPCI2,-78°C~rt \5=s< ^ph Fe *- Fe *?•'/,. + y5==>\ 3) 1-naphthyllithium, rt /f^^vl-Np ^^^S. ^h (R, 1 b=£y 2)PhPCI2l-78°C~rt ^=^( ^Ph Fe — Fe •?■•'/,. /z.—o, 3) 2-naphthylmagnesium A.—>\2-ND 4^^> bromide, -78 °C~rl <^^ P .m^ (Rc-SFe-SP)-5 10 To a solution of (R)-N,N-dimethyl-1-ferrocenylethylamine [(R)-Ugi's amine, (R)-1] (2.06 g, 8 mmol) in Et2O (15 mL) was added 1.5 M t-BuLi solution in pentane (6.0 mL, 9 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h 15 at room temperature. The resulting red solution was cooled to -78 °C again, and dichlorophenylphosphine (1.22 mL, 9 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to room temperature, and stirred for 1.5 h at room temperature. Then the mixture was cooled to -78 °C again, and a solution of 2-naphthylmagnesium bromide 20 [prepared from 2-bromonaphthalene (2.20 g, 10.6 mmol) and magnesium (258 WO 2005/068477 PCT/GB2005/000112 -35- mg, 10.6 mmol) in Et2O (20 mL)] was added via a cannula at -78 °C. The mixture was warmed to room temperature overnight. The reaction was quenched with saturated NH4CI solution (20 mL). The organic layer was separated, and the aqueous layer was extracted with Et2O (20 mL). The 5 combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was purified by chromatography (S1O2, hexane- EtOAc-Et3N = 85:10:5) to afford the title compound (3.42 g, 87%) as single diastereomer. 1H NMR (CDCI3,400.13 MHz): 5 1.28 (d, 3H, J = 6.2 Hz); 1.80 (s, 6H); 3.90 (br. s, 1H); 3.92 (s, 5H); 4.20 (m, 1H), 4.22 (t, 1H, J = 2.2 Hz); 4.38 10 (br. s,. 1H); 7.18 ~ 7.26 (m, 5H); 7.48 (m, 2H), 7.58 (ddd, 1H, J = 8.4, 5.6 and 1.6 Hz); 7.79 (d, 1H, J= 8.4 Hz); 7.83 (m, 2H); 8.18 (d, 1H, J = 9.5 Hz);. 31P NMR (CDCI3,162 MHz): 5 -20.88. Example 7 (Re, SFe, SP)-2-[(1-N,N-Dimethylamino)ethyl]-1(2- 15 biphenyl)phenylphosphino]ferrocene [(Re, SFe, SP)-7]: Me Me K^^r^HUeo 1) t-B"L*. &2O, -78 °C~rt £=£/ 2)PhPCI2,-78°C~rt \s=^f Dh _ P. ^^ S^lgjenyllithium " ^jfe #R»1 (Rc"SFe-Sp)-7 To a solution of (R)-N,N-dimethyl-1-ferrocenylethylamine [(R)-Ugi's amine, (R)- 20 1] (2.57 g, 10 mmol) in Et2O (20 mL) was added 1.5 M t-BuLi solution in WO 2005/068477 PCT/GB2005/000112 -36- pentane (7.33 mL, 11 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again, and dichlorophenylphosphine (1.50 mL, 11 mmol) was added in one 5 portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to room temperature, and stirred for 1.5 h at room temperature. Then the mixture was cooled to -78 °C again, and a suspension of 2-biphenylllthium [prepared from 2-bromobiphenyl (2.24 mL, 13 mmol) and 1.5 M t-BuLi solution in pentane (17.3 mL, 26 mmol) in Et2O (30 mL) at -78 °C] was added via a cannula at -78 10 °C. The mixture was warmed to room temperature overnight and filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified by chromatography (SiO2, hexane-EtOAc-Et3N = 85:10:5) to afford the title compound (4.87 g, 94%) as single diastereomer. 1H NMR (CDCI3,400.13 MHz): δ 1.25 (d, 3H, J = 6.7Hz); 1.85 (s, 6H); 3.69 (s, 5H); 3.76 (m, 1H), 4.17 15 (m, 1H), 4.29 (t, 1H, J = 2.4 Hz); 4.32 (m, 1H); 7.10 ~ 7.19 (m, 5H); 7.31 (m, 1H), 7.37-7.48 (m, 5H), 7.64 (m, 1H); 7.69 (m, 1H); 7.71 (m, 1H). 31P NMR (CDCI3,162 MHz): δ-32.96 Example 8 20 (Re, SFe, SP)-2-[(1-N,N-Dimethylamino)ethyl]-1- (methylphenylphosphino)ferrocene [(Re, SFe, Rp)-8]: WO 2005/068477 PCT/GB2005/000112 -37- Me Me tf^Y^NMe* 1) t-BuLi, Et20, -78 °Ort <^^7^NMe2 VZs=^y 2)PhPCl2,-78°C~rt \==< .Ph Fe *- Fe ^. /p—o>, 3) methylmagnesium A-—N\ Me bromide,-78 °C~rt ^<^> /piw (Rc-SFe-Rp)-8 To a solution of (R)-N,N-dimethyl-1-ferrocenylethylamine [(R)-Ugi's amine, (R)-1] (2.57 g, 10 mmol) in Et20 (20 mL) was added 1.5 M t-BuLi solution in 5 pentane (7.33 mL, 11 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again, and dichlorophenylphosphine (1.50 mL, 11 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to 10 room temperature, and stirred for 1.5 h at room temperature. Then the mixture was cooled to -78 °C again, and 3.0 M solution of MeMgBr in Et2O (4.0 mL, 12 mmol) was added via a syringe at -78 °C. The mixture was warmed to room temperature overnight. The reaction was quenched with saturated NH4CI solution (20 mL). The organic layer was separated, and the aqueous layer was 15 extracted with Et2O (20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was purified by chromatography (SiO2, hexane-EtOAc-Et3N = 85:10:5) to afford the title compound (3.36 g, 89%) as red oil. 1H NMR (CDCI3,400.13 MHz): δ 1.24 (d, 3H, J = 6.7Hz); 1.56 (d, 3H, J = 4.4 Hz); 1.72 (s, 6H); 4.07 (m, 1H), 4.13 (s, 5H); WO 2005/068477 PCT/GB2005/000112 -38- 4.30 (m, 1H), 4.34 (m, 2H); 7.14 ~ 7.20 (m, 3H); 7.30-7.37 (m, 2H). 31P NMR (CDCI3,162 MHz): δ -43.47 Example 9 (Re, SFe, SP)-2-[(1-N,N-Dimethylamino)ethyl]-1- (cyclohexylphenylphosphino)ferrocene [(Re, SFe, RP)-9]: Me Me 'C^^T^^M&o 1) t"8"1-1. Et20. "78 °C~rt <^^7^HMe2 >b=zy 2)PhPCI2,-78°C~rt ^=^C xPh Fe Fe fy,. /,—ov 3) cyclohexylmagnesium />—Ov cv 4^^> chloride,-78 °C~rt 4^^> y #R» 1 (Rc-Spe-RpJ-S To a solution of (R)-N,N-dimethyl-1-ferrocenylethylamine [(R)-Ugi's amine, (R)-10 1] (2.57 g, 10 mmol) in Et2O (20 mL) was added 1.5 M t-BuLi solution in pentane (7.35 mL, 11 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again, and dichlorophenylphosphine (1.50 mL, 11 mmol) was added in one 15 portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to room temperature, and stirred for 1.5 h at room temperature. Then the mixture was cooled to -78 °C again, and 2.0 M solution of cyclohexymagnesium chloride in Et2O (6.0 mL, 12 mmol) was added via a syringe at -78 °C. The mixture was warmed to room temperature overnight. The reaction was 20 quenched with saturated NH4CI solution (20 mL). The organic layer was WO 2005/068477 PCT/GB2005/000112 -39- separated, and the aqueous layer was extracted with Et2O (20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was purified by chromatography (SiO2, hexane-EtOAcEt3N = 90:5:5) to afford the title compound (4.09 g, 92%) as red oil. 1H 5 NMR (CDCI3, 400.13 MHz): 6 1.16 (d, 3H, J = 6.7Hz); 1.19-2.03 (m, 11H); 1.50 (s, 6H); 3.99(m, 1H), 4.11 (s, 5H); 4.30 (m, 1H), 4.32 (t, 1H, J = 2.5 Hz); 4.37 (m, 1H), 7.12 ~ 7.150 (m, 3H); 7.18-7.23 (m, 2H). 31P NMR (CDCI3,162 MHz): δ-14.86 10 Example 10 (Re, SFe, Sp)-2-[(1-N,N-Dimethylamino)ethyl]-1-[methyl(tert-butyl)phenylphosphino)ferrocene [(Re, SFe, Rp)-10]: Me Me ^NMe, 1) t-BuLi, Et20, -78 °C~rt fc-stf R, Fe 7%. >. Fe r^„. ^C^0"^ rt /^^"^ Rc-Spo-Sp-2 Rc-SFe-Sp-11 A solution of (Rc, SFe, Sp)-2 (1.18 g, 2.5 mmol) in acetic anhydride (10 mL) was 20 stirred for 60 h at room temperature. The excess acetic anhydride was removed WO 2005/068477 PCT/GB2005/000112 -41- under reduced pressure (<1 Torr, <30 °C) to give the title compound (1.21 g, 100%) as yellow solid, which is pure enough for the use in the next reaction. 1H NMR (CDCI3, 400.13 MHz): δ1.19 (s, 3H); 1.64 (d, 3H, J = 6.5 Hz); 3.90 (s, 3H); 3.92 (m, 1H); 4.07 (s, 5H); 4.34 (t, 1H, J = 2.6 Hz); 5.55 (m, 1H);6.15 (m, 1H); 6.87 (td, 1H, J - 7.4 and 0.9 Hz); 6.95 (q, 1H, J = 4.8 Hz); 7.08 ~ 7.21 (m, 6H); 7.35 (m, 1H); 31P NMR (CDCI3,162 MHz): δ -39.30. Example 12 10 (Re, SFe, SP)-2-(1-Acetoxyethyl)-1-[(1-naphthyl)phenylphosphino]ferrocene [(Re, SFe, SP)-12]: Me Me r^5/ NM62 „. Rc-Spe-Sp-5 rp—-jr OAC Fe "K''/,. Rc-Spe-Sp-14 ^=3 AC2O rt A solution of (Re, SFe, Sp)-5 (1.47 g, 3.0 mmol) in acetic anhydride (20 mL) was stirred for 60 h at room temperature. The excess acetic anhydride was removed under reduced pressure (<1 Torr, <30 °C) to give the title compound (1.52 g, 100%) as yellow solid, which is pure enough for the use in the next reaction. 1H NMR (CDCI3, 400.13 MHz): δ1.21 (s, 3H); 1.65 (d, 3H, J = 6.5 Hz); 3.83 (m, 1H); 4.03 (s, 5H); 4.33 (t, 1H, J = 2.6 Hz); 4.57 (m, 1H); 6.24 (m, 1H); 7.19 -7.27(m, 5H); 7.46-7.51 (m, 3H), 7.81 (m, 3H), 8.11 (d, 1H, J= 10.4 Hz); 31P NMR (CDCI3,162 MHz): δ -22.89. Example 15 (RC, SFe, Rp)-2-(1-Acetoxyethyl)-1-[(2-naphthyl)phenylphosphino]ferrocene 15 [(Re, SFe, RP)-15]: Rc-Spe-Rp-6 WO 2005/068477 PCT/GB2005/000112 44- A solution of (Re, SFe, Rp)-6 (1.47 g, 3.0 mmol) in acetic anhydride (20 mL) was stirred for 60 h at room temperature. The excess acetic anhydride was removed under reduced pressure (<1 Torr, <30 °C) to give the title compound (1.52 g, 5 100%) as yellow solid, which Is pure enough for the use in the next reaction. 1H NMR (CDCI3, 400.13 MHz): δ 0.92 (s, 3H); 1.64 (d, 3H, J = 6.4 Hz); 3.87 (m, 1H); 4.07 (s, 5H); 4.40 (t, 1H, J = 2.6 Hz); 5.61 (m, 1H); 6.23 (m, 1H); 7.27 (ddd, 1H, J = 8.2, 6.8 and 1.4 Hz), 7.32 - 7.38(m, 3H); 7.39-7.44 (m, 2H), 7.53-7.57 (m, 2H), 7.60 (d, 1H, J = 8.0 Hz), 7.69 (m, 2H), 7.74 (m, 1H); 31P 10 NMR (CDCI3,162 MHz): δ -22.58. Example 16 (Re, SFe, SP)-2-(1-Acetoxyethyl)-1-[(2-biphenyl)phenylphosphino]ferrocene [(Re, SFe, SP)-16]: Me f^V NMej ^NHMe ^—

1-Np ^ \_-< i.Np Jl_ £h'V THF-MeOH(4:1) JV &' 5 RC-SFO-RP-13 Rc-SFo-Rp-19 A solution of (Re, SFe, Rp)-7 (633 mg, 1.25 mmol) and 40% methylamine aqueous solution (3.0 mL) in THF (10 mL) and MeOH (2.5 mL) was stirred for 3 days at 40 °C, and concentrated. The residue was dissolved in Et2O (20 mL), washed with brine (10 mL), dried (Na2SO4), and evaporated under reduced 10 pressure. The crude product was purified by chromatography (SiO2, hexane-EtOAc-Et3N = 85:10:5) to give the title compound (537 mg, 90%) as orange crystals. 1H NMR (CDCI3,400.13 MHz): 5 1.45 (d, 3H, J = 6.5 Hz); 1.83 (s, 3H); 3.82 (m, 1H); 3.97 (m, 1H); 4.07 (s, 5H); 3 4.35 (t, 1H, J = 2.5 Hz); 4.53 (m, 1H); 7.20 (m, 1H); 7.30 ~ 7.36 (m, 5H); 7.40 (m, 1H); 7.56 - 7.61 (m, 2H); 7.78 15 (t, 2H, J = 8.2 Hz), 8.38 (m, 1H). 31P NMR (CDCI3,162 MHz): δ -32.25. Example 20 (Re, SFe, SP)-2-[(1- N-Methylamino)ethyl]-1-[(2-naphthyl)phenylphosphino]ferrocene [(Re, SFe, SP)-20]: WO 2005/068477 PCT/GB2005/000112 48 40% MeNH2 (aq.) THF-MeOH(4:1) NHMe Fe *{';,. 2-Np* Rc-Spe-Sp-I4 RC"SFB"SP"20 A solution of (Re, SFe, SP)-14 (633 mg, 1.25 mmol) and 40% methylamine aqueous solution (3.0 mL) in THF (10 mL) and MeOH (2.5 mL) was stirred for 3 5 days at 40 °C, and concentrated. The residue was dissolved in Et2O (20 mL), washed with brine (10 mL), dried (Na2SO4), and evaporated under reduced pressure. The crude product was purified by chromatography (SiO2, hexane-EtOAc-Et3N = 85:10:5) to give the title compound (513 mg, 86%) as orange crystals. 1H NMR (CDCI3, 400.13 MHz): 6 1.47 (d, 3H, J = 6.7 Hz); 1.98 (s, 3H); 10 3.82 (m, 1H); 3.98 (m, 1H); 4.02 (s, 5H); 4.27 (t, 1H, J = 2.5 Hz); 4.47 (m, 1H); 7.27-7.34 (m, 5H); 7.50 (m, 2H); 7.55 (m, 1H); 7.83 (m, 3H); 8.12 (d, 1H, J = 10.0 Hz). 31P NMR (CDCI3,162 MHz): δ -22.68. Example 21 (Re, SFe, RP)-2-[(1- N-Methylamino)ethyl]-1-[(2- 15 naphthyl)phenylphosphino]ferrocene [(Re, SFe, Rp)-21]: Me Me *NHMe . r2-Np Rc"SFe-Rp"21 0Ac 40% MeNH2 (aq.) ^2-Np ^ , , &'•' THF-MeOH (4:1) Rc"SFe"^p15 ^3^^0Ac 40%MeNH2(aq.) KPh2 Fe *£•/,,. : ► Fe \"„. /£—-Al-Np* toluene, rt, 16 h ,—-Al-Np' Rc-Spe-Sp-18 Rc-Spa-Sp-24 To a solution of (Re, SFe, SP)-18 (477 mg, 1.0 mmol) and Et3N (0.28 mL, 2.0 mmol) in toluene (2.5 mL) was added dropwise chiorodiphenylphosphine (188 uL, 1.05 mmol) at 0 °C. Then the mixture was warmed to room temperature, 10 and stirred overnight (16 h) at room temperature, and filtered through a pad of neutral aluminium oxide and eluted with hexane-EtOAc (9:1) to afford the title compound (595 mg, 90%) as orange foam. 1H NMR (CDCI3,400.13 MHz): δ 1.53 (d, 3H, J = 6.8 Hz); 2.22 (d, 3H, J = 3.3 Hz); 3.44 (s, 5H); 4.26 (m, 1H); 4.39 (t, 1H, J = 2.4 Hz); 4.50 (m, 1H); 5.03 (m, 1H); 6.85 ~ 6.94 (m, 4H); 7.04 15 (tt, 1H, J = 7.2 and 1.4 Hz); 7.09 -7.19 (m, 4H); 7.27 ~ 7.31 (m, 4H); 7.37 ~ 7.43 (m, 3H); 7.48 ~ 7.56 (m, 2H); 7.68 (m, 1H); 7.89 (dd, 2H, J = 8.1 and 4.8 Hz); 9.44 (t, 1H, J = 7.6 Hz). 31P NMR (CDCI3,162 MHz): δ 59.59, -41.03. Example 25 WO 2005/068477 PCT/GB2005/000112 -52- (Rc, SFe, Rp)-2-[1-[(N-Methyl-N-diphenylphosphino)amino]ethyl]-1-[(1- naphthyl)phenylphosphino]ferrocene [(Re, SFe, RP)-25]: Me Me NHMe ^1-Np Ph2PCI, Et3N toluene, rt, 16 h R(j-Spe-Rp«19 Rc-S|ie-Rp-25 5 To a solution of (Re, SFe, RP)-19 (239 mg, 0.5 mmol) and Et3N (0.14 mL, 1.0 mmol) in toluene (2.0 mL) was added dropwise chlorodiphenylphosphine (89 uL, 0.50 mmol) at 0 °C. Then the mixture was warmed to room temperature, and stirred overnight (16 h) at room temperature, and filtered through a pad of neutral aluminium oxide and eluted with hexane-EtOAc (9:1) to afford the title 10 compound (304 mg, 92%) as orange foam. 1H NMR (CDCI3, 400.13 MHz): δ 1.51 (d, 3H, J = 6.8 Hz); 2.08 (d, 3H, J = 3.5 Hz); 3.90 (s, 5H); 4.15 (m, 1H); 4.44 (t, 1H, J = 2.4 Hz); 4.58 (m, 1H); 5.02 (m, 1H); 6.44 (td, 2H, J = 8.0 and 1.8 Hz); 6.62 (td, 2H, J = 8.0 arid 1.2 Hz); 6.80 (tt, 1H, J = 7.4 and 1.2 Hz); 7.20 (m, 1H); 7.15 ~ 7.30 (m, H); 7.58 ~ 7.64 (m, H); 7.70 (dd, 1H, J-6.8 and 1.8 Hz); 15 7.79 (d, 1H, J = 8.0 Hz); 8.20 (dd, 1H, J = 8.2 and 2.4 Hz). 31P NMR (CDCI3. 162 MHz): 5 58.81,-31.16. Example 26 (Rc,SFe,Sp)-2-[1-[(N-Methy!-N-diphenylphosphino)amino]ethyl]-1-[(2-20 biphenyl)phenylphosphino]ferrocene [(Re, SFe, SP)-26]: WO 2005/068477 PCT/GB2005/000112 -53 NHMe _Ph Ph2PCI, Et3N Fe %>',,. * yP==^2-Biph toluene, rt, 16 h Rc~Spe-Sp-22 ^= O toluene, rt, 16 h ^? Rc-SFe-Rp-19 Fe P%1.-Np R{^Spe"Rp, Rg-30 10 To a solution of (Rc, SFe, RP)-19(239 mg, 0.5 mmol) and Et3N (209 uL, 1.5 mmol) in toluene (4 mL) was added (R)-4-chloro-3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a']binaphthalene (175 mg, 0.5 mmol) at 0 °C. Then the mixture was warmed to room temperature, and stirred overnight (16 h) at room temperature, and filtered through a pad of neutral aluminium oxide and 15 eluted with hexane-EtOAc (9:1) to afford the title compound (371 mg, 95%) as orange foam. 1H NMR (CDCI3, 250 MHz): 5 1.64 (d, 3H, J = 3.5 Hz); 1.79 (d, 3H, J = 7.0 Hz); 4.88 (m, 1H); 4.07 (s, 5H); 4.38 (t, 1H, J = 2.3 Hz); 4.52 (m, 1H); 4.91 (dd, 1H, J = 8.5 and 0.8 Hz), 5.37 (m, 1H); 6.91 (m, 1H); 7.10-7.90 WO 2005/068477 PCT/GB2005/000112 -57- (m, 21H), 8.44 (m, 1H). 31P NMR (CDCI3,101 MHz): 5 148.18 (d, J= 54.5 Hz);-32.43 (d, J = 54.5 Hz). Example 31 5 (Rc,SFe,Rp,Sa)-31: (S)- Rc-SFe-Rp. Sa-31 To a solution of (Re, SFe, RP)-1 9(239 mg, 0.5 mmol) and Et3N (209 uL, 1.5 mmol) in toluene (4 mL) was added (S)-4-chloro-3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a']binaphthalene (175 mg, 0.5 mmol) at 0 °C. 10 Then the mixture was warmed to room temperature, and stirred overnight (16 h) at room temperature, and filtered through a pad of neutral aluminium oxide and eluted with hexane-EtOAc (9:1) to afford the title compound (377 mg, 95%) as orange foam. 1H NMR (CDCl3, 250 MHz): δ 1.69 (d, 3H, J = 6.8 Hz); 1.86 (d, 3H, J - 3.5 Hz); 3.97 (s, 5H); 4.07 (m, 1H); 4.43 (t, 1H, J *= 2.3 Hz); 4.58 (m, 15 1H); 5.15 (m, 1H); 5.88 (dd, 1H, J = 8.5 and 0.8 Hz), 6.91 (m, 1H); 7.10-7.92 (m, 22H), 8.31 (m, 1H). 31P NMR (CDCI3,101 MHz): 6 150.64 (d, J = 21.8 Hz); -33.31 (d,J = 21.8 Hz). Example 32 WO 2005/068477 PCT/GB2005/000112 -58-(Rc, SFe Sp,Ra)-32: To a solution of (Re, SFe, SP)-22(252 mg, 0.5 mmol) and ET3N (209 uL, 1.5 mmol) In toluene (4 mL) was added (R)-4-chloro-3,5-dioxa-4- 5 phosphacyclohepta[2,1-a:3,4-ar]binaphthalene (175 mg, 0.5 mmol) at 0 °C. Then the mixture was warmed to room temperature, and stirred overnight (16 h) at room temperature, and filtered through a pad of neutral aluminium oxide and eluted with hexane-EtOAc (9:1) to afford the title compound (392 mg, 96%) as orange foam. 1H NMR (CDCI3, 250 MHz): δ 1.63 (d, 3H, J = 7.0 Hz); 1.76 (d, 10 3H, J = 3.5 Hz); 3.69 (s, 5H); 4.09 (m, 1H); 4.30 (t, 1H, J = 2.3 Hz); 4.34 (m, 1H); 4.89 (m, 1H); 6.71 (dd, 1H, J = 8.5 and 0.8 Hz), 7.07-7.84 (m, 25 H). 31P NMR (CDCI3,101 MHz): 5 149.07 (d, J = 60.5 Hz); -36.59 (d, J = 60.5Hz). Example 33 15 (RC, SFe, SP)-2-(1-Dicyclohexylphosphino)ethyl]-1-[(2- methoxyphenyl)phenylphosphino]ferrocene [(RC, SFe, SP)-33]: WO 2005/068477 PCT/GB2005/000112 -59- Me Me Fe r..,//m ► Fe »J"„. />—A o-Ah AcOH /—v o-An ^^^> rt, 16h rt,16h ^^^ Rc-Spe-Rp-13 Rc-SFe-RP^5 WO 2005/068477 PCT/GB2005/000112 -61- A solution of (Rc, SFe, SP)-13 (506 mg, 1.0 mmol) and dicyclohexylphosphine (243 uL, 1.2 mmol) in acetic acid (3 mL) was stirred overnight at room temperature, and poured into 10% K2CO3 aqueous solution (60 mL) with stirring, extracted with Et20 (2x25 mL). The combined ether layers were dried 5 (MgSO4) and concentrated. The residue was purified by chromatography (SiO2, hexane-EtOAc = 9:1) to afford the title compound (618 mg, 95%) as orange crystals. 1H NMR (CDCL3, 250.13 MHz): δ 0.84-1.85 (m, 25 H), 3.16 (m, 1H), 3.96 (s, 5H), 4.00 (m, 1H), 4.35 (t, 1H, J = 2.3 Hz); 4.41 (m, 1H), 7.29-7.40 (m, 7H), 7.62-7.79 (m, 4 H), 8.33 (m, 1H); 31P NMR (CDCL3, 101.25 MHz): δ14.93 10 (d, J = 22.8 Hz);-34.80 (d, J = 22.8 Hz). Example 36 (Rc, SFe, SP)-2-(1-Dicyclohexylphosphino)ethyl]-1-[(2- naphthyl)phenylphosphino]ferrocene [(Rc, SFe, SP)-36]: Me Me Fe •j'*,/. >* Fe •{»/„. 15 Rc-Spe-Sp-14 Rc-SFe-SP-36 A solution of (Rc, SFe, SP)-14 (506 mg, 1.0 mmol) and dicyclohexylphosphine (243 uL, 1.2 mmol) in acetic acid (3 mL) was stirred overnight at room temperature, and poured into 10% K2CO3 aqueous solution (60 mL) with 20 stirring, extracted with Et2O (2x25 mL). The combined ether layers were dried WO 2005/068477 PCT/GB2005/000112 -62- (MgSO4) and concentrated. The residue was purified by chromatography (SiO2, hexane-EtOAc = 9:1) to afford the title compound (599 mg, 93%) as orange crystals. 1H NMR (CDCI3, 250.13 MHz): δ 1.15-1.71 (m, 25 H), 3.26 (m, 1H), 3.79 (s, 5H), 4.10 (m, 1H), 4.29 (t, 1H, J = 2.3 Hz); 4.37 (m, 1H), 7.17-7.24 (m, 5H), 7.34 (m, 1 H), 7.50 (d, 1H, J = 9.5 Hz); 7.50 (dd, 1H, J = 3.0 and 1.5 Hz); 7.57 (ddd, 1H, J= 8.3, 5.0 and 1.5 Hz); 7.81 (d, 1H, J = 8.5 Hz); 7.87 (m, 1H), 8.31 (d, 1H, J = 9.5 Hz); 31P NMR (CDCI3,101.25 MHz): δ 15.67 (d, J = 30.9 Hz); -34.20 (d, J = 30.9Hz). 10 Example 37 (Rc, SFe, Rp)-2-(1-Dicyclohexylphosphino)ethyl]-1-[(2- naphthyl)phenylphosphino]ferrocene [(Rc, SFe, Rp)-37]: Me Me OAc Cy2PH -► AcOH rt, 16 h Rc-SFe-Rp-15 Rc-Spe-Rp-37 15 A solution of (Re, SFe, SP)-15 (506 mg, 1.0 mmol) and dicyclohexylphosphine (243 uL, 1.2 mmol) in acetic acid (3 mL) was stirred overnight at room temperature, and poured into 10% K2CO3 aqueous solution (60 mL) with stirring, extracted with Et2O (2X25 mL). The combined ether layers were dried 20 (MgSO4) and concentrated. The residue was purified by chromatography (SiO2, WO 2005/068477 PCT/GB2005/000112 -63- hexane-EtOAc = 9:1) to afford the title compound (608 mg, 94%) as orange crystals. 1H NMR (CDCI3, 250.13 MHz): δ 1.07-1.68 (m, 25 H), 3.26 (m, 1H), 3.85 (s, 5H), 4.07 (m, 1H), 4.34 (t, 1H, J = 2.3 Hz); 4.40 (m, 1H), 7.30-7.77 (m, 12H);31PNMR(CDCI3, 101.25 MHz): δ 15.56 (d, J = 33.1 Hz); -25.12 (d, J = 5 33.1 Hz). Example 38 (Re, SFe) SP)-2-(1-Dicyclohexylphosphino)ethyl]-1-[(2- biphenyl)phenylphosphino]ferrocene [(Re, SFe, SP)-38]: Me Me 10 Rc-SFe"Sp"16 Rc-SFe-Sp-38 A solution of (Rc, SFe, SP)-16 (531 mg, 1.0 mmol) and dicyclohexylphosphine (243 uL, 1.2 mmol) in acetic acid (3 mL) was stirred overnight at room temperature, and poured into 10% K2CO3 aqueous solution (60 mL) with 15 stirring, extracted with Et2O (2X25 mL). The combined ether layers were dried (MgSO4) and concentrated. The residue was purified by chromatography (SiO2, hexane-EtOAc = 9:1) to afford the title compound (650 mg, 97%) as orange crystals. 1H NMR (CDCI3,250.13 MHz): δ 1.02-1.72 (m, 25 H), 2.93 (m, 1H), 3.66 (s, 5H), 3.76 (m, 1H), 4.29 (t, 1H, J = 2.3 Hz); 4.32 (m, 1H), 7.14-7.69 (m, WO 2005/068477 PCT/GB2005/000112 -64- 14 H); 31P NMR (CDCI3,101.25 MHz): δ 18.44 (d, J = 36.7 Hz); -37.67 (d, J = 36.7 Hz). 5 Example 39 (Re, SFe, Sp).2l2,-Bis[(1-N,N-dimethylamino)ethyl]-1,1,-bis[(2-methoxyphenyl)phenylphosphino]ferrocene [(Re, SFe, SP)-40]: Me £S>Z Nm^ 2)PhPCI2>-78°C~rt xCJV _.NMe2 Fe ► /__, 3) o-AnLi, -78 °C~rt <^^>^NMe2 MesN p. Me MePh^r'o-An (R,R)-39 Rc-Spe-Sp-40 10 To a solution of (R,R)-1,1 '-bis(1-N,N-dimethylaminoethyl)ferrocene [(R,R)-20] (986 mg, 3.0 mmol) in Et2O (30 mL) was added 1.5 M t-BuLi solution in pentane (6.0 mL, 9 mmol) over 10 min via a syringe at -78 °C. After addition was completed, the mixture was warmed to room temperature, and stirred for 1.5 h at room temperature. The resulting red solution was cooled to -78 °C again, 15 and dichlorophenylphosphine (1.22 mL, 9.0 mmol) was added in one portion. After stirring for 10 min at -78 °C, the mixture was slowly warmed to room temperature, and stirred for 1.5 h at room temperature. The mixture was then cooled to -78 °C again, and a solution of (2-methoxy)phenyllithium [prepared from 2-bromoanisole (1.87 g, 10 mmol) and 1.5 M t-BuLi solution in pentane WO 2005/068477 PCT/GB2005/000112 10 -65- (13.3 mL, 20 mmol) in Et2O (50 mL) at-78 °C] was added slowly via a cannula. The mixture was warmed to room temperature overnight, and filtered through a pad of Celite. The filtrate was concentrated. The residue was purified by chromatography (SiO2, hexane-EtOAc-Et3N = 80:15:5) to afford the title compound (1.10 g, 48%) as yellow foam. 1H NMR (CDCL3, 400.13 MHz): 5 1.28 (d, 6H, J= 6.7 Hz); 1.71 (s, 12H); 3.16 (m, 2H); 3.84 (s, 6H); 4.05 (m, 2H); 4.16 (m, 2H); 4.53 (t, 2H, J = 2.3 Hz); 6.62 (t, 2H, J = 7.4 Hz); 6.73 (dd, 2H, J * 8.1 and 4.6 Hz); 6.85 (ddd, 2H, J = 7.4,5.3 and 1.8 Hz); 7.03 ~ 7.11 (m, 10H); 7.17 (td, 2H, J= 8.5 and 1.6 Hz); 31P NMR (CDCI3,162 MHz): δ -39.53 (s). Example 40 (RC, SFe, Sp)-2,2'-Bis[(1-N,N-dimethylamino)ethyl]-1,1'-bIs[(1- naphthyl)phenylphosphino]ferrocene [(Re, SFe, SP)-41]: Me NMe2 1)t-BuU,EW>I-78«0-ft 2 2)PhPCI2,-78°C~rt Me THF ^ (SFe,aS)-55 (SFe,aS)-56 To a suspension of KH (30%, 3.75 g, 28.1 mmol), washed with hexane) in THF (20 mL) was added a solution of (SP,αS)-2-Bromo-1-[α-(2-diphenylphosphinophenyl)]ferrocenemethanol [(SFe,αS)-55] (12.00 g, 21.6 5 mmol) in THF (180 mL) at 0 °C. After stirring for 2 h at 0 °C, iodomethane (1.48 mL, 23.8 mmoL) was added via a syringe, then the mixture was stirred for 1 h at 0 °C. The reaction was quenched with MeOH (5 mL), and the solvents were removed under reduced pressure. The residue was dissolved in EtOAc (150 mL), washed with water (100 mL) and brine (10o mL), dried (MgS04), and 10 evaporated under reduced pressure. The residue was purified by flash chromatography (SiO2 hexane-EtOAc = 5:1) to give yellow crystals (12.10 g, 98%). 1H NMR (CDCI3, 250 MHz): 6 3.29 (s, 3H), 3.96 (t, 1H, J = 2.5 Hz), 4.01 (m, 1H), 4.27 (s, 5H), 4.33 (m, 1H), 6.09 (d, 1H, J = 7.8 Hz), 7.04 (m, 1H), 7.15 - 7.37 (m, 12H), 7.44 (m, 1H); 31P NMR (CDCI3,101 MHz): 5 -18.46. 15 Example 51 (SFe,SP,αS)-2-[(2-Methoxyphenyl)phenylphosphino]-1-[α-methoxy-(2- dlphenylphosphinophenylmethyl)]ferrocene[(SFe,SP,αS)-57]: WO 2005/068477 -78-OMe PPh, ^'Y^l I^ULL 2) PhPCI2 3)o-AnLi XC^< (SpeiSp, aS)-56 (SpeiSP, aS)-56 To a solution of bromide [(SFe,αS)-56] (2.85 g, 5 mmol) in THF (30 mL) was added slowly 1.7 M t-BuLi (6.5 mL, 11 mmol) via a syringe at -78 °C. After stirring for 10 min at -78 °C, PhPCI2 (746 uL, 5.5 mmoL) was added via a 5 syringe, After stirring for 30 min at -78 °C, the mixture was warmed to room temperature and stirred for 1 h at room temperature, the mixture was cooled to -78 °C again, and a suspension of o-AnLi [prepared from 2-bromoanisole (805 uL, 6.5 mmol) and 1.7 M t-BuLi (7.6 mL, 13 mmol) in Et20 (30 mL) at -78 °C] was added via a cannula, then the mixture was stirred overnight at -78 °C to 10 room temperature. The reaction was quenched with water (20 mL), The organic layer was separated, washed with brine (30 mL), dried (MgS04), and evaporated under reduced pressure. The residue was purified by flash chromatography (Si02, hexane-EtOAc = 10:1) to give yellow crystals (3.21 g, 91%) as a single diastereomer. 1H NMR (CDCfe, 250 MHz): 5 2.71 (s, 3H), 3.67 15 (m, 1H), 3.90 (m, 1H), 3.96 (s, 3H), 4.06 (t, 1H, J = 2.3 Hz), 4.22 (s, 5H), 5.52 (d, 1H, J = 6.5 Hz), 6.80-6.98 (m, 4H), 7.08-7.36 (m, 14H), 7.76 (m, 1H); 31P NMR (CDCI3,101 MHz): 5 -17.98 (d, J = 10.0 Hz), -33.15 (d, J = 10.0 Hz). Example 52 WO 2005/068477 PCT/GB2005/000112 -79- (SFe,SP,αS)-2-[(1-Naphthyl)phenylphosphino]-1-[a-methoxy-(2- diphenylphosphinophenylmethyl)]ferrocene [(SFe,SPjαS)-58] and (SFe,Rp,αS)-2-[(1-Naphthyl)phenylphosphino]-1-[a-methoxy-(2- diphenylphosphinophenylmethyl)]ferrocene[(SFe,Rp,αS)-59]: OMe PPh2 ^VT^ Fe W* (SFe,SP, aS)-S8 (SFe,RP, aS)-59 To a solution of bromide [(SFe,αS)-56] (2.85 g, 5 mmol) in THF (30 mL) was added slowly 1.7 M t-BuLi (6.5 mL, 11 mmol) via a syringe at -78 °C. After stirring for 10 min at -78 °C, PhPCl2 (746 uL, 5.5 mmoL) was added via a syringe, After stirring for 30 min at -78 °C, the mixture was warmed to room 10 temperature and stirred for 1 h at room temperature. Tthe mixture was cooled to -78 °C again, and a suspension of o-AnLi [prepared from 1-bromonaphthalene (900 uL, 6.5 mmol) and 1.7 M t-BuLi (7.6 mL, 13 mmol) in Et20 (30 mL) at -78 °C] was added via a cannula, then the mixture was stirred overnight at -78 °C to room temperature. The reaction was quenched with water (20 mL), The organic 15 layer was separated, washed with brine (30 mL), dried (MgS04), and evaporated under reduced pressure. The residue was purified by flash chromatography (Si02, hexane-EtOAc = 10:1) to give yellow crystals (3.30 g, 91%) as a mixture of two diastereomers (ratio: ~9:1), which was recrystallised from hexane to give pure major product [(SFe,SP,αS)-58] (2.83 g, 78%) as 20 yellow crystals. The mother liquor was concentrated, and the residue was WO 2005/068477 PCT/GB2005/000112 -80- recrystailized from MeOH to afford pure minor product [(SFe,RP,αS)-59] (217 mg, 6%) as yellow crystals. Major product [(SFe,Sp,αS)-58]: 1H NMR (COCI3, 250 MHz): 6 2.96 (s, 3H), 3.74 (m, 1H), 3.84 (s, 5H), 4.13 (t, 1H, J = 2.5 Hz), 4.20 (m, 1H), 6.04 (d, 1H, J = 7.3 Hz), 6.89-7.41 (m, 20H), 7.55 (ddd, 1H, J =* 5 8.0,6.8 and 1.3 Hz), 7.64 (dd. 1H, J - 6.8 and 1.5 Hz), 7.69 (ddd, 1H, J = 5.3, 3.5 and 1.7 Hz), 7.89 (t, 2H, J = 8.0 Hz), 9.32 (dd, 1H, J = 7.5 and 6.8 Hz). 31P NMR (CDCI3,101 MHz): 5 -18.83 (d, J = 21.3 Hz), -35.08 (d, J = 21.3 Hz). Minor product [(SFe,Rp,αS)-59]: 1H NMR (CDCI3, 250 MHz): 5 2.73 (s, 3H), 3.61 (m, 1H), 4.21 (t, 1H, J = 2.5 Hz), 4.22 (s, 5H), 4.28 (m, 1H), 5.86 (d, 1H, J = 7.3 10 Hz), 6.67 (ddd, 1H, J = 7.8,4.3 and 1.3 Hz), 6.79-7.61 (m, 23H), 7.75 (br. d, 1H, J = 8.0 Hz), 8.29 (m, 1H). 31P NMR (CDCI3,101 MHz): δ-18.52 (d, J = 18.4 Hz),-27.69 (d, J = 18.4 Hz). Example 53 15 (SFB, Rp)-2-[(2-Methoxyphenyl)phenylphosphino]ferrocenemethanol [(SFe, RP)-60]: -nun ^ -OH Fe pi-.„ . NaBH4 > THF-MeOH (Spe, Rp)-48 (Spe, Rp)-60 To a solution of aldehyde [(SFe, Rp)-48] (856 mg, 2.0 mmol) In THF (10 mL) was added NaBH4 (38 mg, 1.0 mmol) at 0 °C, then MeOH (2 mL) was added. After 20 stirring for 2 h at 0 °C, the mixture was warmed to room temperature and stirred overnight at room temperature. The reaction was quenched with saturated WO 2005/068477 PCT/GB2005/000112 -81- NH4CI solution (5 mL), and diluted with EtOAc (10 mL). The organic layer was separated, washed with brine (10 mL), dried (MgS04), and evaporated under reduced pressure to give the crude product (857 mg, 100%) as yellow crystals, which was used directly in next step. 1H NMR (CDCI3,250 MHz): 5 3.63 (m, 5 1H), 3.66 (s, 3H), 4.10 (s, 5H), 4.29 (t, 1H, J = 2.0 Hz), 4.41 (d, 1H, J = 12.5 Hz), 4.53 (m, 1H), 4.58 (dd, 1H, J = 12.5 and 2.0 Hz), 6.77-6.90 (m, 3H), 7.28 (m, 1H), 7.34-7.41 (m, 3H), 7.48-7.55 (m, 2H). 31P NMR (CDCI3,101 MHz): δ -35.05. 10 Example 54 (SFe, Rp)-2-[(1-Naphthyl)phenylphosphino] ferrocenemethanol [(SFe, RP)-61]: ##STR( <^T0H° OH ^-^^1-Np NaBH4 ^ ^-^^1-Np ^Z^> ^ * THF-MeOH ^C^> Ph' (SFft,RPM9 (SFo,Rp)-61 To a solution of aldehyde [(SFe, Rp)-49] (897 mg, 2.0 mmol) in THF (10 mL) was 15 added NaBH4 (38 mg, 1.0 mmol) at 0 °C, then MeOH (2 mL) was added. After stirring for 2 h at 0 °C, the mixture was warmed to room temperature and stirred overnight at room temperature. The reaction was quenched with saturated NH4CI solution (5 mL), and diluted with EtOAc (10 mL). The organic layer was separated, washed with brine (10 mL), dried (MgS04), and evaporated under 20 reduced pressure to give the crude product (900 mg, 100%) as yellow crystals, which was used directly in next step. 1H NMR (CDCI3,250 MHz): δ 3.71 (m, WO 2005/068477 PCT/GB2005/000112 -82- 1H), 4.16 (s, 5H), 4.36 (t, 1H, J = 2.5 Hz), 4.41 (d, 1H, J = 12.5 Hz), 4.54 (dd, 1H, J = 12.5 and 1.3 Hz), 4.58 (m, 1H), 7.11 (ddd, 1H, J = 7.0,4.5 and 1.3 Hz), 7.30-7.57 (m, 8H), 7.80 (m, 2H), 8.26 (m, 1H). 31P NMR (CDCI3,101 MHz): 6 - 31.14. 5 Example 55 (SFe, Rp)-2-[(2-Methoxyphenyl)phenylphosphino]ferrocenemethanol acetate [(SFe, RP)-62]: ,o-An . _ ... v~—-y ,o-An Fe ^' AP2O, pyridine w (SFe> R»,)-60 (SFe> Rp)-62 10 A solution of alcohol [(SFe, RP)-60] (857 mg, 2.0 mmol), AczO (2 mL) and pyridine (2 mL) in CH2CI2 (10 mL) was stirred overnight at room temperature. The volatile matters were removed under reduced pressure below 35 °C to give the crude product (880 mg, 100%) as yellow crystals, which was used directly in next step. 1H NMR (CDCI3, 250 MHz): δ 1.62 (s, 3H), 3.64(s, 4H, overlapped), 15 4.10 (s, 5H), 4.30 (t, 1H, J = 2.5 Hz), 4.54 (m, 1H), 5.01 (d, 1H, J = 12.0 Hz), 5.12 (dd, 1H, J = 12.0 and 2.3 Hz), 6.77 (m, 2H), 6.83 (t, 1H, J = 7.5 Hz), 7.25 (m, 1H), 7.37 (m, 3H), 7.51 (m, 2H). 31P NMR (CDCI3,101 MHz): δ -34.60. Example 56 20 (SFe, Rp)-2-[(1-Naphthyl)phenylphosphino]ferrocenemethanol acetate [(SFe, RP)-63]: WO 2005/068477 PCT/GB2005/000112 -83- 10 15 ##STR( ##STR( -OH ^zsr—0Ac ■^^1-Np AC20, pyridine >rS:;1;Np (SFe, RP)-61 (SFe, RP)-63 A solution of alcohol [(SFe, Rp)-61] (900 mg, 2.0 mmol), AC2O (2 mL) and pyridine (2 mL) in CH2Cl2 (10 mL) was stirred overnight at room temperature. The volatile matters were removed under reduced pressure below 35 °C to give the crude product (983 mg, 100%) as yellow crystals, which was used directly in next step. 1H NMR (CDCI3,250 MHz): δ1.46 (s, 3H), 3.74(m, 1H), 4.15 (s, 5H), 4.38(t, 1H, J = 2.5 Hz), 4.59 (m, 1H), 5.00 (d, 1.H, J 1.3.5 Hz), 7.28-7.45 (m, 5H), 7.54 (m, 1H), 7.69 (tt, 1H, J = 7.8 and 1.8 Hz), 7.78 (m, 2H), 8.23 (m, 1H), 8.64 (m, 2H). 3iP NMR (CDCI3,101 MHz): δ -30.85. Example 57 (SFe, Rp)-1 -[(Dicyclohexylphosphino)methyl]-2-[(2- methoxyphenyl)phenylphosphino]ferrocene [(SFe, Rp)-64]: Cy2PH \^( .o-An ► Fe »v%!. AcOH, rt ^Z3* Ph' (SFe, Rp)-64 A solution of (Spe, Rp)-62 (472 mg, 1.0 mmol) and dicyclohexylphosphine (243 uL, 1.2 mmol) in acetic acid (3 mL) was stirred for 7 days at room temperature, and poured into 10% K2C03 aqueous solution (60 mL) with stirring, extracted WO 2005/068477 PCT/GB2005/000112 -84- with Et20 (2x25 mL). The combined ether layers were dried (MgS04) and concentrated. The residue was purified by chromatography (Si02, hexane-EtOAc = 9:1) to afford the title compound (573 mg, 94%) as orange crystals. 1H NMR (CDCI3,250.13 MHz): 6 0.99-1.79 (m, 22 H), 2.56 (br. d, 1H, J = 12.5 5 Hz), 2.73 (br. d, 1H, J = 12.5 Hz), 3.58 (m, 1H), 4.00 (s, 5H), 4.20 (m, 1H), 4.57 (m, 1H); 4.32 (m, 1H), 6.74-7.58 (m, 9 H); 31P NMR (CDCI3,101.25 MHz): 5 -2.93;-35.19. Example 58 10 (SFe, RP)-1-[(Dlcyclohexylphosphino)methyl]-2-[(1-naphthyl)phenylphosphino]ferrocene [(SFe, RP)-65]: Ph'* AcOH, rt 4C2^ (Sfei Rp)-65 A solution of (SFe, Rp)-63 (492 mg, 1.0 mmol) and dicyclohexylphosphine (243 uL, 1,2 mmol) in acetic acid (3 mL) was stirred for 7 days at room temperature, 15 and poured into 10% K2CO3 aqueous solution (60 mL) with stirring, extracted with Et20 (2x25 mL). The combined ether layers were dried (MgS04) and concentrated. The residue was purified by chromatography (Si02, hexane-EtOAc = 9:1) to afford the title compound (599 mg, 95%) as orange crystals. 1H NMR (CDCI3,250.13 MHz): 6 0.83~1.76(m, 22 H), 2.57 (dm, 1H, J = 12.5 Hz), 20 2.70 (dm, 1H, J = 12.5 Hz), 3.67 (m, 1H), 4.06 (s, 5H), 4.27 (t, 1H, J = 2.5 Hz), WO 2005/068477 PCT/GB2005/000112 -85- 4.60 (m, 1H); 7.12 (m, 1H), 7.31-7.82 (m, 10 H);8.28 (m, 1H). 31P NMR (CDCi3, 101.25 MHz): δ-2.19;-31.85. Example 59 5 (So SFe, Rp)-67: ^^ 3)1-NpLi ^j* (S>66 (Sc, SFe, Rp)-67 To a solution of (S)-66 (1.56 g, 5 mmol) and TMEDA (1.0 mL, 6.5 mmol) in Ef2O (50 mL) was added 2.5 M n-BuLi (2.6 mL, 6.5 mmol) at -78 °C, After stirring for 3 h at -78 °C, PhPCl2 (0.95 mL, 7.0 mmol) was added, After stirring for 20 min 10 at -78 °C, the mixture was warmed to room temperature and stirred for 1.5 h at room temperature. The mixture was cooled to -78 °C again, and a suspension of 1-NpLi [prepared from 1-bromonaphthalene (1.39 mL, 10 mmol) and 1.7 M t-BuLi (11.8 mL, 20 mmol) in Et20 (40 mL) at -78 °C] was added via a cannula. The mixture was stirred and warmed to room temperature overnight. The 15 reaction was quenched by water (40 mL). The organic layer was separated, washwd with brine (40 mL), dried (MgS04), and concentrated. The residue was purified by chromatography (SiO2, EtOAc-hexane = 1:5-1:3) to give the product (2.25 g, 85%) as an orange crystals. 1H NMR and 31P NMR analysis show the de is about 9:1. Major product: 1H NMR (CDCI3,400.13 MHz): δ 0.58 (d, 3H, J = 20 6.7 Hz); 0.73 (d, 3H, J = 6.7 Hz); 1.58 (m, 1H), 3.45 3.52 (m, 2H), 3.61 (m, WO 2005/068477 PCT/GB2005/000112 -86- 1H), 3.78 (m, 1H), 4.2g (s, 5H); 4.44 (t, 1H, J'2.6 Hz); 5.05 (m, 1H); 7.08(dd, 1H, J = 7.0 and 4.4 Hz); 7.24 - 7.48 (m, 8H); 7.74 (d, 1H, J = 8.0 Hz); 7.80 (d, 1H, J = 8.0 Hz); 8.37 (dd, 1H, J = 8.3 and 4.3 Hz). 31P NMR (CDCI3,162 MHz): δ-23.52 (s). Asymmetric Hydrogenation-General Procedure: 10 Bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate [Rh(COD)2TfO] (2.3 mg, 5 umol) and the desired ligand (6 umol)) were placed in a vessel which was purged with argon. The desired solvent was degassed with Ar for 15 minutes, then 5.0 mL was added to the reaction vessel via syringe. This solution was stirred at 25 °C. under argon for 15 minutes. The desired substrate (1.0 mmol) 15 was then added to the catalyst solution. The solution was then purged five times with argon and pressurized with hydrogen to the desired pressure and stirred at room temperature. The reactions were run for the desired time at the desired pressure, and then depressurized. Samples were taken and analyzed for enantiomeric excess using standard analytical techniques. 20 Example 60 N-Acetyl L-alanine methyl ester via Hydrogenation in THF: WO 2005/068477 PCT/GB2005/000112 87 NHAc S/SSS^L. ^HAC ^C02Me —',—7ZTZ7Z ' "C02Me * solvent, rt, 2.5 h Methy 2-acetamidoacrylate (143 mg, 1.0 mmol) was hydrogenated according to General Procedure under 50psi of hydrogen in THF using bis(1,5-cyclooctadiene)rhodium trifiuoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (Re, SFe, SP)-23 (3.8 mg; 6 umol; 0.012 equiv) for 2.5 hour to afford 18.6% conversion to amino acid derivative with 88.6% ee as determined by chiral GC analysis. 10 Example 61 N-Acetyl L-alanine methyl ester via Hydrogenation in THF: ^COzMe —, ^ rf ' "^C02Me solvent, rt, 2.5 h Methy 2-acetamidoacrylate (143 mg, 1.0 mmol) was hydrogenated according to 15 General Procedure under 50psi of hydrogen in THF using bis(1,5- cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (Re, SFe, SP)-24 (4.0 mg; 6 umol; 0.012 equiv) for 2.5 hour to afford 100% conversion to amino acid derivative with 98.3% ee as determined by chiral GC analysis. 20 WO 2005/068477 PCT/GB2005/000112 -88- Example 62 N-Acetyl L-alanine methyl ester via Hydrogenation in THF: NHAr Hz (5° ^ NHAC NHAc Rh(COD)2OTf/L* V™* ^C02Me —;—t _, » ^N)02Me 2 solvent rt, 2.5 h Methy 2-acetamidoacryiate (143 mg, 1.0 mmol) was hydrogenated according to General Procedure under 50psi of hydrogen in THF using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (Re, SFe, RP)-25 (4.0 mg; 6 umol; 0.012 equiv) for 2.5 hour to afford 100% conversion to amino acid derivative with 92.3% ee as determined by chiral GC analysis. 10 Example 63 N-Acetyl L-alanine methyl ester via Hydrogenation in MeOH: 15 Methy 2-acetamidoacryiate (143 mg, 1.0 mmol) was hydrogenated according to General Procedure under 50psi of hydrogen in MeOH using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (Re, SFe, SP)-24 (4.0 mg; 6 mumol; 0.012 equiv) for 2.5 hour to afford 100% conversion to amino acid derivative with >99% ee as determined by chiral 20 GC analysis. WO 2005/068477 PCT/GB2005/000112 -89- Example 64 N-Acetyl L-alanine methyl ester via Hydrogenation in THF wit (Re, SFe)-BoaPhoz: MUA„ H2 <50 Psl> NHAc ^HAc Rh(COD)2OTf/L* ?HAc ^C02Me ————TT "^C02Me * solvent, rt, 2.5 h 5 Methy 2-acetamidoacrylate (143 mg, 1.0 mmol) was hydrogenated according to General Procedure under 50psi of hydrogen in THF using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (Rc, SFe)-BoaPhoz (3.7 mg; 6 umol; 0.012 equiv) for 2.5 hour to afford 99% conversion to amino acid derivative with 94.5% ee as determined by 10 chiral GC analysis. Example 65 N-Acetyl L-phenylalanine methyl ester via Hydrogenation in THF: NHAc H2 (100 psi) NHAc ^^ 1^T~ ^^ 15 Methy 2-acetamidocinnamate (219 mg, 1.0 mmol) was hydrogenated according to General Procedure under 100 psi of hydrogen in THF using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (Rc, SFe SP)-23 (3.8 mg; 6 umol; 0.012 equiv) for 2 hour to afford 20 100% conversion to amino acid derivative with 88.0% ee as determined by chiral GC analysis. WO 2005/068477 PCT/GB2005/000112 90 Example 66 N-Acetyl L-phenylalanine methyl ester via Hydrogenation in THF: NHAc H2 (100 psi) NHAc Ph JL RhtCODkOTf/L* ph 7 Methy 2-acetamidocinnamate (219 mg, 1.0 mmoi) was hydrogenated according to General Procedure under 100 psi of hydrogen in THF using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (Rc, SFe, SP)-24 (4.0 mg; 6 mumol; 0.012 equiv) for 2 hour to afford 10 100% conversion to amino acid derivative with 97.0% ee as determined by chiral GC analysis. Example 67 N-Acetyl L-phenylalanine methyl ester via Hydrogenation in 15 THF: NHAc H2 (100ps!) NHAc Methy 2-acetamidocinnamate (219 mg, 1.0 mmoi) was hydrogenated according to General Procedure under 100 psi of hydrogen in THF using bis(1,5- 20 cyc!ooctadiene)rhodium tiifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (Rc, SFe, Rp)-25 (4.0 mg; 6 mumol; 0.012 equiv) for 2 hour to afford WO 2005/068477 PCT/GB2005/000112 -91- 100% conversion to amino acid derivative with 92.4% ee as determined by chiral GC analysis. Example 68 N-Acetyl L-phenylalanine methyl methyl ester via Hydrogenation in THF with (Rc, SFe)-BoaPhoz: NHAc H2(100psi) NHAe "-^ «P "-W 10 Methy 2-acetamidocinnamate (219 mg, 1.0 mmol) was hydrogenated according to General Procedure under 100 psi of hydrogen in THF using bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (2.3 mg; 5 umol; 0.01 equiv) and ligand (Rc, SFe)-BoaPhoz (3.7 mg; 6 umol; 0.012 equiv) for 2 hour to afford 15 100% conversion to amino acid derivative with 95.7% ee as determined by chiral GC analysis. WO 2005/068477 PCT/GB2005/000112 -92- References 1. T. Hayashl, in Ferrocenes, (Eds.: A. Togni, T. Hayashi), VCH, Weinheim, 1995, p. 105. 2. 2. Togni, A.; Breutel, C; Schnyder, A.; Spindler, F.; Landert, H.; Tijani, 5 A. J. Am. Chem. Soc. 1994,116,4062. 3. 3. a. H. U. Blaser.W. Brieden, B. Pugin, F. Spindler, M. Studer, A. Togni, Topics in Catalysis 2002,19,3; b. H. U. Blaser, F.Spindler, M. Studer, Applied Catal. A: General 2001, 221,119. 4. 4. McGarrity, J.; Spindler, F.; Fuchs, R.; Eyer, M. (LONZA AG), EP-A 10 624587 A2,1995; Chem. Abstr. 1995,122, P81369q. 5. 5. a. Blaser, H.-U. Adv. Synth. Catal. 2002, 344,17. b. Blaser, H.-U.; Buser, H.-P.; Coers, K.; Hanreich, R.; Jalett, H.-P.; Jelsch, E.; Pugin, B.; Schneider, H.-D.; Spindler, F.; Wegmann, A. Chimia 1999, 53,275. 6. 6. a. N. W. Boaz, S. D. Debenham, E. B. Mackenzie, S. E. Large, Org. 15 Lett. 2002,4,2421. b. Boaz, N. W.; Debenham, S. D. US 2002/0065417 (2002) 7. a) T. Ireland, G. Grossheimann, C. Wieser-Jeunesse, P. Knochel, Angew. Chem. Int. Ed. 1999,38,3212. b) T. Ireland, K. Tappe, G. Grossheimann, P. Knochel, Chem. Eur. J. 2002,8,843; 20 8. a)M. Lotz, K. Polborn, P. Knochel, Angew. Chem. Int. Ed. 2002,41, 4708. b) K. Tappe; P. Knochel, Tetrahedron: Asymmetry 2004,15,12; c) M. Lotz, P. Knochel, A. Monsees, T. Riermeier, R. Kadyrov, J. J. Almena Perea, Ger. Pat. No. DE 10219490 (Degussa AG). WO 2005/068477 PCT/GB2005/000112 -93- 9. a) T. Sturm, L. Xiao, W. Welssensteiner, Chimia 2001,55,688; b) W. Welssensteiner, T. Sturm, F. Spindler, Adv. Synth. Catal. 2003,345,160; c) Welssenstelner, T. Sturm, F. Spindler, US2003212284. 10. a. Perea, A. J. J.; Borner, A.; Knochel, P. Tetrahedron Lett 1998,39, 5 8073. b. Perea, A. J. J.; Lotz, M.; Knochel, P. Tetrahedron: Asymmetry 1999,10,375. cLotz, M.; Ireland, T.; Perea, A. J. J.; Knochel, P. Tetrahedron: Asymmetry 1999,10,1839. d. Knochel, P.; Perea, A. J. J.; Drauz, K.; Klement, I. US 6,284,925 (2001). 11. (a) Sawamura, M.; Hamashima, H.; Sugawara, M.; Kuwano, N.; Ito, Y. 10 Organometallics 1995,14,4549. (b) Sawamura, M.;Kuwano, R.; Ito, Y. J. Am. Chem. Soc. 1995,117,9602. (c) Kuwano, R.; Sawamura, M.; Ito, Y. Tetrahedron: Asymmetry 1995,6,2521. (d) Kuwano, R.; Okuda, S.; Ito, Y. Tetrahedron: Asymmetry 1998,9,2773. (e) Kuwano, R.; Okuda, S.; Ito, Y. J. Org. Chem. 1998,63,3499. (f) Kuwano, R.; Ito, Y. J. Org. Chem. 1999,64, 15 1232. (g) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000,122, 7614. 12. a) Kang, J.; Lee, J. H.; Ahn, S. H.; Choi, J. S. Tetrahedron Lett. 1998, 39,5523. b) Kang, J.; Lee, J. H.; Kim, J. B.; Kim, G. J. ChiraJlty 2000,12, 378. 20 13. a) Jendralla, H.; Paulus, E. Synlett, 1997,471. b) Jendralla, J. H. US 5,856,540(1999) WO 2005/068477 PCT/GB2005/000112 -94- 14. a) Argouarch, G.; Samuel, O.; Kagan, H. B. Eur. J. Org. Chem. 2000, 2891. b) Argouarch, G.; Samuel, O.; Riant, O.; Daran, J.-C; Kagan, H. B. Eur. J. Org. Chem. 2000,2893. 15. Marinettl, A.; Labrue, F.; Genet, J.-P. Synlett 1999,1975. 5 16. Berens, U.; Burk, M. J.; Gerlach, A.; Hems, W. Angew. Chem., Int. Ed. Engl. 2000, 39,1981. 17. You, J.; Drexler, H.-J.; Zhang, S.; Fischer, C; Heller, D. Angew. Chem., Int. Ed. Engl. 2003,42,913. 18. Maienza, F.; Wo'rie, M.; Steffanut, P.; Mezzetti, A. Organometaliics 10 1999,18,1041. 19. (a) Nettekoven, U.; Widhalm, M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M. Tetrahedron: Asymmetry 1997,8,3185. (b) Nettekoven, U.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Widhalm, M.; Spek, A. L; Lutz, M. J. Org. Chem. 1999,64, 3996. 15 20. Liu, D.; Li, W.; Zhang, X. Org. Lett. 2002,4,4471. 21. Xiao, D.; Zhang, X. Angew. Chem., Int. Ed. Engl. 2001,40,3425. 22. a) M. T. Reetz, A. Gosberg, R. Goddard, S.-H. Kyung, Chem. Commun. 1998,2077; b) M. T. Reetz, A. Gosberg, WO 0014096,1998 (assigned to Studiengesellschaft Kohle MBH); 20 23. a. Nettekoven, U.; Widhalm, M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Mereiter, K.; Lutz, M.; Spek, A. L. Organometaliics 2000,19,2299. b. Nettekoven, U.; Kamer, P. C. J.; Widhalm, M.; van Leeuwen, P. W. N. M. Organometaliics 2000,19,4596. c. Nettekoven, U.; Widhalm, M.; WO 2005/068477 PCT/GB2005/000112 -95- Kalchhauser, H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Lutz, M.; Spek, A. L. J. Org. Chem. 2001,66, 759-770. 24. Barbaro, P.; Bianchini, C; Giambastiani, G.; Togni, A. Chem. Commun. 2002,2672. 5 25. (a) Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I. J. Am. Chem. Soc. 1970,92,5389. (b) Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I. Angew. Chem. Int. Ed. Engl. 1970, 9,371. (c) Hayashi, T.; Yamamoto, K.; Kumada, M. Tetrahedron Lett. 1974,15,405. (d) Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani, M.; Nagashima, N.; 10 Hamada, Y.; Matsumoto, A.; Kawakami, S.; Konishi, M. M.; Yamamoto, K.; Kumada, M. Bull. Chem. Chem. Soc. Jpn. 1980,53,1138 26. Riant, O.; Argouarch, G.; Guillaneux, D.; Samuel, O.; Kagan, H. B. J. Org. Chem. 1998, 63,3511. 27. (a) Riant, O.; Samuel, O.; Flessner, T.; Taudien, S.; Kagan, H. B. J. 15 Org. Chem. 1997,62,6733. (b) Riant, O.; Samuel, O.; Kagan.H. B. J. Am. Chem. Soc. 1993,115, 5835. 28. (a) Richards, J.; Damalidis, T.; Hibbs D. E.; Hursthouse, M. B. Synlett 1995, 74. (b) Sammakai, T.; Latham H. A.; Schaad, D. R. J. Org. Chem. 1995,60,10. (c) Nishibayashi, Y.; Uemura, S. Synlett 1995, 79. (d) 20 Sammakai, T.; Latham, H. A. J. Org. Chem. 1995, 60, 6002. 29. Ganter, C; Wagner, T. Chem. Ber. 1995,128,1157. WO 2005/068477 PCT/GB2005/000112 -96- 30. (a) Enders, D.; Peters, R.; Lochtman, R.; Runsink, J. Synlett 1997, 1462. (b) Enders, D.; Peters, R.; Lochtman, R.; Runsink, J. Eur. J. Org. Chem. 2000, 2839. 31. Lotz, M.; Ireland T.; Tappe, K.; Knochel, P. Chirallty, 2000,12,389. 5 32. Kitzler, R.; Xiao, L; Weissensteiner, W. Tetrahedron: Asymmetry 2000, 11,3459. 33. Widhalm, M.; Mereiter, K.; Bourghida, M. Tetrahedron: Asymmetry 1998,9,2983. 34. Nishibayashi, Y.; Arikawa, Y.; Ohe, K.; Uemura, S. J. Org. Chem. 1996, 10 61,1172. 35. (a) Tsukazaki, M.; Tinkl, M.; Roglans, A.; Chapell, B. J.; Taylor, N. J.; Snieckus, V. J. Am. Chem. Soc. 1996,118,685. (b) Jendralla, H.; Paulus, E. Synlett 1997,471. 36. Price, D.; Simpkins, N. S. Tetrahedron Lett. 1995,36,6135. WO 2005/068477 PCT/GB2005/000112 -97-CLAIMS 1. A metallocene-based phosphine or arsine ligand chiral at phosphorus or arsenic having the Formula (I), (II) or (III): R3, R4m-^=^ R2 M ^R (I) wherein W is phosphorus or arsenic; M is a metal; R1 and R2 are different from each other, and are independently 10 selected from substituted and unsubstituted, branched-and straight-chain alkyl, alkoxy, alkylamino, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkoxy, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocyclic aryloxy, 15 substituted and unsubstituted heteroaryl, substituted and unsubstituted heteroaryloxy, substituted and unsubstituted carbocyclic arylamino and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; WO 2005/068477 PCT/GB2005/000112 -98- R3 and R4 are the same or different, and are independently selected from substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted 5 heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; n is 0 to 3; m is 0 to 5; Q is selected from: R8 y^^WR6R7 10 ^ wherein W is phosphorus or arsenic; R6 and R7 are the same or different, and are independently selected from substituted and unsubstituted, branched- and straight-chain alkyl, alkoxy, alkylamino, substituted and unsubstituted cycloalkyl, 15 substituted and unsubstituted cycloalkoxy, substituted and unsubstituted cycloalkylamino, substituted and unsubstituted carbocyclic aryl, substituted and unsubstituted carbocyclic aryloxy, substituted and unsubstituted heteroaryl, substituted and unsubstituted heteroaryloxy, substituted and unsubstituted 20 carbocyclic arylamino and substituted and unsubstituted heteroarylamino, wherein the or each heteroatom is independently WO 2005/068477 PCT/GB2005/000112 -99- selected from sulphur, nitrogen, and oxygen; and R8 is selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; or Q is selected from: R8 / R9 \ 67 WR°R' wherein W is phosphorus or arsenic; 10 R6, R7 and R8 are, independently, as previously defined; and R9 is selected from hydrogen, substituted and unsubstituted, branched-and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is 15 independently selected from sulphur, nitrogen, and oxygen; or Q is selected from: R _a ,R9 10 >—1a ^U wherein R6, R7, R8 and R9are, independently, as previously defined; and R10 is selected from hydrogen, substituted and unsubstituted, WO 2005/068477 PCT/GB2005/000112 -100- branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and 5 oxygen; or Q is selected from: V fcicr wherein R6, R7, R8 and R9are, independently, as previously defined; and R10" is selected from hydrogen, substituted and unsubstituted, 10 branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; or 15 Q is selected from: WR6R7 wherein W is phosphorus or arsenic; R6, R7 are, as previously defined; R11 is selected from OR13, SR13, NHR13, NR13R14, wherein R13 and R14 are the same or different and 20 are independently selected from hydrogen, substituted and WO 2005/068477 PCT/GB200S/000112 -101- unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and 5 oxygen; R12 is selected from hydrogen, halogen, OR13, SR13, NR13R14, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected 10 from sulphur, nitrogen, and oxygen; wherein R13, R14 are, as previously defined and n' is 0 to 4; or Q is selected from: R8 wherein R8 and R9are as previously defined; 15 R5 is selected from: R1*R16 Y^R17 wherein R15, R16 and R17 are the same or different and are independently selected from hydrogen, OR13, SR13, NR13R14, substituted and unsubstituted, branched- and straight-chain alkyl, 20 substituted and unsubstituted cycloalkyl, substituted and WO 2005/068477 PCT/GB2005/000112 -102- unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; wherein R13, R14 are, as previously defined; or 5 R5 is selected from: R18R18 V^NR^R14 wherein R13, R14 are as previously defined; the two geminal substituents R18 together are a doubly bonded oxygen atom (i.e. (R18)2 is =O), or each substituent R18 on its own is hydrogen; and 10 G is selected from the group consisting of: -CONH-R*-NHCO-, -CO-OR*O-CO-, -CO-R*CO-, -CH=N-R*-N=CH-, -CH2NH-R*-NHCH2-, -CH2NHCO-R*-CONHCH2-, -CH(R8)NH-R*-NH(CH(R8)-, -CH(R8)NHCO-R*-CONHCH(R8)-, -CONH-R-NHCO-, -CO-ORO-CO-, -CO-RCO-, -CH=N-R-N=CH-, -CH2NH-R-NHCH2-, - 15 CH2NHCO-R-CONHCH2, -CH(R8)NH-R-NH(CH(R8)-, -CH(R8)NHCO- R-CONHCH(R8)-; wherein R8 is, independently, as previously defined; -R*- and -R- are selected from the group consisting of: "tx ::x wherein R12 is as previously defined; R19 is selected from hydrogen, 20 substituted and unsubstituted, branched- and straight-chain alkyl, WO 2005/068477 PCT/GB2005/000112 10 -103- substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen; or (R19)2 is -(CH2)m-, n' is 0 to 4; and m' is 1 to 8; 2. Enantiomers of the ligands according to claim 1 having the Formulae (IV), (V) and (VI): M Rn ^>****^^ R5 (IV) (V) , R2,"W'R1 R» T . wherein each of W, M, R1-19, Q, G, n, m, n' and m' have the same meanings as assigned in claim 1, with chirality changes in the substituent groups where required. 15 3. Diastereomers of the ligands according to claim 1 having the Formulae (VII), (VIII) and (IX): WO 2005/068477 PCT/GB2005/000112 (VIII) wherein each of W, M, R1-19, Q, G, n, m, n' and m' have the same meanings as assigned in claim 1, with chirality changes in the 5 substituent groups where required. 4. A metallocene-based phosphine according to any one of claims 1 to 3 having chirality at phosphorus (or arsenic) and at least one other element of chirality (planar chirality and/or chirality at 10 carbon and/or axial chirality). 5. A metallocene-based diphosphine or diarsine ligand according to any one of claims 1 to 4 having three elements of chirality, namely planar chirality, chirality at phosphorus (or arsenic), and chirality at 15 carbon. 6. A metallocene-based diphosphine or diarsine ligand according to any one of claims 1 to 4 having four elements of chirality, namely WO 2005/068477 PCT/GB2005/000112 -105- planar chirality, chirality at phosphorus (or arsenic), chirality at carbon and axial chirality. 7. A ligand according to any one of claims 1 to 6 wherein the 5 metallocene is ferrocene. 8. A ligand according to any one of claims 1 to 7 wherein W is phosphorus. 10 10. Use of the ligand of any one of claims 1 to 8 as a catalyst or catalyst precursor in asymmetric transformation reactions to generate high enantiomeric excesses of formed compounds. 11. A transition metal complex containing a transition metal 15 coordinated to a ligand according to any one of claims 1 to 8. 12. A transition metal catalyst according to claim 11 wherein the transition metal is a Group VIb or a Group VIII metal. 20 13. A method for preparing a ligand according to any one of claims 1 to 8 comprising providing a metallocene-based substrate having a chiral directing substituent on one or both rings, and subjecting the substituted metallocene to ortho-lithiation followed by converting the WO 2005/068477 PCT/GB2005/000112 -106- ortho-lithiated substituted metallocene to a phosphine chiral at phosphorus (or to an arsine chiral at arsenic). 14. A method according to claim 13 for preparing the ligand of 5 Formula (I) or (III) comprising providing a compound of the formula (X) (optionally substituted on one or both cyclopentadiene rings with R3n (top ring) and/or R4m (bottom ring)): (X) wherein X* is a chiral directing group; 10 ortho-lithiating the substrate; reacting the ortholithiated substrate with an R1 substituted phosphine or arsine, and with an R2-bearing Grignard reagent or organolithium compound, and converting X* to Q or G as desired. 15 15. A method according to claim 14 wherein X* is selected from the group consisting of: WO 2005/068477 PCT/GB2005/000112 107 Y^N** y^R. tfX J&* >rT> OMe f ^ R8 R* .Me . ' "" ..Jt OMe wherein Ra and Rb are same or different, and are independently selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected from sulphur, nitrogen, and oxygen. 16. A method according to claim 14 or claim 15 wherein the ortho-lithiation step is conducted using n-butyllithium, sec-butyllithium and/or tert- butyllithium. 17. A method according to claim 16 wherein the resulting monolithium compound is reacted in situ with a dichlorophosphine of the formula R1PCl2 wherein R1 is as defined in claim 1 to yield an intermediate product. WO 2005/068477 PCT/GB2005/000112 -108- 18. A method according to claim 17 comprising reacting the intermediate product with an organometal reagent of the formula R2Z, wherein R2 is as defined in claim 1; Z is Li or MgY wherein Y is a halide, to obtain phosphorus chiral compound having formula (XI): 5 (XI) 19. A method according to claim 18 comprising converting compound XI to compound (I) or (III). 20. A method for preparing the ligand of Formula (I) or (III) 10 comprising providing a compound of the formula XXXVII: Fe ^> (XXXVII) wherein X Is an achiral directing group and subjecting the compound to enantioselective mono-ortho-lithiation using n-butyllithium or sec- butyllithium or tert- butyllithium in the presence of a homochiral 15 tertiary amine, and reacting the resulting chiral monolithium compound in situ with a dichlorophosphine of the formula R1PCl2 followed by reacting with an organometallic reagent of the formula R2Z, wherein R1 and R2 are as defined in claim 1; Z is Li or MgY WO 2005/068477 PCT/GB2005/000112 -109- wherein Y is a halide, to obtain a phosphorus chiral compound having fonnula XXXVIII: (XXXVIH) and converting compound XXXVIH to compound (I) or(lll). 21. A method according to claim 20 wherein X is selected from: o V^NRaRbf-S02Ra yANRaRb |_P(0)RaRb wherein 10 Ra and Rb are same or different, and are independently selected from hydrogen, substituted and unsubstituted, branched- and straight-chain alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted carbocyclic aryl, and substituted and unsubstituted heteroaryl wherein the or each heteroatom is independently selected 15 from sulphur, nitrogen, and oxygen; 22. A method for preparing the ligand of Formula (II) comprising providing a compound of the Formula XXXIX: WO 2005/068477 PCT/GB2005/000112 -110- Fe 4^-x* (XXXIX) wherein X* is as previously defined; and subjecting the compound to bis-ortho-lithiation using n-butyllithium, sec-butyllithium or tert-butyllithium, and reacting the resulting bislithium compound in situ with a dichlorophosphine of the formula R1PCI2 followed by reacting with an organometallic reagent of the formula R2Z wherein R1 and R2 are as defined in claim 1; Z is Li or MgY wherein Y is a halide, to obtain a phosphorus chiral compound having formula XXXX: ,x* _ — P-HR1 Fe R2 (XXXX) 10 and converting compound XXXX to compound II. Dated this 14th day of July 2006 Dr. Gopakumar G. Nair Agent for the Applicant Abstract: The present invention relates to metallocene-based phosphine ligands having chirality at phosphorus and at least one other element of chirality (planar chirality and/or chirality at carbon); and to the use of such ligands in asymmetric transformation reactions to generate high enantiomeric excesses of formed compounds. A method for the preparation of ligands according to the invention involving the conversion of the ortho-lithiated substituted metallocene to a phosphine chiral at phosphorus is also disclosed.

Documents

Application Documents

#	Name	Date
1	835-mumnp-2006-abstract(complete)-(14-7-2006).pdf	2018-08-09
1	835-MUMNP-2006-FORM 3(15-10-2008).pdf	2008-10-15
2	835-mumnp-2006-abstract(granted)-(16-7-2010).pdf	2018-08-09
2	835-MUMNP-2006-FORM 2(TITLE PAGE)-(15-10-2008).pdf	2008-10-15
3	835-mumnp-2006-form 2(15-10-2008).pdf	2008-10-15
3	835-mumnp-2006-abstract.doc	2018-08-09
4	835-MUMNP-2006-DESCRIPTION(COMPLETE)-(15-10-2008).pdf	2008-10-15
4	835-mumnp-2006-abstract.pdf	2018-08-09
5	835-MUMNP-2006-CORRESPONDENCE(15-10-2008).pdf	2008-10-15
5	835-mumnp-2006-assignment(24-9-2009).pdf	2018-08-09
6	835-mumnp-2006-claims(amended)-(15-10-2008).pdf	2008-10-15
6	835-mumnp-2006-cancelled pages(27-4-2009).pdf	2018-08-09
7	835-mumnp-2006-claims(amended)-(27-4-2009).pdf	2018-08-09
7	835-MUMNP-2006-CLAIMS(15-10-2008).pdf	2008-10-15
8	835-mumnp-2006-claims(complete)-(14-7-2006).pdf	2018-08-09
8	835-MUMNP-2006-ABSTRACT(15-10-2008).pdf	2008-10-15
9	835-mumnp-2006-claims(granted)-(16-7-2010).pdf	2018-08-09
9	835-MUMNP-2006-CORRESPONDENCE(27-04-2009).pdf	2009-04-27
10	835-MUMNP-2006-CLAIMS(27-04-2009).pdf	2009-04-27
11	835-mumnp-2006-correspondance-others.pdf	2018-08-09
11	abstract1.jpg	2018-08-09
12	835-mumnp-2006-correspondance-received.pdf	2018-08-09
12	835-MUMNP-2006_EXAMREPORT.pdf	2018-08-09
13	835-mumnp-2006-correspondence(18-4-2007).pdf	2018-08-09
13	835-mumnp-2006-form-pct-ro-101.pdf	2018-08-09
14	835-mumnp-2006-correspondence(24-9-2009).pdf	2018-08-09
14	835-mumnp-2006-form-pct-isa-237.pdf	2018-08-09
15	835-mumnp-2006-correspondence(ipo)-(4-8-2010).pdf	2018-08-09
15	835-mumnp-2006-form-pct-isa-210.pdf	2018-08-09
16	835-mumnp-2006-description (complete).pdf	2018-08-09
16	835-mumnp-2006-form-5.pdf	2018-08-09
17	835-mumnp-2006-form-3.pdf	2018-08-09
17	835-mumnp-2006-description(complete)-(14-7-2006).pdf	2018-08-09
18	835-mumnp-2006-form-2.pdf	2018-08-09
18	835-mumnp-2006-description(granted)-(16-7-2010).pdf	2018-08-09
19	835-mumnp-2006-form 1(15-1-2007).pdf	2018-08-09
20	835-MUMNP-2006-FORM 1(9-3-2007).pdf	2018-08-09
20	835-mumnp-2006-form-1.pdf	2018-08-09
21	835-mumnp-2006-form 18(18-4-2007).pdf	2018-08-09
21	835-mumnp-2006-form 6(24-9-2009).pdf	2018-08-09
22	835-mumnp-2006-form 2(complete)-(14-7-2006).pdf	2018-08-09
22	835-mumnp-2006-form 5(9-3-2007).pdf	2018-08-09
23	835-mumnp-2006-form 2(granted)-(16-7-2010).pdf	2018-08-09
23	835-MUMNP-2006-FORM 5(14-7-2006).pdf	2018-08-09
24	835-mumnp-2006-form 2(title page)-(complete)-(14-7-2006).pdf	2018-08-09
24	835-MUMNP-2006-FORM 26(27-6-2005).pdf	2018-08-09
25	835-mumnp-2006-form 2(title page)-(granted)-(16-7-2010).pdf	2018-08-09
26	835-mumnp-2006-form 2(title page)-(complete)-(14-7-2006).pdf	2018-08-09
26	835-MUMNP-2006-FORM 26(27-6-2005).pdf	2018-08-09
27	835-mumnp-2006-form 2(granted)-(16-7-2010).pdf	2018-08-09
27	835-MUMNP-2006-FORM 5(14-7-2006).pdf	2018-08-09
28	835-mumnp-2006-form 2(complete)-(14-7-2006).pdf	2018-08-09
28	835-mumnp-2006-form 5(9-3-2007).pdf	2018-08-09
29	835-mumnp-2006-form 18(18-4-2007).pdf	2018-08-09
29	835-mumnp-2006-form 6(24-9-2009).pdf	2018-08-09
30	835-MUMNP-2006-FORM 1(9-3-2007).pdf	2018-08-09
30	835-mumnp-2006-form-1.pdf	2018-08-09
31	835-mumnp-2006-form 1(15-1-2007).pdf	2018-08-09
32	835-mumnp-2006-description(granted)-(16-7-2010).pdf	2018-08-09
32	835-mumnp-2006-form-2.pdf	2018-08-09
33	835-mumnp-2006-description(complete)-(14-7-2006).pdf	2018-08-09
33	835-mumnp-2006-form-3.pdf	2018-08-09
34	835-mumnp-2006-description (complete).pdf	2018-08-09
34	835-mumnp-2006-form-5.pdf	2018-08-09
35	835-mumnp-2006-correspondence(ipo)-(4-8-2010).pdf	2018-08-09
35	835-mumnp-2006-form-pct-isa-210.pdf	2018-08-09
36	835-mumnp-2006-form-pct-isa-237.pdf	2018-08-09
36	835-mumnp-2006-correspondence(24-9-2009).pdf	2018-08-09
37	835-mumnp-2006-form-pct-ro-101.pdf	2018-08-09
37	835-mumnp-2006-correspondence(18-4-2007).pdf	2018-08-09
38	835-mumnp-2006-correspondance-received.pdf	2018-08-09
38	835-MUMNP-2006_EXAMREPORT.pdf	2018-08-09
39	835-mumnp-2006-correspondance-others.pdf	2018-08-09
39	abstract1.jpg	2018-08-09
40	835-MUMNP-2006-CLAIMS(27-04-2009).pdf	2009-04-27
41	835-mumnp-2006-claims(granted)-(16-7-2010).pdf	2018-08-09
41	835-MUMNP-2006-CORRESPONDENCE(27-04-2009).pdf	2009-04-27
42	835-MUMNP-2006-ABSTRACT(15-10-2008).pdf	2008-10-15
42	835-mumnp-2006-claims(complete)-(14-7-2006).pdf	2018-08-09
43	835-mumnp-2006-claims(amended)-(27-4-2009).pdf	2018-08-09
43	835-MUMNP-2006-CLAIMS(15-10-2008).pdf	2008-10-15
44	835-mumnp-2006-claims(amended)-(15-10-2008).pdf	2008-10-15
44	835-mumnp-2006-cancelled pages(27-4-2009).pdf	2018-08-09
45	835-MUMNP-2006-CORRESPONDENCE(15-10-2008).pdf	2008-10-15
45	835-mumnp-2006-assignment(24-9-2009).pdf	2018-08-09
46	835-MUMNP-2006-DESCRIPTION(COMPLETE)-(15-10-2008).pdf	2008-10-15
46	835-mumnp-2006-abstract.pdf	2018-08-09
47	835-mumnp-2006-form 2(15-10-2008).pdf	2008-10-15
48	835-mumnp-2006-abstract(granted)-(16-7-2010).pdf	2018-08-09
48	835-MUMNP-2006-FORM 2(TITLE PAGE)-(15-10-2008).pdf	2008-10-15
49	835-mumnp-2006-abstract(complete)-(14-7-2006).pdf	2018-08-09
49	835-MUMNP-2006-FORM 3(15-10-2008).pdf	2008-10-15